tbuckley/cabot-search huggingface dataset:
<i>HSD3B1</i> genotype and abiraterone (Abi) metabolites in patients (pts) with prostate cancer (PCa).
Authors: Hamid Emamekhoo, Mohammad Alyamani, Sunho Park, Jennifer Taylor, Nima Almassi, Sunil Upadhyay, Allison Janine Tyler, Mike Berk, Tae Hyun Hwang, Petros Grivas, Brian I. Rini, Jorge A. Garcia, Richard J. Auchus, Nima Sharifi
Journal: Journal of Clinical Oncology (2018)

325 Background: Abi, a potent inhibitor of 17α-hydroxylase/17,20-lyase (CYP17A1), is an oral treatment option for metastatic PCa in castration-resistant and -sensitive settings. Abi is converted to ∆ 4 , 3-keto-abi (D4A) by 3β-hydroxysteroid dehydrogenase (3βHSD). D4A is further metabolized to multiple downstream steroidal metabolites including 3-keto-5α-Abi (5αA), which is an androgen receptor (AR) agonist and might affect response and/or resistance to Abi. The common HSD3B1(1245C) germline variant encodes for a 3βHSD missense that increases enzyme activity that allows tumors to utilize extragonadal androgens and is a predictive biomarker of resistance to ADT and sensitivity to CYP17A1 inhibition. However, the more active 3βHSD protein might increase 5αA synthesis, possibly limiting the clinical benefit of Abi. Methods: Blood was collected from CRPC pts on Abi and drug metabolites (MA) were extracted from serum, and analyzed by mass spectrometry. To correct for pharmacokinetics (PK) of time from last dose to blood draw in this cohort, data were normalized to the 8-hour time point of a separate PK study of Abi MAs and grouped by HSD3B1 genotype. HSD3B1 genotype was determined using germline DNA. Results: Abi MAs were evaluated in the sera of 30 CRPC pts on Abi. Abi, D4A, 5αA, were detectable in the sera of all pts. There were 8, 19, and 3 pts with homozygous wild-type, heterozygous, and homozygous variant HSD3B1 genotypes. HSD3B1 variant allele inheritance was associated with a statistically significant increase in 5αA concentrations, with highest concentration of 5αA MAs observed in homozygous variant HSD3B1 pts (Table). Conclusions: Germline HSD3B1 variant genotype is associated with higher 5αA metabolites with possible implications for AR stimulation and adverse clinical outcomes on Abi. [Table: see text]
UK consultants are the best paid and least productive in Europe
Authors: Zosia Kmietowicz
Journal: BMJ (2011)

Consultants in the United Kingdom are among the best paid and least productive in Europe—a situation that is unsustainable in the current environment of financial constraints, a meeting heard this week. 

A report for the European Union on pay and productivity of healthcare staff across Europe by KPMG, to be published, shortly shows that UK consultants are in the upper quartile for pay but in the lower quartile for productivity, said Mark Britnell, global lead on healthcare at the consultancy firm KPMG.

The gap between the productivity of the private sector and that of …
Pay review body is too heavily influenced by government, GPs say
Authors: Abi Rimmer
Journal: BMJ (2014)

The Doctors’ and Dentists’ Review Board (DDRB) is “influenced too heavily by the government,” GPs have said.

Delegates at the BMA’s local medical committee (LMC) conference voted unanimously that the review body, which makes recommendations on GPs’ pay, is “influenced too heavily by the government, who claimed a 1% uplift is all that is affordable.”

GPs voted that this was “unbelievable, as how can a 0.28% increase to expenses translate into a 1% increase to take home …
Spiritual issues and needs: perspectives from patients with advanced cancer and nonmalignant disease. A qualitative study
Authors: Elizabeth Grant, Scott A Murray, Marilyn Kendall, Kirsty Boyd, Stephen Tilley, Desmond Ryan
Journal: BMJ (2004)

Objective: Health care professionals and policy makers acknowledge that spiritual needs are important for many patients with life-limiting illnesses. We asked such patients to describe their spiritual needs and how these needs may impinge on their physical, psychological, and social well-being. Patients were also encouraged to explain in what ways their spiritual needs, if they had any, could be addressed. Methods: We conducted two qualitative interviews, 3 months apart, with 20 patients in their last year of life: 13 patients with advanced cancer and 7 with advanced nonmalignant illness. We also interviewed each patient’s general practitioner. Sixty-six interviews were tape-recorded, transcribed, and analyzed. Results: Patients’ spiritual needs centered around their loss of roles and self-identity and their fear of dying. Many sought to make sense of life in relation to a nonvisible or sacred world. They associated anxiety, sleeplessness, and despair with such issues, which at times resulted in them seeking support from health professionals. Patients were best able to engage their personal resources to meet these needs when affirmed and valued by health professionals. Significance of results: Enabling patients to deal with their spiritual needs through affirmative relationships with health professionals may improve quality of life and reduce use of health resources. Further research to explore the relationship between spiritual distress and health service utilization is indicated.
CHANGES IN MITRAL ANNULAR GEOMETRY AFTER TRANSCATHETER AORTIC VALVE REPLACEMENT: IMPLICATIONS ON TRANSCATHETER MITRAL VALVE REPLACEMENT
Authors: Gilbert Hin-Lung Tang, Medha Biswas, Syed Zaid, Hasan Ahmad, Ryan Kaple, Cenap Undemir, Martin Cohen, Steven Lansman
Journal: Journal of the American College of Cardiology (2018)
Phase II LAPACT trial of <i>nab</i>-paclitaxel (<i>nab</i>-P) plus gemcitabine (G) for patients with locally advanced pancreatic cancer (LAPC).
Authors: Pascal Hammel, Jill Lacy, Fabienne Portales, Alberto F. Sobrero, Roberto A. Pazo Cid, Jose Luis Manzano Mozo, Eric Terrebonne, Scot D. Dowden, Jack Shiansong Li, Teng Jin Ong, Thom Nydam, Philip Agop Philip
Journal: Journal of Clinical Oncology (2018)

204 Background: In the phase 3 MPACT study, treatment with nab-P + G resulted in a &gt; 3-fold reduction in primary pancreatic tumor burden vs G in patients with metastatic PC, suggesting the potential for activity against LAPC. This international, multicenter single arm, phase 2 trial (LAPACT) was designed to evaluate the efficacy and safety of an induction phase regimen of nab-P + G in previously untreated patients with LAPC. Methods: Treatment-naive patients with unresectable LAPC and Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 were enrolled. The induction phase was designed as 6 cycles of nab-P 125 mg/m 2 + G 1000 mg/m 2 on D 1, 8, and 15 of each 28-day cycle. After induction, patients without progressive disease or unacceptable adverse events were eligible for continued treatment with nab-P + G, chemoradiation, or surgery per investigator’s choice (IC). Surgery could occur prior to completing 6 induction cycles if the investigator deemed there had been a sufficient tumor response. The primary endpoint was time to treatment failure (TTF) in patients treated with nab-P + G as induction therapy followed by IC treatment. Key secondary endpoints included disease control rate (DCR), overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: Of 107 patients enrolled, 106 were evaluable for the safety analysis. No new toxicities were identified. The most common grade ≥ 3 treatment-emergent adverse events during induction were neutropenia (42%), anemia (11%), and fatigue (10%); grade 3 peripheral neuropathy occurred in 4% of patients. The most frequent reasons for discontinuing induction were adverse events (18%) and progressive disease (7%). Forty-six (43%) patients received IC treatment after induction: 13 (12%) continued nab-P + G, 17 (16%) received chemoradiation, and 16 (15%) underwent surgical resection (R0, n = 7; R1, n = 9). DCR and ORR during induction were 78% and 35%, respectively; with a median TTF of 8.6 months and median PFS of 10.2 months. Conclusion: A nab-P + G induction regimen in LAPC appears tolerable and feasible and is associated with encouraging antitumor activity and promising TTF and PFS. NCT02301143. Clinical trial information: NCT02301143.
The Monocot-Specific Receptor-like Kinase SDS2 Controls Cell Death and Immunity in Rice
Authors: Jiangbo Fan, Pengfei Bai, Yuese Ning, Jiyang Wang, Xuetao Shi, Yehui Xiong, Kai Zhang, Feng He, Chongyang Zhang, Ruyi Wang, Xiangzong Meng, Jinggeng Zhou, Mo Wang, Gautam Shirsekar, Chan Ho Park, Maria Bellizzi, Wende Liu, Jong-Seong Jeon, Ye Xia, Libo Shan, Guo-Liang Wang
Journal: Cell Host & Microbe (2018)
Consideration of the concordance rate of 22C3 and 28-8 antibody in NSCLC and its relation to the effect of nivolumab.
Authors: Kayoko Kibata, Takayasu Kurata, Yuki Takeyasu, Maiko Niki, Naoko Murakami Satsutani, Makoto Ogata, Hiroshige Yoshioka, Tomohito Saito, Tomohiro Murakawa, Koji Tsuta, Shosaku Nomura
Journal: Journal of Clinical Oncology (2018)

143 Background: Anti-PD-1 antibodies (Abs) have improved survival significantly in patients (pts) with advanced non-small cell lung cancer (NSCLC). Depending on the extent of PD-L1 expression, these drugs have become the standard care of initial treatment and 2nd line therapy. However, PD-L1 expression has not yet been recognized as a robust biomarker. Currently, two Anti-PD-1 Abs (Nivolumab, Pembrolizumab) are commercially available in Japan, but have each diagnostic immunohistochemical (IHC) assays (22C3 and 28-8Ab), respectively. The concordance rate of these assays is not yet well understood and the effect of these agents in concordance and inconsistency cases are also unknown. Based on these background, we explored the concordance rate of 22C3 and 28-8 Ab and its relation with the effect of Nivolumab (Nivo). Methods: We investigated the concordance rate of 22C3 and 28-8 as well as treatment effect and response of 24 advanced NSCLC pts treated in Kansai Medical University Hospital from December 2015 and May 2017. All pts had been tumor biopsy for pathologically immunostained and received Nivo at least once. We compared the PD-L1 expression levels of two IHC assays with 22C3 and 28-8Ab measured in different laboratories independently. Results: Pts’ characteristics included adenocarcinoma in 12 pts, squamous cell carcinoma in 11, and others in 1 pts, respectively. In IHC reaction with 22C3Ab, 58.3% and 29.2% of pts expressed PD-L1 on ≥1% and ≥50% of tumor cells and with 28-8Ab, 37.5% and 16.7% of pts expressed PD-L1 on ≥1% and ≥50% of tumor cells, respectively. Of 24 cases, 1 case experienced CR, 5 cases PR. In CR case, expression level was dissociated at 50% with 22C3 and 5% with 28-8. In PR cases, 2 cases had high expression in both, and 2 cases had moderate expression in both assays. However, the remaining one was dissociated as moderate in 22C3 Ab and negative in 28-8. All PD pts expressed 0% with both of the two Abs. Conclusions: Although the number of cases is small, the concordance rate of the two Abs in advanced NSCLC cases is not necessarily high, but the agreement rate in response cases was likely to be high. As both 0% cases were ineffective, measuring with two Abs may be useful for forecasting invalid cases.
Myeloid-targeted immunotherapies act in synergy to induce inflammation and antitumor immunity
Authors: Curtis J. Perry, Andrés R. Muñoz-Rojas, Katrina M. Meeth, Laura N. Kellman, Robert A. Amezquita, Durga Thakral, Victor Y. Du, Jake Xiao Wang, William Damsky, Alexandra L. Kuhlmann, Joel W. Sher, Marcus Bosenberg, Kathryn Miller-Jensen, Susan M. Kaech
Journal: The Journal of Experimental Medicine (2018)

Eliciting effective antitumor immune responses in patients who fail checkpoint inhibitor therapy is a critical challenge in cancer immunotherapy, and in such patients, tumor-associated myeloid cells and macrophages (TAMs) are promising therapeutic targets. We demonstrate in an autochthonous, poorly immunogenic mouse model of melanoma that combination therapy with an agonistic anti-CD40 mAb and CSF-1R inhibitor potently suppressed tumor growth. Microwell assays to measure multiplex protein secretion by single cells identified that untreated tumors have distinct TAM subpopulations secreting MMP9 or cosecreting CCL17/22, characteristic of an M2-like state. Combination therapy reduced the frequency of these subsets, while simultaneously inducing a separate polyfunctional inflammatory TAM subset cosecreting TNF-α, IL-6, and IL-12. Tumor suppression by this combined therapy was partially dependent on T cells, and on TNF-α and IFN-γ. Together, this study demonstrates the potential for targeting TAMs to convert a “cold” into an “inflamed” tumor microenvironment capable of eliciting protective T cell responses.
Effect of IL-11 stimulated by co-culture with CAF on metastasis of gastric cancer cells mediated by upregulation of MUC1.
Authors: Xiaoxun Wang, Xiaofang Che, Yunpeng Liu, Xiujuan Qu
Journal: Journal of Clinical Oncology (2018)

86 Background: Cancer-associated fibroblasts (CAFs), as the activated fibroblasts in tumor stroma, are important modifiers of tumor progression. However, the molecular mechanisms underlying the tumor-promoting properties of CAFs in gastric cancer remain unclear. Methods: We show that when CAFs co-cultured with gastric cancer cells, two kinds of cells produce significant amounts of interleukin-11 (IL-11). CAFs enhances the migration and invasion of gastric cancer cells through the secretion of IL-11 that activates JAK/STAT3 and MAPK/ERK pathways to upregulate MUC1 in gastric cancer cells, while deprivation of IL-11 using a neutralizing antibody or inhibition of JAK/STAT3 and MAPK/ERK pathway with specific inhibitor Stattic and PD-98059 markedly attenuates these phenotypes in gastric cancer cells induced by CAFs. Results: In this study, we find that CAFs in the tumor microenvironment promote the progression of gastric cancer through IL-11-JAK/STAT3 and MAPK/ERK signalings to upregulate MUC1. Conclusions: Taken together, these results suggest that CAFs promote the progression of gastric cancer and IL-11 targeted therapy could be a complementary approach against gastric cancer by exerting their action on stromal fibroblasts.
A patient-reported outcome measure for symptoms of AML/MDS.
Authors: Loretta A. Williams, Araceli Garcia-Gonzalez, Hycienth Ahaneku, Jorge E. Cortes, Guillermo Garcia-Manero, Hagop M. Kantarjian, Qiuling Shi, Gautam Borthakur, Jan Andreas Burger, Elias Jabbour, Koichi Takahashi, Huei-Kai Lin, Achala Limaye, Charles S. Cleeland
Journal: Journal of Clinical Oncology (2015)

e17648 Background: Patient report of symptom burden in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) is scarce. Symptom burden is the combined impact of disease and treatment symptoms on daily functioning. Our aim is to develop a short, valid, reliable patient-reported outcome measure of AML and MDS symptoms for research and practice. Methods: After obtaining IRB approval, patients with AML (N = 115) and MDS (N = 85) are recruited to this cross-sectional, descriptive, behavioral study. Patients rate the 13 core symptom items, 6 proposed AML/MDS symptom items, and 6 interference items of the MD Anderson Symptom Inventory on 0-to-10 scales (0 = not present or no interference; 10 = as bad as can be imagined or complete interference). Patients also complete a single item quality of life (SIQOL; 0 = worst, 10 = best) measure. Patient clinical and demographic information is collected from medical records and analyzed using descriptive statistics. Standard psychometric techniques are used to determine the internal reliability and construct and concurrent validity. Results: For the AML and MDS patients, the composite mean core symptom severity score is 2.4 (SD = 1.6) and 2.0 (SD = 1.6; p= 0.08), the composite mean of the AML/MDS specific items is 2.1 (SD = 1. 7) and 1.6 (SD = 1.5; p 0.05), and the composite mean score of the interference items is 3.4 (SD = 2.5) and 2.7 (SD = 2.4; p= 0.07) respectively. Cronbach's α reliability for all symptom items is 0.88 and for all interference items is 0.89. For concurrent validity, Pearson correlation with the SIQOL is significant for combined symptom (-0.46, p< 0.01) and interference means (-0.61, p< 0.01). Principal factor analysis for construct validity shows a 4-factor solution of general physical, affective, GI, and fatigue symptoms. Additional patient accrual will confirm results. Conclusions: Lack of recognition of symptoms experienced by patients with AML and MDS can lead to inadequate management of symptoms, interference with the ability of patients to function and enjoy life, and could impact the tolerability of and adherence to treatment regimens. Validation of this symptom burden measure for patients with AML and MDS allows more accurate and consistent monitoring of symptoms by clinicians and researchers. Clinical trial information: NCT00505245.
NGS, RNA-Seq, TIL, and PTEN analyses in prostate cancer specimens from patients enrolled in the study of the Akt inhibitor ipatasertib (Ipat) combined with abiraterone acetate (AA).
Authors: Liangxuan Zhang, Hartmut Koeppen, Daniel J. Maslyar, Dimitri Fillos, Na Xu, Wai Y. Chan, Albert Font Pous, Viorel Jinga, Christophe Massard, Sergio Bracarda, George Daniel Radavoi, Ugo De Giorgi, Jose Angel Arranz Arija, Ruth Riisnaes, Daniel Nava Rodrigues, Johann S. De Bono, Steven Gendreau
Journal: Journal of Clinical Oncology (2018)

310 Background: In Phase III studies, ipilimumab did not extend OS in unselected populations with metastatic castration-resistant prostate cancer (mCRPC) (Kwon, 2014; Beer, 2014), suggesting that successful cancer immunotherapy development strategies require the evaluation of treatment effects in biomarker-driven segments. In addition, PTEN loss has been identified as a potential mechanism of resistance to immunotherapy (Peng, 2016). Therefore, we explored possible associations between cancer immunity (CI)-related biomarkers and PTEN loss in mCRPC samples. Methods: Tumor samples obtained in the Phase II study of AA ± Ipat in patients with mCRPC (de Bono, ESMO 2016) were retrospectively profiled. DNA alterations and tumor mutational burden (TMB) were assessed by FoundationOne. RNA-seq analysis of multiple CI-related expression signatures was performed. Tumor-immune lymphocyte (TIL) scores were analyzed in 3 compartments (stromal, sTIL; intratumoral, iTIL; peritumoral, pTIL) based on H&amp;E stained specimens. Up to 10 evenly distributed fields were examined; the average of these fields was used to estimate the %TILs for each compartment. Results: Strong associations were observed between multiple CI-related signatures (e.g., INFγ-induced, immune checkpoints, Treg, checkpoint inhibitors). Fewer than 10% of the samples had a high level (≥ 10% of the tumor area) of TIL infiltration in any compartment (Table). TIL scores, TMB values, PTEN status and Gleason score all appeared to be independently associated, and none were associated with CI-related gene signatures, except for a possible association between pTILs and the B-cell signature (ρ = 0.49, P &lt; 0.0001). Conclusions: Comprehensive high-content profiling of prostate cancer samples suggests that PTEN status and CI-related biomarkers were independently associated, while TMB and TIL values were generally not associated with CI-related signatures. Clinical trial information: NCT01485861. [Table: see text]
5-YEAR DURABILITY RESULTS OF TRANSCATHETER MITRAL VALVE REPAIR WITH THE MITRACLIP® SYSTEM IN PATIENTS WITH SEVERE DEGENERATIVE MITRAL REGURGITATION AND PROHIBITIVE SURGICAL RISK
Authors: D. Scott Lim, Gorav Ailawadi, Saibal Kar, Alfredo Trento, Andrew Wang, Paul Grayburn, Samir Kapadia, Michael Rinaldi, Eric Skipper, Susheel K. Kodali, Brian Whisenant, Atif Qasim, Neil Weissman, Michael J. Mack, Donald Glower, Ted Feldman
Journal: Journal of the American College of Cardiology (2018)
Letter by Poullis Regarding Article, “Associations Between Adding a Radial Artery Graft to Single and Bilateral Internal Thoracic Artery Grafts and Outcomes: Insights From the Arterial Revascularization Trial”
Authors: Michael Poullis
Journal: Circulation (2018)

Taggart et al 1 need to be congratulated on their post hoc analysis of their ART (Arterial Revascularization Trial) data.However, their work raises a number of questions.This study involved the nonrandomized use of the radial artery and, unsurprisingly, has demonstrated its superiority, in common with other nonrandomized publications. 2Nonrandomized trials usually involve patient selection as a major source of bias, hence the need for randomized trials.However, the largest randomized studies with regard to radial artery outcomes, performed by Hayward et al, 3 failed to identify any significant difference.ART was initially powered to investigate whether a survival difference between single and bilateral mammary artery use existed at 10 years, 4 drawing the power of the present analysis by Taggart et al into question.Of note, no power calculation was included in the article.The use of composite end points has been criticized widely from statistical, patient, and researcher points of view. 5The finding of no significant difference between myocardial infarction, cardiovascular death, and repeat revascularization when analyzed separately needs to be noted.By way of example, reanalysis of the data provided in Table 3 after matching with regard to death (1.4% versus 0.8%), return to operating room (4.3% versus 3%), renal replacement therapy (7.1% versus 5.7%), and sternal wounds (4% versus 3%) indicates that radial artery use is associated with a significantly worse outcome compared with saphenous vein graft only (16.8% versus 12.5%; P=0.03).Multiple imputation was used to address missing data.However, no mention was made of how much data were missing for this technique being used, potentially introducing a source of error.Taggart et al have to be congratulated in performing the ART trial; however, post hoc underpowered interpretation needs to be cautioned against.
ENDURANCE EXERCISE TRAINING ATTENUATES NATRIURETIC PEPTIDE RELEASE DURING MAXIMAL EFFORT EXERCISE: BIOCHEMICAL CORRELATES OF THE ATHLETE’S HEART
Authors: Ankit B. Shah, Jodi Zilinski, Marcel G. Brown, Jennifer H. Neary, Rory Weiner, Adolph Hutter, Fred Apple, Michael Picard, James Januzzi, Aaron Baggish
Journal: Journal of the American College of Cardiology (2018)