tbuckley/cabot-search huggingface dataset:
Immune checkpoint inhibitors in MITF family translocation renal cell carcinomas and genetic correlates of exceptional responders
Authors: A. Boilève, M. I. Carlo, P. Barthélémy, S. Oudard, D. Borchiellini, M. H. Voss, S. George, C. Chevreau, J. Landman-Parker, M-D Tabone, D. D. Chism, A. Amin, M. A. Bilen, D. Bosse, A. Coulomb-L’hermine, Xiaoping Su, T. K. Choueiri, Nizar M. Tannir, Gabriel G. Malouf
Journal: Journal for ImmunoTherapy of Cancer (2018)

<h3>Background</h3> <i>Microphthalmia Transcription Factor</i> (<i>MITF</i>)family translocation renal cell carcinoma (tRCC) is a rare RCC subtype harboring <i>TFE3</i>/<i>TFEB</i> translocations. The prognosis in the metastatic (m) setting is poor. Programmed death ligand-1 expression was reported in 90% of cases, prompting us to analyze the benefit of immune checkpoint inhibitors (ICI) in this population. <h3>Patients and methods</h3> This multicenter retrospective study identified patients with <i>MITF</i> family mtRCC who had received an ICI in any of 12 referral centers in France or the USA. Response rate according to RECIST criteria, progression-free survival (PFS), and overall survival (OS) were analyzed. Genomic alterations associated with response were determined for 8 patients. <h3>Results</h3> Overall, 24 patients with metastatic disease who received an ICI as second or later line of treatment were identified. Nineteen (82.6%) of these patients had received a VEGFR inhibitor as first-line treatment, with a median PFS of 3 months (range, 1–22 months). The median PFS for patients during first ICI treatment was 2.5 months (range, 1–40 months); 4 patients experienced partial response (16,7%) and 3 (12,5%) had stable disease. Of the patients whose genomic alterations were analyzed, two patients with mutations in bromodomain-containing genes (<i>PBRM1</i> and <i>BRD8</i>) had a clinical benefit. Resistant clones in a patient with exceptional response to ipilimumab showed loss of <i>BRD8</i> mutations and increased mutational load driven by parallel evolution affecting 17 genes (median mutations per gene, 3), which were enriched mainly for O-glycan processing (29.4%, FDR = 9.7 × 10<sup>− 6</sup>). <h3>Conclusions</h3> <i>MITF</i> family tRCC is an aggressive disease with similar responses to ICIs as clear-cell RCC. Mutations in bromodomain-containing genes might be associated with clinical benefit. The unexpected observation about parallel evolution of genes involved in O-glycosylation as a mechanism of resistance to ICI warrants exploration.
Inhibition of heat shock protein 70 blocks the development of cardiac hypertrophy by modulating the phosphorylation of histone deacetylase 2
Authors: Somy Yoon, Mira Kim, Hyun-Ki Min, Yeong-Un Lee, Duk-Hwa Kwon, Miyoung Lee, Sumin Lee, Taewon Kook, Hosouk Joung, Kwang-Il Nam, Youngkeun Ahn, Young-Kook Kim, Jaetaek Kim, Woo Jin Park, Julie R McMullen, Gwang Hyeon Eom, Hyun Kook
Journal: Cardiovascular Research (2018)

Previously, we reported that phosphorylation of histone deacetylase 2 (HDAC2) and the resulting activation causes cardiac hypertrophy. Through further study of the specific binding partners of phosphorylated HDAC2 and their mechanism of regulation, we can better understand how cardiac hypertrophy develops. Thus, in the present study, we aimed to elucidate the function of one such binding partner, heat shock protein 70 (HSP70).Primary cultures of rat neonatal ventricular cardiomyocytes and H9c2 cardiomyoblasts were used for in vitro cellular experiments. HSP70 knockout (KO) mice and transgenic (Tg) mice that overexpress HSP70 in the heart were used for in vivo analysis. Peptide-precipitation and immunoprecipitation assay revealed that HSP70 preferentially binds to phosphorylated HDAC2 S394. Forced expression of HSP70 increased phosphorylation of HDAC2 S394 and its activation, but not that of S422/424, whereas knocking down of HSP70 reduced it. However, HSP70 failed to phosphorylate HDAC2 in the cell-free condition. Phosphorylation of HDAC2 S394 by casein kinase 2α1 enhanced the binding of HSP70 to HDAC2, whereas dephosphorylation induced by the catalytic subunit of protein phosphatase 2A (PP2CA) had the opposite effect. HSP70 prevented HDAC2 dephosphorylation by reducing the binding of HDAC2 to PP2CA. HSP70 KO mouse hearts failed to phosphorylate S394 HDAC2 in response to isoproterenol infusion, whereas Tg overexpression of HSP70 increased the phosphorylation and activation of HDAC2. 2-Phenylethynesulfonamide (PES), an HSP70 inhibitor, attenuated cardiac hypertrophy induced either by phenylephrine in neonatal ventricular cardiomyocytes or by aortic banding in mice. PES reduced HDAC2 S394 phosphorylation and its activation by interfering with the binding of HSP70 to HDAC2.These results demonstrate that HSP70 specifically binds to S394-phosphorylated HDAC2 and maintains its phosphorylation status, which results in HDAC2 activation and the development of cardiac hypertrophy. Inhibition of HSP70 has possible application as a therapeutic.
Bortezomib in combination with gemcitabine (GEM) and cisplatin (CDDP) in patients with locally advanced/metastatic non-small cell lung cancer (NSCLC): A Hellenic Oncology Research Group multicenter phase II study.
Authors: Sofia Agelaki, Athanasios Kotsakis, Emmanouil Kontopodis, Nikolaos K. Kentepozidis, Konstantinos N. Syrigos, Nikolaos Ziras, Georgia Filippa, Lampros Vamvakas, Dimitrios Mavroudis, Vassilis Georgoulias
Journal: Journal of Clinical Oncology (2014)

e19050 Background: Bortezomib, is a selective reversible proteasome inhibitor with proapoptotic effects. A multicenter phase II study of bortezomib in combination with GEM and CDDP in advanced NSCLC was conducted. Methods: Patients (pts) with inoperable stage IIIB or IV NSCLC, who had not received previous chemotherapy for advanced disease, were administered bortezomib 1 mg/m2 on days 1 and 8, and starting from cycle 2, bortezomib (as described previously) in combination with GEM 1,000 mg/m2, days 1, 8, and CDDP 70 mg/m2, day 1; treatment was repeated every 21-days. Up to 8 cycles of combination therapy could be administered; single-agent bortezomib was continued until disease progression or unacceptable toxicity. Results: Fifty- three pts (median age, 66 years; 79.2% male; 96.2% stage IV; performance status 0/1 73.6%/26.4%; adenocarcinoma 39.6%, squamous cell carcinoma 41.5%, were enrolled. All pts were evaluable for toxicity and 44 for efficacy analysis. Grade 3-4 hematologic toxicity consisted of neutropenia (22.6%) and thrombocytopenia (17%). More common non-hematologic adverse events were fever (24.5%), fatigue (20.8%), respiratory infection (18.9%) and dyspnea (15.1%). No grade 2-3 neurotoxicity was observed. Febrile neutropenia occurred in two (1.9%) patients; moreover, there were two deaths (3.8%) possibly related to treatment. In the intention-to-treat population, the objective response rate was 17% and 26.4% of pts achieved disease stabilization. No difference in response rates was observed in patients with squamous subtype (squamous vs others, 18.2% vs 16.1%, p=0.845). The median time-to-tumor progression was 2.5 months (95% CI 1.4-3.7), the median overall survival 10.6 months (95% CI 8.9-12.4) and the probability of 1-year survival 38.1%. Conclusions: The combination of bortezomib with GEM/CDDP in the dose and schedule used in this study does not seem to enhance the activity of the chemotherapy doublet. Clinical trial information: NCT01633645.
The MMPI-2-Restructured Form (MMPI-2-RF): Assessment of Personality and Psychopathology in the Twenty-First Century
Authors: Martin Sellbom
Journal: Annual Review of Clinical Psychology (2019)

This article describes the Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF) and situates the instrument in contemporary psychopathology and personality literature. The historical evolution of the MMPI instruments is highlighted, including how failure to update the test for several decades resulted in increasing disinterest by basic researchers and how the restructuring efforts beginning in the 2000s promised to realign the instrument with basic research. In this regard, the construct validity associated with MMPI-2-RF scores in the context of contemporary dimensional models of psychopathology is considered. Research supporting the applied utility of the MMPI-2-RF scales in a variety of contexts-including mental health screenings, presurgical evaluations, forensic assessment, and public safety screening-is also reviewed. Critiques of the MMPI-2-RF are described and addressed. Finally, a series of recommendations for future updates of the MMPI-2-RF are described along with a path toward the MMPI-3.
Abstract 15997: Empagliflozin Exerts Short- and Long-term Effects on Plasma Volume in Patients With Type 2 Diabetes: Insight From EMPA-REG OUTCOME
Authors: Morten Schou, Lars Gullestad, David Fitchett, Bernard Zinman, Silvio E Inzucchi, Uwe Hehnke, Max von Eynatten, Jyothis George, Odd Erik Johansen, Christoph Wanner
Journal: Circulation (2017)

Introduction: In EMPA-REG OUTCOME®, empagliflozin (empa) significantly reduced CV death by 38% and hospitalization for heart failure by 35% relative to placebo. Haemodynamic changes and improvement in subclinical congestion mediated by the osmotic diuresis and natriuresis have been proposed as mechanism responsible for these outcomes. We hypothesized that short- and long-term treatment with empa reduced estimated plasma volume (ePV), and further explored whether responses in ePV were influenced by estimated glomerular filtration rate (eGFR) at baseline. Methods: Patients with type 2 diabetes at high CV risk were randomized to receive placebo, empa 10 mg, or empa 25 mg in addition to standard of care. We analyzed short (12 week) - and long-term (up to 206 week) %-changes in ePV from baseline using a validated formula (Strauss formula) that incorporates hematocrit and hemoglobin concentrations (% ePV change = ((100 x [hemoglobin (before)/hemoglobin (after)]) x ([l- hematocrit (after)]/[l- hematocrit (before...
Gender distinctions in the content of prolactin and progesterone in lung cancer tumor knot.
Authors: Vladislav Legostayev, Elena Frantsiyants, Valeriya Bandovkina, Ekaterina Komarova, Svetlana Dmitriyeva, Oleg Babenkov
Journal: Journal of Clinical Oncology (2014)

e22204 Background: Although lung is not a reproductive system organ, a particularity of its malignant tumors is pronounced gender distinctions of incidence. Women are affected with the lung cancer 7-12 times less frequently than men. The gender distinction in the incidence points to the existence of protective endogenic mechanism. Methods: Progesterone (P4) and prolactin (Prl) were studied in 10% homogenates of tumor tissue from 33 men and 22 women having lung cancer (T2-3N0-1M0), the hystostructure being adenocarcinomas. The patients were 62±3.1 years old. The level of hormones was determined by ELISA. As the control, lung tissue obtained in surgical treatment of non-oncological patients was used. Results: In lung tissue of patients having no oncological pathology, the level of prolactin had no gender distinctions, unlike that of progesterone: the concentration of that in women was 2 times higher as the indicator in men. With lung cancer, all men and women had 1.3-1.6 times higher content of Prl in the tumor as compared to the intact tissue. Progesterone was almost non-determinable in the tumor in 74% of men, and it was only in 26% of men that it was not different from the control. In women, the level of P4 was 2.7 times lower in the tumor in 80% of patients, while it was 2.5 times higher in 20% of women only. The low P4level in tumor in women was indicative of high probability of the lung cancer metastasizing into the brain. Conclusions: Probably, one of the protective mechanisms for women in case of lung cancer is initially high level of progesterone in lungs. The fact that it is in menopausal age that the incidence of lung cancer in women is predominant may be related to weakened protector action of sex hormones due to age.
Factors influencing current low‐value follow‐up care after basal cell carcinoma and suggested strategies for de‐adoption: a qualitative study
Authors: S. Egmond, M. Wakkee, A. Rengen, M.T. Bastiaens, T. Nijsten, M. Lugtenberg
Journal: British Journal of Dermatology (2018)

Providing follow‐up to patients with low‐risk basal cell carcinoma (BCC) can be considered as low‐value care. However, dermatologists still provide substantial follow‐up care to this patient group, for reasons not well understood. To identify factors influencing current BCC follow‐up practices among dermatologists and suggested strategies to de‐adopt this low‐value care. In addition, views of patients regarding follow‐up care were explored. A qualitative study was conducted consisting of 18 semistructured interviews with dermatologists and three focus groups with a total of 17 patients with low‐risk BCC who had received dermatological care. The interviews focused on current follow‐up practices, influencing factors and suggested strategies to de‐adopt the follow‐up care. The focus groups discussed preferred follow‐up schedules and providers, as well as the content of follow‐up. All (group) interviews were transcribed verbatim and analysed by two researchers using ATLAS.ti software. Factors influencing current follow‐up care practices among dermatologists included complying with patients' preferences, lack of trust in general practitioners (GPs), financial incentives and force of habit. Patients reported varying needs regarding periodic follow‐up visits, preferred to be seen by a dermatologist and indicated a need for improved information provision. Suggested strategies by dermatologists to de‐adopt the low‐value care encompassed educating patients with improved information, educating GPs to increase trust of dermatologists, realizing appropriate financial reimbursement and informing dermatologists about the low value of care. A mixture of factors appear to contribute to current follow‐up practices after low‐risk BCC. In order to de‐adopt this low‐value care, strategies should be aimed at dermatologists and GPs, and also patients.
Abstract 20541: Multi-Omics Modeling of Carotid Atherosclerotic Plaques Reveals Molecular Networks and Regulators of Stroke
Authors: Yuqi Zhao, Zeyneb Kurt, Xia Yang
Journal: Circulation (2017)

Introduction: Carotid atherosclerotic plaque is an inflammatory lesion associated with a significantly increased risk for stroke. The formation of carotid plaque involves complex processes, such as...
Reduction in Annualized Bleeding and Factor IX Consumption up to 2.5 Years in Adults with Severe or Moderate-Severe Hemophilia B Treated with AMT-060 (AAV5-hFIX) Gene Therapy
Authors: Frank Leebeek, K Meijer, Michiel Coppens, Peter Kampmann, Robert Klamroth, Roger Schutgens, Giancarlo Castaman, Erhard Seifried, J Schwaeble, Halvard Bonig, Eileen K Sawyer, W Miesbach
Journal: Blood (2018)
Sipuleucel-T cellular immunotherapy: Clinical predictors of survival in patients with castration-resistant prostate cancer (CRPC).
Authors: Mehmet Asim Bilen, Kenneth R. Hess, Ana Aparicio, Jeri Kim, Amado J. Zurita, Lance C. Pagliaro, John C. Araujo, Paul Gettys Corn, Bradley J. Atkinson, Nizar M. Tannir, Padmanee Sharma, Sue-Hwa Lin, Christopher Logothetis, Shi-Ming Tu
Journal: Journal of Clinical Oncology (2014)

e16046 Background: Sipuleucel-T was the first cellular immunotherapy shown to prolong the life of patients with advanced prostate cancer. It was of interest to determine who were those patients most likely to benefit from Sipuleucel-T by evaluating clinical predictors of survival in CRPC patients who had received the treatment. Methods: From October 2010 to October 2012, 56 consecutive patients diagnosed with CRPC and treated with Sipuleucel-T were included for this retrospective study. Progression of bone metastasis was defined as appearance of at least 2 bone lesions on a bone scan. Age, number of bone metastases, prior chemotherapy, and alkaline phosphatase (ALP) were used as predictors of survival in a multivariate Cox proportional hazards regression model. Kaplan-Meier method was used to estimate event-free probabilities.Results: Patient characteristics: age, median (range) 67 yrs (51-84); asymptomatic 87%, minimally symptomatic 13%; PSA, median (range) 8.9 ng/ml (2-477); ALP, median (range) 77 IU/L (37-1015); bone metastasis 57% (<6 39%, 6-20 9%, >20 9%), lymphadenopathy 34%, prostate 2%, none 7%; prior therapy – prostatectomy 30%, XRT 25%, both 27%; prior chemotherapy 45%. 22 patients developed bone progression after a median of 22 months follow-up (54% event-free at 2 yrs). 11 deaths were observed after a median of 28 months follow-up (79% surviving at 2 yrs). 48 patients were included in the multivariate analysis for overall survival (OS), which showed that age >70 yrs (p=.012), number of bone metastasis >20 (p=.018), prior chemotherapy (p=.018), and ALP >90 IU/L (p=.010) had prognostic significance. 2-yr OS among 16 patients with two or more of these factors was 36% compared to 93% for 32 patients with one or none (p=.0004). Conclusions: CRPC patients with advanced age (>70 yrs), increased tumor burden in bone (>20 metastases and/or elevated ALP level), and/or prior chemotherapy may rapidly deteriorate on and not benefit from Sipuleucel-T. Results of this study need to be verified in a prospective randomized trial, e.g., the IMPACT trial (Kantoff PW, NEJM 2010).
Importance of durational hormone therapy in breast cancer patients in Germany: Retrospective database analysis.
Authors: Nina Schmidt, Gabriele Haas, Karel Kostev, Peyman Hadji
Journal: Journal of Clinical Oncology (2014)

1603 Background: The ATLAS trial demonstrated an additional benefit in the extension of treatment of breast cancer patients from 5 to 10 years. However, the longer therapy requires good compliance by the patients. The aim of this study is to investigate the actual duration of therapy of breast cancer patients until treatment discontinuation or scheduled termination of therapy. Methods: We used data from the IMS Disease Analyzer database that entails a dataset of more than 20 million patients. Out of this dataset, breast cancer patients with first time tamoxifen (TAM) or aromatase inhibitors (AI) prescriptions between January 1995 to December 2012 in 1,264 genral practitioner and 387 gynecological practices were identified. Treatment discontinuation of hormonal therapy was defined as 180 days without any treatment or switch to an alternative hormonal therapy. Only women, who still visited their physician more than 180 days after therapy end were included in the analysis. For the current persistence analyses, 8,837 women on tamoxifen or aromatase inhibitors met the inclusion/exclusion criteria. Results: The average hormonal therapy duration was 915 days (SD: 784). 88.1% of women discontinued their therapy before the end of the 5th year. Discontinuation rate was 35.4% within first year and increased to 61.4 % within 3 years of follow-up. The compliance rate decreased with increasing age of the patient. Conclusions: The retrospective data analysis showed that the share of patients who stay on hormonal therapy for five years is very small. Therapy discontinuation can be due to side effects, suboptimal communication between physicians and patients or other reasons. Compliance in breast cancer therapy needs to be significantly increased for improved outcome in clinical practice.
Efficacy and Safety of Once-Weekly vs Twice-Weekly Carfilzomib Plus Dexamethasone: Subgroup Analysis of the Phase 3 A.R.R.O.W. Study (NCT02412878) By Prior Lines
Authors: Philippe Moreau, A Keith Stewart, Antonio Lazzaro, Meletios A Dimopoulos, Michele Cavo, Sikander Ailawadhi, Karim Iskander, Mei Huang, Anita Zahlten-Kumeli, Maria-Victoria Mateos
Journal: Blood (2018)
Meta-Analysis of Long-Term Risk of Recurrent Venous Thromboembolism after Stopping Anticoagulation in Men and Women with First Unprovoked Venous Thromboembolism
Authors: Faizan Khan, Alvi Rahman, Marc Carrier, Clive Kearon, Jeffrey I. Weitz, Sam Schulman, Francis Couturaud, Sabine Eichinger, Paul Alexander Kyrle, Cecilia Becattini, Giancarlo Agnelli, Timothy Brighton, Anthonie WA. Lensing, Martin H. Prins, Elham Sabri, Brian Hutton, Laurent Pinede, Mary Cushman, Gualtiero Palareti, George Wells, Paolo Prandoni, Harry R. Büller, Marc A. Rodger
Journal: Blood (2018)
Image Gallery: Necrolytic migratory erythema associated with glucagonoma
Authors: R. Aragón‐Miguel, M. Prieto‐Barrios, A. Calleja‐Algarra, B. Pinilla‐Martin, J. Rodriguez‐Peralto, P. Ortiz‐Romero, R. Rivera‐Diaz
Journal: British Journal of Dermatology (2019)

Funding sources: no external funding. Conflicts of interest: none to declare. Dear Editor, A 57‐year‐old man with diabetes presented with a 30‐year period of pruritic skin lesions concurrent with a 12‐kg loss of weight. The lesions presented as generalized arciform, erythematous and eroded plaques with overlying haemorrhagic crust (a). There was associated angular cheilitis and atrophic glossitis (b). The skin biopsy showed three structures within the epidermis: a layer with basaloid keratinocytes, a spiny zone with cleared cytoplasm cells and another part with thickened eosinophilic stratum corneum, suggestive of necrolytic migratory erythema (c). An abdominal computed tomography scan found a pancreatic mass and liver metastases whose biopsy revealed infiltration by a neuroendocrine tumour with glucagon immunoexpression. Plasma glucagon was increased. The skin lesions resolved following treatment with somatostatin analogues.
Comprehensive molecular profiling of pretreatment metastatic castration resistant prostate cancer (CRPC): Secondary data from NCI 9012, a randomized ETS fusion-stratified phase II trial.
Authors: Scott A. Tomlins, Dan Robinson, Yi-Mi Wu, Robert J Lonigro, Pankaj Vats, Shanker Kalyana Sundaram, Xuhong Cao, Lakshmi Priya Kunju, Nallasivam Palanisamy, Stephanie Daignault, Rohit Mehra, Javed Siddiqui, Arul M. Chinnaiyan, Felix Yi-Chung Feng, Maha Hussain
Journal: Journal of Clinical Oncology (2014)

e16038 Background: Robust molecular subtypes have been identified in castration resistant prostate cancers (CRPC), including those that harbor ETS gene fusions. Preclinical studies suggest that tumors harboring ETS fusions are preferentially sensitive to poly (ADP-ribose) polymerase 1 (PARP1) inhibition. A multi-institutional phase II trial of abiraterone (ABI) +/- the PARP inhibitor veliparib in men with CRPC is assessing the utility of ETS fusion status from metastatic tumor biopsies as a predictive biomarker. In addition, when additional tissue is obtained, we are performing comprehensive molecular profiling through the Mi-Oncoseq initiative. Here we report molecular profiles of response extremes. Methods: Eligible mCRPC pts undergo a metastatic site biopsy to determine ETS fusion status by FISH and/or ISH. Additional tissue is fresh frozen and used for exome and transcriptome sequencing and comprehensive analysis through the Mi-Onocseq pipeline. Results: To date, 86 patients have been enrolled. Of the 86 patients, 12 had sufficient tissue to perform Mi-Oncoseq molecular profiling. Patient 43 (ETS fusion negative, serum PSA 113ng/mL at enrollment) presented with hepatic and nodal metastases and has had radiographic response and achieved undetecatble PSA while on study. Profiling of a pre-study hepatic tumor sample demonstrated an AR 875Y somatic mutation, a low-level AR amplification, and a homozygous, somatic deletion of BRCA2. Patient 26 (ETS fusion positive, serum PSA 3.1ng/mL at enrollment) presented with a bladder recurrence/metastasis and rapidly progressed while on study. Profiling of a pre-study bladder resection specimen demonstrated a TMPRSS2:ERG gene fusion, high level MDM4 amplification, homozygous deletions of PTEN, KDM5A and RB1, and very high expression of proliferation related genes. Additional molecular data on other pts will be presented. Conclusions: Comprehensive, real-time molecular profiling of CRPC is feasible. Point mutations/indels, copy number alterations, gene fusions and transcriptional profiles can be identified and associated with treatment response. Clinical trial information: NCT01576172.