tbuckley/cabot-search huggingface dataset:
Investigating nerve fibre damage in chemotherapy-induced peripheral neuropathy (CIPN): A prospective study.
Authors: Sabrina Ramnarine, Roman Rolke, Lesley A Colvin, Marie T Fallon
Journal: Journal of Clinical Oncology (2018)

e22096 Background: As the incidence of cancer increases and cancer survivorship improves, CIPN will be a major concern. There is a need to further develop our understanding of the clinical course to facilitate prediction and effective management. This study aims to: 1) assess peripheral nerve fibre damage in patients receiving neurotoxic chemotherapy focusing on Aδ and C fibres due to their involvement in pain perception and 2) explore potential differences between cancer/chemotherapy type. Methods: Quantitative Sensory Testing (QST) was used to assess cold and warm detection thresholds (CDT, Aδ; WDT, C fibres) in the upper limb in 24 cancer patients (mean age 62.5±7.7yrs) at baseline, prior to chemotherapy, during cycles (max. 8) and post-chemo (up to 12 months). Patient subgroups included: colorectal (n = 10, oxaliplatin), gynaecological (n = 11, paclitaxel and carboplatin), lung (n = 3, carboplatin). ANOVA was performed by subgroup as between factor and time of investigation (baseline, mean cycles, mean follow up) as within factor. CIPN severity was defined by dose reduction/cessation in accordance with NCI-CTCAE neurotoxicity scores. Results: In this cohort, 14/24 patients (58.3%) required dose reduction/cessation due to CIPN. CDT increased significantly over time: during cycles (18.5% vs. baseline) and during follow up (35.0% vs. baseline) (p < 0.05). While WDT also increased from baseline (4.5% during cycles and 25.2% during follow up) this was not statistically significant. No significant group effects or interactions of group factors or assessment time points were observed. Conclusions: The findings suggest that nerve fibre deficits over time were more pronounced for CDT than WDT reflecting a loss of sensory function with a predilection for myelinated in comparison to unmyelinated fibres. As this pattern was independent of any effect by cancer type it may allude to potentially overlapping mechanisms across chemotherapy (taxanes and platinum agents). The persistence of significant impairment in Aδ fibres in the post-treatment follow up and the changes observed from baseline reinforce the need for earlier identification of CIPN and tailored, focused management.
Association between <i>Helicobacter pylori</i> infection and outcome in advanced gastric cancer patients treated with S-1 adjuvant chemotherapy.
Authors: Satoshi Nishizuka, Gen Tamura, Masahiro Nakatochi, Takeshi Iwaya, Virginia A. Espina, Lance A. Liotta, Keisuke Koeda
Journal: Journal of Clinical Oncology (2018)

4043 Background: The beneficial and deleterious effects of Helicobacter pylori (H. pylori) infection remain to be fully elucidated. A clear understanding of the infectious mechanism is crucial since the potential effect may result in a survival benefit for life-threatening diseases. To understand the potential beneficial effect in advanced gastric cancer, we analyzed survival for patients treated with surgery-only or adjuvant chemotherapy on the basis of H. pylori infection status. Methods: A cohort of 491 patients who underwent R0 resection for locally-advanced gastric cancer between 2000 and 2009 at 12 institutions in northern Japan from the Northern Japan Gastric Cancer Consortium was included. H. pylori infection status was assessed from paraffin-embedded formalin-fixed samples. Overall survival (OS) and disease-free survival (DFS) in surgery-only (Surgery) and adjuvant chemotherapy (S-1) groups were analyzed. A propensity score matching was employed to correct for confounding factors by indication. To evaluate the local immune response from the immune-evasion status of the tumor, immunostaining of Programmed Death-Ligand 1 (PD-L1) protein was performed with PharmDx antibody clone 22C3. Results: H. pylori infection was positive in 175 patients and negative in 316 patients. H. pylori-positive patients showed significantly better survival than H. pylori-negative patients in both OS [hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.42-0.84; p = 0.003)] and DFS (HR 0.68, 95% CI 0.49-0.94; p = 0.018). There were no significant interactions between H. pylori infection status and the clinicopathological background except for S-1 doses in DFS (p = 0.0482). Propensity score matching further confirmed that S-1 was virtually only effective when tumors were H. pylori-positive. The PD-L1 protein expression pattern suggests that H. pylori-positive status confers an advantage that might suppress immune-evasion of tumor cells. Conclusions: The favorable outcome of H. pylori-positive patients suggests that the host immune system is modulated by H. pylori enhancing post-operative chemotherapeutic efficacy (NCT01905969).
Association of thymidylate synthase (TYMS) polymorphism with adverse events (AEs) of 5-FU/capecitabine (CAP) in pts with GI cancers.
Authors: Ruchi Hamal, Margaret Byrne, Hilal Hachem, Lulu Zhang, Wasif M. Saif
Journal: Journal of Clinical Oncology (2018)

e14561 Background: TYMS catalyzes methylation of dUMP to dTMP. As the sole de novo source of thymidylate in the cell it is an important target for 5-FU/CAP. Overexpression of TYMS has been linked to resistance to these agents both in vitro and in vivo. Cause of variability in TYMS expression is unclear, however, polymorphisms in 5 and 3 untranslated regions (5UTR and 3UTR) of TYMS gene have been described previously and these are suggested to have an impact on efficacy of TYMS-targeted chemotherapy. We analyzed TYMS genotyping and its role with outcome in pts treated with 5-FU/CAP. Methods: TYMS genotyping was assessed on 30 pts following severe AEs due to 5-FU/CAP. Evaluated TYMS polymorphisms included a 6 base pair deletion of 3'-UTR (DEL) vs. wild type insertion (INS), a variable number (either 2 or 3) of tandem repeats (2R, 3R) of 5'-TSER, and a G > C SNP in second repeat of 3R allele (3RG, 3RC). AEs were graded according to CTCAE v4.0. Data including age, gender, ethnicity, 5-FU/CAP dose, modifications and outcome were collected. Results: 30 pts tested for TYMS had median age 59 [M:F = 17:13] and included various ethnicities: 21 White, 6 Asian, 2 African American, and 1 other. ≥ 80% pts had advanced stage of GI cancers: 6 anus, 10 CRC , 5 pancreas, 3 stomach, 3 bile duct, 2 small bowel and 1 HCC. Commonly used regimens were FOLFOX, XELOX, EOX, CAP/5-FU-XRT, and Gem-CAP. TYMS genotype distributions for 3'-UTR were: 13% with INS/INS (normal); 33% INS/DEL (intermediate) and 13% DEL/DEL (low). For 5'-TSER, distributions were: 60% with low expression genotypes (10: 2R/2R; 21: 2R/3RC; 23: 3RC/3RC) and 40% with high expression genotypes (11: 2R/3RG, 54: 3RG/3RC, 37: 3RG/3RG). 60% of pts have ≥ 1 abnormality and 10 % had both TYMS and DPD abnormalities. Grade 3/4 AEs were neutropenia (16%), thrombocytopenia (16%), cardiotoxicity (6%), GI (16%), HFS (13%), mucositis (13 %) and neurologic (3%). 4 pts were re-challenged with l CAP and 1 pt tolerated. 2R/2R pts had benefit even with lower doses. Conclusions: Our study suggests that TYMS genotyping serves as a genetic/predictive marker to provide a potential treatment stratification to modulate 5-FU/CAP. These data should further be validated in prospective clinical studies.
Efficacy of cabazitaxel (CABA) rechallenge in heavily-treated patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Constance Thibault, Jean-Christophe Eymard, Anne-Claire Hardy-Bessard, Alison J. Birtle, Michael Krainer, Giulia Baciarello, Aude Flechon, Sylvestre Le Moulec, Dominique Spaeth, Brigitte Laguerre, Orazio Caffo, Jean-Laurent Deville, Philippe Beuzeboc, Ali Hasbini, Marine Gross-Goupil, Carole Helissey, Mostefa Bennamoun, Stephane Oudard
Journal: Journal of Clinical Oncology (2017)

5033 Background: Only 2 chemotherapies have shown an overall survival (OS) benefit in mCRPC: docetaxel (DOC) and CABA. In patients (pts) previously treated with a new hormonal therapy (NHT: enzalutamide or abiraterone), DOC and CABA, therapeutic options are limited. We previously reported some activity of DOC rechallenge in good responders to first-line DOC. We present here the results of a retrospective study evaluating the efficacy and safety of CABA rechallenge. Methods: Records of 70 mCRPC pts rechallenged with CABA were collected in 17 centers (France, Italy, UK, Austria). To be included, pts should have previously received DOC, NHT and CABA with a good response to CABA. Results: Of these 70 pts, 52 received DOC-NHT-CABA, 15 DOC-CABA-NHT and 3 NHT-DOC-CABA. At rechallenge, 83% had a high-volume disease (CHAARTED definition), 10% had visceral mets, 66% consumed narcotic analgesics, 68 % were ECOG 0-1 and median neutrophil/lymphocyte ratio (NLR) was 3.1. CABA was rechallenged for a median of 6 cycles (25 mg/m 2 q3w, 59%; 20 mg/m 2 , 27%; 16 mg/m 2 q3w 11%) with prophylactic G-CSF in 47%. Median time from last CABA cycle was 8.6 months (mo). CABA rechallenge had an acceptable tolerability: 7 pts (10%) had grade 3-4 toxicity (neutropenia). Data on efficacy are reported in Table 1. Median progression-free survival (PFS) was 11.3 mo with DOC, 12 mo with NHT, 11.9 mo with first CABA (median 8 cycles), and 7.8 mo with CABA rechallenge. Median OS calculated from the first life-extending therapy was 59.9 mo (95% CI 47.8; 66.4). Conclusions: This retrospective cohort of heavily treated mCRPC pts suggests that CABA rechallenge has a good activity with a manageable toxicity. CABA rechallenge might be an option in heavily treated pts still fit to receive chemotherapy. [Table: see text]
PD-1, PD-L1 in BRCA1/2-mutated and non-mutated epithelial ovarian carcinomas (EOCs).
Authors: Jasgit C. Sachdev, David Arguello, Brian L. Abbott, Sandeep K. Reddy
Journal: Journal of Clinical Oncology (2016)

e17057 Background: Published trials indicate tumor infiltrating lymphocytes (TILs) and PD-L1 expression may select patients who derive the most benefit from specific drug therapies. In breast cancer, the presence of TILs has been associated with improved responses to trastuzumab and cisplatin in HER2-positive and triple-negative breast cancer (TNBC), respectively. PD-L1 expression, meanwhile, has been associated with improved response to checkpoint inhibition. BRCA loss/mutation in TNBC has been associated with higher PD-L1 expression. These observations could be applicable in advanced EOC. The purpose of this study is to categorize PD-1 and PD-L1 distribution in EOC based on histology and BRCA1/2 molecular status. Methods: 2,510 EOC cases (e.g. clear cell, endometrioid, mixed, mucinous, serous, transitional) were evaluated (Caris Life Sciences) for PD-1 (MRQ-22) and PD-L1 (B7-H1, SP142 antibodies) expression by immunohistochemistry (IHC). BRCA1/2 was evaluated by next-generation sequencing (NGS), with “mutated” defined as pathogenic (i.e. tumorigenic) or presumed pathogenic mutations. Specimens containing only “variants of unknown significance” were excluded. Germline could not be determined. Results: Overall, PD-1-positive TILs were present in 70.8% (1776/2510) while aberrant (i.e. cancer cell) PD-L1 expression was present in 11.0% (275/2510) of cases. In BRCA1/2-mutated patients, PD-1+ TILs were detected in 77.9% (306/393) and PD-L1 expression in 9.4% (37/393) of cases. Where no BRCA1/2 mutations were detected, PD-1 TILs were detected in 66.1% (1243/1880) and PD-L1 expression 10.9% (204/1880) of cases. Statistically significant differences in PD-1 expression were detected between BRCA1/2-mutated and non-mutated serous ovarian carcinomas (77.0% [284/369] and 68.0% [1091/1605], respectively; p = 0.0007). Although other distributions varied between BRCA1/2-mutated and non-mutated EOC, none reached statistical significance. Conclusions: High PD-1/TIL infiltration and aberrant cancer cell PD-L1 imply checkpoint inhibition as an option for those with advanced disease. BRCA mutations were not associated with higher PD-L1 expression in this cohort. Additional investigation is warranted.
The MD Anderson modified cyclophosphamide, bortezomib, doxorubicin, and dexamethasone (mCBAD) for the treatment of newly diagnosed (NDMM) and relapsed/refractory multiple myeloma (RRMM).
Authors: Samer Tabchi, Ranjit Nair, Krina K. Patel, Hans Chulhee Lee, Sheeba K. Thomas, Behrang Amini, Sairah Ahmed, Rohtesh S. Mehta, Qaiser Bashir, Muzaffar H. Qazilbash, Donna M. Weber, Robert Z. Orlowski, Raymond Alexanian, Lei Feng, Elisabet Esteve Manasanch
Journal: Journal of Clinical Oncology (2018)

8044 Background: MM follows a clinical course leading to refractoriness and limited treatment options in RRMM. Aggressive NDMM needs rapid cytoreduction for disease control, which may not be possible with standard novel therapies. We report on a highly effective therapy that offers a salvage option for these patients. Methods: We searched our medical database for MM patients who received mCBAD from 2010-2016 – 28 day cycle of cyclophosphamide 350 mg/m2 IV twice daily + mesna 400mg/m2 IV daily (days 1-4), bortezomib 1.3 mg/m2 SQ (days 1, 4, 8, 11), doxorubicin 9 mg/m2 IV (days 1-4) , dexamethasone 40 mg PO daily (days 1-4, 9-12, 17-20). IMWG criteria were used for response assessment. Descriptive statistics, Fisher’s exact test, Chi-square, Wilcoxon rank sum, and Kaplan-Meier were used for statistical purposes. Results: 80 patients met the inclusion criteria. Baseline characteristics, response, adverse events, PFS/OS are summarized in Table 1. Median follow-up for the censored observations was 21.3 months (1.35 – 69.22). Conclusions: mCBAD offers excellent response rates (ORR > 90%) and favorable PFS/OS in highly refractory high risk MM. It is also an excellent salvage regimen with about half of patients undergoing subsequent transplant. Patient selection is required due high treatment related mortality. NDMM (n = 15) RRMM (n = 65) Age, median (range) 56 (36 -74) 65 (22 -75) ISS, n(%) I 1 (7.1) 15 (24.6) II 1 (7.1) 15 (24.6) III 12 (85.7) 31 (50.8) FISH, n(%) t(4:14) 2 (14.3) 6 (9.5) t(14;16) 0 2 (3.2) deletion 17p 2 (14.3) 21 (33.3) # cycles received, (%) ≤2 80% 80% ≥3 20% 20% # prior therapies, median (range) 0 2 (1 - 7) Prior ASCT, n (%) 0 24 (36.9) ORR^, n (%) 15 (100) 54 (91.5) CR 3 (20) 4 (6.8) VGPR 4 (26.7) 13 (22) PR 8 (53.3) 37 (62.7) PD 0 5 (8.5) Adverse events*, n(%) Neuropathy 3 (20) 20 (31) Febrile neutropenia 2 (13.3) 18 (27.7) Infection 5 (33.3) 26 (40.6) Mortality 0 8 (16%) PFS, mo (95% CI) 19.6 (10.3 - NR) 6 (3.9- 7.2) PFS (followed by ASCT) N/A 8.95 (6.9-15.9) (n = 28) PFS (not followed by ASCT) N/A 3.2 (2.2 - 4.2) (n = 34) OS mo (95% CI) 35.4 (18.1 - NR) 15.8 (9.3 - 23) *related to treatment, ^ best response - 59 evaluable RRMM, ASCT = autologous transplant
Immune related adverse events as a biomarker in non-melanoma patients treated with programmed death 1 inhibitors (PD-1Is).
Authors: Julia Judd, Matthew R. Zibelman, Elizabeth Handorf, John O'Neill, Sasini Bentota, Jamie Doyle, Robert G. Uzzo, Jessica Ruth Bauman, Hossein Borghaei, Elizabeth R. Plimack, Ranee Mehra, Daniel M. Geynisman
Journal: Journal of Clinical Oncology (2016)

3069 Background: The PD-1Is pembrolizumab (P) and nivolumab (N) have demonstrated clinical activity in multiple tumor types. They can lead to unique immune related adverse events (irAEs). Studies have shown conflicting results on whether the development of irAEs correlates with clinical response in melanoma patients (pts). Correlation of irAEs with better response in other cancer subtypes is unknown. Methods: We conducted a retrospective study of non-melanoma pts who received PD-1Is at our institution. The primary objectives were to correlate the development of any irAE, or any irAE requiring steroid use, with clinical response. Incidence of irAEs and steroid use was assessed via review of all relevant patient charts. Response was recorded at first restaging scan, and endpoints included overall response rate (ORR) per RECIST, overall survival (OS), and time to next therapy or death (TTNTD). Fisher’s exact tests were used to determine the association between irAE incidence and ORR and Kaplan-Meier curves with log-rank tests for the comparison of OS and TTNTD. Results: From November 2011-December 2015, 135 patients were treated with N or P; average age was 64 years, 88 (65%) were male. The majority received N (101, 75%). Cancer sub-type was as follows: non-small cell lung cancer (59, 44%), renal cell carcinoma (31, 23%), head and neck cancer (24, 18%), urothelial carcinoma (18, 13%), other (3, 2%). Overall, irAEs were noted in 60 (45.9%) with steroids required in 41 (30.4%). Endocrinopathies, dermatitis and colitis occurred in 25.9%, 7.4% and 6.7% of patients, respectively. Of the 112 pts for whom complete response data was available, we found no significant correlation between ORR and either incidence of any irAE (p = 0.21) or the use of steroids (p = 0.27). There was also no significant association of irAE incidence or steroid use with OS (p = 0.981, p = 0.954 respectively) or TTNTD (p = 0.277, p = 0.377 respectively). Conclusions: This retrospective review showed no association between the development of irAEs and outcomes in non-melanoma pts treated with PD-1Is. This data may be limited by sample size and disease heterogeneity, or may reflect differences in biology as compared to patients with melanoma.
18F-FDG PET/CT evaluation of tumor response to the implantation of RENCA macrobeads (RMB) in phase I and II clinical trials [INDBB 10091] in advanced, treatment-resistant metastatic colorectal cancer (mCRC).
Authors: Angelica Nazarian, Sudipta Sureshbabu, Zoe Padua Andrada, Joanne Thomas, Anna Arreglado, Nathaniel Berman, David J. Wolf, Lawrence S. Gazda, Thomas J. Fahey, Allyson J. Ocean, Barry H. Smith
Journal: Journal of Clinical Oncology (2017)

e15046 Background: RMB, a cytostatic, biological system form of anti cancer therapy have been used in Ph I &amp; II clinical trials in mCRC w/ evidence of improved survival benefit &amp; QOL. Evaluation of metastatic tumor response by standard CT RECIST criteria however has been unsatisfactory. We hypothesized that using 18F FDG PET/CT scan to evaluate tumor anatomy &amp; metabolism could provide a more accurate picture of tumor response to RMB Methods: 48 mCRC pts (14, Ph 1; 34, Ph 2a) who failed available treatments were implanted intraperitoneally w/ RMB (8mb/kg). Physicals, biomarkers &amp; lab evaluation were obtained at baseline &amp; days 14-90, with PET CT imaging at baseline &amp; day 90. PET scan was acquired 1 hour after FDG injection of 9.4 mCi. CT was used for attenuation correction. Correlation between 18F FDG PET SUVmax findings &amp; CEA &amp; or CA19-9 responses was assessed. Positive response was defined as ≥20% decrease post implant in CEA, CA19-9 &amp; SUV. Only tumors w/ SUVmax ≥ 2.5 were evaluated. SUV measurements were made by 1 radiologist experienced in PET-CT scanning &amp; SUV determination Results: 123 FDG positive mCRC lesions (39, Ph 1; 84 Ph 2a) were detected in 37 evaluable pts (14 m, 23 f; mean age 58.2; SUVmax 2.5-17.5). Of the 37 pts, 28 (76%) showed stabilization &amp; or decreased FDG uptake (4 w/ frank necrosis) as well as stable/decreased CT tumor measurements. Pts w/ pulmonary lesions showed greater responses than those w/ hepatic lesions. 9 (24%) of 37 pts showed increased SUVs. 23 pts (62%) showed decrease in CEA &amp; or CA 19-9 ≥ 20%. 17 pts (74%; 13 decrease, 4 central &amp; peripheral necrosis) had correlation between decreased SUVs/necrosis &amp; biomarkers decrease Conclusions: We conclude SUVs are useful in monitoring mCRC lesions response to RMB therapy. Changes in SUVs correlate w/ CEA &amp; CA 19-9 changes. Taken together the combined data indicate anti tumor effect in these Ph 1/2a trials &amp; offer preliminary support for our hypothesis that 18FDG can be useful in evaluating cell system therapies. Issues of SUVmax standardization &amp; effects of intra tumor heterogeneity however must be considered. Further studies are merited &amp; ongoing, including a planned Ph 3 trial Clinical trial information: NCT01053013; NCT00283075.
Abstract 12001: CHA2DS2-VASc Score Are More Predictive of Clinical Outcomes Compared With SYNTAX Score in Patients With Coronary Artery Disease
Authors: Daisuke Abe, Akira Sato, Tomohiko Harunari, Masako Misaki, Yuki Kakefuda, Tomoya Hoshi, Kazutaka Aonuma
Journal: Circulation (2014)

Purpose: To investigate the association among clinical outcomes, clinical variables (CHA2DS2-VASc score), and anatomical variables (SYNTAX score) in patients undergoing percutaneous coronary intervention (PCI) with coronary artery disease (CAD). Methods: A cohort of 1701 patients (69.7±10.7 years old, 77% male) who underwent PCI for CAD was analyzed from ICAS (Ibaraki Cardiovascular Assessment Study) multi-center registry between April 2007 to April 2010. We divided patients into 3 groups according to tertile of SYNTAX score; Low SYNTAX (0-8: n=567), Mid SYNTAX (9-15: n=567), and High SYNTAX (≧16: n=567). And we also divide into 3 subgroups on the basis of CHA2DS2-VASc score (low: 0-2, mid: 3-5, high: 6-8 point). Clinical outcomes were defined as major adverse cardiovascular event (MACE) which included all cause death, myocardial infarction, stroke, or hospitalization for worsening heart failure. Results: Mean follow up period was 440 days. Incidence of MACE was significantly increased according to increasing CHA2DS2-VASc score in high and low SYANTAX groups (figure). There was no relation between increasing SYNTAX score and MACE in each CHA2DS2-VASc subgroups. Receiver operating characteristics curve (ROC) showed area under the curve (AUC) was larger in CHA2DS2-VASc score than SYNTAX score for MACE (0.613 vs. 0.498). CHA2DS2-VASc score was an independent predictor of MACE after adjustment of multiple cofounders (per increase, OR: 1.30, 95% confidence interval: 1.17-1.43, p&lt;0.001), but not SYNTAX score (per increase, OR: 0.99, 95% confidence interval: 0.98-1.01, p=0.56). Conclusion: High CHA2DS2-VASc score provides worse clinical outcomes compared with SYNTAX score in patients with CAD in this registry.