The DOI matches its Crossref record; 157 of the 165 references it cites were found in a registry or an index; 110 of the 167 sources its claims cite were checked for support.
Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma
Open accessAbstract
Liver cancer, specifically hepatocellular carcinoma (HCC), is the sixth most common cancer and the third leading cause of cancer mortality worldwide. The development of effective systemic therapies, particularly those involving immune-checkpoint inhibitors (ICIs), has substantially improved the outcomes of patients with advanced-stage HCC. Approximately 30% of patients are diagnosed with early stage disease and currently receive potentially curative therapies, such as resection, liver transplantation or local ablation, which result in median overall survival durations beyond 60 months. Nonetheless, up to 70% of these patients will have disease recurrence within 5 years of resection or local ablation. To date, the results of randomized clinical trials testing adjuvant therapy in patients with HCC have been negative. This major unmet need has been addressed with the IMbrave 050 trial, demonstrating a recurrence-free survival benefit in patients with a high risk of relapse after resection or local ablation who received adjuvant atezolizumab plus bevacizumab. In parallel, studies testing neoadjuvant ICIs alone or in combination in patients with early stage disease have also reported efficacy. In this Review, we provide a comprehensive overview of the current approaches to manage patients with early stage HCC. We also describe the tumour immune microenvironment and the mechanisms of action of ICIs and cancer vaccines in this setting. Finally, we summarize the available evidence from phase II/III trials of neoadjuvant and adjuvant approaches and discuss emerging clinical trials, identification of biomarkers and clinical trial design considerations for future studies.
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Claims the paper makes
50 Partly supported · 27 No full text of the sources · 26 Supported · 17 Own interpretation · 8 No basis given · 2 Supported so far · 2 Not supported · 2 Couldn’t confirm · 1 Mixed support · 1 Sources not found · 1 Not checked yet · accuracy not yet measured
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“Consequently, the reported outcomes differ widely depending on the selection criteria applied, with 5-year survival rates ranging between 50% in China to 70% in Europe28.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Management of early stage HCC > Resection
What the sources say
- Disputedcites [28] Reveron-Thornton, R. F. et al. Global and regional long-term survival following resection for HCC in the recent decade: a meta-analysis of 110 studies. Hepatol. Commun. 6, 1813–1826 (2022). sourceExperimental — accuracy not yet measured
The Results (Overall survival; page unavailable) report 5-year survival of 48.30% in Europe, not about 70%, and 57.03% in Asia. The Discussion (page unavailable) suggests there may not be much difference in patient selection among regions, contrary to the claimed explanation for the regional differences. (LLM, conf=0.91)
Checked by a reasoning model — may be wrong.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Disputed
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“This study highlights the concept of immunodominance, whereby T cells targeting a dominant clone are primarily expanded at the expense of T cells reactive to subdominant clones.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Mechanisms of action of neoadjuvant versus adjuvant approaches
What the sources say
- Disputedcites [110] Friedman, J. et al. Neoadjuvant PD-1 immune checkpoint blockade reverses functional immunodominance among tumor antigen-specific T cells. Clin. Cancer Res. 26, 679–689 (2020). sourceExperimental — accuracy not yet measured
The Discussion supports the existence of immunodominance: dominant-antigen-specific T cells suppress responses to subdominant antigens. But it explicitly says the study did not demonstrate differential clonal expansion; instead, it found functional suppression of subdominant T cells associated with PD-1 expression. That contradicts the claim that dominant T cells primarily expand at their expense. (LLM, conf=0.89)
Checked by a reasoning model — may be wrong.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Disputed
Every source the paper cites for this claim was checked and supports it.
In the paper
“In 2023, however, the treatment landscape for patients with early stage HCC evolved following positive results from IMbrave 050, in which adjuvant therapy with the ICI atezolizumab plus the anti-angiogenic agent bevacizumab significantly improved recurrence-free survival (RFS) over active surveillance in patients with a high risk of disease recurrence12.”
- Also stated in: § IMbrave 050 · boosted
“Results from the global, open-label, phase III IMbrave 050 trial12 have shown a significant RFS improvement in patients with HCC at high risk of recurrence after resection or local ablation who received adjuvant atezolizumab plus bevacizumab compared with those who underwent active surveillance in patients (Box 1).”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Introduction
What the sources say
- Supportedcites [12] Qin, S. et al. Atezolizumab plus bevacizumab versus active surveillance in patients with resected or ablated high-risk hepatocellular carcinoma (IMbrave 050): a randomised, open-label, multicentre, phase 3 trial. Lancet 402, 1835–1847 (2023). source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: A recurrence-free survival improvement is sufficient to regard adjuvant atezolizumab plus bevacizumab as a major advance in hepatocellular carcinoma management, even before overall survival benefit is shown.
- Also stated in: § IMbrave 050 · boosted
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“However, this remarkable progress in systemic therapy has not been paralleled by improvements in the treatment of early stage HCC, which typically involves administration of therapies with curative intent, such as resection, liver transplantation or local ablation1,2.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Introduction
What the sources say
- Not checked — no full text of the sourcecites [1] Llovet, J. M. et al. Hepatocellular carcinoma. Nat. Rev. Dis. Prim. 7, 7 (2021). source
- Partly supportedcites [2] Llovet, J. M. et al. Molecular pathogenesis and systemic therapies for hepatocellular carcinoma. Nat. Cancer 3, 386–401 (2022). sourceExperimental — accuracy not yet measured
The Introduction describes major advances in systemic therapy, and 'Placing systemic therapies in the context of HCC management' identifies resection, transplantation and ablation as curative options for early-stage HCC. 'Future directions' calls neoadjuvant and adjuvant therapies an unmet need, but the paper does not establish the broader claim that early-stage treatment has not improved. (LLM, conf=0.84)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Every source the paper cites for this claim was checked and supports it.
In the paper
“In particular, regimens including immune-checkpoint inhibitors (ICIs) are currently adopted as first-line therapies in clinical guidelines7.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Introduction
What the sources say
- Supportedcites [7] Singal, A. G. et al. AASLD practice guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology 78, 1922–1965 (2023). source
Guidance statement 46a (indexed under section 45; page unavailable) recommends atezolizumab plus bevacizumab or durvalumab plus tremelimumab as preferred first-line options for patients with advanced HCC and Child-Turcotte-Pugh A cirrhosis. The Systemic therapy section identifies atezolizumab, durvalumab, and tremelimumab as immune-checkpoint inhibitors. (LLM, conf=0.95)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“those testing such approaches in HCC after potentially curative resection or local ablation have not yielded positive results over the preceding decades11.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Introduction
What the sources say
- Partly supportedcites [11] Haber, P. K. et al. Evidence-based management of hepatocellular carcinoma: systematic review and meta-analysis of randomized controlled trials (2002–2020). Gastroenterology 161, 879–898 (2021). sourceExperimental — accuracy not yet measured
The Discussion (page not specified) says only one of seven high-quality adjuvant trials met its primary endpoint, supporting the point that positive results were rare. But the Results > Adjuvant Treatments section reports a positive trial of CIK cells after resection or local ablation, so the categorical claim that the trials yielded no positive results is too strong. (LLM, conf=0.88)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In parallel, early phase clinical studies testing ICIs in HCC, either as monotherapy or in combination, in the neoadjuvant setting have reported favourable outcomes13–15.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Introduction
What the sources say
- Supportedcites [13] Marron, T. U. et al. Neoadjuvant cemiplimab for resectable hepatocellular carcinoma: a single-arm, open-label, phase 2 trial. Lancet Gastroenterol. Hepatol. 7, 219–229 (2022). source
The Methods/Findings passage describes an early-phase trial of neoadjuvant cemiplimab monotherapy in resectable hepatocellular carcinoma and reports pathological responses. The Discussion also describes a separate neoadjuvant trial testing nivolumab alone or with ipilimumab. This paper supports the cited sentence’s broad account of favourable early outcomes, without establishing a survival benefit. (LLM, conf=0.92)
- Not matchedcites [14] Ho, W. J. et al. Neoadjuvant cabozantinib and nivolumab converts locally advanced HCC into resectable disease with enhanced antitumor immunity. Nat. Cancer 2, 891–903 (2021).
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Supportedcites [15] Kaseb, A. O. et al. Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: a randomised, open-label, phase 2 trial. Lancet Gastroenterol. Hepatol. 7, 208–218 (2022). source
The Results (page not supplied) report major pathological responses after neoadjuvant nivolumab alone and after nivolumab plus ipilimumab. The Discussion describes these early efficacy findings as promising, supporting the cited trial as an example of a favourable early-phase HCC study. (LLM, conf=0.91)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Over the past two decades, the development of effective systemic therapies has substantially improved the outcomes of patients with advanced-stage HCC2–6.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Introduction
What the sources say
- Supportedcites [2] Llovet, J. M. et al. Molecular pathogenesis and systemic therapies for hepatocellular carcinoma. Nat. Cancer 3, 386–401 (2022). source
The Introduction describes the shift from sorafenib to immunotherapy combinations and reports that atezolizumab plus bevacizumab outperformed sorafenib on overall survival and other endpoints. “Current systemic therapies in HCC” says the expanded treatment options have improved expected outcomes. The paper qualifies the immune-checkpoint point: its monotherapy section says single-agent inhibitors may not significantly improve overall survival in unselected patients. (LLM, conf=0.91)
- Partly supportedcites [3] Llovet, J. M. et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378–390 (2008). sourceExperimental — accuracy not yet measured
The Results in the Abstract report that sorafenib improved median overall survival from 7.9 to 10.7 months in patients with advanced hepatocellular carcinoma, supporting the cited sentence’s point that an effective systemic therapy improved outcomes. This 2008 trial does not establish a two-decade trend across multiple therapies or support the supplied claim’s emphasis on immune-checkpoint inhibitors, which the verbatim citing sentence does not mention. (LLM, conf=0.88)
- Partly supportedcites [4] Finn, R. S. et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N. Engl. J. Med. 382, 1894–1905 (2020). sourceExperimental — accuracy not yet measured
The Discussion reports significantly better overall and progression-free survival with atezolizumab plus bevacizumab than with sorafenib in previously untreated patients with advanced unresectable HCC. This supports improved outcomes from a systemic regimen containing a checkpoint inhibitor, but not the broader implication that checkpoint inhibitors generally produced substantial improvements over two decades: the paper says single-agent PD-1 inhibitors did not significantly improve overall survival in phase 3 studies. (LLM, conf=0.85)
- Not checked — no full text of the sourcecites [5] Llovet, J. M. et al. Immunotherapies for hepatocellular carcinoma. Nat. Rev. Clin. Oncol. 19, 151–172 (2022). source
- Supportedcites [6] Cappuyns, S., Virginia, C., Yarchoan, M., Finn, R. S. & Llovet, J. M. Critical appraisal of guideline recommendations on systemic therapies for advanced hepatocellular carcinoma. JAMA Oncol. https://doi.org/10.1001/jamaoncol.2023.2677 (2023). source
The Abstract reports that the growing number of effective regimens has been associated with improved median overall survival in advanced HCC, from 8 months in a placebo arm to 19.2 months with atezolizumab plus bevacizumab. It also describes immune-checkpoint inhibitor combinations as having revolutionized treatment. No page number is provided in our copy. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Patients with HCCs classified as non-inflamed tend to have a low likelihood of benefiting from immunotherapies72,83.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Tumour immune microenvironment in HCC > HCC immune types
What the sources say
- Partly supportedcites [72] Haber, P. K. et al. Molecular markers of response to anti-PD1 therapy in advanced hepatocellular carcinoma. Gastroenterology 164, 72–88.e18 (2023). sourceExperimental — accuracy not yet measured
The Results section (‘Molecular Features of Patients With HCC Responding to Anti-PD1 in Front Line’; page unavailable) reports fewer objective responses in the non-inflamed Intermediate and Excluded classes than in the Inflamed class (5/19 versus 7/9). This supports a lower likelihood of response, but the study tested frontline anti-PD1 monotherapy, not immunotherapies generally. (LLM, conf=0.84)
- Supportedcites [83] Pinyol, R., Sia, D. & Llovet, J. M. Immune exclusion-Wnt/CTNNB1 class predicts resistance to immunotherapies in HCC. Clin. Cancer Res. 25, 2021–2023 (2019). source
The Abstract describes immune-excluded HCCs as ‘cold’ tumors that are resistant to immunotherapies. It also says the HCC Exclusion class might have innate resistance to immune checkpoint inhibitors, supporting the claim’s qualified wording. (LLM, conf=0.92)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
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In the paper
“Furthermore, a high TMB does not correlate with increased immune infiltration70,71.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Tumour immune microenvironment in HCC > Immune cell types, tumour neoantigens and mechanisms of immune response and escape
What the sources say
- Partly supportedcites [70] Bassaganyas, L. et al. Copy-number alteration burden differentially impacts immune profiles and molecular features of hepatocellular carcinoma. Clin. Cancer Res. 26, 6350–6361 (2020). sourceExperimental — accuracy not yet measured
The Results report that low-broad-CNA HCCs had fewer mutations but greater immune infiltration than high-broad-CNA HCCs, consistent with infiltration not increasing with mutation burden in those groups. The paper does not report a direct correlation analysis of high TMB and immune infiltration; it also notes that only 2% of the HCC samples had TMB above 10 mutations/Mb. The claim is therefore broader than the comparison studied. (LLM, conf=0.84)
- Supportedcites [71] Sia, D. et al. Identification of an immune-specific class of hepatocellular carcinoma, based on molecular features. Gastroenterology 153, 812–826 (2017). source
The Results section (page not provided) reports no association between the HCC Immune class and overall mutation rate; the median mutation counts were 175 in the Immune class and 212 in the remaining patients (p=0.1). The Discussion likewise states that mutational load was not associated with the Immune class, supporting the claim that higher TMB did not correspond to greater immune infiltration in this analysis. (LLM, conf=0.93)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“studies in other tumour types have demonstrated that T cell expansion is greater when ICIs are administered before complete surgical removal of the tumour as opposed to after surgery104.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Mechanisms of action of neoadjuvant versus adjuvant approaches
What the sources say
- Could not verifycites [104] Garg, M. et al. Tumour gene expression signature in primary melanoma predicts long-term outcomes. Nat. Commun. 12, 1137 (2021). sourceExperimental — accuracy not yet measured
The Introduction (page unavailable) discusses checkpoint inhibitors given after melanoma resection, and the Discussion (page unavailable) discusses immune infiltration before treatment. Neither compares T-cell expansion when inhibitors are given before versus after tumour removal. Searches for neoadjuvant treatment, the timing comparison, and T-cell expansion found no passage addressing that claim. (LLM, conf=0.76)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Could not verify
Every source the paper cites for this claim was checked and supports it.
In the paper
“Results from other studies suggest that a metabolic-related fatty liver disease-related aetiology might be related to a decreased response owing to unique immunological traits hampering antitumoural surveillance11,101.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Adjuvant therapies in HCC > Prediction of response to ICIs
What the sources say
- Supportedcites [11] Haber, P. K. et al. Evidence-based management of hepatocellular carcinoma: systematic review and meta-analysis of randomized controlled trials (2002–2020). Gastroenterology 161, 879–898 (2021). sourceExperimental — accuracy not yet measured
The Discussion says recent evidence suggests that NASH-related hepatocellular carcinoma responds less well to immune-checkpoint inhibitors because of dysfunctional immune-cell infiltration. It also describes the paper’s subgroup meta-analysis as finding lower immunotherapy efficacy for nonviral than viral etiologies, while noting that NASH-specific trial data were unavailable. The citing sentence’s tentative wording reflects those qualifications. (LLM, conf=0.92)
- Supportedcites [101] Pfister, D. et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature 592, 450–456 (2021). sourceExperimental — accuracy not yet measured
In “Hepatic CD8+PD1+ T cells increase in NASH” (page unavailable), NASH-associated liver tumours failed to regress after checkpoint inhibition, unlike tumours in other mouse models, and the authors conclude that NASH impaired anti-tumour surveillance. “Lack of immunotherapy response in human NASH–HCC” (page unavailable) also reports shorter survival after checkpoint inhibition among patients with NAFLD-associated HCC. Together, these findings support the citing sentence’s hedged claim. (LLM, conf=0.92)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“However, owing to issues with trial design (insufficient power, unbalanced prognostic characteristics among treatment arms) and the lack of external confirmation, this approach is not recommended by any clinical guidelines.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Adjuvant therapies in HCC > Past and ongoing phase III trials in HCC
What the sources say
- Partly supportedcites [94] Lee, J. H. et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology 148, 1383–1391.e6 (2015). sourceExperimental — accuracy not yet measured
The Abstract (page not given) says that current scientific guidelines do not recommend adjuvant therapy after curative treatment for hepatocellular carcinoma, and the Discussion (page not given) acknowledges imbalanced baseline characteristics between the trial arms. The paper does not say the guideline position is caused by insufficient power or lack of external confirmation; it describes a sample-size calculation and reports similar results from earlier trials. (LLM, conf=0.87)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
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In the paper
“In a mouse model of HCC, activation of WNT–β-catenin signalling promotes immune escape by impairing recruitment of dendritic cells and interfering with recognition by natural killer cells73.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Tumour immune microenvironment in HCC > Immune cell types, tumour neoantigens and mechanisms of immune response and escape
What the sources say
- Partly supportedcites [73] Ruiz de Galarreta, M. et al. β-Catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma. Cancer Discov. 9, 1124–1141 (2019). sourceExperimental — accuracy not yet measured
The Results and Discussion report that β-catenin activation promotes immune escape in the mouse HCC model by impairing recruitment of CD103+ dendritic cells and the ensuing antigen-specific CD8+ T-cell response. The Results report no significant difference in natural killer cell numbers between the compared livers, but do not establish impaired recognition by those cells. Page numbers were not available in our copy. (LLM, conf=0.90)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The liver also contains an abundance of MDSCs that produce factors suppressing T cell activation63.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Tumour immune microenvironment in HCC > Immune cell types, tumour neoantigens and mechanisms of immune response and escape
What the sources say
- Partly supportedcites [63] Hoechst, B. et al. A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells. Gastroenterology 135, 234–243 (2008). sourceExperimental — accuracy not yet measured
The Discussion (page not available in our copy) reports that MDSCs are increased in the tumors and peripheral blood of hepatocellular carcinoma patients and suppress T-cell responses through arginase activity. It does not establish that the liver generally contains abundant MDSCs; its finding is specific to patients with liver cancer. (LLM, conf=0.87)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“The mTOR inhibitor sirolimus did not significantly change RFS in the SiLVER trial also, involving 525 patients with HCC undergoing liver transplantation91.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Adjuvant therapies in HCC > Past and ongoing phase III trials in HCC
What the sources say
- Supportedcites [91] Geissler, E. K. et al. Sirolimus use in liver transplant recipients with hepatocellular carcinoma: a randomized, multicenter, open-label phase 3 trial. Transplantation 100, 116–125 (2016). source
The Results report that 525 patients were randomized in the SiLVER trial and that the difference in recurrence-free survival between treatment groups was not statistically significant at study end (P = 0.2796). The Methods identify the population as liver transplant recipients with HCC. The paper also reports an early RFS benefit, so the no-significant-difference finding refers to the study-end comparison. (LLM, conf=0.94)
plainn = 525- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Additionally, 8.4% versus 1% of patients had irAEs requiring systemic corticosteroids.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Adjuvant therapies in HCC > IMbrave 050
What the sources say
- Supportedcites [12] Qin, S. et al. Atezolizumab plus bevacizumab versus active surveillance in patients with resected or ablated high-risk hepatocellular carcinoma (IMbrave 050): a randomised, open-label, multicentre, phase 3 trial. Lancet 402, 1835–1847 (2023). source
The Results report immune-mediated adverse events requiring systemic corticosteroids in 28 patients receiving atezolizumab plus bevacizumab and three under active surveillance. Using the safety-population denominators in the Results (332 and 330), these are 8.4% and 0.9%, respectively; 1% is the paper's rounded figure. Page numbers were not provided in our copy. (LLM, conf=0.94)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In a phase III trial of adjuvant adoptive cell therapy with cytokine-induced killer cells generated by incubation of peripheral blood mononuclear cells with IL-2 and an anti-CD3 antibody of patients, median RFS was improved with cytokine-induced killer cell therapy (44.0 versus 30.0 months with placebo; HR 0.63, 95% CI 0.43–0.94; P = 0.010)94.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Adjuvant therapies in HCC > Past and ongoing phase III trials in HCC
What the sources say
- Partly supportedcites [94] Lee, J. H. et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology 148, 1383–1391.e6 (2015). sourceExperimental — accuracy not yet measured
The Abstract and Efficacy section report a phase 3 trial with median recurrence-free survival of 44.0 versus 30.0 months, HR 0.63 (95% CI 0.43–0.94), and P = .010. However, the Abstract describes an open-label trial comparing immunotherapy with no adjuvant therapy, not placebo. (LLM, conf=0.90)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
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In the paper
“Transforming growth factor-β signalling contributes to an immunosuppressive cancer field effect74.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Tumour immune microenvironment in HCC > Immune cell types, tumour neoantigens and mechanisms of immune response and escape
What the sources say
- Partly supportedcites [74] Moeini, A. et al. An immune gene expression signature associated with development of human hepatocellular carcinoma identifies mice that respond to chemopreventive agents. Gastroenterology 157, 1383–1397.e11 (2019). sourceExperimental — accuracy not yet measured
The Results section, “The immune-mediated cancer field contains 3 distinct molecular subtypes” (page not available), reports increased TGF-β signaling in the immunosuppressive subtype. It establishes an association, but does not show that TGF-β signaling itself causes or contributes to the field’s immunosuppression. (LLM, conf=0.83)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Independent review facility-assessed time to recurrence was longer in the intervention group (HR 0.67, 95% CI 0.52–0.88; P = 0.003).”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Adjuvant therapies in HCC > IMbrave 050
What the sources say
- Supportedcites [12] Qin, S. et al. Atezolizumab plus bevacizumab versus active surveillance in patients with resected or ablated high-risk hepatocellular carcinoma (IMbrave 050): a randomised, open-label, multicentre, phase 3 trial. Lancet 402, 1835–1847 (2023). source
The Results report a 33% lower risk of independent review facility-assessed disease recurrence with atezolizumab plus bevacizumab than with active surveillance, with HR 0.67, interval 0.52–0.88, and descriptive p=0.0030. The Outcomes section identifies independent review facility-assessed time to recurrence as a reported secondary endpoint. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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In the paper
“neoadjuvant but not adjuvant administration of ICIs preserves T cell clones reactive to less-common immunogenic clones in mouse models of head and neck squamous cell carcinoma110.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Mechanisms of action of neoadjuvant versus adjuvant approaches
What the sources say
- Supportedcites [110] Friedman, J. et al. Neoadjuvant PD-1 immune checkpoint blockade reverses functional immunodominance among tumor antigen-specific T cells. Clin. Cancer Res. 26, 679–689 (2020). source
The Results (page not specified) report that neoadjuvant, but not adjuvant, PD-1 blockade induced responses to subdominant tumor antigens in mouse models. They also report that neoadjuvant treatment produced immunologic memory against tumors lacking the dominant antigen, whereas adjuvant treatment alone did not. (LLM, conf=0.92)
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In a mouse model of triple-negative breast cancer, neoadjuvant induction and activation of dendritic cells in primary tumours enhanced systemic antitumour immunity and improved survival107.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Mechanisms of action of neoadjuvant versus adjuvant approaches
What the sources say
- Supportedcites [107] Oba, T., Kajihara, R., Yokoi, T., Repasky, E. A. & Ito, F. Neoadjuvant in situ immunomodulation enhances systemic antitumor immunity against highly metastatic tumors. Cancer Res. 81, 6183–6195 (2021). source
The Abstract describes orthotopic mouse models of triple-negative breast cancer and reports that neoadjuvant treatment generated systemic tumor-specific T-cell responses and improved survival. The Discussion likewise states that induction and activation of cDC1 dendritic cells in primary tumors produced systemic antitumor immunity and improved survival. (LLM, conf=0.95)
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Significant tumour necrosis occurred in 33% of 9 patients treated with nivolumab and 27% of 11 patients treated with nivolumab–ipilimumab.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Phase I/II neoadjuvant trials in HCC
What the sources say
- Supportedcites [15] Kaseb, A. O. et al. Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: a randomised, open-label, phase 2 trial. Lancet Gastroenterol. Hepatol. 7, 208–218 (2022). source
The Results report major pathological response in 33% (3/9) of resected patients given nivolumab and 27% (3/11) given nivolumab plus ipilimumab. The Abstract Findings define this response by substantial tumour necrosis, and Methods > Procedures specifies one preoperative dose of ipilimumab in the combination arm. (LLM, conf=0.94)
plainn = 9- Asserted: passes — The authors put it forward as true.
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In the paper
“Of note, these niches were more frequent in tumours from responders even before undergoing treatment.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Pathological response to ICIs in the neoadjuvant setting
What the sources say
- Supportedcites [82] Magen, A. et al. Intratumoral dendritic cell–CD4+ T helper cell niches enable CD8+ T cell differentiation following PD-1 blockade in hepatocellular carcinoma. Nat. Med. 29, 1389–1399 (2023). source
The Results section (“PD-1 hi Progenitor CD8+ T cells accumulate in mregDC/CXCL13+ TH niches”; page unavailable) reports that, in pretreatment tumour biopsies, triads including TCF1+ CD4+ T cells were more easily detected in responders and de-enriched in nonresponders. It notes that triads containing CXCL13+ TH cells had lower detection before treatment. (LLM, conf=0.90)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Several studies have shown that T cell infiltration in solid tumours is a predictive biomarker of response to ICIs69,82,100,111.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Pathological response to ICIs in the neoadjuvant setting
What the sources say
- Not checked — no full text of the sourcecites [69] Zhu, A. X. et al. Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma. Nat. Med. 28, 1599–1611 (2022). source
- Partly supportedcites [82] Magen, A. et al. Intratumoral dendritic cell–CD4+ T helper cell niches enable CD8+ T cell differentiation following PD-1 blockade in hepatocellular carcinoma. Nat. Med. 29, 1389–1399 (2023). sourceExperimental — accuracy not yet measured
The Abstract describes tumour T-cell infiltration as a prognostic factor for response to immune checkpoint blockade, supporting the broad association. But it explicitly says that a T-cell-rich pattern is not an accurate predictor, and the Results report that 40% of nonresponsive HCC lesions were also highly infiltrated. Calling infiltration a predictive biomarker omits that qualification. (LLM, conf=0.86)
- Supportedcites [100] Litchfield, K. et al. Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition. Cell 184, 596–614.e14 (2021). source
In Results, under “Benchmarking of previously reported biomarkers of CPI response,” the meta-analysis finds significant associations between checkpoint-inhibitor response and immune-infiltration markers, including CD8A expression and a T-cell-inflamed gene-expression signature. The Discussion reports that the analysis spans seven tumor types, supporting the claim’s broad solid-tumour context. (LLM, conf=0.89)
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In a phase II clinical trial with results published in 2022, patients with early stage HCC received neoadjuvant treatment with the anti-PD-1 antibody cemiplimab13. Significant tumour necrosis, the prespecified primary end point, was 20%.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Pathological response to ICIs in the neoadjuvant setting
What the sources say
- Partly supportedcites [13] Marron, T. U. et al. Neoadjuvant cemiplimab for resectable hepatocellular carcinoma: a single-arm, open-label, phase 2 trial. Lancet Gastroenterol. Hepatol. 7, 219–229 (2022). sourceExperimental — accuracy not yet measured
The Methods identify significant tumour necrosis (>70%) as the primary endpoint, and the Results report it in four of 20 evaluable patients (20%). The description of the cohort as early-stage HCC is imprecise: the Results list stage IIIb and BCLC stage C patients as well as earlier-stage patients. (LLM, conf=0.87)
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“profound pathological responses can occur as little as 22 days before surgery13”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Phase I/II neoadjuvant trials in HCC
What the sources say
- Partly supportedcites [13] Marron, T. U. et al. Neoadjuvant cemiplimab for resectable hepatocellular carcinoma: a single-arm, open-label, phase 2 trial. Lancet Gastroenterol. Hepatol. 7, 219–229 (2022). sourceExperimental — accuracy not yet measured
The Results report profound pathological responses, including complete tumour necrosis in three patients. They also report that one patient underwent surgery 22 days after starting immunotherapy, but do not say whether that patient had a pathological response. The 22-day response claim is therefore not established by our copy. (LLM, conf=0.85)
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Event-free survival was significantly improved among patients who received pembrolizumab both before and after surgery (72% versus 49% with adjuvant-only pembrolizumab at 2 years; HR 0.58, 95% CI 0.39–0.87; P = 0.004; median follow-up 14.7 months)9.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Neoadjuvant trials with ICIs in several cancer types
What the sources say
- Partly supportedcites [9] Patel, S. P. et al. Neoadjuvant–adjuvant or adjuvant-only pembrolizumab in advanced melanoma. N. Engl. J. Med. 388, 813–823 (2023). sourceExperimental — accuracy not yet measured
The Results > Efficacy passage reports significantly longer event-free survival with neoadjuvant–adjuvant pembrolizumab, including 72% versus 49% at 2 years, P=0.004, and median follow-up of 14.7 months. Our copy does not report the claimed HR of 0.58 or its 95% CI of 0.39–0.87; the hazard ratio of 0.64 in Methods > Statistical Analysis is a trial-design assumption, not the observed result. No page numbers are provided for these passages. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Given that mutation-associated neoantigens are not expressed on any non-malignant cell, vaccines targeting them might avoid central or peripheral tolerance mechanisms, resulting in robust immune responses131.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > (Neo)adjuvant clinical trials with cancer vaccines
What the sources say
- Supportedcites [131] Yarchoan, M., Johnson, B. A., Lutz, E. R., Laheru, D. A. & Jaffee, E. M. Targeting neoantigens to augment antitumour immunity. Nat. Rev. Cancer 17, 209–222 (2017). source
In “TSAs, TAAs and CTAs as targets” (page not provided), the review says normal host antigens are subject to central and peripheral tolerance, whereas tumour-specific antigens are less likely to establish tolerance and can elicit more vigorous immune responses. It also says these targets are not expressed on normal cells. The citing sentence appropriately frames the vaccine response as a possibility, not a guaranteed outcome. (LLM, conf=0.90)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“analyses of samples derived from patients with melanoma who received neoadjuvant ICIs112,113 have revealed the presence of the three primary patterns of T cell infiltration identified in solid tumours.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Pathological response to ICIs in the neoadjuvant setting
What the sources say
- Not checked — no full text of the sourcecites [112] Rozeman, E. A. et al. LBA75 — 18-months relapse-free survival (RFS) and biomarker analyses of OpACIN-neo: a study to identify the optimal dosing schedule of neoadjuvant (neoadj) ipilimumab (IPI) + nivolumab (NIVO) in stage III melanoma. Ann. Oncol. 30, v910 (2019). source
- Partly supportedcites [113] Amaria, R. N. et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat. Med. 24, 1649–1654 (2018). sourceExperimental — accuracy not yet measured
The paper’s immune-profiling results (page unavailable in our copy) report analyses of melanoma samples taken before and during neoadjuvant checkpoint blockade and describe differences in CD8+ T-cell infiltration between responders and non-responders. They do not identify three primary patterns of T-cell infiltration; searches for those patterns and their names found no such classification in our copy. (LLM, conf=0.82)
plain- Asserted: passes — The authors put it forward as true.
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The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“the study of nivolumab–ipilimumab revealed that ipilimumab is more effective in patients with cold tumours, supporting the theory that CTLA4 blockade might be most beneficial in patients lacking pre-existing antitumour immunity15.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Phase I/II neoadjuvant trials in HCC
What the sources say
- Partly supportedcites [15] Kaseb, A. O. et al. Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: a randomised, open-label, phase 2 trial. Lancet Gastroenterol. Hepatol. 7, 208–218 (2022). sourceExperimental — accuracy not yet measured
The Discussion reports that nivolumab plus ipilimumab generated major pathological responses in tumours with low baseline immune infiltration, whereas nivolumab alone required high baseline infiltration. But it presents this as a finding to test further and says the small study was not powered to formally compare outcomes between arms; the claim’s definitive statement that ipilimumab was more effective overstates the evidence. (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“the study of nivolumab–ipilimumab revealed that ipilimumab is more effective in patients with cold tumours, supporting the theory that CTLA4 blockade might be most beneficial in patients lacking pre-existing antitumour immunity15.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Phase I/II neoadjuvant trials in HCC
What the sources say
- Supportedcites [15] Kaseb, A. O. et al. Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: a randomised, open-label, phase 2 trial. Lancet Gastroenterol. Hepatol. 7, 208–218 (2022). source
The Discussion reports that nivolumab plus ipilimumab generated major pathological responses in resectable hepatocellular carcinomas with low baseline immune infiltration, whereas nivolumab alone required high baseline infiltration. It presents this as evidence that adding anti-CTLA-4 treatment may benefit patients with less pre-existing tumour immunity; it does not establish the claim beyond this treatment and setting. (LLM, conf=0.89)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Nonetheless, these data provide evidence that (neo)adjuvant administration of ICIs results in superior antitumour immune responses than adjuvant-only administration.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Neoadjuvant trials with ICIs in several cancer types
What the sources say
- Partly supportedcites [9] Patel, S. P. et al. Neoadjuvant–adjuvant or adjuvant-only pembrolizumab in advanced melanoma. N. Engl. J. Med. 388, 813–823 (2023). sourceExperimental — accuracy not yet measured
The Discussion reports better event-free survival with neoadjuvant–adjuvant pembrolizumab and interprets this as consistent with a proposed T-cell mechanism. It also describes a smaller, separate trial that found greater expansion of tumor-resident T-cell clones with preoperative treatment. This paper’s own trial did not establish that its regimen produced superior antitumour immune responses; the claim states that mechanistic inference as a demonstrated result. Page numbers were not supplied. (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“This impaired response was attributed to IFNγ-mediated depletion of tumour-reactive T cells owing to activation-induced cell death.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Mechanisms of action of neoadjuvant versus adjuvant approaches
What the sources say
- Supportedcites [109] Pai, C.-C. S. et al. Clonal deletion of tumor-specific T cells by interferon-γ confers therapeutic resistance to combination immune checkpoint blockade. Immunity 50, 477–492.e8 (2019). source
The Discussion states that combination treatment during early tumor development heightened IFN-γ production, causing apoptosis of dominant tumor-specific T cells through activation-induced cell death. It links that mechanism to compromised anti-tumor effects in the studied setting. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In a similar model, depletion of Treg cells potentiated the effect of ICIs when applied to primary tumours108.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Mechanisms of action of neoadjuvant versus adjuvant approaches
What the sources say
- Partly supportedcites [108] Hughes, E. et al. Primary breast tumours but not lung metastases induce protective anti-tumour immune responses after Treg-depletion. Cancer Immunol. Immunother. 69, 2063–2073 (2020). sourceExperimental — accuracy not yet measured
The Results and discussion section reports that Treg depletion controlled growth of some primary 4T1 tumours. It does not report that Treg depletion potentiated immune checkpoint inhibitors: its comparison with Liu and colleagues describes Treg depletion or anti-PD1/anti-CD137 treatment as alternatives, not a combination. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“some of the preoperative trials with results published to date have highlighted a discordance among pathological response, significant tumour necrosis (quantified using high-resolution MRI) and standard RECIST13”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Pathological response to ICIs in the neoadjuvant setting
What the sources say
- Supportedcites [13] Marron, T. U. et al. Neoadjuvant cemiplimab for resectable hepatocellular carcinoma: a single-arm, open-label, phase 2 trial. Lancet Gastroenterol. Hepatol. 7, 219–229 (2022). source
The Results (page not specified) report that substantial necrosis on MRI and pathology often did not register as a RECIST 1.1 response. The Discussion (page not specified) also identifies individual cases where MRI underestimated pathological necrosis, while noting that MRI and pathological assessments were strongly correlated overall. (LLM, conf=0.88)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Deeper analyses revealed a robust correlation between pathological responses to neoadjuvant cemiplimab and the presence of intratumoural triads comprising regulatory dendritic cells, PD-1hi progenitor CD8+ T cells and CD4+ T cells expressing features of T follicular helper cells (such as CXCL13 and IL-21)82.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Pathological response to ICIs in the neoadjuvant setting
What the sources say
- Partly supportedcites [82] Magen, A. et al. Intratumoral dendritic cell–CD4+ T helper cell niches enable CD8+ T cell differentiation following PD-1 blockade in hepatocellular carcinoma. Nat. Med. 29, 1389–1399 (2023). sourceExperimental — accuracy not yet measured
The section “PD-1 hi Progenitor CD8+ T cells accumulate in mregDC/CXCL13+ TH niches” reports that these intratumoural triads were denser in responders than nonresponders. The Results and participant-details sections show that the analysis included both cemiplimab- and nivolumab-treated patients; the cited triad finding is not reported specifically for responses to cemiplimab. (LLM, conf=0.86)
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Currently, guidelines for HCC trial design have not adopted pathological response as a surrogate of RFS.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Pathological response to ICIs in the neoadjuvant setting
What the sources say
- Supportedcites [119] Llovet, J. M. et al. Trial design and endpoints in hepatocellular carcinoma: AASLD consensus conference. Hepatology 73, 158–191 (2021). source
In “Early HCC stages: design of trials for resection, transplantation and local ablation” (page unavailable), the panel recommends recurrence-free survival or time to recurrence for adjuvant trials and says pathological response may be considered for neoadjuvant trials. It does not designate pathological response as a surrogate for recurrence-free survival; the claim should not be read as saying the panel excludes pathological response as an endpoint altogether. (LLM, conf=0.83)
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“sipuleucel-T, a cancer vaccine for castrate-resistant metastatic prostate cancer, has conclusively provided a survival benefit in a large RCT131.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > (Neo)adjuvant clinical trials with cancer vaccines
What the sources say
- Partly supportedcites [131] Yarchoan, M., Johnson, B. A., Lutz, E. R., Laheru, D. A. & Jaffee, E. M. Targeting neoantigens to augment antitumour immunity. Nat. Rev. Cancer 17, 209–222 (2017). sourceExperimental — accuracy not yet measured
The section on therapeutic approaches for targeting predicted neoantigens states that sipuleucel-T has conclusively demonstrated a survival benefit in castration-resistant metastatic prostate cancer. Our copy does not state that the benefit was shown in a large randomized controlled trial; its reference list identifies a sipuleucel-T study but gives no trial design or size. (LLM, conf=0.87)
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Now the positive results of IMbrave 050 (ref. 12) have led to a revised management algorithm for patients with early stage HCC by incorporating adjuvant therapies in this disease setting7 (Fig. 4).”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Role of adjuvant therapy in HCC management
What the sources say
- Supportedcites [12] Qin, S. et al. Atezolizumab plus bevacizumab versus active surveillance in patients with resected or ablated high-risk hepatocellular carcinoma (IMbrave 050): a randomised, open-label, multicentre, phase 3 trial. Lancet 402, 1835–1847 (2023). source
Reference 12 is attached to the positive results of IMbrave050, not to the revised management algorithm, which the sentence associates with reference 7. The Added value of this study section calls IMbrave050 the first positive phase 3 adjuvant-treatment trial in hepatocellular carcinoma and reports improved recurrence-free survival in high-risk patients after resection or ablation. (LLM, conf=0.92)
- Supportedcites [7] Singal, A. G. et al. AASLD practice guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology 78, 1922–1965 (2023). source
The Surgical resection section reports positive IMbrave 050 results in the adjuvant setting. Guidance statement 32 incorporates adjuvant immune checkpoint inhibitor-based therapy after resection or local ablation, specifically for patients at high risk of recurrence; the section also refers to a management figure for recurrence after adjuvant therapy. The claim is supported with that eligibility qualification. (LLM, conf=0.90)
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Although further confirmatory studies are needed, these results provide initial clinical evidence that personalized therapeutic cancer vaccines can enhance responses to ICIs, with many other studies planned.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > (Neo)adjuvant clinical trials with cancer vaccines
What the sources say
- Partly supportedcites [136] Rojas, L. A. et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature 618, 144–150 (2023). sourceExperimental — accuracy not yet measured
The Discussion (page not available) reports that the personalized vaccine, given with atezolizumab and chemotherapy, generated neoantigen-specific T cells and that vaccine responses correlated with delayed pancreatic cancer recurrence. But the paper does not establish that vaccination enhanced the response to the checkpoint inhibitor: atezolizumab preceded vaccination, and the Vaccine response and clinical outcome section says atezolizumab response did not correlate with vaccine response. (LLM, conf=0.87)
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“In patients with successful downstaging, which indirectly reflects more-favourable tumour biology, transplantation can be considered145,146.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Role of adjuvant therapy in HCC management > Recurrence at intermediate stages
What the sources say
- Supportedcites [145] Mehta, N. et al. Downstaging outcomes for hepatocellular carcinoma: results from the multicenter evaluation of reduction in tumor size before liver transplantation (MERITS-LT) consortium. Gastroenterology 161, 1502–1512 (2021). source
The Introduction describes response to downstaging treatment as a way to select patients with favourable tumour biology. It also states that patients successfully downstaged to within Milan criteria are eligible for priority transplant listing under the cited protocol. (LLM, conf=0.92)
- Supportedcites [146] Mazzaferro, V. et al. Liver transplantation in hepatocellular carcinoma after tumour downstaging (XXL): a randomised, controlled, phase 2b/3 trial. Lancet Oncol. 21, 947–956 (2020). source
The Discussion states that tumour response to downstaging therapies correlates with HCC biological behaviour. It also says that a three-month observation period after successful downstaging helped select patients with favourable tumour biology, supporting the claim that downstaging response is an indirect indicator. (LLM, conf=0.89)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“the approval of numerous new systemic agents for advanced-stage HCC has left substantial knowledge gaps in choosing the optimal first-line regimen and the subsequent sequencing of these agents after disease progression6.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Conclusions
What the sources say
- Supportedcites [6] Cappuyns, S., Virginia, C., Yarchoan, M., Finn, R. S. & Llovet, J. M. Critical appraisal of guideline recommendations on systemic therapies for advanced hepatocellular carcinoma. JAMA Oncol. https://doi.org/10.1001/jamaoncol.2023.2677 (2023). source
The Abstract (page not provided) says that rapid new evidence, limited first-line cross-trial comparisons, and diverging guidelines leave no clear treatment flowchart or sequence. The Sequential Treatment Strategies section (page not provided) explicitly identifies knowledge gaps in sequencing drugs after newer first-line combinations. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“For patients with advanced-stage HCC, the current availability of ~10 systemic regimens1,2,5,35,40 has resulted in a shift from median OS durations of 6–8 months to 19–20 months after first-line treatment and 10–14 months after second-line treatment (Fig. 4a).”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Role of adjuvant therapy in HCC management
What the sources say
- Not checked — no full text of the sourcecites [1] Llovet, J. M. et al. Hepatocellular carcinoma. Nat. Rev. Dis. Prim. 7, 7 (2021). source
- Partly supportedcites [2] Llovet, J. M. et al. Molecular pathogenesis and systemic therapies for hepatocellular carcinoma. Nat. Cancer 3, 386–401 (2022). sourceExperimental — accuracy not yet measured
The paper’s “Current systemic therapies in HCC” section lists eight approved regimens, plus two combinations with recently reported trial results; it does not establish that about ten regimens were available. “Selection of patients and expected outcomes” reports about 19 months’ survival with one first-line combination, but 13–14 months with other first-line treatments and 8–11 months with the second-line treatments it discusses. The first-line trials section reports 7.9 months for placebo, broadly consistent with the claimed earlier baseline, but the paper does not support the stated 10–14-month second-line range or attribute the entire survival shift to the availability of regimens alone. Page numbers were not provided in our copy. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [5] Llovet, J. M. et al. Immunotherapies for hepatocellular carcinoma. Nat. Rev. Clin. Oncol. 19, 151–172 (2022). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Every source the paper cites for this claim was checked and supports it.
In the paper
“patients enrolled in the trial with an immunologic response against the vaccine had longer median RFS than those without such a response136.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > (Neo)adjuvant clinical trials with cancer vaccines
What the sources say
- Supportedcites [136] Rojas, L. A. et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature 618, 144–150 (2023). source
The ‘Vaccine response and clinical outcome’ section reports that, among 16 biomarker-evaluable patients, the 8 vaccine responders had a longer median recurrence-free survival (not reached) than the 8 non-responders (13.4 months; P = 0.003). This directly supports the cited comparison. (LLM, conf=0.95)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“To date, IMbrave 050 is the only phase III trial that supports such an approach in the setting of HCC12.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Role of adjuvant therapy in HCC management > Recurrence after (neo)adjuvant therapy at advanced stages or TACE unsuitable
What the sources say
- Supportedcites [12] Qin, S. et al. Atezolizumab plus bevacizumab versus active surveillance in patients with resected or ablated high-risk hepatocellular carcinoma (IMbrave 050): a randomised, open-label, multicentre, phase 3 trial. Lancet 402, 1835–1847 (2023). source
The Added value of this study section calls IMbrave050 the first positive phase 3 trial of adjuvant treatment for hepatocellular carcinoma. The Discussion repeats that it was the first such trial to report positive results, supporting the citing sentence’s time-qualified claim. (LLM, conf=0.91)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Small-cohort studies have suggested that patients receiving ipilimumab plus nivolumab after previous therapy with ICIs have an ORR of ~16% (ref. 150).”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Role of adjuvant therapy in HCC management > Recurrence after (neo)adjuvant therapy at advanced stages or TACE unsuitable
What the sources say
- Partly supportedcites [150] Wong, J. S. L. et al. Ipilimumab and nivolumab/pembrolizumab in advanced hepatocellular carcinoma refractory to prior immune checkpoint inhibitors. J. Immunother. Cancer 9, e001945 (2021). sourceExperimental — accuracy not yet measured
The Results report a 16% objective response rate in 25 patients with advanced hepatocellular carcinoma treated after prior ICI progression. But the Demographics section says only 48% received ipilimumab plus nivolumab; 52% received ipilimumab plus pembrolizumab. The 16% figure is for the combined cohort, not specifically the nivolumab combination. (LLM, conf=0.88)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Currently, clinical decisions are based on clinical factors including, but not limited to, performance status, tumour burden, liver function and comorbidities7.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Conclusions
What the sources say
- Supportedcites [7] Singal, A. G. et al. AASLD practice guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology 78, 1922–1965 (2023). source
The STAGING section says tumor burden, liver dysfunction, and performance status should be documented before treatment recommendations. The Advance Care Planning section also says the HCC treatment cascade is governed in part by comorbidity. Together, these passages support the cited list of clinical factors; page numbers are unavailable in our copy. (LLM, conf=0.90)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In this trial, 8 of 16 patients with resected pancreatic ductal adenocarcinoma remained free of cancer after a median follow-up of 18 months136.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > (Neo)adjuvant clinical trials with cancer vaccines
What the sources say
- Partly supportedcites [136] Rojas, L. A. et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature 618, 144–150 (2023). sourceExperimental — accuracy not yet measured
The Safety, feasibility and immunogenicity section reports that 16 patients received the vaccine, and Vaccine response and clinical outcome reports a median follow-up of 18 months. But the eight patients identified there were vaccine immune responders, not explicitly eight patients who remained cancer-free; their median recurrence-free survival was not reached. The cited result therefore does not establish the claimed cancer-free count. (LLM, conf=0.87)
plainn = 16- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
In the paper
“Local ablation offers a potentially curative treatment for small tumours (≤3 cm in largest diameter, maximum three nodules), providing excellent outcomes with minimally invasive procedures40.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Management of early stage HCC > Local ablation
What the sources say
- Not checked — no full text of the sourcecites [40] Llovet, J. M. et al. Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. 18, 293–313 (2021). source
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Currently, the main immunotherapeutic approach for patients with HCC — regardless of tumour stage — involves restoring antitumour immunity with ICIs, which are monoclonal antibodies that block inhibitory checkpoints or their ligands5.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Tumour immune microenvironment in HCC > Immune-checkpoint inhibitors
What the sources say
- Not checked — no full text of the sourcecites [5] Llovet, J. M. et al. Immunotherapies for hepatocellular carcinoma. Nat. Rev. Clin. Oncol. 19, 151–172 (2022). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The immune microenvironment features and immunotherapy principles described for hepatocellular carcinoma apply across tumour stages, including the early-stage setting.
In the paper
“High numbers of tumour-associated macrophages are associated with a poor prognosis in patients with HCC61.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Tumour immune microenvironment in HCC > Immune cell types, tumour neoantigens and mechanisms of immune response and escape
What the sources say
- Not checked — no full text of the sourcecites [61] Zhang, Q. et al. Landscape and dynamics of single immune cells in hepatocellular carcinoma. Cell 179, 829–845.e20 (2019). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“In HCC, the value of PD-L1 expression ≥1% or TMB as predictive biomarkers of response to ICIs has not been demonstrated69.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Adjuvant therapies in HCC > Prediction of response to ICIs
What the sources say
- Not checked — no full text of the sourcecites [69] Zhu, A. X. et al. Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma. Nat. Med. 28, 1599–1611 (2022). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Data from a landmark study using an orthotopic model of breast cancer showed that neoadjuvant ICIs might outperform adjuvant ICIs106.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Mechanisms of action of neoadjuvant versus adjuvant approaches
What the sources say
- Not checked — no full text of the sourcecites [106] Liu, J. et al. Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease. Cancer Discov. 6, 1382–1399 (2016). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Most of the available preclinical and clinical evidence suggests that response and resistance to ICIs in early stage cancers are dependent on similar principles as those in advanced-stage disease103.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Mechanisms of action of neoadjuvant versus adjuvant approaches
What the sources say
- Not checked — no full text of the sourcecites [103] Topalian, S. L. et al. Neoadjuvant immune checkpoint blockade: a window of opportunity to advance cancer immunotherapy. Cancer Cell 41, 1551–1566 (2023). source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Key cells involved in immune evasion in HCC include tissue-resident macrophages (Kupffer cells), regulatory T (Treg) cells, monocyte-derived macrophages and immature granulocytic cells often collectively referred to as myeloid-derived suppressor cells (MDSCs)5 (Fig. 1).”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Tumour immune microenvironment in HCC > Immune cell types, tumour neoantigens and mechanisms of immune response and escape
What the sources say
- Not checked — no full text of the sourcecites [5] Llovet, J. M. et al. Immunotherapies for hepatocellular carcinoma. Nat. Rev. Clin. Oncol. 19, 151–172 (2022). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“In the liver, the immune microenvironment primarily comprises immunosuppressive cells and signals that create a tolerogenic niche1,5,59.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Tumour immune microenvironment in HCC > Immune cell types, tumour neoantigens and mechanisms of immune response and escape
What the sources say
- Not checked — no full text of the sourcecites [1] Llovet, J. M. et al. Hepatocellular carcinoma. Nat. Rev. Dis. Prim. 7, 7 (2021). source
- Not checked — no full text of the sourcecites [5] Llovet, J. M. et al. Immunotherapies for hepatocellular carcinoma. Nat. Rev. Clin. Oncol. 19, 151–172 (2022). source
- Not checked — no full text of the sourcecites [59] Ringelhan, M., Pfister, D., O’Connor, T., Pikarsky, E. & Heikenwalder, M. The immunology of hepatocellular carcinoma. Nat. Immunol. 19, 222–232 (2018). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“However, in the IMbrave 150 study4, which demonstrated an OS benefit with atezolizumab plus bevacizumab versus the tyrosine-kinase inhibitor (TKI) sorafenib as first-line treatment for patients with unresectable HCC, no significant association between TMB and either ORR or survival was detected69.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Tumour immune microenvironment in HCC > Immune cell types, tumour neoantigens and mechanisms of immune response and escape
What the sources say
- Not checked — no full text of the sourcecites [69] Zhu, A. X. et al. Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma. Nat. Med. 28, 1599–1611 (2022). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The highest pathological response rates were reported in patients with tumours enriched with IFNγ-related signatures along with a high TMB, suggesting that these two mechanisms are required for a favourable response.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Pathological response to ICIs in the neoadjuvant setting
What the sources say
- Not checked — no full text of the sourcecites [112] Rozeman, E. A. et al. LBA75 — 18-months relapse-free survival (RFS) and biomarker analyses of OpACIN-neo: a study to identify the optimal dosing schedule of neoadjuvant (neoadj) ipilimumab (IPI) + nivolumab (NIVO) in stage III melanoma. Ann. Oncol. 30, v910 (2019). source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Compared with ICIs, pathological response to neoadjuvant BRAF–MEK inhibitors seems to have less predictive value in melanoma.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Pathological response to ICIs in the neoadjuvant setting
What the sources say
- Not checked — no full text of the sourcecites [105] Lucas, M. W., Versluis, J. M., Rozeman, E. A. & Blank, C. U. Personalizing neoadjuvant immune-checkpoint inhibition in patients with melanoma. Nat. Rev. Clin. Oncol. 20, 408–422 (2023). source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“analyses of data from clinical trials of neoadjuvant ICIs in patients with melanoma112 have revealed that patients with a higher TMB have improved pathological responses relative to those with lower TMB.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Pathological response to ICIs in the neoadjuvant setting
What the sources say
- Not checked — no full text of the sourcecites [112] Rozeman, E. A. et al. LBA75 — 18-months relapse-free survival (RFS) and biomarker analyses of OpACIN-neo: a study to identify the optimal dosing schedule of neoadjuvant (neoadj) ipilimumab (IPI) + nivolumab (NIVO) in stage III melanoma. Ann. Oncol. 30, v910 (2019). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Biomarkers to stratify patients therapeutically that are based on pretreatment tissue have yet to be clinically validated.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Pathological response to ICIs in the neoadjuvant setting
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“patterns of immune cell infiltration have been linked with distinct levels of pathological response.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Pathological response to ICIs in the neoadjuvant setting
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Most of these vaccines targeted tumour-associated antigens, namely, shared antigens expressed on cancer cells that are also expressed at lower levels on non-malignant cells.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > (Neo)adjuvant clinical trials with cancer vaccines
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“The highest pathological response rates were reported in patients with tumours enriched with IFNγ-related signatures along with a high TMB, suggesting that these two mechanisms are required for a favourable response.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Pathological response to ICIs in the neoadjuvant setting
What the sources say
- Not checked — no full text of the sourcecites [112] Rozeman, E. A. et al. LBA75 — 18-months relapse-free survival (RFS) and biomarker analyses of OpACIN-neo: a study to identify the optimal dosing schedule of neoadjuvant (neoadj) ipilimumab (IPI) + nivolumab (NIVO) in stage III melanoma. Ann. Oncol. 30, v910 (2019). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“neoadjuvant ICIs can be used to downstage tumours of patients and thus improve surgical outcomes for some patients14,124.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Phase I/II neoadjuvant trials in HCC
What the sources say
- Not matchedcites [14] Ho, W. J. et al. Neoadjuvant cabozantinib and nivolumab converts locally advanced HCC into resectable disease with enhanced antitumor immunity. Nat. Cancer 2, 891–903 (2021).
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not checked — no full text of the sourcecites [124] Spicer, J. et al. Surgical outcomes from the phase 3 CheckMate 816 trial: nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo alone as neoadjuvant treatment for patients with resectable non-small cell lung cancer (NSCLC). J. Clin. Oncol. 39, 8503 (2021). source
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Not matched
In the paper
“For other cancer types, such as pancreatic ductal adenocarcinoma117, the results from clinical trials are contradictory.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Pathological response to ICIs in the neoadjuvant setting
What the sources say
- Not checked — no full text of the sourcecites [117] Springfeld, C. et al. Neoadjuvant therapy for pancreatic cancer. Nat. Rev. Clin. Oncol. 20, 318–337 (2023). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“the median OS of patients with early HCC has been substantially extended (beyond 60 months) as a result of the use of resection, liver transplantation and local ablation.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Role of adjuvant therapy in HCC management
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“This situation has prompted some initiatives calling for the development of a specific biomarker approval pathway102.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Conclusions
What the sources say
- Not checked — no full text of the sourcecites [102] Llovet, J. M. Exploring a new pathway for biomarker-based approval of immunotherapies. Nat. Rev. Clin. Oncol. 20, 279–280 (2023). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Despite advances in the development of biomarkers predicting response to ICIs, no companion biomarker that enables identifying subgroups of patients with HCC who are most likely to benefit from these therapies has been approved.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Conclusions
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: No companion biomarker identifying HCC subgroups most likely to benefit from immune checkpoint inhibitors has been approved.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although the concept of unsuitability for TACE has gained widespread recognition, currently no consensus exists regarding the threshold at which upfront systemic therapy should be used, particularly in patients with disease recurrence after adjuvant therapy.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Role of adjuvant therapy in HCC management > Recurrence at intermediate stages
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Such biomarkers include not only tissue-based assays but also those based on circulating tumour cells, cell-free DNA and other liquid biopsy approaches, which have received increasing interest in the past decade151.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Conclusions
What the sources say
- Not checked — no full text of the sourcecites [151] von Felden, J., Garcia-Lezana, T., Schulze, K., Losic, B. & Villanueva, A. Liquid biopsy in the clinical management of hepatocellular carcinoma. Gut 69, 2025–2034 (2020). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the use of systemic therapies in the neoadjuvant setting has raised valid safety concerns, including the risk of inducing irAEs, that potentially delay or preclude potentially curative surgery.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Conclusions
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Perhaps the greatest opportunity from trials of systemic therapy in early stage HCC is the chance to perform detailed, relevant translational studies, given that paired tissue samples (at the time of diagnostic biopsy and resection) are usually available.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Conclusions
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the benefit of other ICI-based regimens, such as the FDA-approved combinations of durvalumab plus tremelimumab or ipilimumab plus nivolumab, after atezolizumab and bevacizumab, is not known.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Role of adjuvant therapy in HCC management > Recurrence after (neo)adjuvant therapy at advanced stages or TACE unsuitable
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Clinically, this is a scenario similar to that of patients with disease progression while receiving first-line therapy.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Role of adjuvant therapy in HCC management > Recurrence after (neo)adjuvant therapy at advanced stages or TACE unsuitable
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“locoregional therapies have extended the median OS of patients with intermediate-stage HCC to 25–30 months.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Role of adjuvant therapy in HCC management
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“patients with disease recurrence during or within 12 months of completing adjuvant treatment can have inherent resistance to such a regimen and a change of treatment is warranted.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Role of adjuvant therapy in HCC management > Recurrence after (neo)adjuvant therapy at advanced stages or TACE unsuitable
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“In this context, no other treatment has demonstrated improved RFS in a phase III study.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Role of adjuvant therapy in HCC management > Recurrence at intermediate stages
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“given that mutation-associated neoantigens tend to be unique to each tumour, such vaccines need to be personalized for each patient with cancer.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > (Neo)adjuvant clinical trials with cancer vaccines
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 47
- Probably not a substantial claim. 12
- The quote only partly states this claim. 1
Some cited sources support this claim and some don’t — read each source’s verdict below.
In the paper
“Given the lack of successful trials in the perioperative space in HCC, no surrogate end point has been validated yet, as is the case for pCR in patients with NSCLC20,120 and breast cancer8.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Phase I/II neoadjuvant trials in HCC
What the sources say
- Disputedcites [20] Forde, P. M. et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N. Engl. J. Med. 386, 1973–1985 (2022). sourceExperimental — accuracy not yet measured
The Discussion says that a trial-level association between pathological complete response and survival in NSCLC had not been shown prospectively. It describes pathological complete response as promising and says its association with survival benefit requires further evaluation, contrary to the claim that it is a validated surrogate endpoint in NSCLC. This paper does not assess surrogate-endpoint validation in HCC. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
- Partly supportedcites [120] Wakelee, H. et al. Perioperative pembrolizumab for early-stage non-small-cell lung cancer. N. Engl. J. Med. 389, 491–503 (2023). sourceExperimental — accuracy not yet measured
The Methods (Assessments and Endpoints; page not provided) identify pathological complete response as a secondary endpoint in the NSCLC trial, and the Results (Efficacy; page not provided) report that pembrolizumab improved it. Neither passage establishes that pathological complete response is a validated surrogate endpoint in NSCLC. The HCC and breast-cancer portions of the sentence are not attributed to this source. (LLM, conf=0.82)
- Partly supportedcites [8] Schmid, P. et al. Event-free survival with pembrolizumab in early triple-negative breast cancer. N. Engl. J. Med. 386, 556–567 (2022). sourceExperimental — accuracy not yet measured
The End Points section lists pathological complete response (pCR) as a primary endpoint in a breast-cancer trial, and the Efficacy section reports event-free survival by pCR status. Neither section says pCR is a validated surrogate endpoint in breast cancer; the paper measures event-free survival separately. The HCC and NSCLC portions of the citing sentence are not attributed to this source. (LLM, conf=0.84)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Disputed
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Surgical resection is recognized worldwide as the preferred treatment for patients with early stage HCC, whereas liver transplantation is indicated in those with early stage disease who are not deemed suitable for resection7,22.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Management of early stage HCC > Resection
What the sources say
- Partly supportedcites [7] Singal, A. G. et al. AASLD practice guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology 78, 1922–1965 (2023). sourceExperimental — accuracy not yet measured
The Surgical resection section calls resection the treatment of choice for localized HCC without cirrhosis and recommends it for selected patients with compensated cirrhosis. The Liver transplantation section supports transplantation for early-stage patients ineligible for resection because of liver dysfunction or multifocality. The claim overgeneralizes resection as preferred for all early-stage patients worldwide and omits transplant eligibility; page numbers were not available in our copy. (LLM, conf=0.85)
- Not checked — no full text of the sourcecites [22] Galle, P. R. et al. EASL Clinical Practice Guidelines: management of hepatocellular carcinoma. J. Hepatol. 69, 182–236 (2018). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“Despite an impressive median overall survival (OS) beyond 60 months after resection or local ablation, up to 30–50% of patients have disease recurrence at 3 years, often resulting from intrahepatic metastases or de novo tumours arising in the underlying liver pathology1,2.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Introduction
What the sources say
- Not checked — no full text of the sourcecites [1] Llovet, J. M. et al. Hepatocellular carcinoma. Nat. Rev. Dis. Prim. 7, 7 (2021). source
- Could not verifycites [2] Llovet, J. M. et al. Molecular pathogenesis and systemic therapies for hepatocellular carcinoma. Nat. Cancer 3, 386–401 (2022). sourceExperimental — accuracy not yet measured
The ‘Placing systemic therapies in the context of HCC management’ section (page unavailable) identifies resection and ablation as curative options for early-stage HCC, but gives neither median survival after those treatments nor a three-year recurrence rate. Searches for 60-month survival, three-year recurrence, and recurrence after resection or ablation found no passage supporting those figures; the paper’s 30–50% figures refer to other populations or treatments. (LLM, conf=0.75)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In general, European and US guidelines recommend more-restrictive criteria for resection than Asian guidelines7,22–27.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Management of early stage HCC > Resection
What the sources say
- Partly supportedcites [7] Singal, A. G. et al. AASLD practice guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology 78, 1922–1965 (2023). sourceExperimental — accuracy not yet measured
The Surgical resection section says resection is mainly limited to BCLC stage 0/A and advises that extended indications be considered only in high-volume centers after multidisciplinary discussion. It notes that most evidence for resection in patients with portal vein tumor thrombus comes from Asia, but it does not compare the eligibility criteria recommended by European, US, and Asian guidelines. The claimed regional ranking is therefore not established by this source. (LLM, conf=0.79)
- Not checked — no full text of the sourcecites [22] Galle, P. R. et al. EASL Clinical Practice Guidelines: management of hepatocellular carcinoma. J. Hepatol. 69, 182–236 (2018). source
- Not checked — no full text of the sourcecites [23] Kudo, M. et al. Management of hepatocellular carcinoma in Japan: JSH Consensus Statements and Recommendations 2021 Update. Liver Cancer 10, 181–223 (2021). source
- Partly supportedcites [24] Xie, D., Shi, J., Zhou, J., Fan, J. & Gao, Q. Clinical practice guidelines and real-life practice in hepatocellular carcinoma: a Chinese perspective. Clin. Mol. Hepatol. 29, 206–216 (2023). sourceExperimental — accuracy not yet measured
The Hepatectomy section says Chinese guidelines prefer resection for CNLC stages Ia–IIa and permit it for selected IIb and IIIa cases. This supports the account of Chinese eligibility criteria, but our copy does not state that European and US guidelines are more restrictive than Asian guidelines generally. (LLM, conf=0.80)
- Partly supportedcites [25] Goh, M. J. et al. Clinical practice guideline and real-life practice in hepatocellular carcinoma: a Korean perspective. Clin. Mol. Hepatol. 29, 197–205 (2023). sourceExperimental — accuracy not yet measured
The TREATMENT > Hepatic resection section (page unavailable) says the Korean guidelines selectively permit limited resection for some patients with mild portal hypertension or hyperbilirubinemia. That establishes a Korean eligibility criterion, but our copy does not compare it with European or US resection guidelines, so the claimed regional ranking is unsupported. (LLM, conf=0.76)
- Not checked — no full text of the sourcecites [26] Roayaie, S. et al. The role of hepatic resection in the treatment of hepatocellular cancer. Hepatology 62, 440–451 (2015). source
- Not checked — no full text of the sourcecites [27] Llovet, J. M., Schwartz, M. & Mazzaferro, V. Resection and liver transplantation for hepatocellular carcinoma. Semin. Liver Dis. 25, 181–200 (2005). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“ORRs and RFS after local ablation are inversely proportional to tumour size, with optimal outcomes observed for patients with small HCCs in whom 3-year RFS and OS are approximately 45% and 75%, respectively42,43, and 5-year OS is around 60% (refs. 44–47).”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Management of early stage HCC > Local ablation
What the sources say
- Not checked — no full text of the sourcecites [42] Doyle, A. et al. Outcomes of radiofrequency ablation as first-line therapy for hepatocellular carcinoma less than 3 cm in potentially transplantable patients. J. Hepatol. 70, 866–873 (2019). source
- Partly supportedcites [43] Shiina, S. et al. Radiofrequency ablation for hepatocellular carcinoma: 10-year outcome and prognostic factors. Am. J. Gastroenterol. 107, 569–577 (2012). sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Not checked — no full text of the sourcecites [44] Charalel, R. A. et al. Long-term survival after surgery versus ablation for early liver cancer in a large, nationally representative cohort. J. Am. Coll. Radiol. 19, 1213–1223 (2022). source
- Not checked — no full text of the sourcecites [45] Pompili, M. et al. Long-term effectiveness of resection and radiofrequency ablation for single hepatocellular carcinoma ≤ 3 cm. Results of a multicenter Italian survey. J. Hepatol. 59, 89–97 (2013). source
- Not checked — no full text of the sourcecites [46] Kudo, M. et al. Report of the 22nd nationwide follow-up Survey of Primary Liver Cancer in Japan (2012–2013). Hepatol. Res. 52, 5–66 (2022). source
- Could not verifycites [47] Yoon, J. S. et al. Hepatocellular carcinoma in Korea between 2008 and 2011: an analysis of Korean Nationwide Cancer Registry. J. Liver Cancer 20, 41–52 (2020). sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 2 unverifiable. Expand the claim to see per-atom verdicts.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Percutaneous ethanol injection was the original ablation technique, although this has been largely replaced by radiofrequency ablation (RFA) or microwave ablation (MWA), which provide both superior OS and objective response rates (ORRs) with fewer sessions41.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Management of early stage HCC > Local ablation
What the sources say
- Partly supportedcites [41] Lin, S.-M., Lin, C.-J., Lin, C.-C., Hsu, C.-W. & Chen, Y.-C. Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and percutaneous acetic acid injection to treat hepatocellular carcinoma of 3 cm or less. Gut 54, 1151–1156 (2005). sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) reports higher overall survival with radiofrequency thermal ablation (RFTA) than with percutaneous ethanol injection (PEI) for hepatocellular carcinomas of 3 cm or less. The Complete tumour necrosis section (page unavailable) reports a higher necrosis rate and fewer treatment sessions with RFTA, but does not label the necrosis measure an objective response rate. The paper does not study microwave ablation or establish that either technique has largely replaced PEI. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Several gene signatures capturing the inflamed components of the TME have been associated with a favourable response to ICIs69,72,78–81, but none has been clinically validated thus far.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Tumour immune microenvironment in HCC > HCC immune types
What the sources say
- Not checked — no full text of the sourcecites [69] Zhu, A. X. et al. Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma. Nat. Med. 28, 1599–1611 (2022). source
- Partly supportedcites [72] Haber, P. K. et al. Molecular markers of response to anti-PD1 therapy in advanced hepatocellular carcinoma. Gastroenterology 164, 72–88.e18 (2023). sourceExperimental — accuracy not yet measured
The Results section (‘Molecular Features of Patients With HCC Responding to Anti-PD1 in Front Line’; page unavailable) reports that several inflammatory gene signatures were enriched in HCC patients responding to first-line anti-PD1 therapy. The Discussion says the only FDA-approved anti-PD1 biomarkers are tumor mutational burden and microsatellite instability, and that the authors’ new signature still needs phase III evaluation. The paper therefore supports the association and the lack of established clinical use, but does not establish that no such signature has been clinically validated across all immune-checkpoint inhibitors and settings. (LLM, conf=0.82)
- Partly supportedcites [78] Montironi, C. et al. Inflamed and non-inflamed classes of HCC: a revised immunogenomic classification. Gut 72, 129–140 (2023). sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) reports two inflammatory signatures associated with ICI response in advanced HCC, and the Results (page unavailable) find higher expression of the paper’s Inflamed signature in responders than non-responders. The paper describes a continuing need for clinically useful biomarkers, but it does not establish the categorical claim that none of these signatures has been clinically validated. (LLM, conf=0.82)
- Not checked — no full text of the sourcecites [79] Fehrenbacher, L. et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 387, 1837–1846 (2016). source
- Supportedcites [80] Sangro, B. et al. Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma. J. Hepatol. 73, 1460–1469 (2020). source
The Results section reports that several inflammatory gene-expression signatures were associated with objective response or survival in nivolumab-treated patients with advanced hepatocellular carcinoma. The citation is attached to the association claim; the subsequent statement about clinical validation is not attributed to this source. (LLM, conf=0.91)
- Supportedcites [81] Ayers, M. et al. IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J. Clin. Invest. 127, 1–11 (2017). source
The Results report that IFN-γ- and T-cell–associated gene signatures were associated with improved outcomes after pembrolizumab treatment. The Discussion says the 18-gene profile had undergone analytical validation but remained under development as a clinical-grade diagnostic device; the Results say formal evaluation of clinical utility depended on developmental trials. Thus, the paper supports the distinction between an observed response association and clinical validation. (LLM, conf=0.88)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“At a median follow-up duration of 17.4 months, median RFS had not been reached in either group, although statistical analyses favoured intervention over active surveillance (HR 0.72, 95% CI 0.56–0.93; P = 0.012).”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Adjuvant therapies in HCC > IMbrave 050
What the sources say
- Partly supportedcites [12] Qin, S. et al. Atezolizumab plus bevacizumab versus active surveillance in patients with resected or ablated high-risk hepatocellular carcinoma (IMbrave 050): a randomised, open-label, multicentre, phase 3 trial. Lancet 402, 1835–1847 (2023). sourceExperimental — accuracy not yet measured
The Results (Figure 2; page not supplied) report that median recurrence-free survival was not reached in either group and that atezolizumab plus bevacizumab was favoured at a median follow-up of 17.4 months (HR 0.72; p=0.012). The reported adjusted 95% CI is 0.53–0.98, not the claimed 0.56–0.93. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In summary, most of the studies failed to identify any clinical benefit and, among the positive studies, validation in trials conducted in Western countries is awaited.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Adjuvant therapies in HCC > Past and ongoing phase III trials in HCC
What the sources say
- Partly supportedcites [11] Haber, P. K. et al. Evidence-based management of hepatocellular carcinoma: systematic review and meta-analysis of randomized controlled trials (2002–2020). Gastroenterology 161, 879–898 (2021). sourceExperimental — accuracy not yet measured
The Results (Adjuvant Treatments; page unavailable) report that only one of seven high-quality adjuvant trials met its primary endpoint, supporting the claim that most did not show benefit. The positive trial was conducted in Korea, and the Discussion notes important caveats, but our copy does not state that validation in Western-country trials is awaited. (LLM, conf=0.86)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“B cells have a dual role in HCC immunobiology, promoting tumour development but also enhancing the response to immunotherapy by producing antitumour antibodies and activating T cells65.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Tumour immune microenvironment in HCC > Immune cell types, tumour neoantigens and mechanisms of immune response and escape
What the sources say
- Partly supportedcites [65] Finkin, S. et al. Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma. Nat. Immunol. 16, 1235–1244 (2015). sourceExperimental — accuracy not yet measured
The Results section, “ELSs express high amounts of growth promoting cytokines” (page unavailable), finds that B lymphocytes express LTβ within tumor-promoting ectopic lymphoid structures, supporting a role in HCC development. The paper does not report that B cells enhance immunotherapy response by producing antitumour antibodies or activating T cells. (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“The incidence of grade 3–4 adverse events was 41% and 13% with intervention and active surveillance, respectively, and 8.7% of patients discontinued both atezolizumab and bevacizumab owing to adverse events.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Adjuvant therapies in HCC > IMbrave 050
What the sources say
- Supportedcites [12] Qin, S. et al. Atezolizumab plus bevacizumab versus active surveillance in patients with resected or ablated high-risk hepatocellular carcinoma (IMbrave 050): a randomised, open-label, multicentre, phase 3 trial. Lancet 402, 1835–1847 (2023). source
The Results report grade 3 or 4 adverse events in 136/332 patients (41%) receiving atezolizumab plus bevacizumab and 44/330 (13%) under active surveillance. They also report that adverse events led 29 treated patients to discontinue both drugs; 29/332 is 8.7% before rounding (reported as 9%). (LLM, conf=0.94)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In certain tumour types, the number of neoantigens in a tumour (or tumour mutational burden (TMB)) is correlated with responsiveness to ICIs67,68.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Tumour immune microenvironment in HCC > Immune cell types, tumour neoantigens and mechanisms of immune response and escape
What the sources say
- Supportedcites [67] Jardim, D. L., Goodman, A., de Melo Gagliato, D. & Kurzrock, R. The challenges of tumor mutational burden as an immunotherapy biomarker. Cancer Cell 39, 154–173 (2021). source
The “Utility and Challenges of Using TMB as a Biomarker” section (page unavailable) reports that higher TMB correlates with better responses to immune-checkpoint inhibitors, including in melanoma and urothelial cancer. The Introduction (page unavailable) links higher TMB to more neoantigens. The paper also notes that the correlation does not hold in every setting, consistent with the claim’s qualification to certain tumour types. (LLM, conf=0.93)
- Partly supportedcites [68] Samstein, R. M. et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat. Genet. 51, 202–206 (2019). sourceExperimental — accuracy not yet measured
The Abstract (page not specified in our copy) reports that higher TMB was associated with better survival among patients treated with immune-checkpoint inhibitors across many cancer types. The paper proposes that higher TMB may mean more tumour neoantigens, but it does not report a direct correlation between neoantigen number and treatment response. (LLM, conf=0.85)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“MYC overexpression leads to PD-L1 overexpression, whereas TP53 mutations promote the recruitment of immunosuppressive cells75.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Tumour immune microenvironment in HCC > Immune cell types, tumour neoantigens and mechanisms of immune response and escape
What the sources say
- Partly supportedcites [75] Xu, Y. et al. Translation control of the immune checkpoint in cancer and its therapeutic targeting. Nat. Med. 25, 301–311 (2019). sourceExperimental — accuracy not yet measured
The Results section ('MYC reprograms PD-L1 expression at the translation level'; page unavailable) reports increased PD-L1 protein in MYC-expressing, KRAS-mutant liver tumors. The paper does not support the claim that TP53 mutations recruit immunosuppressive cells: its immune-cell findings concern MYC and KRAS, not TP53. (LLM, conf=0.90)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Overall, patients with inflamed HCCs tend to have a favourable prognosis and are the most likely to have improved outcomes when receiving ICIs owing to the presence of responsive immune cells72,78.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Tumour immune microenvironment in HCC > HCC immune types
What the sources say
- Partly supportedcites [72] Haber, P. K. et al. Molecular markers of response to anti-PD1 therapy in advanced hepatocellular carcinoma. Gastroenterology 164, 72–88.e18 (2023). sourceExperimental — accuracy not yet measured
The Results section, “Molecular Features of Patients With HCC Responding to Anti-PD1 in Front Line” (page unavailable), reports a higher objective-response rate for the Inflamed class than for the Intermediate and Excluded classes (7/9 versus 5/19). It does not establish a generally favourable prognosis for patients with inflamed HCC; the class’s progression-free-survival difference was a nonsignificant trend. The Discussion links immune-cell composition to response but does not establish that responsive cells cause the improved outcomes. (LLM, conf=0.87)
- Partly supportedcites [78] Montironi, C. et al. Inflamed and non-inflamed classes of HCC: a revised immunogenomic classification. Gut 72, 129–140 (2023). sourceExperimental — accuracy not yet measured
In the Results (Inflamed class; page unavailable), the Inflamed signature was higher in ICI responders than non-responders, supporting the suggestion that these tumors may benefit from ICIs. The Results (Defining inflamed and non-inflamed HCCs; page unavailable) report better survival only for the Immune Active subclass; the Immune-like subclass showed no survival difference from non-inflamed profiles, so a favourable prognosis is not established for the Inflamed class as a whole. (LLM, conf=0.88)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Conversely, RCTs conducted in China have reported clinical benefits with (neo)adjuvant therapies.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Adjuvant therapies in HCC > Past and ongoing phase III trials in HCC
What the sources say
- Supportedcites [92] Li, S.-H. et al. Postoperative adjuvant hepatic arterial infusion chemotherapy with FOLFOX in hepatocellular carcinoma with microvascular invasion: a multicenter, phase III randomized study. J. Clin. Oncol. 41, 1898–1908 (2023). source
The Methods describe a randomized trial conducted at five centers in China, and the Results (Efficacy Analysis; page unavailable) report better disease-free survival with adjuvant FOLFOX hepatic arterial infusion. The Discussion (page unavailable) also reports survival benefits from adjuvant TACE after resection in patients with microvascular invasion. This paper supports the adjuvant examples; it does not itself test neoadjuvant therapy. (LLM, conf=0.91)
- Not checked — no full text of the sourcecites [93] Wang, Z. et al. Adjuvant transarterial chemoembolization for HBV-related hepatocellular carcinoma after resection: a randomized controlled study. Clin. Cancer Res. 24, 2074–2081 (2018). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“By contrast, late HCC recurrence (>12 months) probably reflects new primary tumours (also known as de novo HCCs) and is related to the underlying liver disease.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Management of early stage HCC > Unmet clinical needs
What the sources say
- Partly supportedcites [58] Xu, X.-F. et al. Risk factors, patterns, and outcomes of late recurrence after liver resection for hepatocellular carcinoma: a multicenter study from China. JAMA Surg. 154, 209–217 (2019). sourceExperimental — accuracy not yet measured
The Abstract and Discussion associate late recurrence with de novo tumours and underlying hepatitis or cirrhosis. But the paper defines late recurrence as more than 2 years after surgery, not more than 12 months; its findings therefore do not establish the claim for recurrences between 12 and 24 months. Page numbers are not available in the supplied copy. (LLM, conf=0.90)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Indeed, in HCC, the presence of large-scale copy-number alterations results in the loss of genes involved in antigen presentation, suggesting that copy-number alterations contribute shaping of the TME70.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Tumour immune microenvironment in HCC > Immune cell types, tumour neoantigens and mechanisms of immune response and escape
What the sources say
- Partly supportedcites [70] Bassaganyas, L. et al. Copy-number alteration burden differentially impacts immune profiles and molecular features of hepatocellular carcinoma. Clin. Cancer Res. 26, 6350–6361 (2020). sourceExperimental — accuracy not yet measured
The Results report that losses of antigen-presentation genes, including HLA-DQB1, were enriched in HCC tumors with high burdens of broad copy-number alterations. The Discussion proposes that these losses could affect the tumor immune environment, but says further studies are needed to establish causality. Thus, “results in” overstates the evidence. Page numbers were not available in our copy. (LLM, conf=0.88)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The most common immune-related AEs (irAEs) were hepatitis (32% versus 15%), rash (20% versus 2%) and hypothyroidism (20% versus <1%), mostly of grade 1–2 (ref. 12).”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Adjuvant therapies in HCC > IMbrave 050
What the sources say
- Partly supportedcites [12] Qin, S. et al. Atezolizumab plus bevacizumab versus active surveillance in patients with resected or ablated high-risk hepatocellular carcinoma (IMbrave 050): a randomised, open-label, multicentre, phase 3 trial. Lancet 402, 1835–1847 (2023). sourceExperimental — accuracy not yet measured
The Results (page not available in our copy) identify hepatitis-related events and hypothyroidism as the most common immune-mediated adverse events and say most were grade 1–2. They do not identify rash among those events or give the cited immune-related percentages. Table 2 reports rash and hypothyroidism under adverse events regardless of causality, with different percentages, so it does not verify those figures. (LLM, conf=0.86)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Inflamed tumours constitute ~30% of HCCs and exhibit extensive immune cell infiltration and immune activity, detected as increased expression of immune checkpoints (such as PD-1 or its ligand PD-L1), activation of IFN signalling and a low burden of large chromosomal alterations70,71,78.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Tumour immune microenvironment in HCC > HCC immune types
What the sources say
- Partly supportedcites [70] Bassaganyas, L. et al. Copy-number alteration burden differentially impacts immune profiles and molecular features of hepatocellular carcinoma. Clin. Cancer Res. 26, 6350–6361 (2020). sourceExperimental — accuracy not yet measured
The Introduction (page unavailable) describes an HCC Immune Class comprising about one third of cases, with high immune infiltration and PD-1/PD-L1 expression. The Results (page unavailable) link low broad copy-number alteration burden to interferon signalling, immune infiltration, and higher checkpoint expression. But low-burden tumours account for 17% of HCCs, and the paper reports an association with the Immune Class—not that all inflamed tumours have low alteration burden. (LLM, conf=0.86)
- Supportedcites [71] Sia, D. et al. Identification of an immune-specific class of hepatocellular carcinoma, based on molecular features. Gastroenterology 153, 812–826 (2017). source
The Results sections describe an Immune class with immune-cell signatures, PD-1 signalling, IFN signalling, and fewer broad chromosomal gains and losses. The Discussion estimates its prevalence at about 25% of HCCs; the validation Results report an average of 27% in fresh-frozen datasets and 30% in one FFPE dataset, consistent with the claim’s approximate 30%. (LLM, conf=0.88)
- Supportedcites [78] Montironi, C. et al. Inflamed and non-inflamed classes of HCC: a revised immunogenomic classification. Gut 72, 129–140 (2023). source
The Introduction and Discussion describe the Inflamed class as comprising about 35% of HCCs, with immune infiltration and high interferon and PD-1 signalling. The Results (Inflamed class) report increased expression of PD-1 and PD-L1; the Results (Non-inflamed classes) find more broad chromosomal alterations in non-inflamed classes than in the Inflamed class. Page numbers are unavailable in our copy. (LLM, conf=0.90)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“These findings are from a study in a tumour type that tends to be responsive to ICIs and thus, their relevance to less-responsive tumour types, such as HCC, remains to be demonstrated.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Neoadjuvant trials with ICIs in several cancer types
What the sources say
- Supportedcites [9] Patel, S. P. et al. Neoadjuvant–adjuvant or adjuvant-only pembrolizumab in advanced melanoma. N. Engl. J. Med. 388, 813–823 (2023). source
The Methods (Patients; page unavailable) identify S1801 as a melanoma trial, and the Results (Efficacy; page unavailable) report responses to pembrolizumab. The comparison with HCC and the need to demonstrate relevance there are the citing authors’ extrapolation, not findings attributed to S1801. (LLM, conf=0.87)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“neoadjuvant ICIs can induce a more robust immune response than adjuvant ICIs, given the immunosuppressive systemic effects of invasive surgery125–127.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Phase I/II neoadjuvant trials in HCC
What the sources say
- Not matchedcites [125] Lissoni, P. et al. Effects of the conventional antitumor therapies surgery, chemotherapy, radiotherapy and immunotherapy on regulatory T lymphocytes in cancer patients. Anticancer Res. 29, 1847–1852 (2009).
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Partly supportedcites [126] Tang, F., Tie, Y., Tu, C. & Wei, X. Surgical trauma-induced immunosuppression in cancer: recent advances and the potential therapies. Clin. Transl. Med. 10, 199–223 (2020). sourceExperimental — accuracy not yet measured
The Background and Conclusion and Future Prospects sections describe systemic immunosuppression after surgery and link its severity to the invasiveness of surgical trauma. The Combination therapy of immunotherapy and surgery section discusses preoperative immune stimulation and checkpoint blockade, but does not compare immune responses to neoadjuvant versus adjuvant checkpoint inhibitors. (LLM, conf=0.86)
- Partly supportedcites [127] Bakos, O., Lawson, C., Rouleau, S. & Tai, L.-H. Combining surgery and immunotherapy: turning an immunosuppressive effect into a therapeutic opportunity. J. Immunother. Cancer 6, 86 (2018). sourceExperimental — accuracy not yet measured
The Checkpoint inhibitors section reports better survival with neoadjuvant than adjuvant checkpoint treatment in two mouse models, alongside markers of antitumor immunity. The Background describes surgery-induced immunosuppression, and the authors suggest that treatment before surgery might help preserve immune activation. The paper does not establish that the neoadjuvant treatment produced a more robust immune response than the adjuvant treatment; its direct comparison is of survival. (LLM, conf=0.82)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Since results from one of the first clinical trials of such a therapeutic approach in patients with NSCLC were reported in 2018 (ref. 19), the efficacy and safety of neoadjuvant ICIs have been firmly established in multiple tumour types, with FDA approvals for two indications (NSCLC20,120 and triple-negative breast cancer8).”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Neoadjuvant trials with ICIs in several cancer types
What the sources say
- Not checked — no full text of the sourcecites [19] Yang, X. et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N. Engl. J. Med. 379, e14 (2018). source
- Supportedcites [20] Forde, P. M. et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N. Engl. J. Med. 386, 1973–1985 (2022). source
The Discussion reports that neoadjuvant nivolumab plus chemotherapy improved outcomes in resectable NSCLC without increasing adverse events, and that the regimen was approved in the United States for eligible adults with resectable NSCLC. This source is cited for the NSCLC indication, not the separate triple-negative breast cancer indication. (LLM, conf=0.94)
- Supportedcites [120] Wakelee, H. et al. Perioperative pembrolizumab for early-stage non-small-cell lung cancer. N. Engl. J. Med. 389, 491–503 (2023). source
This source is cited for the NSCLC part of the sentence, not the separately cited triple-negative breast cancer indication. The Introduction reports a benefit from neoadjuvant checkpoint inhibition in NSCLC and states that neoadjuvant nivolumab plus chemotherapy is FDA-approved; the Discussion reports a consistent safety profile for the studied perioperative regimen. (LLM, conf=0.90)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“These three initial studies highlight the utility of the neoadjuvant ‘window-of-opportunity’ setting and provide insight on the mechanisms of action of ICIs, given the potential to use resected tumour tissue for in-depth immune analysis rather than relying on scant on-treatment biopsy samples128.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Phase I/II neoadjuvant trials in HCC
What the sources say
- Partly supportedcites [128] Marron, T. U. et al. Neoadjuvant clinical trials provide a window of opportunity for cancer drug discovery. Nat. Med. 28, 626–629 (2022). sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Out of the 20 patients who underwent resection, 20% had significant tumour necrosis.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Phase I/II neoadjuvant trials in HCC
What the sources say
- Supportedcites [13] Marron, T. U. et al. Neoadjuvant cemiplimab for resectable hepatocellular carcinoma: a single-arm, open-label, phase 2 trial. Lancet Gastroenterol. Hepatol. 7, 219–229 (2022). source
The Findings passage reports that 20 patients underwent successful resection and four (20%) had significant tumour necrosis. The Methods describe two neoadjuvant doses, and the Results report that one patient underwent surgery 22 days after starting treatment. (LLM, conf=0.95)
plainn = 20- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one. The quote only partly states this claim.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In the trial of neoadjuvant cemiplimab82, the analysis of samples taken at the time of resection (after treatment) revealed that responsive tumours had high levels of T cell infiltration, although some non-responsive HCCs also had T cell enrichment (Fig. 2).”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Pathological response to ICIs in the neoadjuvant setting
What the sources say
- Partly supportedcites [82] Magen, A. et al. Intratumoral dendritic cell–CD4+ T helper cell niches enable CD8+ T cell differentiation following PD-1 blockade in hepatocellular carcinoma. Nat. Med. 29, 1389–1399 (2023). sourceExperimental — accuracy not yet measured
The Results report that all treatment-responsive lesions and 40% of nonresponsive lesions were highly infiltrated with T cells after resection. However, this analysis included 20 patients treated with cemiplimab in the trial and nine treated with nivolumab off trial, so the paper does not establish the stated finding for cemiplimab-trial samples alone. The indexed copy provides no page number for this passage. (LLM, conf=0.86)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Cancer-prevention vaccines, such as those for human papillomavirus and HBV, have greatly reduced the incidence or certain virally driven cancers, including HBV-related HCC130.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > (Neo)adjuvant clinical trials with cancer vaccines
What the sources say
- Partly supportedcites [130] Schiller, J. T. & Lowy, D. R. Vaccines to prevent infections by oncoviruses. Annu. Rev. Microbiol. 64, 23–41 (2010). sourceExperimental — accuracy not yet measured
The Hepatitis B Virus section documents a reduction in childhood HCC incidence in Taiwan following universal HBV vaccination. It also says HBV was the only oncovirus vaccine shown to prevent human cancer; the cited paper does not establish that HPV vaccination had already reduced cancer incidence. (LLM, conf=0.90)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“in mouse models of colon and prostate cancer, combined administration of anti-CTLA4 and anti-PD-1 antibodies in the low tumour burden state (following resection of the primary tumour) provided improved control of established tumours but compromised antitumour immunity109.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Mechanisms of action of neoadjuvant versus adjuvant approaches
What the sources say
- Partly supportedcites [109] Pai, C.-C. S. et al. Clonal deletion of tumor-specific T cells by interferon-γ confers therapeutic resistance to combination immune checkpoint blockade. Immunity 50, 477–492.e8 (2019). sourceExperimental — accuracy not yet measured
The Results section on low tumour burden reports that adding anti-PD-1 to anti-CTLA-4 compromised tumour control, and the section on memory responses reports weaker protection on tumour re-challenge. The cited experiments treated mice after tumour implantation, not after primary-tumour resection. Improved control with the combination is therefore not supported in the low-burden setting described by the claim. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“long-term PD-1 blockade predisposes patients to a higher risk of irAEs and increased financial burden without a proven effect on outcomes129.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Phase I/II neoadjuvant trials in HCC
What the sources say
- Supportedcites [129] Marron, T. U. et al. Considerations for treatment duration in responders to immune checkpoint inhibitors. J. Immunother. Cancer 9, e001901 (2021). source
The sections on physical and financial toxicity from prolonged immunotherapy (page unavailable) say that extended treatment carries physical risk, including late-onset irAEs, and has a significant financial impact. The discussion of treatment duration says prospective trials are still needed to determine whether stopping treatment affects survival outcomes, supporting the claim that an outcome benefit from prolonged treatment is unproven. (LLM, conf=0.87)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“guidelines on trial design for patients with HCC119 recommend the use of modified Response Evaluation Criteria In Solid Tumors (mRECIST) for assessing responses to therapies in patients with early stage and intermediate-stage HCC, and both RECIST and mRECIST to evaluate responses to systemic therapies in the advanced-stage setting.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Pathological response to ICIs in the neoadjuvant setting
What the sources say
- Partly supportedcites [119] Llovet, J. M. et al. Trial design and endpoints in hepatocellular carcinoma: AASLD consensus conference. Hepatology 73, 158–191 (2021). sourceExperimental — accuracy not yet measured
The paper’s 'Overall assessment of tumor response by RECIST' section lists RECIST 1.1 or mRECIST for assessing tumor response. The passages found do not establish the claimed stage-specific recommendations: mRECIST for early- and intermediate-stage HCC, and both criteria for advanced-stage systemic therapies. (LLM, conf=0.72)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“At present, atezolizumab plus bevacizumab4, durvalumab plus tremelimumab148, lenvatinib149 and sorafenib3 are approved globally for the first-line treatment of advanced-stage HCC, although clearly no patients in the studies that led to these approvals received previous adjuvant systemic therapy1,2,6.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Role of adjuvant therapy in HCC management > Recurrence after (neo)adjuvant therapy at advanced stages or TACE unsuitable
What the sources say
- Partly supportedcites [4] Finn, R. S. et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N. Engl. J. Med. 382, 1894–1905 (2020). sourceExperimental — accuracy not yet measured
The Patients section (p. not available) says participants in the atezolizumab–bevacizumab trial had not previously received systemic therapy for liver cancer, supporting the statement about prior adjuvant systemic therapy for this trial. The paper establishes that this combination was studied as first-line treatment, but our copy does not establish its global approval. The other regimens have separate citations in the citing sentence and are not attributed to this paper. (LLM, conf=0.84)
- Not checked — no full text of the sourcecites [148] Abou-Alfa, G. K. et al. Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA. J. Clin. Oncol. 40, 379 (2022). source
- Partly supportedcites [149] Kudo, M. et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 391, 1163–1173 (2018). sourceExperimental — accuracy not yet measured
The Background (p. 5) identifies this as a first-line lenvatinib trial, and the Discussion (p. 16) reports noninferior overall survival versus sorafenib. Study Eligibility (p. 8) says patients with prior systemic therapy for HCC were excluded. The paper does not establish the citing sentence’s later claim that lenvatinib was approved globally; citation 149 is attached to lenvatinib, not to the other named regimens. (LLM, conf=0.84)
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Cancer mRNA-based vaccines tend to be administered alone or in combination with ICIs, and after resection, although they have also been used in neoadjuvant–adjuvant treatment approaches136,138,139 (Fig. 3c,d).”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > (Neo)adjuvant clinical trials with cancer vaccines
What the sources say
- Partly supportedcites [136] Rojas, L. A. et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature 618, 144–150 (2023). sourceExperimental — accuracy not yet measured
The Main and Discussion describe an mRNA vaccine given after surgery for pancreatic cancer, in combination with the checkpoint inhibitor atezolizumab. This trial supports that treatment approach as an example, but it does not establish that cancer mRNA vaccines are typically administered this way or document a neoadjuvant–adjuvant approach. (LLM, conf=0.84)
- Partly supportedcites [138] Ott, P. A. et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547, 217–221 (2017). sourceExperimental — accuracy not yet measured
The Abstract (page unavailable) describes vaccination after surgical resection and reports that two patients later received anti-PD-1 therapy. But this was a long-peptide vaccine, not an mRNA vaccine; the paper does not establish typical practice for mRNA vaccines or describe a neoadjuvant–adjuvant approach. (LLM, conf=0.88)
- Not checked — no full text of the sourcecites [139] mRNA vaccine slows melanoma recurrence. Cancer Discov. 13, 1278 (2023). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“those with a large intrahepatic tumour burden (such as bilobar multifocal disease) might be considered unsuitable for TACE and therefore as candidates for systemic therapies, given a lower likelihood of objective responses and a higher risk of liver injury with embolic therapies147.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Role of adjuvant therapy in HCC management > Recurrence at intermediate stages
What the sources say
- Supportedcites [147] Kudo, M. et al. Lenvatinib as an initial treatment in patients with intermediate-stage hepatocellular carcinoma beyond up-to-seven criteria and Child–Pugh a liver function: a proof-of-concept study. Cancers 11, 1084 (2019). source
The Discussion reports that, in patients with intermediate-stage HCC beyond the up-to-seven criteria, lenvatinib achieved higher response rates than TACE and prevented liver-function deterioration. It also reports liver-function deterioration after TACE in patients with bilobar multifocal disease, supporting the cited rationale for considering systemic treatment in this high-tumour-burden group. (LLM, conf=0.92)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The estimated duration of neoadjuvant approaches — aimed to achieve a balance between exposure to ICIs and prevention of tumour progression — is estimated to be around 6–8 weeks, but longer time frames might be justified based on clinical activity of a regimen13,15.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Conclusions
What the sources say
- Partly supportedcites [13] Marron, T. U. et al. Neoadjuvant cemiplimab for resectable hepatocellular carcinoma: a single-arm, open-label, phase 2 trial. Lancet Gastroenterol. Hepatol. 7, 219–229 (2022). sourceExperimental — accuracy not yet measured
The Discussion (page unavailable) supports balancing treatment exposure against the risks of delaying surgery: it says longer preoperative therapy can increase toxicity and the risk of disease progression. The Methods describe two cemiplimab doses three weeks apart, but the paper does not estimate a general 6–8-week duration or say that a regimen’s clinical activity justifies longer treatment; it says the optimal duration remains to be identified. (LLM, conf=0.83)
- Partly supportedcites [15] Kaseb, A. O. et al. Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: a randomised, open-label, phase 2 trial. Lancet Gastroenterol. Hepatol. 7, 208–218 (2022). sourceExperimental — accuracy not yet measured
The Methods (Procedures; page not available) schedule surgery at week 6, and the Discussion (page not available) suggests that some patients might have developed a response with continued treatment. The paper does not estimate a general 6–8-week duration for neoadjuvant approaches or establish that this duration balances ICI exposure against tumour progression. (LLM, conf=0.85)
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In a salvage liver transplantation study involving 110 patients, the 5-year OS in the intention-to-treat population was 69%, with 55% of patients achieving cure after resection or successful salvage liver transplantation144.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Role of adjuvant therapy in HCC management > Recurrence at intermediate stages
What the sources say
- Partly supportedcites [144] de Haas, R. J. et al. Curative salvage liver transplantation in patients with cirrhosis and hepatocellular carcinoma: an intention-to-treat analysis. Hepatology 67, 204–215 (2018). sourceExperimental — accuracy not yet measured
The Study Population section reports 110 enrolled patients, and Long-Term Outcomes reports 69% five-year overall survival from initial resection. But Success of the SLT Strategy reports cure in 60 of 108 patients (56%) after excluding two rescue transplants, rather than the cited 55% of 110. (LLM, conf=0.88)
plainn = 110- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
In the paper
“The likelihood of disease recurrence after resection or local ablation remains substantial, ranging from 50% to 70% at 5 years (Table 1); the risk of recurrence is highest during the first 12 months following curative treatment54.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Management of early stage HCC > Unmet clinical needs
What the sources say
- Not checked — no full text of the sourcecites [54] Tabrizian, P., Jibara, G., Shrager, B., Schwartz, M. & Roayaie, S. Recurrence of hepatocellular cancer after resection: patterns, treatments, and prognosis. Ann. Surg. 261, 947–955 (2015). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Such interactions are more likely to occur when a large burden of primary tumour (containing the antigens targeted by the immune system) is still present, providing a potential mechanistic rationale for why neoadjuvant immunotherapies might be preferable to adjuvant immunotherapies (Fig. 3).”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Mechanisms of action of neoadjuvant versus adjuvant approaches
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Antitumour immune responses with immunotherapy depend on interactions among T cells, antigen-presenting cells, and tumour cells.
In the paper
“Similarly, analyses of samples from patients enrolled in IMbrave 150 led to the identification of molecular predictors of improved outcomes (CD8+ T cell density, effector T (Teff) cell signature and high expression of PD-L1) and also inferior outcomes (high Treg:Teff cell ratio) with atezolizumab plus bevacizumab69.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Adjuvant therapies in HCC > Prediction of response to ICIs
What the sources say
- Not checked — no full text of the sourcecites [69] Zhu, A. X. et al. Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma. Nat. Med. 28, 1599–1611 (2022). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Adjuvant ICIs stimulate antitumour immunity against micrometastases after the primary tumour is removed, whereas neoadjuvant immunotherapies use the primary tumour as a source of antigens to stimulate such responses; in both situations, those micrometastases can eventually lead to disease recurrence.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Mechanisms of action of neoadjuvant versus adjuvant approaches
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Antitumour immune responses with immunotherapy depend on interactions among T cells, antigen-presenting cells, and tumour cells.
In the paper
“Similarly, the phase III STORM trial compared sorafenib versus placebo after resection or local ablation in 1,114 patients with HCC and did not show an improvement in RFS (33.3 versus 33.7 months)90.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Adjuvant therapies in HCC > Past and ongoing phase III trials in HCC
What the sources say
- Not checked — no full text of the sourcecites [90] Bruix, J. et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 16, 1344–1354 (2015). source
plainn = 1,114- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“ICIs can promote de novo induction of T cell-mediated immunity, expansion of pre-existing antitumour T cells and development of a more diverse tumour-specific T cell repertoire more efficiently than after tumour removal (adjuvant setting)105 (Fig. 3a,b).”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Mechanisms of action of neoadjuvant versus adjuvant approaches
What the sources say
- Not checked — no full text of the sourcecites [105] Lucas, M. W., Versluis, J. M., Rozeman, E. A. & Blank, C. U. Personalizing neoadjuvant immune-checkpoint inhibition in patients with melanoma. Nat. Rev. Clin. Oncol. 20, 408–422 (2023). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Out of the 15 patients enrolled, 12 successfully underwent resection and 5 had a major pathological response defined as ≥90% tumour necrosis.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Phase I/II neoadjuvant trials in HCC
What the sources say
- Not matchedcites [14] Ho, W. J. et al. Neoadjuvant cabozantinib and nivolumab converts locally advanced HCC into resectable disease with enhanced antitumor immunity. Nat. Cancer 2, 891–903 (2021).
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plainn = 15- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“In certain tumour types, such as melanoma and breast cancer, pathological response has been proven to be superior to radiological assessment115,116 and is currently an accepted surrogate for RFS.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Pathological response to ICIs in the neoadjuvant setting
What the sources say
- Not checked — no full text of the sourcecites [115] Rozeman, E. A. et al. Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomised, controlled trial. Lancet Oncol. 20, 948–960 (2019). source
- Not checked — no full text of the sourcecites [116] von Minckwitz, G. et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J. Clin. Oncol. 30, 1796–1804 (2012). source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Delivering ICIs after surgery enabled T cell expansion, and yielded the best antitumour activity while also decreasing toxicity106.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Mechanisms of action of neoadjuvant versus adjuvant approaches
What the sources say
- Not checked — no full text of the sourcecites [106] Liu, J. et al. Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease. Cancer Discov. 6, 1382–1399 (2016). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“All of these end points were defined arbitrarily owing to the paucity of data from studies testing neoadjuvant approaches in HCC, underscoring the need for more comprehensive studies to establish appropriate surrogate end points.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Pathological response to ICIs in the neoadjuvant setting
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although the T cell-rich infiltration pattern is the most favourable in terms of response to ICIs, this pattern is not a definitive predictor of response.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Pathological response to ICIs in the neoadjuvant setting
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The histopathological features of response to neoadjuvant ICIs in patients with NSCLC have also been described111. These features include increased infiltration of lymphocytes and macrophages in tumours, presence of tertiary lymphoid structures, proliferative fibrosis and neovascularization.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Pathological response to ICIs in the neoadjuvant setting
What the sources say
- Not checked — no full text of the sourcecites [111] Cottrell, T. R. et al. Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC). Ann. Oncol. 29, 1853–1860 (2018). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Complete responders had a significantly higher 1-year and 2-year RFS than those without a pCR (88% versus 63% and 79% versus 13%, respectively, although no significant difference in RFS was observed between patients with a pathological partial response and those with a pathological non-response)105.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Pathological response to ICIs in the neoadjuvant setting
What the sources say
- Not checked — no full text of the sourcecites [105] Lucas, M. W., Versluis, J. M., Rozeman, E. A. & Blank, C. U. Personalizing neoadjuvant immune-checkpoint inhibition in patients with melanoma. Nat. Rev. Clin. Oncol. 20, 408–422 (2023). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Given that HCC recurrence after resection has a bimodal distribution”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Conclusions
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
- Rests on an assumption: HCC recurrence after resection has a bimodal distribution.
In the paper
“an alternative pathway for biomarker-based approval of immunotherapies has been proposed”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Conclusions
What the sources say
- Not checked — no full text of the sourcecites [102] Llovet, J. M. Exploring a new pathway for biomarker-based approval of immunotherapies. Nat. Rev. Clin. Oncol. 20, 279–280 (2023). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Now the demonstration of a role for an ICI-based regimen in the adjuvant setting opens the door to studies evaluating these regimens in the neoadjuvant setting before locoregional curative approaches.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Conclusions
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“whether or not the use of systemic therapy in the adjuvant setting improves OS remains to be established”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Conclusions
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“limited data are available to guide the ‘best choice’ in such a situation but many clinicians would probably favour other approved first-line therapies.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Role of adjuvant therapy in HCC management > Recurrence after (neo)adjuvant therapy at advanced stages or TACE unsuitable
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“subsequent treatments for patients with disease progression during or after adjuvant atezolizumab plus bevacizumab are under debate and have not yet been tested in clinical trials.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Role of adjuvant therapy in HCC management
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The management of patients with HCC has improved markedly since the first BCLC classification was proposed in 1999143.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Role of adjuvant therapy in HCC management
What the sources say
- Not checked — no full text of the sourcecites [143] Llovet, J. M., Brú, C. & Bruix, J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin. Liver Dis. 19, 329–338 (1999). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Given that disease recurrence in this setting is incurable, local ablative therapies can be considered only in certain situations such as patients with oligometastatic disease and recurrence after a very long disease-free interval (years).”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Role of adjuvant therapy in HCC management > Recurrence after (neo)adjuvant therapy at advanced stages or TACE unsuitable
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
In the paper
“This approach resulted in improved RFS compared with pembrolizumab alone (78.6% versus 62.2% at 18 months; HR 0.56, 95% CI 0.31–1.02), with no major increases in toxicity140.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > (Neo)adjuvant clinical trials with cancer vaccines
What the sources say
- Not checked — no full text of the sourcecites [140] Weber et al. Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study. Lancet 403, 632–644 (2024). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“some patients will be cured with resection or local ablation alone”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Conclusions
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
- Rests on an assumption: Some patients with HCC are cured by resection or local ablation alone.
The paper relies on this without support.
A recurrence-free survival improvement is sufficient to regard adjuvant atezolizumab plus bevacizumab as a major advance in hepatocellular carcinoma management, even before overall survival benefit is shown.
“This result is a major advance in the management of HCC7.”
“Whether this RFS benefit translates into an improvement in OS (a key secondary end point of the trial) remains to be determined.”
The paper relies on this without support.
The immune microenvironment features and immunotherapy principles described for hepatocellular carcinoma apply across tumour stages, including the early-stage setting.
“Currently, the main immunotherapeutic approach for patients with HCC — regardless of tumour stage — involves restoring antitumour immunity with ICIs, which are monoclonal antibodies that block inhibitory checkpoints or their ligands5.”
The authors state this as an assumption.
Early recurrences after resection are caused by occult micrometastases that were already present at the time of resection.
“which are presumed to be related to occult micrometastases already present at the time of resection.”
The paper relies on this without support.
Therapeutic cancer vaccines have largely failed to improve outcomes despite decades of research.
“despite decades of intensive research efforts, vaccines designed to treat cancer have largely failed to improve outcomes for patients with cancer.”
The paper relies on this without support.
Micrometastases present during adjuvant therapy are less immunogenic than macroscopically detectable lesions.
“micrometastases, which can be present during adjuvant therapy, are believed to be less immunogenic than macroscopically detectable lesions.”
The paper relies on this without support.
Antitumour immune responses with immunotherapy depend on interactions among T cells, antigen-presenting cells, and tumour cells.
“Antitumour immune responses with immunotherapy depend on interactions among T cells, antigen-presenting cells and tumour cells.”
The paper relies on this without support.
Most anti-PD-(L)1 antibodies have a half-life longer than 3 weeks and remain in circulation well into postoperative recovery.
“most anti-PD-(L)1 antibodies have a half-life of >3 weeks and remain in circulation well into postoperative recuperation.”
The paper relies on this without support.
Some patients with HCC are cured by resection or local ablation alone.
“some patients will be cured with resection or local ablation alone”
The paper relies on this without support.
HCC recurrence after resection has a bimodal distribution.
“HCC recurrence after resection has a bimodal distribution”
The paper relies on this without support.
No companion biomarker identifying HCC subgroups most likely to benefit from immune checkpoint inhibitors has been approved.
“no companion biomarker that enables identifying subgroups of patients with HCC who are most likely to benefit from these therapies has been approved.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Mechanisms of action of neoadjuvant versus adjuvant approaches
“Data from a landmark study using an orthotopic model of breast cancer showed that neoadjuvant ICIs might outperform adjuvant ICIs106.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Mechanisms of action of neoadjuvant versus adjuvant approaches
“Delivering ICIs after surgery enabled T cell expansion, and yielded the best antitumour activity while also decreasing toxicity106.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Adjuvant therapies in HCC > Past and ongoing phase III trials in HCC
“effective antiviral therapy has substantially reduced the incidence of disease recurrence in patients with viral-related HCC95.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Adjuvant therapies in HCC > Past and ongoing phase III trials in HCC
“Similarly, the use of antiviral agents against HBV after resection seems to decrease RFS compared with no antiviral therapy, although we note that this was a two-stage longitudinal study98.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Pathological response to ICIs in the neoadjuvant setting
“a third trial of a longer course of neoadjuvant cabozantinib and nivolumab defined exploratory major pathological response as >90% necrosis (<10% viable tumour cells)14.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Neoadjuvant ICIs in solid tumours > Phase I/II neoadjuvant trials in HCC
“Out of the 15 patients enrolled, 12 successfully underwent resection and 5 had a major pathological response defined as ≥90% tumour necrosis.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Role of adjuvant therapy in HCC management > Recurrence at intermediate stages
“In this context, no other treatment has demonstrated improved RFS in a phase III study.”
§ Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma > Adjuvant therapies in HCC > Past and ongoing phase III trials in HCC
“In a phase III trial of adjuvant adoptive cell therapy with cytokine-induced killer cells generated by incubation of peripheral blood mononuclear cells with IL-2 and an anti-CD3 antibody of patients, median RFS was improved with cytokine-induced killer cell therapy (44.0 versus 30.0 months with placebo; HR 0.63, 95% CI 0.43–0.94; P = 0.010)94.”
Citations
Cites
Sorafenib in advanced hepatocellular carcinoma
Llovet, J. M., Ricci, S., Mazzaferro, V., Hilgard, P., Gane, E., Blanc, J.-F., de Oliveira, A. C., Santoro, A., Raoul, J.-L., Forner, A., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0708857 · Cited by 13,097
Self-citationEASL Clinical Practice Guidelines: Management of hepatocellular carcinoma
Galle, P. R., Forner, A., Llovet, J. M., Mazzaferro, V., Piscaglia, F., Raoul, J.-L., Schirmacher, P., & Vilgrain, V. (2018) · Journal of Hepatology · doi:10.1016/j.jhep.2018.03.019 · Cited by 11,406
Self-citationAtezolizumab plus bevacizumab in unresectable hepatocellular carcinoma
Finn, R. S., Qin, S., Ikeda, M., Galle, P. R., Ducreux, M., Kim, T.-Y., Kudo, M., Breder, V., Merle, P., Kaseb, A. O., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa1915745 · Cited by 7,470
Self-citationPushko, P., Pumpens, P., & Grens, E. (2013) · Intervirology · doi:10.1159/000346773 · Cited by 5,975
A New Era of Systemic Therapy for Hepatocellular Carcinoma with Regorafenib and Lenvatinib
Kudo, M. (2017) · Liver Cancer · doi:10.1159/000462153 · Cited by 5,974
Self-citationKudo, M., Finn, R. S., Qin, S., Han, K.-H., Ikeda, K., Piscaglia, F., Baron, A., Park, J.-W., Han, G., Jassem, J., et al. (2018) · The Lancet · doi:10.1016/s0140-6736(18)30207-1 · Cited by 5,497
Self-citationmRNA vaccines — a new era in vaccinology
Pardi, N., Hogan, M. J., Porter, F. W., & Weissman, D. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.243 · Cited by 4,667
Tumor mutational load predicts survival after immunotherapy across multiple cancer types
Samstein, R. M., Lee, C.-H., Shoushtari, A. N., Hellmann, M. D., Shen, R., Janjigian, Y. Y., Barron, D. A., Zehir, A., Jordan, E. J., Omuro, A., et al. (2019) · Nature Genetics · doi:10.1038/s41588-018-0312-8 · Cited by 4,071
Prognosis of Hepatocellular Carcinoma: The BCLC Staging Classification
Llovet, J., Brú, C., & Bruix, J. (1999) · Seminars in Liver Disease · doi:10.1055/s-2007-1007122 · Cited by 3,805
Self-citationIFN-γ–related mRNA profile predicts clinical response to PD-1 blockade
Ayers, M., Lunceford, J., Nebozhyn, M., Murphy, E., Loboda, A., Kaufman, D. R., Albright, A., Cheng, J. D., Kang, S. P., Shankaran, V., et al. (2017) · Journal of Clinical Investigation · doi:10.1172/jci91190 · Cited by 3,788
Research works printed but not linked: 1
- Ho, W. J. et al. Neoadjuvant cabozantinib and nivolumab converts locally advanced HCC into resectable disease with enhanced antitumor immunity. Nat. Cancer 2, 891–903 (2021).
Cited by
Sorted by citations
Biomarkers for diagnosis and therapeutic options in hepatocellular carcinoma
Chan, Y.-T., Zhang, C., Wu, J., Lu, P., Xu, L., Yuan, H., Feng, Y., Chen, Z.-S., & Wang, N. (2024) · Molecular Cancer · doi:10.1186/s12943-024-02101-z · Cited by 313
Chan, S. L., Sun, H., Xu, Y., Zeng, H., El‐Serag, H. B., Lee, J. M., Schwartz, M., Finn, R. S., Seong, J., Wang, X. W., et al. (2025) · The Lancet · doi:10.1016/s0140-6736(25)01042-6 · Cited by 262
Self-citationHepatocellular carcinoma: Epidemiology, diagnosis and treatment
Mauro, E., de Castro, T., Zeitlhoefler, M., Sung, M. W., Villanueva, A., Mazzaferro, V., & Llovet, J. M. (2025) · JHEP Reports · doi:10.1016/j.jhepr.2025.101571 · Cited by 104
Self-citationTaddei, T. H., Brown, D. B., Yarchoan, M. M., Mendiratta‐Lala, M., & Llovet, J. M. (2025) · Hepatology · doi:10.1097/hep.0000000000001269 · Cited by 82
Self-citationWang, Z., Fan, J., Zhou, S., Sun, Y., Liang, F., Ji, Y., Gu, F., Li, T., Peng, L., Peng, T., et al. (2025) · The Lancet · doi:10.1016/s0140-6736(25)01720-9 · Cited by 72
Metadata
- Authors
- Llovet, J. M., Pinyol, R., Yarchoan, M., Singal, A. G., Marron, T. U., Schwartz, M., Pikarsky, E., Kudo, M., & Finn, R. S.
- Affiliations
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Hospital Clínic de Barcelona (ES)
- Johns Hopkins University (US)
- The University of Texas Southwestern Medical Center (US)
- Tisch Cancer Institute (US)
- Icahn School of Medicine at Mount Sinai (US)
- Hebrew University of Jerusalem (IL)
- Kindai University Hospital (JP)
- University of California, Los Angeles (US)
- Corresponding author
- Llovet, Josep M.
- ORCID
- Venue
- Nature Reviews Clinical Oncology
- Published
- 2024-02-29
- Volume
- 21
- Issue
- 4
- Pages
- 294-311
- ISSN
- 1759-4774 (ISSN-L)
- 1759-4782
- PMC
- PMC11984461
- OpenAlex
- W4392298264
- Cited by
- 391
- References
- 165
- Citations by year
- 2026: 141 · 2025: 187 · 2024: 63
- FWCI
- 28.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Reviews Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (acceptedVersion)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, public-domain)
- Funders
- Cancer Research UK (C9380/A268-13, A26813, 26813)
- European Commission (101136622)
- Fundación Científica Asociación Española Contra el Cáncer (C9380/A26813, PRYGN223117LLOV)
- Generalitat de Catalunya
- Ministerio de Ciencia e Innovación (PID2022)
- Associazione Italiana per la Ricerca sul Cancro (A26813, C9380/A26813)
- National Institutes of Health (RO1DK56621)
- HORIZON EUROPE Framework Programme
- Japan Society for the Promotion of Science (21K07950)
- Agència de Gestió d'Ajuts Universitaris i de Recerca
- National Cancer Institute (R01CA273932, R01CA285544)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK056621, R01DK128289)
- Topics
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Epidemiology › Hepatitis B Virus Studies
- Keywords
- hepatocellular carcinoma, adjuvant immunotherapy, neoadjuvant immunotherapy, immune checkpoint inhibitors, atezolizumab, bevacizumab, early-stage liver cancer, tumor immune microenvironment, cancer vaccines, recurrence, hepatectomy, liver transplantation, local ablation, biomarkers, clinical trial design
- MeSH terms
- Carcinoma, Hepatocellular, Humans, Immunotherapy, Liver Neoplasms, Neoplasm Recurrence, Local, Neoadjuvant Therapy, Tumor Microenvironment
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-09-28, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-09-28 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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