tbuckley/cabot-search huggingface dataset:
Recombinant humanized anti-PD-1 monoclonal antibody (JS001) as salvage treatment for advanced gastric adenocarcinoma: Preliminary results of an open-label, multi-cohort, phase Ib/II clinical study.
Authors: Rui-hua Xu, Fenghua Wang, Nong Xu, Lin Shen, Guanghai Dai, Xianglin Yuan, Jianhua Shi, Shujun Yang, Ji Feng Feng, Xi-Chun Hu, Qingyuan Zhang, Ye Chen, Xiaoyan Lin, Yi Ba, Yunpeng Liu, Yi Jiang, Shu Yongqian, Qi Li, Wei Li, Sheng Yao
Journal: Journal of Clinical Oncology (2018)

108 Background: Patients with gastric adenocarcinoma (GC) or gastroesophageal junction cancer (GEC) often present with advanced or metastatic disease, which has poor prognosis and limited treatment options and represent an important unmet medical need especially in China/Asia. JS001, a humanized recombinant IgG4 antibody against PD-1, selectively blocks the interactions of PD-1 with its ligands PD-L1 and PD-L2, and promotes antigen specific T-cell activation. A phase I study of JS001 in Chinese patients with heavily pretreated solid tumors has demonstrated an acceptable safety profile in doses up to 10 mg/kg Q2W. Here we report the safety and efficacy of JS001 in a phase Ib/II clinical study in Chinese patients with refractory/metastatic GC. (Clinical trial ID: NCT02915432) Methods: Refractory/metastatic GC Patients receive JS001 3 mg/kg Q2W until disease progression or unacceptable toxicity. All patients with measurable disease will be assessed for clinical response every 8 weeks according to the RECIST 1.1 criteria. Tumor PD-L1 expression as well as additional potential predictive biomarkers are monitored for correlation with clinical response. Results: Between Apr 19, 2017 and Sep 11, 2017, 48 GC pts (74.5% received at least 2 Lines of treatment) were enrolled into the study. Treatment related adverse events occurred were mostly grade 1 or 2. As of Sep 11, 2017, 25 GC pts have been evaluated for clinical efficacy. 5 PR (partial response) and 10 SD (stable disease) were observed (ORR 20% and DCR 60%). The PD-L1 expression positivity (defined as positive staining ³1% on Tumor Cell or on Immune Cell by SP142) in EC tumor was 14.3% (7/48). 3/5 (60%) PD-L1+ patients and 2/20 (10%) PD-L1 negative patients achieved partial responses. Conclusions: JS001 showed a promising preliminary clinical activity in heavily pre-treated metastatic GC pts with a manageable safety profile. Of the 25 evaluable GC patients by 9/11/2017, 5 PR and 10 SD were observed (ORR 20% and DCR 60%). Among PD-L1 positive patients (n=5), ORR was 60% and DCR 80%. Pts will be continuously monitored for safety and efficacy upon JS001 treatment. Clinical trial information: NCT02915432.
Efficacy of nivolumab in patients treated by corticosteroid due to immune-related adverse events.
Authors: Ryoko Inaba Higashiyama, Hidehito Horinouchi, Katsutoshi Sekine, Yuji Matsumoto, Shuji Murakami, Yasushi Goto, Shintaro Kanda, Yutaka Fujiwara, Noboru Yamamoto, Yuichiro Ohe
Journal: Journal of Clinical Oncology (2018)

163 Background: Nivolumab is a standard treatment for metastatic or refractory non-small cell lung cancer (NSCLC). Because immune-related adverse events (irAEs) are common and can be severe, a number of these patients require systemic corticosteroids. irAEs are reportedly associated with improved survival in melanoma patients treated with nivolumab. To date, little information is available regarding the effect of corticosteroid on the efficacy of nivolumab in terms of progression-free survival (PFS) and overall survival (OS). Methods: We reviewed consecutive patients who received nivolumab for metastatic or refractory NSCLC between December 2015 and August 2017. Nivolumab was administered at the standard dose of 3 mg/kg every two weeks. We recorded the patient demographics, efficacy and safety of nivolumab, previous and subsequent treatments, information about irAEs, corticosteroid usage, and survival. PFS and OS were calculated from the start of nivolumab treatment. A Cox proportional hazards regression model was applied using variables with the potential to influence the PFS: sex, age, performance status (PS), smoking history, driver gene alterations, histology, line of nivolumab treatment, and irAEs. Results: A total of 184 patients received nivolumab. Among them, 117 (64%) were male, the median age was 64 years (range, 34-83 years), 23 (13%) had a PS of 2 or more, 125 (68%) were ex-smokers, 37 (20%) had squamous NSCLC, and 37 (20%) had some kind of driver gene alteration, mainly EGFR mutation. Fifty patients (27%) experienced some grade of irAEs, and 37 (20%) patients required corticosteroid treatment. A multivariate analysis identified the occurrence of irAEs (hazard ratio [HR], 0.55; 95% confidence interval [CI] 0.33-0.91) and smoking (HR, 0.60;95% CI, 0.36-0.99) as independent predictors of a favorable PFS. There were no apparent differences in the proportions of patients who survived with or without the use of corticosteroid for irAEs: 73% vs. 71% at 6 months and 46% vs. 45% at 18 months. Conclusions: The occurrence of irAEs was positively associated with the PFS, and corticosteroid treatment did not have an adverse effect on OS in patients with NSCLC who were treated with nivolumab.
<i>NRAS</i>-Mutated Rhabdomyosarcoma Cells Are Vulnerable to Mitochondrial Apoptosis Induced by Coinhibition of MEK and PI3K<b>α</b>
Authors: Nadezda Dolgikh, Manuela Hugle, Meike Vogler, Simone Fulda
Journal: Cancer Research (2018)

Sequencing studies have revealed recurrent mutations in the RAS pathway in rhabdomyosarcoma (RMS). However, RAS effector pathways in RMS are poorly defined. Here, we report that coinhibition of NRAS or MEK plus PI3Kα triggers widespread apoptosis in NRAS-mutated RMS cells. Subtoxic concentrations of the MEK inhibitor MEK162 and the PI3Kα-specific inhibitor BYL719 synergized to trigger apoptosis in NRAS-mutated RMS cells in vitro and in vivoNRAS- or HRAS-mutated cell lines were more vulnerable to MEK162/BYL719 cotreatment than RAS wild-type cell lines, and MEK162/BYL719 cotreatment was more effective to trigger apoptosis in NRAS-mutated than RAS wild-type RMS tumors in vivo We identified BCL-2-modifying factor (BMF) as an inhibitory target of oncogenic NRAS, with either NRAS silencing or MEK inhibition upregulating BMF mRNA and protein levels, which BYL719 further increased. BMF silencing ablated MEK162/BYL719-induced apoptosis. Mechanistic investigations implicated a proapoptotic rebalancing of BCL-2 family members and suppression of cap-dependent translation in apoptotic sensitivity upon MEK162/BYL719 cotreatment. Our results offer a rationale for combining MEK- and PI3Kα-specific inhibitors in clinical treatment of RAS-mutated RMS.Significance: These findings offer a mechanistic rationale for combining MEK- and PI3Kα-specific inhibitors in the clinical treatment of RAS-mutated forms of often untreatable rhabdomyosarcomas. Cancer Res; 78(8); 2000-13. ©2018 AACR.
STROKE RATES IN VARIOUS ANTIPLATELET AND ANTICOAGULANT REGIMENS FOLLOWING TRANSCATHETER AORTIC VALVE REPLACEMENT
Authors: Sarah Gorgis, Elsheikh Abdelrahim, Dee Dee Wang, Janet Fredal Wyman, Gaetano Paone, Adam Greenbaum, Brad Kendall, William W. O’Neill, Marvin Eng
Journal: Journal of the American College of Cardiology (2018)
Co-administration of resveratrol with doxorubicin in young mice attenuates detrimental late-occurring cardiovascular changes
Authors: Nobutoshi Matsumura, Beshay N Zordoky, Ian M Robertson, Shereen M Hamza, Nirmal Parajuli, Carrie-Lynn M Soltys, Donna L Beker, Marianne K Grant, Maria Razzoli, Alessandro Bartolomucci, Jason R B Dyck
Journal: Cardiovascular Research (2018)

Doxorubicin (DOX) is among the most effective chemotherapies used in paediatric cancer patients. However, the clinical utility of DOX is offset by its well-known cardiotoxicity, which often does not appear until later in life. Since hypertension significantly increases the risk of late-onset heart failure in childhood cancer survivors, we investigated whether juvenile DOX exposure impairs the ability to adapt to angiotensin II (Ang II)-induced hypertension later in life and tested a treatment that could prevent this.Five-week-old male mice were administered a low dose of DOX (4 mg/kg) or saline once a week for 3 weeks and then allowed to recover for 5 weeks. Following the 5-week recovery period, mice were infused with Ang II or saline for 2 weeks. In another cohort, mice were fed chow containing 0.4% resveratrol 1 week before, during, and 1 week after the DOX administrations. One week after the last DOX administration, p38 mitogen-activated protein kinase (MAPK) was activated in hearts of DOX-treated mice demonstrating molecular signs of cardiac stress; yet, there was no change in cardiac function between groups. However, DOX-treated mice failed to develop compensatory cardiac hypertrophy in response to Ang II-induced hypertension later in life. Of importance, mice receiving DOX with resveratrol co-administration displayed normalization in p38 MAPK activation in the heart and a restored capacity for cardiac hypertrophy in response to Ang II-induced hypertension.We have developed a juvenile mouse model of DOX-induced cardiotoxicity that displays no immediate overt physiological dysfunction; but, leads to an impaired ability of the heart to adapt to hypertension later in life. We also show that co-administration of resveratrol during DOX treatment was sufficient to normalize molecular markers of cardiotoxicity and restore the ability of the heart to undergo adaptive remodelling in response to hypertension later in life.
Does treatment approach for small renal masses affect survival in patients 70 years old?
Authors: Lukas Hockman, Tyler Haden, Alex Henderson, Naveen Pokala
Journal: Journal of Clinical Oncology (2018)

658 Background: With the advent of modern imaging techniques small renal masses are being diagnosed more frequently. Many of these masses are benign, and those that are malignant are often low grade and rarely affect the survival. Surveillance is more commonly being advocated as an option for these masses. This study elucidates survival following different treatment approaches. Methods: SEER 18 data from 2004-13 identified 10,477 patients 70 years and older with renal cell carcinoma and tumors greater than or equal to 3 cm. Exclusion criteria included multiple primaries, distant metastasis and node positive disease. Data was collected on demographics, treatment patterns, overall survival and cancer specific survival. Kaplan-Meier analysis and Cox regression models were used to compare outcomes. Results: After exclusion 5084 patients remained. The mean age was 76.4 years. The mean tumor size was 2.3cm. Tumor laterality was right in 2610, left in 2467, bilateral in 2 and unspecified in 5. Racial analysis identified 84% of patients as white, 9% as black and 7% as other. Gender split was 51% male. Treatment methods included 791 ablations and 3324 surgical resections (radical or partial nephrectomy). The remaining 969 patients did not have treatment (surveillance). Survival was measured at 60 and 118 months. The overall survival was 75% and 54% respectively for ALL patients, 82% and 62% for ablation, 42% and 19% for surveillance and 82% and 62% for resection. Cancer specific survival was 97% and 96% for ablation, 83% and 74% for surveillance and 96% and 94% for resection. Surgical resection or ablation significantly improved survival at 5 and 10 years (p = &lt; 0.0001). Multivariate analysis showed survival was affected by age and year of diagnosis, but not by tumor size. Conclusions: The significant difference in overall survival suggests appropriate selection of patients for surveillance based on medical comorbidities. Treatment with curative intent improves survival in patients with greater than or equal to 3 cm renal masses, even in patients 70 years and older, and must be offered to patients without significant comorbidities.
A decision-support tool to assist muscle-invasive bladder cancer patients choosing between radical cystectomy and chemoradiotherapy.
Authors: Brian Christopher Baumann, Wei-Ting Hwang, Sharadha Srinivasan, Xingmei Wang, Ronac Mamtani, David J. Vaughn, Leilei Xia, S. Bruce Malkowicz, Thomas J. Guzzo, John Paul Christodouleas
Journal: Journal of Clinical Oncology (2018)

505 Background: Patients with high-risk muscle-invasive bladder cancer (MIBC) who are borderline medically operable for radical cystectomy (RC) face a difficult decision between RC which has higher short-term treatment-related morbidity/mortality &amp; chemoradiotherapy (CRT) which is better tolerated in the short-term but may have worse long-term cancer control outcomes. There are no existing decision support tools to assist patients &amp; providers in understanding these trade-offs. Herein, we developed a visualization tool to inform patients &amp; providers how the relative risks &amp; benefits of RC &amp; CRT vary over time with respect to overall survival (OS). Methods: We identified cT2-3 N0 M0 urothelial bladder cancer patients ≥65 y/o treated with RC +/- chemo (n = 5981) or definitive-dose CRT after TURBT (n = 793) in the National Cancer Database, 2003-2011. The database was split into a development &amp; validation cohort. Multivariate Cox regression with time-varying hazard ratio was performed to assess pre-treatment factors associated with OS. The inverse probability of treatment weighting method using the propensity score was employed to reduce selection bias. External validation was performed. Visualization tool showing adjusted survival curves based on pre-op patient features was generated with input from patients &amp; a multidisciplinary expert panel. Tool calculates median OS &amp; the “break-even point,” where the short-term OS disadvantage of RC equals the long-term advantage of RC (i.e. the point where the restricted mean survival for RC &amp; CRT are equal). Results: On MVA, significant predictors of OS were age, Charlson Deyo comorbidity index, &amp; cT stage (p &lt; 0.001 for all). Using these results, we iteratively developed a web application that utilizes clinical inputs to generate patient-specific survival curves that display estimated OS differences over time. Median OS, the break-even point, &amp; percent alive at the break-even point are provided. Conclusions: This is the first decision-support tool developed to assist high-risk borderline operable MIBC patients &amp; their providers in understanding the short-term &amp; long-term trade-offs between RC &amp; CRT. Additional testing is underway.
NEW TEST WHICH CAN PREDICT WHICH PATIENT WILL BE READMITTED AFTER HOSPITALIZATION FOR HEART FAILURE
Authors: Thach N. Nguyen, Tuan Si Nguyen, Gianluca Rigatelli, Vien Truong, Lanh V. Nguyen, Nhan Minh Tri Nguyen
Journal: Journal of the American College of Cardiology (2018)
Shared decision making for prostate cancer screening: Reality or farce?
Authors: Daniel Pucheril, Sean A. Fletcher, Dimitar V. Zlatev, Matthew Mossanen, Matthew D. Ingham, Steven Lee Chang, Adam S. Kibel, Quoc-Dien Trinh
Journal: Journal of Clinical Oncology (2018)

107 Background: A core tenant of major cancer society guidelines regarding prostate cancer screening (PSAS) is that providers discuss both the advantages and disadvantages of screening with eligible patients in a shared decision making (SDM) process. We sought to determine contemporary trends of SDM in regards to PSAS. Methods: Consistent with the AUA guidelines for PSAS, data was abstracted from the 2012-2016 Behavioral Risk Factor Surveillance System for men 55-69, without a personal history of prostate cancer, and having answered all questions within the PSAS module. PSAS occurred if a man had a PSA test within the last two years for reasons other than "a prostate problem” or “prostate cancer”. SDM occurred if the respondent was informed about both advantages and disadvantages of PSAS by a health professional. Descriptive statistics were generated for demographic covariates by year. The Chi-Square test was used to compare the distribution of covariate proportions amongst years. Separate multivariable regression models were built to identify independent predictors of both receipt of PSA screening and SDM. Results: A weighted estimate of 56.7 million men (n = 138,492) met inclusion criteria. Reported rates of PSAS decreased each year (56.7% in 2012 to 52.6% in 2014 to 49.1% in 2016, p &lt; 000.1). There were no significant changes in rates of SDM (p = 0.82); in all three years, less than one-third of respondents reported SDM. After controlling for known confounders, possession of a personal physician (OR 2.24,95%CI 2.02-2.48), receipt of information regarding the advantages of PSAS (OR 3.93, 95%CI 3.63-4.26), and receiving a physician recommendation to undergo PSAS (OR 7.78, 95%CI 7.25-8.35) were most strongly associated with odds of undergoing PSAS. Odds of reporting participation in SDM were strongest amongst black respondents (2.09 95%CI 1.92-2.28) and those who received a physician recommendation to undergo PSAS (OR 4.64, 95%CI 4.32-4.99). Conclusions: Despite recommendations that physicians engage patients in a SDM process, our findings suggest that less than a third of patients are advised of both the advantages and disadvantages of PSAS. With the likely revision of the USPSTF PSAS recommendation to Grade C, a renewed effort towards SDM is needed.
Life as a visually impaired doctor
Authors: Rhianwen Elen Stiff
Journal: BMJ (2004)

<h3>Background/Aim</h3> Physical inactivity (PIA) is a growing global health problem and evidence suggests that PIA is a key driver for cardiovascular and chronic diseases. Recent data from South Africa revealed that only about half of the children achieved recommended daily physical activity (PA) levels. Assessing the intensity of PA in children from low socioeconomic communities in low-income and middle-income countries is important to estimate the extent of cardiovascular risk and overall impact on health. <h3>Methods</h3> We conducted a cross-sectional survey in eight quintile 3 primary schools in disadvantaged communities in the Port Elizabeth region, South Africa. Children aged 10–15&nbsp;years were subjected to PA, blood pressure, cholesterol, blood glucose and skinfold thickness assessments. Cardiovascular risk markers were converted into standardised z-scores and summed, to obtain a clustered cardiovascular risk score. <h3>Results</h3> Overall, 650 children had complete data records. 40.8% of the children did not meet recommended PA levels (ie, logged &lt;60&nbsp;min of moderate-to-vigorous physical activity (MVPA) per day). If quartiles were developed based on children’s cardiorespiratory fitness (CRF) and MVPA levels, a significant difference was found in clustered cardiovascular risk among children in the highest versus lowest fitness (p&lt;0.001) or MVPA (p&lt;0.001) quartiles. <h3>Conclusions</h3> CRF and objectively assessed PA are closely linked with children’s clustered cardiovascular risk. Given that 4 out of 10 South African schoolchildren from marginalised communities do not meet international PA recommendations, efforts should be made to ensure that promoting a physically active lifestyle is recognised as an important educational goal in primary schools. <h3>Trial registration numbers</h3> ISRCTN68411960 and H14-HEA-HMS-002.
Exposure to Peanut Flour through Disturbed Skin Initiates Peanut Allergy via the T Follicular Helper T (Tfh) Cell-Dependent Pathway in Mice
Authors: Koji Iijima, Takao Kobayashi, James W. Krempski, Takayasu Nomura, Hirohito Kita
Journal: Journal of Allergy and Clinical Immunology (2018)
Synthesis and biological evaluation of novel tricyclic matrinic derivatives as potential anti-filovirus agents
Authors: Xin Zhang, Qiang Liu, Qianqian Li, Yinghong Li, Zhandong Liu, Hongbin Deng, Sheng Tang, Yanxiang Wang, Youchun Wang, Danqing Song
Journal: Acta Pharmaceutica Sinica B (2018)

Twenty-six novel tricyclic sophoridinic and matrinic derivatives containing a common chlorinated benzene fragment were designed, synthesized and evaluated for their anti-ebolavirus (EBOV) activities. Structureactivity relationship analysis indicated: (i) 12N-dichlorobenzyl motif was beneficial for the activity; (ii) the chiral configuration at C5 atom might not affect the activity much. Among the target compounds, compound 7d exhibited the most potent potency against EBOV with an IC50 value of 5.29 μmol/L and an SI value of over 37.8. Further in vivo anti-EBOV assay of 7d identified its high effectiveness, and in vivo anti-MARV assay of 7d suggested its inspiring broad-spectrum anti-filovirus activity. The results provided powerful information on further strategic optimization and development of this kind of compounds against filoviruses.
A COMPLEX CASE OF CARDIAC SARCOIDOSIS PRESENTING WITH VENTRICULAR TACHYCARDIA, RIGHT VENTRICULAR THROMBUS COMPLICATED BY COMPLETE AV-BLOCK
Authors: Rudin Gjeka, Murad Abdelsalam, Yashwant Agrawal, Jacqueline Sennott, Rajiv Nair
Journal: Journal of the American College of Cardiology (2018)
Impact of a geriatric oncology (GO) clinic on cancer treatment plans and supportive care for older adults with genitourinary (GU) cancer.
Authors: Shabbir M.H. Alibhai, Allison Loucks, Rana Jin, Martine Puts, Sarah Watt, Arielle Berger
Journal: Journal of Clinical Oncology (2018)

238 Background: Older adults with cancer are complex due to multiple comorbidities, polypharmacy, and functional/cognitive impairments, leading to over-treatment and undertreatment. Studies examining the impact of geriatric assessment (GA) in older adults with various cancers found a median of 39% of treatment plans were revised after the GA ( Ann Oncol 2014; 25:307). Although these findings support the need for a GO clinic, whether such a clinic leads to changes in treatment in patients with GU malignancies is not clear. We examined the impact on the treatment plan of a GO assessment in GU patients, along with other enhancements to patient care for consecutive patients referred to the GO clinic in a tertiary care hospital. Methods: All referred older adults (age 65+) with a GU malignancy seen in the GO clinic at the Princess Margaret Cancer Centre, Toronto, Canada between July 2015 and June 2017 were included. Patients were seen by a geriatric oncologist and GO nurse and treatment recommendations were provided to the referring oncologist. Pre- and post-GO clinic treatment plans and enhancements to supportive care were recorded prospectively. Analyses were descriptive. Results: 98 patients (mean age 80) were seen in the GO clinic, of whom 35 were seen pre-treatment (25 prostate, 5 kidney, 5 bladder). 31 of 35 were referred for input on the treatment plan. The initial treatment plan included surgery (n = 6), radiation (n = 14), systemic therapy (n = 8), and hormonal therapy (n = 11). The final treatment plan was intensified in 1 patient, reduced in 6 patients, changed to best supportive care in 8 patients, and unchanged in 15 patients. Overall, GO resulted in a treatment modification in 52% of patients. Enhancements to care included comorbidity management (87%), educational support (94%), disease-related symptoms (39%), and peri-operative management (19%). Conclusions: The GO clinic results in modifications to the proposed treatment plan in over half of referred patients (predominantly a reduction in treatment intensity), and enhancements to care in the vast majority of patients. GO clinics have the potential to avoid overtreatment and improve care for older adults with GU malignancies.
Workload is rising and morale is falling among UK doctors, BMA survey shows
Authors: Caroline White
Journal: BMJ (2012)

The reorganisation of the NHS, an increasingly heavy and complex workload, and the financial ramifications of the government’s changes to pensions have caused doctors’ morale to tumble, indicate the preliminary results of a BMA survey.

General practitioners seem to have been the most badly affected, with almost three quarters of those surveyed reporting that morale was worse than it was a year ago.

The findings, yet to be published in full, are based on responses from almost 4000 doctors in all branches of medicine across the UK who were surveyed over the summer.

The preliminary results …