tbuckley/cabot-search huggingface dataset:
Safety of bevacizumab in cancer patients with inflammatory bowel disease.
Authors: Ruth Gabriela Herrera Gomez, Claire Gallois, Marcel Adler, David Malka, David Planchard, Barbara Pistilli, Michel Ducreux, Olivier Mir
Journal: Journal of Clinical Oncology (2019)

664 Background: Digestive and non-digestive cancers in patients with inflammatory bowel disease (IBD) are potentially sensitive to bevacizumab-based chemotherapy. Previous reports have suggested an increased toxicity in IBD patients receiving anti-VEGF agents. The safety of bevacizumab in this population is poorly documented. Methods: A retrospective review of records of patients with IBD treated with bevacizumab-containing chemotherapy for metastatic solid tumors in Gustave Roussy hospital between 2007 and 2016. Results: Twenty eight patients (median age 43, range: 23-73) with a past history of IBD (6 ulcerative colitis, 22 Crohn’s disease) were identified. IBD was considered severe in four pts (13%). Patients presented a good control of IBD symptoms with a median number of 0 (range: 0-2) disease flares during the two years before bevacizumab initiation. Three patients were receiving corticosteroids, and another four were receiving mesalazine for IBD. No patient had abscess, fistula or hemorrhage at the time of bevacizumab initiation. The treated cancer was: colon (n = 8), rectum (n = 5), small bowel (n = 5), NSCLC (n = 4), ovary (n = 1), breast (n = 3) and other (n = 2). Patients received chemotherapy [5-FU-based (LV5FU2, FOLFOX or FOLFIRI) in 17, oxaliplatin in 7, irinotecan in 8, taxanes in 7] with bevacizumab given at the approved dose-intensities of 2.5 mg/kg/week (19 pts) or 5 mg/kg/week (7 pts). Records of chemotherapy from 2 patients were missing. A median number of 8 cycles of bevacizumab(range: 2-39) was given concomitantly to chemotherapy and then as maintenance therapy, with the following grade ≥2 toxicities: hypertension in 6 cases (20%) and proteinuria in 3 cases (10%). No dose-limiting toxicity was observed. No change in IBD treatment was required. One patient developed grade 2 rectorragia (identified as Crohn’s disease flare-up) after 6 months of bevacizumab+ FOLFIRI. After withdrawal of irinotecan, the patient was re-challenged with bevacizumab for another 6 cycles without recurrence of bleeding. Conclusions: In our experience, bevacizumab can be given to cancer patients with quiescent IBD at conventional doses with good clinical tolerance.
Celiac plexus radiosurgery for pain management in advanced cancer patients: An international phase II trial.
Authors: Yaacov Richard Lawrence, Tikva Meron, Adam P. Dicker, Camilla Zimmermann, Maoz Ben-Ayun, David Hausner, Talia Golan, Ofir Morag, Aliza Ackerstein, Raphael M. Pfeffer, Laura A. Dawson, Nir Shlomo, Nitin Ohri, Ashwatha Narayana, Andrew Gaya, Dayssy Alexandra Diaz Pardo, Inessa Yanovsky, Ronen Fluss, Laurence S Freedman, Zvi Symon
Journal: Journal of Clinical Oncology (2019)

TPS466 Background: Many cancer patients, especially those with pancreatic cancer, suffer from severe back/epigastric pain. Contemporary approaches (opioids, celiac blocks, systemic chemotherapy) are often inadequate. This clinical trial investigates a new approach in which high-dose radiation (radiosurgery) is focused on the retroperitoneal celiac plexus nerve bundle. Preliminary results from a single institution pilot trial NCT02356406 are promising: pain relief is substantial and side effects minimal. The main aim of the trial is to establish safety/efficacy in the setting of an international multicenter study. Exploratory analyses will examine the relationship between pain reduction and subjects’ quality-of-life, functionality, and caregiver burden. Methods: Eligibility criteria include a diagnosis of metastatic/unresectable malignancy, uncontrolled pain defined as ≥ 5 on 11-point BPI-SF scale despite analgesic use, typical retroperitoneal pain syndrome, prognosis &gt; 8 weeks, ECOG 0-2, anatomical involvement of the celiac plexus (e.g. any pancreatic cancer, or any other cancer involving the celiac trunk). Exclusion criteria include previous upper abdo. radiation. The intervention consists of a single 25 Gy radiation fraction delivered to the celiac plexus, using anterolateral aspect of the aorta from the 12th thoracic to 2nd lumbar vertebral body as a surrogate structure. The primary tumour may be irradiated at physicians’ discretion. Dose-painting technique limits dose to organs at risk. Pain intensity will be measured using Brief Pain Inventory Short Form (BPI-SF), and quality of life with FACT-Hep. The primary endpoint is complete or partial pain response, defined as a decrease between the score immediately before treatment and 3 weeks’ post-treatment. A change of two or more on the BPI 11-point pain scale is defined as clinically significant. Secondary endpoints include other BPI pain endpoints, pain at 6 weeks, analgesic use, toxicity (CTCAE v4.03), quality of life and functional measures. Analgesia is not restricted. Expected accrual is 100 subjects over three years. Supported by Gateway for Cancer Research, additional support from Israel Cancer Association. Clinical trial information: NCT03323489.
Forward Genetic Screen Reveals Genetic Causes of Atopy
Authors: Jeffrey A. SoRelle, Takuma Misawa, Zhe Chen, Sara HIldebrand, Jianhui Wang, Tao Yue, Jin H. Choi, Kuan-wen Wang, Xue Zhong, Jamie Russell, Lindsay Scott, Tao Wang, Xiaowei Zhan, Chun Hui Bu, Eva MY. Moresco, Bruce Beutler
Journal: Journal of Allergy and Clinical Immunology (2019)
T cell checkpoint regulators in the heart
Authors: Nir Grabie, Andrew H Lichtman, Robert Padera
Journal: Cardiovascular Research (2019)

T lymphocyte-mediated immune responses in the heart are potentially dangerous because they can interfere with the electromechanical function. Furthermore, the myocardium has limited regenerative capacity to repair damage caused by effector T cells. Myocardial T cell responses are normally suppressed by multiple mechanisms of central and peripheral tolerance. T cell inhibitory molecules, so called immune checkpoints, limit the activation and effector function of heart antigen-reactive T cells that escape deletion during development in the thymus. Programmed cell protein death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) are checkpoint molecules homologous to the costimulatory receptor CD28, and they work to block activating signals from the T cell antigen receptor and CD28. Nonetheless, PD-1 and CTLA-4 function in different ways and at different steps in a T cell response to antigen. Studies in mice have established that genetic deficiencies of checkpoint molecules, including PD-1, PD-L1, CTLA-4, and lymphocyte activation gene-3, result in enhanced risk of autoimmune T cell-mediated myocarditis and increased pathogenicity of heart antigen-specific effector T cells. The PD-1/PD-L1 pathway appears to be particularly important in cardiac protection from T cells. PD-L1 is markedly up-regulated on myocardial cells by interferon-gamma secreted by T cells and PD-1 or PD-L1 deficiency synergizes with other defects in immune regulation in promoting myocarditis. Consistent with these studies, myocarditis has emerged as a serious adverse reaction of cancer therapies that target checkpoint molecules to enhance anti-tumour T cell responses. Histopathology and immunohistochemical analyses of myocardial tissue from immune checkpoint blockade (ICB)-treated patients echoes findings in checkpoint-deficient mice. Many questions about myocarditis in the setting of cancer immunotherapy still need to be answered, including the nature of the target antigens, genetic risk factors, and variations in the disease with combined therapies. Addressing these questions will require further immunological analyses of blood and heart tissue from patients treated with ICB.
Estimating CDKN2A mutation carrier probability among global familial melanoma cases using GenoMELPREDICT
Authors: Nicholas J. Taylor, Nandita Mitra, Lu Qian, Marie-Françoise Avril, D. Timothy Bishop, Brigitte Bressac-de Paillerets, William Bruno, Donato Calista, Francisco Cuellar, Anne E. Cust, Florence Demenais, David E. Elder, Anne-Marie Gerdes, Paola Ghiorzo, Alisa M. Goldstein, Thais C. Grazziotin, Nelleke A. Gruis, Johan Hansson, Mark Harland, Nicholas K. Hayward, Marko Hocevar, Veronica Höiom, Elizabeth A. Holland, Christian Ingvar, Maria Teresa Landi, Gilles Landman, Alejandra Larre-Borges, Graham J. Mann, Eduardo Nagore, Håkan Olsson, Jane M. Palmer, Barbara Perić, Dace Pjanova, Antonia L. Pritchard, Susana Puig, Helen Schmid, Nienke van der Stoep, Margaret A. Tucker, Karin A.W. Wadt, Xiaohong R. Yang, Julia A. Newton-Bishop, Peter A. Kanetsky
Journal: Journal of the American Academy of Dermatology (2019)
Phase I Trial of Inducible Caspase 9 T Cells in Adult Stem Cell Transplant Demonstrates Massive Clonotypic Proliferative Potential and Long-term Persistence of Transgenic T Cells
Authors: Ping Zhang, Jyothy Raju, Md Ashik Ullah, Raymond Au, Antiopi Varelias, Kate H. Gartlan, Stuart D. Olver, Luke D. Samson, Elise Sturgeon, Nienke Zomerdijk, Judy Avery, Tessa Gargett, Michael P. Brown, Lachlan J. Coin, Devika Ganesamoorthy, Cheryl Hutchins, Gary R. Pratt, Glen A. Kennedy, A. James Morton, Cameron I. Curley, Geoffrey R. Hill, Siok-Keen Tey
Journal: Clinical Cancer Research (2019)

Inducible caspase 9 (iCasp9) is a cellular safety switch that can make T-cell therapy safer. The purpose of this phase I trial was to investigate the use of iCasp9-transduced T-cell addback in adult patients undergoing haploidentical stem cell transplantation for high-risk hematologic malignancies.Patients undergoing myeloablative, CD34-selected haploidentical stem cell transplantation were treated with 0.5-1.0 × 106/kg donor-derived iCasp9-transduced T cells on day +25 or 26 post-transplant, with additional doses allowed for disease relapse, infection, or mixed chimerism.Three patients were enrolled. iCasp9-transduced T cells were readily detectable by 4 weeks post-infusion in all patients and remained at high level (114 cells/μL, 11% of T cells) in 1 patient alive at 3.6 years. One patient developed donor-derived Epstein-Barr virus-associated post-transplant lymphoproliferative disease (EBV-PTLD), which was followed by a marked expansion of iCasp9 T cells and cytokine release syndrome (CRS). These iCasp9-transduced T cells infiltrated the affected lymph nodes and secreted IFNγ and IL-10. They peaked at 1,848 cells/μL and were found to be monoclonal by T-cell receptor (TCR) clonotype and oligoclonal by viral integrant analysis, representing a 6-log in vivo expansion of the dominant T-cell clone. These T cells were not autonomous and contracted with the resolution of EBV-PTLD, which did not recur.iCasp9-transduced T cells could persist long-term. They retained very high in vivo clonotypic proliferative capacity and function, and could cause CRS in response to de novo lymphoma development.
Abstract 12941: MURC/Cavin-4 Deficiency Reduces Infarct Size and Preserves Cardiac Function in a Mouse Model of Ischemia-Reperfusion Injury
Authors: Masahiro Nishi, Takehiro Ogata, Naohiko Nakanishi, Takeru Kasahara, Naoki Maruyama, Yusuke Higuchi, Satoaki Matoba
Journal: Circulation (2016)

Introduction: Cardiac ischemia-reperfusion (I/R) injury is considered clinically important issue in cardioprotective strategy for ischemic heart disease. Muscle-restricted coiled-coil protein (MURC)/Cavin-4 is a member of the cavin family, which is a component of caveola. MURC/Cavin-4 is involved in myofibrillar organization by regulating Rho/ROCK signaling pathway and cardiac hypertrophy through ERK1/2 activation. MURC/Cavin-4 mutations are observed in patients with dilated cardiomyopathy. However, the role of MURC/Cavin-4 in cardiac I/R injury remains unknown. Methods and Results: Cardiac I/R was performed on MURC/Cavin-4-/- mice and WT mice. Mice were subjected to 1 hour ischemia by ligating left anterior descending artery, followed by 24 hours reperfusion. MURC/Cavin-4 mRNA expression was continuously increased after reperfusion in WT mouse hearts. Compared with WT mice, MURC/Cavin-4-/- mice exhibited significantly smaller infarct size (IS), which was assessed as proportion of the area at risk (AAR) (IS/AAR[%], MURC/Cavin-4-/- vs. WT: 52.7 ± 3.1 vs. 69.8 ± 12.3, p &lt; 0.05). Echocardiography showed that MURC/Cavin-4 deficiency significantly preserved cardiac function (LVEF[%], MURC/Cavin-4-/- vs. WT: 54.2 ± 5.6 vs. 36.2 ± 2.0, p &lt; 0.01; FS[%], MURC/Cavin-4-/- vs. WT: 27.0 ± 3.7 vs. 16.9 ± 1.1, p &lt; 0.01, respectively). Hydrogen peroxide (H 2 O 2 ), the most abundant form of reactive oxygen species (ROS) produced during I/R, causes inflammation, apoptosis and subsequent tissue damages. In neonatal rat cardiomyocytes, MURC/Cavin-4 siRNA reduced cell death induced by H 2 O 2 compared with control siRNA, as determined by TUNEL staining (TUNEL positive cells[%],MURC/Cavin-4 siRNA vs. control siRNA: 45.1 ± 7.2 vs. 65.7 ± 12.1, p &lt; 0.05). Western blot analysis showed that p38 MAPK activation by H 2 O 2 was inhibited in cardiomyocytes transfected with MURC/Cavin-4 siRNA compared with control siRNA. Akt/PKB signaling was not influenced by MURC/Cavin-4 siRNA transfection. Conclusions: Our results indicate that MURC/Cavin-4 plays a crucial role in the development of cardiac I/R injury through ROS-induced apoptosis signaling pathway in cardiomyocytes. MURC/Cavin-4 might be a novel therapeutic target for cardiac I/R injury.
A Comprehensive FISH- and Array-Based Diagnostic Screeningstrategy for the Assessment of Clinically Relevant Genetic Parameters: A Prospective Analysis of 205 Childhood ALL Cases
Authors: Oskar A. Haas, Karin Nebral, Sabrina Haslinger, Andrea Inthal, Margit König, Sabine Strehl, Renate Panzer-Grümayer, Andishe Attarbaschi, Georg Mann
Journal: Blood (2018)
Inflammation and ER stress differentially regulate STAMP2 expression and localization in adipocytes
Authors: Jørgen Sikkeland, Torstein Lindstad, Hatice Zeynep Nenseth, Xavier Dezitter, Su Qu, Ridhwan M. Muhumed, Meric Erikci Ertunc, Margaret F. Gregor, Fahri Saatcioglu
Journal: Metabolism (2019)
Decellularized Extracellular Matrix Materials for Cardiac Repair and Regeneration
Authors: Donald Bejleri, Michael E. Davis
Journal: Advanced Healthcare Materials (2019)

Abstract Decellularized extracellular matrix (dECM) is a promising biomaterial for repairing cardiovascular tissue, as dECM most effectively captures the complex array of proteins, glycosaminoglycans, proteoglycans, and many other matrix components that are found in native tissue, providing ideal cues for regeneration and repair of damaged myocardium. dECM can be used in a variety of forms, such as solid scaffolds that maintain native matrix structure, or as soluble materials that can form injectable hydrogels for tissue repair. dECM has found recent success in many regeneration and repair therapies, such as for musculoskeletal, neural, and liver tissues. This review focuses on dECM in the context of cardiovascular applications, with variations in tissue and species sourcing, and specifically discusses advances in solid and soluble dECM development, in vitro studies, in vivo implementation, and clinical translation.
The efficacy of neoadjuvant treatment in locally advanced rectal cancer with dMMR.
Authors: Yanhong Deng, Jianwei Zhang
Journal: Journal of Clinical Oncology (2019)

615 Background: The incidence of Mismatch repair gene deficiency (dMMR) was about 15% in colorectal cancer, but mostly in right side colon cancer, while in locally advanced rectal cancer, it is very rare. As is known, adjuvant chemotherapy with 5FU alone was not recommended in stage II colon cancer with dMMR or MSI. However, in locally advanced rectal cancer with dMMR or MSI, the efficacy of neoadjuvant treatment with 5FU was not yet known. Methods: We enrolled patients with locally advanced rectal cancer from three prospective clinical trials, including the FOWARC study (N = 309), the mFOLFOXIRI neoadjuvant chemotherapy trial (N = 106) and the total neoadjuvant treatment with FOLFOX and radiotherapy (N = 129). From the 544 patients, 35 (6.4%) patients were dMMR, 133 patients with unknown status of MMR. Among the 35 patients, 10 patients received 5FU concurrent with radiotherapy (group A), nine patients underwent FOLFOX concurrent with radiation (group B), and 12 patients received FOLFOX neoadjuvant chemotherapy alone (group C). Another four patients underwent mFOLFOXIRI neoadjuvant chemotherapy alone (group D), including one patient with nivolumab as neoadjuvant treatment after chemotherapy. Results: Totally, 4 (11.4%) patients achieved pathologic complete response, and 13 (37%) patients had tumor downstaging to ypT0-2N0M0 (stage 0-I). In group A, the pCR rate was 10% (1/10), the tumor downstaging rate was 20% (2/10); In group B, the pCR rate was 33.3% (3/9), the tumor downstaging rate was 55.6% (5/9); In group C, the tumor downstaging rate was 41.7% (5/12). In group D, only one patient achieved pCR, and it is the one who received nivolumab as neoadjuvant treatment. Conclusions: The efficacy of neoadjuvant in locally advanced rectal cancer seemed not affected by the MMR status. But further study was needed.
Comparison of concurrent chemoradiation with stereotactic body radiation therapy versus conventionally fractionated radiation therapy following induction chemotherapy for unresected locally advanced pancreatic cancer.
Authors: Sung Jun Ma, Austin J Iovoli, Kavitha M Prezzano, Gregory Hermann, Lucas M Serra, Anurag K Singh
Journal: Journal of Clinical Oncology (2019)

378 Background: Induction chemotherapy (iC) followed by concurrent chemoradiation has been shown to improve overall survival (OS) for locally advanced pancreatic cancer (LAPC). A recent National Cancer Data Base (NCDB) analysis has also shown improved OS with the use of stereotactic body radiation therapy (SBRT) versus conventionally fractionated radiation therapy (CFRT). This NCDB analysis evaluated outcomes of concurrent chemoradiation with SBRT compared to CFRT, following iC. Methods: The NCDB was queried for primary stage III, cT4N0-1M0 unresected pancreatic adenocarcinoma treated with concurrent chemoradiation following iC (2004-2015). CFRT was defined as 1.8-2.5 Gy per fraction up to a total dose of 45-70 Gy, whereas SBRT was defined as &gt; 4.0 Gy per fraction up to a total dose of 20-60 Gy. Baseline patient, tumor, and treatment characteristics were examined. The primary endpoint was overall survival (OS). Kaplan-Meier analysis, Cox proportional hazards method, logistic regression, and propensity score matching were used. Results: Among 872 patients, 738 patients underwent CFRT and 134 patients received SBRT. Median follow-up was 24.3 months and 22.9 months for the CFRT and SBRT cohorts, respectively. The use of SBRT showed improved survival in the multivariable analysis compared to CFRT (HR 0.78, p = 0.025). Using 1:1 propensity score matching, a total of 240 patients were matched, with 120 patients in each cohort. The receipt of SBRT remained statistically significant for improved OS, including median OS (18.1 months vs 15.9 months) and 2-year OS (37.3% vs 25.5%) compared to the CFRT (p = 0.0040). Conclusions: This NCDB analysis shows a significant survival benefit with the use of SBRT versus CFRT, in the setting of definitive management for LAPC following iC. Further prospective studies evaluating the use of SBRT in the definitive treatment of this challenging population are warranted.
Drug Sensitivity Screening on Multiple Myeloma for Precision Cancer Therapy
Authors: Deepak Balaji balaji Thimiri Govinda Raj, Mariaserena Giliberto, Andrea Cremaschi, Sigrid Strand Skånland, Alexandra Gade, Geir Erland Tjønnfjord, Fredrik H. Schjesvold, Ludvig Andre Munthe, Kjetil Tasken
Journal: Blood (2018)
Bone Marrow Hematopoietic Dysfunction in Untreated Chronic Lymphocytic Leukemia Is Partially Mediated By Exposure to Constituents of the Leukemic Microenvironment
Authors: Bryce Manso, Kimberly Gwin, Charla R Secreto, Henan Zhang, Wei Ding, Sameer A. Parikh, Neil E. Kay, Kay L. Medina
Journal: Blood (2018)
PHOX2B mutations and familial neuroblastoma
Authors: Patrizia Perri, Tiziana Bachetti, Luca Longo, Ivana Matera, Marco Seri, Gian Paolo Tonini, Isabella Ceccherini
Journal: Cancer Research (2005)

1304  Neuroblastoma (NB), a childhood malignancy affecting neural crest deriving cell lineages, is characterized by great clinical variability and histological heterogeneity. Rare associations of NB with other neurocristopathies such as Hirschsprung disease (HSCR), Congenital Central Hypoventilation Syndrome (CCHS) and Neurofibromatosis type 1 (NF1) are also described. As NB usually occurs as sporadic form, molecular studies were mainly carried out on tumor samples and derived cell lines, leading to the identification of several somatic alterations. Because of the rarity of familial NB cases only a few linkage data are available and no mutations in candidate genes have been demonstrated up till now. The first evidence of germline mutations in NB pedigrees has been recently reported in the paired-like homeobox 2B (PHOX2B) gene, an essential regulator in the development of autonomic neural crest derivatives, suggesting its role in NB predisposition. On the basis of this indication we have screened three Italian families with recurrence of NB and one family with occurrence of ganglioneuroblastoma and isolated Hirschsprung disease for PHOX2B mutations. Our analysis by direct sequencing of constitutional DNA of 11 NB patients has not shown any mutation in the gene coding sequence, excluding PHOX2B as the susceptibility gene in the NB families we analyzed. Therefore, as PHOX2B mutations have been found only in a few NB families with multifocal and syndromic NB but not others without these features, we suggest that PHOX2B mutations represent second-site modifications responsible for a specific phenotype rather than causal mutations of a major locus. Combining our findings with those achieved by other PHOX2B mutation screenings and by genome-wide linkage analyses that indicate a remarkable genetic heterogeneity of NB, the hypothesis of a single gene predisposing to NB cannot be supported. An oligogenic model of disease transmission through the involvement of different loci genetically interacting to cause and/or modify the disease-phenotype seems to be more appropriate to explain the genetic basis of familial NB.