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Cited by 68Radiopharmaceutical Chemistry and ApplicationsNeuroendocrine Tumor Research AdvancesPeptidase Inhibition and Analysis

Alpha-peptide receptor radionuclide therapy using actinium-225 labeled somatostatin receptor agonists and antagonists

Open access
Shi, Mengqi, Jakobsson, Vivianne, Greifenstein, Lukas, Khong, Pek-Lan, Chen, Xiaoyuan, Baum, Richard P., Zhang, Jingjing·2022·Frontiers in Medicine
DOI 10.3389/fmed.2022.1034315PMC PMC9767967
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Abstract

Peptide receptor radionuclide therapy (PRRT) has over the last two decades emerged as a very promising approach to treat neuroendocrine tumors (NETs) with rapidly expanding clinical applications. By chelating a radiometal to a somatostatin receptor (SSTR) ligand, radiation can be delivered to cancer cells with high precision. Unlike conventional external beam radiotherapy, PRRT utilizes primarily β or α radiation derived from nuclear decay, which causes damage to cancer cells in the immediate proximity by irreversible direct or indirect ionization of the cells’ DNA, which induces apoptosis. In addition, to avoid damage to surrounding normal cells, PRRT privileges the use of radionuclides that have little penetrating and more energetic (and thus more ionizing) radiations. To date, the most frequently radioisotopes are β – emitters, particularly Yttrium-90 ( 90 Y) and Lutetium-177 ( 177 Lu), labeled SSTR agonists. Current development of SSTR-targeting is triggering the shift from using SSTR agonists to antagonists for PRRT. Furthermore, targeted α-particle therapy (TAT), has attracted special attention for the treatment of tumors and offers an improved therapeutic option for patients resistant to conventional treatments or even beta-irradiation treatment. Due to its short range and high linear energy transfer (LET), α-particles significantly damage the targeted cancer cells while causing minimal cytotoxicity toward surrounding normal tissue. Actinium-225 ( 225 Ac) has been developed into potent targeting drug constructs including somatostatin-receptor-based radiopharmaceuticals and is in early clinical use against multiple neuroendocrine tumor types. In this article, we give a review of preclinical and clinical applications of 225 Ac-PRRT in NETs, discuss the strengths and challenges of 225 Ac complexes being used in PRRT; and envision the prospect of 225 Ac-PRRT as a future alternative in the treatment of NETs.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes preclinical and clinical use of actinium-225-labeled somatostatin receptor agonists and antagonists for peptide receptor radionuclide therapy in neuroendocrine tumors, emphasizing the short range and high linear energy transfer of α-particles. It concludes that 225Ac-PRRT is promising, especially for β-radiation-refractory NETs, but still faces major supply, imaging, dosimetry, chelation, and quality-control challenges.

Key findings

  • 225Ac has a 9.9-day half-life and yields four α and three β− emissions per decay; α-particles have high LET of 50–230 keV/μm and tissue range not exceeding 100 μm, compared with β-particles at 0.05–12 mm, allowing more selective tumor-cell killing.
  • The first clinical 225Ac-DOTATOC study included 46 treatment cycles in 34 patients, determined a maximum tolerable dose of 40 MBq, and found doses of 18.5 MBq every 2 months or 25 MBq every 4 months safe, with cumulative activity of 75 MBq regarding delayed toxicity. A later 225Ac-DOTATATE study in 91 GEP-NET patients showed improved overall survival even in patients refractory to prior 177Lu-DOTATATE, with transient and acceptable adverse effects.
  • SSTR antagonists such as LM3 and JR11 showed higher tumor uptake, longer retention, and improved tumor-to-background ratios than agonists; in a pilot study, 177Lu-DOTA-JR11 gave 1.7–10.6 times higher tumor dose and 1.1–7.2 times higher tumor-to-kidney and tumor-to-bone marrow ratios than 177Lu-DOTATATE, while a phase I study in 20 patients reported 45% best overall response and median progression-free survival of 21 months but grade 4 hematotoxicity in 4 of 7 patients after two cycles.
  • The authors’ own case was a 40-year-old pancreatic-NET patient with liver and extensive bone metastases who received 225Ac-DOTA-LM3 at 10 MBq in March and 15 MBq in May 2022, after cumulative 66.7 GBq 177Lu and 25 MBq 225Ac; restaging showed partial remission by THERCIST, with dramatic improvement especially in bone metastases.

Methods

  • Narrative review of preclinical and clinical applications of 225Ac-PRRT in NETs, including tables of selected radioisotopes, medically relevant α-emitters, and 225Ac-PRRT studies.
  • Data summarized include preclinical xenograft and in vitro studies and clinical studies/case reports in Table 3, plus one institutional case report of 225Ac-DOTA-LM3.
  • Main analysis is a qualitative synthesis of efficacy, safety, dosimetry, production, chelation, and future directions; no systematic search strategy or meta-analysis is described.

Limitations

  • Stated: limited 225Ac supply is the most important challenge, with current global production of approximately 68 GBq per year; imaging, dosimetry, chelator stability/recoil, and quality control remain problematic; confirmed literature on PRRT using an α-emitter with an SSTR antagonist has yet to be published.
  • Evident: as a narrative review, it reports no systematic search strategy, inclusion criteria, or risk-of-bias assessment.
  • Evident: the highlighted 225Ac-DOTA-LM3 clinical evidence is a single case report, limiting generalizability.

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

Integrity signals

Registry

Crossref · 10.3389/fmed.2022.1034315

Cites

169 of 169 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 120 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The most recent PET/CT showed dramatic improvement, especially concerning the previous innumerable bone metastases in the spine, ribs, and pelvis.

    “As shown in the most recent PET/CT, there is dramatic improvement, especially concerning the previous innumerable bone metastases in the spine, ribs, and pelvis.”
    Quote in the paperNot a substantial claim
  • Findingown data

    This case with β-radiation refractory metastatic NET demonstrated an auspicious therapeutic response after two cycles of 225Ac-DOTA-LM3, especially concerning the bone metastases.

    “This case with β-radiation refractory metastatic NET demonstrated incredibly auspicious therapeutic response after two cycles of 225Ac-DOTA-LM3, especially concerning the bone metastases.”
    Quote in the paperSubstantial claim
  • Findingown data

    Restaging in July 2022 showed excellent response to 225Ac-DOTA-LM3 treatment with partial remission according to the THERCIST.

    “Restaging result in July 2022 showed excellent response to 225Ac-DOTA-LM3 treatment with partial remission according to the THERCIST.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    90Y-PRRT has a small potential of causing renal toxicity when used without nephroprotection, especially in patients with compromised renal function.

    “It has been demonstrated that 90Y-PRRT has a small potential of causing renal toxicity when used without nephroprotection, especially in patients with compromised renal function (53, 54).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [53] Bodei, 2008, Long-term evaluation of renal toxicity after peptide receptor radionuclide therapy with 90Y-DOTATOC and 177Lu-DOTATATE: the role of associated risk factors., Eur J Nucl Med Mol Imaging. source

      Not checked in the free run.

    • cites [54] Cremonesi, 2018, Correlation of dose with toxicity and tumour response to 90Y- and 177Lu-PRRT provides the basis for optimization through individualized treatment planning., Eur J Nucl Med Mol Imaging. source

      Not checked in the free run.

  • Premisereasoning

    Targeted alpha-particle therapy offers a therapeutic option for patients resistant to beta-irradiation treatments.

    “Targeted α-particle therapy (TAT) offers a therapeutic option for patients resistant to β-irradiation treatments.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 24
  • May combine two claims. 50

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

    Findingown data

    The patient had previously undergone laparoscopic subtotal pancreatic resection and splenectomy, CAPTEM chemotherapy, transarterial chemoembolization (TACE) of right liver lobe and resection of abdominal lesion, and had previous ineffective treatment with Lanreotide, Everolimus, and Sunitinib.

    “The patients had previously undergone laparoscopic subtotal pancreatic resection and splenectomy, CAPTEM chemotherapy, transarterial chemoembolization (TACE) of right liver lobe and resection of abdominal lesion. In addition, the patient had previous ineffective treatment with Lanreotide, Everolimus, and Sunitinib.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    In total, the patient had received eight cycles of PRRT, and had a very poor prognosis, extensive bone metastases, even after multiple cycles treatment with 177Lu-DOTATATE.

    “In total, the patient had received eight cycles of PRRT, and had a very poor prognosis, extensive bone metastases, even after multiple cycles treatment with 177Lu-DOTATATE (A,B, 68Ga-DOTATOC PET/CT before and after 177Lu-DOTATATE treatment).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    A 40-year-old pancreatic-NET patient had bilobar liver metastases and extensive bone metastasis even after multiple cycles of PRRT with 177Lu-DOTATATE, and compromised therapeutic response after one cycle of 177Lu-DOTA-LM3.

    “A 40-year-old pancreatic-NET patient suffered from bilobar liver metastases and extensive bone metastasis even after multiple cycles of PRRT with 177Lu-DOTATATE, and compromised therapeutic response after one cycle of 177Lu-DOTA-LM3 treatment, was suggested for PRRT with 225Ac-DOTA-LM3.”
    Quote in the paperSubstantial claim

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

    Findingnone given

    After the last PRRT, the patient only experienced mild alopecia and mild pain in the upper right abdomen over 1 week, and has been physically active and gained 3 kg body weight over the past 2 months.

    “After the last PRRT, he only experienced mild alopecia and mild pain in the upper right abdomen over 1 week, and has been physically active and gained 3 kg body weight over the past 2 months.”
    Quote in the paperNot a substantial claim

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

    Findingnone given

    The patient was diagnosed with poorly differentiated non-functioning pancreatic-NET with bilobar liver and extensive bone metastases, Ki-67 index of 25% NEN-G3 without known mutations.

    “A 40-year-old patient was diagnosed with poorly differentiated non-functioning pancreatic-NET with bilobar liver and extensive bone metastases, Ki-67 index of 25% NEN-G3 without known mutations.”
    Quote in the paperNot a substantial claim

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

    Findingnone given

    The patient felt dramatically better in comparison to the previous treatments.

    “The patient felt dramatically better in comparison to the previous treatments.”
    Quote in the paperNot a substantial claim

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

    Findingnone given

    The primary tumor in the pancreas, and the liver and bone metastases further decreased in size and number, and no new metastatic lesions were noted.

    “The primary tumor in the pancreas, and the liver and bone metastases further decreased in size and number, and no new metastatic lesions were noted.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Current development of SSTR-targeting is triggering the shift from using SSTR agonists to antagonists for PRRT.

    “Current development of SSTR-targeting is triggering the shift from using SSTR agonists to antagonists for PRRT.”
    Quote in the paperNot a substantial claim

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

    Premisereasoning

    Due to its short range and high linear energy transfer, alpha-particles significantly damage the targeted cancer cells while causing minimal cytotoxicity toward surrounding normal tissue.

    “Due to its short range and high linear energy transfer (LET), α-particles significantly damage the targeted cancer cells while causing minimal cytotoxicity toward surrounding normal tissue.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Despite the success of 90Y-DOTATOC and 177Lu-DOTATATE in progression-free survival, there were problems with 90Y concerning renal toxicity and a low rate of complete remissions, suggesting an improvement in PRRT efficacy is required.

    “Despite the success of [90Y]Y-DOTATOC and [177Lu]Lu-DOTATATE in the treatment of NETs in terms of progression-free survival, there were problems with 90Y concerning renal toxicity and a low rate of complete remissions, suggesting an improvement in PRRT efficacy is required (27, 41)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [27] Feijtel, 2020, Peptide receptor radionuclide therapy: looking back, looking forward., Curr Top Med Chem. source

      Not checked in the free run.

    • cites [41] Lewington, 2003, Targeted radionuclide therapy for neuroendocrine tumours., Endocr Relat Cancer. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given

    By chelating a radiometal to a somatostatin receptor ligand, radiation can be delivered to cancer cells with high precision.

    “By chelating a radiometal to a somatostatin receptor (SSTR) ligand, radiation can be delivered to cancer cells with high precision.”
    Quote in the paperSubstantial claim

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

    Premisereasoning

    Targeted alpha-particle therapy has attracted special attention for the treatment of tumors and offers an improved therapeutic option for patients resistant to conventional treatments or even beta-irradiation treatment.

    “Furthermore, targeted α-particle therapy (TAT), has attracted special attention for the treatment of tumors and offers an improved therapeutic option for patients resistant to conventional treatments or even beta-irradiation treatment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Because of the double-positive charge, alpha-particles deliver dense ionization along a linear track, often described as high linear energy transfer, ranging from 50 to 230 keV/μm.

    “Because of the double-positive charge, α-particles deliver dense ionization along a linear track, often described as high linear transfer (LET), ranging from 50 to 230 keV/μm (Figure 3) (60).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Pouget, 2021, Revisiting the radiobiology of targeted alpha therapy., Front Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The primary target of high-LET alpha-particles is DNA, and a low number of particles can result in irreparable double strand breaks and lack of oxygen effects on cytotoxicity.

    “Moreover, the primary target of high-LET α-particle is DNA, and a low number of particles can result in irreparable DSBs and lack of oxygen effects on cytotoxicity (62–64).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [62] Zalutsky, 1996, Radioimmunotherapy with alpha-particle emitting radioimmunoconjugates., Acta Oncol. source

      Not checked in the free run.

    • cites [63] Zalutsky, 1996, Two approaches for enhancing radioimmunotherapy: alpha emitters and hyperthermia., Recent Results Cancer Res. source

      Not checked in the free run.

    • cites [64] Poty, 2018, α-Emitters for Radiotherapy: From Basic Radiochemistry to Clinical Studies-Part 1., J Nucl Med. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given

    PRRT utilizes primarily beta or alpha radiation derived from nuclear decay, which causes damage to cancer cells in the immediate proximity by irreversible direct or indirect ionization of the cells' DNA, inducing apoptosis.

    “Unlike conventional external beam radiotherapy, PRRT utilizes primarily β or α radiation derived from nuclear decay, which causes damage to cancer cells in the immediate proximity by irreversible direct or indirect ionization of the cells’ DNA, which induces apoptosis.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    Actinium-225 has been developed into potent targeting drug constructs including somatostatin-receptor-based radiopharmaceuticals and is in early clinical use against multiple neuroendocrine tumor types.

    “Actinium-225 (225Ac) has been developed into potent targeting drug constructs including somatostatin-receptor-based radiopharmaceuticals and is in early clinical use against multiple neuroendocrine tumor types.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    To date, the most frequently used radioisotopes are beta-minus emitters, particularly Yttrium-90 and Lutetium-177, labeled SSTR agonists.

    “To date, the most frequently radioisotopes are β– emitters, particularly Yttrium-90 (90Y) and Lutetium-177 (177Lu), labeled SSTR agonists.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The treatment was found to be safe with doses of 18.5 MBq every 2 months or 25 MBq every 4 months, and a cumulative activity of 75 MBq in regard to delayed toxicity.

    “The treatment was found to be safe with doses of 18.5 MBq every 2 months or 25 MBq every 4 months, and a cumulative activity of 75 MBq in regard to delayed toxicity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [87] Kratochwil, 2015, Ac-225-DOTATOC - an empiric dose finding for alpha particle emitter based radionuclide therapy of neuroendocrine tumors., J Nucl Med.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 10 NET patients, the first intra-arterial targeted alpha peptide radionuclide therapy using 225Ac-DOTATOC was very well-tolerated and effective.

    “The very first intra-arterial targeted alpha peptide radionuclide therapy using 225Ac DOTATOC225Ac DOTATOC PRRT was very well-tolerated and effective.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [158] Zhang, 2019, From bench to bedside-the bad berka experience with first-in-human studies., Semin Nucl Med. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The great reduction of growth and improved efficacy compared with 177Lu-labeled SSAs suggests that 225Ac-DOTATATE/DOTATOC has significant potential for improving PRRT in NETs and for clinical translation in NET.

    “The great reduction of growth and improved efficacy compared with 177Lu-labeled SSAs suggested that 225Ac-DOTATATE/DOTATOC has significant potential for improving PRRT in NETs and for the clinical translation in NET.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In 91 GEP-NET patients, 225Ac-DOTATATE TAT showed improved overall survival, even in patients refractory to prior 177Lu-DOTATATE treatment, with transient and acceptable adverse effects.

    “225Ac-DOTATATE TAT showed improved overall survival, even in patients refractory to prior 177Lu-DOTATATE treatment with transient and acceptable adverse effects”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [168] Ballal, 2022, Survival outcomes in metastatic gastroenteropancreatic neuroendocrine tumor patients receiving concomitant 225Ac-DOTATATE targeted alpha therapy and capecitabine: a real-world scenario management based long-term outcome study., J Nucl Med. source

      Not checked in the free run.

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

    Premisereasoning

    The feasibility of using 225Ac for imaging is debatable because the amount administered for therapy may not produce enough gamma emission to be effectively detected by gamma camera.

    “Although the feasibility of using 225Ac for imaging is debatable because the amount administered for therapy may not produce enough gamma emission to be effectively detected by gamma camera.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The first-in-human phase I dose escalation trial used 225Ac-DOTA-HuM195, which demonstrated the safety of 225Ac and its antileukemic activity, and suggested that targeted therapy with an in vivo alpha-particle nanogenerator is a feasible approach in humans.

    “The first-in-human phase I dose escalation trial used 225Ac-DOTA-HuM195, which not only demonstrated the safety of 225Ac and its antileukemic activity, but also suggested that targeted therapy with an in vivo α-particle nanogenerator is a feasible approach in humans (82).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [82] Rosenblat, 2007, Phase I trial of the targeted alpha-particle nano-generator Actinium-225 (225Ac)-HuM195 (Anti-CD33) in Acute Myeloid Leukemia (AML)., Blood. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a liver NET case report, 225Ac-PRRT in a beta-radiation-refractory NET patient was shown to be safe and effective.

    “225Ac-PRRT in a β-radiation-refractory NET patient was shown to be safe and effective.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [162] Zhang, 2020, Peptide Receptor Radionuclide Therapy Using 225Ac-DOTATOC Achieves Partial Remission in a Patient With Progressive Neuroendocrine Liver Metastases After Repeated β-emitter peptide receptor radionuclide therapy., Clin Nucl Med. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Considering the minimal/acceptable side effects and the improved therapeutic efficacy and survival, 225Ac-PRRT provides an alternative in the treatment of beta-radiation-refractory NETs.

    “Considering the minimal/acceptable side effects, and the improved therapeutic efficacy and survival, one can conclude that 225Ac-PRRT not only provides an alternative in the treatment of β-radiation-refractory NETs”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In a pancreatic NET case report, 225Ac-DOTATATE was well-tolerated at the early stage of treatment, and the patient demonstrated excellent response.

    “225Ac-DOTATATE was well-tolerated at early stage of treatment, and patient demonstrated excellent response.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [166] Budlewski, 2022, Innovative radioisotope therapy for patients with neuroendocrine tumors using an alpha (225Ac) emitter labeled somatostatin analog: octreotate. a promising new treatment for advanced, progressive neuroendocrine neoplasms., Pol Arch Intern Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The short range of alpha-particles allows for selective ablation of the targeted tumor cells whilst minimizing damage to surrounding healthy tissues.

    “This allows for selective ablation of the targeted tumor cells whilst minimizing the damage to surrounding healthy tissues (67).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Koh, 2021, Targeted alpha-particle therapy in neuroendocrine neoplasms: a systematic review., World J Nucl Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    225Ac-DOTATOC reduced growth of NETs and improved therapeutic efficacy.

    “Reduced growth of NETs, and improved therapeutic efficacy”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [117] Miederer, 2008, Preclinical evaluation of the alpha-particle generator nuclide 225Ac for somatostatin receptor radiotherapy of neuroendocrine tumors., Clin Cancer Res. source

      Not checked in the free run.

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

    Premisecitation

    In 34 NET patients, 225Ac-DOTATOC showed promising treatment efficacy in various patients, suggesting comparative trials of alpha and beta are needed.

    “Promising treatment efficacy in various patientsSuggesting comparative trials of α and β are needed.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [87] Kratochwil, 2015, Ac-225-DOTATOC - an empiric dose finding for alpha particle emitter based radionuclide therapy of neuroendocrine tumors., J Nucl Med.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    With this proof of concept, 225Ac was attached to PSMA-617 for prostate cancer therapy and also bound to SSA-based pharmaceuticals for treating NETs.

    “With this proof of concept, 225Ac was then attached to PSMA-617 for prostate cancer therapy (83–86) and also bound to SSA-based pharmaceuticals for treating NETs.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [83] Kratochwil, 2016, 225Ac-PSMA-617 for PSMA-Targeted α-Radiation therapy of metastatic castration-resistant prostate cancer., J Nucl Med. source

      Not checked in the free run.

    • cites [84] Kratochwil, 2017, Targeted α-Therapy of metastatic castration-resistant prostate cancer with (225)Ac-PSMA-617: dosimetry estimate and empiric dose finding., J Nucl Med. source

      Not checked in the free run.

    • cites [85] Sathekge, 2019, (225)Ac-PSMA-617 in chemotherapy-naive patients with advanced prostate cancer: a pilot study., Eur J Nucl Med Mol Imaging. source

      Not checked in the free run.

    • cites [86] Sathekge, 2020, Predictors of Overall and Disease-Free Survival in Metastatic Castration-Resistant Prostate Cancer Patients Receiving 225Ac-PSMA-617 Radioligand Therapy., J Nucl Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    225Ac-DOTATATE significantly decreased tumor volume, increased tumor growth delay, and prolonged time to experimental endpoint for animals bearing both tumor types.

    “Significantly decreased tumor volume, increased tumor growth delay, and prolonged time to experimental endpoint for animals bearing both tumor types”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [157] Tafreshi, 2021, Preclinical evaluation of [225Ac]Ac-DOTA-TATE for treatment of lung neuroendocrine neoplasms., Eur J Nucl Med Mol Imaging. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The typical tissue range of alpha-particles does not exceed 100 μm, which is significantly shorter than that of beta-particles (0.05-12 mm).

    “On the other hand, the typical tissue range of α-particles does not exceed 100 μm, which is significantly shorter than that of β-particles (0.05–12 mm) (Figure 3) (16, 58).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [16] Dash, 2013, Targeted radionuclide therapy–an overview., Curr Radiopharm. source

      Not checked in the free run.

    • cites [58] Kassis, 2005, Radiobiologic principles in radionuclide therapy., J Nucl Med.

      Not checked in the free run.

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

    Premisecitation

    In a rectal NET case report, whole-body and SPECT/CT imaging results encourage the use of 225Ac-DOTATATE as a primary modality of treatment in advanced NET with metastases.

    “Whole-body and SPECT/CT imaging results encourage the use of 225Ac -DOTATATE as a primary modality of treatment in advanced NET with metastases.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [161] Kamaleshwaran, 2020, Whole-body and Single-Photon Emission Computed Tomography/Computed Tomography Postpeptide Receptor Alpha Radionuclide Therapy Images of Actinium 225-Tetraazacyclododecanetetraacetic Acid-Octreotide as a Primary Modality of Treatment in a Patient with Advanced Rectal Neuroendocrine Tumor with Metastases., Indian J Nucl Med. source

      Not checked in the free run.

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

    Premisecitation

    Despite treatment response observed in several patients, further investigations were found to be necessary to improve patient selection and dosage regimens.

    “Despite the treatment response observed in several patients, further investigations were found to be necessary to improve patient selection and dosage regimens (87).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [87] Kratochwil, 2015, Ac-225-DOTATOC - an empiric dose finding for alpha particle emitter based radionuclide therapy of neuroendocrine tumors., J Nucl Med.

      Not checked in the free run.

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

    Premisenone given

    Gamma-H2AX was suggested as an early key parameter in predicting tumor response to alpha-PRRT.

    “γH2AX was suggested as early key parameter in predicting tumor response to α-PRRT.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The cytotoxicity of alpha-particles may be extremely effective and may also be more dose independent than beta-emissions, with cell death occurring from a single or a few alpha-particle traversals of the cell nucleus.

    “Thus, the cytotoxicity of α-particle may be extremely effective and may also be more dose independent than β-emissions with cell death occurring from a single or a few α-particle traversals of the cell nucleus (65, 66).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [65] Nikula, 1999, Alpha-emitting bismuth cyclohexylbenzyl DTPA constructs of recombinant humanized anti-CD33 antibodies: pharmacokinetics, bioactivity, toxicity and chemistry., J Nucl Med.

      Not checked in the free run.

    • cites [66] Raju, 1991, Radiobiology of alpha particles. III. Cell inactivation by alpha-particle traversals of the cell nucleus., Radiat Res. source

      Not checked in the free run.

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

    Premisecitation

    The use of two photopeaks at 218 keV and 440 keV has long been suggested for clinical imaging of alpha-particles.

    “The use of two photopeaks at 218 keV and 440 keV has long been suggested for clinical imaging of α-particles (106)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [106] Ackerman, 2012, The potential for Cerenkov luminescence imaging of alpha-emitting radionuclides., Phys Med Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Medium-energy proton irradiation of 226Ra in a cyclotron using the reaction 226Ra(p,2n)225Ac offers advantages over natTh spallation and is currently the most promising method of large-scale and cost-effective production of 225Ac.

    “Medium-energy proton irradiation of 226Ra in a cyclotron using the reaction 226Ra(p,2n)225Ac offers a number of advantages over the natTh spallation, and is currently the most promising method of large-scale and cost-effective production of 225Ac.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Macropa, crown, and py4pa are new chelators with improved radiochemical yield and specific activity, as well as achievable labeling conditions.

    “Macropa, crown, and py4pa are new chelators with improved radiochemical yield and specific activity, as well as achievable labeling conditions.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [118] Yang, 2022, Harnessing α-emitting radionuclides for therapy: radiolabeling method review., J Nucl Med. source

      Not checked in the free run.

    • cites [119] Yang, 2020, Synthesis and evaluation of a macrocyclic Actinium-225 Chelator, Quality Control and In Vivo Evaluation of (225) Ac-crown-αMSH Peptide., Chemistry. source

      Not checked in the free run.

    • cites [120] Thiele, 2017, An Eighteen-Membered Macrocyclic Ligand for Actinium-225 Targeted Alpha Therapy., Angew Chem Int Ed Engl. source

      Not checked in the free run.

    • cites [121] Li, 2021, (225)Ac-H(4)py4pa for Targeted Alpha Therapy., Bioconjug Chem. source

      Not checked in the free run.

    • cites [122] Pretze, 2021, Ac-EAZY! Towards GMP-Compliant Module Syntheses of 225Ac-Labeled Peptides for Clinical Application., Pharmaceuticals. source

      Not checked in the free run.

    • Rests on an assumption: DOTA has decreased thermodynamic stability when used with larger metal ions.

  • May combine two claims.

    Premisecitation

    Fr-221 has a line at 218 keV and Bi-213 at 440 keV.

    “Fr-221 has a line at 218 keV and Bi-213 at 440 keV (122, 124).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [122] Pretze, 2021, Ac-EAZY! Towards GMP-Compliant Module Syntheses of 225Ac-Labeled Peptides for Clinical Application., Pharmaceuticals. source

      Not checked in the free run.

    • cites [124] Thakral, 2021, In-House Preparation and Quality Control of Ac-225 Prostate-Specific Membrane Antigen-617 for the Targeted Alpha Therapy of Castration-Resistant Prostate Carcinoma., Ind J Nucl Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    None of the new chelators has been investigated enough to confirm in vivo stability, and their potential to translate into clinical application is yet to be assessed.

    “However, none of the new chelators was investigated enough so far to confirm in vivo stability, and their potential to translate into clinical application is yet to be assessed (118–122).”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [118] Yang, 2022, Harnessing α-emitting radionuclides for therapy: radiolabeling method review., J Nucl Med. source

      Not checked in the free run.

    • cites [119] Yang, 2020, Synthesis and evaluation of a macrocyclic Actinium-225 Chelator, Quality Control and In Vivo Evaluation of (225) Ac-crown-αMSH Peptide., Chemistry. source

      Not checked in the free run.

    • cites [120] Thiele, 2017, An Eighteen-Membered Macrocyclic Ligand for Actinium-225 Targeted Alpha Therapy., Angew Chem Int Ed Engl. source

      Not checked in the free run.

    • cites [121] Li, 2021, (225)Ac-H(4)py4pa for Targeted Alpha Therapy., Bioconjug Chem. source

      Not checked in the free run.

    • cites [122] Pretze, 2021, Ac-EAZY! Towards GMP-Compliant Module Syntheses of 225Ac-Labeled Peptides for Clinical Application., Pharmaceuticals. source

      Not checked in the free run.

    • Rests on an assumption: DOTA has decreased thermodynamic stability when used with larger metal ions.

  • May combine two claims.

    Premisereasoning

    Unbound α-emitting daughter nuclides are redistributed in vivo, causing substantial harm to normal tissue and reducing the therapeutic effect.

    “Subsequently, the unbound α-emitting daughter nuclides are redistributed in vivo causing substantial harm to normal tissue and reducing the therapeutic effect.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The Institute of Physics and Power Engineering in Russia reported an estimated production of 22 GBq 225Ac annually, with no direct clinical application reported yet.

    “while the Institute of Physics and Power Engineering (IPPE) in Russia reported an estimated production of 22 GBq annually (92) with no direct clinical application reported yet to our knowledge.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [92] Samsonov, 2017, Isolation of alpha-emitting radionuclides for nuclear medicine in JSC “SSC RF–IPPE”., Proceedings of the 10th International Symposium on Targeted Alpha Therapy.

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    At the current level of supply, 225Ac-based treatments will continue to be available for only some few hundred patients per year, which is insufficient to meet the growing demand.

    “At this level of supply, 225Ac-based treatments will continue to only be available for some few 100 patients per year, which obviously is insufficient to meet the growing demand of 225Ac labeled compounds in hospitals worldwide (81, 93).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [81] Morgenstern, 2020, Supply and clinical application of Actinium-225 and Bismuth-213., Semin Nucl Med. source

      Not checked in the free run.

    • cites [93] Morgenstern, 2018, An overview of targeted alpha therapy with 225Actinium and 213Bismuth., Curr Radiopharm. source

      Not checked in the free run.

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

    Premisecitation

    Imaging using the additional 78 keV photopeak was suggested to yield higher counts, better images, and more lesion delineations.

    “Although imaging using the additional 78 keV photopeak was suggested to yield higher counts, better images, and more lesion delineations”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [107] Rasheed, 2019, Alpha Therapy with 225Actinium Labeled Prostate Specific Membrane Antigen: Reporting New Photopeak of 78 Kilo-electron Volts for Better Image Statistics., Indian J Nucl Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The recoil effect associated with α-decay of 225Ac imparts an energy thousands of times greater than the binding energy of any chemical bond, resulting in an inevitable release of the daughter nuclide from the chelate moiety.

    “The recoil effect associated with α-decay of 225Ac imparts an energy that is thousands of times greater than the binding energy of any chemical bond (75), resulting in an inevitable release of the daughter nuclide from the chelate moiety.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [75] de Kruijff, 2015, Critical review of alpha radionuclide therapy-how to deal with recoiling daughters?, Pharmaceuticals. source

      Not checked in the free run.

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

    Premisereasoning

    Supply limitations bring about a high cost that is considered unaffordable by many researchers.

    “Unfortunately, but understandably, these supply limitations bring about a high cost that is considered unaffordable by many researchers.”
    Quote in the paperNot a substantial claim

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

    Premisereasoning

    Standardized quality control of radiopharmaceuticals remains a problem in routine clinical production.

    “In addition to complicated handling, standardized quality control of radiopharmaceuticals remains a problem in routine clinical production.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Bi-213, with a half-life of 45.6 min, takes hours to reach equilibrium.

    “In contrast, Bi-213, with a half-life of 45.6 min, takes hours to reach equilibrium.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Radiolabeled SSTR antagonists may perform better than agonists despite the lack of receptor-mediated internalization.

    “In 2006, Ginj et al. presented the idea that radiolabeled SSTR antagonists may perform better than agonists despite the lack of receptor-mediated internalization (127).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [127] Ginj, 2006, Radiolabeled somatostatin receptor antagonists are preferable to agonists for in vivo peptide receptor targeting of tumors., Proc Natl Acad Sci U.S.A. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Despite its lack of internalization, SSTR antagonist demonstrated higher tumor uptake with a higher tumor-to-normal ratio and longer tumor retention time than agonist, possibly due to its capability to bind a larger variety of receptor conformations.

    “Despite its lack of internalization, SSTR antagonist demonstrated higher tumor uptake with a higher tumor-to-normal ratio and longer tumor retention time than that of agonist, possibly due to its capability to bind larger variety of receptor conformations, than that of SSTR agonists (130).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [130] Baum, 2021, First-in-Humans Study of the SSTR Antagonist 177Lu-DOTA-LM3 for Peptide Receptor Radionuclide Therapy in Patients with Metastatic Neuroendocrine Neoplasms: Dosimetry, Safety, and Efficacy., J Nucl Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    177Lu-DOTA-LM3 was reported to have a 3-5.1 times higher absorbed doses and a 22 h longer whole-body effective half-life than the agonist 177Lu-DOTATOC.

    “177Lu-DOTA-LM3 was reported to have a 3–5.1 times higher absorbed doses and a 22 h longer whole-body effective half-life than the agonist 177Lu-DOTATOC.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [130] Baum, 2021, First-in-Humans Study of the SSTR Antagonist 177Lu-DOTA-LM3 for Peptide Receptor Radionuclide Therapy in Patients with Metastatic Neuroendocrine Neoplasms: Dosimetry, Safety, and Efficacy., J Nucl Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A phase I study with 20 grade 1-3 patients reported a best overall response of 45% (RECIST 1.1 criteria) and a median progression-free survival of 21 months (95% CI: 13.6-not reported).

    “A phase I study with 20 grade 1–3 patients reported a best overall response of 45% (RECIST 1.1 criteria) and a median progression-free survival of 21 months (95% CI: 13.6-not reported).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [138] Reidy-Lagunes, 2019, Phase I Trial of Well-Differentiated Neuroendocrine Tumors (NETs) with Radiolabeled Somatostatin Antagonist 177Lu-Satoreotide Tetraxetan., Clin Cancer Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 20 patients with adequate follow-up, no grade 3/4 renal toxicities and a 90% (95% CI: 68.3-98.8%) disease control rate was reported.

    “In 20 patients with adequate follow-up, no grade 3/4 renal toxicities and a 90% (95% CI: 68.3–98.8%) disease control rate was reported (139).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [139] Nicolas, 2020, 1160O An international open-label study on safety and efficacy of 177Lu-satoreotide tetraxetan in somatostatin receptor positive neuroendocrine tumours (NETs): An interim analysis., Ann Oncol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SSTR2-selective 111In-DOTA-BASS and SSTR3-selective ODN-8, the first generation of radiolabeled SSTR antagonists, all recognized a larger number of binding sites and revealed an in general twofold higher uptake level in vitro than their agonist counterparts.

    “SSTR2-selective 111In-DOTA-BASS (125) and SSTR3-selective ODN-8 (126, 127), the first generation of radiolabeled SSTR antagonists all recognized a larger number of binding sites and revealed an in general twofold higher uptake level in vitro than their agonist counterparts (128).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [128] Wang, 2012, Comprehensive evaluation of a somatostatin-based radiolabelled antagonist for diagnostic imaging and radionuclide therapy., Eur J Nucl Med Mol Imaging. source

      Not checked in the free run.

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

    Premisenone given

    To this date, confirmed literature on PRRT using an α-emitter with a SSTR antagonist has yet to be published.

    “To this date, confirmed literature on PRRT using an α-emitter with a SSTR antagonist has yet to be published, and obviously, there are still many hurdles to overcome.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Among all potential SSTR2 antagonists, LM3 and JR11 were the most interesting, having the highest hydrophilicity and best affinity.

    “Among all the potential SSTR2 antagonists, LM3 and JR11 were the most interesting, having the highest hydrophilicity and best affinity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    All patients tolerated therapy well without any serious acute adverse effects, in particular, there was no nephrotoxicity observed.

    “All patients tolerated therapy well without any serious acute adverse effects, in particular, there was no nephrotoxicity observed (130).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [130] Baum, 2021, First-in-Humans Study of the SSTR Antagonist 177Lu-DOTA-LM3 for Peptide Receptor Radionuclide Therapy in Patients with Metastatic Neuroendocrine Neoplasms: Dosimetry, Safety, and Efficacy., J Nucl Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NET expression of SSTR subtypes is heterogeneous, and contradictory expression profiles due to different detection methods make it more difficult.

    “However, NET expression of SSTR subtypes is heterogeneous, and things are made even more difficult by contradictory expression profiles due to different detection methods (20, 143–153).”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [20] Reubi, 2003, Concomitant expression of several peptide receptors in neuroendocrine tumours: molecular basis for in vivo multireceptor tumour targeting., Eur J Nucl Med Mol Imaging. source

      Not checked in the free run.

    • cites [143] Papotti, 2002, Expression of somatostatin receptor types 1-5 in 81 cases of gastrointestinal and pancreatic endocrine tumors. a correlative immunohistochemical and reverse-transcriptase polymerase chain reaction analysis., Virchows Arch. source

      Not checked in the free run.

    • cites [144] Kulaksiz, 2002, Identification of somatostatin receptor subtypes 1, 2A, 3, and 5 in neuroendocrine tumours with subtype specific antibodies., Gut. source

      Not checked in the free run.

    • cites [145] Jaïs, 1997, Somatostatin receptor subtype gene expression in human endocrine gastroentero-pancreatic tumours., Eur J Clin Invest. source

      Not checked in the free run.

    • cites [146] Hu, 2021, Role of somatostatin receptor in pancreatic neuroendocrine tumor development, diagnosis, and therapy., Front Endocrinol. source

      Not checked in the free run.

    • cites [147] Wängberg, 1997, Somatostatin receptors in the diagnosis and therapy of neuroendocrine tumor., Oncologist. source

      Not checked in the free run.

    • cites [148] Remes, 2019, Immunohistochemical expression of somatostatin receptor subtypes in a panel of neuroendocrine neoplasias., J Histochem Cytochem. source

      Not checked in the free run.

    • cites [149] Jonas, 1995, Somatostatin receptor subtypes in neuroendocrine tumor cell lines and tumor tissues., Langenbecks Arch Chir. source

      Not checked in the free run.

    • cites [150] Lambertini, 2013, Evaluation of somatostatin receptor subtype expression in human neuroendocrine tumors using two sets of new monoclonal antibodies., Regul Pept. source

      Not checked in the free run.

    • cites [151] Lou, 2022, Differential expression of somatostatin receptor (SSTR) subtypes across a spectrum of neuroendocrine neoplasms (NENs)., J Clin Oncol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the same four patients with grade 1-3 metastatic NET, 177Lu-DOTA-JR11 showed a 1.7-10.6 times higher tumor dose, and at the same time a 1.1-7.2 times higher tumor-to-kidney and tumor-to-bone marrow ratio, compared with 177Lu-DOTATATE.

    “In the same four patients with grade 1–3 metastatic NET, it showed a 1.7–10.6 times higher tumor dose, and at the same time a 1.1–7.2 times higher tumor-to-kidney and tumor-to-bone marrow ratio, compared with 177Lu-DOTATATE (136, 137).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [136] Wild, 2014, Comparison of somatostatin receptor agonist and antagonist for peptide receptor radionuclide therapy: a pilot study., J Nucl Med. source

      Not checked in the free run.

    • cites [137] Fani, 2022, Radiolabeled somatostatin analogs-a continuously evolving class of radiopharmaceuticals., Cancers. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Measurement with radio-TLC is not a valid method to determine the yield and purity of a radiopharmaceutical, and additional radio-HPLC methods are required.

    “However, the measurement with radio-TLC is not a valid method to determine the yield and purity of a radiopharmaceutical and additional radio-HPLC methods are required.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Antagonists recognize more binding sites than agonists, providing more targeting opportunities.

    “Moreover, antagonists recognize more binding sites than agonists, providing more targeting opportunities (140).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [140] Mansi, 2021, Distinct In Vitro Binding Profile of the Somatostatin Receptor Subtype 2 Antagonist [177Lu]Lu-OPS201 Compared to the Agonist [177Lu]Lu-DOTA-TATE., Pharmaceuticals. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The antagonist showed faster association, but slower dissociation, as well as longer cellular retention time compared to the agonist.

    “The antagonist showed faster association, but slower dissociation, as well as longer cellular retention time compared to the agonist.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [140] Mansi, 2021, Distinct In Vitro Binding Profile of the Somatostatin Receptor Subtype 2 Antagonist [177Lu]Lu-OPS201 Compared to the Agonist [177Lu]Lu-DOTA-TATE., Pharmaceuticals. source

      Not checked in the free run.

63 of 63

  • The paper relies on this without support.

    DOTA has decreased thermodynamic stability when used with larger metal ions.

    “However, DOTA has a decreased thermodynamic stability when used with larger metal ions.”

  • The paper relies on this without support.

    Downregulation or loss of SSTR2 in advanced stages is associated with worse disease prognosis, compromised image sensitivity, and suboptimal therapy with SSTR2-specific radiolabeled SSAs.

    “Also, the downregulation or loss of SSTR2 in advanced stages is inherently associated with worse disease prognosis, compromised image sensitivity, and suboptimal therapy with SSTR2-specific radiolabeled SSAs.”

  • The paper relies on this without support.

    The shorter range of α-emitters causes less damage to surrounding healthy tissue and more powerful damage to tumor cells.

    “The shorter range gives “precision” in precision medicine a new meaning: Even less damage to surrounding healthy tissue and even more powerful damage to tumor cells.”
3 of 3

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?

  • PRRT interacts with diverse somatostatin receptor subtypes, demonstrating versatility in addressing various NET manifestations.

    “PRRT’s ability to interact with diverse somatostatin receptor subtypes adds complexity, demonstrating its versatility in addressing various NET manifestations [104].”

    From Radiopharmaceuticals: navigating the frontier of precision medicine and therapeutic innovation (2024) · cites this paper as [104]

    The Introduction (page unavailable) says NETs express various somatostatin receptor subtypes and that PRRT targets receptor-expressing tissue. But the “Cocktail approach” section (page unavailable) says existing PRRT has depended substantially on SSTR2; targeting multiple subtypes to address heterogeneous NETs is a proposed approach, not a demonstrated versatility of current PRRT. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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.

  • Table 1 conflicts with the stated imaging and therapy uses

    Minor

    The text says every radionuclide in Table 1 other than 68Ga is used for both therapy and SPECT imaging, but the table lists 111In only for imaging and 90Y only for therapy.

  • A poorly differentiated tumor is called a NET despite the paper's definition

    Minor

    The introduction defines NETs as well-differentiated neoplasms, whereas the Figure 6 caption calls the patient's poorly differentiated tumor a pancreatic-NET.

2 of 2

Cites

Flagged first, then by citations

5 of the 174 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. Kratochwil, 2015, Ac-225-DOTATOC - an empiric dose finding for alpha particle emitter based radionuclide therapy of neuroendocrine tumors., J Nucl Med., 56, 1232
  2. Samsonov, 2017, Isolation of alpha-emitting radionuclides for nuclear medicine in JSC “SSC RF–IPPE”., Proceedings of the 10th International Symposium on Targeted Alpha Therapy.

Cited by

Sorted by citations

Related

Authors
Shi, M., Jakobsson, V., Greifenstein, L., Khong, P.-L., Chen, X., Baum, R. P., & Zhang, J.
Affiliations
  • National University of Singapore (SG)
  • Agency for Science, Technology and Research (SG)
Corresponding author
Zhang, Jingjing
ORCID
Venue
Frontiers in Medicine
Publisher
Frontiers Media SA
Published
2022-12-07
Volume
9
Pages
1034315-1034315
ISSN
2296-858X (ISSN-L)
DOI
10.3389/fmed.2022.1034315
PMC
PMC9767967
OpenAlex
W4311702746
Semantic Scholar
275876a05df8b17d6529199533091bb62bb690a5
Cited by
68
References
174
Citations by year
2026: 14 · 2025: 24 · 2024: 21 · 2023: 9
FWCI
2.29
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
National University of Singapore (NUHSRO/2021/097/Startup/13, NUHSRO/ 2020/133/Startup/08)
Topics
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Radiopharmaceutical Chemistry and Applications
  • Health Sciences › Medicine › Epidemiology › Neuroendocrine Tumor Research Advances
  • Health Sciences › Medicine › Oncology › Peptidase Inhibition and Analysis
Keywords
actinium-225, peptide receptor radionuclide therapy, somatostatin receptors, somatostatin receptor agonists, somatostatin receptor antagonists, targeted alpha therapy, neuroendocrine tumors, radiopharmaceuticals, alpha therapy, linear energy transfer

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 2026-10-10.

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

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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