tbuckley/cabot-search huggingface dataset:
The utility of bi-weekly eribulin therapy for metastatic breast cancer: A Japanese multicenter phase II study (JUST-STUDY).
Authors: Tetsuhiro Yoshinami, Norikazu Masuda, Takahiro Nakayama, Fumikata Hara, Yasuaki Sagara, Hidetoshi Kawaguchi, Ken-ichi Watanabe, Masako Sato, Kenjiro Aogi, Kenji Higaki, Takashi Morimoto, Yasushi Shigeoka, Shinya Tokunaga, Hirotaka Morishima, Yasuhiro Yanagita, Junji Tsurutani, Shinichi Baba, Kazuhisa Katayama, Satoshi Morita, Shoichiro Ohtani
Journal: Journal of Clinical Oncology (2015)

1026 Background: The EMBRACE study established eribulin as a standard treatment for metastatic breast cancer (MBC). However, eribulin at the standard dose and schedule (1.4 mg/m2 on days 1 and 8 every 3 weeks) frequently leads to adverse events. The aim of this study was to investigate a new approach to control eribulin toxicity by schedule modification rather than dose modification. Methods: We conducted a multicenter phase 2 study to evaluate the efficacy and safety of bi-weekly eribulin. Eligibility criteria included MBC treated with both anthracycline and taxane, and up to three prior regimens of chemotherapy for MBC. Eribulin was started at the standard dose and schedule, but the schedule was changed to bi-weekly without dose reduction, if any of administration criteria were not satisfied by day 8 of the 1st cycle or day 1 of the 2nd cycle, or remained unchanged if all administration criteria were met at both time points. The primary endpoint was clinical benefit rate (CBR) of bi-weekly therapy based on RECIST v. 1.1. Secondary endpoints included time to treatment failure (TTF), OS, and safety. Results: From July 2012 to April 2014, 86 patients were enrolled, and 42 and 38 patients were placed in bi-weekly and standard therapy, respectively. The remaining 6 patients did not continue eribulin mainly due to disease progression just after first administration. Both treatment groups had a median of 2 prior chemotherapy regimens for MBC and similar characteristics. In the bi-weekly and standard therapy groups, the median dose intensity was 60.4% and 94.8% and the CBR was 31.0% and 21.1%, respectively. The median TTF was 81.5 days, and the median OS was 486 days in the bi-weekly group. No severe adverse event was reported in both groups. Conclusions: Bi-weekly eribulin therapy is effective and safe for patients unable to continue on the standard schedule of eribulin. This is the first report to show the utility of bi-weekly scheduling about eribulin. A phase 3 standard-of care trial of bi-weekly eribulin is needed.Clinical trial information: UMIN000008491.
Childhood, adolescent, and young adult cancer survivors (CAYACS) research program of British Columbia: Data linkage: Results to date
Authors: P. C. Rogers, M. Lorenzi, A. Broemeling, V. Glickman, K. Goddard, S. Pritchard, S. Sheps, L. Siegel, J. Spinelli, M. McBride
Journal: Journal of Clinical Oncology (2009)

9555 Background: Long-term survivors of childhood and adolescent cancers are at risk for late mortality and morbidity. Using database linkages we assessed the extent of these issues and health care utilization in a population based cohort in British Columbia. Methods: Retrospective cohorts of 3,483 survivors (&gt;5 years from diagnosis), and representative comparison groups, have been identified from population-based registries. Linkages were made with administrative databases of risk factors and outcomes. Late mortality, second cancers, late morbidity, health services utilization, continuity of care, and educational outcomes, among those diagnosed before age 20 between 1970 to 1995, and followed to 2000, have been examined. Results: Survivors experienced a 9-fold increase in mortality (SMR 9.1, 95% CI 7.8–10.5). Risk of developing a second cancer was 5 times higher than in the general population (SIR 5.0, 95% CI 3.8–6.5). Survivors had three times the odds of being hospitalized (OR 2.97, 95% CI 2.56–3.45) in a three-year period (1998–2000). Survivors were significantly more likely than the population group to consult any physician (excluding oncologists) (adj. RR 1.61, 95% CI 1.51–1.70). Survivors were found to experience a drop in continuity of primary health care as they aged and transitioned into adult care. Survivors were significantly more likely than their peers to receive special education (32.5% vs. 14.1%), most significantly among CNS survivors who received cranial irradiation. Conclusions: Survivors of childhood and adolescent cancers have severe long term health issues and increased health care utilization. Survivors of CNS tumors were at highest risk of poor health and educational outcomes measured. Data linkage provides useful insights for survivorship research. No significant financial relationships to disclose.
Rituximab Added to an Intensified Salvage Chemotherapy Program Followed by Autologous Stem Cell Transplantation Improve in Relapsed and Refractory Aggressive Non-Hodgkin-Lymphoma.
Authors: Michal Sieniawski, Jan-Peter Glossmann, Thorsten Reineke, Volker Diehl, Andreas Engert, Andreas Josting
Journal: Blood (2005)
Towards qualification of FDG PET as biomarker of response to neo-adjuvant therapy: A meta-analysis.
Authors: Andrew D. Vincent, Saiyada N. F. Rizivi, Harm van Tinteren, Ingrid Riphagen, Otto S. Hoekstra
Journal: Journal of Clinical Oncology (2013)

e22128 Background: For FDG PET to qualify as a biomarker of response to cancer therapy beyond proof of principle, the evidence should be aggregated. Methods: A systematic literature search (Jan 1995-May 2011) for studies in solid extracerebral tumors with distinct cohorts of n≥10 patients, PET before and after cytotoxic neoadjuvant systemic therapy (with or without radiotherapy), dichotomized histopathological (PA) response. For model development we selected studies reporting individual or dichotomous aggregated level data, and performed bivariate SROC meta-regression. Results: 52 studies were identified, comprising data from 1,710 patients: rectal (32%), esophageal (21%), sarcoma (20%), breast (13%) and other cancers (14%). Most PET measures were SUVmax (65%) and other SUV measures (32%). Treatment type ChT (38%) and ChRT (62%); 46% were PA responders. The meta-regression indicated a weak increase in specificity for chemotherapy studies over chemoradiotherapy studies (p=0.08), however this disappeared after adjusting for publication bias. High baseline uptake rates improved diagnostic sensitivity (p=0.01). The SROC-AUC after adjusting for publication bias was 0.77. Maximal sensitivity and specificity was achieved with a PET reduction of 60%. Conclusions: There is a moderate association between FDG-PET change and histopathological response. This relation appears to be a function of baseline uptake, which may (at least in part) relate to repeatability issues.
Autologous-collected anti-CD19 chimeric antigen receptor T cells (19CARTs) for pediatric acute lymphocytic leukemia (ALL) and non-Hodgkin lymphoma (NHL): Clinical activity and cytokine release without graft versus host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT).
Authors: Daniel Warnell Lee, Nirali Shah, Maryalice Stetler-Stevenson, Marianna Sabatino, Kelly Richards, Cindy Delbrook, James Kochenderfer, Steven A. Rosenberg, Dave Stroncek, Crystal Mackall, Alan S. Wayne
Journal: Journal of Clinical Oncology (2013)

10008 Background: Despite intensive chemotherapy and HSCT, outcomes in relapsed/refractory pediatric B cell ALL and NHL are poor. To treat children with or without prior allogeneic-HSCT and quickly deliver therapy, we developed a Phase I trial of 19CARTs for both HSCT-naive and post-allo-HSCT patients where autologous-collected T cells are manufactured in 11 days. Methods: T cells collected on Day -11 by lymphopheresis were positively selected and activated using anti-CD3/CD28 beads then transduced with the CD19-CAR gene via retrovirus. Cells were infused after 7 additional days of expansion. Patients (Pt) received fludarabine and cyclophosphamide prior to receiving 1e6 19CARTs/kg. Results: A 59-65 fold expansion of 19CARTs with 39-65% transduction efficiency was achieved in Pt 1 and 3 (ALL, NHL). Pt 1 achieved a complete response (CR). Mild cytokine release syndrome was observed (Gr 3 fever, Gr 2 hypotension) correlating with mild elevation in IL6, GM-CSF, INFg and C reactive protein (CRP; Table). No other non-hematologic, CAR-related Gr ≥3 toxicities were observed. Pt 2 (ALL) received 2.8% of the targeted cell dose due to lack of cell expansion likely from recent prior chemotherapy but experienced a transient CR with significant 19CART expansion (15% blood, 5% marrow, 6% CSF). Importantly, 19CARTs were well tolerated without evidence of GVHD in these post-allo HSCT patients. Conclusions: Autologous-collected allogeneic derived 19CART cells can be rapidly manufactured and safely administered to children with ALL and NHL. Clinical activity can be achieved without GVHD despite inflammatory cytokine generation. 19CARTs offer a potentially effective strategy to treat post-HSCT relapse warranting further study. Clinical trial information: NCT01593696. [Table: see text]
Combination therapy with potent PI3K and MAPK inhibitors overcomes adaptive kinome resistance to single agents in preclinical models of glioblastoma
Authors: Robert S McNeill, Demitra A Canoutas, Timothy J Stuhlmiller, Harshil D Dhruv, David M Irvin, Ryan E Bash, Steven P Angus, Laura E Herring, Jeremy M Simon, Kasey R Skinner, Juanita C Limas, Xin Chen, Ralf S Schmid, Marni B Siegel, Amanda E D Van Swearingen, Michael J Hadler, Erik P Sulman, Jann N Sarkaria, Carey K Anders, Lee M Graves, Michael E Berens, Gary L Johnson, C Ryan Miller
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Prognosis remains poor despite multimodal therapy. Developing alternative treatments is essential. Drugs targeting kinases within the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) effectors of receptor tyrosine kinase (RTK) signaling represent promising candidates.We previously developed a non-germline genetically engineered mouse model of GBM in which PI3K and MAPK are activated via Pten deletion and KrasG12D in immortalized astrocytes. Using this model, we examined the influence of drug potency on target inhibition, alternate pathway activation, efficacy, and synergism of single agent and combination therapy with inhibitors of these 2 pathways. Efficacy was then examined in GBM patient-derived xenografts (PDX) in vitro and in vivo.PI3K and mitogen-activated protein kinase kinase (MEK) inhibitor potency was directly associated with target inhibition, alternate RTK effector activation, and efficacy in mutant murine astrocytes in vitro. The kinomes of GBM PDX and tumor samples were heterogeneous, with a subset of the latter harboring MAPK hyperactivation. Dual PI3K/MEK inhibitor treatment overcame alternate effector activation, was synergistic in vitro, and was more effective than single agent therapy in subcutaneous murine allografts. However, efficacy in orthotopic allografts was minimal. This was likely due to dose-limiting toxicity and incomplete target inhibition.Drug potency influences PI3K/MEK inhibitor-induced target inhibition, adaptive kinome reprogramming, efficacy, and synergy. Our findings suggest that combination therapies with highly potent, brain-penetrant kinase inhibitors will be required to improve patient outcomes.
Comparing diets for weight loss and improvement in biomarkers in men with prostate cancer on surveillance: A pilot study.
Authors: Sharon Benson
Journal: Journal of Clinical Oncology (2017)

159 Background: Weight loss is recommended for treatment of prostate cancer, yet the most efficacious diet is not clear. The diet should improve biomarkers for prostate cancer, not increase risk of other chronic diseases, and be acceptable for long term use. Ascertaining appropriate dietary treatment for men on surveillance is crucial in preventing future cardiovascular disease, which is the leading cause of death in these men. Methods: Men with prostate cancer on surveillance and/or with untreated biochemical relapse followed 2 diets for 8 weeks of weight loss with random assignment to the order: (1) the diet recommended by the Prostate Cancer Foundation (PCF); (2) a plant-based, olive oil diet (PBOO), which included 3 tablespoons of extra virgin olive oil/ daily. After completing both diets, participants selected one of the diets for 6 months of follow-up (FU). Results: 30 started the protocol; 12 dropped out, 11 due to diet compliance (n = 3 PBOO; n = 8 PCF); 18 completed the 8 weeks of both diets and are reported here. Mean age: 66.6 + 5.9; baseline BMI: 30.9 + 2.7 kg/m 2 . Thirteen of the 18 have chosen the PBOO for FU. Conclusions: These results suggest a benefit with the PBOO diet in lowering insulin and glucose, and improving insulin function compared to the PCF diet. Despite similar weight loss, energy intake was higher on the PBOO diet. In addition, the PBOO diet was preferred over the PCF diet for long-term use. [Table: see text]
Population-based patterns of granulocyte colony stimulating factor (GCSF) use in breast cancer (BrCa) patients receiving myelosuppressive chemotherapy.
Authors: Michelle Lehmkuhl, Leo Chen, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2013)

9625 Background: Prophylaxis with GCSF can reduce hospitalization due to neutropenic fever, but early studies show that use of GCSF is frequently suboptimal. Our aims were to 1) characterize patterns of GCSF use in a population-based cohort of BrCa patients, 2) determine the rate of neutropenia and neutropenic fever in those who received and did not receive GCSF, and 3) identify patient and physician factors associated with appropriate GCSF prophylaxis. Methods: Patients diagnosed with BrCa from January to December 2008, seen at any 1 of 5 regional cancer centers in British Columbia, Canada and treated with chemotherapy protocols that posed &gt;20% risk of neutropenic fever were reviewed. Using regression models that adjusted for confounders, the relationship between GCSF use and 1) various patient and physician characteristics and 2) treatment outcomes, such as neutropenic fever, were analyzed. Results: A total of 525 women were included: median age was 51 years (IQR 45 to 59 years), 38% reported smoking, 50% used alcohol regularly, 62% were ECOG 0, and 26% had private health insurance. In the entire cohort, 203 (38%) patients were given GCSF. Among those treated with GCSF, 80 (39%) and 123 (61%) individuals received GCSF as primary and secondary prophylaxis, respectively. Overall, neutropenia was noted in 292 (56%) cases while neutropenic fever was experienced by 117 (22%) patients. When compared to those who did not use GCSF, patients who used GCSF experienced a lower rate of neutropenia (15 vs 49%, p&lt;0.01) and a decreased incidence of neutropenic fever (7 vs 13%, p&lt;0.01). In regression models, patients lacking extended medical coverage (35 vs 49%, p=0.02), poor performance status (31 vs 53%, p=0.03), and those who were evaluated at non-teaching institutions (24 vs 68% p&lt;0.01) were less likely to receive GCSF. Patients seen at non-teaching institutions were also given primary GCSF prophylaxis less frequently (15 vs 57%, p&lt;0.01) than those at teaching centers. Conclusions: GCSF prophylaxis was associated improved neutropenia-related outcomes. However, use of GCSF was low in this population-based cohort of BrCa patients, especially in specific marginalized subgroups.
Effect of reflex testing by pathologists on molecular testing rates in lung cancer patients: Experience from a community-based academic center.
Authors: Cengiz Inal, Emrullah Yilmaz, Haiying Cheng, Changcheng Zhu, James Pullman, Rasim A. Gucalp, Steven M. Keller, Roman Perez-Soler, Bilal Piperdi
Journal: Journal of Clinical Oncology (2014)

8098 Background: IASLC/CAP and NCCN guidelines recommend molecular testing for non-squamous non-small cell lung carcinoma (NSCLC) patients. Testing is usually performed upon request by medical oncologist. Reflex testing by pathologists for ER/PR/HER-2 is routinely done in breast cancer patients. We instituted reflex molecular testing at Montefiore Medical Center (MMC) on all non-squamous NSCLC patients in Jan 2012. Methods: We retrospectively reviewed our cancer registry database from Jan 2009 to July 2013 and analyzed all non-squamous NSCLC patients with pathology in our system. We examined annual molecular testing rates as well as testing rates before and after institution of reflex testing. Integrated Oncology (Labcorp) performed EGFR and KRAS testing by PCR-based technology. For patients with wild type EGFR and KRAS, the MMC cytogenetics laboratory performed ALK testing by FISH (Vysis assay). Results: From 2009 to July of 2013, 1,910 patients with lung cancer were identified in our cancer registry and 874 of these had non-squamous NSCLC with pathology diagnosed at MMC. At least 1 set of molecular tests was performed in 14, 25, 46, 64, and 69 % of patients in 2009, 2010, 2011, 2012 and 2013 respectively. The molecular testing rates pre (prior to 2012) and post (after 2012) reflex testing were 28% (166/598) vs 64% (177/276). The testing rates pre and post-reflex testing for EGFR, KRAS and ALK are 26 vs 62%, 6 vs 43% and 7 vs 23% respectively. Among the tested patients, the incidence of EGFR, KRAS and ALK positivity were 14% (46/326), 40% (61/152), and 1.9% (2/106) respectively. Of 276 patients post reflex testing, 52 (19%) had cytology-only NSCLC diagnoses; 75% (39/52) of these patients did not have any molecular testing. Conclusions: Reflex testing by pathologists increased the rate of molecular testing in a community based academic center. Despite the institution of reflex testing, ~30% of patients still do not have guideline recommended molecular testing. The reason for this is unclear; it may be in part due to lack of tissue available for molecular testing, particularly for cytology-only cases. We will further examine factors that influence the lack molecular testing in these patients.
Dietary emulsifiers directly alter human microbiota composition and gene expression ex vivo potentiating intestinal inflammation
Authors: Benoit Chassaing, Tom Van de Wiele, Jana De Bodt, Massimo Marzorati, Andrew T Gewirtz
Journal: Gut (2017)

<h3>Objective</h3> The intestinal microbiota plays a central role in the development of many chronic inflammatory diseases including IBD and metabolic syndrome. Administration of substances that alter microbiota composition, including the synthetic dietary emulsifiers polysorbate 80 (P80) and carboxymethylcellulose (CMC), can promote such inflammatory disorders. However, that inflammation itself impacts microbiota composition has obfuscated defining the extent to which these compounds or other substances act directly upon the microbiota versus acting on host parameters that promote inflammation, which subsequently reshapes the microbiota. <h3>Design</h3> We examined the direct impact of CMC and P80 on the microbiota using the mucosal simulator of the human intestinal microbial ecosystem (M-SHIME) model that maintains a complex stable human microbiota in the absence of a live host. <h3>Results</h3> This approach revealed that both P80 and CMC acted directly upon human microbiota to increase its proinflammatory potential, as revealed by increased levels of bioactive flagellin. The CMC-induced increase in flagellin was rapid (1 day) and driven by altered microbiota gene expression. In contrast, the P80-induced flagellin increase occurred more slowly and was closely associated with altered species composition. Transfer of both emulsifier-treated M-SHIME microbiotas to germ-free recipient mice recapitulated many of the host and microbial alterations observed in mice directly treated with emulsifiers. <h3>Conclusions</h3> These results demonstrate a novel paradigm of deconstructing host–microbiota interactions and indicate that the microbiota can be directly impacted by these commonly used food additives, in a manner that subsequently drives intestinal inflammation.
Blinded comparator study of immunohistochemistry (IHC) versus a 92-gene cancer classifier in the diagnosis of primary site in metastatic tumors.
Authors: Lawrence M. Weiss, Peiguo Chu, Brock Schroeder, Veena Singh, Yi Zhang, Mark G. Erlander, Catherine A. Schnabel
Journal: Journal of Clinical Oncology (2012)

e21019 Background: Metastatic tumors of uncertain or unknown origin pose diagnostic and therapeutic challenges. Accurate tumor classification is fundamental to inform predictive biomarker testing and optimize therapy. Standard of care employs IHC analysis for tumor classification that is varied in approach and interpretation. More recently, gene expression-based tests have been proposed as diagnostic aids. This study directly compared the diagnostic accuracy of IHC vs molecular classification with a 92-gene RT-PCR assay (CancerTYPE ID) for determination of primary tumor site. Methods: In this prospectively-defined, blinded study, 132 high grade, metastatic cases were selected by City of Hope (COH). Cases were reviewed and reference diagnoses established by clinical correlation (eg, patient history, imaging). Blinded FFPE sections were evaluated by either IHC or the 92-gene RT-PCR assay. Results were scored within a clinically-relevant categorization system designated by COH for main tumor type and subtype. The primary endpoint was concordance with the reference diagnosis. Study unblinding and data analysis were conducted by an independent third party. Results: Final analysis included 123 cases (mean age±SD: 61.2±14.4y, 52% female; grades 3/4; 90% metastatic); 9 cases were excluded (8: RNA quality; 1: insufficient tumor tissue). The 92-gene assay demonstrated an overall accuracy of 78% for tumor classification vs 68% for IHC (P = 0.017). For tumor subclassification, the 92-gene assay correctly identified 72% of tumors compared to 61% with IHC (P=0.029). Sensitivities were similar for GI (77%) and kidney (77%). The 92-gene assay demonstrated higher sensitivities for lung (75% vs 67%), urinary bladder (75% vs 42%), and breast (73% vs 55%). Mean IHC use was 7.8 stains per case (median: 8, range: 2-15). Conclusions: This is the first study to directly compare the diagnostic accuracy of IHC vs molecular classification. Results from this blinded series of high grade metastatic cases demonstrate superior accuracy with the 92-gene assay vs standard of care IHC, and strongly support the diagnostic utility of molecular classification in difficult to diagnose metastatic cancer.