tbuckley/cabot-search huggingface dataset:
Heat shock protein 90 (HSP90) inhibition in squamous cell carcinoma of the head and neck (SCCHN): An in vitro analysis with a focus on p16 status.
Authors: Kirtesh R Patel, Jing Wen, Susan Muller, Jingjing Gao, Roberto Diaz, Nabil F. Saba
Journal: Journal of Clinical Oncology (2013)

2552 Background: Despite advances in therapy, the overall 5 year survival for SCCHN is close to 50%. Cisplatin and radiation therapy remain the current standard for treating locally advanced SCCHN. Novel treatment approaches are urgently needed, especially in HPV negative disease. We examined the expression of HSP90 in HPV positive and negative SCCHN and investigated if the HSP90 inhibitor ganetespib can sensitize mutant p53 SCCHN to cisplatin and radiation therapy in vitro. Methods: Phase 1 trials of ganetespib at 150 mg/m 2 have shown the maximum clinically achievable concentration (CAC) in patients to be ~166 nM. We treated p53 deficient or mutant p53 SCCHN cells (SCC25 and Detroit 568, CAL27and FADU, respectively) with ganetespib at 10-50 nM alone and in combination with cisplatin or radiation therapy and assessed survival. We measured HSP90, HSP70 and p53 protein expression levels in SCCHN cell lines by immunoblotting and analyzed HSP90 protein levels in p16 positive and p16 negative SCCHN tumor samples by immunohistochemistry. Results: Ganetespib at CAC was significantly more cytotoxic in mutant p53 compared to p53 deficient SCCHN cells (p &lt; 0.05). When combined with CAC doses of cisplatin or radiation therapy, ganetespib displayed strong sensitizing activity (p &lt; 0.05 and p &lt; 0.01 respectively). Ganetespib treatment upregulated HSP70 and HSP90 expression while decreasing p53 expression in the mutant cell lines. HSP90 expression was significantly higher in p16 negative than p16 positive SCCHN tumor samples (79.5% vs. 51%, ANOVA p = 0.016). Conclusions: Our results demonstrate a potential efficacy of ganetespib as a single agent and in combination with cisplatin and radiation therapy in SCCHN. HSP90 expression is upregulated in p16 negative SCCHN. Further exploration of the role of HSP90 in SCCHN, and utility of HSP90 inhibitors, is warranted.
Initial results of a phase III investigation of safety/efficacy of nivolumab and ABI-009 (<i>nab</i>-sirolimus) in advanced undifferentiated pleomorphic sarcoma (UPS), liposarcoma (LPS), chondrosarcoma (CS), osteosarcoma (OS), and Ewing sarcoma.
Authors: Victoria S. Chua-Alcala, Katherine Kim, Nupur Assudani, Ahmad Al-Shihabi, Doris Quon, Steven Wong, Sant P. Chawla, Erlinda Maria Gordon
Journal: Journal of Clinical Oncology (2019)

21 Background: Objectives: (1) To investigate the MTD of ABI-009 when given with nivolumab, a PD-1 inhibitor, in previously treated advanced undifferentiated pleomorphic sarcoma, liposarcoma, chondrosarcoma, osteosarcoma and Ewing sarcoma; (2) To investigate the disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) of this combination therapy in the above mentioned patient group, and (3) To correlate PFS with PD-L1 and other biomarker expression in patients’ tumors. Methods: This is an IRB approved protocol with 2 parts. The Phase 1 part is a dose-finding study using the “cohort of three design”, wherein standard doses of nivolumab 240 mg is given iv every 3 weeks (Day 1 of every 21-day Cycle). ABI-009 will be given IV on Days 8 and 15 of each cycle starting on Cycle 2 following the 2 nd nivolumab dose. The starting dose of ABI-009 is 56 mg/m 2 , and sequentially escalating doses are 75, and 100 mg/m 2 . The Phase 2 part of study will enroll 31 additional patients to further assess efficacy and safety at the MTD. Results: The Phase 1 part of study is closed, after 9 patients were treated successfully at 3 dose levels. No dose-limiting toxicities (DLTs) were observed, the MTD was not reached, and 100 mg/m 2 ABI-009 was designated as the recommended phase 2 dose. Safety analysis: At Dose 1 (n=3): Grade 3 treatment-related adverse events (TRAEs) included hyperdyslipidemia (n=1), and hyperglycemia (n=1). At Dose 2 (n=3): Grade 3 TRAEs included increased ALT (n=1). At Dose 3 (n=3): Grade 3 TRAEs included hypophosphatemia (n=1). Seven of 9 patients have discontinued treatment: 5 patients due to PD, 2 with SD opted to stop treatment due to drug-related Grade 2 AEs (pruritus, acneiform rash, and 2 with SD are still on therapy at Dose 3. Conclusions: The primary objective has been met with no DLTs, the MTD was not reached and Dose 3 has been designated as the phase 2 dose of ABI-009 which is on-going. Clinical trial information: NCT03190174.
Phase III KEYNOTE-716 study: Adjuvant therapy with pembrolizumab versus placebo in resected high-risk stage II melanoma.
Authors: Jason J. Luke, Paolo Antonio Ascierto, Matteo S. Carlino, Alexander M. M. Eggermont, Jean-Jacques Grob, Axel Hauschild, John M. Kirkwood, Georgina V. Long, Peter Mohr, Caroline Robert, Jeffrey E. Gershenwald, Andrew Stewart Poklepovic, Merrick I. Ross, Richard A. Scolyer, Charles Yoon, James R. Anderson, Sama Ahsan, Nageatte Ibrahim, Vernon K. Sondak
Journal: Journal of Clinical Oncology (2019)

TPS145 Background: Adjuvant pembrolizumab showed significantly longer recurrence-free survival compared with placebo in resected stage III melanoma in the KEYNOTE-054 study [1]. KEYNOTE-716 is a randomized, placebo-controlled, multicenter phase 3 study of adjuvant pembrolizumab in patients with surgically resected high-risk stage II melanoma. Methods: Patients must be ≥12 years of age and have newly diagnosed, completely resected stage IIB/IIC cutaneous melanoma, defined by the AJCC Cancer Staging Manual, 8th edition [2] (wide excision and negative sentinel lymph node biopsy, with no evidence of distant metastasis). Patients cannot have mucosal or uveal melanoma or have received prior treatment for melanoma, including radiation, beyond resection of primary disease within 12 weeks of the start of study therapy. The study has a 2-part design. In the double-blind phase (part 1), patients will be randomly assigned 1:1 to receive pembrolizumab 200 mg for patients ≥18 years or 2 mg/kg for patients 12-17 years (maximum dose, 200 mg) or placebo every 3 weeks for 17 cycles. Stratification: 1 stratum for pediatric patients (12-17 years); 3 strata for adult patients per T stage (T3b/T4a/T4b). Study treatment will begin within 12 weeks of complete resection. Tumor imaging will be performed every 24 weeks while treatment is ongoing, at the end of treatment, every 6 months for the first 3 years off treatment, and then yearly for up to 2 years or until recurrence (up to 5 years of total imaging). Adverse events will be graded per NCI Common Terminology Criteria for Adverse Events, version 4.0. In the unblinded phase (part 2), patients with confirmed recurrence may be rechallenged (patients received pembrolizumab in part 1) or crossed over to pembrolizumab (patients received placebo in part 1). Resected local or distant recurrence or unresectable disease will be treated for an additional 17 or 35 cycles, respectively. Tumor imaging in part 2 will occur every 12 weeks while treatment is ongoing. The primary end point is recurrence-free survival; secondary end points are distant metastasis-free survival, overall survival, and safety. Approximately 954 patients will be enrolled. Clinical trial information: NCT03553836.
Added screen time linked to more depression in adolescents, study finds
Authors: Susan Mayor
Journal: BMJ (2019)

Increased use of social media and computers and longer television viewing times are linked to higher rates of depressive symptoms in adolescents, but playing video games does not increase depression, a Canadian study1 has found.

“To our knowledge, this study is the first to use developmental data from a large sample of adolescents to examine the association between four types of screen time and depression,” said the study authors, led by Elroy Boers, postdoctoral researcher at the department of psychiatry, University of Montreal, Canada.

The researchers added, “The most important finding was that increased social media and television …
John William Powles
Authors: Hebe Naomi Gouda, Adela Sanz, Rebecca Powles, Carol Brayne
Journal: BMJ (2019)

It is with great sadness that we write of the recent passing of a brilliant academic and a devoted public health educator, our colleague John William Powles. Born in 1943, John grew up in rural Australia, in the Riverina region of New South Wales (NSW), where his father had numerous business interest and his mother worked as a nurse. After briefly considering a career in the seminary, John studied medicine at the University of Sydney.

Even as a young student, his calling to work on social issues was evident. At university, John was a keen advocate for social justice. He founded the Sydney University Humanist Society, which was involved in the Campaign for Nuclear Disarmament. In 1965 he was the vice president of the group Student Action for Aborigines (SAFA), led by Charlie Perkins, the first aboriginal student to graduate from Sydney University. The group organised the “SAFA bus tour,” also known as the “Freedom Ride,” around regional New South Wales, modelled on civil rights actions in the US. The Freedom Riders drew national and international media attention to the issue of racial segregation in Australia, helping to prompt public debate on racism that led eventually to the 1967 referendum and the transfer of aboriginal affairs from state to federal government, making it possible to include aboriginal people in national censuses. In 1966 John’s interest in global cultures took him on a study tour to China in the midst of the Cultural Revolution …
FXR modulates the gut-vascular barrier by regulating the entry sites for bacterial translocation in experimental cirrhosis
Authors: Marcel Sorribas, Manuel O. Jakob, Bahtiyar Yilmaz, Hai Li, David Stutz, Yannik Noser, Andrea de Gottardi, Sheida Moghadamrad, Moshin Hassan, Agustin Albillos, Ruben Francés, Oriol Juanola, Ilaria Spadoni, Maria Rescigno, Reiner Wiest
Journal: Journal of Hepatology (2019)
Evidence is sweet
Authors: Fiona Godlee
Journal: BMJ (2019)

The man most likely to be the UK’s next prime minister has called for a review of what he calls “stealth sin taxes” (doi:10.1136/bmj.l4557). Boris Johnson says he is concerned about their disproportionate effect on poor people. He also wants to base the UK’s tax policy “on clear evidence.” If so, all of us who want to improve the public’s health can rest easy: the accumulating evidence in favour of such taxes is becoming hard to counter.

First comes the evidence of the damage caused by excessive intake of sugar and of sugary drinks in particular. To the long and evidence …
Autoimmune toxicities with anti-PD-1 treatment of metastatic melanoma in predominantly older patients: A single institutional experience.
Authors: Harsh V Parmar, Phil Kerr, Christina Elizabeth Stevenson, Sophie Masternak, Upendra P. Hegde
Journal: Journal of Clinical Oncology (2019)

144 Background: Anti-PD-1 therapy has become an effective method of treating patients including elderly subjects diagnosed with un-resectable or metastatic melanoma. While effective, toxicity reports in elderly are conflicting. Some reports indicate no added autoimmunity with older melanoma patients, while we had previously reported our concerns of heightened autoimmune toxicity with anti-PD-1 treatment of melanoma in elderly subjects. This report includes updated results in 36 patients receiving anti-PD-1 treatment for melanoma with an increased proportion of older subjects from a single institute. Methods: Between 2014-2018, we performed retrospective review of charts of patients treated with anti-PD-1 agents for stage III and IV melanoma following IRB approval. Data for treatment outcomes and grade III and IV immune related adverse events were collected. Results: 36 patients were treated with either Pembrolizumab or Nivolumab that included stage IV melanoma (28 pts), un-resectable stage III (5 pts) and stage III melanoma in adjuvant setting (3 pts). 30 out of 36 patients were over 60 years of age (median age 77, range 62-90) and 6 patients were younger than 60 years (median age 48, range 24-56). 16 out of 30 patients over age of 60 years (53%) experienced grade III or IV toxicities following anti-PD-1 therapy compared to none (0%) in age below 60 years. Overall, 19 patients are alive either with disease or on treatment with stable, partial or complete responses. 17 patients have died, out of which 12 died of progressive disease, 2 elderly patients died suddenly and 3 elderly patients died of autoimmune toxicity (myasthenia gravis like syndrome, acute inflammatory demyelinating polyneuropathy, pneumonitis). Some unusual autoimmune toxicity seen in elderly subjects included diabetes mellitus, Behcet disease, acute inflammatory demyelinating polyneuropathy, retinitis, Bell's palsy and bullous pemphigoid). Conclusions: Our data continue to indicate that increased risk of severe autoimmune toxicity following anti-PD-1 treatment involved older patients over 60 years of age. This finding may highlight the increased susceptibility of autoimmunity with aging.
Inferior survival after microbiota injury: A multicenter allo-HCT study.
Authors: Jonathan U. Peled, Antonio L.C. Gomes, Sean M. Devlin, Eric R. Littmann, Ying Taur, Anthony Derek Sung, Daniela Weber, Daigo Hashimoto, Roberta J. Wright, Luigi Amoretti, Emily Fontana, Miguel-Angel Perales, Sergio Giralt, Robert R. Jenq, Takanori Teshima, Nelson J. Chao, Ernst Holler, Joao B. Xavier, Eric G. Pamer, Marcel R. M. Van Den Brink
Journal: Journal of Clinical Oncology (2019)

7015 Background: Relationships between microbiota composition and clinical outcomes following allogeneic hematopoietic cell transplantation (allo-HCT) have been described in single-center studies. Geographic variations in human microbial communities and differences in clinical practices across institutions raise the question of whether these associations are generalizable. We report the first multi-center study of the intestinal microbiota in allo-HCT. Methods: Intestinal communities in 8,768 fecal samples from 1,362 allo-HCT patients at 4 centers on 3 continents were profiled by 16S sequencing. Associations between microbiota composition and clinical outcomes were analyzed with proportional-hazards analysis in an observational study. Results: We observed reproducible patterns of microbiota injury characterized by loss of diversity and domination by single taxa. Low diversity in the neutrophil engraftment period was reproducibly associated with increased risk of death (multivariate HR 0.48 [0.30-0.77] p = 0.002 in the largest cohort). These reductions in OS were in part due to an increased risk of transplant-related mortality and graft-vs-host disease. Baseline pre-HCT samples already bore evidence of microbiome disruption; low diversity prior to transplantation was associated with poor survival. A bacterial-composition risk score that was trained in one cohort predicted mortality in the other three cohorts (multivariate HR 1.42 [1.04-1.93] p = 0.03), indicating that not only a diversity metric but also a signature of specific bacterial abundances is informative about post-HCT mortality risk across independent institutions. Conclusions: We demonstrate a relationship between microbiota and survival after allo-HCT that is independent of transplant center and geographic location. The diversity of clinical practices across institutions imposed significant heterogeneity in the study, yet we observed reproducible microbiota injury patterns and associations with outcomes. This concordance suggests that approaches to manipulate the intestinal microbiota in allo-HCT may be generalizable.
The importance of surgical margins in dedifferentiated liposarcoma survival.
Authors: Sara Albagoush, Jonathan Gootee, Kevin Nguyen, Sarah J Aurit, Christina Curtin, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2019)

e22528 Background: Among the types of soft tissue sarcomas (STS), liposarcoma is the most common malignant STS. Considering therapeutic options, surgical resection is the most utilized therapeutic option. In this study, we aim to explore the effects of varying degrees of surgical margins on survival in patients with dedifferentiated liposarcoma. Methods: The National Cancer Database (NCDB) was used to select patients with dedifferentiated liposarcoma to determine if surgical margins and other variables were associated with worse overall survival after accounting for age, gender, race, Charlson-Deyo score, anatomic site, treatment approach, tumor size, tumor grade, and presence of metastases through multivariable analysis. Results: Of the 1,004 patients, 64.4% were male, 87.0% were white, and the median age was 63 years. Approximately 95% had no metastases at the time of diagnosis, and 91.5% had high grade liposarcoma. For the status of surgical margins, 50.8% had no residual tumors, 26.1% had microscopic residual tumors, and 4.3% had macroscopic residual tumors. In general, the risk of death was higher for older males (25.8% increased risk of mortality) and those with metastases (312.9% increased risk of mortality) as well as patients with high grade liposarcoma (112.4% increased risk of mortality). When compared to no residual tumor after surgery, patients with macroscopic residual tumors, had a 96.7% increased risk of death (HR 95% CI:1.24 to 3.13; p= 0.004). Conclusions: Older age, presence of metastasis, male patients, retroperitoneal/abdomen primary site, high grade tumors, and macroscopic or residual tumor present after surgery led to an increased risk of mortality.
Painful Indurated Plaques on the Vulva
Authors: Zhen Zhang, Hong Yu, Zhirong Yao
Journal: JAMA Dermatology (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal
Abstract 12119: Class I Indication for Statin Therapy in Primary Prevention by Three Cholesterol Guidelines and Prevalence of Coronary Artery Calcium in Asymptomatic Adults: Multi-ethnic Study of Atherosclerosis (MESA)
Authors: Peter Flueckiger, Waqas Qureshi, Michael Blaha, Gregory Burke, Veit Sandfort, Erin D Michos, David Herrington, Joseph Yeboah
Journal: Circulation (2015)

Introduction:Statin therapy for secondary prevention of atherosclerotic cardiovascular disease (ASCVD) events provides greater relative risk reduction compared with primary prevention. Coronary artery calcium (CAC) identifies individuals with established but subclinical ASCVD disease. Identifying a population with a higher prevalence of CAC may improve the benefit and efficacy of statin therapy in the primary prevention of ASCVD. We assessed the accuracy of class I statin eligibility criterion for primary prevention by the 2013 ACC/AHA cholesterol guidelines for the presence of CAC and compared it with class I criterion for lipid lowering therapy eligibility by the 2004 NCEP/ATP III and 2011 ESC/EAS cholesterol guidelines. Methods:4723 out of the 6814 total participants not taken statins during the baseline exam and with complete data including CAC were included in analysis. We evaluated the sensitivity (SN), specificity (SP), positive predictive value (PPV), negative predictive value (NPV) of class I recommendation for lipid lowering therapy (high risk designation) by the three cholesterol guidelines for three categories of prevalent CAC [CAC present/absent; CAC ≥ 100; CAC ≥300 Agatston] in participants of the Multi Ethnic Study of Atherosclerosis (MESA) Results:Mean age 59±9 years, 47% male, 37% white, 28% black, 23% Hispanic, 12% Asian, 7.5% with diabetes, 35% current/former smokers, mean glomerular filtration rate of 83±18 ml/min and mean BMI of 28±6 kg/m2. 1978(41.9%), 816(17.3%) and 392(8.3%) had CAC present, CAC ≥100 and CAC ≥300 respectively. Table 1 shows the results. Conclusions:The SN, SP, PPV and NPV of class I statin eligibility criteria by the 3 guidelines for subclinical ASCVD depends significantly on the definition of CAC. The 2013 ACC/AHA class I statin eligibility has a higher SN, lower SP, and higher NPV when compared with the 2004 NCEP/ATP III and 2011 ESC/EAS class I criterion for statin therapy across all three CAC categories.
Peripheral blood TCRB chain convergence and clonal expansion following cytomegalovirus infection: Implications for the biomarker use of TCR-seq.
Authors: Timothy Looney, Jianping Zheng, Denise Topacio-Hall, Geoffrey Lowman, Fiona Hyland
Journal: Journal of Clinical Oncology (2019)

134 Background: Human cytomegalovirus (CMV) is a common immune-evasive herpes family virus leading to lifelong asymptomatic infection in 50 to 80% of humans. The effect of CMV infection on the T cell repertoire may be relevant given interest in identifying T cell repertoire features predictive of response to checkpoint blockade immunotherapy (CPI) for cancer. Here we sought to identify features of CMV infection using TCRB profiling of peripheral blood (PBL) total RNA. Methods: Total RNA from PBL was obtained from 35 blood donors of known CMV status, then used for TCRB sequencing via the Oncomine TCRB-LR assay (amplicon spanning CDR1, 2 and 3) and the Ion Torrent S5. In parallel, we prepared libraries via the Oncomine TCRB-SR assay (CDR3 only). Data were used to identify TCRB repertoire features correlated with CMV status and compare repertoire features across the two assays. Results: T cell clone evenness was reduced in CMV positive individuals irrespective of age, predictive of CMV status (AUC = .86, p = 2E-4, Wilcoxon), and strongly correlated between LR and SR assays (Spearman cor = .96). TCR convergence was elevated in CMV positive individuals and uncorrelated with evenness (Spearman cor = -.03) such that the combination of convergence and evenness improved the performance of a logistic regression classifier (AUC = .93). Conclusions: We identify reduced T cell evenness and elevated TCR convergence as features of chronic CMV infection. CMV infection appears to significantly alter the T cell repertoire, suggesting that CMV status may be required for proper interpretation of T cell expansion in the context of CPI for cancer.
Effects of Fecal Microbiota Transplantation With Oral Capsules in Obese Patients
Authors: Jessica R. Allegretti, Zain Kassam, Benjamin H. Mullish, Austin Chiang, Madeline Carrellas, Jonathan Hurtado, Julian R. Marchesi, Julie A.K. McDonald, Alexandros Pechlivanis, Grace F. Barker, Jesús Miguéns Blanco, Isabel Garcia-Perez, Wing Fei Wong, Ylaine Gerardin, Michael Silverstein, Kevin Kennedy, Christopher Thompson
Journal: Clinical Gastroenterology and Hepatology (2019)
Clinical impact of an educational antimicrobial stewardship program associated with infectious diseases consultation targeting patients with cancer: Results of a 9-year quasi-experimental study with an interrupted time-series analysis
Authors: José Molina, Manuel Noguer, José Antonio Lepe, María Antonia Pérez-Moreno, Manuela Aguilar-Guisado, Roberto Lasso de la Vega, Germán Peñalva, Juan Carlos Crespo-Rivas, María Victoria Gil-Navarro, Javier Salvador, José Miguel Cisneros
Journal: Journal of Infection (2019)