tbuckley/cabot-search huggingface dataset:
Molecular testing in patients with refractory gastro-esophageal cancer: Is it time yet?
Authors: Sameh Mikhail, Anne M. Noonan, Kristen Keon Ciombor, Christina Sing-Ying Wu, Weiqiang Zhao, Lai Wei, Kristina Mathey, Melissa Yereb, Tanios S. Bekaii-Saab
Journal: Journal of Clinical Oncology (2015)

e15012 Background: Targeting HER2 has improved outcomes in metastatic gastroesophageal (mGE) cancer. Recently, targeting patients (pts) with refractory c-Met amplified mGE tumors with AMG 337 has shown very promising results. The list of actionable molecular alterations continues to expand. We aim to explore the utility and feasibility of genomic profiling in pts with refractory mGE cancer in routine clinical practice Methods: Archival formalin fixed paraffin embedded (FFPE) samples of 80 pts with mGE cancer were analyzed with commercially available foundation medicine next generation sequencing (NGS) or FISH for c-Metamplification and/or FISH and/or IHC for HER2 in the second line setting. Results: 80 patient samples were analyzed (37 by NGS and 43 by FISH for c-Met amplification). 76/80 pts also underwent IHC and/or FISH for HER2. Of the pts who underwent NGS, 35/37 (95%) had at least one actionable molecular alteration. The most notable actionable alterations included cell cycle abnormalities (CDKN2A loss, CCNE amplification, CDK4/6 amplification, and CCND amplification) in 21/37 (57%) pts, Erbb2 amplification in 8/37 (22%) pts, PIK3CA mutations in 6/37 (16%) pts, mcl1 amplification in 5/37 (14%) pts, PTEN loss in 4/37 (11%) pts, CDH1 mutation in 1/37 (3%) pts and c-Met amplification in 1/37 (3%) pts. Overall, a total of 4/80 pts (5%) demonstrated c-Met amplification (3 by FISH and 1 by NGS) with 3 expiring on first line chemotherapy before receiving any c-Met directed therapy. One pt with c-MET amplification was offered c-MET directed therapy. 7/8 (88%) pts with Erbb2 amplification were positive for HER2 by FISH and/or IHC. In contrast, only 7/12 pts positive for HER2 by IHC and/or FISH demonstrated Erbb2amplification by NGS. Conclusions: Comprehensive molecular testing is feasible in clinical practice and provides a platform for screening pts for molecularly guided clinical trials. We suggest identifying potential targets earlier in the course of disease given the limited window of opportunity as observed in the c-Met amplified group.
Abstract P204: Birth Cohort Effects and Lipid Trends—The Impact of the Obesity Epidemic: Evidence From Cohorts Born Between 1930 and 1998 in the United States
Authors: Thanh-Huyen T Vu, Donald Lloyd-Jones, Mercedes R Carnethon, John T Wilkins, Hy Tran, Sadiya S Khan
Journal: Circulation (2019)

Background: Decreasing total cholesterol (TC) and increasing high-density lipoprotein cholesterol (HDL-C) levels have been observed over the past several decades in the US population. It is not clear if the obesity epidemic has mitigated these favorable changes. Hypothesis: Associations between birth cohort and TC and HDL-C levels are partially attenuated by body mass index (BMI). Methods: We examined differences in TC and HDL-C levels across US birth cohorts born between 1930-1998 from the National Health and Nutrition Examination Surveys (NHANES) exam cycles 1999-2016, and the impact of body mass index (BMI) on these differences. A series of 10-year birth cohorts were constructed (1930-1998). Survey-weighted multivariable-adjusted linear regression models were used. Results: Among 40,273 participants, 50% were women and 22% non-Hispanic Blacks. After adjustment for age, sex, race, and lipid-lowering medication use, (and age 2 for the TC model), population mean TC decreased by 5.15 mg/dL and mean HDL-C increased by 1.34 mg/dL for each more recent birth cohort (all P&lt;.001) ( Table ). There was an interaction between age and birth cohort for TC, with greater decreases with aging; for example, the mean of TC was 4.14, 6.48, and 8.83 mmHg lower for each more recent birth cohorts at the age of 30, 50, and 70, respectively. BMI was positively associated with TC and negatively associated with HDL-C. However, BMI only slightly influenced the association of birth cohort with TC (2%), but it strongly influenced the birth cohort effect on HDL-C (31%). Conclusion: More recent birth cohorts had lower TC levels and higher HDL-C levels than older birth cohorts in the US. These favorable birth cohort effects were partially compromised by BMI. Research into the environmental and behavioral differences between 20 th century US birth cohorts is needed to support future efforts to reduce the prevalence of dyslipidemia.
A phase II, multicenter, single-arm trial of CV301 plus atezolizumab (Atezo) in locally advanced (unresectable) or metastatic urothelial cancer (UC).
Authors: Guru Sonpavde, Benjamin Louis Maughan, Xiao X. Wei, Bradley Alexander McGregor, Kerry L. Kilbridge, Richard J. Lee, Evan Yu, Michael Thomas Schweizer, Robert B. Montgomery, Heather H. Cheng, Andrew Caleb Hsieh, Ruemu E. Birhiray, Nashat Y. Gabrail, John J. Nemunaitis, Arash Rezazadeh, Peter J. Van Veldhuizen, Nicholas J. Vogelzang, Christopher Ryan Heery, Petros Grivas
Journal: Journal of Clinical Oncology (2019)

TPS494 Background: Anti-PD1/PD-L1 can achieve durable responses in advanced UC but most patients (pts) do not respond. Combination strategies with agents that “prime” the immune system may improve outcomes. CV301 comprises two recombinant poxviruses, Modified Vaccinia Ankara (MVA) and Fowlpox (FPV), encoding the human transgenes for CEA, MUC-1, and a Triad of Co-stimulatory Molecules (TRICOM: ICAM-1, LFA-3, and B7-1). MVA-CV301 is used for priming doses and FPV-CV301 is used for booster doses to achieve a heterologous prime boost regimen. In preclinical studies, BN-platform vaccine plus PD1/PD-L1 inhibitors exhibited synergistic anti-tumor efficacy, T-cell infiltration, and PD-L1 upregulation in tumors. CEA and MUC-1 are expressed, in 41-90% and 55-91% of any stage UC, respectively, and in ~100% of metastatic UC. An ongoing Phase Ib trial of CV301 plus anti-PD-1 agent has demonstrated a similar safety profile to anti-PD-1 monotherapy with only mild vaccine-related adverse events (AEs). Methods: This is a Phase 2, single-arm, multi-institutional trial designed to study CV301 plus atezo as 1st-line treatment in pts with advanced UC ineligible for cisplatin-based chemotherapy regardless of PD-L1 (Cohort 1) and as salvage treatment in pts with UC progressing after platinum-based chemotherapy (Cohort 2). MVA-CV301 is given subcutaneously (SC) on Days 1 and 22 and FPV-CV301 SC every 21 days for 4 doses, then every 6 weeks until 6 months, then every 12 weeks until 2 years. Atezo 1200mg is given every 21 days. Primary endpoint is objective response rate (ORR; RECIST 1.1). Secondary endpoints: immune response, OS, PFS, response duration, AEs. Tumor and serial blood samples will be collected for biomarker analyses; 1-sided α is 0.025/cohort in this design. With a 2-stage design, success criteria are based on historic ORR (H0) and alternative ORR (H1) with ≥70% power. For Cohort 1, assuming H0 = 0.23, H1 = 0.43, then Cohort 1 sample size N 1 = 14, responders required at stage 1 to continue R 1 ≥3, total accrual goal N = 33, total responders to reject H0, R≥13. For Cohort 2, assuming H0 = 0.15, H1 = 0.33, then N 1 = 13, R 1 ≥2, N = 35, R≥10. Accrual has begun; completion is expected within 1 year. Clinical trial information: NCT03628716.
Beat of the Same Drum
Authors: Arielle Elkrief
Journal: JAMA Oncology (2019)

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Intentional content in psychopathologies requires an expanded interpretivism
Authors: Marc Slors, Jolien C. Francken, Derek Strijbos
Journal: Behavioral and Brain Sciences (2019)

Abstract We argue that the explanatory role of intentional content in connecting symptoms in a network approach to psychopathology hinges neither on causality nor on rationality. Instead, we argue that it hinges on a pluralistic body of practical and clinical know-how. Incorporating this practical approach to intentional state ascription in psychopathological cases expands and improves traditional interpretivism.
Brain Tumor Trials Collaborative Bayesian Adaptive Randomized Phase II trial of bevacizumab plus vorinostat versus bevacizumab alone in adults with recurrent glioblastoma (BTTC-1102).
Authors: Vinay K. Puduvalli, Jing Wu, Ying Yuan, Terri S. Armstrong, Morris D. Groves, Jeffrey J. Raizer, Pierre Giglio, Howard Colman, David M. Peereboom, Tobias Walbert, Nicholas George Avgeropoulos, Fabio Massaiti Iwamoto, Marc C. Chamberlain, Nina Paleologos, Karen L. Fink, Ryan Merrell, W. K. Alfred Yung, Mark R. Gilbert
Journal: Journal of Clinical Oncology (2015)

2012 Background: Bevacizumab (Bev) is approved in the US for patients (pts) with recurrent glioblastoma based on response rate. However, adaptive resistance to antiangiogenic agents can result in tumor recurrence. Deacetylase inhibitors such as vorinostat (Vor) have pleotropic effects against several pathways potentially relevant to adaptive resistance to Bev. Methods: We conducted a phase II multicenter trial with Bayesian adaptive randomization of patients to Bev alone or Bev+Vor with a primary endpoint of progression-free survival (PFS) and secondary end points of overall survival (OS) and patient-reported symptoms using the M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT). Eligible patients were adults ( ≥ 18y) with histologically confirmed GB who had recurrent disease after prior radiation and temozolomide therapy, KPS ≥ 60, and no prior Bev or HDAC inhibitors. Results: Of the 90 pts (Bev+V: 49, Bev: 41) enrolled between Oct 2012 and Oct 2014, 83 were evaluable for the primary endpoint (Bev+V: 46, Bev: 37). MDASI-BT scores were available for 81 pts. There was no significant difference between the two arms in median PFS (4.2 vs.3.6 months, p = 0.53) or median OS (8.3 vs. 7.0 months, p = 0.93). Analysis of the MDASI-BT scores showed no significant differences between the two arms in overall symptom burden or interference (p = 0.48, 0.71 respectively). Overall, 61 pts had died by the time of analysis (Bev+V: 35, Bev: 26) with one treatment related death due to pulmonary embolism. Toxicity ≥ grade 3 included hypertension (n = 17), neurological changes (n = 2), infections (n = 2), wound dehiscence (n = 2), DVT/PE (n = 2), and colonic perforation (n = 1). Conclusions: In this trial, Bev+Vor did not yield an improved PFS or OS or clinical benefit in terms of reduced symptom burden compared with Bev alone in patients with recurrent GB and does not warrant further investigation. To our knowledge, this trial represents the first prospective Bayesian adaptive randomized therapeutic study against gliomas and demonstrates the feasibility of conducting studies with adaptive trial designs in a multicenter setting. Clinical trial information: NCT01266031.
Abstract 19162: Dual Mechanisms of Cardiac Sodium Channel Inhibition by Wnt/β-catenin Signaling
Authors: Aizhu Lu, Maryam Kamkar, Bin Xu, Yawen Chen, Weixin Liu, Eduardo Marban, Wenbin Liang
Journal: Circulation (2017)

Background and Hypothesis: Wnt/β-catenin signaling is activated in arrhythmogenic heart disease. We have recently demonstrated that activation of Wnt/β-catenin signaling leads to reductions in cardiac Na+ current (INa), a condition that promotes arrhythmias. But the underlying mechanisms are not known. Here, we report evidence that support two separate mechanisms for INa inhibition: Wnt/β-catenin leads to transcriptional activation of Tbx3, which suppresses expression of Scn5a (the cardiac Na+ channel α subunit gene); in addition, Wnt/β-catenin directly inhibits Scn5a transcription. Methods and Results: 1) activation of Wnt/β-catenin signaling in neonatal rat ventricular myocytes (NRVMs) by exposure to Wnt3a protein led to reductions (p<0.05) in both Nav1.5 protein and Scn5a mRNA levels; 2) qRT-PCR screening of a group of transcription factors that are known to regulate Scn5a expression identified Tbx3, a transcriptional suppressor, as a gene upregulated by Wnt/β-catenin; bioinformatics analysis of the Tb...
Direct evidence of a clonal and tumor-directed T cell response to prostate cancer brachytherapy.
Authors: Scott Williams, Simon Keam, Heloise Halse, Catherine Mitchell, Franco Caramia, David Byrne, Sue Haupt, Georgina Ryland, Phil Darcy, Shahneen Kaur Sandhu, Piers Blombery, Ygal Haupt, Paul J Neeson
Journal: Journal of Clinical Oncology (2019)

22 Background: We characterised the immune response in human prostate cancer (PC) to high dose rate brachytherapy (HDRBT) using serial pre- and post-HDRBT biopsies. Methods: Prostate biopsies and peripheral blood samples were obtained from 9 men with clinically localised PC at baseline and again 14 days following a 10 Gy fraction of HDRBT. Immune infiltrates were characterised using multiplex immunohistology (T cell and pan-immune panels) and targeted gene expression profiling (Nanostring pan-cancer immune panel). T cell repertoire was assessed using T cell receptor (TCR) Vbeta CDR3 deep sequencing. Results: HDRBT induced profound but heterogenous immune responses. At the extremes, one patient had an extensive tumor-infiltrating lymphocyte (TIL) response post-HDRBT, comprising T cells (CD4 + &gt; CD8 + &gt; Treg), B cells, and PDL1 + antigen presenting cells (macrophages and CD11c+ dendritic cells); another had a substantial baseline immune infiltrate eliminated by HDRBT. TIL-hi cases (either before or after HDRBT) had a conserved signature of T cell activation, differentiation, and trafficking, with upregulation of checkpoint molecules PD1, IDO1, BTLA, CTLA4, ICOS, B7-H3 and FoxP3. Those TIL-hi specifically in response to HDRBT also had down-regulation of genes regulating myeloid differentiation and granulocyte chemotaxis pre-HDBRT. Conversely, a monocyte-like myeloid-derived suppressor cell signature was seen in the TIL-lo responders. The median number of dominant clones ( &gt; 1% prevalence) determined by TCR sequencing was 24.5 and 26.5 pre- and post-HDRBT respectively. Only 2 clones (in 1 patient) were present at both time points with the T cell repertoire otherwise being completely new following HDRBT. A subset of PC-associated T cell dominant clones was also present in the PB in all patients, suggesting HDRBT can induce systemic immunity. Conclusions: We have shown that treatment of localized prostate cancer with HDRBT induces a marked clonal TIL infiltrate dominated by T cells likely to be operating under the control of multiple checkpoints. These first-in-human data may be able to inform the rational selection of immunotherapy to combine with HDRBT.
A phase II trial to evaluate pemetrexed clinical responses in relation to tumor methylthioadenosine phosphorylase (MTAP) gene status in patients with previously treated metastatic urothelial carcinoma.
Authors: Omar Alhalabi, Matthew T Campbell, Rebecca Slack-Tidwell, Arlene O. Siefker-Radtke, Amishi Yogesh Shah, Eleni Efstathiou, Wei-Lien Wang, Mark Anton Titus, Bogdan Czerniak, Miao Zhang, Charles Guo, Christopher Logothetis, Jianjun Gao
Journal: Journal of Clinical Oncology (2019)

385 Background: According to The Cancer Genome Atlas, 26.8% of bladder tumors harbor homozygous deletion of the MTAP gene, which encodes for an essential enzyme for the salvage pathway of nucleotide synthesis. Pemetrexed is a well-known anti-folate agent that inhibits the de novo pathway of nucleotide synthesis. Therefore, we hypothesized that tumors with MTAP gene loss have a synthetic lethality to pemetrexed due to loss of both essential nucleotide synthesis pathways. We proposed a study to determine pemetrexed response rate in patients with MTAP-deficient metastatic urothelial carcinoma (mUC). Methods: We carried out a single-arm, open-label, phase II clinical trial with pemetrexed in patients with mUC and MTAP loss by immunohistochemistry. This is an interim analysis of results. Each patient receives pemetrexed (500 mg/m2) on day 1 of each 21-day cycle. Pemetrexed is continued until progression of disease (PD) and a repeat biopsy is obtained at that time. Pre- and post-treatment blood, urine and tumor samples are obtained for dynamic monitoring of immune and molecular correlates to clinical activity. Results: Six patients have been enrolled on this trial and all have received at least one previous treatment including a cisplatin-containing regimen in 5 (83%) patients and an immune checkpoint inhibitor in 4 (66%) patients. Of these 6 patients, 1 (17%) had complete response (CR); two (33%) had partial response (PR); 1 (17%) had stable disease; 1 (17%) was not evaluable; 1 (17%) had PD. Treatment was generally well tolerated with mostly grade 1 or 2 adverse events. Only 2 of 6 patients developed grade 3 anemia. Immunologic and molecular analyses are ongoing on all collected samples. Conclusions: Our study show that in heavily pretreated MTAP deficient mUC patients, pemetrexed is still an effective and well-tolerated therapy with an objective response rate (ORR=CR+PR) of 50%, which is higher than previously reported pemetrexed activity (ORR=8-28%) as first or second line treatment for mUC. Clinical trial information: NCT02693717.
The novel butyrate derivative phenylalanine‐butyramide protects from doxorubicin‐induced cardiotoxicity
Authors: Michele Russo, Fiorentina Guida, Lorella Paparo, Giovanna Trinchese, Rosita Aitoro, Carmen Avagliano, Antonella Fiordelisi, Fabiana Napolitano, Valentina Mercurio, Valentina Sala, Mingchuan Li, Daniela Sorriento, Michele Ciccarelli, Alessandra Ghigo, Emilio Hirsch, Roberto Bianco, Guido Iaccarino, Pasquale Abete, Domenico Bonaduce, Antonio Calignano, Roberto Berni Canani, Carlo G. Tocchetti
Journal: European Journal of Heart Failure (2019)
Using preclinical PD/E correlations to derive an optimal PD threshold for phase-1 decision-making.
Authors: Ekta Kadakia, Andrew Chen, Munjal Patel, Cindy Xia, Marc Hyer, Yuko Ishii, Dean Bottino, Jing-Tao Wu, Jeffrey Ecsedy, Arijit Chakravarty
Journal: Journal of Clinical Oncology (2015)

e13579 Background: During phase-1 oncology trials, early pharmacodynamic (PD) signals are often interpreted as predicting later outcomes of antitumor activity (E). A major complication in making this assessment is that most PD biomarkers are necessary but not sufficient in nature (i.e. low PD translates into no E, but high PD may or may not result in E). In the following work we present a novel model-based approach using receiver operating characteristic (ROC) analyses, to improve the predictive power of xenograft based preclinical PD/E correlations to guide phase-1 decisions. This approach, which relies on the assumption that the PD/E relationship in (human-derived) xenograft tumors and (human) clinical tumors is roughly the same, is illustrated here using a blinded preclinical PD/E data set. Methods: PK/PD/E modeling was performed on preclinical data for drug X in 5-6 different tumor models. Preclinical PD/E correlations were established for Marker 1 and Marker 2. Both markers appeared to be necessary but not sufficient for antitumor activity. Using projected human PK parameters, the PD/E correlation was updated to resemble the projected clinical setting. The predicted clinical PD/E correlation was empirically modeled to estimate the population parameters describing the observed PD/E curves and simulate a population (5000) of PD/E curves for both the PD markers. Using ROC analyses on the simulated data, PD thresholds were optimized to predicts anti-tumor activity of stasis or greater. Results: Modeling and simulation of the predicted clinical PD/E correlation enabled us to quantitatively factor in the uncertainty associated in using PD markers to predict E. Optimizing PD thresholds using ROC analyses improved the sensitivity, specificity and predictive value of the PD markers. Conclusions: Necessary but not sufficient PD markers are hard to use in decision-making, as they only probabilistically enrich for efficacy. Using ROC analyses on preclinical PD/E correlations, we can optimize PD thresholds to predict a given level of antitumor activity and also quantify its predictive value. This method provides an objective approach to set PD thresholds at the end of phase-1 to assist clinical decision making.
Clinical significance of serum claudin-7 levels in patients with colorectal cancer.
Authors: Fatma Aydogan, Mehmet Karabulut, Halil Alis, Senem Karabulut, Koray Celebi, Hamza Ugur Bozbey, Kayhan Ertürk, Sezai Vatansever, Nuri Faruk Aykan
Journal: Journal of Clinical Oncology (2015)

e14533 Background: Claudin-7 (CLDN7) belongs to the claudin family which consists of 24 subtypes of essential tight junction integral membrane proteins with molecular weights of 20-27 kDa. Tight junction proteins in the cell organize paracellular permeability and they play a critical role in apical cell-to-cell adhesion and epithelial polarity. Their decreased expression in colorectal cancer seems to have critical effects on cell proliferation, motility, invasion, and immune response against the tumor. We investigated the interrelationship between clinicopathological findings and serum levels of CLDN7 in colorectal cancer (CRC). Methods: One hundred forty CRC patients were enrolled into this study. Pre-treatment serum CLDN7 levels were determined by enzyme-linked immunosorbent assay (ELISA) method. Age- and sex-matched 40 healthy controls were included in the analysis. Results: Median age of patients was 60 years old, range 24 to 84 years. The localization of tumor in majority of the patients was colon (n = 81, 58%). Median follow-up time was 14 months, while forty-three (31%)patients experienced disease progression, thirty-one (22%) of the remaining patients died. The number of patients who received neoadjuvant treatment and adjuvant chemotherapy (CTX) were 37, 71, respectively. Of the patients who received palliative CTX, 24 had oxaliplatin-based combination whereas 22 and 9 had irinotecan-based combination and single agent FU/capecitabine, respectively.Thirty-six and 15 of the patients who received targeted therapy had bevacizumab and cetuximab, respectively.Thirty-one percent of 55 metastatic patients who received palliative CTX were CTX-responsive. The baseline median serum CLDN7 levels were significantly lower in patients than in the healthy control group (p < 0.001). Moreover, known clinical variables including low T status and normal CEA were found to be correlated with high serum CLDN7 concentrations (p = 0.04 and p = 0.02, respectively).Our study results did not show statistically significant serum CLDN7 concentrations regarding progression-free survival and overall survival. Conclusions: Reduced serum levels of CLDN7 might be useful markers in the differential diagnosis of CRC than healthy controls.