tbuckley/cabot-search huggingface dataset:
Are <i>BRAF</i> mutated metastatic colorectal cancer (mCRC) tumors more responsive to VEGFR-2 blockage? Analysis of patient outcomes by RAS/RAF mutation status in the RAISE study—A global, randomized, double-blind, phase III study.
Authors: Takayuki Yoshino, Radka Obermannova, Gyorgy Bodoky, Jana Prausová, Rocio Garcia-Carbonero, Tudor-Eliade Ciuleanu, Pilar Garcia Alfonso, David Craig Portnoy, Allen Lee Cohn, Eric Van Cutsem, Kentaro Yamazaki, Philip Clingan, Kei Muro, Tae Won Kim, Sameera R. Wijayawardana, Rebecca Hozak, Federico Nasroulah, Josep Tabernero
Journal: Journal of Clinical Oncology (2018)

622 Background: The RAISE trial (NCT01183780) demonstrated that ramucirumab (RAM) plus leucovorin, fluorouracil, and irinotecan (FOLFIRI) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo (PBO) plus FOLFIRI as second-line mCRC treatment. RAS/RAF mutations are associated with resistance to anti-EGFR therapies and poor prognosis, particularly BRAF mutations. The extensive RAISE biomarker program assessed the association of multiple candidate markers with efficacy outcomes. Here we present the results for RAS/ RAF mutations. Methods: Plasma and tumor tissue collection were mandatory. KRAS mutation status was determined locally before randomization. Further RAS and RAF mutations were assessed centrally by multiplex qPCR using the Modaplex system (Qiagen) only in samples that were initially reported as KRAS wild type. Thus, patients were classified into one of the 3 categories in the table. OS and PFS by RAS and RAF subgroups were evaluated by Kaplan-Meier and Cox proportional hazards analyses. Results: As with previously reported KRAS analyses, the favorable RAM treatment effect was similar between patients with expanded RAS mutations compared with patients with RAS/ RAF wild-type tumors. However, in the 41 patients with BRAF mutated tumors, the RAM benefit was even more notable for both OS (hazard ratio [HR] 0.54; 95% CI 0.25–1.13) and PFS (HR 0.55; 95% CI 0.28–1.08). Conclusions: RAISE demonstrated that the addition of RAM to FOLFIRI improved patient outcomes regardless of RAS mutation status. The noteworthy signal for patients with BRAF mutant tumors is encouraging due to their poor prognosis but requires further validation in other clinical trials. Clinical trial information: NCT01183780. [Table: see text]
Dysregulation of serum bile acids and FGF19 in alcoholic hepatitis
Authors: Katharina Brandl, Phillipp Hartmann, Lily J. Jih, Donald P. Pizzo, Josepmaria Argemi, Meritxell Ventura-Cots, Sally Coulter, Christopher Liddle, Lei Ling, Stephen J. Rossi, Alex M. DePaoli, Rohit Loomba, Wajahat Z. Mehal, Derrick E. Fouts, Michael R. Lucey, Francisco Bosques-Padilla, Philippe Mathurin, Alexander Louvet, Guadalupe Garcia-Tsao, Elizabeth C. Verna, Juan G. Abraldes, Robert S. Brown, Victor Vargas, Jose Altamirano, Juan Caballería, Debbie Shawcross, Peter Stärkel, Samuel B. Ho, Ramon Bataller, Bernd Schnabl
Journal: Journal of Hepatology (2018)
Blood eosinophil counts as predictive marker in advanced melanoma patients treated with anti-PD1 therapies.
Authors: Lydia Gaba, Iván Victoria, Francisco Aya, Gustavo Ruiz, Estela Pineda, Òscar Reig, Aranzazu Fernandez-Martinez, Aleix Prat, Ana Arance
Journal: Journal of Clinical Oncology (2017)

66 Background: Anti-PD1 antibodies (Abs) Nivolumab (Nivo) and Pembrolizumab (Pembro) have both demonstrated to improve the overall survival (OS) in patients (pts) with advanced or metastatic melanoma (MM) in the first line setting. We previously reported that an increase in absolute eosinophil counts (AEC) of 100/mm3 over baseline at week 3 and an AEC &gt; 400/mm3 at week 12 during anti-PD1 treatment (tmt) might identify pts with MM most likely to experience long-term disease control (1) . AEC could serve as an important marker allowing the detection of those patients who may benefit from the therapy with anti-PD1 Abs. Methods: This retrospective observational study included pts with MM who received anti-PD1 tmt in a single institution. The objective was to identify whether an increase over the upper limit of normal AEC (&gt;400/mm3) at any time during the tmt could predict better outcomes. Blood tests were performed before every tmt administration. Progression free survival (PFS) and OS were evaluated. Descriptive statistics were used to analyze patient baseline characteristics. PFS and OS were estimated by the Kaplan-Meier method. Results: From March 2013 to February 2016, 50 pts were treated with anti-PD1 Abs (39 pts with Pembro and 11 pts with Nivo). Median age was 58 years (33-84). 72% had received previous systemic tmt for MM, 64% had stage M1c disease, and 50% had elevated LDH levels. BRAF V600 mutations were observed in 34%. The median time to increase AEC &gt; 400/mm2 was 42 (14-196) days. Pts who experienced an increase &gt; 400/mm3 at 12 weeks demonstrated better outcomes in terms of PFS (21,9 [95% CI: 11,1-32,6] vs. 7,5 [95% CI: 4,3-10,7] months, p=0.017) and OS (38,0 [95% CI: 30,8-45,1] vs. 20,5 [95% CI: 15,7-25,3] months, p=0.025) compared with those who did not. Moreover, according to our previous results, pts with an increase of at least 100/mm3 in AEC over the baseline at 12 weeks also showed better OS (32,5 [95% CI: 26,3-38,8] vs. 16,3 [95% CI: 11,1-21,6] months, p=0.008). Conclusions: An increase in AEC of 100/mm3 over baseline and an absolute AEC &gt; 400/mm3 at week 12 during anti-PD1 tmt might identify pts with MM most likely to experience clinical benefit with anti-PD1 Abs which could be relevant for pts management.
Somatosensory changes at forearm donor sites following three different surgical flap techniques
Authors: Fang Wang, Xu Ding, Jinglu Zhang, Xiaomeng Song, Yunong Wu, Peter Svensson, Kelun Wang
Journal: International Journal of Surgery (2018)

The aim of this study was to investigate the somatosensory changes at the forearm donor region after using different types of modified flap surgical techniques. Thirty-one patients, who underwent oral and maxillofacial reconstructive surgery involving the use of a traditional radial forearm flap (TRFF) or two modified radial forearm flap techniques (MRFF-I; MRFF-II), participated in the study. Cold detection threshold (CDT), warm detection threshold (WDT), cold pain threshold (CPT), heat pain threshold (HPT), pressure pain threshold (PPT), mechanical detection threshold (MDT), and mechanical pain threshold (MPT) were assessed at four sites of the forearms corresponding to the middle of the vascular pedicle (VP) area, the middle of the forearm flap area, and the corresponding contralateral sites (cVP and cFF) at about 5.0 ± 1.9 months after the surgery. Data were analysed with one-way ANOVA, and post-hoc tests were performed using Tukey's Honest Significant Difference test. Significant differences between the VP and cVP sites were detected for WDT (P < 0.001) in TRFF and for WDT (P < 0.001) and MDT (P = 0.006) in MRFF-I. Significant differences among TRFF, MRFF-I, and MRFF-II at the VP site were detected for CDT (P = 0.022), WDT (P < 0.001), and MDT (P = 0.015). MRFF-II was associated with significantly higher sensitivity compared to that of TRFF for WDT (P = 0.017) and higher sensitivity compared to that of MRFF-I for CDT (P = 0.017), WDT (P < 0.001), and MDT (P = 0.013). Significant sensory loss was detected for all types of surgical procedures with free forearm flaps. However, the MRFF-II was associated with a better sensory recovery at short follow-up after surgery. These results suggest that a longer follow-up period and larger sample size should be included in future studies.
Peripherally derived macrophages can engraft the brain independent of irradiation and maintain an identity distinct from microglia
Authors: James C. Cronk, Anthony J. Filiano, Antoine Louveau, Ioana Marin, Rachel Marsh, Emily Ji, Dylan H. Goldman, Igor Smirnov, Nicholas Geraci, Scott Acton, Christopher C. Overall, Jonathan Kipnis
Journal: The Journal of Experimental Medicine (2018)

Peripherally derived macrophages infiltrate the brain after bone marrow transplantation and during central nervous system (CNS) inflammation. It was initially suggested that these engrafting cells were newly derived microglia and that irradiation was essential for engraftment to occur. However, it remains unclear whether brain-engrafting macrophages (beMφs) acquire a unique phenotype in the brain, whether long-term engraftment may occur without irradiation, and whether brain function is affected by the engrafted cells. In this study, we demonstrate that chronic, partial microglia depletion is sufficient for beMφs to populate the niche and that the presence of beMφs does not alter behavior. Furthermore, beMφs maintain a unique functional and transcriptional identity as compared with microglia. Overall, this study establishes beMφs as a unique CNS cell type and demonstrates that therapeutic engraftment of beMφs may be possible with irradiation-free conditioning regimens.
Rendezvous biliary recanalization with combined percutaneous transhepatic cholangioscopy and double-balloon endoscopy
Authors: Hiroshi Kawakami, Tesshin Ban, Yoshimasa Kubota, Shinya Ashizuka, Ichiro Sannomiya, Naoya Imamura, Takeomi Hamada
Journal: Endoscopy (2018)

Despite advances in biliary stenting in patients with altered gastrointestinal anatomy, it is still a challenging procedure [1]. We present a case where percutaneous transhepatic cholangioscopy (PTCS) was combined with double-balloon endoscopy (DBE) for biliary stenting in a patient with complete obstruction of a choledochojejunostomy.
Effect of dendritic cells (DC) transduced with chimeric antigen receptor (CAR) on CAR T-cell cytotoxicity.
Authors: Hyung Chan Suh, Katherine Pohl, Anna Patricia L. Javier, Dennis J. Slamon, John P Chute
Journal: Journal of Clinical Oncology (2017)

144 Background: T cells interacting DC could be superior in T cell cytotoxicity. CD141+/Cleg9a+ intra-tumoral DC play a critical role in tumor cytotoxicity. Therefore, combining intra-tumoral DC in CAR T cell would safely increase localized CAR T cell cytotoxicity. We hypothesized that bioengineered DC compartment could be an excellent source for enhanced CAR T cell cytotoxicity. Methods: DC precursors and T cells of PBMC were transduced with a CAR (pCCL-anti-CD33-4-1BB-CD3z-T2A-GFP; CAR-DC or CAR T). For comparison, additional DC were transduced with 4-1BB cDNA (pCCL-4-1BB-T2A-GFP; 4-1BB-DC) or mock control (pCCL-eGFP). In addition to lentivirus transduction, differentiation of DC in vitro employed Flt3L/GM-CSF/IL-4. Transduced CAR T and CAR-DC were sorted by GFP expression at day 5. After further 10 days of culture, cells were harvested and analyzed for phenotype. An acute myeloid leukemia (AML) cell line (Kasumi-1) was treated with CAR T +/- CAR-DC, 4-1BB-DC, or mock control for functional assays. Results: Frequencies of cells expressing CD141+/Cleg9a+ were higher in 4-1BB-DC vs. control DC (33% vs. 1.5%). After mixing CAR T and CAR-DC (5X10 5 ) with Kasumi-1 (1X10 5 ) for 6 hours, CAR T/CAR-DC showed 100% Kasumi-1 cell cytotoxicity compared to 70% of CAR T by trypan blue. CAR T/CAR-DC also demonstrated higher Annexin V positive Kasumi-1 cells compared with CAR-T (91% vs. 52%). CAR T with or without CAR-DC were also assessed with multiplex immunoassays. CAR T cells mixed with CAR-DC induced higher level of IFN-gamma (10,316 vs. 6,186 pg/ml), IL-2 (68,840 vs. 64,708 pg/ml), and TNFalpha (1,361 vs. 905 pg/ml) (Kasumi-1 cells mixed with CAR-T cells of 10 E/T ratio) than CAR T cells. CAR-DC produced significantly higher IL-12 cytokine production (1,352 vs. 161 pg/ml) than CAR T cells in response to CD33 but independent to T cells, confirmed by comparing IL-12 production with CAR T/4-1BB-DC. Conclusions: These data show that in vitro differentiation of DC bearing 4-1BB increases CD141+/Cleg9a+ DC population and that interaction with CAR-DC to CAR T cells enhances anti-AML cytotoxicity. Our finding may implicate the development of CAR-DC therapy combined to CAR T cells to increase the efficiency of cancer immunotherapy.
Germline deletion of CIN85 in humans with X chromosome–linked antibody deficiency
Authors: Baerbel Keller, Moneef Shoukier, Kathrin Schulz, Arshiya Bhatt, Ines Heine, Valentina Strohmeier, Carsten Speckmann, Niklas Engels, Klaus Warnatz, Jürgen Wienands
Journal: The Journal of Experimental Medicine (2018)

Ubiquitously expressed Cbl-interacting protein of 85 kD (CIN85) is a multifunctional adapter molecule supposed to regulate numerous cellular processes that are critical for housekeeping as well as cell type–specific functions. However, limited information exists about the in vivo roles of CIN85, because only conditional mouse mutants with cell type–specific ablation of distinct CIN85 isoforms in brain and B lymphocytes have been generated so far. No information is available about the roles of CIN85 in humans. Here, we report on primary antibody deficiency in patients harboring a germline deletion within the CIN85 gene on the X chromosome. In the absence of CIN85, all immune cell compartments developed normally, but B lymphocytes showed intrinsic defects in distinct effector pathways of the B cell antigen receptor, most notably NF-κB activation and up-regulation of CD86 expression on the cell surface. These results reveal nonredundant functions of CIN85 for humoral immune responses.
Donor telomere length and causes of death after unrelated hematopoietic cell transplantation in patients with marrow failure
Authors: Shahinaz M. Gadalla, Geraldine Aubert, Tao Wang, Michael Haagenson, Stephen R. Spellman, Lingxiao Wang, Hormuzd A. Katki, Sharon A. Savage, Stephanie J. Lee
Journal: Blood (2018)
Planning of dosing regimen and schedule of assessments for first in human oncology clinical trials for therapeutic monoclonal antibodies.
Authors: Galina Bernstein, John Oldenhof
Journal: Journal of Clinical Oncology (2017)

11 Background: Planning of the dosing regimen for oncology therapeutics, based on the pre-clinical information about the monoclonal antibody, is an important step in the development of a clinical program. Accumulated material about previously developed monoclonal antibodies allows for the rational approach to plan a dosing regimen and the assessments of biomarkers based on structural similarities and the mode of action. Methods: The structural approach to predict the elimination half-life and related frequency of dosing was applied to plan first in human clinical trials for monoclonal therapeutics. The following attributes were taken into account: glycosylation content and related affinity to Fcγ receptors (t1/2 ↑), glycosylation and affinity to non-specific receptors – asialoglycoprotein receptor and mannose receptor (t1/2 ↓), oxidation of hinge Met and affinity to FcRn receptor(t1/2 ↑), immunogenicity (t1/2 ↓), mechanism of action – binding to solid or soluble target, ADCC, CDC, aggregate state and impurities. Literature data on monoclonal antibodies with similar qualities, attributes, and mechanism of action were used as input for the predictive estimates. The schedule of biomarker assessments was developed on a similar approach. The structural characterization was aided by the data on the pharmacokinetics in animal species. Results: A risk-based approach, taking into account estimates of effective elimination half-life, was used to determine an optimal dosing regimen for either IV infusion or SC injection. The interim PK analyses completed early in the conduct of the study aided in study planning and conduct to ensure balanced concentration of the drug without excessive accumulation. Conclusions: The knowledge acquired in the field of immune-oncology allows for effective planning of dosing regimen and schedule of biomarker assessments for novel monoclonal antibodies. The results of the predictive estimates were used in the clinical studies protocol with follow-up interim PK analysis. The results of the study will be published at a later presentation.
Response to nivolumab in radiation induced, BRCA-2 N372H variant, programed death ligand-1 negative, pleomorphic undifferentiated sarcoma.
Authors: Yevgeniya Gora Foster, Michael Cecchini, Dennis Slater, Veronique Neumeister, Zenta Walther, Zain Husain, Benjamin Judson, Hari Anant Deshpande
Journal: Journal of Clinical Oncology (2017)

61 Background: Early results from recent studies using immune checkpoint blockade targeting programmed death 1 (PD-1) have suggested that pleomorphic undifferentiated sarcomas may have response rates of over 40%. As of now predictive biomarkers for response and resistance have been incompletely characterized. Methods: A 58-year-old man who received radiation for a head and neck squamous cell cancer, developed a radiation-induced undifferentiated pleomorphic sarcoma (UPS) in his neck in 2014. His sarcoma was resected but recurred in 2015. He received adjuvant radiation after surgical debulking in September 2015 and was found on radiation simulation scan to have new widespread metastatic disease involving liver, lung, and bone. He started treatment on nivolumab in November 2015 and has had a sustained near complete response in all lesions. Results: All sites had a near complete response to nivolumab treatment. Pre treatment tissue analysis revealed no mutations or amplifications in 134 cancer-related genes, on the Oncomine Assay (Life Technologies, Inc.). Normal tissue was noted to be heterozygous for BRCA2 N372H, while the allelic fraction of the 372H variant in the tumor was found to be 85%. Programmed death ligand-1 (PDL-1) immunohistochemistry staining of the tumor tissue was negative. Tumor infiltrating lymphocytes were not noted in the tumor tissue specimen. Conclusions: This patient exhibited a near complete response to all sites of disease, with remaining PET avidity in a single hilar node. The role of the BRCA2 variant and radiation just prior to starting nivolumab is unknown. BRCA2 N372H is a common single nucleotide polymorphism (SNP) in the population with a minor allele frequency of 0.25. Although the effect of the 372H variant on BRCA2 protein structure is predicted to be minimal, population studies have suggested a slightly increased risk of breast and ovarian cancer in homozygotes. It is possible that the radiation treatment to the site of recurrence in the head and neck, resulted in an abscopal effect enhancing the therapeutic effect of nivolumab therapy. Additional testing on his tissue is being done to further investigate the response.
ME1 Regulates NADPH Homeostasis to Promote Gastric Cancer Growth and Metastasis
Authors: Yun-Xin Lu, Huai-Qiang Ju, Ze-Xian Liu, Dong-Liang Chen, Yun Wang, Qi Zhao, Qi-Nian Wu, Zhao-lei Zeng, Hai-Bo Qiu, Pei-Shan Hu, Zhi-Qiang Wang, Dong-Sheng Zhang, Feng Wang, Rui-Hua Xu
Journal: Cancer Research (2018)

Abstract Genomic alterations of tumor suppressorsoften encompass collateral protein-coding genes that create therapeutic vulnerability to further inhibition of their paralogs. Here, we report that malic enzyme 2 (ME2) is frequently hemizygously codeleted with SMAD4 in gastric cancer. Its isoenzyme ME1 was upregulated to replenish the intracellular reducing equivalent NADPH and to maintain redox homeostasis. Knockdown of ME1 significantly depleted NADPH, induced high levels of reactive oxygen species (ROS), and ultimately cell apoptosis under oxidative stress conditions, such as glucose starvation and anoikis, in ME2-underexpressed cells. Moreover, ME1 promoted tumor growth, lung metastasis, and peritoneal dissemination of gastric cancer in vivo. Intratumoral injection of ME1 siRNA significantly suppressed tumor growth in cell lines and patient-derived xenograft–based models. Mechanistically, ME1 was transcriptionally upregulated by ROS in an ETV4-dependent manner. Overexpression of ME1 was associated with shorter overall and disease-free survival in gastric cancer. Altogether, our results shed light on crucial roles of ME1-mediated production of NADPH in gastric cancer growth and metastasis. Significance: These findings reveal the role of malic enzyme in growth and metastasis. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/8/1972/F1.large.jpg. Cancer Res; 78(8); 1972–85. ©2018 AACR.
Abstract 19831: Local Myocardial Intensity on Cardiac Computed Tomography is Associated With Scar Substrate in Post-Infarct Ventricular Tachycardia
Authors: Satish Misra, Sohail Zahid, Adityo Prakosa, Esra G Ipek, Tarek Zghaib, Hari Tandri, David Spragg, Joseph E Marine, Aravindan Kolandaivelu, Ronald Berger, Natalia Trayanova, Hugh Calkins, Henry Halperin, Stefan Zimmerman, Saman Nazarian
Journal: Circulation (2016)

Introduction: Catheter ablation of post-infarct ventricular tachycardia (VT) reduces risk of recurrent ICD shocks but long-term success rates are suboptimal. Contrast enhanced CT (CE-CT) can identi...
193TiP Phase 3 study of epacadostat plus pembrolizumab with or without platinum-based chemotherapy vs pembrolizumab plus chemotherapy for first-line metastatic non-small cell lung cancer (mNSCLC): ECHO-306/KEYNOTE-715
Authors: M. Garassino, S. Rubin, Y. Zhao, Y. Luo, A. Samkari, R. Hui
Journal: Journal of Thoracic Oncology (2018)
Factors that influence adult neurogenesis as potential therapy
Authors: Belal Shohayeb, Mohamed Diab, Mazen Ahmed, Dominic Chi Hiung Ng
Journal: Translational Neurodegeneration (2018)

Adult neurogenesis involves persistent proliferative neuroprogenitor populations that reside within distinct regions of the brain. This phenomenon was first described over 50 years ago and it is now firmly established that new neurons are continually generated in distinct regions of the adult brain. The potential of enhancing the neurogenic process lies in improved brain cognition and neuronal plasticity particularly in the context of neuronal injury and neurodegenerative disorders. In addition, adult neurogenesis might also play a role in mood and affective disorders. The factors that regulate adult neurogenesis have been broadly studied. However, the underlying molecular mechanisms of regulating neurogenesis are still not fully defined. In this review, we will provide critical analysis of our current understanding of the factors and molecular mechanisms that determine neurogenesis. We will further discuss pre-clinical and clinical studies that have investigated the potential of modulating neurogenesis as therapeutic intervention in neurodegeneration.
Ethical Ruminations of a Rheumatologist: Autoimmunity Is an Important Consideration for Immunotherapy Trials
Authors: Jane S. Kang
Journal: The American Journal of Bioethics (2018)

"Ethical Ruminations of a Rheumatologist: Autoimmunity Is an Important Consideration for Immunotherapy Trials." The American Journal of Bioethics, 18(4), pp. 75–76
The systemic response to surgery triggers the outgrowth of distant immune-controlled tumors in mouse models of dormancy
Authors: Jordan A. Krall, Ferenc Reinhardt, Oblaise A. Mercury, Diwakar R. Pattabiraman, Mary W. Brooks, Michael Dougan, Arthur W. Lambert, Brian Bierie, Hidde L. Ploegh, Stephanie K. Dougan, Robert A. Weinberg
Journal: Science Translational Medicine (2018)

Anti-inflammatories prevent surgery-induced outgrowth of distant tumors in mouse models and may reduce early metastatic relapse in patients.
#sportsuisse2018 – ‘Best of’ in Bern – again! 15–16 November 2018
Authors: Mario Bizzini, Nicolas Mathieu
Journal: British Journal of Sports Medicine (2018)

The Swiss Sports Physiotherapy Association (SSPA) will host the first combined conference with the Swiss Sports Medicine Society (SSMS) on 15-16 November 2018 at the BernExpo centre in Bern (figure 1 – the  British Journal of Sports Medicine’s cover for this issue). We previously organised a two-day event in 2015, with the successful 1st World Congress of Sports Physical Therapy and almost 800 participants from 50 countries worldwide. Again, we hope to welcome sports PTs, MDs and others to enjoy our top-notch programme, and engage in discussions with peers from Switzerland and the world.



Figure 1 
Join the Swiss Sports Physiotherapy Association (SSPA) and the Swiss Sports Medicine Society (SSMS) in Bern on 15-16 November 2018.



The main topics of #sportsuisse2018 will be: …