tbuckley/cabot-search huggingface dataset:
Prognostic significance of tumor-infiltrating immune cells and PD-L1 expression in oesphageal squamous cell carcinoma.
Authors: Yu-Bo Jiang, Jian-Ming Xu, Anthony W.I. Lo, Angela Wong, Wen-Feng Chen, Yan Wang, Li Lin
Journal: Journal of Clinical Oncology (2017)

13 Background: Programmed death-1 receptor (PD-1) and its ligand (PD-L1) play an integral role in the immune response against cancer. This study investigated the prognostic significance of PD-L1 expression and tumor-infiltrating immune cells (TILs) in tumor microenvironment in Chinese patients with esophageal squamous cell carcinoma (ESCC). Methods: A total of 428 archival formalin-fixed, paraffin-embedded (FFPE) ESCC samples were collected between 2004 and 2014 from treatment naïve patients with ESCC after surgery or by diagnostic endoscopic biopsy. Expression of PD-L1 was assessed by IHC. The degree of TILs infiltration was evaluated by examining the H&amp;E-stained specimens. Associations of PD-L1 expression and TILs with clinicopathological features were evaluated by non-zero correlation test. Survival distribution was compared by Kaplan-Meier and a log-rank test. The median follow-up time was 34.4 months(0.3-147.1 m). Changes of PD-L1 expression between paired tumor samples, which were collected before and after chemotherapy (2 cycles and 4 cycles or more), were also evaluated. Results: In the entire cohort, 79.7% (341/428) of specimens were PD-L1+ (defined as having ≥ 1% of tumor cell membranes showing ≥ 1+ intensity). In the intent-to-treat group (patients received curative esophagectomy or definitive chemoradiation therapy), PD-L1 positivity was associated with a significantly poorer DFS and OS. Neither PFS nor OS in palliative chemotherapy group presented a significant difference corresponding to PD-L1 expression. Furthermore, PD-L1 expression was positively associated with TIL density. Changes in PD-L1 expression was examined in 17 paired tumor tissues collected before and after treatments. Results showed that an increase in PD-L1 expression was associated with disease progression, a decrease in PD-L1 expression was associated with satisfactory chemotherapy treatment response. Conclusions: PositivePD-L1 expression was associated with a significantly worse prognosis in ESCC. These observations suggest that PD-L1 may play a critical role in ESCC cancer progression and provide a rationale for developing PD-L1 inhibitors for treatment of a subset of ESCC patients.
Gemox versus surveillance following surgery of localized biliary tract cancer: Results of the PRODIGE 12-ACCORD 18 (UNICANCER GI) phase III trial.
Authors: Julien Edeline, Franck Bonnetain, Jean Marc Phelip, Jérôme Watelet, Pascal Hammel, Jean-Paul Joly, Meher Ben Abdelghani, Olivier Rosmorduc, Karine Bouhier-Leporrier, Jean-Louis Jouve, Roger Faroux, Véronique Guerin Meyer, Eric Assenat, Jean Francois Seitz, David Malka, Christophe Louvet, Aurelie Bertaut, Beata Juzyna, Trevor Stanbury, Eveline Boucher
Journal: Journal of Clinical Oncology (2017)

225 Background: No standard post-surgery adjuvant treatment is currently recommended in localized biliary tract cancer (BTC). Gemcitabine combined with platinum is the standard chemotherapy for advanced BTC. The aim of this phase III randomized trial was to assess whether GEMOX would increase relapse-free survival (RFS) while maintaining health-related quality of life (HrQoL). Methods: We performed a multicenter randomized phase III trial. Patients were randomized, within 3 months of R0 or R1 resection of a localized BTC (intra-hepatic, perihilar, extra-hepatic cholangiocarcinoma or gallbladder cancer), to receive either GEMOX 85 for 12 cycles (Experimental Arm A) or surveillance (Standard Arm B). Co-primary objectives were RFS and HrQoL. 190 patients and 126 RFS events were required to show an increase of median RFS from 18 to 30 months. Results: Between July 2009 and February 2014, 196 patients were included in 33 French centers. Baseline characteristics were balanced, with similar primary sites, R0 resection rates were 86.2% (Arm A) vs 87.9% (Arm B), lymph node invasion present in 37.2% vs 36.4%. In Arm A, a median of 12 cycles was delivered (mean: 9.3, range: 0-12). Maximal grade of adverse events were grade 3 in 57.5% vs 22.2%, and grade 4 in 17.0% vs 9.1%. During treatment one patient died in each arm. The main grade ≥ 3 adverse events in the year following inclusion were peripheral neuropathy (50.0% vs 1.1%), and neutropenia (22.3% vs 0%). Median follow-up was 44.3 months, with 54 and 64 RFS events in arms A vs B. There was no significant difference in RFS between the arms (log-rank p = 0.31), with a hazard ratio of 0.83 [95% CI: 0.58-1.19], p = 0.31 (futility boundaries were crossed). Median RFS was 30.4 [95% CI: 15.4-45.8] vs 22.0 months [95%CI: 13.6-38.3] in arms A &amp; B respectively, and 4-years RFS was 39.3% [95%CI: 28.4%-50.0%] vs 33.2% [95%CI: 23.1-43.7%]. Global Health HrQoL scores were not different at 12 months (70.8 vs 83.3, p = 0.18) and at 24 months (75.0 vs 83.3, p = 0.50). Conclusions: Adjuvant chemotherapy in BTC with GEMOX was feasible and associated with expected toxicities and no deterioration of HrQoL. There was no significant difference in RFS between GEMOX and surveillance. Clinical trial information: NCT01313377.
Cognitive Decline and Disrupted Cognitive Trajectory in Schizophrenia
Authors: Richard S. E. Keefe, René S. Kahn
Journal: JAMA Psychiatry (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Psychiatry HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Purchase Options: Buy this article Rent this article Subscribe to the JAMA Psychiatry journal
Rapid implementation of a personalized medicine research program (PMRP), using a targeted next-generation sequencing (NGS) assay, in the community setting.
Authors: Thomas David Brown, Philip Jordan Gold, Charles Drescher, John M. Pagel, J. David Beatty, Patra K Grevstad, Desiree Iriarte, Mariko Tameishi, April Smith, Danbin Xu, Anna B Berry
Journal: Journal of Clinical Oncology (2015)

e22055 Background: Cancer care is evolving to a model of precision medicine where somatic genomic changes in a patient’s (pt’s) tumor are increasingly used to inform individualized management. We report rapid implementation of a PMRP in the hybrid setting of a non-university, community based research practice. Methods: A custom designed gene alteration (GA) panel covering all relevant regions of 68 genes was developed using sequencing by synthesis on an NGS platform. The NGS results were used to: 1-prioritize standard therapies; 2-match pts with clinical trials (CTs); and 3-serve as a data mining resource. An Institutional Review Board (IRB) approved prospective registration protocol was activated in September, 2014 with the objective of establishing a centralized longitudinal clinical, molecular phenotypic, and research data repository for newly diagnosed pts. Analysis endpoints include proportion of pts where NGS influenced management or enrollment in CTs. NGS results were categorized as actionable (approved treatment options), applicable (off-label drugs or clinical trials), or of unknown significance. Billing for NGS was under medical necessity. Molecular Tumor Board was initiated in January, 2015. Results: As of 1/31/2015, 228 pts gaveinformed consent, with 225 pts eligible; 169 pts had results reported; 33 pts had report pending; 11 pts had inadequate DNA or tissue; 12 pts had NGS not ordered or cancelled. The most common primary sites included: colorectal-44; breast-36; lung-23; esophagus-11; kidney-11; ovary-7; gastric-4; unknown primary-3. 3 pts had no GAs. 52 pts (31%) had actionable GAs, and 94 pts (56%) had applicable GAs. The most common GAs were: TET2-131; KDR-75; RET-62; TP53-61; PIK3CA-53; APC-49; KRAS-44; ASXL1-21; EZH2-21; SMAD4-17; TYMS-17. 54 actionable GAs included: KRAS-44; EGFR-4; BRAF-3; NRAS-2; KIT-1. The most common of the 136 applicable GAs, included: TP53-48; PIK3CA-26; TYMS-17; TPMT-16; CTNNB1-8; JAK3-3; PTEN-3. Conclusions: Rapid development and implementation of an IRB approved PMRP in this setting is feasible. GAs were identified in 98% of pts, with actionable or applicable GAs identified in a majority of pts (72%).
Evaluation of a pharmacist-driven oral chemotherapy adherence program.
Authors: Iris Chen Zhao, Josephine Lai, Brian Seiki, Machelle Wilson, Laura A Brennan, Tianhong Li, Theodore Wun
Journal: Journal of Clinical Oncology (2015)

6569 Background: Oral anticancer drug therapy has increased: about 1/3 of new oncology drugs in development are for oral administration. The question of adherence may complicate interpretation of response and adverse events. In a study of adjuvant tamoxifen in women with breast cancer, Partridge showed a progressive decrease in adherence from 83% in the 1st year to 50% by the 4thyear of therapy. Strategies to improve adherence should optimize efficacy and minimize toxicity. We created an Oral Chemotherapy Adherence Program (OCAP), which provides education, adherence and toxicity monitoring, coverage verification, co-pay assistance, and delivery services. The purpose of this study was to assess the effect of OCAP on adherence to oral anticancer drugs. Methods: Patients enrolled in OCAP from October 2013 to October 2014 were ascertained. Adherence analysis was conducted for those on oral anticancer agents for 2 or more cycles both pre- and post-enrollment. Adherence rates for these patients were measured by medication possession ratio (MPR). MPR was calculated by dividing total days of drug supply by expected duration of therapy. MPR ranged from 0-1(1 = 100% adherence). High adherence was 80-100%. Pre- and post-enrollment MPR were compared using the paired t-test. Results: A total of 148 patients were enrolled in OCAP. Of these, 40 patients had received 2 or more cycles of therapy pre- and post-enrollment. Prior to enrollment, the mean (SD) adherence rate was 90.3% (19.9%) with 20% of patients falling into the 65-85% adherence range. 7.5% of patients fell below 40% adherence. After enrollment, the mean (SD) adherence rate was 99.3% (8.7%) with 97.5% of patients at 85% adherence or above. The lowest adherence rate post-enrollment was 68.5% in a patient with unreliable means of contact. The mean increase in adherence was 9.08% (23.2%), which was statistically significant (P = 0.02). Conclusions: Higher adherence rates were observed after enrollment into our oncology pharmacist-driven oral chemotherapy adherence program. Enrollment of patients into OCAP at the time of initiation of oral anticancer therapy would likely result in increased overall adherence rates. Effects of OCAP on other important outcomes, such as adverse events and costs, are ongoing.
Bevacizumab (BV) plus irinotecan (I) in recurrent glioblastoma multiforme (GBM): A single center experience.
Authors: Eluska Iruarrizaga, Eider Azkona, Unai Aresti, Itziar Rubio, Mikel Arruti, Sergio Carrera, Natalia Fuente, Ines Marrodan, Cristina Lopez Escola, Elizabeth Condori, Joan Manel Mane, Guillermo Lopez-Vivanco
Journal: Journal of Clinical Oncology (2013)

e13000 Background: Glioblastoma multiforme constitutes the most common and malignant form of primary brain tumor. Median survival for recurrent disease is 3-9 months. Combining bevacizumab with irinotecan represents an option of treatment in recurrent GBM. Methods: We performed a retrospective review of patients with recurrent GBM treated with bevacizumab (10 mg/kg) and irinotecan (340 mg/m 2 for patients receiving enzyme-inducing antiepileptic drugs –EIAEDs- and 125 mg/m 2 for patients not receiving EIAEDs) every 14 days on a 4-week cycle. Inclusion criteria: age ≥ 18, histology of GBM, progression after radiotherapy and temozolomide and signed informed consent for bevacizumab compassionate use. MRI-FLAIR sequence was used every 8 weeks to assess response. Results: From October 2009 to December 2012, a total of 26 patients were included; 15 (57.7%) male/11 (42.3%) female. Median age of the patients was 52 years (32-69); ECOG 0/1/2/3: 7.7/46.2/38.5/7.7% respectively; 19.23 % of patients received EIAEDs. Median number of cycles was 2.5 (1-14). Response rate was 30.8% (23.1% PR; 7.7 % CR); SD 23.1 %. Median PFS was 23 weeks; median OS was 30 weeks. Most common grade 3 toxicities were: asthenia 26.9%, arthromyalgia 3.8%, diarrhea 3.8% and hepatotoxicity 15.4%; grade 2 thromboembolic complications: 3.8 %. Conclusions: Combination of bevacizumab and irinotecan is effective against recurrent GBM and prolongs PFS and OS compared with historical controls, with mild toxicity.
Immunogenicity and safety of glucarpidase for methotrexate toxicity.
Authors: Brigitte C. Widemann, Stefan Schwartz, Emma Thomas, Nikhil Chauhan, Thomas King, Scott C. Howard
Journal: Journal of Clinical Oncology (2014)

e20648 Background: Glucarpidase converts methotrexate to non-toxic metabolites and is approved for treatment of high-dose methotrexate (HDMTX) induced renal dysfunction. Because it is a protein, an immune response to glucarpidase is possible, and if present could affect its safety. We determined the frequency of formation of anti-glucarpidase antibodies (AGA) and the impact of such antibodies on glucarpidase safety. Methods: Patients treated from 2007-2012 under an emergencyIND for patients with impaired MTX clearance secondary to renal dysfunction post-HDMTX received glucarpidase 50 U/kg IV over 5 minutes. Serum samples for AGA immunoassay were collected at pre-specified time intervals, and glucarpidase-related adverse events (AEs) were recorded. Results: Of the 205 patients assessed for AGA, the median age was 16.0 years (range: 0-85 years), 129 were male (62.9%), and diagnoses included ALL (38.0%), NHL (22.4%), and other cancers (39.6%). The median MTX dose was 5.0 g/m2 (range: 0.7 to 20 g/m2) given as infusions over 3-24 hours. The median first glucarpidase dose was 50.0 U/kg (range: 20.4-90.1 U/kg). 176 patients (87.8%) received 1 dose of glucarpidase and 29 (12.2%) received 2 or 3 doses (within a few days of the first dose). 190 serum samples for AGA were collected 1-2 weeks post-glucarpidase, 176 at weeks 4-6, 128 at months 2-4, and 118 at months 5-7. (See Table.) Five of 43 (11.6%) patients who were AGA+ had a glucarpidase related AE, compared to 10/162 (6.2%) who were not AGA+ (p=0.32). Conclusions: The likelihood of becoming AGA+ was higher after repeat doses of glucarpidase, but there was no association between glucarpidase-related AEs and presence of AGA after glucarpidase. The impact of prior antibody formation in the unlikely event that an AGA+ patient should require retreatment with glucarpidase is unknown. Clinical trial information: NCT00481559. All patients (N=205) Single dose of glucarpidase (n=176) ≥2 glucarpidase doses (n=29) AGA+ 43 (21%) 32 (18%) 11 (37.9%) AGA neutralization antibodies+ 22 (10%) 14 (8.0%)* 8 (27.6%)** *p=0.025; **p=0.005 for comparison between doses and formation of AGA neutralization antibody.
Patterns and predictors of psychological distress in adult survivors of childhood cancer: A Childhood Cancer Survivor Study (CCSS).
Authors: Norma Mammone D'Agostino, Kim Edelstein, Nan Zhang, Christopher J. Recklitis, Tara M. Brinkman, Deokumar Srivastava, Wendy M. Leisenring, Leslie L. Robison, Gregory T. Armstrong, Kevin R. Krull
Journal: Journal of Clinical Oncology (2015)

10065 Background: Screening for psychological distress is an important part of comprehensive survivorship care. While elevated symptoms of depression and anxiety have been reported, patterns of emotional comorbidity have not been examined. The aims of this study are to identify clusters of distress symptoms and to examine disease, treatment and demographic predictors. Methods: Latent profile analysis was conducted using 3 domains (depression, anxiety, somatization) from the Brief Symptom Inventory – 18 in siblings (N = 3085) and 5+ year survivors (N = 16032) from the CCSS. High distress was defined using t-score > 63. Bayesian information criterion and Lo-Mendell-Rubin adjusted certainty were used to select the optimal cluster number. Multinomial logistic regression was used among survivors to identify disease, treatment and demographic predictors of cluster membership stratified by sex. Results: Four latent clusters were identified: low distress on all 3 domains (well-adjusted); high distress on all 3 domains (global distress); high somatization relative to anxiety and depression (somatic distress); high anxiety and depression relative to somatization (affective distress). Compared to siblings, fewer survivors were well-adjusted (62% v. 74%) and more had global distress (11% v. 5%), both p’s < 0.0001. Diagnosis-specific patterns of distress were identified (leukemia and bone cancer: global distress, CNS: affective distress, Hodgkin lymphoma and neuroblastoma: somatic distress). More male (66%) than female (58%) survivors were well-adjusted, but more females reported somatic (17% vs 10%) and global (12% vs 9%) distress, all p’s < 0.0001. Among females, fair/poor perceived health (OR 30.9, 95% CL 19.4-49.1; compared to excellent health), headache (OR 2.69, 95% CL 2.24-3.24), and antimetabolite chemotherapy (OR 1.31, 95% CL 1.10-1.55) were associated with global distress. Perceived health and pain were associated with global distress in males. Conclusions: Results support the conceptual distinction between physical (somatic) versus affective (anxiety and depression) symptoms of distress and highlight sex differences and health-related predictors of distress.
Phase I study of weekly oral docetaxel (ModraDoc001) plus ritonavir in patients with advanced solid tumors.
Authors: Serena Marchetti, Frederik Stuurman, Stijn Koolen, Johannes Moes, Jeroen Hendrikx, Bas Thijssen, Alwin D.R. Huitema, Bastiaan Nuijen, Hilde Rosing, Marianne Keessen, Emile E. Voest, M. Mergui-Roelvink, Jos H. Beijnen, Jan H. M. Schellens
Journal: Journal of Clinical Oncology (2012)

2550 Background: ModraDoc001 is a novel oral formulation containing docetaxel as a solid dispersion. Oral administration of docetaxel is feasible in combination with the CYP3A4 inhibitor ritonavir. Objectives were to determine the safety, maximum tolerated dose (MTD) and pharmacokinetics (PK) of weekly oral docetaxel (as ModraDoc001) in combination with ritonavir. Methods: Patients with advanced solid tumors, WHO PS ≤ 2, no concomitant use of MDR or CYP3A modulating drugs, adequate bone marrow (ANC ≥ 1.5x10 9 /L), liver (bilirubin ≤ 1.5xULN, ALAT/ASAT ≤ 2.5xULN) and renal function (creatinine ≤ 1.5xULN or clearance ≥ 50 ml/min) were eligible. Docetaxel (ModraDoc001 10mg capsule) and ritonavir (Norvir 100mg) were simultaneously given once weekly in a ‘3+3 cohort’ dose escalation design. MTD was defined as the highest dose resulting in &lt;1/6 probability of causing a dose limiting toxicity in the first 4 weeks of treatment. This cohort was expanded with 6 patients. PK was determined on days 1 and 8. Results: 40 patients (25 male, 35 evaluable for safety) were enrolled in 6 dose levels (30/100, 40/100, 60/100, 80/100, 60/200 and 80/200 mg docetaxel/ritonavir). Common treatment related adverse events in the 4 highest dose levels were diarrhea (68%), nausea (62%) and fatigue (62%), mostly CTC grade 1-2 (80%, 95% and 73% respectively). Five patients experienced a DLT (grade 3 diarrhea (4), elevated ASAT/ALAT (1), grade 4 dehydration and grade 3 mucositis (1), grade 3 fatigue (2)). The MTD was 60 mg/200 mg docetaxel/ritonavir. Partial remission was seen in 4 patients (CUP, NSCLC, gastric and mamma ca) and sustained stable disease in 15 patients (6x NSCLC). Both drugs were rapidly absorbed after oral administration. Mean Tmax was 2.0 hours (CV=73%) for docetaxel. Cmax and AUC of docetaxel increased less than proportionally with dose to 162 ng/ml (CV= 67%) and 1615 ng/ml*hr (CV= 81%), respectively, in 15 patients at the MTD. Conclusions: At the MTD (once weekly 60 mg docetaxel and 200 mg ritonavir) ModraDoc001 is safe, well tolerated and shows encouraging antitumor activity. The exposure of docetaxel with this regimen is comparable to weekly intravenous administration of 35 mg/m 2 docetaxel. Phase II studies in solid tumors are planned.
Gleason grade 5 and the risk of death from prostate cancer following radiation with or without 6 months of conventional androgen deprivation therapy.
Authors: Laura Elizabeth Warren, Ming-Hui Chen, James William Denham, Allison Steigler, Andrew A. Renshaw, Marian J. Loffredo, Philip W. Kantoff, Anthony Victor D'Amico
Journal: Journal of Clinical Oncology (2015)

e16099 Background: Conventional androgen deprivation therapy (cADT; e.g. Zoladex) and radiotherapy (RT) in the treatment of high-risk prostate cancer (PC) reduces PC-specific morality (PCSM) compared to RT alone. Whether cADT reduces this risk to the same extent in men with Gleason grade (Gg) 3 and/or 4 vs. 5 PC remains unknown and was investigated. Methods: Individual patient data collected in 1995-2001 from 743 men with high-risk PC from two randomized trials (TROG 96.01, DFCI 95096) in which PCSM decreased when 6 months (mos) of cADT was added to RT formed the basis of the study cohort. Competing risks regression adjusting for PC prognostic factors, age at and year of randomization was used to determine the impact of 6 mos of cADT on PCSM risk in men with or without Gg 5 PC. Results: At a median follow-up of 11.64 and 11.50 years in the 38 and 499 TROG patients w/ and w/o Gg 5 PC, 20 (52.6%) and 83 (16.6%) experienced PCSM. The respective values after 15.09 and 14.31 years in the 22 and 184 DFCI patients were 6 (27.3%) and 18 (9.8%). Increased Gg 5 PC was present at biopsy when comparing the TROG vs. DFCI cohort (p=0.06; Table). Among men with Gg 3 and/or 4 PC, both trials observed a significant reduction in the risk of PCSM (DFCI: adjusted hazard ratio (AHR), 0.30; 95% confidence interval (CI), 0.09-0.96; P=0.04. TROG: AHR, 0.46; 95% CI, 0.28-0.75; P=0.002); whereas a significant reduction was not observed in men w/ Gg 5 PC (DFCI: AHR, 0.10; 95% CI, 0.002-6.1; p=0.27. TROG: AHR, 0.51; 95% CI, 0.16-1.65; P=0.26). Therefore, adding 6 mos of cADT to RT did not significantly reduce PCSM in men w/ Gg 5 PC and the AHR for treatment w/ 6 mos of cADT was higher in the TROG cohort where Gg 5 PC was more prevalent compared with DFCI. Together, these data provide evidence to support the hypothesis that 6 mos of cADT may be less effective in reducing PCSM in men w/ Gg 5 compared to Gg 3 and/or 4 PC. Conclusions: Gg 5 PC may be less sensitive to cADT compared to Gg 3 and/or 4 PC. Ongoing trials will address whether the addition of docetaxel or enzalutamide to cADT and RT will reduce PCSM risk in men w/ Gg 5 PC. Gleason score (GS) category TROG (n=38) DFCI (n=22) Fisher exact P Value GS 7 w tertiary Gg 5 0 (0%) 3 (14%) 0.06 GS 9 35 (92%) 18 (82%) GS 10 3 (8%) 1 (5%)