tbuckley/cabot-search huggingface dataset:
Is CTLA4 targeting the Achilles’ heel of Merkel cell carcinoma?
Authors: Richard Cheng Han Wu, Kari Lynn Kendra, Dukagjin Blakaj, Hiral A. Shah, Joanne M. Jeter, Claire F. Verschraegen
Journal: Journal of Clinical Oncology (2021)

e21567 Background: Merkel Cell Carcinoma (MCC) is a cutaneous malignancy with neuroendocrine differentiation, linked to infection with polyomavirus (MCPyV) in 80% of cases. PD1 inhibitors have recently been approved for this indication with ORR, 33-56%; CR, 11-24%; PFS, about 17 months; OS, about 12 months. Nivolumab was tested in the neoadjuvant setting with similar responses with pathological CR, 47%. Methods: Adjuvant pilot study (NCT03798639) with two immunotherapy regimens administered for one year to patients with completely resected MCC at high risk of recurrence (primary lesion of 2 cm or greater, positive or close margins ( &lt; 2 cm), perineural or lymphovascular invasion, mitotic index ≥ 20 mitotic figures per mm 2 , lymph node involvement (stage pIIIA or pIIIB) with or without extracapsular extension, or completely resected stage IV disease). Arm 1, nivolumab 480 mg q 4 wks and radiation therapy (RT) 50-60 Gy in 25-30 fractions, per standard of care. Arm 2, nivolumab 240 mg q 2 wks and ipilimumab 1 mg/kg q 6 wks. Primary objective was feasibility and completion of treatment in this population. Safety profile (CTCAE v5.0) and recurrence-free survival (RFS) after 18 months were secondary endpoints. Patients were randomly allocated 1:1. Results: Ten patients were screened from January 2019 until April 2020, when COVID put the study on hold and the sponsor discontinued the free drug supply. Seven were enrolled. Four were allocated to Arm 1 and three to Arm 2. Patient characteristics in Table. All patients have completed treatment and are in follow-up. Arm 1: all four patients completed radiation therapy and immunotherapy with no dose modifications or delays. Arm 2: one patient had nivolumab delayed 2 weeks for cellulitis, and another missed the last four last doses of nivolumab for cholecystitis and pancreatitis requiring surgery, unrelated to the immunotherapy. Adverse events (AE) were as expected. Arm1 caused more grade 2 and 3 AEs then Arm2 (no grade 3). One patient each discontinued treatment, in Arm 1 for progression and Arm 2 for immunotoxicity (temporal arteritis grade 2). One recurrence was observed in Arm 1 and none in Arm 2. Conclusions: The number of patients expected to recur at 1 year is 20%. Our observed data is insufficient to establish efficacy. However with no patient recurring in the ipilimumab arm after 18 months of follow-up and lower observed side effects, we would favor this regimen for the next trial. Clinical trial information: NCT03798639. [Table: see text]
Optimising the Heart Failure Treatment Pathway: The Role of SGLT2 Inhibitors
Authors: Marc Evans, Angharad R. Morgan, Zaheer Yousef, Gethin Ellis, Umesh Dashora, Dipesh C. Patel, Pam Brown, Wasim Hanif, Johnathan N. Townend, Naresh Kanumilli, Jim Moore, John P. H. Wilding, Stephen C. Bain
Journal: Drugs (2021)
A conversation with Jesse Roth, Ron Kahn, and Jeff Flier
Authors: Ushma S. Neill
Journal: Journal of Clinical Investigation (2021)

as part of the JCI's salute to the 100th anniversary of the discovery of insulin.Roth, Kahn, and Flier (Figure 1) all played instrumental roles in the discovery and description of the insulin receptor and in elucidating the critical role it plays in diabetes.See the JCI website (https://www.jci.org/videos/cgms) for the full interview with their full anecdotes and to get a glimpse of their extraordinary camaraderie.JCI: Jesse, can you set the stage for us with what the scientific world thought about metabolic signaling and membrane-bound receptors in the 60s?Roth: The story starts on July 1st, 1963, when I showed up at the NIH.I had spent the previous two years in New York with Rosalyn Yalow and Solomon Berson, working on growth hormone.I was challenged to move on to something else, so my friend Ira Pastan and I decided to develop a method to measure the first step by which hormones like insulin interact with cells to bring about their actions.In fact, in those days, most people thought that insulin immediately went into the cells, found enzymes that it could bind to, and became coenzymes.We started to label insulin with radioactive iodine, but initial efforts didn't work well.It would bind to too many things, so we had to develop a way to make insulin that was very gently labeled so it would retain biological activity.We labeled only a small fraction of the insulin, and instead of breaking up tissues, if you worked with whole cells, that worked well.In fact, if you started out with the popular insulin-sensitive tissues, like fat or muscle or liver, it didn't work so well.But if you went to blood
Long-term follow-up of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in advanced squamous cell carcinoma of the head and neck (SCCHN).
Authors: Byoung Chul Cho, Amaury Daste, Alain Ravaud, Sébastien Salas, Nicolas Isambert, Edward Francis McClay, Ahmad Awada, Christian Borel, Christoph Helwig, P. Alexander Rolfe, Laureen S. Ojalvo, James L. Gulley, Nicolas Penel
Journal: Journal of Clinical Oncology (2021)

6020 Background: Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β “trap”) fused to a human IgG1 mAb blocking PD-L1. A previous report of an expansion cohort from a phase 1 study (NCT02517398) suggested that bintrafusp alfa had a manageable safety profile and early signs of clinical activity in patients with heavily pretreated, advanced SCCHN after a median follow-up of 86.4 weeks. Here we report long-term efficacy and safety for this cohort. Methods: Patients with advanced SCCHN that progressed/recurred after platinum therapy in the recurrent/metastatic setting, or &lt; 6 months after platinum therapy in the locally advanced setting, received bintrafusp alfa 1200 mg every 2 weeks until confirmed progressive disease, unacceptable toxicity, or trial withdrawal. The primary endpoint was confirmed best overall response assessed per RECIST 1.1 assessed by independent review committee (IRC); safety was a secondary endpoint. Results: As of May 15, 2020, 32 patients had received bintrafusp alfa for a median of 2.8 months (range, 0.5-29.9 months), no patient remained on treatment, and median follow-up to data cutoff was 41.7 months (range, 39.8-43.5 months). The objective response rate (ORR; 13%) was unchanged since the previous report; median duration of response (DOR) was increased at 21.4 months (95% CI, 5.5 months to not reached [NR]). While the clinical activity of bintrafusp alfa may be improved in patients with HPV-positive tumors (Table), outcomes were generally similar between PD-L1 subgroups (≥1% vs &lt; 1% tumor cells). The overall safety profile was consistent with the previous report for this cohort, without grade 4 nor 5 treatment-related adverse events (TRAEs); no new TRAEs of grade 3 or that led to discontinuation of bintrafusp alfa were reported. Conclusions: With a median follow-up of over 3 years in patients with heavily pretreated advanced SCCHN, bintrafusp alfa showed sustained clinical activity and 3-year OS of 24.0%, which compares favorably to historical data. Clinical activity appeared to be greater in patients with HPV-positive tumors than those with HPV-negative tumors. The safety profile was manageable and consistent with earlier analysis. Further investigation of bintrafusp alfa in SCCHN and other HPV-associated cancers is ongoing. Clinical trial information: NCT02517398. [Table: see text]
Phase 1b dose escalation study to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of GS-3583, a FLT3 agonist Fc fusion protein, in patients with advanced solid tumors.
Authors: Joshua Brody, John A. Thompson, Anthony W. Tolcher, Michelle R. Kuhne, Xi (Rochelle) Huang, Ellen Kwan, Michael Petrarca, Anees Dauki, Indrajeet Singh, Nishanthan Rajakumaraswamy, Shivaani Kummar
Journal: Journal of Clinical Oncology (2021)

TPS3147 Background: Productive antitumor immune responses in nonclinical models depend on a type of dendritic cell (DC), conventional DC subtype 1 (cDC1), which in the context of cancer, primes tumor-reactive T cells through presentation of tumor-derived antigens. FMS-related tyrosine kinase 3 ligand (FLT3L) is a hematopoietic growth factor that binds to and activates FLT3 on terminally differentiated DCs. Activated FLT3 promotes proliferation, inhibits cell death, and is required for the differentiation, expansion, and maintenance of DCs in peripheral and lymphoid organs. GS-3583 is a fusion protein composed of the extracellular domain of recombinant human FLT3L fused to an engineered fragment crystallizable (Fc) region of human immunoglobulin G4. GS-3583 has PK properties that support sustained cDC in patients and potential combination with established immunotherapies. This phase 1b, open-label, multicenter, dose-finding study will evaluate safety, tolerability, PK, and preliminary efficacy of GS-3583 monotherapy in patients with advanced solid tumors (NCT04747470). Methods: Approximately 33 adults aged ≥18 years with a histologically or cytologically confirmed locally advanced or metastatic malignant solid tumor that is refractory to or intolerant of standard therapy or for which no standard therapy is available will be enrolled. The study employs a 3+3 dose escalation design in which GS-3583 is administered intravenously for up to 52 weeks or until progressive disease or unacceptable toxicity. Up to five dose escalation cohorts have been planned. The maximum tolerated dose is the highest dose with incidence of DLT in &lt; 33% of 6 or more patients in the first 28 days of GS-3583 dosing; recommended phase 2 dose will be determined. Assessments include safety, PK, pharmacodynamics including cDCs, immunogenicity, and efficacy by RECIST 1.1 in CT/MRI imaging conducted every 8 weeks. Accrual at approximately 3-4 centers in the US is ongoing. Clinical trial information: NCT04747470.
A small molecule LN435a targeting TGF<b>β</b>R1 exerts promising antitumor effects on breast cancer.
Authors: Yuzhu Zhang, Huachao Li, Hongyan Zhang, Xiaoyuan Liu, Tianyu Luo, Huan Lin, Rui Xu, Liping Ren, Dongmei Li, Yihua Chen, Qianjun Chen, Luqi Huang
Journal: Journal of Clinical Oncology (2021)

e15069 Background: Breast cancer has overtaken lung cancer as the most diagnosed cancer. Despite conventional treatment, metastases occur in 20-30% of patients, resulting in death. This study aims to screen of effective drugs by metastatic patient-derived organoid and the potential molecular mechanism. Methods: Breast Cancer patient-derived organoid (PDO) model was established from the patient who have multiple drug resistance, multiple visceral and contralateral breast metastases. The organoid morphologies was tested by hematoxylin-eosin (HE) staining and immunohistochemistry (IHC). Then, pharmacological activity assay of 2370 natural product monomer (from Selleck) was performed with organoids. we modified the structure of harmine(HM) and screened the best active drugs. Cell proliferation assay and wound healing assay were used to detect LN435a anticancer activity in vitro. Orthotopic, Metastatic Xenograft and Patient-Derived tumor Xenograft(PDX) model of Breast Cancer were used to detect LN435a anticancer activity in vivo. In order to explore the anti-cancer target of LN435a, we used RNA transcriptome and proteomics sequencing. To further validate anti-cancer targets,TGFβ receptor 1 (TGFβR1), we used real-time quantitative qPCR, western blot, lentiviral packing and biolayer interferometry assay. To investigate whether LN435a inhabition of EMT and stem cell markers, we performed flow cytometry, immunohistochemistry and fluorescence. Results: We observe that organoid morphologies typically matched the histopathology, hormone receptor status, and HER2 status of the original tumor. In the first anti-cancer drug screening, HM showes the best effect on PDO. Because HM contains β-carbine alkaloids as the structural units, we designe a series of active drugs based on this and did anticancer screening. We find LN435a as one of the lead compounds exerting anti-metastatic activity in the nanomolar range in PDO and breast cancer cells. Proteomic and biochemical studies identify TGFβR1 as the direct target of LN435a. And then it inhibits EMT and stem cell markers. In parallel, loss of TGFβR1 or pharmacological inhibition of TGFβR1 by LN435a reduces breast cancer extravasation into the lung in an experimental metastasis mouse model, which reveals an essential role of TGFβR1 in breast cancer progression. Conclusions: Altogether, LN435a is a novel inhibitor of promising anti-tumor effects on breast cancer that works by blocking TGFβ signaling pathways.
FMD and SCAD: Sex-Biased Arterial Diseases With Clinical and Genetic Pleiotropy
Authors: Esther S.H. Kim, Jacqueline Saw, Daniella Kadian-Dodov, Malissa Wood, Santhi K. Ganesh
Journal: Circulation Research (2021)

Multifocal fibromuscular dysplasia (FMD) and spontaneous coronary artery dissection are both sex-biased diseases disproportionately affecting women over men in a 9:1 ratio. Traditionally known in the context of renovascular hypertension, recent advances in knowledge about FMD have demonstrated that FMD is a systemic arteriopathy presenting as arterial stenosis, aneurysm, and dissection in virtually any arterial bed. FMD is also characterized by major cardiovascular presentations including hypertension, stroke, and myocardial infarction. Similar to FMD, spontaneous coronary artery dissection is associated with a high prevalence of extracoronary vascular abnormalities, including FMD, aneurysm, and extracoronary dissection, and recent studies have also found genetic associations between the two diseases. This review will summarize the relationship between FMD and spontaneous coronary artery dissection with a focus on common clinical associations, histopathologic mechanisms, genetic susceptibilities, and the biology of these diseases. The current status of disease models and critical future research directions will also be addressed.
Therapeutic liver repopulation by transient acetaminophen selection of gene-modified hepatocytes
Authors: Anne Vonada, Amita Tiyaboonchai, Sean Nygaard, Jeffrey Posey, Alexander Mack Peters, Shelley R. Winn, Alessio Cantore, Luigi Naldini, Cary O. Harding, Markus Grompe
Journal: Science Translational Medicine (2021)

Acetaminophen treatment can be used to increase transgene expression for liver gene therapy into the therapeutic range in mice.
Analysis of two poor prognosis subgroups in ACIS evaluating apalutamide + abiraterone acetate plus prednisone (APA + AAP) versus placebo (PBO) + AAP in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Fred Saad, Eleni Efstathiou, Gerhardt Attard, Thomas W. Flaig, Fabio Franke, Oscar Goodman, Stephane Oudard, Thomas Steuber, Hiroyoshi Suzuki, Christopher Michael Pieczonka, Francis Parnis, Daphne Wu, Kesav Yeruva, Peter De Porre, Sabine Doris Brookman-May, Susan Li, Jinhui Li, Suneel Mundle, Sharon Anne McCarthy, Dana E. Rathkopf
Journal: Journal of Clinical Oncology (2021)

5037 Background: In the double-blind PBO-controlled ACIS study, investigator-assessed radiographic progression-free survival (rPFS) was significantly improved with APA + AAP vs PBO + AAP in chemo-naive mCRPC, with no significant new safety signals (Rathkopf ASCO GU 2021). Among prespecified subgroups, efficacy and safety were explored in two difficult to treat subgroups: pts with visceral disease (VD; liver, lung, and/or adrenal gland metastasis) or age ≥ 75 y. Methods: Pts with mCRPC with ongoing ADT and no prior life-prolonging treatment were randomized 1:1 to APA (240 mg QD) + AA (1000 mg QD) + P (5 mg BID) or PBO + AAP. Stratified: presence or absence of VD, ECOG PS 0 or 1, geographic region. Primary end point: rPFS (randomization to radiographic progression or death); secondary end points: overall survival (OS), time to initiation of cytotoxic chemotherapy, time to chronic opioid use, time to pain progression, safety. Results: 982 pts enrolled. 14.6% had VD and 35.9% were ≥ 75 y. Median rPFS, OS, and time to pain progression favored APA + AAP vs AAP (HR &lt; 1) in both subgroups (Table). For pts ≥ 75 y, rPFS and OS were ≥ 7 mo longer with APA + AAP. Overall, treatment-emergent adverse events (TEAEs) were similar (all &gt; 94%) in pts with VD, ≥ 75 y, and overall safety population; hypertension was more frequent with APA + AAP vs AAP mainly in pts ≥ 75 y (31.7% vs 17.6%). Grade 3/4 TEAEs (APA + AAP vs AAP): VD, 60.8%, n = 74 vs 48.5%, n = 68; ≥ 75 y, 71.5%, n = 186 vs 68.5%, n = 165; overall, 63.3%, n = 490 vs 56.2%, n = 489. TEAEs leading to discontinuation: VD, 17.6% vs 5.9%; ≥ 75 y, 26.3% vs 20.6%; overall, 16.9% vs 12.5%. TEAEs leading to death: VD, 6.8% vs 5.9%; ≥ 75 y, 5.4% vs 13.9%; overall, 3.5% vs 7.6%. Conclusions: In this analysis of two difficult to treat subgroups, addition of APA to AAP favored rPFS and OS. Safety, while generally consistent with the overall population, showed higher hypertension rate in ≥ 75 y and TEAEs leading to discontinuation in VD. Clinical trial information: NCT02257736. [Table: see text]
Cutaneous Langerhans cell histiocytosis in adults: A retrospective cohort study of adult patients presenting to a single academic cancer center between 2003 and 2017
Authors: Ai-Tram N. Bui, Cecilia Larocca, Anita Giobbie-Hurder, Eric D. Jacobsen, Nicole R. LeBoeuf
Journal: Journal of the American Academy of Dermatology (2021)
Determination of endocrine sensitivity by response of the proliferative marker KI67 after short-term preoperative endocrine therapy and their correlation to oncotype score platform.
Authors: Serafin Morales Murillo, Ariadna Gasol Cud"S, Ester Morera Morillo, Carles Canosa Morales, Jordi Melé Olivé, Felipe Vilardell Villellas, Douglas René Sánchez Guzmán, Antonieta Salud Salvia
Journal: Journal of Clinical Oncology (2021)

e12609 Background: Endocrine sensitivity (ES) determined by response to the Ki67 index to short-term preoperative endocrine therapy (ET) is accepted but not included in adjuvant treatment decision. However, genomic platforms have been incorporated into decision guides. Therefore, it would be interesting to analyze the correlation between both tools to improve the determination of endocrine sensitivity. Methods: A prospective series of 129 patients with early N0/N1 ES breast cancer was analyzed and Oncotype Dx platform was performed. Clinicopathological variables, and changes in ki67 index less than 10% (ES) were correlated with Oncotype Dx Recurrence Score (RS). Results: Median age was of 58 (23-84), 32% were premenopausal, median tumor size was of 22mm (7-90), nodal involvement was of 31%, 20% were progesterone receptor negative and initial median ki67 index of 24% (5-70). RS distribution: 27% RS 0-11, 29% RS 11-18, 23% RS 18-25, 21% RS &gt; 26. All premenopausal patients received Tamoxifeno as preoperative ET and letrozole for postmenopausal. Globally, 62% of patients had ES with a decrease &lt; 10% of ki67 after preoperative ET: 24/41 in premenopausal and 56/87 in postmenopausal. In all series ES according to RS was distributed: 80% in RS &lt; 11, 61% RS 11-18, 55% RS 18-25 and 50% RS &gt; 26. In premenopausal patients, ES and RS distribution was: 75% RS &lt; 11, 62% RS 11-18, 57% RS 18-25 and 33% RS &gt; 26. In postmenopausal patients, ES and RS distribution was: 83% RS &lt; 11, 61% RS 11-18, 55% RS 18-25 and 58% RS &gt; 26. ES results were not conditioned by tumor size or nodal involvement. RS &gt; 26 was strongly associated with less ES with an OD of 4 (p = 0.014) and RS 18-25 with an OD of 3.25 (p = 0.037). The sensitivity and specificity for ES and RS &lt; 11, was of 80% and 44%, respectively. Conclusions: We have found an ES of 62% in the whole population with the following distribution according RS: 80% in RS &lt; 11, 61% RS 11-18, 55% RS 18-25 and 50% RS &gt; 26. Of note, in premenopausal patients, ES rate in RS &gt; 26 is only of 33%. Determination of ES by response of ki67 is feasible and correlates with data of genomic platforms. Both tools could help to predict ES in this setting.
Efficacy of an anti-EGFR after ctDNA conversion from mutated RAS status of metastatic colorectal cancer: Results of a pilot study.
Authors: Mohamed Bouchahda, Raphael Saffroy, Abdoulaye Karaboué, Jocelyne Hamelin, Pasquale Innominato, Faouzi Saliba, Francis Levi, Nelly Bosselut, Antoinette Lemoine
Journal: Journal of Clinical Oncology (2021)

e15574 Background: This pilot study aimed at the evaluation of the efficacy of anti-EGFR therapy in patients with initially RAS-mutated metastatic colorectal cancer, whose liquid biopsy found no RAS mutation after prior chemotherapy failure. Methods: Sixteen patients with RAS-mutated metastatic colorectal cancer in the solid tumor were included, after they had received 1 to 3 prior chemotherapy lines without anti-EGFR. Before inclusion, RAS genotyping was performed in circulating tumor DNA (ctDNA) from liquid biopsy, after a median duration of ̃24 months after the initial RAS status determination. No RAS mutation was detected in the circulating tumor DNA from 9 patients (56%), who then received cetuximab-FOLFIRI. The 7 patients who had persistent RAS mutation in the liquid biopsy (44%) were treated according to standard recommendations without anti-EGFR. Results: The median progression free survival was 8.2 months [95%CL, 4.5 – 11.8] in patients without detectable ctDNA RAS mutation, as compared to 3.5 months [2.1 – 4.9] in the ctDNA mutated patients (p &lt; 0.001). The median overall survival was 22.3 months [17.3 - 27.3] in the patients with undetectable ctDNA RAS mutation, whereas it was 4.7 months [2.6 - 6.7] in those with ctDNA RAS mutation (p = 0.013). These results suggested the efficacy of cetuximab-based chemotherapy in patients with initially RAS mutated metastatic colorectal cancer, who later displayed no detectable ctDNA RAS mutation. Conclusions: The introduction of an anti-EGFR could provide an additional treatment option for patients with metastatic colorectal cancer with apparent conversion of initial RAS mutation, based on ctDNA assessment after prior failure on anti-EGFR-free chemotherapy.