tbuckley/cabot-search huggingface dataset:
Deletion of Tmtc4 activates the unfolded protein response and causes postnatal hearing loss
Authors: Jiang Li, Omar Akil, Stephanie L. Rouse, Conor W. McLaughlin, Ian R. Matthews, Lawrence R. Lustig, Dylan K. Chan, Elliott H. Sherr
Journal: Journal of Clinical Investigation (2018)

Hearing loss is a significant public health concern, affecting over 250 million people worldwide. Both genetic and environmental etiologies are linked to hearing loss, but in many cases the underlying cellular pathophysiology is not well understood, highlighting the importance of further discovery. We found that inactivation of the gene Tmtc4 (transmembrane and tetratricopeptide repeat 4), which was broadly expressed in the mouse cochlea, caused acquired hearing loss in mice. Our data showed Tmtc4 enriched in the endoplasmic reticulum, and that it functioned by regulating Ca2+ dynamics and the unfolded protein response (UPR). Given this genetic linkage of the UPR to hearing loss, we demonstrated a direct link between the more common noise-induced hearing loss (NIHL) and the UPR. These experiments suggested a novel approach to treatment. We demonstrated that the small-molecule UPR and stress response modulator ISRIB (integrated stress response inhibitor), which activates eIF2B, prevented NIHL in a mouse model. Moreover, in an inverse genetic complementation approach, we demonstrated that mice with homozygous inactivation of both Tmtc4 and Chop had less hearing loss than knockout of Tmtc4 alone. This study implicated a novel mechanism for hearing impairment, highlighting a potential treatment approach for a broad range of human hearing loss disorders.
Design and validation of an Observational Standard Clinical Examination (OSCE) for clinical oncology based on ASCO/ASH curricular milestones.
Authors: Ernesto Gil Deza, Gustavo De Simone, Carlos Fernando Garcia Gerardi, Estefania E Kaminski, Mariano G Fernandez, Luis Loviscek, Monica Montiel, Alfredo Navigante, Daniela Gercovich, Gaston Martin Reinas, Eduardo L. Morgenfeld, Rancati Alberto, Edgardo G. J. Rivarola, Felipe G. Gercovich
Journal: Journal of Clinical Oncology (2016)

e18150 Background: In the last 30 years the Objective Structured Clinical Examination (OSCE) has gained popularity as an objective assessment tool of medical skills. In 2014 the 39 ASCO/ASH curricular milestones (CM) were published as a guideline for the design of postgraduate training for the hematology/oncology career. Using this CM, we designed an OSCE for HM-ONCUSAL Methods: Between 26/06/2015 and 15/10/2015, professors at HM-ONCUSAL designed a 180 minute OSCE which included as many ASCO/ASH CM as possible. Eleven CM were excluded: five because they were restricted to hematology (CM: 8-9-10-21-22) and six because they were related to learning processes or complex practices that required medical simulators (CM:15-16-17-24-29-32). The OSCE designed consisted of 9 stations to evaluate the remaining 28 CM: Station 1: diagnosis and staging (CM:1-2-37); Station 2: recurrence and chemotherapy (CM:3-4-5-6-18-37); Station 3: palliative care (CM:7-11-12-37); Station 4: Tumor Board (CM:14-19-20-25-26-28-31-33-38-39); Station 5: Ethics Committee (CM:26-27-33-34-35-36-38); Station 6: Image evaluation (CM:4); Station 7: Toxicity evaluation (CM: 5); Station 8: Genetic test interpretation (CM: 13-23); Station 9: Interpreting a scientific paper (CM:30). All stations had to be completed in 180 minutes. Results: On November 7th, 2015, 28 students from HM-ONCOUSAL, 9 actors and 18 observers participated in a validation study for the OSCE designed. All students went through the 9 stations in the provided time. At the end of the OSCE, each participant rated the experience on a scale of 0 to 10. The average rating amongst students was 8.3 (r 6-10); actors and observers had an average rating of 9.3 (r 7-10). All the participants recommended this exam for new students. The most lauded aspects of the OSCE were: the variety of examined topics and the realism when interacting with simulated patients. Conclusions: 1) The designed 9 station OSCE for HM-ONCOUSAL using 28 ASCO/ASH CM is feasible and can be done in 180 minutes. 2) The exam was rated highly by students, actors and observers. 3) This method allows the evaluation of a student’s skills in multiple topics and with different perspectives.
Evidence for Genetic Contribution to Variation in Posttraumatic Osteoarthritis in Mice
Authors: Nobuaki Chinzei, Muhammad Farooq Rai, Shingo Hashimoto, Eric J. Schmidt, Ken Takebe, James M. Cheverud, Linda J. Sandell
Journal: Arthritis & Rheumatology (2018)

Objective Recombinant inbred mouse strains generated from an LG /J and SM /J intercross offer a unique resource to study complex genetic traits such as osteoarthritis ( OA ). We undertook this study to determine the susceptibility of 14 strains to various phenotypes characteristic of posttraumatic OA . We hypothesized that phenotypic variability is associated with genetic variability. Methods Ten‐week‐old male mice underwent surgical destabilization of the medial meniscus ( DMM ) to induce posttraumatic OA . Mice were killed 8 weeks after surgery, and knee joints were processed for histology to score cartilage degeneration and synovitis. Micro–computed tomography was used to analyze trabecular bone parameters including subchondral bone plate thickness and synovial ectopic calcifications. Gene expression in the knees was assessed using a QuantiGene Plex assay. Results Broad‐sense heritability ranged from 0.18 to 0.58, which suggested that the responses to surgery were moderately heritable. The LGXSM ‐33, LGXSM ‐5, LGXSM ‐46, and SM /J strains were highly susceptible to OA , while the LGXSM ‐131b, LGXSM ‐163, LGXSM ‐35, LGXSM ‐128a, LGXSM‐6, and LG /J strains were relatively OA resistant. This study was the first to accomplish measurement of genetic correlations of phenotypes that are characteristic of posttraumatic OA . Cartilage degeneration was significantly positively associated with synovitis (r = 0.83–0.92), and subchondral bone plate thickness was negatively correlated with ectopic calcifications (r = −0.59). Moreover, we showed that 40 of the 78 genes tested were significantly correlated with various OA phenotypes. However, unlike the OA phenotypes, there was no evidence for genetic variation in differences in gene expression levels between DMM ‐operated and sham‐operated knees. Conclusion For these mouse strains, various characteristics of posttraumatic OA varied with genetic composition, which demonstrated a genetic basis for susceptibility to posttraumatic OA . The heritability of posttraumatic OA was established. Phenotypes exhibited various degrees of correlations; cartilage degeneration was positively correlated with synovitis, but not with the formation of ectopic calcifications. Further investigation of the genome regions that contain genes implicated in OA , as well as further investigation of gene expression data, will be useful for studying mechanisms of OA and identifying therapeutic targets.
The hippo brain study: A phase II feasibility trial of hippocampus sparing whole brain radiotherapy to patients with SCLC.
Authors: Jon A. Lykkegaard Andersen, Svetlana Borissova, Eva Ekas Wilken, Poul F. Geertsen, Anders Mellemgaard
Journal: Journal of Clinical Oncology (2016)

e20097 Background: The natural history of small cell lung cancer (SCLC) is one of rapid tumor growth and early dissemination. Prophylactic cranial irradiation (PCI) can reduce the frequency of subsequent intracranial relapse and improve survival for patients with both limited (LD) and extensive (ED) SCLC. However long-term toxicity, especially loss in neurocognitive function (NCF) is a concern. Studies suggest that the cause of radiation-induced NCF is radiation-induced damage to proliferating neuronal stem cells in the hippocampus region. Methods: Between march 2013 and april 2014 we conducted a phase II feasibility study of hippocampus sparring whole brain radiotherapy (HSWBRT) to patients with SCLC LD and ED considered to be eligible to receive PCI. Patients were treated with standard-of-care PCI with 2.5 Gy x 10 F, 5F/W. We used MRI planning and IMRT technique to lower the dose to the hippocampus area in accordance with the specifications of RTOG 0933. Patients were tested prior to HSWBRT, 1 month and 3 month after with the Addenbroke´s Cognitive Examination (ACE), which is a brief cognitive test that assesses five cognitive domains. The test includes a Mini-mental state examination (MMSE) test. Total score is 100. Results: 22 patients were included (12 female, 10 male) in the study. All patients had SCLC (9 with LD) median age of 65.5 years. 18 patients in performance status of 0-1, 4 patients with a PS of 2. The median ACE score prior to treatment was 87.2. There was marginally numerical drop in ACE score for 15 patients after 1 month (median 86.1) Only 9 patients were tested after 3 months with no change in ACE score. Almost 60 % of patients reported toxicity grade 2 especially headache, dizziness, hearing loss after 1 month, declined to 15 % at 3 months. 18 % reported cognitive impairment after 3 months especially concentration and short term memory loss grade 2. Median OS (SCLC LD & SLCL ED) was 19.9 months. 3 patiens had CNS relapse, none in the hippocampal area. Conclusions: HSWBRT is technically feasible; survival is comparable to earlier findings. Some degree of loss of cognitive function was observed and whether HSWBRT offers a more safe way of administering PCI must be examined in a randomized trial.
A novel LPS-responsive beige-like anchor protein (LRBA) mutation presents with normal cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and overactive TH17 immunity
Authors: Marieke De Bruyne, Delfien J. Bogaert, Koen Venken, Lien Van den Bossche, Carolien Bonroy, Lisa Roels, Simon J. Tavernier, Els van de Vijver, Ann Driessen, Marielle van Gijn, Laura Gámez-Diaz, Dirk Elewaut, Bodo Grimbacher, Filomeen Haerynck, Nicolette Moes, Melissa Dullaers
Journal: Journal of Allergy and Clinical Immunology (2018)
Bridging the gap in knowledge between dyspnoea scientists and clinicians
Authors: Dan Adler
Journal: European Respiratory Journal (2018)

Dyspnoea can be defined as "a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity" [1]. It derives from interactions among multiple physiological, psychological, social and environmental factors, and may induce secondary physiological and behavioural responses. The current definition of dyspnoea highlights the importance of the multidimensional nature of dyspnoea (sensory–perceptual, affective distress and impact domains), which in turn has led to the development of multidimensional tools to assess dyspnoea [2, 3]. Our current understanding of dyspnoea has been fostered by the ongoing efforts of a community of scientists focused on the multidisciplinary/translational aspects of dyspnoea research. As a result of continuous education, in which the European Respiratory Society was also involved, clinicians caring for these patients in daily practice finally agreed that dyspnoea is a neutral word to "hide" major respiratory suffering in individual patients [4]. Indeed, chronic breathlessness is very often compared with chronic pain and shares many neurophysiological similarities [5, 6]. A study in the ERJ suggests that dyspnoea per se is a major clinical endpoint in a chain of events leading to physical disability <http://ow.ly/QGEg30l6gfj>
A population-based analysis of the effectiveness of docetaxel for castration-sensitive prostate cancer (CSPC).
Authors: Jean-Michel Lavoie, Kevin Zou, Daniel Khalaf, Bernhard J. Eigl, Christian K. Kollmannsberger, Joanna Vergidis, Krista Noonan, Muhammad Zulfiqar, Daygen L. Finch, Kim N. Chi
Journal: Journal of Clinical Oncology (2018)

e17026 Background: Phase III clinical trials have demonstrated efficacy for the addition of docetaxel (DOC) to androgen deprivation therapy (ADT) in the treatment of metastatic CSPC. The effectiveness of DOC with ADT in the general patient (pt) population remains undefined. Methods: A population-based retrospective review was conducted of pts with mCSPC who received DOC in British Columbia from 04/2015 to 02/2017. Results: 156 pts received DOC in the mCSPC setting. Baseline characteristics: median age 67 years (44-86); visceral metastases in 11%; high volume disease in 80%; de-novo metastatic disease in 76%. All 6 DOC cycles were delivered in 81% of cases; it was stopped early for: toxicity 10%, pt preference 3% or disease progression 6% cases. Dose reductions and delays were required in 39% and 16% cases. Grade 3-5 adverse events were noted in 40% cases, with 18% febrile neutropenia (FN). Patients with high-volume disease were more likely to develop FN (HR 8.6, p = 0.038); there was no effect from age, baseline performance status, PSA, visceral involvement, or time from ADT start to docetaxel. With a median follow-up of 23 months (m), 116 pts remain alive. Overall survival: median not reached, 1-year 91%; Time to Treatment Failure (TTF): median 14.6 m, 1-year 59%; Time to Treatment for CRPC (TTC): median 20.0 m, 1-year 72%. On multivariate analysis, number of bone metastases > 3 was the only factor predicting TTF (HR 11.0, p < 0.001) and TTC (HR = 16.1, p < 0.001). Of 95 pts who progressed to CRPC, 84 required treatment (88%), with most pts receiving either abiraterone (ABI) or enzalutamide (ENZA, 90%) with a PSA decline ≥50% occurring in 44% of pts. Median time to treatment failure 3.4 m. with no difference between ABI and ENZA. Conclusions: Effectiveness of docetaxel with ADT in a general population of patients with mCSPC was associated with poorer outcomes and high rates of toxicity, relative to reported phase III studies. Pts with high volume disease are at higher risk of FN, and > 3 bone metastases predicted more rapid progression. Response rates to first-line treatment for mCRPC with abiraterone or enzalutamide appear similar to those previously reported.
Thermo reversible hydrogel based delivery of mitomycin C for treatment of upper tract urothelial carcinoma (UTUC).
Authors: Jeffery Shyh-Jye Lin, Nir Kleinmann, Gregory J Wirth, Surena F. Matin, Gil Mayer, Ofer Nativ, Alfred Witjes, Asaf Shvero, Karim Chamie, Allan J. Pantuck, Angela Smith, Mark Schoenberg, Nadav Malchi, Gil Hakim, Yael Agmon-Gerstein, Michal Jeshurun-Gutshtat, Ifat Klein, Helen Kopelen, Seth P. Lerner
Journal: Journal of Clinical Oncology (2017)

e16089 Background: There is a large unmet need for novel drug delivery systems and effective therapy for UTUC, especially for patients with CKD and anatomic solitary kidneys. A temperature sensitive water-soluble gel formulation of Mitomycin C (MMC) demonstrated increased drug delivery time (4 to 6 hrs) and safety in the pelvicalyceal system of swine and human bladders. We report the efficacy and safety of gel+MMC as primary treatment (tx) of UTUC on a compassionate use basis. Methods: Compassionate use approval was obtained on an individual patient basis from the respective regulatory authorities and IRBs. 22 patients were approved for tx to date from 14 institutions in 4 countries. Tx included 6 weekly instillations instilled via ureteral catheter or percutaneous nephrostomy. Gel volume ranged from 5-20cc and MMC concentration was 2-6 mg/cc. Adverse events were recorded throughout treatment. Ureteroscopy was performed 2-6 weeks following tx completion for response determination. Results: Median age of the cohort was 75 yrs, with 15 males. 18 patients (pts) had low-grade (LG) tumor, 2 high-grade (HG), and 2 indeterminate grade. 16 (73%) completed treatment - 9 pts had a complete response, CR (41%; 59% of those who completed tx), 5 pts had a partial response, PR (23%; 31%), and 2 pts had no response, NR (9.1%, 12.5%). 4 patients could not complete tx due to adverse events (pyelonephritis, acute renal failure, pancytopenia, and unstable cardiac condition), 1 patient was diagnosed with a non-urothelial cancer during treatment, and 1 patient died prior to the third instillation due to suspected pulmonary embolus, determined to be unrelated to treatment with MitoGel. A total of 77 adverse events were recorded with 6 events related to MitoGel and serious (requiring intervention), and 21 events related to treatment and not serious. CR (9) and PR (5) were observed in 14 of 15 evaluable patients completing treatment for LG tumors. Conclusions: This compassionate use program of a thermosensitive gel+MMC for chemoablation of UTUC demonstrates proof of concept for treatment of low-grade tumors. A single arm Phase III multi-center registration trial to treat patients with low-grade renal pelvis tumors has been activated.
TCT-483 PARADIGM-EXTEND Prospective Academic Trial Of CGuard™ MicroNET-Covered Self-Expandable Stent System In All-Comer Symptomatic And Increased-Stroke-Risk Asymptomatic Carotid Stenosis: Cumulative 3-Year Clinical And Duplex Ultrasound Evidence For Safety, Efficacy And Durability Of Stroke Prevention
Authors: Piotr Musialek, Adam Mazurek, Anna Borratyńska, Tomasz Tomaszewski, Mateusz Brozda, Urszula Gancarczyk, Piotr Wilkolek, Wojciech Zajdel, Tomasz Drazkiewicz, Lukasz Partyka
Journal: Journal of the American College of Cardiology (2018)
Clinical applications of genetic sequencing in lymphoma: A retrospective review.
Authors: Maryann Shango, Sumana Devata, Ryan A. Wilcox, Tycel Jovelle Phillips
Journal: Journal of Clinical Oncology (2017)

e23169 Background: Personalized therapy through the identification of targetable mutations within individual tumors has increasingly become a focus in the management of patients (pts) with relapsed/refractory malignancy. To better understand how this is clinically applied, we reviewed 29 cases of B- and T-cell lymphomas that had genetic sequencing of their tumor. Methods: The electronic medical records of 29 pts who underwent Michigan Oncology Sequencing (MI-ONCOSEQ) testing at the University of Michigan from 2013-2016 were reviewed for disease and treatment history. Reports from whole-genome tumor sequencing were obtained for each patient to identify putative molecular targets. Results: Sixteen male and 13 female pts had a median age of 59 years (range 30-80 years) and median disease stage of IV at diagnosis. Five had CTCL, 5 PTCL, 11 follicular, 1 CLL/ mantle cell (MC), 1 MC, 1 marginal zone, 1 Waldenstrom’s (WM) and 4 DLBCL. Pts received a median of 2 therapies prior to MI-ONCOSEQ biopsy. Targetable mutations were identified in 15 pts and a total of 5 pts underwent MI-ONCOSEQ-based treatments. Bosutinib was given for FYB-FGR fusion, imatinib for FLI1-PDGFRB fusion, and everolimus for activating mTOR mutation with an avg. treatment duration of 3.6 weeks due to progressive disease. Bosutinib and imatinib were 3 rd line therapies and everolimus was 5 th . Another 2 pts were treated with ibrutinib for transformed WM with MYD88 mutation and bortezomib after classification of DLBCL as ABC-type based on MI-ONCOSEQ results, with CR in both. Other targetable mutations identified include BRAF, CDK, BCL2, EZH2 and NOTCH. Of the remaining 12 pts with targetable mutations, 8 pursued clinical trials, 2 responded to standard therapy, 1 died shortly after genetic analysis and 1 declined further therapy. About 50% of these pts remain alive. Conclusions: Our results demonstrate that targeted therapy is favored after standard therapy or clinical trial options are exhausted. Barriers to its use include the availability of clinical trials, off-label drug access and our incomplete knowledge of driver mutations. With further understanding of disease pathogenesis, we expect personalized therapy will be possible for all patients.
Efficacy and safety of FOLFIRINOX in advanced cholangiocarcinoma.
Authors: Byung Moon Kim, Vincent Anthony Armenio
Journal: Journal of Clinical Oncology (2017)

e15620 Background: Cholangiocarcinomas are invasive carcinomas of uncommon diagnosis and often diagnosed at an advanced and metastatic stage. To this date, there is limited clinical data to support a standard chemotherapy regimen. Single agent systemic chemotherapy such as 5FU or gemcitabine achieves ORR of about 25% while combination regimens including 5-FU, adriamycin, mitomycin or 5-FU and cisplatin has OS of less than a year. Methods: We conducted a single institution retrospective analysis of survival, response and toxicity in patients with advanced or metastatic hepatobiliary carcinoma who had been treated with fluoropyrimidine, irinotecan, and oxaliplatin combination therapy from October 2008 to May 2015. Primary endpoint was PFS measured as the date of first treatment until evidence of clinical progression and/or death. Secondary endpoint was toxicity based on National Cancer Institute Common Terminology Criteria for Adverse Events(NCI CTCAE) for non hematologic and hematologic toxicity. Patients were age greater or equal to 18, histologically confirmed, locally advanced unresectable or metastatic adenocarcinoma of the biliary tract (intrahepatic or extrahepatic cholangiocarcinoma), treatment naive or one prior chemotherapy, ECOG performance status of 0-2. Results: Twenty-five patients were eligible for analysis. A total of six patients (24%) received FOLFIRINOX either as first line therapy or as a second line therapy after progression on gemcitabine based regimen. The median PFS was 5 months (151 days). The median OS was about 14.5 months (436 days). Frequency of hematologic toxicity was more common than non-hematologic toxicity. Thrombocytopenia (67%) and nausea (67%) were the most common adverse event. No treatment related death was recorded. All patients discontinued therapy due to disease progression. Conclusions: In this single institution retrospective outcome analysis, FOLFIRINOX was shown to have activity in maintaining disease control as either a first or second line therapy in advanced cholangiocarcinoma. Hematologic and non-hematologic side effects were frequent but manageable without significant treatment delay or discontinuation. There was no treatment related deaths.
FDG-PET/CT in small cell lung cancer (SCLC): A value analysis.
Authors: Alona Zer, Noa Gordon, Richard Duszak, Daniel A. Goldstein
Journal: Journal of Clinical Oncology (2016)

6626 Background: Despite limited data, PET-CT has become increasingly used as an initial staging tool in patients with SCLC. The test was endorsed by ASCO in September 2015 for staging in patients presenting with clinically suspected limited disease (LD) and considered