tbuckley/cabot-search huggingface dataset:
FORECAST-1: Feasibility of organoid response assessment to define effective treatments for patients with colorectal cancer after failure of standard therapy.
Authors: Grace Gard, Margaret Lee, Yumiko Hirokawa, Jeanne Tie, Jordan Clarke, Niall C. Tebbutt, Tao Tan, Azim Jalali, Dmitri Mouradov, Belinda Lee, Oliver Sieber, Peter Gibbs
Journal: Journal of Clinical Oncology (2021)

e15571 Background: Many patients with metastatic colorectal cancer (mCRC) that have failed standard first- and second-line therapies remain fit and eager for further treatment. Therapeutic options include two agents with proven but modest survival benefit, a clinical trial of an investigational agent, rechallenge with agents successfully used in earlier lines of treatment, or agents that have shown some activity in non-randomised phase II studies. Patient derived tumouroid (PDT) are self-organizing three-dimensional in vitro models cultured from a fresh tumour biopsy. They potentially represent a robust personalized model for real-time drug sensitivity testing to determine optimal anti-cancer therapies for individual patients. Methods: FORECAST-1 is an observational, non-randomized study to determine the feasibility of PDT based drug sensitivity screening for patients with mCRC that have failed at least two lines of therapy. Once established, PDTs undergo drug sensitivity screening including agents regorafenib, trifluridine/tipiracil (TAS102), oxaliplatin, irinotecan, 5-fluorouracil (5FU), erlotinib (a surrogate EGFR-inhibitor), gemcitabine, pemetrexed and temozolomide. Patients are treated at clinician discretion, with clinical response to be correlated with PDT response. Results: Since September 2020 we have enrolled 18 of a planned 30 patients, median age 55 years (range 44 – 81). 17 patients were ECOG 0-1. Four patients had received prior TAS102 treatment. Biopsies were obtained from liver (n = 6), soft tissue/peritoneal metastases (5), lung (2), lymph node (2), primary (1), brain (1) and bone (1). Drug sensitivity testing has been performed on seven PDTs at a median of 62 days from biopsy (range 42 – 128), one PDT culture has failed. A standardised reporting template has been developed. Treatments received by patients to date include TAS102 (n = 5), regorafenib (2), FOLFOX (3), FOLFIRI (1) FOLFIRI plus EGFR-inhibitor (1), capecitabine plus bevacizumab (1) and an immunotherapy-based clinical trial (1). Four patients did not receive further anti-cancer therapy post enrolment, and one patient is yet to commence further systemic therapy. Conclusions: Enrolment to this feasibility study has been rapid demonstrating this to be an area of clinical need. PDTs have been successfully established from a high proportion of patients, but with variable growth rates. Methods to accelerate PDT culture and drug testing are being pursued to increase the feasibility of a planned prospective study of PDT sensitivity informing patient management. Clinical trial information: ACTRN12620001353987.
ATRT-09. IDENTIFICATION OF POTENTIAL GENETIC DRIVERS OF METHOTREXATE (MTX) RESISTANCE IN ATYPICAL TERATOID RHABDOID TUMOURS (ATRT) THROUGH A GENOME-WIDE RNAI SCREEN
Authors: Sunand Kannappan, Mehul Gupa, SungMyung Kang, Andy Son Tran, Satbir Singh Thakur, Mohit Jain, Aru Narendran
Journal: Neuro-Oncology (2021)

Abstract ATRT of the CNS constitute a group of rare and aggressive early childhood tumors with poor prognosis. While there are differing chemotherapeutic regimens for ATRT, high-dose MTX is a crucial component of many therapeutic protocols. Currently, the biological mechanisms contributing to the generation of MTX resistance in ATRT are unknown. To identify genes involved in MTX resistance in ATRT, an unbiased genome-wide RNAi screen on ATRT cell lines was conducted using 24,000 distinct shRNAs covering 8,000 genes. ATRT cells were transfected with a retrovirus containing pRS-shRNA vectors and treated with puromycin for selection. The resulting cells were treated with MTX to identify resistant clones and resistant colonies were then isolated and amplified individually. Presence of shRNA inserts in each colony was determined by PCR using pRS forward and reverse primers. PCR products within each of the three resistant colonies were sequenced, leading to the identification of three distinct genes, TGIF1, HIF3A and PGAM2, as potential indicators of resistance. Western blotting verified depletion of these proteins in their respective colonies. Proliferation assays were then conducted on cells from each resistant colony alongside control cells to confirm that the identified drivers conferred resistance. Sensitivity to MTX was significantly lower in TGIF1-depleted (IC50=212±8.48nM, n=3), HIF3A-depleted (IC50=52±4.68nM, n=3) and PGAM2-depleted (IC50=41±4.13nM, n=3) cells compared to control cells (IC50=19±2.87nM, n=3), (p&amp;lt;0.001). In addition, more than 60% of TGIF1, HIF3A, and PGAM2-depleted cells survived the maximum MTX treatment (100nM), while less than 20% of control cells survived this treatment. Our study using an unbiased genome-wide RNAi screen approach has shown that depletion of TGIF1, HIF3A and PGAM2 are potential molecular markers of MTX resistance in ATRT. Screening for their occurrence may help to identify patients at high risk of MTX resistance and may also serve as targets for future novel therapeutics development.
Oral fexinidazole for stage 1 or early stage 2 African Trypanosoma brucei gambiense trypanosomiasis: a prospective, multicentre, open-label, cohort study
Authors: Victor Kande Betu Ku Mesu, Wilfried Mutombo Kalonji, Clélia Bardonneau, Olaf Valverde Mordt, Digas Ngolo Tete, Séverine Blesson, François Simon, Sophie Delhomme, Sonja Bernhard, Hélène Mahenzi Mbembo, Christian Mpia Moke, Steven Lumeya Vuvu, Junior Mudji E'kitiak, Felix Akwaso Masa, Melchias Mukendi Ilunga, Dieudonné Mpoyi Muamba Nzambi, Tim Mayala Malu, Serge Kapongo Tshilumbwa, Franck Botalema Bolengi, Mathieu Nkieri Matsho, Crispin Lumbala, Bruno Scherrer, Nathalie Strub-Wourgaft, Antoine Tarral
Journal: The Lancet Global Health (2021)

Staging and treatment of human African trypanosomiasis caused by Trypanosoma brucei gambiense (g-HAT) required lumbar puncture to assess cerebrospinal fluid (CSF) and intravenous drugs that cross the blood-brain barrier for late-stage infection. These procedures are inconvenient in rural health systems of disease-endemic countries. A pivotal study established fexinidazole as the first oral monotherapy to be effective against non-severe stage 2 g-HAT. We aimed to assess the safety and efficacy of fexinidazole in early g-HAT.
Trends in modifiable behaviorally related cancers: Who is affected the most?
Authors: John Chan, Michelle Ann P. Caesar, Chloe Chan, Michael Richardson, Daniel Stuart Kapp, Alex Andrea Francoeur, Cheng-I Liao
Journal: Journal of Clinical Oncology (2021)

e13531 Background: To examine trends in modifiable behaviorally related cancers among racial groups in the United States. Methods: Data were obtained from the United States Cancer Statistics (USCS) database for all cancers diagnosed between 2001 and 2017. Alcohol-associated cancers, HPV-associated, obesity-associated, physical inactivity-associated, and tobacco-associated were defined using ICD-O-3 site codes. SEER*Stat 8.3.8 and Joinpoint regression program 4.8.0.1 were used to calculate the trends of associated cancers expressed per 100,000. Results: In women, the incidence of all cancers has decreased significantly or remain unchanged for all racial groups in 2017, with the exception of an increase of HPV related cancers in white women (APC = 0.77%, p &lt; 0.001), obesity related cancers in Hispanic women (APC = 0.46%, p &lt; 0.001), and postmenopausal breast cancer in Black and Asian women (APC 0.78%, 1.06%, p &lt; 0.001). The incidence of alcohol, tobacco, obesity, and physical inactivity associated cancer decreased significantly in men for all racial groups in 2017. HPV related cancers increased annually by 3.13% (p &lt; 0.001) in White men and 0.90% in Asian men (p = 0.022). The highest decrease in modifiable factors associated with cancers was in physical inactivity related cancers in black men from the west (APC = -3.79, p &lt; 0.001). The intersection of black race and U.S. region had the highest decreases in all cancers except obesity-related cancers where the intersection of Asian race and Midwest region had the highest decrease. Conclusions: In women, most modifiable factors associated with cancer are decreasing except in obesity related cancers and physical inactivity/obesity related postmenopausal breast cancer. In men, these rates of cancer are decreasing for all racial groups except HPV related cancers in White and Asian men.
Pertuzumab plus trastuzumab (P+T) in patients (Pts) with uterine cancer (UC) with <i>ERBB2 or ERBB3</i> amplification, overexpression or mutation: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.
Authors: Hussein Moustapha Ali-Ahmad, Michael Rothe, Pam K. Mangat, Liz Garrett-Mayer, Eugene Ahn, John Chan, Michael L. Maitland, Ani Sarkis Balmanoukian, Sapna R. Patel, Zachary Reese, Charles W. Drescher, Charles A. Leath, Rui Li, Apostolia Maria Tsimberidou, Richard L. Schilsky
Journal: Journal of Clinical Oncology (2021)

5508 Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of UC pts with ERBB2 or ERBB3 amplification , overexpression or mutation treated with P+T are reported. Methods: Eligible pts had advanced UC, no standard treatment options, measurable disease, ECOG PS 0-2, and adequate organ function. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts matched to P+T had UC with ERBB2 or ERBB3 amplification or overexpression or a pre-specified ERBB2 mutation. Recommended dosing was P at an initial dose of 840 mg intravenously (IV) over 60 minutes (m), then 420 mg IV over 30-60 m every 3 weeks (wks), and T at an initial dose of 8 mg/kg IV over 90 m, then 6 mg/kg IV over 30-60 m every 3 wks until disease progression. Simon 2-stage design tested the null disease control (DC) - defined as partial (PR), complete response (CR) or stable disease at 16+ weeks (SD 16+) - rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have DC, 18 more pts are enrolled. If ≥7 of 28 pts have DC, the null DC rate is rejected. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: Twenty-eight female pts were enrolled from August 2017 to November 2019; all pts were evaluable for efficacy and toxicity. Demographics and outcomes are summarized in Table. Twenty-two pts had tumors with ERBB2 amplification (21) or overexpression (1); 4 tumors had ERBB2 mutations; 1 tumor had ERBB3 amplification; 1 tumor had both an ERBB2 amplification and mutation. Two PR and 7 SD16+ were observed in pts with ERBB2 amplification, and 1 SD16+ was observed in a pt with ERBB2 V8421 mutation only (no amplification) for DC and objective response (OR) rates of 37% (95% CI, 21% to 50%) and 7.1% (95% CI, 0.8% to 24%), respectively. One pt experienced grade 3 muscle weakness at least possibly related to P+T. Conclusions: P+T demonstrated evidence of anti-tumor activity in heavily pre-treated UC pts with ERBB2 amplification or certain mutations. Additional study is warranted to confirm the efficacy of P+T in this pt population. Clinical trial information: NCT02693535. [Table: see text]
Effect of time to relapse on overall survival (OS) in mantle cell lymphoma (MCL) patients (pts) following frontline high-dose therapy and autologous hematopoietic cell transplantation (autoHCT).
Authors: Peter A. Riedell, Mehdi Hamadani, Kwang Woo Ahn, Carlos Litovich, Mohamed Kharfan-Dabaja, Alex Francisco Herrera, Craig Steven Sauter, Sonali M. Smith
Journal: Journal of Clinical Oncology (2021)

7521 Background: In MCL, outcomes are heterogeneous and the clinical significance of the timing of relapse following autoHCT and its impact on OS is not well defined. Using the CIBMTR database, we evaluate the effect of post-autoHCT time to relapse on OS over time. Methods: Adult MCL pts treated with up to two lines of rituximab-based induction therapy followed by first autoHCT within 1-year of diagnosis were identified between 2000-2018. Primary outcomes included OS and post-relapse OS. A dynamic landmark analysis was performed at 6-month intervals following autoHCT to evaluate the impact of relapse on OS while adjusting for significant patient- and disease-related variables. Post-relapse OS was evaluated in pts who experienced relapse. Results: Of the 461 pts included in the analysis, the median age was 60 years (range 29-78), 57% had a KPS of ≥ 90, 83% had stage III-IV disease at diagnosis, and 76% had extranodal involvement. BEAM was the most common conditioning regimen (58%) and 23% of pts received post-autoHCT maintenance rituximab. With a median follow-up of 67 months, the 5-year progression-free survival was 45.8% with a 5-year OS of 69.6%. On multivariate analysis, age ≥60 years was associated with worse OS (HR= 1.55, 95% CI 1.08-2.24, p=0.0191) at all landmark timepoints. Additionally, the impact of relapse on OS varied with time (p=0.006) and was greatest at the 6-month (HR=7.68), 12-month (HR=6.68), and 18-month (HR=5.81) landmark timepoints. The risk of death for relapsing pts decreased with time and was mirrored by an improvement in adjusted OS for both relapsing and non-relapsing pts. In total, 9.3% of patients relapsed prior to the 18-month landmark timepoint. Relapse at the 6-month, 12-month, and 18-month landmark timepoints correlated with a poor median post-relapse OS of 9 months, 24 months, and 34 months, respectively (Table). Conversely, patients relapsing after the 18-month landmark timepoint experienced a median post-relapse OS ranging from 44-67 months. Conclusions: In MCL, early relapse (&lt; 18-months) following autoHCT defines a high-risk group with inferior post-relapse OS. This population should be considered for clinical trials or novel therapeutic approaches including early utilization of chimeric antigen receptor T-cell therapy.[Table: see text]
Cardiac risk factors and adverse events among patients receiving first-line CLL treatment in a real-world community practice setting.
Authors: Anthony R. Mato, Boxiong Tang, Soraya Azmi, Keri Yang, Nicola Wallis, Jennifer C Stern, Eric Hedrick, Jane Huang, Jeff Porter Sharman
Journal: Journal of Clinical Oncology (2021)

e24044 Background: First-line (1L) ibrutinib monotherapy (IM) is commonly prescribed for CLL but is associated with cardiovascular adverse events (CVAEs) that may lead to discontinuation. Existing data are largely from clinical trials (both 1L and relapsed/refractory), and real-world evidence is limited. The aim of this study was to compare baseline cardiac risk factors and CVAEs in patients (pts) receiving 1L IM vs intensive therapy (IT; aggressive, less tolerable, majority were bendamustine plus anti-CD20 antibody) or non-intensive therapy (NIT; less aggressive, more tolerable, majority were anti-CD20 antibody alone). Methods: We compared 3 treatment groups (IM, IT, and NIT) in terms of clinical characteristics, baseline CV risk factors, and subsequent CVAEs. Pts were selected from the Flatiron Health database based on the following criteria: aged ≥18 years, CLL/SLL diagnosis, had ≥2 clinic encounters, and initiated 1L treatment between 1/1/2016 and 12/31/2019. Baseline characteristics and subsequent CVAEs were descriptively compared between IM and IT/NIT groups; significance was assumed if p &lt; 0.05. Results: Data on 515 pts were included (IM, 191; IT, 195; NIT, 129). Age at baseline differed significantly between the IM group (mean 71.2 years) and the other 2 groups (IT, 66.2 years; NIT, 74.5 years). The proportion of del(17p) was significantly higher in the IM group vs IT/NIT groups (IM, 26.7%; IT, 3.6%; NIT, 3.1%). Significant differences between IM and IT groups were seen in baseline ECOG (ECOG 0: IM, 28.8%; IT, 43.1%), diabetes mellitus (IM, 56.0%; IT, 44.1%), and hypercholesterolemia (IM, 68.6%; IT, 58.0%). Significant differences between IM and NIT groups were seen in baseline angina/coronary revascularization (2.6% vs 8.5%), atrial fibrillation/atrial flutter (AF; 14.1% vs 26.4%), and cerebrovascular disease (8.9% vs 20.2%). The rate of any CVAE was significantly higher in IM (35.6%) vs IT and NIT groups (IT, 20.0%; NIT, 24.8%) (Table). For IM vs IT treated pts, significant differences were observed in new or worsening (N/W) AF (11.5% vs 5.1%), other arrhythmias (9.4% vs 3.1), and hypertension (HTN; 20.4% vs 8.2%). Conclusions: This is one of the first real-world studies focused specifically on 1L CLL to describe baseline CV risk factors and compare CVAE events in CLL pts treated with IM as compared to IT or NIT. Results show higher CVAE rates of AF, other arrhythmias, and HTN for IM vs IT. [Table: see text]
Preoperative chemoradiotherapy to improve overall survival in pancreatic cancer: Long-term results of the multicenter randomized phase III PREOPANC trial.
Authors: Casper H.J. Van Eijck, Eva Versteijne, Mustafa Suker, Karin Groothuis, Marc G.H. Besselink, Olivier R.C. Busch, Bert A. Bonsing, Bas Groot Koerkamp, Ignace H.J.T. de Hingh, Sebastiaan Festen, Gijs A. Patijn, Judith de Vos-Geelen, Aeilko H. Zwinderman, Cornelis J. A. Punt, Geertjan van Tienhoven
Journal: Journal of Clinical Oncology (2021)

4016 Background: Preoperative chemoradiotherapy (CRT) may improve overall survival in resectable pancreatic cancer (RPC) and borderline resectable pancreatic cancer (BRPC). Long term results are presented. Methods: In this multicenter phase III trial, patients with RPC or BRPC were randomized between preoperative CRT, (gemcitabine 1000 mg/m 2 weekly for 7 of 10 weeks, and 15x2.4 Gy radiotherapy in week 4 to 6), followed by surgery and four cycles of adjuvant gemcitabine (1000 mg/m 2 weekly for 3 of 4 weeks), or immediate surgery followed by 6 cycles of adjuvant gemcitabine (1000 mg/m 2 weekly for 3 of 4 weeks). Primary endpoint was overall survival by intention-to-treat (ITT). Results: From April 2013 to July 2017, 246 eligible patients were accrued by 16 Dutch centers and randomized, 119 to preoperative CRT and 127 to immediate surgery. After a median follow up of 56 months (35.3-92.0 months), 210 patients have died, 93 (78%) in the preoperative CRT arm and 117 (92%) in the immediate surgery arm. Three- and five-year overall survival ITT was 27.7% and 20.5% after preoperative CRT versus 16.5% and 6.5% after immediate surgery (HR 0.73; 95% CI 0.56 to 0.96; p = 0.025). In addition, disease-free survival (HR 0.70; p = 0.009) locoregional failure-free interval (HR 0.57; p = 0.004) and distant metastases free interval (HR 0.74; p = 0.071) improved after preoperative CRT. Also in the stratified subsets RPC and BRPC, preoperative CRT improved OS: RPC (n = 133, HR 0.79; 95% CI 0.54 to 1.16; P = 0.23). BRPC (n = 113, HR 0.67; 95% CI 0.45 to 0.99; p = 0.045). We could not demonstrate a difference in treatment effect between these subsets (interaction test p = 0.56). Conclusions: Preoperative gemcitabine-based CRT for RPC or BRPC improves long term overall survival compared to immediate surgery with adjuvant gemcitabine. Clinical trial information: NTR3709.
Biologically optimized schedule of gemcitabine and nab-paclitaxel regimen in metastatic pancreatic adenocarcinoma.
Authors: Laith I. Abushahin, Anne M. Noonan, John L. Hays, Pannaga G. Malalur, Ashish Manne, Ning Jin, Arjun Mittra, Rifat T. Elkhatib, Sameek Roychowdhury, Terence Marques Williams
Journal: Journal of Clinical Oncology (2021)

TPS4168 Background: Metastatic pancreatic adenocarcinoma has a poor prognosis, and improvements in therapy have been challenging. Alongside efforts in developing novel agents, there is a need to optimize and maximize the benefit of currently approved drugs. Gemcitabine + nab-paclitaxel is a frequently used regimen for pancreatic adenocarcinoma. Nab-paclitaxel is albumin–bound chemotherapy; hence the role of albumin uptake is critical for its effect. Caveolae are small membrane invaginations essential for transendothelial albumin uptake. Cav-1 is the principal structural component of caveolae. Williams and colleagues have published a series of preclinical studies demonstrating that tumor cell-specific Cav-1 expression directly correlates with albumin and albumin-bound chemotherapy uptake and subsequent apoptotic response in tumor cells. In vitro studies showed that exposure of pancreatic cancer cells to Gemcitabine resulted in up-regulation of Cav-1 peaking 48 hours after gemcitabine exposure. This Cav-1 up-regulation correlated with increased temporal albumin cellular uptake. In addition, Williams and colleagues noted that exposure of pancreatic cancer cell lines to Gemcitabine resulted in a time–specific re-entry of cells into the G2/M phase (nab-paclitaxel cytotoxicity phase) between 48-60 hours after gemcitabine treatment. Collectively this data suggest that infusing nab-paclitaxel after 48 hours of gemcitabine infusion would be optimal for both increased uptake as well as increased susceptible tumor cells. We had previously shown this effect on multiple cell lines as well as mouse models. Methods: This is a phase II trial; patients will receive a standard of care chemotherapy regimen consisting of FDA-approved Gemcitabine + nab-paclitaxel with modification of the schedule to deliver nab-paclitaxel 48 hours (2 days) after gemcitabine infusions. The primary endpoint is ORR, with a null hypothesis of 20% vs. a target of 35%. Employing a 2-stage design (minimax) and assuming 80% power and a 0.05 significance level, a total of 53 patients will be required. In the first stage, if at least 7/31 patients respond to therapy, an additional 22 patients will be added for a total of 53 patients. The study will be terminated early if ≤ six patients respond in the first stage. Observation of response in at least 16/53 patients would be required to warrant further investigation of this infusion schedule of combination therapy. The secondary endpoints include the safety of the regimen schedule, Relative dose intensity, disease control rate, PFS, and OS. The trial opened to enrollment in June 2020 and is accepting patients. Clinical trial information: NCT04115163.
リソソーム脆弱性の安定化によるL2細胞の低酸素障害に対するウリナスタチン(クニッツ型タンパク質分解酵素阻害剤)の細胞保護効果
Authors: Nakahama H, Kuribayashi K, Sugita M
Journal: American Journal of Respiratory and Critical Care Medicine (1999)