tbuckley/cabot-search huggingface dataset:
Advances in the evaluation of anorectal function
Authors: Emma V. Carrington, S. Mark Scott, Adil Bharucha, François Mion, Jose M. Remes-Troche, Allison Malcolm, Henriette Heinrich, Mark Fox, Satish S. Rao
Journal: Nature Reviews Gastroenterology & Hepatology (2018)

Faecal incontinence and evacuation disorders are common and substantially impair quality of life. In this Consensus Statement, the authors describe recommended tests for the evaluation of anorectal function and the clinical relevance of these tests in the management of patients to help guide the practising clinician. Faecal incontinence and evacuation disorders are common, impair quality of life and incur substantial economic costs worldwide. As symptoms alone are poor predictors of underlying pathophysiology and aetiology, diagnostic tests of anorectal function could facilitate patient management in those cases that are refractory to conservative therapies. In the past decade, several major technological advances have improved our understanding of anorectal structure, coordination and sensorimotor function. This Consensus Statement provides the reader with an appraisal of the current indications, study performance characteristics, clinical utility, strengths and limitations of the most widely available tests of anorectal structure (ultrasonography and MRI) and function (anorectal manometry, neurophysiological investigations, rectal distension techniques and tests of evacuation, including defecography). Additionally, this article provides our consensus on the clinical relevance of these tests.
Combined analysis of tumor budding and tumor microenvironment in patients with stage III colorectal cancer.
Authors: Hiromichi Nakajima, Naoko Inoshita, Chihiro Kondoh, Yukinori Ozaki, Kenji Tomizawa, Yutaka Hanaoka, Shigeo Toda, Yuko Tanabe, Yuji Miura, Jin Moriyama, Shuichiro Matoba, Hiroya Kuroyanagi, Toshimi Takano
Journal: Journal of Clinical Oncology (2018)

652 Background: Tumor budding (TB) represents the epithelial-mesenchymal transition (EMT) and is a novel marker that predicts metastasis and poor survival in patients with colorectal cancer. Although recent preclinical studies have elucidated the interaction between the EMT process and tumor microenvironment (TME), the clinicopathological correlation between TB and TME remains unclear. Methods: Formalin-fixed paraffin-embedded blocks of specimens were obtained from patients with stage III colorectal cancer who underwent surgical resection and adjuvant chemotherapy at our institution between January 2009 and July 2012. TB, tumor stroma percentage (TSP), and inflammatory reaction (IR) graded using the Klintrup-Mäkinen method were evaluated on hematoxylin and eosin sections. The densities of CD8 + T-cells at the tumor centers and invasive margins were analyzed using immunohistochemistry and digital image analysis. Cox proportional hazards models were used to assess the effect of clinicopathological variables on relapse-free survival (RFS). Results: One hundred and ninety-five patients were included in this analysis. The median age was 62 years (range 32–84 years). The median follow-up duration of this study was 5.8 years. High TB ( &gt; 5 buds/0.785 mm 2 ) was observed in 106 patients (54.4%) and was associated with high TSP (P &lt; 0.01), but not with IR and CD8 expression. Multivariate analysis, including clinicopathological factors such as histology, TB, TSP, and IR revealed that high TB was an independent poor prognostic factor (hazard ratio, 1.89; 95% confidence interval, 1.04–3.45; P = 0.04). Patients with high TB and low IR (21.0%) exhibited a shorter survival than others; the 5-year RFS rates were 82.7%, 81.1%, 78.4%, and 40.8% in patients with low TB and high IR, low TB and IR, high TB and high IR, and high TB and low IR, respectively. Conclusions: Our study demonstrated that high TB was an adverse prognostic factor, regardless of TME status. The combined analysis of TB plus IR could improve prognostic value in patients with stage III colorectal cancer. Patients with high TB and low IR may need novel therapeutic approaches.
196TiP CheckMate 384: A phase 3b/4 dose-frequency optimization trial of nivolumab in advanced or metastatic NSCLC
Authors: E. Garon, N. Reinmuth, R. Harris, P. Mitchell, J. Zhu, G. Selvaggi, S. Agrawal, E. Pichon
Journal: Journal of Thoracic Oncology (2018)
Abstract 13694: Hsf1 Attenuates Pressure Overload Induced-cardiac Fibrosis via Inhibiting Smad3 Phosphorylation and Nuclear Translocation
Authors: Ning Zhou, Yong Ye, Xingxu Wang, Jian Wu, Lei Li, Dao Wen Wang, Yunzeng Zou
Journal: Circulation (2015)

Introduction: Heat shock transcription factor 1 (HSF1) is an intrinsic cardioprotective factor against cardiac hypertrophy. However, little is known about the role of HSF1 in cardiac fibrosis. Here we hypothesize that HSF1 reverses pressure overload induced-cardiac fibrosis via inhibiting Smad3 phosphorylation and nuclear translocation. Methods: Human tissue samples were collected from the left ventricles of dilated cardiomyopathy patients undergoing heart transplant and normal heart donors for control and were interrogated via western blot and realtime-PCR. A HSF1 transgenic (TG) mouse was generated. Transverse aortic constriction (TAC) was performed with wild type (WT) mice as control and cardiac structure and function were measured by echocardiography and pathological test. Cardiomyocytes (CMs) isolated from neonatal mice were imposed with mechanical stretch (MS) in vitro. Results: HSF1 phosphorylation at Ser230 was significantly decreased in failing hearts (55% vs normal hearts) characterized with significant cardiac fibrosis manifested with increased expression of collagen III and connective tissue growth factor (CTGF) . WT mice and TG mice were subjected to TAC. After 4 weeks of TAC, WT mice developed a remarkable maladaptive hypertrophy and cardiac fibrosis in comparison to WT mice. TG mice exhibited a smaller LV end-diastolic diameter (LVEDD), higher ejection fraction (EF), decreased LV weight/tibial length (LW/TL) and CMs cross sectional area (CSA), less interstitial and perivascular fibrosis, as well as preserved expression of collagen III and CTGF compared to WT mice. TG mouse hearts also showed reduced phosphorylation and nuclear translocation of Smad3 than WT mice. MS was found to significantly inhibit HSF1 phosphorylation, but promoted the Smad3 phosphorylation and nuclear translocation in CMs. Co-Immunoprecipitation showed that HSF1 directly binds Smad3 in CMs in vitro, which was decrease by MS or treatment with KNK437 (HSF1 inhibitor). TG mice demonstrate more of HSF1 and Smad3 binding and less phosphorylation and nuclear translocation of Smad3 compared to WT mice after TAC. Conclusion: HSF1 attenuates pressure overload induced-cardiac fibrosis by inhibiting Smad3 phosphorylation and nuclear translocation.
Immunological changes following intraperitoneal administration of a formulated IL-12 plasmid in combination with standard neoadjuvant chemotherapy in patients with newly diagnosed advanced stage ovarian cancer.
Authors: Khursheed Anwer, Junko Matsuzaki, Wiam Bshara, Amit Lugade, Angela Omilian, Premal H. Thaker, William Hampton Bradley, Charles A. Leath, Camille Catherine Gunderson, Jason Fewell, Nicholas Borys, Lauren Musso, Kunle Odunsi
Journal: Journal of Clinical Oncology (2017)

156 Background: The translational component of a Phase I study of weekly intraperitoneal GEN-1, an IL-12 plasmid formulated with polyethyleneglycol-polyethyleneimine cholesterol lipopolymer, in combination with dose-dense weekly taxane (T) and carboplatinum (C) every 3 weeks in newly diagnosed epithelial ovarian, fallopian tube, or primary peritoneal cancer (EOC) patients undergoing neoadjuvant therapy (NAC). Our hypothesis is that the GEN-1 plus NAC treatment will reprogram the tumor immune microenvironment towards a potent antitumor immune response. Methods: Patients received GEN-1 at escalating dose levels from 36 mg/m 2 , 47 mg/m 2 , 61 mg/m 2 , to 79 mg/m 2 weekly for 8 treatments with concurrent T/C. Tumor samples collected at time of diagnostic laparoscopy and interval debulking (IDB). Blood and peritoneal ascites were collected before and after treatment. The immunological analysis included frequency of immune cell populations and cytokine levels in tumor, blood, and peritoneal ascites and cell-specific mRNA expression profile. Results: The preliminary results obtained from first two cohorts show that GEN-1 may be enhancing post-treatment changes in immune cell populations including an increase in cytotoxic CD8+ T-cells and decrease in immunosuppressive FoxP3+ T-reg cells in tumor at IDB. The CD8:Foxp3 ratio appeared to be skewing beneficially towards more cytotoxic T lymphocyte and away from suppressive cells in most patients. The analysis of circulating immune cells 21 days after first GEN-1 treatment showed a decrease in circulating CD123+ plasmacytoid dendritic cells, but no change in CD11c+ myeloid dendritic cells. There were no major changes in the frequency of circulating T-cells. Additional analyses from this study are in progress. Conclusions: Based on preliminary analyses of cohorts 1 &amp; 2 samples analyzed, the treatment of EOC patients with GEN-1 and NAC has resulted in favorable immunological responses. Updated results to be presented at meeting. Clinical trial information: NCT02480374.
Flow cytometric detection of MDSC populations in unfractionated blood.
Authors: C. Marcela Diaz-Montero, Patricia A. Rayman, Jin Sub Kim, Paul G Pavicic, Charles Tannenbaum, Vamsidhar Velcheti, Pauline Funchain, Jennifer S Ko, Petros Grivas, Brian I. Rini, Alberto J. Montero, James Finke
Journal: Journal of Clinical Oncology (2017)

56 Background: MDSCs are a phenotypically diverse population of bone-marrow-derived cells that play an important role in tumor progression based on their immunosuppressive and pro-angiogenic properties. Mobilization of MDSCs from the bone marrow into the blood stream is dependent on tumor derived factors. Therefore, it is likely that levels of circulating MDSCs in cancer patients are reflective of tumor activity. However, the clinical applicability of MDSCs as a predictive biomarker in cancer has been hindered by a lack of consensus on the surface markers that defines them. Although there have been several attempts at harmonizing the nomenclature and characterization standards of MDSCs, there is still a lot of confusion particularly in the detection of MDSCs in unfractionated peripheral blood. To address this issue we have devised a simple flow cytometric test that reliably detects in whole blood the MDSCs subtypes that have been consistently reported to have clinical relevance in cancer. Methods: Whole blood from cancer patients and normal volunteers was stained with Lin cocktail, HLADR, CD33, CD15, CD14, and CD11b antibodies. After staining, red blood cells were lysed, samples were washed and analyzed by flow cytometry. Results: This approach identifies monocytic MDSCs (Linlo/CD33+/HLADR-/CD14+/CD15-), granulocytic or polymorphonucleated polymorphonuclear MDSCs (Linlo/CD33+/HLADR-/CD14-/CD15+), and promyelocytic or immature MDSCs (Linlo/CD33+/HLADR-/CD14-/CD15-), as well as Linlo/HLADR-/CD33+/CD11b+ MDSCs. This latter subpopulation has been reported by us and others to correlate with disease stage and tumor burden in several solid malignancies. This assay also allows the accurate determination of absolute numbers of each MDSC population when white blood cell counts are taken into consideration. Conclusions: Our proposed simple and rapid flow cytometry-based assay allows the measurement of frequency and absolute numbers of circulating MDSC subpopulations in unfractionated blood, and could provide a reference for their further characterization as predictive biomarkers for solid malignancies.
CD70 as a novel target of CAR-T-cell therapy for gliomas.
Authors: Linchun Jin, Haitao Ge, Changlin Yang, Yu Long, Yifan(Emily) Chang, Luyan Mu, Elias Sayour, Gabriel De leon, Qiong J. Wang, James C. Yang, Jeffrey Drake, Paul Kubilis, Dunyue Lu, Yingjun Kong, Li Hu, Qi Jiping, Yunhe Gu, Zhiguo Lin, Duane Anthony Mitchell, Jianping Huang
Journal: Journal of Clinical Oncology (2017)

148 Background: Gliomas are the most common primary malignant brain tumor and are uniformly lethal. Cancer immunotherapy has the potential to target gliomas; however, its antitumor effects are restricted by limitations in clinically useful tumor specific targets. Chimeric antigen receptor modified T-cell (CAR-T) therapy is a highly promising option for cancer treatment, due to its combination of precision antibody recognition and T-cell tumor-specific killing. CD70 is an antigen expressed by limited subsets of normal lymphocytes and dendritic cells but is aberrantly overexpressed by glioma cells, which makes it an outstanding glioma-antigen target. Methods: The gene and protein expression of CD70 were evaluated to identify its potential as a glioma target. Human and mouse versions of CD70-specific CAR-T cells were generated, and human primary GBM lines as well as murine lines (GL-261, KR-158B) were used as human and mouse tumor targets, respectively. The antitumor effect of the human and mouse CD70-sepecific CARs were tested in vitro and in orthotopic xenograft and syngeneic murine models. Results: CD70 is only overexpressed by tumor cells in a subset of low-grade gliomas and GBM. The elevated gene and protein expression are associated with increased tumor grade and poor patient survival. Co-culturing CD70-specific CAR-T cells with CD70-positive glioma cells resulted in potent secretion of IFN-gamma and tumor-specific killing in a CD70-dependent manner. Irradiation enhances CD70 expression on glioma cells and thus increases CAR T-cell recognition. Adoptive transfer of the human and mouse CD70 CAR-T cells resulted in tumor regression of immunocompetent and immunodeficient mice, respectively. Conclusions: CD70 can be an excellent tumor target for gliomas, and CD70-specific CAR-T cells have potent antitumor activity against CD70-positive gliomas both in vitro and in vivo. Our study provides crucial preclinical evidence to support the future clinical application of CD70 CAR-T cells to treat gliomas.
Postmarketing Modifications of Drug Labels for Cancer Drugs Approved by the US Food and Drug Administration Between 2006 and 2016 With and Without Supporting Randomized Controlled Trials
Authors: Daniel Shepshelovich, Ariadna Tibau, Hadar Goldvaser, Consolación Molto, Alberto Ocana, Bostjan Seruga, Eitan Amir
Journal: Journal of Clinical Oncology (2018)

Purpose Modifications in cancer drug indications, dosing, and related toxicities after Food and Drug Administration approval are common. It is unclear whether drug approval without a supporting randomized controlled trial (RCT) influences the probability of such modifications. Methods We searched the Drugs@FDA Web site for new drug indications for solid tumors approved between January 2006 and December 2016. Study characteristics, regulatory pathways, and label modifications from approval to October 2017 were collected from drug labels. Label modifications were considered to be major if defined as such in the drug label. Indications approved with and without supporting RCTs were compared using logistic regression. The Benjamini-Hochberg false discovery rate method was used to adjust for multiplicity. Results We identified 59 individual drugs for 109 solid tumor indications. Of these, 17 indications (15.6%) were not supported by an RCT, with no change over time. Indications not supported by RCTs were more likely to require companion diagnostic tests (odds ratio [OR], 3.90; P = .02), to include surrogate end points as primary outcomes (OR, 7.88; P < .001), and to receive breakthrough therapy designation (OR, 7.62; P = .006) or accelerated approval (OR, 17.67; P < .001). Indications not supported by RCTs were associated with significantly higher odds of postapproval modifications in common adverse events (71% v 29%; OR, 5.78; P = .002). A nonsignificantly higher odds of postapproval major modifications in warnings and precautions was also observed (88% v 62%; OR, 4.61; P = .051). Postapproval major modifications in indication and usage, dosing and administration, boxed warnings, and contraindications were comparable in the two groups. Conclusion Cancer drug indications not supported initially by RCTs are associated with more postmarketing safety-related label modifications. Health care professionals should be vigilant for unrecognized adverse effects when prescribing drugs approved without a supporting RCT.
A phase Ib study of safety and clinical activity of atezolizumab (A) and cobimetinib (C) in patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Johanna C. Bendell, Yung-Jue Bang, Cheng Ean Chee, David P. Ryan, Autumn Jackson McRee, Laura Q. Chow, Jayesh Desai, Matthew Wongchenko, Yibing Yan, Bethany Pitcher, Paul Foster, Edward Cha, William Grossman, Tae Won Kim
Journal: Journal of Clinical Oncology (2018)

560 Background: The majority of pts with mCRC have microsatellite stable (MSS) tumors with minimal response to PD-L1/PD-1 blockade. MEK inhibition upregulates tumor major histocompatibility complex-I expression, promotes intratumoral T-cell accumulation and improves anti–PD-L1 responses (Ebert, Immunity. 2016), supporting clinical evaluation of combined anti–PD-L1 (A) plus MEKi (C) in pts with mCRC. Methods: Pts with chemotherapy-refractory or locally advanced mCRC were evaluated. A was administered IV q2w at 800 mg. C was dosed PO daily at 20 to 60 mg during dose escalation and 60 mg during dose expansion (14/14 or 21/7 d on/off schedule). Primary endpoints were safety and tolerability. Investigator-assessed ORR and PFS by RECIST v1.1 and OS were secondary endpoints. Microsatellite instability (MSI) status was locally reported and centrally confirmed by NGS-based scoring. Results: As of May 10, 2017, 84 pts (57 KRASmt, 25 KRASwt, 2 unknown) were enrolled and evaluable. 66 pts had received 5+ prior therapies; 38 had known MSI status at baseline (MSS [n = 29], MSI-low [n = 8], MSI-H [n = 1]). A + C combination was tolerable. Treatment-related Gr 1-2 and Gr 3-4 AEs occurred at 60% and 37%, respectively. The most frequent related Gr 3-4 AEs were increased blood CPK, rash, diarrhea and fatigue (5% each). No treatment-related Gr 5 AEs occurred. 13% and 24% of pts experienced AEs leading to A and C withdrawal, respectively. Median follow-up was 14.3 mo (range, 0.5-29.8). Confirmed PR was observed in 7 pts (8%; locally reported MSS [n = 3], MSI-low [n = 1], MSI unknown [n = 3]). Median DOR was 14.8 mo (95% CI: 6.0, NE); DCR (PR + SD) was 31%. Median PFS was 1.9 mo (95% CI: 1.8, 2.3); median OS was 10.0 mo (95% CI: 6.2, 14.1). The 6-mo and 1-y OS rates were 65% (95% CI: 54, 76) and 46% (95% CI: 34, 58), respectively. Molecular determinants and immune biomarkers of response will be presented. Conclusions: A + C demonstrated a tolerable safety profile and improvements in OS vs those reported with SOC in heavily pretreated pts with mCRC. Objective responses observed in pts with MSS/MSI-low mCRC were durable, suggesting benefit of this novel combination in a pt population refractory to immune therapies. Clinical trial information: NCT01988896.
Disruption of Renal Arginine Metabolism Promotes Kidney Injury in Hepatorenal Syndrome in Mice
Authors: Zoltan V. Varga, Katalin Erdelyi, Janos Paloczi, Resat Cinar, Zsuzsanna K. Zsengeller, Tony Jourdan, Csaba Matyas, Balazs Tamas Nemeth, Adrien Guillot, Xiaogang Xiang, Adam Mehal, György Haskó, Isaac E. Stillman, Seymour Rosen, Bin Gao, George Kunos, Pal Pacher
Journal: Hepatology (2018)

Tubular dysfunction is an important feature of renal injury in hepatorenal syndrome (HRS) in patients with end‐stage liver disease. The pathogenesis of kidney injury in HRS is elusive, and there are no clinically relevant rodent models of HRS. We investigated the renal consequences of bile duct ligation (BDL)‐induced hepatic and renal injury in mice in vivo by using biochemical assays, real‐time polymerase chain reaction (PCR), Western blot, mass spectrometry, histology, and electron microscopy. BDL resulted in time‐dependent hepatic injury and hyperammonemia which were paralleled by tubular dilation and tubulointerstitial nephritis with marked upregulation of lipocalin‐2, kidney injury molecule 1 (KIM‐1) and osteopontin. Renal injury was associated with dramatically impaired microvascular flow and decreased endothelial nitric oxide synthase (eNOS) activity. Gene expression analyses signified proximal tubular epithelial injury, tissue hypoxia, inflammation, and activation of the fibrotic gene program. Marked changes in renal arginine metabolism (upregulation of arginase‐2 and downregulation of argininosuccinate synthase 1), resulted in decreased circulating arginine levels. Arginase‐2 knockout mice were partially protected from BDL‐induced renal injury and had less impairment in microvascular function. In human‐cultured proximal tubular epithelial cells hyperammonemia per se induced upregulation of arginase‐2 and markers of tubular cell injury. Conclusion: We propose that hyperammonemia may contribute to impaired renal arginine metabolism, leading to decreased eNOS activity, impaired microcirculation, tubular cell death, tubulointerstitial nephritis and fibrosis. Genetic deletion of arginase‐2 partially restores microcirculation and thereby alleviates tubular injury. We also demonstrate that BDL in mice is an excellent, clinically relevant model to study the renal consequences of HRS. (H epatology 2018; 00:000‐000).
Pretreatment neutrophil to lymphocyte ratio as an independent predictor of disease-specific survival in resectable GE junction and gastric adenocarcinoma.
Authors: Sam C Wang, Joanne F. Chou, Vivian E. Strong, Murray F. Brennan, Marinela Capanu, Daniel G. Coit
Journal: Journal of Clinical Oncology (2014)

4056 Background: Preoperative methods to estimate disease specific survival (DSS) for resectable gastroesophageal junction and gastric adenocarcinoma (GEJ/GA) are inadequate. The patient’s inflammatory state may impact cancer outcome, as suggested by the consistent association of decreased DSS with postoperative complications or transfusions. The aim of this study was to evaluate the relationship between DSS and pretreatment neutrophil to lymphocyte ratio (NLR), which may reflect the systemic inflammatory state, following complete resection of GEJ/GA. Methods: Review of a prospective database identified all patients diagnosed with primary GEJ/GA who underwent complete resection from 1998-2013. Patient, tumor, treatment characteristics and pretreatment neutrophil and lymphocyte counts were recorded. Patients were stratified into quartiles based on NLR values. Five year DSS was estimated by the Kaplan-Meier method. A Cox proportional hazards model was used to evaluate the independent associations between clinicopathologic variables and DSS. Results: We identified 1,498 patients, with median follow-up of four years. On univariate analysis, elevated NLR was associated with increased age, male gender, Caucasian race, increased T and N stage, and neoadjuvant therapy. On multivariate analysis, decreased DSS was associated with Caucasian race (p=0.02), increased T stage (p<0.01), increased N stage (p<0.01) and neoadjuvant therapy (p<0.01). Elevated pre-treatment NLR was also independently associated with worse DSS (HR=1.09 [95%CI: 1.05-1.13], p<0.01, Table). Conclusions: In patients with resectable GEJ/GA, pretreatment NLR is significantly and independently associated with DSS. NLR is a simple and effective value available during treatment planning to help risk stratify patients with GEJ/GA for cancer specific outcome. Five-year DSS and multivariate DSS using NLR as quartiles. NLR N Five-year DSS Adjusted HR* 95% CI Quartile 1 0.23-2.00 389 70% Ref Quartile 2 2.00-2.76 362 66% 1.1 0.8-1.4 Quartile 3 2.76-3.85 374 56% 1.2 0.9-1.5 Quartile 4 >3.85 372 50% 1.5 1.1-1.9 *Adjusted for age, gender, race, T stage, N stage, and neoadjuvant therapy.