tbuckley/cabot-search huggingface dataset:
Immunotherapy using activated T cells with chemotherapy for metastatic colorectal cancer.
Authors: Yoichiro Yoshida, Naoya Aisu, Hideki Nagano, Akira Komono, Daibo Kojima, Toshiyuki Mera, Toshihiro Tanaka, Keiko Naitoh, Kosei Yasumoto, Takashi Kamigaki, Shigenori Goto, Suguru Hasegawa
Journal: Journal of Clinical Oncology (2017)

767 Background: The programmed death-1 (PD-1), an inhibitory receptor expressed on activated T cells, is demonstrated to induce an immune-mediated response and play a critical role in tumor initiation and development. T cell activation induces effective antitumor immune response in cancer patients. Adoptive immunotherapy of cancer is evolving with the development of novel technologies that generate proliferation of large number of T cells. We evaluated the safety and efficacy of the combination of adoptive immunotherapy using αβ T cells with chemotherapy for metastatic colorectal cancer (mCRC). Methods: Seventeen patients with mCRC received XELOX + bevacizumab + ex vivo expanded αβ T lymphocytes as a first-line chemoimmunotherapy. Results: Median age of the 17 patients (6 men, 11 women) was 64 years (range:38–80). The T cell number was more than 5.0×10 9 for each infusion. Median progression-free survival was 15.2 months. Response rate was 80% (complete response (CR) = 23.5%, partial response (PR) = 47.1%, stable disease (SD) = 29.4% and progressive disease (PD) = 0%). Most adverse events were mild to moderate in intensity and immunotherapy-associated toxicity was minimal. Conclusions: Combination of adoptive αβ T cell immunotherapy with chemotherapy for mCRC is safe and effective.
Adjuvant chemoradiation for node-positive pancreatic adenocarcinoma: A propensity-matched analysis.
Authors: Mustafa Raoof, Laleh Golkar Melstrom, Susanne Warner, Yanghee Woo, Gagandeep Singh, Yi-Jen Chen, Yuman Fong
Journal: Journal of Clinical Oncology (2017)

347 Background: American Society of Clinical Oncology guidelines recommend adjuvant chemoradiation (ACR) for margin-positive(R1) and/or node-positive (N+) pancreatic cancers. However, randomized trials and meta-analyses have have not shown superiority of ACR over AC. Methods: National Cancer Database (NCDB) was used to analyze patients with N+ and/or R1 pancreatic adenocarcinoma who underwent ACR or AC over a ten-year period (2004-2014). Patients who received neoadjuvant radiation, no adjuvant treatment or adjuvant radiation alone were excluded. Propensity score nearest-neighbor 1:1 matching (PSM) was performed between ACR and AC groups based on age, sex, race, insurance, comorbidities, T-stage, nodal status, margin status, grade, and neoadjuvant chemotherapy. Primary outcome was overall survival (OS). Results: A total of 9,732 patients were eligible. After PSM two well-balanced groups of 4000 patients each were analyzed. ACR resulted in superior OS in patients with N+ and/or R1 disease as compared to AC alone (HR: 0.83, 95% CI 0.78-0.87; Median OS 22 vs. 19 months, p&lt;0.001). Subset analyses demonstrated overall survival benefit of ACR compared to AC in N+, margin-negative patients (HR: 0.82, 95% CI 0.77-0.88; Median OS 24 vs. 20 months, p&lt;0.001), as well as N+, R1 patients (HR: 0.77, 95% CI 0.68-0.87; Median OS 17 vs. 15 months, p&lt;0.001); but no benefit in node-negative, R1 patients (HR: 1.12, 95% CI 0.84-1.48; Median OS 18 vs. 22 months, p = 0.43). Conclusions: This is the largest study to date that shows superiority of ACR over AC in N+ patients irrespective of margin status. The study failed to show a survival benefit in R1, node-negative patients.
Determining the maximum tolerated frequency (MTF) of intraperitoneal fluorouracil/folinic acid (FU/FA) administered with adjuvant intravenous FU/FA in patients with colorectal and upper GI tumours
Authors: S. P. Joel, F. R. Halstead, M. D. Hasleton, J. R. King, M. L. Slevin, M. T. Seymour
Journal: Journal of Clinical Oncology (2004)

3668 Background: Intraperitoneal (IP) FU/FA may confer a survival advantage when added to IV adjuvant therapy in patients (pts) with colorectal cancer (Br J Cancer 77:1349, 1998). The aims of this study were to determine the MTF and pharmacokinetics (PK) of IP FU/FA when added to weekly IV FU/FA. Methods: Pts were recruited after complete resection of GI cancers where there was peritoneal involvement, after which a peritoneal port was implanted for IP treatment and PK sampling. Pts received IV FU/FA (400/20 mg/m2) weekly for 24 wks. IP FU/FA, (400/20 mg/m2) in 1500ml of 4% icodextrin, was given with increasing frequency from 4-weekly to weekly in successive cohorts, with weekly monitoring of toxicity. IP and plasma FU PK was investigated in 11 pts. Results: 57 pts were registered, of whom 53 had ports inserted. 44 (37 colorectal, 7 other) pts received 1 or more IP treatments (299 in total), but 3 withdrew early due to port failure, leaving 41 evaluable for MTF. IP FU/FA was tolerable with 4, 3 or 2-weekly IP dosing, but not with weekly dosing, with 11/13, 7/8, 10/13 and 0/7 pts respectively completing treatment without IP dose modifications. Good fluid distribution was observed by ultrasound in 41/42 pts at baseline, and in 26/27 pts after 5–13 (median 8) IP treatments. FU AUC in IP fluid was 1148 ± 567 μg/ml.hr, compared to 1.12 ± 0.61 μg/ml.hr in plasma after IP treatment alone, giving an IP/plasma ratio of >1000. Following IV and IP treatment plasma FU AUC was 11.5 ± 2.4 μg/ml.hr, with an IP/plasma ratio of 100. Systemic FU bioavailability after IP FU was 11.1 ± 6.6%. 3½ years after the end of accrual, 41% of pts have relapsed. Peritoneal relapse has occurred in 3/24 (12.5%) pts who received ≥ 7 IP doses, and in 7/20 (35%) who received ≤ 6 (χ2 p=0.06). Conclusions: The addition of IP FU/FA every 2 weeks to a standard IV regimen is safe, tolerable and practical and results in a 100-fold higher local exposure to FU than is achieved with standard IV therapy. A more reliable peritoneal administration system would improve the feasibility of this promising therapeutic approach. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ML Laboratories PLC
Genomic analysis of circulating tumor DNA (ctDNA) in plasma of metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with abiraterone acetate (abi) and enzalutamide (enza).
Authors: Arun Azad, Stanislav Volik, Alexander Wyatt, Anne Haegert, Colin Collins, Kim N. Chi
Journal: Journal of Clinical Oncology (2014)

5021 Background: CollectingctDNA represents a promising and minimally invasive approach for profiling the cancer genome of mCRPC pts, which may reveal key resistance mechanisms to agents such as abi and enza. Methods: Plasma was collected from 51 mCRPC pts at cessation of abi (n=26), enza (n=17) or other agents (n=8) due to any of biochemical, objective or clinical progression. DNA was extracted and subjected to array Comparative Genomic Hybridization (aCGH) for chromosome copy number analysis and next generation sequencing of exon 8 of the androgen receptor (AR) ligand-binding domain (LBD). Results: Sufficient DNA was available for aCGH in 48 of 51 pts (94%). 8p loss, 8q gain and AR gain were seen in 29% (14/48), 40% (19/48) and 54% (26/48) of pts respectively, with AR amplification status being concordant between ctDNA and fluorescence in situ hybridization (FISH) of concurrent metastatic tumour biopsies in 3 of 4 pts. Other copy number changes detected included high CCND1 and CCNE1 gain (4% each). Correlation of clinical and genomic data showed that AR amplification was significantly more frequent in pts progressing on enza compared to those progressing on abi (76% vs. 39%, p=0.027; Chi-square). In 26 pts switched onto enza after ceasing abi/other agents, those with AR amplification at initiation of enza were significantly more likely to have enza-refractory disease (i.e. no PSA decline on treatment) compared to pts without AR amplification (60% vs. 19%, p=0.046; Chi-square). AR sequencing in 29 pts detected several high frequency mutations including T877A and F876L in 41% (12/29) and 10% (3/29) of pts respectively. The F876L mutation, linked with resistance to enza pre-clinically, was detected in two enza-naïve pts, both of whom progressed within 3 months on subsequent enza therapy. Conclusions: Genomic analysis of ctDNA from mCRPC pts identified key aberrations that may be associated with therapeutic resistance including AR amplification and the F876L AR mutation. Our data illustrate the potential utility of profiling ctDNA to characterize the genomic landscape of mCRPC.
Circulating androgen receptor and serum chromogranin A in castration-resistant prostate cancers (CRPC) patients treated with abiraterone and enzalutamide.
Authors: Vincenza Conteduca, Samanta Salvi, Valentina Casadio, Cristian Lolli, Giorgia Gurioli, Giuseppe Schepisi, Filippo Martignano, Cecilia Menna, Salvatore Luca Burgio, Sara Testoni, Gerhardt Attard, Ugo De Giorgi
Journal: Journal of Clinical Oncology (2017)

160 Background: Circulating aberrations (copy number/point mutation] of androgen receptor ( AR) as well as serum chromogranin A (CgA) have been associated to treatment response and clinical outcome in CRPC patients (pts) treated with abiraterone (abi)/enzalutamide(enza). Methods: We determined AR aberrations by digital PCR, Taqman and targeted-next generation sequencing on pre-treatment plasma from 169 CRPC pts treated with abi 1g/od (n = 96) and prednisone 5mg/bid or enza 160mg/od (n = 73) (Romanel, 2015; Salvi, 2015; Salvi, 2016). All pts were subdivided into 3 groups using receiver-operating characteristic (ROC) curves (Burgio, 2014; Conteduca, 2014) to evaluate properly the impact of CgA levels: serum CgA level was normal when &lt; 120 ng/ml (group A,n = 76); within 3 times the upper normal value(UNV) when between 120 and 360(group B,n = 57), more than 3 times UNV when &gt; 360(group C,n = 36). The primary endpoint was the correlation between AR aberrations and CgA level. The secondary endpoints were progression-free/overall survival (PFS/OS) and PSA response rate (RR) ( &gt; 50% PSA decline after 12 weeks of therapy) stratified by AR status and CgA level. Results: We observed AR gain in 57(33.7%) of 169 pts, 29(30.2%) of 96 pts treated with abi and 28(38.3%) of 73 treated with enza. Circulating AR status was independent from baseline CgA levels in all pts (p = 0.36). In only AR-normal pts, we showed a significant survival difference among 3 CgA groups (P &lt; 0.0001), particularly Group C vs. A+B [HR (hazard ratio) 5.1, 95%CI (confidence interval) 2.37-10.96 and HR 3.7 95%CI 1.79-7.69, respectively for PFS/OS]. We reported no difference of PFS/OS in AR-gained pts (P = 0.6 and P = 0.1, respectively with HR~0.6 in all CgA groups). In addition, group C vs. A+B had a significant PSA RR [P = 0.03 odds ratio (OR) 2.7 95%CI 1.02-7.30] in AR-normal pts. No PSA RR difference was observed in AR-gained pts (P = 1.0 OR 0.97 95%CI 0.18-5.26). Conclusions: In CRPC pts treated with abi/enza, baseline CgA levels may be an additional predictive/prognostic factor, especially in a particular set of CRPC pts with normal plasma AR status and worse treatment outcome. This association needs a prospective larger study.
Is there an alternative explanation to the evolutionary account for financial and prosocial biases in favor of attractive individuals?
Authors: Junhua Dang
Journal: Behavioral and Brain Sciences (2017)

Abstract All three critical points of the evolutionary explanation proposed by Maestripieri et al. may not withstand close scrutiny. Instead, there should be an alternative explanation that has nothing to do with genetic continuity, but stresses the rewarding property of attractiveness that results mainly from sociocultural value assignment and sexual experience pursuit.
Implementation of distress testing: Lessons learned at the Kaiser Permanente Oakland Medical Center.
Authors: Pamela Kim Washington, Lisa Belote, Rosalind Harder, Patricia Livingston, Kevin Nguyen, Sarah Piper, Bonnie Chen, Carol Piper, Nakeia Warren, Kay Stodd, Raymond Carraway, Richard Roston, Nicole M Barnett, James Duffy
Journal: Journal of Clinical Oncology (2017)

202 Background: The Commission on Cancer (CoC) requires accredited facilities to evaluate cancer patients for distress a minimum of one time at a pivotal visit during their cancer journey. Here we describe lessons learned with the implementation of distress testing at the Kaiser Permanente Oakland Medical Center. Methods: The implementation timeframe was April to December 2015. Testing guidelines were created including a definition of pivotal visit. Use of the validated NCCN Distress Thermometer was approved by the East Bay Comprehensive Cancer Committee. A workflow was developed whereby a paper copy of the tool was given to patients at their first cycle of chemotherapy. A RN Case Manager or Social Worker then triaged completed forms. Referrals were made by the case manager, social worker, or attending physician based on patients’ self-reported disposition and level of distress. This information was subsequently entered into patients’ electronic medical record. Completed forms were then entered into an Excel database to facilitate data analysis. Results: Overall, patients were receptive to testing. 232 tests were completed. 55.7% (n = 125) self-reported a score between 0 to 3 (low distress). Worry, fatigue, problems with sleep, financial issues, and problems with transportation were the most common stressors. 42.7% patients received a referral. Referrals to a MSW or RN Case Manager were most common. Interestingly, there were no referrals to psychiatric services. Conclusions: Careful consideration to workflow processes be must factored into implementing distress testing. Findings from our 2015 pilot informed the expansion of testing in all outpatient cancer clinics in 2016.
Prostate-Apoptosis-Response-Gene-4 Increases Sensitivity to TRAIL-Induced Apoptosis.
Authors: Simone Boehrer, Daniel Nowak, Elena Puccetti, Martin Ruthardt, Nicole Sattler, Bettina Trepohl, Bernd Schneider, Dieter Hoelzer, Paris S. Mitrou, Kai Uwe Chow
Journal: Blood (2005)
A phase I trial of the ɣ-secretase inhibitor (GSI) MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma (PDAC).
Authors: Natalie Cook, Bristi Basu, Donna-Michelle Smith, Aarthi Gopinathan, Thomas Jeff Evans, William P. Steward, Thorsten Hagemann, Balaji Venugopal, David A. Tuveson, Mirela Hategan, David Alan Anthoney, Hayley Farmer, Helen Turner, Robert McLeod, Sarah E. R. Halford, Duncan Ian Jodrell
Journal: Journal of Clinical Oncology (2014)

4116 Background: The Notch pathway is frequently activated in cancer. Pathway inhibition by GSIs has been shown to be effective in models of PDAC, in combination with gemcitabine (GEM). Methods: A multi-centre, non-randomised Bayesian adaptive design study of MK-0752, administered p.o. weekly (starting dose; 1,200mg), and GEM i.v. on days 1, 8 and 15 (28 day cycle) at 800 or 1000 mg/m2, is being performed to determine the safety (using CTCAE v4.02) of combination treatment and recommend a Phase 2 dose (RP2D) combination. Other objectives are tumor response (RECIST 1.1), plasma and tumor MK-0752 concentration, and inhibition of the Notch pathway in hair follicles (expression profiling) and tumor (IHC). Results: 29 patients (pts) were registered on the study, of whom 27 received treatment (17 WHO PS 1; 10 PS 0). All patients received GEM/MK-0752 as first line treatment for metastatic disease. The RP2D of both single agents could be administered in combination (MK-0752 1800mg and GEM 1000 mg/m2). As no DLTs were experienced at this dose combination, the Bayesian algorithm allowed further dose escalation, but dose limiting toxicity (G3 hypokalaemia) was observed at MK-0752 2,400mg in 1 pt. Gastrointestinal related adverse events (AEs) were common (diarrhoea 18 pts; nausea 19 pts; vomiting 17 pts). Other (>10% pts) AEs included fatigue, thrombocytopenia (G4 in 1 pt) and transaminitis. Tumor response evaluation was available after 10 weeks of treatment in 18 pts (6 withdrew early due to AEs, 1 pt was not evaluable, 2 pts still on treatment): 11/18 achieved stable disease and a confirmed partial response was observed at 12 weeks (time to subsequent progression 38 weeks). Plasma PK analysis revealed Cmax at 1,800mg of 61-104 µg/mL (n=7, Tmax, 4-8 hours) with a long half-life: quantifiable (>50 ng/mL) MK-0752 in plasma, 7 days after a single administration in 5/7 pts. A signature of Notch pathway inhibition was observed in 16/18 pts in hair follicles and paired biopsies (20 pts) are being analysed for tumor PK and Hes1 IHC. Conclusions: GEM and MK-0752, can be combined at full, single agent RP2Ds and the regimen is well tolerated. Clinical activity was seen, which will require confirmation in a Phase II trial. Clinical trial information: NCT01098344.
Leptin-dependent serotonin control of appetite: temporal specificity, transcriptional regulation, and therapeutic implications
Authors: Vijay K. Yadav, Franck Oury, Kenji F. Tanaka, Tiffany Thomas, Ying Wang, Serge Cremers, Rene Hen, Andree Krust, Pierre Chambon, Gerard Karsenty
Journal: The Journal of Experimental Medicine (2011)
CDK4/6 Inhibitor Palbociclib for Treatment of KMT2A-Rearranged Acute Myeloid Leukemia: Interim Analysis of the AMLSG 23-14 Trial
Authors: Stefan Fröhling, Mridul Agrawal, Nikolaus Jahn, Lars R. Fransecky, Claudia D. Baldus, Ralph Wäsch, Michael Lübbert, Gina Walter, Patrizia Jensen, Claudia Scholl, Marianne Habdank, Konstanze Döhner, Hartmut Döhner, Richard F. Schlenk
Journal: Blood (2016)
Therapy of advanced metastatic lung cancer with an anti-Trop-2-SN-38 antibody-drug conjugate (ADC), sacituzumab govitecan (IMMU-132): Phase I/II clinical experience.
Authors: Michael J. Guarino, Alexander Starodub, Gregory A. Masters, Rebecca Suk Heist, Wells A. Messersmith, Aditya Bardia, Allyson J. Ocean, Sajeve Samuel Thomas, Pius P Maliakal, William A. Wegener, Robert M. Sharkey, Francois Wilhelm, David M. Goldenberg
Journal: Journal of Clinical Oncology (2015)

2504 Background: Sacituzumab govitecan (IMMU-132) is a new ADC comprising SN-38, the active metabolite of the topoisomerase inhibitor, camptothecin (irinotecan), conjugated to an anti-Trop-2 antibody. In vitro and in vivopreclinical data suggest that IMMU-132 is a unique ADC, being most efficacious at a high drug-antibody ratio (DAR) of 7.6, and capable of delivering up to 136-fold more SN-38 than its parental drug, irinotecan, in a human cancer xenograft. Trop-2 is widely expressed in most epithelial cancers, including non-small and small cell lung cancers (NSCLC and SCLC). Therefore, the safety and efficacy of this new ADC is being examined in advanced metastatic lung cancers. Methods: A phase I/II clinical trial (ClinicalTrials.gov, NCT01631552) is ongoing in subsets of previously-treated patients with metastatic lung cancer, administering IMMU-132 on days 1 and 8 of 21-day treatment cycles. Treatment is continued based on tolerance or until progression, with safety and response assessments made every week and at 8-12 weeks, respectively. Dose reductions and delays allowed most patients to continue treatment until progression. Results: Thirty-four lung cancer (15 NSCLC and 19 SCLC) patients with a median of 3 (range, 1-7) prior therapies were given IMMU-132 doses at 8 mg/kg (N = 22), 10 mg/kg (N = 10), 12 mg/kg (N = 2). Tumor responses, including squamous and adenocarcinoma NSCLC types having PR, are summarized in the table below. Neutropenia was the only Grade 3/4 toxicity (G3, 15%; G4, 3%). Other drug-related G3 toxicities included diarrhea (9%), anemia (6%), leucopenia (3%), lymphopenia (3%), pneumonia (3%), vomiting (3%), dizziness (3%). No differences were found between 8 and 10 mg/kg dosing. No pt developed antibodies (ELISA) to the conjugate. Conclusions: Repeated cycles of IMMU-132 monotherapy are well tolerated. Objective responses in previously treated metastatic lung cancer encourage further study of IMMU-132 in these cancers. Clinical trial information: NCT01631552. Tumor type PR Disease stabilization (PR+SD) Clinical benefit (PR+ SD) > 6 mo Median TPP (Mo) NSCLC (N = 15) 27% 73% 42% 3.3+ SCLC (N = 19) 26% 53% 29% 2.8+
Proton radiotherapy for prostate cancer in the Medicare population: Patterns of care and comparison of early toxicity with IMRT.
Authors: James B. Yu, Pamela R. Soulos, Laura D. Cramer, Kenneth B Roberts, Jeph Herrin, Arnold L. Potosky, Cary P. Gross
Journal: Journal of Clinical Oncology (2012)

4651 Background: Proton radiotherapy (PRT) is a costly treatment used for prostate cancer despite little evidence supporting its use. We examined patterns of PRT use in the Medicare program and assessed the short-term toxicity of PRT vs. intensity modulated radiation therapy (IMRT). Methods: Using national Medicare claims from 2008-2009, we identified a sample of prostate cancer patients ages 66-94 who had received PRT or IMRT. We used multivariable logistic regression to identify patient and regional factors associated with receipt of PRT. We searched claims for procedure and diagnosis codes indicative of treatment-related complications and grouped the complications into genitourinary (GU), gastrointestinal (GI), and other complications. To compare the effect of PRT and IMRT on short-term toxicity, we used a Mahalanobis distance approach to match each PRT patient to two IMRT patients, achieving balanced distribution of clinical and sociodemographic characteristics. We compared six-month and one-year outcomes between the two treatment groups using conditional logistic regression. Results: We identified 27,647 men; 421 (2%) received PRT and 27,226 (98%) received IMRT. Patients who received PRT were widely geographically distributed, with some patients traveling &gt;500 miles for treatment. PRT patients were younger, healthier, and of higher socioeconomic status. Although PRT was associated with a significant reduction in GU complications at six-months compared with IMRT (6.1% vs. 12.0%, OR 0.60 [95% CI 0.38-0.96], p=0.03), at one-year post-treatment there was no longer any difference in cumulative complication rates (18.9% vs. 21.9%, OR 0.96 [95% CI 0.61-1.53], p=0.88). There was no significant difference in GI or other complications at six-months or one-year post-treatment. Conclusions: Although PRT remains a scarcely used treatment, some prostate cancer patients traveled great distances for treatment. While PRT was associated with a reduction in six-month GU toxicity, there were no differences in toxicity at one-year. Further study on longer-term effects and other clinical and patient-reported outcomes is needed to inform the widespread application of PRT.