tbuckley/cabot-search huggingface dataset:
Leveraging a robust patient-derived xenograft platform to characterize predictors for engraftment and oncologic outcomes in renal cell carcinoma patients.
Authors: Nirmish Singla, Layton Woolford, Christina Stevens, Vanina Tcheuyap, Oreoluwa Onabolu, Zhiqun Xie, Renee McKay, Tao Wang, Alana Christie, Jeffrey Gahan, Aditya Bagrodia, Ganesh Raj, Arthur I. Sagalowsky, Yair Lotan, Jeffrey A Cadeddu, Vitaly Margulis, Payal Kapur, James Brugarolas
Journal: Journal of Clinical Oncology (2019)

e16100 Background: Patient-derived xenograft (PDX) models of renal cell carcinoma (RCC) preserve the biological features of patient tumors, providing a platform for biomarker identification and preclinical drug testing. We sought to identify predictors of successful tumor engraftment and evaluate the prognostic value of engraftment in patients with RCC using a robust murine PDX platform. Methods: 1,200 specimens derived from nephrectomy, thrombectomy, metastasectomy, or biopsy were orthotopically (renally) implanted into NOD/SCID mice between 2008-2018. Non-RCC pathology was excluded. Stable engraftment was defined by successful passage of tumor tissue at least twice with histologic confirmation. Clinicopathologic characteristics were stratified by engraftment status, and multivariate (MVA) logistic regression was used to identify predictors of engraftment. Kaplan-Meier and Cox regression analyses were used to assess the prognostic value of engraftment on patient overall (OS) and disease-free (DFS) survival. Results: 1,003 independent PDX lines derived from 770 RCC patients were included. 157 (15.6%) lines successfully engrafted and exhibited higher tumor grade, stage, size, and presence of sarcomatoid or rhabdoid components. 79.3% of all tumors were of clear cell histology, and histologic distribution did not vary by engraftment status. We have completed whole exome sequencing and RNAseq on 197 and 213 PDX lines, respectively, and downstream analyses will be reported. On MVA, sarcomatoid (OR 5.71, p &lt; 0.001), rhabdoid (OR 2.79, p = 0.046), and advanced stage (OR 1.72, p = 0.049) were significant predictors for engraftment, while high grade and metastatic tumor source were significant only on UVA. Engraftment was associated with poor OS (HR 2.11, p &lt; 0.001) and DFS (HR 1.85, p = 0.020) in patients after controlling for sarcomatoid, rhabdoid, grade, stage, and age on MVA. Conclusions: Aggressive RCC biology correlates with successful engraftment in PDX models. Engraftment remains independently predictive of OS and DFS even after controlling for adverse pathologic features. Engraftment in mice may illuminate aspects of tumor biology not captured by clinicopathologic variables and provide insight into novel determinants of tumor aggressiveness and metastasis.
The burden of diabetes and use of diabetes care in humanitarian crises in low-income and middle-income countries
Authors: Sylvia Kehlenbrink, James Smith, Éimhín Ansbro, Daniela C Fuhr, Anson Cheung, Ruwan Ratnayake, Philippa Boulle, Kiran Jobanputra, Pablo Perel, Bayard Roberts
Journal: The Lancet Diabetes & Endocrinology (2019)
Abstract P009: Association Between Intracranial Subclinical Vessel Diseases and Cognition in a Community-Based Sample of Japanese Men: Shiga Epidemiological Study of Subclinical Atherosclerosis (SESSA)
Authors: Takahiro Ito, Akira Fujiyoshi, Takayoshi Ohkubo, Akihiko Shiino, Kazuhiko Nozaki, Naoko Miyagawa, Sayuki Torii, Takashi Hisamatsu, Katsuyuki Miura, Hirotsugu Ueshima
Journal: Circulation (2019)

Background and Purpose: Intracranial subclinical vessel diseases are considered important indicators of cognitive impairment. However, comprehensive assessment on various types of vessel disease is lacking. We aim to compare various types of intracranial vessel disease in association with cognitive function among a community-based male population. Method: The Shiga Epidemiological Study of Subclinical Atherosclerosis (SESSA) randomly recruited and examined participants from Shiga, Japan in 2006-08 at baseline. Among 824 male participants in the follow-up exam (2010-12), we restricted our analyses to those who underwent the Cognitive Abilities Screening Instrument (CASI), cranial magnetic resonance imaging/angiogram (MRI/MRA, 1.5-Tesla), and free of stroke or neurodegenerative disease. Using MRI/MRA, we assessed intracranial arterial stenosis and four types of small vessel diseases: lacunar infarction and microbleed, periventricular hyperintensity (PVH), deep and subcortical white matter hyperintensity (DSWMH). We graded each vessel disease into 3 grades by severity. Cerebral artery stenosis was graded according to the presence of most stenotic lesions in the major 11 vessels: no stenosis (grade 1), 1-50% stenosis at least 1 vessel (grade 2), ≥ 50% stenosis at least 1 vessel (grade 3). Lacunar infarct was graded according to number of infarct: 0 (grade 1), 1-2 (grade 2), &gt;2 (grade 3). Microbleed was graded according to number of microbleed: 0 (grade 1), 1 (grade 2), ≥2 (grade 3). PVH and DSWMH were graded according to Shinohara’s scale (a modified Fazekas scale): scale 0 to 1 (grade 1), scale 2 (grade 2), scale ≥3 (grade 3). Using linear regression, CASI score (ranging from 0 to 100 with a higher score indicating better cognition) was calculated according to the grade of each vessel disease adjusted for age and education year attained. Results: We analyzed 693 men. Mean (standard deviation) age and CASI score was 67.9 (8.1) years, and 91.2 (5.4), respectively. Significant inverse trends were observed between disease grade and CASI score for DSWMH and PVH: adjusted CASI scores of grade 1, 2, and 3 were 91.7, 91.2, and 90.4 (P trend 0.015) for DSWMH, and 91.5, 90.4, and 89.8 (P trend 0.007) for PVH. No clear trend across the grade was observed in other vessel diseases. Conclusion: Among various types of intracranial subclinical vessel diseases assessed with MRA/MRI, white matter hyperintensity (PVH, and DSWMH) had significant dose-response relationships to cognitive function in a community-based male sample that has a relatively well-preserved cognition level. Our finding suggests that white matter hyperintensity is an important early predictor of cognitive functions among subclinical vessel diseases.
Synthetic miR-143 Exhibited an Anti-Cancer Effect via the Downregulation of K-RAS Networks of Renal Cell Cancer Cells In Vitro and In Vivo
Authors: Tomoaki Takai, Takuya Tsujino, Yuki Yoshikawa, Teruo Inamoto, Nobuhiko Sugito, Yuki Kuranaga, Kazuki Heishima, Tomoyoshi Soga, Kotaro Hayashi, Kanjiro Miyata, Kazunori Kataoka, Haruhito Azuma, Yukihiro Akao
Journal: Molecular Therapy (2019)
Dengue-specific CD8+ T cell subsets display specialized transcriptomic and TCR profiles
Authors: Yuan Tian, Mariana Babor, Jerome Lane, Grégory Seumois, Shu Liang, N.D. Suraj Goonawardhana, Aruna D. De Silva, Elizabeth J. Phillips, Simon A. Mallal, Ricardo da Silva Antunes, Alba Grifoni, Pandurangan Vijayanand, Daniela Weiskopf, Bjoern Peters, Alessandro Sette
Journal: Journal of Clinical Investigation (2019)

Accumulating evidence demonstrates that CD8+ T cells contribute to protection from severe dengue virus (DENV) disease and vaccine efficacy. Nevertheless, molecular programs associated with DENV-specific CD8+ T cell subsets have not been defined. Here, we studied the transcriptomic profiles of human DENV-specific CD8+ T cells isolated after stimulation with DENV epitopes from donors who had been infected with DENV multiple times and would therefore be expected to have significant levels of adaptive immunity. We found that DENV-specific CD8+ T cells mainly consisted of effector memory subsets, namely CD45RA−CCR7− effector memory (Tem) and CD45RA+CCR7− effector memory re-expressing CD45RA (Temra) cells, which enacted specific gene expression profiles upon stimulation with cognate antigens. DENV-specific CD8+ T cell subsets in general, and Temra cells in particular, were fully activated and polyfunctional, yet associated with relatively narrow transcriptional responses. Furthermore, we found that DENV-specific CD8+ Tem and Temra cells showed some unique T cell receptor features in terms of overlap and variable (V) gene usage. This study provides a transcriptomic definition of DENV-specific activated human CD8+ T cell subsets and defines a benchmark profile that vaccine-specific responses could aim to reproduce.
Association of inflammation and clinical outcomes (CO) in metastatic renal cell carcinoma (mRCC) patients (pts) treated with cabozantinib (cabo).
Authors: Dylan J Martini, Julie M. Shabto, Yuan Liu, Bradley Curtis Carthon, Alexandra Speak, Elise Hitron, Greta Russler, Sarah Caulfield, Kenneth Ogan, Wayne Harris, Omer Kucuk, Viraj A. Master, Mehmet Asim Bilen
Journal: Journal of Clinical Oncology (2019)

612 Background: Ratios of neutrophils, monocytes, and platelets to lymphocytes (NLR, MLR, and PLR) are associated with poor CO in cancer pts. We investigated the association of NLR, MLR, and PLR and CO in mRCC pts treated with cabo. Methods: We performed a retrospective study of 65 mRCC pts treated with cabo at Winship Cancer Institute from 2016-2018. Overall survival (OS) and progression free survival (PFS) were calculated from first dose to date of death and radiographic or clinical progression, respectively. NLR, MLR, and PLR were obtained at baseline (BL) and 6 (±2) weeks (6W) after cabo initiation. Optimal cut (OC) was determined searching all cuts and testing them by bias adjusted log rank test to associate with PFS. Multivariate analysis (MVA) was performed using Cox proportional hazard model. Results: The medians were: 2.8 (NLR), 0.4 (MLR), and 176.7 (PLR). Increased NLR, MLR, and PLR were significantly associated with worse CO (Table). Conclusions: High NLR, MLR, and PLR may be poor prognostic factors in mRCC pts treated with cabo. Larger studies are needed to validate the results of this study. [Table: see text]
Transgenerational genomic effect of chemotherapy exposure in testicular cancer survivors.
Authors: Eliezer Mendel Van Allen, Gregory Kryukov, Craig Bielski, Kaitlin Samocha, Menachem Fromer, Sara Seepo, Carleen Gentry, Benjamin Neale, Christopher Sweeney, Levi A. Garraway, Mary-Ellen Taplin
Journal: Journal of Clinical Oncology (2015)

1543 Background: Cancer survivors who receive chemotherapy express concern that these exposures may induce germ cell mutations that lead to transmissible genetic damage in post-treatment children. Preclinical models suggest these mutagenic exposures may result in considerable genomic alterations in post-exposure progeny (e.g. elevated mutation rates, chromosomal abnormalities). Epidemiological studies have not demonstrated a significant increase in congenital abnormalities or genetic syndromes in post-treatment children of cancer survivors, although comprehensive genomic assessments have not yet been performed in this patient population. Methods: We identified two testicular cancer survivors who were cured with chemotherapy (bleomycin, etoposide, cisplatin) and had children before and after therapy without cryopreserved sperm. We acquired saliva from patients and their families and performed whole genome sequencing (WGS) from extracted DNA. Genome analysis and de novo mutation discovery were performed using established methods. Results: Genomes were sequenced to 50X mean depth. There was no increase in the de novo mutation rate of post-exposure children compared to their pre-exposure counterparts (Table). In fact, post-exposure offspring born two years after treatment had fewer de novo mutations than pre-exposure counterparts. There were no differences in recombination frequency or rearrangements between offspring. Conclusions: In two families of male cancer survivors, there was no genomic alteration increase in post-exposure children. The lower de novo mutation rate in early post-treatment children may indicate heightened selective pressure, especially when accounting for increasing paternal age. This study provides possible reassuring evidence for patients undergoing chemotherapy who are unable to have pre-treatment sperm cryopreservation. Broadly, this study illustrates the potential for using WGS to identify environmental cancer treatment effects on the inherited genome. Offspring data. Family Exposure status Years before(-)/after(+) chemotherapy de novo mutations mutations/Mb 1 Pre -3.8 148 0.08 1 Post +2.2 126 0.07 2 Pre -1.6 125 0.07 2 Post +2.4 88 0.05 2 Post +5 136 0.08
Efficacy of HLA-Matched PLT Transfusions for Platelet Transfusion Refractoriness in HSCT Patients
Authors: Keisuke Seike, Nobuharu Fujii, Keiko Fujii, Yasuhisa Sando, Makoto Nakamura, Kyosuke Saeki, Yusuke Meguri, Noboru Asada, Daisuke Ennishi, Hisakazu Nishimori, Ken-Ichi Matsuoka, Yoshinobu Maeda
Journal: Blood (2018)
Acute liver injury in the context of immune checkpoint inhibitor-related colitis treated with infliximab
Authors: Hao Chi Zhang, Wenyi Luo, Yinghong Wang
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Immune checkpoint inhibitors (ICPIs), used to treat different advanced malignancies, are associated with a wide range of immune-related adverse reactions (irAEs) that deserve close monitoring of patients. Gastrointestinal reactions and hepatotoxicity may occur, which warrant careful evaluation to confirm the etiology and attribution to ICPIs as these events&nbsp;could affect future management. <h3>Case presentation</h3> We describe a case of a patient&nbsp;with prostate adenocarcinoma, treated with dual ICPIs comprised&nbsp;of ipilimumab and nivolumab, who developed elevated liver enzymes in the context of infliximab therapy prescribed to treat gastrointestinal irAE from his ICPIs. The patient's grade 3 colitis became steroid-refractory, requiring a one-time infusion of infliximab, a biologic agent used commonly in inflammatory bowel disease, as a rescue therapy, to which he responded. The patient subsequently developed liver injury. This presented a diagnostic dilemma involving differential diagnoses of hepatotoxicity due to ICPI or infliximab exposure. A careful review of the clinical history, evaluation of the chronology of events, and exclusion of other causes of acute hepatitis were employed to make the final diagnosis of this event as infliximab-associated hepatotoxicity. <h3>Conclusion</h3> ICPIs such as CTLA-4 and PD-1 inhibitors have the&nbsp;potential to cause&nbsp;both gastrointestinal reactions&nbsp;and hepatotoxicity. An additional confounding factor in our patient's case was the exposure to infliximab used to manage an established&nbsp;irAE that developed&nbsp;after the last exposure to ICPIs. The clinical history and data supported infliximab-associated hepatotoxicity, rather than an irAE. With the increasing application of ICPIs for different cancers, in conjunction with potential risks for irAE, the&nbsp;liver profile should be closely monitored during treatment with ICPI as well as with&nbsp;anti-TNF-α agents in this patient population.
Prognostic Impact of Immune Checkpoint Inhibitor Expression and Its Association with Epithelial-to-Mesenchymal Transition in Hepatocellular Carcinoma
Authors: Ritu Shrestha, Prashanth Prithiviraj, Kim Bridle, Matthew Anake, Darrell H. G. Crawford, Aparna Jayachandran
Journal: Hepatology (2018)
Violence against women and girls with disabilities during and after the 2015 Nepal earthquake: thematic analysis of qualitative data
Authors: Sapana Basnet Bista, Shaurabh Sharma
Journal: The Lancet Global Health (2019)

BackgroundDisasters affect people with disabilities disproportionately. Violence against women and girls, including sexual and psychological violence, has been reported to increase during and after natural disasters. Despite worldwide attention on the devastation caused by the 2015 earthquake in Nepal, the risk of violence against women and girls with disabilities and their experiences during the crisis and recovery phases remain under-researched. In this study, we aim to explore the experiences of violence against disabled women and girls immediately after the earthquake and during the post-earthquake recovery period.MethodsWe undertook a thematic analysis of qualitative data collected through semi-structured interviews and focus group discussions with women and girls with disabilities from the districts worst affected by the 2015 Nepal earthquake: Kathmandu valley (n=16), Dhading (n=8), Sindhupalchok (n=8), and Gorkha (n=8). These qualitative data were a part of two larger studies; one that explored the experiences of people with disabilities during the 2015 Nepal earthquake and another that studied the effect of post-earthquake mental health and psychosocial support in women with disabilities. All participants for this part of the study were recruited through a snowball sampling technique.FindingsWe analysed data from interviews with 40 participants conducted between May, 2015, and February, 2018. Five focus group discussions each with eight participants lasted between 1 h and 1·5 h. Semi-structured interviews lasted between 30 mins and 45 mins. By comparison with their pre-earthquake experiences, women and girls with disabilities reported increased psychological, physical, and sexual violence immediately after the earthquake mostly in and around temporary shelters. Physical and psychological violence were reported to be committed by partners, family members, relatives, and sometimes by people who lived in the same community; sexual violence against girls with disabilities were reported to be committed by close relatives, family members, or an opportunist stranger.InterpretationOur findings highlight that being female with a disability, having limited rights and independence, and having limited access to financial resources lead to increased longer-term violence, even during the recovery and reconstruction phase of a natural disaster. We recommend that emergency responders undertake gender and disability sensitisation training to remove barriers and stigma against women and girls with disabilities. Government, national, and international humanitarian agencies should work together with local-level organisations to strengthen gender and disability-inclusive preventative, reporting, and justice mechanisms.FundingNone.
Risk of death due to heart disease after radiotherapy for esophageal cancer: A SEER study.
Authors: Jonathan Evans Frandsen, Dustin Boothe, David K. Gaffney, Brent Wilson, Shane Lloyd
Journal: Journal of Clinical Oncology (2015)

4025 Background: Radiation therapy (RT) improves local control as well as overall survival when combined with chemotherapy for patients with esophageal cancer (EC). Significant doses of RT are delivered to the heart during treatment for EC, but little data exist regarding the long term heart morbidity after RT for EC. We hypothesized an increased risk of heart disease related death (HDRD) among patients in the Surveillance, Epidemiology, and End Results (SEER) database who received RT as part of their initial treatment for EC. Methods: Using the SEER Program, all individuals from 1973 to 2011 with EC were identified. Two cohorts were created: (1) patients who received RT as part of their initial therapy and (2) those who did not. The primary endpoint, heart disease specific survival (HDSS), was analyzed using Kaplan Meier methods. Cox proportional-hazards regression methods were used for univariate and multivariate analyses. Results: We identified 40,778 patients with EC. 26,377 patients received RT and 14,401 patients did not. HDSS analysis revealed increased risk of HDRD in those receiving RT (P < 0.05), with an absolute risk of HDRD of 2.8%, 5.3% and 9.4% at 5-, 10- and 20-years, respectively. Log rank test of HDSS revealed that the risk of HDRD became significant at 8 months with an absolute risk of HDRD of 0.4% (p < 0.05). The following were associated with HDRD: RT, age, race, stage at presentation, time period of diagnosis, and known comorbid condition keeping one from esophagectomy. On multivariate analysis, RT remained predictive of HDRD (hazard ratio [HR] 1.46, p < 0.05). When considering only candidates for definitive therapy, RT remained predictive of HDRD on univariate (HR 1.53, p < 0.05) and multivariate (HR 1.62, p < 0.05). Conclusions: RT plays an important part of the current treatment paradigm for EC, but the use of RT leads to increased risk of HDRD that is detectable as early as eight months from diagnosis. More research is needed to define optimal dose volume parameters to prevent cardiac death. Consideration should be given to this risk in relation to the patients expected survival.
A multicentric phase II randomized trial of docetaxel (D) plus enzalutamide (E) versus docetaxel (D) as first-line chemotherapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): CHEIRON study.
Authors: Orazio Caffo, Erica Palesandro, Franco Nole, Donatello Gasparro, Claudia Mucciarini, Michele Aieta, Vittorina Zagonel, Roberto Iacovelli, Ugo De Giorgi, Sabrina Rossetti, Lucia Fratino, Cosimo Sacco, Maurizio Nicodemo, Monica Giordano, Donata Sartori, Daniela Scapoli, Elena Verri, Stefania Kinspergher, Giovanni L. Pappagallo, Massimo Aglietta
Journal: Journal of Clinical Oncology (2019)

148 Background: D and E demonstrated to be efficacious in the treatment of mCRPC pts. Due to different antitumor mechanism of action of these agents, it could be postulated that their combination can improve disease control. CHEIRON study tried to demonstrate the candidate efficacy of chemo-hormonal combination D+E versus D in mCRPC first-line. Methods: Eligibility criteria included untreated mCRPC diagnosis, ECOG PS ≤ 2, adequate renal, hepatic and hematological functions. Pts were randomized to receive D 75 mg/m 2 IV d1 q3w plus prednisone 5 mg PO BID for 8 courses alone or plus E 160 mg PO daily for 24 weeks. Stratification criteria were presence of pain and visceral metastases. The primary endpoint of the study was the rate of pts without disease progression (according to PCWG2) at 6 mos after randomization. Results: Between 09/2014 and 10/2017, 246 pts (median age 70 years, range 44-88, pain reported by 54 pts, visceral metastases present in 50 pts) were randomized to DE (120) or D (126). The rate of pts without disease progression at 6 mos was significantly higher in DE arm compared to D arm [87.3% (CI95% 64-80) vs 72.6% (CI95% 80-92); p = 0.006). Similarly, a higher proportion of DE pts achieved a PSA reduction ≥ 50% compared to the baseline values compared to the D pts [92.2%(CI95% 61-77) vs 70.0%(CI95% 86-96); p &lt; 0.0001). No differences were observed in terms of objective response rate. Major haematological toxicities consisted of grade 3-4 anemia (3 pts DE – 1 pt D) and grade 3-4 neutropenia (23 pts DE – 19 pts D); febrile neutropenia was observed in 10 DE pts and in 5 D pts. At a median follow-up of 20 mos, the median progression free survival was 11.3 mos (CI95% 10.0-12.7) and 9.1 mos (CI95% 8.9-9.2) in DE and D arm, respectively (p = 0.004). In D arm the median overall survival was 30.5 mos (CI95% 24.1-36.8) compared to 28.7 mos (CI95% 20.7-36.6) of the experimental arm (p NS). Conclusions: From the present study, the first phase II randomized trial testing the addition of a new generation hormone agent to D, DE improved the 6-mo disease control with a prolongation of PFS compared to the standard chemotherapy. Clinical trial information: NCT02453009.