tbuckley/cabot-search huggingface dataset:
Oxaliplatin desensitization after hypersensitivity reaction: A single-center experience on more than 300 procedures.
Authors: Florence Le Roy, Eugénie Rigault, David Regnault, Nicole Hubert, Pascal Burtin, Antoine Hollebecque, David Malka, Valerie Boige, Michel Ducreux
Journal: Journal of Clinical Oncology (2018)

610 Background: Oxaliplatin is an essential drug in gastrointestinal oncology. Hypersensitivity reactions (HSR) occur frequently (incidence varying from 10% to 25%), leading to permanent treatment discontinuation. The present study aimed to report our experience of oxaliplatin desensitization in patients with history of HSR to oxaliplatin. Methods: We retrospectively reviewed all patients who received at least one infusion of oxaliplatin according to a desensitization protocol after prior history of HSR to oxaliplatin, from June 2011 until June 2017. HSRs were classified from NCI CTC-AE grade 1 (transient rash, fever &lt; 38°C) to grade 4 (anaphylaxis). We applied in all cases a desensitization protocol in which the oxaliplatin infusion rate is gradually increased from 1mL/hr. to 150mL/hr., on an inpatient basis. Intravenous or hepatic arterial infusion was used depending on clinical setting. Results: Overall, 54 patients were included in this study, in whom HSR to oxaliplatin occurred after a median of 9 infusions (range, 1-31). The severity of HSRs was grade 1-2 in 33 patients (61%) and grade 3-4 in 21 patients (39%). A total of 305 oxaliplatin infusions according to a desensitization protocol were performed in these 54 patients (median, 5 infusions; range, 1-20). These infusions were by intravenous route in 42 patients (78%), by hepatic arterial route in 11 patients (18%), and both in 2 patients (4%). Infusions were well tolerated in 41 patients (76%), without new HSR. The remaining 13 patients (24%) experienced HSR recurrence (grade 2, 9 patients [69%]; grade 3, 4 patients [31%]). No anaphylaxis or oxaliplatin-related death occurred. In the 21 patients with a prior history of severe (grade 3-4) HSR, oxaliplatin desensitization procedure was effective and sustained in 16 patients (79%). Among 32 evaluable patients, 23 (72%) experienced disease control (14 partial responses, 9 stable diseases). Conclusions: Rechallenging Oxaliplatin desensitization procedure was successful in three out of four patients with prior history of HSR to oxaliplatin. Our retrospective study confirms that oxaliplatin desensitization is safe, and allows patients who developed HSR to continue an effective treatment.
Effects of promoting longer-term and exclusive breastfeeding on adolescent adiposity, blood pressure, and longitudinal growth trajectories:: evidence from the PROBIT cluster-randomized trial
Authors: Richard Martin, Michael S. Kramer, Rita Patel, Sheryl L Rifas-Shiman, Jennifer Thompson, Seungmi Yang, Konstantin Vilchuck, Natalia Bogdanovich, Mikhail Hameza, Kate Tilling, Emily Oken
Journal: JAMA (2017)
NCCN Guidelines Insights: Colon Cancer, Version 2.2018
Authors: Al B. Benson, Alan P. Venook, Mahmoud M. Al-Hawary, Lynette Cederquist, Yi-Jen Chen, Kristen K. Ciombor, Stacey Cohen, Harry S. Cooper, Dustin Deming, Paul F. Engstrom, Ignacio Garrido-Laguna, Jean L. Grem, Axel Grothey, Howard S. Hochster, Sarah Hoffe, Steven Hunt, Ahmed Kamel, Natalie Kirilcuk, Smitha Krishnamurthi, Wells A. Messersmith, Jeffrey Meyerhardt, Eric D. Miller, Mary F. Mulcahy, James D. Murphy, Steven Nurkin, Leonard Saltz, Sunil Sharma, David Shibata, John M. Skibber, Constantinos T. Sofocleous, Elena M. Stoffel, Eden Stotsky-Himelfarb, Christopher G. Willett, Evan Wuthrick, Kristina M. Gregory, Deborah A. Freedman-Cass
Journal: Journal of the National Comprehensive Cancer Network (2018)

The NCCN Guidelines for Colon Cancer provide recommendations regarding diagnosis, pathologic staging, surgical management, perioperative treatment, surveillance, management of recurrent and metastatic disease, and survivorship. These NCCN Guidelines Insights summarize the NCCN Colon Cancer Panel discussions for the 2018 update of the guidelines regarding risk stratification and adjuvant treatment for patients with stage III colon cancer, and treatment of
Phase II study of oxaliplatin and sorafenib in advanced gastric cancer after failure of cisplatin-fluoropyrimidine-based (PF) treatment.
Authors: Rosa Gallego, Marta Martin-Richard, Carles Pericay, Jesus Garcia-Foncillas, Bernardo Queralt, Esther Casado, Jaime Feliu, Iranzazu Vega, Ignacio Juez, Laura Visa, Eugeni Saigí, Xabier Garcia-Albeniz, Agust Barnadas, Joan Maurel
Journal: Journal of Clinical Oncology (2012)

4079 Background: PF-based chemotherapy is the standard first line treatment in advanced GC. Although some drugs as taxanes or oxaliplatin (Ox) have shown efficacy in combination with P or F, no established second line exists. RAF/MEK/ERK pathway activation as well as VEGF expression have been related with more advanced GC. Sorafenib (S) is a potent Raf and VEGFR inhibitor and Ox has demonstrated non-cross resistance with P. Methods: A multicenter phase II to evaluate the efficacy of OX- S combination in gastric or GEJ adenocarcinoma (pts) with progressive disease after CF based first line chemotherapy, was planned. Other inclusion criteria: ECOG 0-2, measurable disease and adequate organ function. Treatment doses were Ox 130mg/m 2 /3 weeks and S 800 mg/bid/d until progression or toxicity. CT scan evaluation every 3 cycles. The study followed a A-Hern single-stage design (HR = 1.67, median expected PFS of 4.3m if treatment ineffective, sample size: 43). The study was closed with the inclusion of 40 pts, maintaining a power &gt; 87%. Ten pts would have to be alive and free of progression at 12m to consider the study positive. Results: Forty pts were included and evaluable for PFS. Thirty-six pts were evaluable for response. Median age was 63 ( range 39 - 76) years, ECOG 0/1/2 in 36/59/5 % of pts. PFS to 1st line was &gt; 6m in 59% of pts. One CR and, 47.2% of SD were observed. Gr ¾ toxicity (%) was: neutropenia (9.8), thrombocitopenia (7.3), neurotoxicity (4.9) and diarrhea (4.9). Median PFS was 3 (95 %CI: 2.3-4.1 )m and median OS was 6.5 ( 95% CI: 5.2-9.6)m. PFS at 12 m was 0%. Median OS in pts with PFS to 1º line &gt; 6m/ &lt;6m was 9.7m and 5.6m respectively (p0.04). Conclusions: The combination of Oxaliplatin-Sorafenib in advanced GC patients previously treated with CF shows a safe profile but these results do not support the implementation of a phase III trial. Our results show that PFS under a CP-based first line therapy determine subgroups of GC patients with different clinical behaviors.
Somatic mutation of the cohesin complex subunit confers therapeutic vulnerabilities in cancer
Authors: Yunhua Liu, Hanchen Xu, Kevin Van der Jeught, Yujing Li, Sheng Liu, Lu Zhang, Yuanzhang Fang, Xinna Zhang, Milan Radovich, Bryan P. Schneider, Xiaoming He, Cheng Huang, Chi Zhang, Jun Wan, Guang Ji, Xiongbin Lu
Journal: Journal of Clinical Investigation (2018)

A synthetic lethality-based strategy has been developed to identify therapeutic targets in cancer harboring tumor-suppressor gene mutations, as exemplified by the effectiveness of poly ADP-ribose polymerase (PARP) inhibitors in BRCA1/2-mutated tumors. However, many synthetic lethal interactors are less reliable due to the fact that such genes usually do not perform fundamental or indispensable functions in the cell. Here, we developed an approach to identifying the "essential lethality" arising from these mutated/deleted essential genes, which are largely tolerated in cancer cells due to genetic redundancy. We uncovered the cohesion subunit SA1 as a putative synthetic-essential target in cancers carrying inactivating mutations of its paralog, SA2. In SA2-deficient Ewing sarcoma and bladder cancer, further depletion of SA1 profoundly and specifically suppressed cancer cell proliferation, survival, and tumorigenic potential. Mechanistically, inhibition of SA1 in the SA2-mutated cells led to premature chromatid separation, dramatic extension of mitotic duration, and consequently, lethal failure of cell division. More importantly, depletion of SA1 rendered those SA2-mutated cells more susceptible to DNA damage, especially double-strand breaks (DSBs), due to reduced functionality of DNA repair. Furthermore, inhibition of SA1 sensitized the SA2-deficient cancer cells to PARP inhibitors in vitro and in vivo, providing a potential therapeutic strategy for patients with SA2-deficient tumors.
Immune checkpoint inhibitor responses in humanized mouse melanoma models using patient-derived xenografts.
Authors: Rajasekharan Somasundaram
Journal: Journal of Clinical Oncology (2017)

99 Background: Melanoma patients develop resistance to both chemo- and targeted-therapy drugs. Promising pre-clinical and clinical results with immune checkpoint inhibitors using antibodies directed against CTLA-4 and PD-1 have re-energized the field of immune-based therapies in melanoma. However, only a third of melanoma patients respond to immune checkpoint blockade. Currently available mouse xenograft and transgenic mouse melanoma models have a number of short comings and are unable to address the basis of drug resistance and immune non-responsiveness that are frequently observed in melanoma patients. Thus there is an urgent need to establish an in vivo model with a human immune microenvironment that can address issues of therapy resistance. Methods: Our laboratory has developed a humanized mouse melanoma model using patient-derived xenografts (PDX). Results: Immunodeficient NSG mice were reconstituted with human CD34+ cells and after 7-9 weeks, mature human CD45+ cells were observed in circulating blood. Humanized mice were then challenged with HLA-matched melanoma PDX and the functional ability of human immune cells to restrict tumor growth was monitored. Delayed tumor growth was observed in humanized mice indicating in vivo sensitization of human immune cells to melanoma. This was confirmed by in vitro demonstration of human lymphocytes from tumor-bearing mice showing enhanced cytokine expression after stimulation with melanoma antigen peptides. Further, cytotoxic T-cells derived from melanoma peptide stimulation were able to functionally lyse tumor cells in vitro. In preliminary therapy studies, a majority of tumor-bearing humanized mice treated with anti-PD-1 antibody showed restricted tumor growth and a combination of BRAF inhibitor and anti-PD1 antibody treatment showed prolonged survival. Conclusions: Our results suggest that humanized mouse melanoma model can be explored further to understand the causes of therapy resistance and immune non-responsiveness.
Adipocyte p62/SQSTM1 Suppresses Tumorigenesis through Opposite Regulations of Metabolism in Adipose Tissue and Tumor
Authors: Jianfeng Huang, Angeles Duran, Miguel Reina-Campos, Tania Valencia, Elias A. Castilla, Timo D. Müller, Matthias H. Tschöp, Jorge Moscat, Maria T. Diaz-Meco
Journal: Cancer Cell (2018)
Abstract 16109: A Selective Cargo of Non-coding RNAs Mediate Therapeutic Potential of Human CD34+ Stem Cell-derived Exosomes
Authors: Prabhu Mathiyalagan, Yaxuan Liang, David Kim, Douglas W Losordo, Roger J Hajjar, Susmita Sahoo
Journal: Circulation (2015)

Introduction: Clinical application of human CD34+ stem cells is associated with improved exercise tolerance and therapeutic angiogenesis in patients with myocardial ischemia. We reported the first description of independent therapeutic potential of CD34+ stem cell-derived exosomes (CD34Exo) to that of parent cell by mechanisms that still remain poorly understood. Hypothesis: Herein, we tested the hypothesis that CD34Exo may selectively carry non-coding RNA (ncRNA) cargo targeted for pro-angiogenic signaling and ischemic tissue repair. Methods and Results: Murine models of myocardial ischemia employed throughout the study. Cell-free CD34Exo replicated the therapeutic activity of their parent cells by significantly improving myocardial ischemia (ejection fraction, 42±4 v 22±6%; capillary density, 113±7 v 66±6/HPF; fibrosis, 27±2 v 48±7%; p&lt;0.05, n=7-12) compared with a PBS control. Confocal imaging and flow cytometry analyses revealed that CD34Exo was selectively internalized into endothelial cells and cardiomyocytes in the CD34Exo-injected ischemic hearts. MicroRNA (miR) profiling identified several pro-angiogenic miRs including miR-126 that are selectively enriched in CD34Exo. Mice injected with CD34Exo show elevated miR-126 and several pro-angiogenic mRNAs in ischemic myocardium, however did not affect endogenous miR-126 synthesis suggestive of direct CD34Exo-mediated miR-126 transfer. Depletion of miR-126 reduced the therapeutic efficacy of CD34Exo both in vitro and in vivo indicating a critical role for miR-126. Using fluorescent-tagged miR-126, we monitored in real-time the uptake and transfer of miR-126 by endothelial cells both in vitro and in vivo. We finally provide novel insights underlying CD34Exo function in regulating endothelial proliferation through identification of novel pathways regulated by miR-126 in endothelial cells. Conclusion: Our results reveal specific CD34Exo-shuttled microRNAs and pathways regulated in the ischemic myocardium. Our work presents a molecular framework for CD34Exo mechanism and function in therapeutic angiogenesis. Precise understanding of CD34Exo mechanisms could significantly amplify the therapeutic benefits of CD34Exo in ischemic tissue regeneration and repair.
Conversion of CCL18-recruited naïve CD4<sup>+</sup> T cells to tumor-infiltrating regulatory T cells in breast cancer and suppression of antitumor immunity.
Authors: Shicheng Su, Jianyou Liao, Jiang Liu, Qiang Liu, Erwei Song
Journal: Journal of Clinical Oncology (2017)

114 Background: Tumor-infiltrating regulatory T cells (Tregs) play a central role in tumor immunosuppression. However, it remains unclear whether they are directly recruited from peripheral blood or converted from infiltrating naive T cells. Methods: We use full-length TCR ¦Á/¦Â repertoire to analyse the difference of T cell subsets from peripheral blood, primary tumors and draining lymph nodes in patents. Results: Infiltration of naive CD4+ T cells and Tregs are closely correlated, both indicating poor prognosis for breast cancer patients. Naive CD4+ T cells in the tumors are recruited by tumor-associated macrophages (TAMs) via CCL18. In addition, naive T cells and memory T cells exhibit distinctive chemotactic response due to different expression of regulator of G-protein signaling 1(RGS1). Specific silencing CCL18 receptor-PITPNM3 in naive CD4+ T cells using CD4 aptamer-siRNA blocks their chemotaxis, and thus reduces infiltrating Tregs and inhibits tumor progression in humanized mice. By comparison, silencing RGS1 in memory CD8+ T cells using CD8 aptamer-siRNA enhance their recruitment to tumors and anti-tumor immune response in vivo. Conclusions: These findings provide mechanistic insights for Treg enrichment in breast cancer and suggest that modification of the CCL18-PITPNM3-RGS1 signaling pathway may be an attractive strategy for anticancer immunotherapy.
Single nucleotide polymorphisms (SNPs) in COL4A2, PPP1R17, and ARHGAPP44 and prognostic value in metastatic colorectal cancer (mCRC).
Authors: Amanda Rose Townsend, Rebecca Asher, Timothy Jay Price, Chee Khoon Lee, Hilary Dorward, Val Gebski, Yoko Tomita, Niall C. Tebbutt, Jennifer Hardingham
Journal: Journal of Clinical Oncology (2018)

720 Background: Our previous study has identified COL4A2, PPP1R17 and ARHGAP44 SNPs using whole exome sequencing with potential prognostic significance (Townsend et al. ASCO GI 2017). COL4A2 encodes a subunit of type IV collagen, the C-terminal of which is an inhibitor of angiogenesis. We assessed prognostic impact of these variants in patients from the phase III MAX study (capecitabine +/- bevacizumab (+/- mitomycin C)). An analysis of predictive effect on bevacizumab was also undertaken. Methods: DNA was extracted from archival macrodissected formalin fixed paraffin embedded tumor tissue and genotyped using Agena Bioscience MassARRAY system (AGRF). Univariate association of variant group (WT versus mutation (MT)) with progression free survival (PFS) and overall survival (OS) was assessed using Kaplan-Meier curves and Cox regression models. Logistic regression models were used to assess association with response rate (RR). A cox regression model with treatment, variant status and their interaction investigated if variants were predictive of bevacizumab effect. Results: Of the available 145 of 471 (31%) patients in the MAX study, 25 (17%) had COL4A2 MT, 29 (20%) PPP1R17 MT, 14 (10%) ARHGAP44 MT. Patient demographics were comparable across treatment groups and outcomes similar to whole study population. On univariate analysis median PFS was numerically longer for WT vs MT in all 3 variants, but these differences were not significant (COL4A2 WT 8.4m v MT 6.0m, p=0.09; PPP1R17 WT 7.8m v MT 7.5m, p=0.76; ARHGAP44 WT 8.2m v MT 6.5m, p=0.86). There was also no significant association between variant type and OS. Multivariate analysis for COL4A2 MT v WT showed no significant difference in PFS or OS (HR 1.42; 95% CI 0.91-2.22, p=0.13 and HR 1.33; 95% CI 0.85-2.1, p=0.21). There was no association between treatment response and variant status. Variant status was not predictive of bevazicumab efficacy for treatment response, PFS or OS. Conclusions: There was no significant prognostic or predictive impact of novel gene variants in patients treated with bevacizumab. This may be due to small numbers of MT variants in this study and further studies in larger populations may be useful.
Retrospective comparison of modified FOLFIRINOX with full-dose FOLFIRINOX for advanced pancreatic cancer: A Japanese cancer center experience.
Authors: Akihiro Ohba, Hideki Ueno, Yasunari Sakamoto, Shunsuke Kondo, Chigusa Morizane, Takuji Okusaka
Journal: Journal of Clinical Oncology (2018)

469 Background: Various modified FOLFIRINOX (mFFX) regimens have been reported and widely used in clinical practice. Although there are retrospective studies and single-arm phase 2 studies comparing modified regimens to the full-dose regimen of the historical control group, head-to-head comparisons in the same population are limited. This study aimed to compare mFFX with full-dose FOLFIRINOX (fFFX) in patients with advanced pancreatic cancer (APC). Methods: We reviewed 85 patients with APC who received mFFX (no bolus fluorouracil and irinotecan 150 mg per square) or fFFX as first-line chemotherapy between January 2014 and December 2016. mFFX has been used since January 2016 on the basis of results of a Japanese phase 2 study. The efficacy, safety, and dose reduction pattern were evaluated. Results: A total of 56 eligible patients (26 treated with mFFX and 30 with fFFX) were selected. Baseline characteristics of each group were well-balanced. The median relative dose intensities of oxaliplatin, irinotecan, bolus fluorouracil, and continuous infusion fluorouracil were 68.6%, 78.5%, 0%, and 88.5% in the mFFX group, and 80.5%, 76.5%, 25.6%, and 83.6% in the fFFX group, respectively. Second cycle dose reduction occurred in 38% of the patients in the mFFX group and in 62% of those in the fFFX group. The median overall survival (OS) was 19.0 months in the mFFX group, compared to 13.2 months in the fFFX group (HR 0.60, 95% CI 0.25–1.47, P = 0.27). In a multivariate analysis to adjust for prognostic factors for OS, the hazard ratio for death with mFFX was significant (adjusted HR 0.36, 95% CI 0.14–0.93, P = 0.04). The median progression-free survival was 8.3 months in the mFFX group and 5.9 months in the fFFX group (HR 0.83, 95% CI 0.44–1.54, P = 0.55). The response rate was 35% in the mFFX group versus 30% (P = 0.78) in the fFFX group, respectively. Grade 3 or 4 leucopenia (15% versus 40%), neutropenia (42% versus 70%), febrile neutropenia (8% versus 17%), and nausea (4% versus 13%) were decreased in the mFFX group, but the differences were not statistically significant. Conclusions: mFFX had equivalent or higher efficacy and improved safety compared to fFFX in the same population.
Protein expression by genetic mutations identified in gene panels (hotspots) and efficacy of targeted treatments.
Authors: Stephen Charles Benz, Shahrooz Rabizadeh, John Z Sanborn, Charles Joseph Vaske, Gary A. Palmer, Patrick Soon-Shiong
Journal: Journal of Clinical Oncology (2015)

11005 Background: Treatment decision support by next generation sequencing of gene panels is currently limited to the analysis of somatic (tumor) data from DNA sequencing without taking into consideration expression of mutated genes. We present here a supercomputer-driven, cloud-based integrated analysis of genomic (DNA) and transcriptomic (RNA) sequencing data to 1) directly identify driver variants between somatic and germline (normal) DNA and 2) to determine expression of identified mutations in a cohort of 3,784 patients, thereby establishing therapeutic relevance of the mutated genes overcoming the limitations of panels. Methods: This large scale 3,784 patient genomic (DNA and RNA sequencing) data set from 19 anatomical tumor types was processed to detect DNA variants (germline vs somatic) and RNA expression, and to establish not only the existence but also the expression level of hotspot mutations in the following oncogenes: PIK3CA, KRAS, NRAS, AKT1, BRAF, IDH1, CTNNB1, and IDH2. Results: Of the 3,784 patients in this analysis, 720 were found to have mutations in the oncogenes listed above. Remarkably, only 38 (5.3%) of these patients had better than 90% expression by RNAseq, and 36 patients (5.0%) with identified hotspot mutations had no or low ( < 10%) expression. For example, mutations at position E545 in the PI3K protein encoded by the PIK3CA gene, which has been targeted by both pan-PI3K and mutant-targeted drugs in clinical trials, showed low or no expression in 12% (5/41) of breast cancer patients and not a single patient showed relatively maximal ( > 90%) expression. Similarly of the 204 thyroid cancer patients with a BRAF V600 hotspot mutation, 7.5% (15/204) had low or no expression and none had relatively maximal expression. Conclusions: These findings illustrate that genetic mutations in gene panels (hotspots) do not always result in protein expression. Given that many gene mutations were not expressed, we conclude that an informed molecularly-driven clinical treatment decision requires insight into downstream protein expression and not just DNA alterations alone.