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Cited by 892Adrenal and Paraganglionic TumorsNeuroendocrine Tumor Research AdvancesAdrenal Hormones and Disorders

Adrenocortical carcinoma

Open access
Else, Tobias, Kim, Alex C., Sabolch, Aaron, Raymond, Victoria M., Kandathil, Asha, Caoili, Elaine M., Jolly, Shruti, Miller, Barbra S. +2 more·2014·Endocrine Reviews
DOI 10.1210/er.2013-1029PMC PMC3963263
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Abstract

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy, often with an unfavorable prognosis. Here we summarize the knowledge about diagnosis, epidemiology, pathophysiology, and therapy of ACC. Over recent years, multidisciplinary clinics have formed and the first international treatment trials have been conducted. This review focuses on evidence gained from recent basic science and clinical research and provides perspectives from the experience of a large multidisciplinary clinic dedicated to the care of patients with ACC.

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Written from the paper’s full text.

TL;DR

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with an often unfavorable prognosis, and this review summarizes its diagnosis, epidemiology, pathophysiology, and therapy. It emphasizes multidisciplinary care, complete surgical resection as the only curative approach, and the limited but evolving evidence for adjuvant mitotane, radiation, chemotherapy, and targeted therapy.

Key findings

  • ACC incidence is estimated at 1–2 per million per year, with SEER estimating approximately 0.72 per million per year and 0.2% of all cancer deaths in the United States; median age at diagnosis is 46 years in German and French registries and 55 years in SEER, with a female-to-male ratio of 1.5–2.5:1.
  • Germline TP53 mutations underlie ACC in ∼50%–80% of children and 3%–7% of adults; Lynch syndrome prevalence in ACC is ∼3%; MEN1 patients have adrenal lesions in 20%–55% of cases, with up to 14% of those malignant; ACC comprises 5%–15% of malignancies in Beckwith-Wiedemann syndrome.
  • At presentation, 40%–60% of patients have hormone excess, 20%–30% are diagnosed incidentally, and tumors average 10–13 cm; metastatic disease at presentation has decreased from 49% in earlier studies to 25%–30% currently.
  • Complete tumor resection is the only curative therapy; mitotane produces stable disease or partial remission in about 30% of advanced cases, and in FIRM-ACT, etoposide/doxorubicin/cisplatin/mitotane had a 20% response rate (50% including stable disease) with median progression-free survival of 5 months versus 2 months for streptozotocin/mitotane.

Methods

  • Narrative review by a multidisciplinary University of Michigan group, synthesizing basic science and clinical research and providing expert opinion where evidence is lacking.
  • Evidence base includes literature, cancer registries (SEER, German ACC Registry, National Cancer Data Base, Dutch Adrenal Network Registry), clinical trials (FIRM-ACT, GALACCTIC, ADIUVO), and institutional experience from the Michigan Endocrine Oncology Repository containing data from >400 ACC patients.
  • Main analysis is qualitative synthesis of diagnosis, epidemiology, genetic predisposition, pathology, molecular pathways, prognostic factors, and surgical, medical, radiation, and other therapies; no systematic search or meta-analysis is described.

Limitations

  • The paper states that valid incidence data are lacking, many ACC studies are retrospective, single-center, small, heterogeneous, and often lack cross-sectional imaging; prospective randomized data for adjuvant mitotane and radiation are missing except for ongoing trials such as ADIUVO.
  • The paper notes that targeted therapy trials have been disappointing, often conducted in heavily pretreated patients and confounded by concurrent mitotane and CYP3A4 drug interactions.
  • The text makes evident that this is a narrative review rather than a systematic review, relying partly on expert opinion and unpublished institutional data, and it reflects a single-center multidisciplinary perspective that may introduce referral bias.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1210/er.2013-1029

Cites

381 of 381 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 374 cited sources checked · 0 supported · 0 flagged

  • Findingcitation
    § III. Genetic Predisposition

    All tested ACCs were microsatellite stable at the usual microsatellite markers.

    “Immunohistochenistry was informative in most cases; however, all tested ACCs were microsatellite stable at the usual microsatellite markers.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [62] Raymond, 2013, Adrenocortical carcinoma is a Lynch syndrome-associated cancer, J Clin Oncol source

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  • Findingown data
    § VIII. Prognostic Factors

    In the Michigan Endocrine Oncology Repository, roughly 5% of all patients diagnosed with ACC will have a disease course of >10 years.

    “In the Michigan Endocrine Oncology Repository, roughly 5% of all patients diagnosed with ACC will have a disease course of >10 years (T.E., unpublished results).”
    Quote in the paperNot a substantial claim
  • Findingcitation
    § 3. Open vs laparoscopic surgery

    In the University of Michigan study, there were more R1 or R2 resections or notation of intraoperative tumor spill in the LA group (50% vs 18%).

    “Furthermore, there were more R1 or R2 resections or notation of intraoperative tumor spill (50% vs 18%).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [262] Miller, 2010, Laparoscopic resection is inappropriate in patients with known or suspected adrenocortical carcinoma, World J Surg source

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  • Findingcitation
    § 3. Open vs laparoscopic surgery

    In the German ACC Registry case-control study, 37% of all patients had no data regarding margin status.

    “and 37% of all patients had no data regarding margin status.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [261] Brix, 2010, Laparoscopic versus open adrenalectomy for adrenocortical carcinoma: surgical and oncologic outcome in 152 patients, Eur Urol source

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  • Findingown data
    § 4. Surgery for recurrent disease

    Patients with tumor bed recurrence who have undergone LA are much more likely to have disease too small to be detected by imaging elsewhere in the peritoneal cavity compared with those having undergone OA, based on the authors' experience.

    “Patients with tumor bed recurrence who have undergone LA are much more likely to have disease too small to be detected by imaging elsewhere in the peritoneal cavity compared with those having undergone OA based on our experience.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 58
  • May combine two claims. 131

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    Findingcitation
    § IV. Patient Presentation/Clinical Characteristics

    In the Michigan Endocrine Oncology Repository (>400 patients), the mean stage at diagnosis is: stage 1, 14%; stage 2, 45%; stage 3, 27%; and stage 4, 24%.

    “In the Michigan Endocrine Oncology Repository that contains data from >400 patients with a diagnosis of ACC, the mean stage at diagnosis is as follows: stage 1, 14%; stage 2, 45%; stage 3, 27%; and stage 4, 24% (T.E., unpublished results).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites T.E., unpublished results

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    Findingcitation
    § 3. Open vs laparoscopic surgery

    In the German ACC Registry case-control study, 3 times as many OA patients had stage 3 disease and only 4 LA patients (11%) had stage 3 disease, potentially introducing bias toward more advanced disease in the OA group.

    “However, 3 times as many patients in the OA group had stage 3 disease and only 4 patients (11%) undergoing LA were found to have stage 3 disease, potentially introducing a bias toward more advanced disease in the OA group”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [261] Brix, 2010, Laparoscopic versus open adrenalectomy for adrenocortical carcinoma: surgical and oncologic outcome in 152 patients, Eur Urol source

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  • May combine two claims.

    Findingown data
    § 3. Open vs laparoscopic surgery

    After LA, 30% had positive margins or intraoperative tumor spill compared with 16% of OA patients despite larger tumors and more stage 3 tumors.

    “After LA, 30% had positive margins or intraoperative tumor spill compared with 16% of OA patients despite larger tumors and more stage 3 tumors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation
    § 3. Open vs laparoscopic surgery

    In the University of Michigan study, despite on average smaller tumors in the LA group (7.0 cm) compared with the OA group (12.3 cm), the LA group had a significantly earlier recurrence (9.2 vs 19.2 months).

    “despite on average smaller tumors in the LA group (7.0 cm) compared with the OA group (12.3 cm), the LA group had a significantly earlier recurrence (9.2 vs 19.2 months).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [262] Miller, 2010, Laparoscopic resection is inappropriate in patients with known or suspected adrenocortical carcinoma, World J Surg source

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  • May combine two claims.

    Findingown data
    § 4. Surgery for recurrent disease

    University of Michigan data show the site of first metastasis can be used to predict survival, with tumor recurrence in the peritoneum outside the tumor bed having the worst survival.

    “In addition, University of Michigan data show the site of first metastasis can also be used to predict survival, with those having tumor recurrence in the peritoneum outside the tumor bed having the worst survival.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation
    § 3. Open vs laparoscopic surgery

    A University of Michigan retrospective study reviewed 88 ACC patients, 17 of whom underwent LA; 79% of operations were performed at outside facilities, and no laparoscopic operations for ACC were performed at the University of Michigan, potentially introducing referral bias.

    “A retrospective study from the University of Michigan reviewed 88 ACC patients, 17 of whom underwent LA, and 79% of the operations were performed at outside facilities, and no laparoscopic operations for ACC were performed at the University of Michigan, potentially introducing a referral bias (262).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [262] Miller, 2010, Laparoscopic resection is inappropriate in patients with known or suspected adrenocortical carcinoma, World J Surg source

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    Findingnone given
    § 2. Cytotoxic chemotherapy

    The overall response to chemotherapeutic regimens is 30% and 50% when counting stable disease as a response, but the response is invariably transient and short-lived (6-18 months).

    “The overall response to chemotherapeutic regimens is 30% and 50%, when counting stable disease as a response. However, the response is invariably transient and short-lived (6–18 months).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § II. Epidemiology

    SEER database estimates ACC incidence at approximately 0.72 per million cases per year, leading to 0.2% of all cancer deaths in the United States.

    “The Surveillance, Epidemiology, and End Results (SEER) database provides an estimation of incidence of approximately 0.72 per million cases per year leading to 0.2% of all cancer deaths in the United States (4).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Kebebew, 2006, Extent of disease at presentation and outcome for adrenocortical carcinoma: have we made progress?, World J Surg source

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    Premisecitation
    § II. Epidemiology

    The median age of ACC diagnosis is in the fifth to sixth decade, with the German ACC Registry reporting a median age of 46 years.

    “The median age of diagnosis is in the fifth to sixth decade, with the German ACC Registry reporting a median age at diagnosis of 46 years (9).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Fassnacht, 2009, Clinical management of adrenocortical carcinoma, Best Pract Res Clin Endocrinol Metab source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § II. Epidemiology

    ACC incidence is believed to be 1 to 2 per million per year, but valid data are lacking.

    “The incidence is believed to be 1 to 2 per million per year, but valid data are lacking (3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Allolio, 2006, Clinical review: Adrenocortical carcinoma: clinical update, J Clin Endocrinol Metab source

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    Premisecitation
    § II. Epidemiology

    In Southern Brazil, childhood ACC incidence is 2.9 to 4.2 per million per year, compared with 0.2 to 0.3 per million children per year worldwide.

    “In Southern Brazil, the incidence during childhood is 2.9 to 4.2 per million per year compared with an estimated incidence of 0.2 to 0.3 per million children per year worldwide (5).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Pianovski, 2006, Mortality rate of adrenocortical tumors in children under 15 years of age in Curitiba, Brazil, Pediatr Blood Cancer source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given
    § Abstract

    Adrenocortical carcinoma (ACC) is a rare endocrine malignancy, often with an unfavorable prognosis.

    “Adrenocortical carcinoma (ACC) is a rare endocrine malignancy, often with an unfavorable prognosis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § II. Epidemiology

    Adrenal tumors affect 3% to 10% of the human population, and the majority are small benign nonfunctional adrenocortical adenomas.

    “Adrenal tumors are very common, affecting 3% to 10% of the human population, and the majority are small benign nonfunctional adrenocortical adenomas (ACA) (1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Mansmann, 2004, The clinically inapparent adrenal mass: update in diagnosis and management, Endocr Rev source

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    Premisecitation
    § III. Genetic Predisposition

    ACC comprises 5% to 15% of malignancies in BWS.

    “Although data vary significantly, ACC comprises 5% to 15% of malignancies in BWS (43, 44).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [43] Lapunzina, 2005, Risk of tumorigenesis in overgrowth syndromes: a comprehensive review, Am J Med Genet C Semin Med Genet source

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    • cites [44] Wiedemann, 1983, Tumours and hemihypertrophy associated with Wiedemann-Beckwith syndrome, Eur J Pediatr source

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    Premisecitation
    § III. Genetic Predisposition

    Approximately 3% to 10% of LFS-associated cancers are ACCs, suggesting that germline TP53 mutations infer a significant relative risk increase.

    “Approximately 3% to 10% of LFS-associated cancers are ACCs, suggesting that germline TP53 mutations infer a significant relative risk increase (31, 32).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [31] Li, 1988, A cancer family syndrome in twenty-four kindreds, Cancer Res

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    • cites [32] Bougeard, 2008, Molecular basis of the Li-Fraumeni syndrome: an update from the French LFS families, J Med Genet source

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    Premisecitation
    § II. Epidemiology

    A review of data from the 1986 National Mortality Followback Survey identified smoking in men and contraceptive use in women, especially before age 25, as risk factors for ACC.

    “A review of data from the 1986 National Mortality Followback Survey identified smoking in men and contraceptive use in women, especially before age 25 as risk factors (18).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Hsing, 1996, Risk factors for adrenal cancer: an exploratory study, Int J Cancer source

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    Premisecitation
    § II. Epidemiology

    A large single center series in France reported a median age of 46 years, consistent with the German registry.

    “This is in accordance with a median age of 46 years in a large single center series in France (10).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Luton, 1990, Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy, N Engl J Med source

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    Premisecitation
    § III. Genetic Predisposition

    Most TP53 mutations affect the DNA binding and tetramerization domains.

    “Most TP53 mutations affect the DNA binding and tetramerization domains (14).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Wasserman, 2012, Towards an understanding of the role of p53 in adrenocortical carcinogenesis, Mol Cell Endocrinol source

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    Premisecitation
    § III. Genetic Predisposition

    The p.R337H mutation causes other LFS-associated tumors as well as a Li Fraumeni-like syndrome in affected families.

    “Although it was initially believed that this mutation specifically predisposes to ACC development in childhood, it is now well recognized that this mutation causes other LFS-associated tumors as well as a Li Fraumeni-like syndrome in affected families (37).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Custódio, 2012, Molecular epidemiology of adrenocortical tumors in southern Brazil, Mol Cell Endocrinol source

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    Premisecitation
    § II. Epidemiology

    1.3% of all childhood cancers are ACCs, as opposed to 0.02% to 0.2% of adult cancers, confirming a higher relative incidence early in life.

    “The fact that 1.3% of all childhood cancers are ACCs as opposed to 0.02% to 0.2% of adult cancers confirms a higher relative incidence early in life (12, 15–17).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [12] Wajchenberg, 2000, Adrenocortical carcinoma: clinical and laboratory observations, Cancer source

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    • cites [15] Schteingart, 2005, Management of patients with adrenal cancer: recommendations of an international consensus conference, Endocr Relat Cancer source

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    • cites [16] Crucitti, 1996, The Italian Registry for Adrenal Cortical Carcinoma: analysis of a multiinstitutional series of 129 patients. The ACC Italian Registry Study Group, Surgery source

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    • cites [17] Michalkiewicz, 2004, Clinical and outcome characteristics of children with adrenocortical tumors: a report from the International Pediatric Adrenocortical Tumor Registry, J Clin Oncol source

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    Premisecitation
    § III. Genetic Predisposition

    The relative increase in childhood ACC incidence is mainly explained by germline TP53 mutations, which are the underlying genetic cause of ACC in ∼50% to 80% of children with ACC.

    “The relative increase in incidence in childhood is mainly explained by germline TP53 mutations, which are the underlying genetic cause of ACC in ∼50% to 80% of children with ACC (Table 1)(28–30).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [28] Rodriguez-Galindo, 2005, Biology, clinical characteristics, and management of adrenocortical tumors in children, Pediatr Blood Cancer source

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    • cites [29] Varley, 1999, Are there low-penetrance TP53 alleles? Evidence from childhood adrenocortical tumors, Am J Hum Genet source

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    • cites [30] Wagner, 1994, High frequency of germline p53 mutations in childhood adrenocortical cancer, J Natl Cancer Inst source

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    Premisecitation
    § II. Epidemiology

    Recent in vitro studies confirm growth-promoting effects of estrogen on the ACC cell line NCI-H295.

    “Interestingly, recent in vitro studies confirm growth-promoting effects of estrogen on the ACC cell line NCI-H295 (20).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Sirianni, 2012, Targeting estrogen receptor-α reduces adrenocortical cancer (ACC) cell growth in vitro and in vivo: potential therapeutic role of selective estrogen receptor modulators (SERMs) for ACC treatment, J Clin Endocrinol Metab source

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    Premisecitation
    § II. Epidemiology

    In both adult and pediatric populations, there is a predilection for the female gender, with a female-to-male ratio ranging from 1.5-2.5:1.

    “In the adult as well as in the pediatric population, there is a predilection for the female gender (the ratio of female to male ranges from 1.5–2.5:1) (10, 17).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [10] Luton, 1990, Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy, N Engl J Med source

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    • cites [17] Michalkiewicz, 2004, Clinical and outcome characteristics of children with adrenocortical tumors: a report from the International Pediatric Adrenocortical Tumor Registry, J Clin Oncol source

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    Premisecitation
    § III. Genetic Predisposition

    Up to 25% of TP53 mutations occur de novo, and these patients lack a significant family history.

    “Up to 25% of TP53 mutations occur de novo, and these patients lack a significant family history (34).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Chompret, 2000, P53 germline mutations in childhood cancers and cancer risk for carrier individuals, Br J Cancer

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    Premisecitation
    § III. Genetic Predisposition

    Recent analyses suggest a founder effect for the p.R337H mutation in most cases, although de novo mutations may still exist.

    “The p.R337H mutation was initially considered not to be a result of common ancestry; however, recent analyses suggest a founder effect in most cases, although in some cases, de novo mutations may still exist (7, 39).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7] Garritano, 2010, Detailed haplotype analysis at the TP53 locus in p.R337H mutation carriers in the population of Southern Brazil: evidence for a founder effect, Hum Mutat source

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    • cites [39] Ribeiro, 2001, An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma, Proc Natl Acad Sci U S A source

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    § III. Genetic Predisposition

    The common sequelae of these changes are upregulation of IGF2 expression and downregulation of the other two transcripts.

    “The common sequelae of all these changes are an upregulation of IGF2 expression and a downregulation of the other two transcripts (41).”
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    • cites [41] Weksberg, 2005, Beckwith-Wiedemann syndrome, Am J Med Genet C Semin Med Genet source

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    Premisecitation
    § II. Epidemiology

    A role of estrogens in ACC has been suggested by the observation of a probable relative increase of diagnosis during pregnancy.

    “A role of estrogens has also been suggested by the observation of a probable relative increase of diagnosis of ACC during pregnancy (10, 19).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [10] Luton, 1990, Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy, N Engl J Med source

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    • cites [19] Icard, 2001, Adrenocortical carcinomas: surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons study group, World J Surg source

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    Premisecitation
    § II. Epidemiology

    Analysis of the SEER database gives a slightly older mean age of 55 years.

    “Analysis of the SEER database gives a slightly older mean age of 55 years (11).”
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    • cites [11] Bilimoria, 2008, Adrenocortical carcinoma in the United States: treatment utilization and prognostic factors, Cancer source

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    Premisecitation
    § III. Genetic Predisposition

    Patients with Lynch syndrome have a significant increase in lifetime risk of cancer, specifically for colorectal and endometrial cancer.

    “Patients with Lynch syndrome have a significant increase in lifetime risk of cancer, specifically for the core malignancies, colorectal and endometrial cancer (57).”
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    • cites [57] Stoffel, 2009, Calculation of risk of colorectal and endometrial cancer among patients with Lynch syndrome, Gastroenterology source

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    Premisecitation
    § III. Genetic Predisposition

    Patients with CAH commonly develop adrenal myelolipomas.

    “However, it has become clear over the last decade that patients with CAH commonly develop adrenal myelolipomas (77).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] Nermoen, 2011, High frequency of adrenal myelolipomas and testicular adrenal rest tumours in adult Norwegian patients with classical congenital adrenal hyperplasia because of 21-hydroxylase deficiency, Clin Endocrinol (Oxf) source

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    Premisecitation
    § III. Genetic Predisposition

    The vast majority of Lynch syndrome-associated colorectal cancers show loss of immunostaining for at least 1 of the gene products and are microsatellite unstable.

    “The vast majority of Lynch syndrome-associated colorectal cancers show loss of immunostaining for at least 1 of the gene products and are microsatellite unstable (59).”
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    • cites [59] Hampel, 2005, Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer), N Engl J Med source

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    Premisecitation
    § III. Genetic Predisposition

    Some cases of ACC in conjunction with congenital adrenal hyperplasia (CAH) have been described.

    “Some cases of ACC in conjunction with congenital adrenal hyperplasia (CAH) have been described (75).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75] Bauman, 1982, Virilizing adrenocortical carcinoma. Development in a patient with salt-losing congenital adrenal hyperplasia, JAMA source

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    Premisecitation
    § IV. Patient Presentation/Clinical Characteristics

    Tumor-associated hypoglycemia is a well-described phenomenon, historically termed Anderson's syndrome, which may be attributed to IGF-2-mediated hypoglycemia.

    “However, tumor-associated hypoglycemia is a well-described phenomenon, historically termed Anderson's syndrome, which may be attributed to IGF-2–mediated hypoglycemia (79–81).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [79] Ishikura, 2010, Cushing's syndrome and big IGF-II associated hypoglycaemia in a patient with adrenocortical carcinoma, BMJ Case Rep source

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    • cites [80] Anderson, 1930, A tumor of the adrenal gland with fatal hypoglycemia, Am J Med Sci source

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    • cites [81] Rustin, 1983, Adrenocortical carcinoma with tumour-induced hypoglycaemia, J R Soc Med source

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    Premisecitation
    § III. Genetic Predisposition

    Recent analysis of a French multicenter registry determined that ∼10% of MEN1 patients have distinct adrenal tumors, and of these, up to 14% are malignant.

    “Recent analysis of a French multicenter registry determined that ∼10% of MEN1 patients have distinct adrenal tumors, and of these, up to 14% are malignant (48).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Gatta-Cherifi, 2012, Adrenal involvement in MEN1. Analysis of 715 cases from the Groupe d'etude des Tumeurs Endocrines database, Eur J Endocrinol source

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    § III. Genetic Predisposition

    ACC has been reported in 2 cases of patients with Carney complex.

    “Most recently, ACC has also been reported in 2 cases of patients with Carney complex (73, 74).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [73] Anselmo, 2012, A large family with Carney complex caused by the S147G PRKAR1A mutation shows a unique spectrum of disease including adrenocortical cancer, J Clin Endocrinol Metab source

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    • cites [74] Morin, 2012, Carney complex with adrenal cortical carcinoma, J Clin Endocrinol Metab source

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    Premisecitation
    § IV. Patient Presentation/Clinical Characteristics

    Other rare paraneoplastic syndromes are hyperreninemic hyperaldosteronism, erythropoietin-associated polycythemia, and leukocytosis (caused by chemokine release from the tumor).

    “Other rare paraneoplastic syndromes are hyperreninemic hyperaldosteronism, erythropoietin-associated polycythemia, and leukocytosis (caused by chemokine release from the tumor) (82–84).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [82] Yamanaka, 2000, A case of renin-producing adrenocortical cancer, Endocr J source

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    • cites [83] Oka, 1996, Erythropoietin-producing adrenocortical carcinoma, Urol Int source

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    • cites [84] Schteingart, 2001, Overexpression of CXC chemokines by an adrenocortical carcinoma: a novel clinical syndrome, J Clin Endocrinol Metab source

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    Premisecitation
    § III. Genetic Predisposition

    Screening for Lynch syndrome has been proven cost-effective, and surveillance for colon cancer with regular colonoscopies significantly decreases morbidity and mortality in affected patients.

    “Screening has been proven cost-effective, and surveillance for colon cancer with regular colonoscopies significantly decreases morbidity and mortality in affected patients (60, 61).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [60] Dinh, 2011, Health benefits and cost-effectiveness of primary genetic screening for Lynch syndrome in the general population, Cancer Prev Res source

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    • cites [61] Järvinen, 2000, Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer, Gastroenterology source

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    § IV. Patient Presentation/Clinical Characteristics

    Roughly 20% to 30% of ACCs are incidentally diagnosed by imaging procedures for unrelated medical issues.

    “Roughly 20% to 30% of ACCs are incidentally diagnosed by imaging procedures for unrelated medical issues (25).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Fassnacht, 2010, Epidemiology of adrenocortical carcinoma

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    Premisecitation
    § III. Genetic Predisposition

    The prevalence of Lynch syndrome in patients with ACC is ∼3%, comparable to the prevalence in colorectal and endometrial cancer (2% to 5%).

    “Recently, a systematic analysis has defined the prevalence of Lynch syndrome in patients with ACC to be ∼3%, comparable to the prevalence in colorectal and endometrial cancer, estimated at 2% to 5% (62).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [62] Raymond, 2013, Adrenocortical carcinoma is a Lynch syndrome-associated cancer, J Clin Oncol source

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    Premisenone given
    § V. Diagnosis

    Most patients with cortisol-secreting tumors will have suppressed ACTH (<10 pg/mL) and increased cortisol on a spontaneous 8:00 am blood draw.

    “Most patients with cortisol-secreting tumors will have suppressed ACTH (<10 pg/mL) and increased cortisol on a spontaneous 8:00 am blood draw.”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § C. Differential diagnosis

    Mineralocorticoid excess can be caused by either bilateral hyperplasia or ACA, and these lesions are usually small (<2 cm).

    “Mineralocorticoid excess can be caused by either bilateral hyperplasia or ACA, and these lesions are usually small (<2 cm) (115).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [115] Funder, 2008, Case detection, diagnosis, and treatment of patients with primary aldosteronism: an Endocrine Society clinical practice guideline, J Clin Endocrinol Metab source

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    Premisenone given
    § IV. Patient Presentation/Clinical Characteristics

    Concurrent androgen and cortisol production is evident in roughly half of all ACC patients with hormone excess.

    “Concurrent androgen and cortisol production is evident in roughly half of all ACC patients with hormone excess.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § IV. Patient Presentation/Clinical Characteristics

    The most common metastatic sites are lung (40%-80%), liver (40%-90%), and bone (5%-20%).

    “The most common metastatic sites are lung (40%–80%), liver (40%–90%), and bone (5%–20%) (92).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [92] Allolio, 2004, Management of adrenocortical carcinoma, Clin Endocrinol (Oxf) source

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    Premisecitation
    § V. Diagnosis

    The risk for malignant adrenal tumors increases with tumor size, with sensitivity 97% and specificity 52% for tumors >4 cm and sensitivity 91% and specificity 80% for tumors >6 cm.

    “The risk for malignant adrenal tumors increases with tumor size, with the index of suspicion increasing for tumors >4 cm (sensitivity, 97%; specificity, 52%) and >6 cm (sensitivity, 91%; specificity, 80%) (89).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] Sturgeon, 2006, Risk assessment in 457 adrenal cortical carcinomas: how much does tumor size predict the likelihood of malignancy?, J Am Coll Surg source

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    § IV. Patient Presentation/Clinical Characteristics

    Other sites, such as brain and skin, are much less affected by tumor spread (<5%).

    “Other sites, such as brain and skin, are much less affected by tumor spread (<5%).”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § IV. Patient Presentation/Clinical Characteristics

    Earlier studies found 49% of patients with metastatic disease (stage 4) at presentation, but currently only 25% to 30% of patients present with metastatic disease.

    “Although earlier studies found 49% of patients with metastatic disease (stage 4) at presentation, currently only 25% to 30% of patients present with metastatic disease (9, 13, 25).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [9] Fassnacht, 2009, Clinical management of adrenocortical carcinoma, Best Pract Res Clin Endocrinol Metab source

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    • cites [13] Wooten, 1993, Adrenal cortical carcinoma. Epidemiology and treatment with mitotane and a review of the literature, Cancer source

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    • cites [25] Fassnacht, 2010, Epidemiology of adrenocortical carcinoma

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    § IV. Patient Presentation/Clinical Characteristics

    A contralateral adrenal tumor can be found in ∼5% of ACC patients.

    “A contralateral adrenal tumor can be found in ∼5% of patients, although it is difficult to differentiate this from metachronous or synchronous tumors.”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § V. Diagnosis

    ACCs are bilateral in 2% to 10% of cases.

    “They are bilateral in 2% to 10% of cases (98, 99).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [98] Bharwani, 2011, Adrenocortical carcinoma: the range of appearances on CT and MRI, AJR Am J Roentgenol source

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    • cites [99] Dunnick, 1982, CT appearance of adrenal cortical carcinoma, J Comput Assist Tomogr source

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    § IV. Patient Presentation/Clinical Characteristics

    Estrogen production occurs in 1% to 3% of male ACC patients, causing gynecomastia and testicular atrophy.

    “Estrogen production occurs in 1% to 3% of male ACC patients, causing gynecomastia and testicular atrophy (through suppression of the gonadal axis).”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § IV. Patient Presentation/Clinical Characteristics

    Only a minority of ACC tumors are <6 cm (9%-14%), with only 3% presenting as lesions <4 cm.

    “Only a minority of tumors are <6 cm (9%–14%), with only 3% presenting as lesions <4 cm (89, 90).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [89] Sturgeon, 2006, Risk assessment in 457 adrenal cortical carcinomas: how much does tumor size predict the likelihood of malignancy?, J Am Coll Surg source

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    • cites [90] Paton, 2006, Outcomes of adrenal cortical carcinoma in the United States, Surgery source

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  • Classified as probably not a substantial claim.

    Premisenone given
    § V. Diagnosis

    The hallmark of a biochemical evaluation is the measurement of steroid hormones produced by the tumor.

    “The hallmark of a biochemical evaluation is the measurement of steroid hormones produced by the tumor (Table 3 and Figure 2).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Table 3

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    • cites Figure 2

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    § IV. Patient Presentation/Clinical Characteristics

    After initial resection, locoregional recurrence becomes a challenge with pelvic, peritoneal, or retroperitoneal metastases.

    “After initial resection, locoregional recurrence becomes a challenge with pelvic, peritoneal, or retroperitoneal metastases.”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § 2. [18F]FDG PET/CT imaging

    Intensity of FDG uptake is related to survival in patients with ACC, with a maximum SUV of >10 indicating poor prognosis.

    “Intensity of FDG uptake was found to be related to survival in patients with ACC, with a maximum SUV of >10 indicating poor prognosis (111).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [111] Mackie, 2006, Use of [18F]fluorodeoxyglucose positron emission tomography in evaluating locally recurrent and metastatic adrenocortical carcinoma, J Clin Endocrinol Metab source

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    Premisecitation
    § C. Differential diagnosis

    In hormonal evaluation of incidentally discovered adrenal masses, a 1 mg DST is preferred because it has greater specificity in diagnosing subclinical Cushing's syndrome.

    “In the hormonal evaluation of such lesions, a 1 mg DST is preferred because it has a greater specificity in diagnosing subclinical Cushing's syndrome (93).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [93] Nieman, 2008, The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline, J Clin Endocrinol Metab source

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    § IV. Patient Presentation/Clinical Characteristics

    The second most commonly produced hormones in patients with ACC are adrenal androgens, accounting for 40%-60% of hormone-secreting ACCs.

    “The second most commonly produced hormones in patients with ACC are adrenal androgens (40%–60% of hormone-secreting ACCs), causing rapid-onset male pattern baldness, hirsutism, virilization, and menstrual irregularities in women.”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § 1. Clonality and DNA content

    One of the first flow cytometry assessments revealed aneuploidy in 4 of 4 ACCs, yet only diploidy or tetraploidy in normal adrenal cortices and benign adrenal tumors.

    “One of the first genetic assessments with flow cytometry revealed aneuploidy (a genomic aberration consistently observed in most cancers) in 4 of 4 ACCs, yet only diploidy or tetraploidy in normal adrenal cortices and benign adrenal tumors (180).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [180] Klein, 1985, Flow cytometric determinations of ploidy and proliferation patterns of adrenal neoplasms: an adjunct to histological classification, J Urol source

      Not checked in the free run.

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    Premisecitation
    § 4. Gene expression arrays

    ACCs with poor outcome are enriched for genes involved in cell cycle and proliferation, whereas ACCs in the better outcome group exhibit overexpression of genes involved in differentiation, metabolism, and intracellular transport.

    “ACCs with poor outcome were enriched for genes involved in cell cycle and proliferation, whereas ACCs in the better outcome group exhibited overexpression of genes involved in differentiation, metabolism, and intracellular transport.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [191] de Reyniès, 2009, Gene expression profiling reveals a new classification of adrenocortical tumors and identifies molecular predictors of malignancy and survival, J Clin Oncol source

      Not checked in the free run.

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    Premisenone given
    § VI. Pathology

    Using accepted proliferation immunomarkers such as Ki67, a general consensus is that ACCs have a Ki67 labeling index >5%, whereas ACAs generally show a much lower index.

    “Using accepted proliferation immunomarkers, such as Ki67, a general consensus has emerged that ACCs have a Ki67 labeling index >5%. Conversely, ACAs generally show a much lower index, although there is some overlap observed depending on the particular study.”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § VI. Pathology

    High-grade ACCs are enriched for mutations of TP53 and/or CTNNB1, and these mutations tend to be mutually exclusive.

    “High-grade ACCs are enriched for mutations of TP53 (14, 140–142) and/or CTNNB1 (143–149), and these mutations tend to be mutually exclusive (reviewed in Ref. 150).”
    Quote in the paperNot a substantial claim0 of 10 sources checked
    • cites [14] Wasserman, 2012, Towards an understanding of the role of p53 in adrenocortical carcinogenesis, Mol Cell Endocrinol source

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    • cites [140] Ohgaki, 1993, p53 mutations in sporadic adrenocortical tumors, Int J Cancer source

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    • cites [141] Lin, 1994, Mutations of the p53 gene in human functional adrenal neoplasms, J Clin Endocrinol Metab

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    • cites [142] Reincke, 1994, p53 mutations in human adrenocortical neoplasms: immunohistochemical and molecular studies, J Clin Endocrinol Metab

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    • cites [143] Heaton, 2012, Progression to adrenocortical tumorigenesis in mice and humans through insulin-like growth factor 2 and β-catenin, Am J Pathol source

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    • cites [144] Berthon, 2012, Wnt/β-catenin signalling in adrenal physiology and tumour development, Mol Cell Endocrinol source

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    • cites [145] Leal, 2011, Wnt/β-catenin pathway deregulation in childhood adrenocortical tumors, J Clin Endocrinol Metab source

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    • cites [146] Gaujoux, 2011, β-Catenin activation is associated with specific clinical and pathologic characteristics and a poor outcome in adrenocortical carcinoma, Clin Cancer Res source

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    • cites [147] El Wakil, 2011, The Wnt/β-catenin pathway in adrenocortical development and cancer, Mol Cell Endocrinol source

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    • cites [148] Masi, 2009, Investigation of BRAF and CTNNB1 activating mutations in adrenocortical tumors, J Endocrinol Invest source

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    Premisenone given
    § 2. Chromosomal aberrations

    Chromosome 17, specifically at 17p13, contains the well-known tumor suppressor gene TP53.

    “Chromosome 17, specifically at 17p13, contains the well-known tumor suppressor gene TP53.”
    Quote in the paperNot a substantial claim

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    Premisereasoning
    § VI. Pathology

    In the Weiss system, tumors with 3 or more malignant histological features most often behave malignantly and can be classified as ACC, whereas tumors with 0-2 features do not metastasize and can be classified as ACA.

    “Tumors with an abundance of these features (3 or more, as in the Weiss system) most often behave in a malignant fashion and can be classified as ACC, whereas tumors without these features (0–2 in the Weiss system) do not metastasize and can be classified as ACA.”
    Quote in the paperSubstantial claim

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    Premisecitation
    § 1. Clonality and DNA content

    Most ACAs and all ACCs initiate from monoclonal cell populations, suggesting that mutation events lead to clonal expansion and ultimate progression to cancer.

    “Most ACAs and all ACCs initiate from monoclonal cell populations, suggesting that mutation events lead to clonal expansion and ultimate progression to cancer (177, 178).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [177] Beuschlein, 1994, Clonal composition of human adrenocortical neoplasms, Cancer Res

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    • cites [178] Gicquel, 1994, Clonal analysis of human adrenocortical carcinomas and secreting adenomas, Clin Endocrinol (Oxf) source

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    Premisenone given
    § C. Differential diagnosis

    Hypercortisolism in connection with ACC is due to autonomous cortisol secretion, and the resultant ACTH-independent Cushing's syndrome is accompanied by a low ACTH level (<10 pg/mL).

    “Hypercortisolism in connection with ACC is due to autonomous cortisol secretion. The resultant ACTH-independent Cushing's syndrome is accompanied by a low ACTH level (<10 pg/mL).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 3. Epigenetic changes

    H19, PLAGL1, G0S2, and NDRG2 are silenced genes in ACCs.

    “identified H19, PLAGL1, G0S2, and NDRG2 as silenced genes (188).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [188] Barreau, 2013, Identification of a CpG Island Methylator Phenotype in Adrenocortical Carcinomas, J Clin Endocrinol Metab source

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    Premisenone given
    § C. Differential diagnosis

    The levels of DHEAS and testosterone are usually markedly higher in ACC, the onset of hormone excess symptoms is more pronounced, and most symptoms develop over a relatively short period of time (months).

    “However, the levels of DHEAS and testosterone are usually markedly higher in ACC, the onset of hormone excess symptoms is more pronounced, and most symptoms develop over a relatively short period of time (months).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 4. Gene expression arrays

    ACCs with high histological grade exhibit marked overexpression of cell cycle and functional aneuploidy genes, which correlates with decreased overall survival.

    “Giordano et al (192) determined that ACCs with high histological grade exhibited marked overexpression of cell cycle and functional aneuploidy genes, which correlated with decreased overall survival.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [192] Giordano, 2009, Molecular classification and prognostication of adrenocortical tumors by transcriptome profiling, Clin Cancer Res source

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    Premisecitation
    § 5. MicroRNAs

    Examination of 36 adrenocortical samples revealed differential expression of 22 miRNAs, with 14 miRNAs preferentially expressed in ACCs.

    “The examination of 36 adrenocortical samples (10 normal tissues, 10 nonfunctional ACAs, 9 cortisol-secreting adenomas, and 7 ACCs) revealed differential expression of 22 miRNAs, with 14 miRNAs preferentially expressed in ACCs.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [197] Tömböl, 2009, Integrative molecular bioinformatics study of human adrenocortical tumors: microRNA, tissue-specific target prediction, and pathway analysis, Endocr Relat Cancer source

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    Interpretationreasoning
    § VI. Pathology

    ACC exhibits a large degree of intratumor heterogeneity, which supports a clonal model of step-wise progression from low- to high-grade carcinoma.

    “ACCs exhibit a large degree of intratumor heterogeneity, an unsurprising finding given their large size and the evolutionary nature of cancer progression.”
    • Also stated in: § VI. Pathology · hedged
      “Taken together, these observations provide support for a clonal model in which ACC can exhibit step-wise progression from low- to high-grade carcinoma.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § 5. MicroRNAs

    Upregulated miRNAs in ACCs include miR-184, miR-210, and miR-503; downregulated include miR-214, miR-375, and miR-511.

    “Upregulated miRNAs in ACCs included miR-184, miR-210, and miR-503. Downregulated miRNAs included miR-214, miR-375, and miR-511 (197).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [197] Tömböl, 2009, Integrative molecular bioinformatics study of human adrenocortical tumors: microRNA, tissue-specific target prediction, and pathway analysis, Endocr Relat Cancer source

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    Premisecitation
    § 2. Chromosomal aberrations

    Whereas ACAs have few regions of chromosomal losses and gains, ACCs exhibit complex chromosomal alterations.

    “A number of studies have found that whereas ACAs have few regions of chromosomal losses and gains, ACCs exhibited complex chromosomal alterations.”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § 5. MicroRNAs

    In pediatric adrenal neoplasms, unsupervised clustering of miRNA expression clearly differentiates tumors from normal controls, but cannot differentiate ACA from ACC.

    “Unsupervised clustering of the samples according to miRNA expression resulted in clear differentiation of the tumors from the normal controls. Further differentiation between ACA and ACC could not be achieved.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [199] Doghman, 2010, Regulation of insulin-like growth factor-mammalian target of rapamycin signaling by microRNA in childhood adrenocortical tumors, Cancer Res source

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    Premisecitation
    § 6. Gene mutations

    TP53 is the most commonly mutated gene in ACC, present in at least one-third of ACCs.

    “TP53 located on 17p13 is the most commonly mutated gene in ACC, present in at least one-third of ACCs (140, 142, 202).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [140] Ohgaki, 1993, p53 mutations in sporadic adrenocortical tumors, Int J Cancer source

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    • cites [142] Reincke, 1994, p53 mutations in human adrenocortical neoplasms: immunohistochemical and molecular studies, J Clin Endocrinol Metab

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    • cites [202] Barzon, 2001, Molecular analysis of CDKN1C and TP53 in sporadic adrenal tumors, Eur J Endocrinol source

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    Premisecitation
    § 5. MicroRNAs

    In pediatric ACCs, miR-483 is significantly upregulated, while a majority of differentially expressed miRNAs are downregulated, most notably miR-99a and miR-100.

    “In this study, similar to the adult ACC study, miR-483 was found to be significantly upregulated in pediatric ACCs. However, a majority of the differentially expressed miRNAs were downregulated in ACCs, most notably miR-99a and miR-100.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [199] Doghman, 2010, Regulation of insulin-like growth factor-mammalian target of rapamycin signaling by microRNA in childhood adrenocortical tumors, Cancer Res source

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    Premisecitation
    § 5. MicroRNAs

    miR-483 is significantly upregulated in ACC (diagnostic sensitivity 80%, specificity 100%), and miR-195 and miR-335 are downregulated in ACC.

    “the study identified a significant upregulation of miR-483 (diagnostic sensitivity of 80% and specificity of 100%) and downregulation of miR-195 and miR-335 in ACC (198).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [198] Soon, 2009, miR-195 and miR-483-5p Identified as Predictors of Poor Prognosis in Adrenocortical Cancer, Clin Cancer Res source

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    Premisecitation
    § 1. IGF pathway

    High IGF2 expression levels in adrenal tumors are associated with a 5-fold increased risk for recurrence and a shorter disease-free survival.

    “High IGF2 expression levels in adrenal tumors, when analyzing malignant and benign tumors, are associated with a 5-fold increased risk for recurrence and a shorter disease-free survival (184, 191).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [184] Gicquel, 2001, Molecular markers and long-term recurrences in a large cohort of patients with sporadic adrenocortical tumors, Cancer Res

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    • cites [191] de Reyniès, 2009, Gene expression profiling reveals a new classification of adrenocortical tumors and identifies molecular predictors of malignancy and survival, J Clin Oncol source

      Not checked in the free run.

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    Premisecitation
    § 2. WNT signaling pathway

    In the normal adrenal gland, the WNT/β-catenin signaling pathway plays a crucial role in both embryonic development and maintenance of the adrenal cortex.

    “In the normal adrenal gland, the WNT/β-catenin signaling pathway plays a crucial role in both embryonic development and maintenance of the adrenal cortex (228).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [228] Kim, 2008, Targeted disruption of β-catenin in Sf1-expressing cells impairs development and maintenance of the adrenal cortex, Development source

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    Premisecitation
    § 5. MicroRNAs

    miR-99a and miR-100 are bioinformatically predicted to target IGF1R, RPTOR, and FRAP1 (mTOR) and were experimentally confirmed to target several components of the IGF-1 signaling pathway.

    “MiR-99a and miR-100 are bioinformatically predicted to target the 3′-untranslated regions of IGF1R, RPTOR, and FRAP1 (mTOR) and were experimentally confirmed to target several components of the IGF-1 signaling pathway (199).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [199] Doghman, 2010, Regulation of insulin-like growth factor-mammalian target of rapamycin signaling by microRNA in childhood adrenocortical tumors, Cancer Res source

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    Premisecitation
    § 2. WNT signaling pathway

    When Apc-knockout mice were crossed with adrenal-specific Igf2 overexpression mice, early-onset adrenal nodular hyperplasia evolving to large tumors later in life was observed, suggesting synergistic effects on adrenocortical tumorigenesis.

    “However, when the Apc-knockout mice were crossed with adrenal-specific Igf2 overexpression mice, early-onset adrenal nodular hyperplasia evolving to large tumors later in life (including an invasive cortical tumor similar to an ACC) was observed, suggesting that both pathways may have synergistic effects on adrenocortical tumorigenesis (143).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [143] Heaton, 2012, Progression to adrenocortical tumorigenesis in mice and humans through insulin-like growth factor 2 and β-catenin, Am J Pathol source

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    Premisenone given
    § 3. Open vs laparoscopic surgery

    LA has become the gold standard for resection of benign adrenal masses, and it results in significantly lower morbidity, less pain, shorter hospital stays, and decreased overall time to recovery compared with OA.

    “LA has become the gold standard for resection of benign adrenal masses, and it has been shown to result in significantly lower morbidity, less pain, shorter hospital stays, and decreased overall time to recovery when compared with open adrenalectomy (OA).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 3. Open vs laparoscopic surgery

    Two studies from M.D. Anderson reported a recurrence rate of 86% in the OA group (154 patients) and 100% in the LA group (6 patients).

    “Two studies published by the M.D. Anderson Cancer Center reported a recurrence rate of 86% in the OA group (154 patients) and 100% in the LA group (6 patients) (251, 257).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [251] Gonzalez, 2005, Laparoscopic resection of adrenal cortical carcinoma: a cautionary note, Surgery source

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    • cites [257] Grubbs, 2010, Recurrence of adrenal cortical carcinoma following resection: surgery alone can achieve results equal to surgery plus mitotane, Ann Surg Oncol source

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    Premisecitation
    § 2. WNT signaling pathway

    In mice with incomplete β-catenin knockout, at age 45 weeks postpartum, they exhibited thinned and disorganized adrenal cortex with increased apoptosis.

    “In mice harboring incomplete β-catenin knockout (knockout of β-catenin in a subset of adrenocortical cells), although normal adrenal development occurred, at age 45 weeks postpartum, these mice exhibited thinned and disorganized adrenal cortex in the setting of increased apoptosis (228).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [228] Kim, 2008, Targeted disruption of β-catenin in Sf1-expressing cells impairs development and maintenance of the adrenal cortex, Development source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given
    § 3. Open vs laparoscopic surgery

    ACCs can invade through the tumor capsule and are frequently microscopically present at the surface of the gland.

    “ACCs can invade through the tumor capsule and are frequently microscopically present at the surface of the gland.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given
    § IX. Therapy

    Currently, the only curative approach to ACC is complete tumor resection.

    “Currently, the only curative approach to ACC is complete tumor resection.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 2. WNT signaling pathway

    An activating Ser45 β-catenin mutation and activated β-catenin signaling were identified in the NCI-H295 ACC cell line.

    “An activating Ser45 β-catenin mutation as well as activated β-catenin signaling was also identified in the NCI-H295 ACC cell line (149).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [149] Tissier, 2005, Mutations of β-catenin in adrenocortical tumors: activation of the Wnt signaling pathway is a frequent event in both benign and malignant adrenocortical tumors, Cancer Res source

      Not checked in the free run.

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    Premisecitation
    § IX. Therapy

    In the United States, 45% of adrenalectomies for ACC are performed in community hospitals, 30% in academic centers, and only 15% in National Cancer Institute-designated Cancer Centers.

    “However, in the United States, 45% of adrenalectomies for ACC are performed in community hospitals, 30% in academic centers, and only 15% in National Cancer Institute-designated Cancer Centers, suboptimal treatment of a rare and aggressive disease requiring specialized knowledge of surgical technique (11).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Bilimoria, 2008, Adrenocortical carcinoma in the United States: treatment utilization and prognostic factors, Cancer source

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    Premisecitation
    § 4. Surgery for recurrent disease

    A 1999 study reported median survival of 74 months (5-year survival, 57%) in those undergoing complete second resections versus median survival of 16 months (5-year survival, 0%) in those undergoing incomplete second resection.

    “A 1999 study reported median survival of 74 months (5-year survival, 57%) in those undergoing complete second resections vs a median survival of 16 months (5-year survival, 0%) in those undergoing incomplete second resection.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [266] Schulick, 1999, Long-term survival after complete resection and repeat resection in patients with adrenocortical carcinoma, Ann Surg Oncol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 1. Mitotane

    In dog adrenal glands, mitotane leads to cell death, most likely via necrosis, followed by emergence of a dense inflammatory infiltrate.

    “In dog adrenal glands, mitotane leads to cell death, most likely via necrosis, and is followed by the emergence of a dense inflammatory infiltrate (283).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [283] Schteingart, 1993, Comparison of the adrenalytic activity of mitotane and a methylated homolog on normal adrenal cortex and adrenal cortical carcinoma, Cancer Chemother Pharmacol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § 3. Open vs laparoscopic surgery

    Use of LA in ACC leads to a shorter disease-free interval and a higher incidence of incomplete resections.

    “the use of LA in ACC leads to a shorter disease-free interval and a higher incidence of incomplete resections.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given
    § 1. Mitotane

    The pharmacological mechanism by which mitotane exerts its adrenolytic effect is still not completely understood.

    “The pharmacological mechanism by which mitotane exerts its adrenolytic effect is still not completely understood.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation
    § 4. Surgery for recurrent disease

    These results closely correspond with surgical outcomes from other solid malignancies, in which a survival benefit is often seen after complete resection with negative margins but not in those with positive margins.

    “These results closely correspond with the surgical outcomes from a variety of other solid malignancies, in which a survival benefit is often seen in patients after a complete resection with negative margins but not in those with positive margins (19, 91, 244, 267, 273–275).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [19] Icard, 2001, Adrenocortical carcinomas: surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons study group, World J Surg source

      Not checked in the free run.

    • cites [91] Fassnacht, 2009, Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a Revised TNM Classification, Cancer source

      Not checked in the free run.

    • cites [244] Gonzalez, 2007, Response to mitotane predicts outcome in patients with recurrent adrenal cortical carcinoma, Surgery source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given
    § 4. Surgery for recurrent disease

    Until recently, conclusive data regarding the efficacy of adjuvant radiation and adjuvant mitotane had been missing, and adjuvant therapy remains a controversy.

    “However, until recently, conclusive data regarding the efficacy of both of these adjuvant treatment modalities had been missing, and adjuvant therapy remains a controversy.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 4. Surgery for recurrent disease

    Tumor grade and additional nonsurgical treatment influence outcome, although subsequent recurrence is expected.

    “data from other studies note their influence on outcome, although subsequent recurrence is expected (267, 268).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [267] Bellantone, 1997, Role of reoperation in recurrence of adrenal cortical carcinoma: results from 188 cases collected in the Italian National Registry for Adrenal Cortical Carcinoma, Surgery source

      Not checked in the free run.

    • cites [268] Jensen, 1991, Recurrent or metastatic disease in select patients with adrenocortical carcinoma. Aggressive resection vs chemotherapy, Arch Surg source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § 4. Surgery for recurrent disease

    In low-grade tumors, tempo of disease progression can be slower and lead to longer survival with resection of sites of recurrence or metastasis.

    “In those with low-grade tumors, tempo of disease progression can be slower and lead to longer survival with resection of sites of recurrence or metastasis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § 4. Surgery for recurrent disease

    An analysis of almost 4000 patients from the National Cancer Data Base found that 9% of ACC patients treated with surgery had microscopically positive margins (R1), and a further 10% had macroscopically positive margins (R2).

    “an analysis of almost 4000 patients from the National Cancer Data Base, which found that 9% of ACC patients treated with surgery had microscopically positive margins (R1), whereas a further 10% had macroscopically positive margins (R2) (11).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Bilimoria, 2008, Adrenocortical carcinoma in the United States: treatment utilization and prognostic factors, Cancer source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 3. Open vs laparoscopic surgery

    A case-control study from the German ACC Registry Group reported no difference in overall or disease-free survival, tumor capsule violation, or peritoneal carcinomatosis among 117 patients undergoing OA and 35 patients undergoing LA for stage 1 to 3 ACCs less than 10 cm.

    “A case-control study from the German ACC Registry Group reported no difference in overall or disease-free survival, tumor capsule violation, or peritoneal carcinomatosis among 117 patients undergoing OA and 35 patients undergoing LA for stage 1 to 3 ACCs less than 10 cm (261).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [261] Brix, 2010, Laparoscopic versus open adrenalectomy for adrenocortical carcinoma: surgical and oncologic outcome in 152 patients, Eur Urol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 4. Surgery for recurrent disease

    Patients with positive margins had a dismal prognosis compared with those with uninvolved margins; 5-year survival was 10% after R2 resection, 21% after R1, and 49% after R0.

    “patients with positive margins had a dismal prognosis compared with those with uninvolved margins; 5-year survival was 10% after R2 resection, 21% after R1, and 49% after R0 (11).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Bilimoria, 2008, Adrenocortical carcinoma in the United States: treatment utilization and prognostic factors, Cancer source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 1. Mitotane

    Mitotane inhibits 5α-reductase, reducing the generation of more potent androgens.

    “Furthermore, mitotane has recently been shown to inhibit 5α-reductase, reducing the generation of more potent androgens (299).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [299] Chortis, 2013, Mitotane therapy in adrenocortical cancer induces CYP3A4 and inhibits 5α-reductase, explaining the need for personalized glucocorticoid and androgen replacement, J Clin Endocrinol Metab source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given
    § 1. Mitotane

    Roughly 40% of mitotane is absorbed from the GI tract, and a significant amount is distributed to fatty tissues.

    “Roughly 40% of mitotane is absorbed from the GI tract, and a significant amount is distributed to fatty tissues.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given
    § 1. Mitotane

    Most mitotane studies were single-center studies and often included only a relatively small number of patients.

    “In addition, most studies were single-center studies, often including only a relatively small number of patients.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § 2. Cytotoxic chemotherapy

    Suramin tested in 2 studies led to an overall response rate of approximately 20%, but treatment had a narrow therapeutic range and serious side effects.

    “Subsequently, suramin has been tested in 2 studies where it led to an overall response rate of ∼20%. However, treatment had a narrow therapeutic range and serious side effects (312, 313).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [312] Arlt, 1994, Suramin in adrenocortical cancer: limited efficacy and serious toxicity, Clin Endocrinol (Oxf) source

      Not checked in the free run.

    • cites [313] LaRocca, 1991, Use of suramin in treatment of prostatic carcinoma refractory to conventional hormonal manipulation, Urol Clin North Am source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 1. Mitotane

    The decrease in free T4 is not a laboratory artifact because mitotane does not interfere with thyroid hormone measurements.

    “It has been determined that this is not a laboratory artifact because mitotane does not interfere with thyroid hormone measurements (300).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [300] Zatelli, 2010, Therapeutic concentrations of mitotane (o,p'-DDD) inhibit thyrotroph cell viability and TSH expression and secretion in a mouse cell line model, Endocrinology source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given
    § 2. Cytotoxic chemotherapy

    Initial studies in the 1970s and 1980s evaluated single-compound regimens with minor success and a response rate ranging from 10% to 20%.

    “Initial studies in the 1970s and 1980s evaluated single-compound regimens with minor success and a response rate ranging from 10% to 20%.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § 1. Mitotane

    Platinum-based cytotoxic drugs, doxorubicin, and etoposide are also metabolized by CYP3A4, potentially reducing their antineoplastic effect.

    “Other drugs regularly used in combination with mitotane, such as platinum-based cytotoxic drugs, doxorubicin, and etoposide are also metabolized by CYP3A4, potentially reducing their antineoplastic effect.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § 1. Mitotane

    Doses greater than 20 g regularly result in neurological side effects, which are reversible with normalization of plasma levels.

    “Doses greater than 20 g regularly result in neurological side effects, which are reversible with normalization of plasma levels (288).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [288] Terzolo, 2010, Mitotane

      Not checked in the free run.

  • May combine two claims.

    Premisenone given
    § 1. Mitotane

    All studies of mitotane in recurrent or advanced disease have been retrospective and uncontrolled, and a subgroup of patients shows very slow disease progress, possibly confounding interpretation.

    “All studies have been retrospective and uncontrolled, and it is the general experience that a subgroup of patients shows a very slow disease progress, possibly confounding interpretation of these results.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given
    § 1. Mitotane

    All studies evaluating mitotane as adjuvant therapy or for advanced ACC are retrospective, and older studies lack the advantage of cross-sectional imaging.

    “However, all studies are retrospective, and older studies lack the advantage of cross-sectional imaging.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § 1. Mitotane

    In ex vivo adrenal perfusion experiments, mitotane can be extracted in the adrenal gland and further metabolized.

    “In ex vivo adrenal perfusion experiments, it was shown that mitotane can be extracted in the adrenal gland and further metabolized (284).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [284] Martz, 1980, Metabolism and covalent binding of 1-(o-chlorophenyl)-1-(p-chlorophenyl)-2,2-dichloroethane (o,p,'-DDD). Correlation between adrenocorticolytic activity and metabolic activation by adrenocortical mitochondria, Drug Metab Dispos source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given
    § 1. Mitotane

    Alkaline phosphatase and GGT can increase significantly and the rise is usually of no clinical significance, but AST and ALT show only mild elevation.

    “Alkaline phosphatase and γ-glutamyl transferase (GGT) can increase significantly and the rise is usually of no clinical significance, but aspartate aminotransferase (AST) and alanine aminotransferase (ALT) show only mild elevation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given
    § 1. Mitotane

    A low-dose loading protocol has been described, probably leading to fewer side effects, the same efficacy, and increased patient compliance.

    “A low-dose loading protocol has also been described, probably leading to fewer side effects, the same efficacy, and increased patient compliance.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning
    § 1. Mitotane

    Adrenal insufficiency occurs invariably in patients on mitotane and is treated preemptively.

    “Adrenal insufficiency occurs invariably and is treated preemptively.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given
    § 1. Mitotane

    Mitotane may affect mineralocorticoid synthesis and replacement with fludrocortisone may become necessary.

    “Occasionally, mitotane may affect mineralocorticoid synthesis and replacement therapy with fludrocortisone therapy may become necessary.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given
    § 1. Mitotane

    Neurological side effects are dependent on plasma mitotane levels and usually do not occur until blood levels rise higher than 20 mg/L.

    “Neurological side effects are dependent on plasma mitotane levels and usually do not occur until blood levels rise higher than 20 mg/L.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 2. Cytotoxic chemotherapy

    Suramin had been found to induce adrenal insufficiency in humans and to have adrenolytic activity in animal experiments, where it led to inflammatory changes of the adrenal cortex.

    “Suramin, a compound used traditionally for the treatment of sleeping sickness, had been found to induce adrenal insufficiency in humans and to have adrenolytic activity in animal experiments, where it led to inflammatory changes of the adrenal cortex (310, 311).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [310] Feuillan, 1987, Effects of suramin on the function and structure of the adrenal cortex in the cynomolgus monkey, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [311] Kaplan, 1987, Lack of response to suramin in patients with AIDS and AIDS-related complex, Am J Med source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation
    § 1. Mitotane

    Common drugs metabolized by CYP3A4 include statins, opiates, benzodiazepines, warfarin, and some antibiotics.

    “Common drugs metabolized by this enzyme are statins, opiates, benzodiazepines, warfarin, and some antibiotics (for a complete list see Ref. 301).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [301] Kroiss, 2011, Drug interactions with mitotane by induction of CYP3A4 metabolism in the clinical management of adrenocortical carcinoma, Clin Endocrinol (Oxf) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 1. Mitotane

    With regard to fetal health, data are conflicting; there is a clear theoretical concern for disorders of sexual development in the developing fetus, but there is little supporting evidence.

    “With regard to fetal health, data are conflicting. Although there is a clear theoretical concern for disorders of sexual development in the developing fetus, there is little supporting evidence.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given
    § 1. Mitotane

    Even after discontinuation of mitotane therapy, CYP3A4 induction and mitotane levels persist up to several months.

    “Even after discontinuation of mitotane therapy, CYP3A4 induction and mitotane levels persist up to several months.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation
    § 1. Mitotane

    Most studies, including a large retrospective analysis, have defined the therapeutic mitotane level to be 14 to 20 mg/L.

    “Most studies, including a large retrospective analysis, have defined the therapeutic mitotane level to be 14 to 20 mg/L (296).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [296] Hermsen, 2011, Plasma concentrations of o,p'DDD, o,p'DDA, and o,p'DDE as predictors of tumor response to mitotane in adrenocortical carcinoma: results of a retrospective ENS@T multicenter study, J Clin Endocrinol Metab source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given
    § 1. Mitotane

    Side effects of mitotane are mainly GI, neurological, and metabolic/endocrinological and can usually be managed when mild.

    “Side effects are mainly GI, neurological, and metabolic/endocrinological in nature and can usually be managed when mild (Table 8).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning
    § 2. Cytotoxic chemotherapy

    Interpretation of early chemotherapy studies is difficult due to different study populations, ranging from microscopically remaining tumor to advanced pretreated metastasized disease, and responses are defined differently.

    “The interpretation of early studies is difficult due to different study populations, ranging from microscopically remaining tumor to advanced pretreated metastasized disease. Responses are defined differently in these studies”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § 2. Cytotoxic chemotherapy

    An initial study of gossypol suggested a response rate of 14%, but the results of repeat studies are pending.

    “An initial study suggested a response rate of 14%, but the results of repeat studies are pending (314).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [314] Flack, 1993, Oral gossypol in the treatment of metastatic adrenal cancer, J Clin Endocrinol Metab

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given
    § 1. Mitotane

    After a usual daily dose of 5 to 15 g/d, plasma levels range between 0 and 90 mg/L.

    “After a usual daily dose of 5 to 15 g/d, plasma levels range between 0 and 90 mg/L.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 1. Mitotane

    In 1 case, an abortion was performed and minor abnormalities of the morphology of the adrenal gland were described.

    “In 1 case, an abortion was performed and minor abnormalities of the morphology of the adrenal gland were described (308).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [308] Leiba, 1989, The protracted effect of o,p'-DDD in Cushing's disease and its impact on adrenal morphogenesis of young human embryo, Ann Endocrinol

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 1. Mitotane

    RRM1 expression is inversely correlated with mitotane response; low RRM1 expression predicts response to mitotane therapy with prolonged tumor-free survival.

    “On the molecular level, RRM1 expression has been found to be inversely correlated with mitotane response. Low RRM1 expression was a predictor of response to mitotane therapy with prolonged tumor-free survival (298).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [298] Volante, 2012, Ribonucleotide reductase large subunit (RRM1) gene expression may predict efficacy of adjuvant mitotane in adrenocortical cancer, Clin Cancer Res source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given
    § 1. Mitotane

    Major endocrine abnormalities result from the effect of mitotane on steroid hormone biosynthesis via three mechanisms: inhibition of steroid hormone biosynthesis at CYP11B1 and CYP11A1, induction of CYP3A4 and increased 6β-hydroxylation of cortisol, and induction of cortisol binding globulin.

    “Major endocrine abnormalities result from the effect of mitotane on steroid hormone biosynthesis. Three main mechanisms lead to adrenal insufficiency and decreased bioavailability of cortisol: 1) inhibition of steroid hormone biosynthesis at the level of CYP11B1 and CYP11A1, 2) induction of CYP3A4 and increased 6β-hydroxylation of cortisol, and 3) induction of cortisol binding globulin (CBG).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 1. Mitotane

    At least 6 pregnancies with conception during or shortly after mitotane therapy have been reported; four children were born evidently healthy, and no birth defects were encountered.

    “At least 6 pregnancies with conception during or shortly after mitotane therapy have been reported. Four children were born evidently healthy, and no birth defects were encountered (305–307).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [305] Baszko-Błaszyk, 2011, Pregnancy in a patient with adrenocortical carcinoma during treatment with Mitotane - a case report, Endokrynologia Polska

      Not checked in the free run.

    • cites [306] Coonrod, 1995, Virilizing adrenal carcinoma in a woman of reproductive age: a case presentation and literature review, Am J Obstet Gynecol source

      Not checked in the free run.

    • cites [307] Kojori, 2011, Normal adrenal function in an infant following a pregnancy complicated by maternal adrenal cortical carcinoma and mitotane exposure, J Pediatr Endocrinol Metab source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given
    § 1. Mitotane

    GI side effects are most commonly dependent on the actual dose in contact with the lumen of the GI tract, are rarely dose limiting, and can be attenuated by distributing mitotane into 3 or 4 daily doses.

    “The GI side effects (nausea and diarrhea) are most commonly dependent on the actual dose in contact with the lumen of the GI tract. These effects are rarely dose limiting and can be attenuated by distributing the mitotane amount into 3 or 4 daily doses.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given
    § 1. Mitotane

    Mitotane induces SHBG and increases total testosterone but decreases the bioavailable fraction.

    “Mitotane induces SHBG and increases total testosterone but decreases the bioavailable fraction.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation
    § 1. Mitotane

    Changes in thyroid function are due to partial central hypothyroidism, backed by experiments in cell lines where mitotane directly induces apoptosis in thyrotrope cells.

    “One interpretation is that the changes are due to partial central hypothyroidism. This is further backed up by experiments in cell lines, where mitotane directly induces apoptosis in thyrotrope cells (300).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [300] Zatelli, 2010, Therapeutic concentrations of mitotane (o,p'-DDD) inhibit thyrotroph cell viability and TSH expression and secretion in a mouse cell line model, Endocrinology source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given
    § 1. Mitotane

    There is a general concern that pregnancy may lead to increased likelihood of relapse and increased tumor growth, but supporting evidence is minimal.

    “There is a general concern that pregnancy may lead to increased likelihood of relapse and increased tumor growth. However, supporting evidence is minimal.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Greater than half of women with ACC are diagnosed during childbearing age.

  • May combine two claims.

    Premisecitation
    § 1. Mitotane

    A recent case report analyzed blood levels in a 21-week gestation normally developed fetus from a pregnancy terminated for ACC recurrence; amnion fluid and cord blood levels of mitotane were undetectable, arguing that there may be minimal exposure to the fetus.

    “A recent case report analyzed blood levels in a 21-week gestation normally developed fetus from a pregnancy terminated for ACC recurrence (309). In this study, amnion fluid and cord blood levels of mitotane were undetectable, arguing that there may be minimal exposure to the fetus.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [309] Tripto-Shkolnik, 2013, Pregnancy in a patient with adrenal carcinoma treated with mitotane: a case report and review of literature, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 1. Mitotane

    Some trials report an occasional complete remission with mitotane, but these are rare events.

    “Some trials report an occasional complete remission, but these are rare events (294).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [294] Boven, 1984, Complete response of metastasized adrenal cortical carcinoma with o,p'-DDD. Case report and literature review, Cancer source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § 4. Therapy for hormone excess

    Aminoglutethimide is an inhibitor of CYP11A1 and CYP11B1 and was initially introduced as an antiepileptic medication.

    “Aminoglutethimide is an inhibitor of CYP11A1 and CYP11B1 and was initially introduced as an antiepileptic medication (322, 323).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [322] Santen, 1977, Adrenal suppression with aminoglutethimide. I. Differential effects of aminoglutethimide on glucocorticoid metabolism as a rationale for use of hydrocortisone, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [323] Schteingart, 1967, Effects of aminoglutethimide upon adrenal function and cortisol metabolism in Cushing's syndrome, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given
    § 3. Targeted therapy

    The phase 3 GALACCTIC trial compared OSI906, a small-molecule inhibitor of IGF-1R and insulin receptor, with placebo in patients with stage 4 ACC, with two-thirds receiving study drug and one-third receiving placebo.

    “The phase 3 trial GALACCTIC compared OSI906, a small-molecule inhibitor of IGF-1R and insulin receptor, in patients with stage 4 disease in a placebo-controlled fashion, with two-thirds receiving study drug and one-third receiving placebo.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § 4. Therapy for hormone excess

    Ketoconazole inhibits CYP17A1, CYP11A1, and to some extent CYP11B1.

    “Ketoconazole inhibits CYP17A1, CYP11A1, and to some extent CYP11B1 (320).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [320] Auchus, 2010, Pharmacotherapy for hormone excess in adrenocortical carcinoma

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given
    § 3. Targeted therapy

    Children with BWS have higher levels of IGF-2, and IGF2 is the most highly expressed gene in sporadic ACCs when compared with ACAs or normal tissues.

    “based on the knowledge that children with BWS have higher levels of IGF-2 and that IGF2 is the most highly expressed gene in sporadic ACCs when compared with ACAs or normal tissues.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § 2. Cytotoxic chemotherapy

    Although FIRM-ACT established EDPM as an efficacious therapy, it also underscored the limitations of chemotherapy for ACC.

    “Although this study established EDPM as an efficacious therapy, it also underscored the limitations of chemotherapy for ACC.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § 4. Therapy for hormone excess

    Due to inhibition of CYP11B1, a relative increase in adrenal androgens may occur, possibly worsening symptoms related to hyperandrogenemia.

    “Due to the inhibition of CYP11B1, a relative increase in adrenal androgens may occur, possibly worsening symptoms related to hyperandrogenemia.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [321] Hartzband, 1988, Assessment of hypothalamic-pituitary-adrenal (HPA) axis dysfunction: comparison of ACTH stimulation, insulin-hypoglycemia and metyrapone, J Endocrinol Invest source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisereasoning
    § 2. Cytotoxic chemotherapy

    All FIRM-ACT study patients received concurrent mitotane therapy, and with the recent finding of increased metabolism of other drugs due to CYP3A4 induction, there is criticism regarding whether chemotherapy without mitotane may be more successful.

    “All study patients received concurrent mitotane therapy and with the recent finding of increased metabolism of other drugs due to CYP3A4 induction (eg, affecting cisplatin metabolism), there is criticism regarding whether chemotherapy without mitotane may be more successful.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § 1. Radiation therapy in nonmetastatic ACC

    Advances in radiation oncology have improved outcomes in a number of different cancers.

    “This has resulted in improved outcomes in a number of different cancers (2, 342–350).”
    Quote in the paperNot a substantial claim0 of 10 sources checked
    • cites [2] Viani, 2009, Higher-than-conventional radiation doses in localized prostate cancer treatment: a meta-analysis of randomized, controlled trials, Int J Radiat Oncol Biol Phys source

      Not checked in the free run.

    • cites [342] Arriagada, 1996, Conservative treatment versus mastectomy in early breast cancer: patterns of failure with 15 years of follow-up data. Institut Gustave-Roussy Breast Cancer Group, J Clin Oncol source

      Not checked in the free run.

    • cites [343] Blichert-Toft, 1992, Danish randomized trial comparing breast conservation therapy with mastectomy: six years of life-table analysis. Danish Breast Cancer Cooperative Group, J Natl Cancer Inst

      Not checked in the free run.

    • cites [344] Fisher, 2002, Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer, N Engl J Med source

      Not checked in the free run.

    • cites [345] Johansen, 2008, Extended radical mastectomy versus simple mastectomy followed by radiotherapy in primary breast cancer. A fifty-year follow-up to the Copenhagen Breast Cancer randomised study, Acta Oncol source

      Not checked in the free run.

    • cites [346] Kuban, 2008, Long-term results of the M.D. Anderson randomized dose-escalation trial for prostate cancer, Int J Radiat Oncol Biol Phys source

      Not checked in the free run.

    • cites [347] Poggi, 2003, Eighteen-year results in the treatment of early breast carcinoma with mastectomy versus breast conservation therapy: the National Cancer Institute Randomized Trial, Cancer source

      Not checked in the free run.

    • cites [348] van Dongen, 2000, Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial, J Natl Cancer Inst source

      Not checked in the free run.

    • cites [349] Veronesi, 2002, Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer, N Engl J Med source

      Not checked in the free run.

    • cites [350] Zietman, 2005, Comparison of Conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial, JAMA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 2. Cytotoxic chemotherapy

    The FIRM-ACT phase 3 trial confirmed the efficacy of chemotherapy and proved the superiority of EDPM over streptozotocin plus mitotane.

    “To establish a gold standard of cytotoxic chemotherapy for ACC, a recent phase 3 trial (FIRM-ACT, First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment) compared the most promising regimens (etoposide, doxorubicin, cislatin, mitotane [EDPM] vs streptozotocin, mitotane). This study confirmed the efficacy of chemotherapy and proved the superiority”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § 3. Targeted therapy

    Concomitant mitotane treatment negatively affected patient response to sunitinib, and sunitinib and mitotane levels were anticorrelated.

    “Interestingly, concomitant mitotane treatment negatively affected patient response, and sunitinib and mitotane levels were anticorrelated.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [304] Kroiss, 2012, Sunitinib in refractory adrenocortical carcinoma: a phase II, single-arm, open-label trial, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premiseown data
    § 2. Cytotoxic chemotherapy

    In FIRM-ACT, the response rate was 20% and 50% when stable disease was included; median progression-free survival was short with a median of 5 months (and 2 months in the streptozotocin plus mitotane group).

    “The response rate was 20% and 50%, when stable disease was included. However, the median progression-free survival, again, was short with a median of 5 months (and even 2 months in the streptozotocin, mitotane group).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § 1. Radiation therapy in nonmetastatic ACC

    Two early reports state radiotherapy is ineffective but offer no details regarding patient or treatment characteristics.

    “For example, 2 early reports state that radiotherapy is ineffective, but they offer no details regarding patient or treatment characteristics (266, 339).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [266] Schulick, 1999, Long-term survival after complete resection and repeat resection in patients with adrenocortical carcinoma, Ann Surg Oncol source

      Not checked in the free run.

    • cites [339] Cohn, 1986, Adrenocortical carcinoma, Surgery

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 4. Therapy for hormone excess

    Radiotherapy has been shown in several recent series to offer a significant improvement in disease control in both adjuvant and palliative settings, although such improvement has not been universally demonstrated.

    “Although traditionally considered ineffective for ACC (327–331), radiotherapy has been shown in several recent series to offer a significant improvement in disease control in both the adjuvant and palliative settings (247, 332–337), although such an improvement has not been universally demonstrated (338).”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [247] Sabolch, 2011, Adjuvant and definitive radiotherapy for adrenocortical carcinoma, Int J Radiat Oncol Biol Phys source

      Not checked in the free run.

    • cites [332] Fassnacht, 2006, Efficacy of adjuvant radiotherapy of the tumor bed on local recurrence of adrenocortical carcinoma, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [333] Hermsen, 2010, Response to radiation therapy in adrenocortical carcinoma, J Endocrinol Invest source

      Not checked in the free run.

    • cites [334] Markoe, 1991, Radiation therapy for adjunctive treatment of adrenal cortical carcinoma, Am J Clin Oncol source

      Not checked in the free run.

    • cites [335] Percarpio, 1976, Radiation therapy of adrenal cortical carcinoma, Acta Radiol Ther Phys Biol source

      Not checked in the free run.

    • cites [336] Polat, 2009, Radiotherapy in adrenocortical carcinoma, Cancer source

      Not checked in the free run.

    • cites [337] Magee, 1987, Adrenal cortical carcinoma: survival after radiotherapy, Clin Radiol source

      Not checked in the free run.

    • cites [338] Habra, 2013, A retrospective cohort analysis of the efficacy of adjuvant radiotherapy after primary surgical resection in patients with adrenocortical carcinoma, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 3. Targeted therapy

    In a phase 2 study of figitumumab in patients with advanced ACC, 8 of 14 patients had stable disease as their best response, but after 7 cycles (~6 months) all patients showed disease progression.

    “Eight of 14 patients had stable disease as their best response. However, after 7 cycles (∼6 months), all patients showed disease progression.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [316] Haluska, 2010, Safety, tolerability, and pharmacokinetics of the anti-IGF-1R monoclonal antibody figitumumab in patients with refractory adrenocortical carcinoma, Cancer Chemother Pharmacol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 3. Targeted therapy

    In a phase 2 study of cixutumab (IMCA12) in treatment-naive stage 4 ACC, a first phase enrolled 19 patients to mitotane plus IMCA12 to assess toxicity, but the trial was terminated early due to lack of overall response and recruitment difficulties.

    “Although the initial trial design was to compare mitotane plus IMCA12 vs mitotane alone, a first phase of this trial enrolled 19 patients to mitotane and IMCA12 to assess toxicity. However, due to the lack of overall response and recruitment difficulties, the trial was terminated early (G.D.H., unpublished results).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites G.D.H., unpublished results

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § 4. Therapy for hormone excess

    Steady infusion of etomidate can be safe because doses used are only 1/10 of the anesthetic dose (2-3 vs 20-30 mg/h).

    “Steady infusion can be safe because doses used are only 1/10 of the anesthetic dose (2–3 vs 20–30 mg/h).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § 3. Targeted therapy

    Drugs targeting the IGF-1R system are currently being tried in phase 1 and phase 2 trials in several tumor entities.

    “Drugs targeting the IGF-1R system are currently being tried in phase 1 and phase 2 trials in several tumor entities (315).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [315] Arnaldez, 2012, Targeting the insulin growth factor receptor 1, Hematol Oncol Clin North Am source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 1. Radiation therapy in nonmetastatic ACC

    In Habra et al, local recurrence rate for patients receiving adjuvant radiotherapy after surgery was 44%, compared with 14% in Fassnacht et al and 20% in Sabolch et al.

    “More specifically, although Habra et al (338) found a local recurrence rate of 44% for such patients, Fassnacht et al (332) showed a 14% local failure rate and Sabolch et al (247) found a 20% rate.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [338] Habra, 2013, A retrospective cohort analysis of the efficacy of adjuvant radiotherapy after primary surgical resection in patients with adrenocortical carcinoma, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [332] Fassnacht, 2006, Efficacy of adjuvant radiotherapy of the tumor bed on local recurrence of adrenocortical carcinoma, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [247] Sabolch, 2011, Adjuvant and definitive radiotherapy for adrenocortical carcinoma, Int J Radiat Oncol Biol Phys source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 3. Radiation therapy techniques

    Adrenal tumors, including ACC, have a tendency to undergo hemorrhage and might lead to bleeding complications.

    “Adrenal tumors, including ACC, have a tendency to undergo hemorrhage and might lead to bleeding complications (356).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [356] Thacker, 2009, Embolization of nonliver visceral tumors, Semin Intervent Radiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 3. Radiation therapy techniques

    In the largest series to date, 103 lesions in 29 patients were treated with TACE with response in 21% of patients and stabilization in 62%.

    “In the largest series to date, 103 lesions in 29 patients were treated with response in 21% of patients and stabilization in 62% (357).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [357] de Baere, 2010, Predictive factors for hypertrophy of the future remnant liver after selective portal vein embolization, Ann Surg Oncol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 3. Radiation therapy techniques

    Treatment of metastasis with TACE is fairly safe, but caution is demanded when treating primary adrenal tumors.

    “Although treatment of metastasis is fairly safe, caution is demanded when treating primary adrenal tumors.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [356] Thacker, 2009, Embolization of nonliver visceral tumors, Semin Intervent Radiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 3. Radiation therapy techniques

    ACC has a well-documented propensity for lymphatic dissemination, with involved nodal disease in approximately 15% to 27% of patients at the time of surgery.

    “ACC has a well-documented propensity for lymphatic dissemination (11, 91, 351), with involved nodal disease in approximately 15% to 27% of patients at the time of surgery (11, 91).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [11] Bilimoria, 2008, Adrenocortical carcinoma in the United States: treatment utilization and prognostic factors, Cancer source

      Not checked in the free run.

    • cites [91] Fassnacht, 2009, Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a Revised TNM Classification, Cancer source

      Not checked in the free run.

    • cites [351] King, 1979, Adrenal cortical carcinoma: a clinical and pathologic study of 49 cases, Cancer source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning
    § 1. Radiation therapy in nonmetastatic ACC

    Patients in Habra et al were treated outside an academic center and might not have benefited from the multidisciplinary approach that such centers offer, particularly for rare cancers.

    “Although it is difficult to determine from retrospective series the reasons for such discordant outcomes, the patients reported on by Habra et al (338) were treated outside of an academic center and might not have benefited from the multidisciplinary approach that such centers offer, particularly for rare cancers.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [338] Habra, 2013, A retrospective cohort analysis of the efficacy of adjuvant radiotherapy after primary surgical resection in patients with adrenocortical carcinoma, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 1. Radiation therapy in nonmetastatic ACC

    In Fassnacht et al, radiotherapy after complete resection in 14 patients with nonmetastatic ACC did not improve survival but significantly improved local control; at 5 years, local recurrence-free survival was 86% in the radiation group vs 11% in those who did not receive radiation.

    “Although radiotherapy did not improve survival, it did significantly improve local control: at 5 years, local recurrence-free survival was 86% in the group that received radiation compared with 11% in those that did not (332).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [332] Fassnacht, 2006, Efficacy of adjuvant radiotherapy of the tumor bed on local recurrence of adrenocortical carcinoma, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 3. Radiation therapy techniques

    Predictors of response to TACE were a size of <3 cm and high lipidol uptake.

    “Predictors of response were a size of <3 cm and high lipidol uptake.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [357] de Baere, 2010, Predictive factors for hypertrophy of the future remnant liver after selective portal vein embolization, Ann Surg Oncol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 1. Radiation therapy in nonmetastatic ACC

    In Sabolch et al, radiotherapy was not associated with a survival benefit but significantly improved local control.

    “Results from this study showed that whereas radiotherapy was not associated with a survival benefit, it did significantly improve local control.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [247] Sabolch, 2011, Adjuvant and definitive radiotherapy for adrenocortical carcinoma, Int J Radiat Oncol Biol Phys source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § 3. Radiation therapy techniques

    General limitations for RFA include highly vascularized metastasis or proximity to large vessels, because both function as a heat sink preventing the full destructive effect of RFA.

    “There are general limitations for RFA, such as in cases of highly vascularized metastasis or proximity to large vessels, because both function as a heat sink preventing the full destructive effect of RFA (353).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [353] Bauditz, 2009, Radiofrequency thermal ablation of hepatic metastases of adrenocortical cancer–a case report and review of the literature, Exp Clin Endocrinol Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § 1. Radiation therapy in nonmetastatic ACC

    In Sabolch et al, local failure occurred in 33% of those treated with surgery alone but only 12% of those whose regimen involved radiation.

    “Local failure occurred in 33% of those treated with surgery alone but only in 12% of those whose regimen involved radiation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [247] Sabolch, 2011, Adjuvant and definitive radiotherapy for adrenocortical carcinoma, Int J Radiat Oncol Biol Phys source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given
    § XI. Future Perspectives

    Mitotane is the only approved drug to treat ACC, is of limited efficacy, and may interfere with trials using new therapeutic agents.

    “Although it is true that it is the only approved drug to treat ACC, it is also of limited efficacy and may interfere with trials using new therapeutic agents.”
    Quote in the paperSubstantial claim
160 of 160

  • The paper relies on this without support.

    Patients with malignant disease are best cared for by multidisciplinary teams of physicians and associated healthcare providers.

    “In recent years, it has become evident that patients with malignant disease are best cared for by multidisciplinary teams of physicians and associated healthcare providers.”

  • The paper relies on this without support.

    The care for patients with rare diseases by the nonexpert is often based on extrapolation from other more common diseases or from the scarce evidence available through the medical literature.

    “The care for patients with rare diseases by the nonexpert is often based on extrapolation from other more common diseases or from the scarce evidence available through the medical literature.”

  • The paper relies on this without support.

    The formation of dedicated multidisciplinary clinics providing care for a larger referral community is a crucial step in gathering, preserving, and enhancing knowledge about uncommon disorders.

    “The formation of dedicated multidisciplinary clinics providing care for a larger referral community (eg, state- or nationwide) is a crucial step in gathering, preserving, and enhancing knowledge about these uncommon disorders.”

  • The paper relies on this without support.

    These multidisciplinary clinics have become essential for the exchange of scientific and clinical knowledge, the coordination of international multicenter trials, and the ultimate enrichment of evidence-based care for patients with rare disorders.

    “These multidisciplinary clinics have become essential for the exchange of scientific and clinical knowledge, the coordination of international multicenter trials, and the ultimate enrichment of evidence-based care for patients with rare disorders.”

  • The paper relies on this without support.

    The first operation is the best chance for long-term local control of malignancy.

    “The first operation is the best chance for long-term local control of malignancy.”

  • The paper relies on this without support.

    Poor initial surgical treatment can rarely be corrected, whether by reoperation, radiotherapy, or chemotherapy.

    “Poor initial surgical treatment can rarely be corrected, whether by reoperation, radiotherapy, or chemotherapy.”

  • The paper relies on this without support.

    Greater than half of women with ACC are diagnosed during childbearing age.

    “Greater than half of the women with ACC are diagnosed during childbearing age.”

  • The paper relies on this without support.

    Mitotane therapy almost invariably leads to an increase in liver enzymes and hypercholesterolemia.

    “Mitotane therapy almost invariably leads to an increase in liver enzymes and hypercholesterolemia.”

  • The paper relies on this without support.

    Mitotane levels can persist for up to 1 year after therapy, and the effect on CYP3A4 can last at least as long.

    “As mentioned above, mitotane levels can persist for up to 1 year after therapy, and the effect on CYP3A4 can last at least as long.”

  • The paper relies on this without support.

    With the exception of mifepristone and mitotane, treatment of hormone excess with all substances mentioned below is regarded as off-label treatment in most countries.

    “With the exception of mifepristone and mitotane, treatment of hormone excess with all substances mentioned below is regarded as off-label treatment in most countries.”

  • The paper relies on this without support.

    Mitotane inhibits CYP11A1 and CYP11B1 and together with its adrenolytic effects may lead to some control of hormone levels.

    “Mitotane inhibits CYP11A1 and CYP11B1 and together with its adrenolytic effects may lead to some control of hormone levels.”

  • The paper relies on this without support.

    Aminoglutethimide is no longer available in most countries.

    “However, aminoglutethimide is no longer available in most countries.”

  • The paper relies on this without support.

    Neither ACTH nor glucocorticoid levels can be used to guide therapy with mifepristone.

    “However, neither ACTH nor glucocorticoid levels can be used to guide therapy.”

  • The paper relies on this without support.

    The most common side effects of mifepristone are hypokalemia and hypertension due to direct effects of very high cortisol levels on renal mineralocorticoid receptors.

    “The most common side effects are hypokalemia and hypertension due to the direct effects of the very high cortisol levels on the renal mineralocorticoid receptors.”

  • The paper relies on this without support.

    None of RFA or TACE have been explored in clinical trials.

    “None of these methods have been explored in clinical trials.”

  • The paper relies on this without support.

    Both TACE and RFA have a tolerable side effect profile and often less negative impact on well-being than surgery.

    “Both TACE and RFA have a tolerable side effect profile and often less negative impact on well-being than surgery.”

  • The paper relies on this without support.

    TACE advantage is that selective embolization achieves high intratumor levels of cytotoxic substances while minimizing systemic effects.

    “The advantage is that with selective embolization, high intratumor levels of cytotoxic substances can be achieved and at the same time systemic effects can be minimized.”
17 of 17

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Adrenocortical carcinomas have been noted in familial adenomatous polyposis, neurofibromatosis type 1, and Carney complex.

    “ACCs have also been noted in familial adenomatous polyposis (FAP gene), neurofibromatosis type 1 (NF1 gene), and Carney complex (PRKAR1A gene) (161).”

    From Adrenal incidentaloma (2020) · cites this paper as [161]

  • Routine serum biochemistry detects steroid hormone excess in 60% to 70% of adrenocortical carcinoma patients, with glucocorticoid and androgen excess dominating.

    “Routine serum biochemistry detects steroid hormone excess in 60% to 70% of ACC patients, with glucocorticoid and androgen excess dominating (1, 188); however, urine GC-MS profiling demonstrated steroid excess in >90% (1).”

    From Steroid Metabolome Analysis in Disorders of Adrenal Steroid Biosynthesis and Metabolism (2019) · cites this paper as [188]

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.

  • Mitotane studies called retrospective despite prospective entries

    Minor

    The text says all the mitotane studies are retrospective, but Table 7 labels several studies as prospective.

  • Mean response percentage in Table 7 is incorrect

    Minor

    The mean of the ten study percentages is 26.686%, not the reported 26.01%.

    Reported 26.01 · recomputed 26.686

  • Stage-at-diagnosis percentages total 110%

    Minor

    The four reported stage percentages sum to 110%, although the stages are mutually exclusive.

    Reported 100 · recomputed 110

  • High-grade mitotic-rate threshold uses conflicting denominators

    Minor

    The pathology section defines high-grade ACC as more than 20 mitoses per 50 high-power fields, but the prognostic-factors section states more than 20 per high-power field. These are substantially different thresholds for a stated prognostic indicator.

4 of 4

Cites

Flagged first, then by citations

34 of the 415 references couldn’t be matched to a known paper.

Research works printed but not linked: 9

  1. Chompret, 2000, P53 germline mutations in childhood cancers and cancer risk for carrier individuals, Br J Cancer, 82, 1932
  2. Else, 2010, Overview of genetic syndromes associated with adrenocortical cancer, 153
  3. Mantero, 2000, A survey on adrenal incidentaloma in Italy. Study Group on Adrenal Tumors of the Italian Society of Endocrinology, J Clin Endocrinol Metab, 85, 637
  4. Ragazzon, 2011, Transcriptome analysis of adrenocortical cancers: from molecular classification to the identification of new treatments, Endocrine-related cancer, 18, R15
  5. Terzolo, 2010, Mitotane, 369
  6. Auchus, 2010, Pharmacotherapy for hormone excess in adrenocortical carcinoma, 383
  7. Murphy, 1967, Radiation Therapy
  8. Stratakis CA , HorvathA. Carney complex. In: PagonRABT, DolanCR, . eds. GeneReviews. Seattle, WA: University of Washington; 2003. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1286/.
  9. Burgess, 1993, Chemotherapy with cis-platinum and etoposide (VP-16) for patients with advanced adrenal cortical carcinoma, Proc Am Soc Clin Oncol, 12, 188

Cited by

Sorted by citations

Related

Authors
Else, T., Kim, A. C., Sabolch, A., Raymond, V. M., Kandathil, A., Caoili, E. M., Jolly, S., Miller, B. S., Giordano, T. J., & Hammer, G. D.
Affiliations
Michigan Medicine (US)
ORCID
Venue
Endocrine Reviews
Publisher
The Endocrine Society
Published
2013-12-20
Volume
35
Issue
2
Pages
282-326
ISSN
  • 0163-769X (ISSN-L)
  • 1945-7189
DOI
10.1210/er.2013-1029
PMC
PMC3963263
OpenAlex
W4292166992
Cited by
892
References
415
Citations by year
2026: 42 · 2025: 76 · 2024: 77 · 2023: 101 · 2022: 102 · 2021: 113 · 2020: 88 · 2019: 72 · 2018: 74 · 2017: 43 · 2016: 52 · 2015: 43 · 2014: 8
FWCI
6.08
Type
journal article
Language
en
Open access
Locations
  • Endocrine Reviews (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Cancer Institute (R01CA134606)
  • National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007245, P30DK020572)
Topics
  • Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
  • Health Sciences › Medicine › Epidemiology › Neuroendocrine Tumor Research Advances
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Keywords
adrenocortical carcinoma, endocrine malignancy, diagnosis, pathophysiology, treatment, multidisciplinary care, prognosis, clinical trials
MeSH terms
Adrenal Cortex Neoplasms, Humans, Prevalence, Adrenocortical Carcinoma, Genetic Predisposition to Disease

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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.

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