tbuckley/cabot-search huggingface dataset:
Unleashing the therapeutic potential of oncolytic viruses
Authors: Praveen K. Bommareddy, Howard L. Kaufman
Journal: Journal of Clinical Investigation (2018)

Oncolytic viruses (OVs) are a versatile new class of therapeutic agents based on native or genetically modified viruses that selectively replicate in tumor cells and can express therapeutic transgenes designed to target cells within the tumor microenvironment and/or host immunity. To date, however, confirmation of the underlying mechanism of action and an understanding of innate and acquired drug resistance for most OVs have been limited. In this issue of the JCI, Zamarin et al. report a comprehensive analysis of an oncolytic Newcastle disease virus (NDV) using both murine melanoma tumor models and human tumor explants to explore how the virus promotes tumor eradication and details of the mechanisms involved. These findings have implications for the optimization of oncolytic immunotherapy, at least that based on NDV, and further confirm that specific combinatorial approaches are promising for clinical development.
Treatment duration and utilization patterns in metastatic castration-resistant prostate cancer patients receiving enzalutamide or abiraterone acetate.
Authors: Vahan Kassabian, Scott Flanders, Samuel Wilson, Bruce A. Brown, Yan Song, Hongbo Yang, Stanislav Lechpammer, Neil M. Schultz
Journal: Journal of Clinical Oncology (2018)

229 Background: Enzalutamide (ENZA) and abiraterone acetate (ABI) are approved hormonal therapies for men with metastatic castration-resistant prostate cancer (mCRPC). This study assessed real-world treatment duration and utilization patterns in patients receiving ENZA or ABI. Methods: Adult mCRPC patients initiating ENZA or ABI before or after cytotoxic chemotherapy were identified from the Truven MarketScan ® claims database (2012–2015). The index date was the first initiation of ENZA or ABI; continuous insurance enrollment for ≥6 months prior to and ≥3 months after the index date was required. Treatment discontinuation was defined as a prescription gap of ≥45 days. Median treatment duration was estimated using Kaplan–Meier method. Treatment switching was defined as starting a new mCRPC-related therapy within 30 days before to 45 days after the discontinuation date. Analyses were separately conducted for chemo-naïve and chemo-experienced patients. Results: The study included 3230 chemo-naive (ENZA 920; ABI 2310) and 692 chemo-experienced patients (ENZA 262; ABI 430). Among chemo-naive patients, ENZA cohort was older (mean age 74.5 vs 73.5; p = 0.013), with a higher proportion of comorbidities vs ABI cohort. Treatment duration was longer for ENZA cohort than ABI cohort (log-rank p = 0.008; median = ENZA 10.7 vs ABI 8.8 months). Within 1 year of initiation, 55.7% of ENZA and 60.8% of ABI cohort discontinued treatment and 22.5% and 34.7%, respectively, switched to other mCRPC therapies. Results were consistent among subgroups with specific comorbidities. Treatment duration was shorter among chemo-experienced patients than chemo-naïve; the difference between ENZA vs ABI among chemo-experienced patients was not statistically significant (log-rank p = 0.255; median = ENZA 7.5 vs ABI 7.1 months). Conclusions: Despite a more complex profile at baseline, chemo-naive mCRPC patients in the ENZA cohort had a longer treatment duration and lower proportion of switching to other prostate-cancer-directed therapies vs the ABI cohort. The difference of treatment duration between the two cohorts was not statistically significant for chemo-experienced patients.
Effect of bypass kinase pathways on acquired CDK4/6 inhibitor resistance.
Authors: Renee De Leeuw, Christopher McNair, Matthew Joseph Schiewer, Neermala Poudel Neupane, Michael Augello, Zhen Li, Larry Cheng, Akihiro Yoshida, Alan Diehl, Starr Hazard, Sean Courtney, Gary Hardiman, Maha Hussain, Justin Drake, William Kevin Kelly, Karen E. Knudsen
Journal: Journal of Clinical Oncology (2018)

379 Background: Cyclin Dependent Kinase-4/6 (CDK4/6) kinase inhibitors have shown clinical benefit in treatment of solid tumor types, including breast cancer. However, resistance is common, and the underpinning mechanisms of action are not well understood. Given the dependence of CDK4/6 inhibitors on retinoblastoma tumor suppressor (RB) function for activity, this class of agents may be particularly effective in tumor types for which RB loss is infrequent or occurs late in tumor progression. Methods: Here, models of acquired palbociclib resistance were generated in early stage, RB positive cancers, wherein it was shown acquired palbociclib resistance resulted in cross-resistance to other CDK4/6 inhibitors under clinical testing. Results: Cells showing acquired resistance exhibited aggressive in vitro and in vivo phenotypes without genetic loss of RB or RB pathway members, including enhanced proliferative capacity, migratory potential, and characteristics of epithelial to mesenchymal transition. Further analyses through integration of RNA sequencing and phospho-proteomics identified activation of the MAPK signaling pathway as a mediator of CDK4/6 inhibitor resistance, capable of bypassing CDK4/6 activity. However, this altered kinase dependence resulted in sensitization to MEK inhibitors, suggestive of new clinical opportunities in CDK4/6 resistant tumors. Conclusions: In sum, the studies herein not only identify activation of the MAPK pathway as capable of bypassing the CDK4/6 requirement and promoting aggressive tumor characteristics, but nominate MEK inhibitors as potential mechanisms to treat or prevent CDK4/6 inhibitor resistance.
Review condemns treatment of trust staff who blew whistle on poor care
Authors: Gareth Iacobucci
Journal: BMJ (2018)

An NHS trust “bullied and harassed” staff that raised concerns about poor care and swingeing staffing cuts, an independent review has found.1

The review, commissioned by the regulator NHS Improvement, identified “appalling instances of staff treatment” at Liverpool Community Health Trust between 2010 and 2014, as the trust tried to suppress systemic failings that caused harm to patients.

It found that the trust failed to learn from serious incidents that occurred because of failings in the care it provided. These included the deaths of up to 19 people in custody at HMP Liverpool, five patients having the wrong tooth …
FUT2 genotype and secretory status are not associated with fecal microbial composition and inferred function in healthy subjects
Authors: Williams Turpin, Larbi Bedrani, Osvaldo Espin-Garcia, Wei Xu, Mark S. Silverberg, Michelle I. Smith, David S. Guttman, Anne Griffiths, Paul Moayyedi, Remo Panaccione, Hien Huynh, Hillary Steinhart, Guy Aumais, Konstantin Shestopaloff, Levinus A. Dieleman, Dan Turner, Andrew D. Paterson, Kenneth Croitoru
Journal: Gut Microbes (2018)

Heritability analysis of the microbiota has demonstrated the importance of host genotype in defining the human microbiota. The alpha (1,2)-fucosyltransferase 2 encoded by FUT2 is involved in the formation of the H antigen and the SNP, rs601338 is associated with ABO histo-blood group antigen secretion in the intestinal mucosa. Previous studies have provided non replicated results for the association of this polymorphism with the composition and inferred function of intestinal microbiota. We aimed to assess this relationship in a large cohort of 1,190 healthy individuals. Genotyping was performed using the HumanCoreEXOME chip, microbial composition was addressed by 16S rRNA gene sequencing. Firmicutes, Bacteroidetes, and Actinobacteria were the dominant phyla in this cohort. Although we have sufficient power to detect significant associations of FUT2 genotype/ inferred phenotype with the microbiota, our data demonstrate that FUT2 genotype and secretor status is not associated with microbial alpha diversity, microbial composition or inferred microbial function after correction for multiple testing. Thus, FUT2 genotype and inferred phenotype are not associated with human fecal microbial composition and imputed function.
A phase II trial of first-line FOLFIRINOX for patients with advanced gastroesophageal adenocarcinoma.
Authors: Haeseong Park, Andrea Wang-Gillam, Rama Suresh, Caron E. Rigden, Manik A. Amin, Benjamin R. Tan, Katrina Pedersen, Kian-Huat Lim, Nikolaos Trikalinos, Katherine Navo, Ashley Morton, Lindsey Schrumpf, Samantha Marquez, Kathryn Trinkaus, A. Craig Lockhart
Journal: Journal of Clinical Oncology (2018)

89 Background: Standard first-line regimens for patients with metastatic gastroesophageal adenocarcinomas have an approximate 40% objective response rate (ORR). FOLFIRINOX has been used in first line therapy in other GI cancers (i.e pancreatic and CRC) with impressive efficacy signals. Methods: This is a phase II study of first line combination chemotherapy with fluorouracil (5-FU), irinotecan, and oxaliplatin in patients with advanced gastric, esophageal, or gastroesophageal junction adenocarcinoma (NCT01928290). Starting doses were 5-FU 400mg/m 2 bolus followed by 2400 mg/m 2 over 46 hours with leucovorin 400 mg/m 2 , irinotecan 180 mg/m 2 , and oxaliplatin 85 mg/m 2 . Trastuzumab was administered as 6 mg/kg loading dose then 4 mg/kg every 14 days if patients had HER2+ cancer. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression free survival (PFS), overall survival (OS), time to progression (TTP), clinical benefit rate (CBR), and duration of response. Enrollment of 41 patients with HER2- disease was planned to reach one-sided = 0.10 and power 0.90 with goal of detecting true ORR60%. No enrollment goal was planned for HER2+. Results: From Nov 2013 to July 2017, 58 patients were enrolled, 25 out of 58 (43%) had HER2+ disease. Forty-nine patients were evaluable for response as they completed at least one restaging scan. ORR was 78% (38/49) in all patients, 67% (18/27) in HER2-, 91% (20/22) in HER2+. One patient (2%) had complete response, 37 (76%) had partial response, 7 (14%) had stable disease &gt; 6 months; therefore, CBR was 92%. Median PFS is 11.9 months, median OS is 17.4 months and median follow up time 16.1 months. 41 (83.7%) had dose modification or delay during treatment. There were no unexpected toxicities. Conclusions: FOLFIRINOX with or without trastuzumab showed remarkable ORR and PFS in patients with advanced gastroesophageal adenocarcinoma in the first-line setting. This regimen may be a reasonable therapeutic option for patients with preserved performance status. Further investigation in larger population is warranted. Clinical trial information: NCT01928290.
DETECTION OF FAMILIAL HYPERCHOLESTEROLEMIA IN SOUTH AFRICA VIA CASCADE SCREENING: THE WITS FIND-FH PROGRAM
Authors: Frederick Raal, Belinda Stevens, Raulene du Toit, Dominick Troendle, Gillian Pilcher, Matthew Kelso, Traci Turner, Evan Stein
Journal: Journal of the American College of Cardiology (2018)
The Change in Living Kidney Donation in Women and Men in the United States (2005–2015): A Population-Based Analysis
Authors: Jagbir Gill, Yayuk Joffres, Caren Rose, Julie Lesage, David Landsberg, Matthew Kadatz, John Gill
Journal: Journal of the American Society of Nephrology (2018)

The factors underlying the decline in living kidney donation in the United States since 2005 must be understood to inform strategies to ensure access to this option for future patients. Population-based estimates provide a better assessment of donation activity than do trends in the number of living donor transplants. Using data from the Scientific Registry of Transplant Recipients and the United States Census, we determined longitudinal changes in living kidney donation between 2005 and 2015, focusing on the effect of sex and income. We used multilevel Poisson models to adjust for differences in age, race, the incidence of ESRD, and geographic factors (including population density, urbanization, and daily commuting). During the study period, the unadjusted rate of donation was 30.1 and 19.3 per million population in women and men, respectively, and the adjusted incidence of donation was 44% higher in women (incidence rate ratio [IRR], 1.44; 95% confidence interval [95% CI], 1.39 to 1.49). The incidence of donation was stable in women (IRR, 0.95; 95% CI, 0.84 to 1.07) but declined in men (IRR, 0.75; 95% CI, 0.68 to 0.83). Income was associated with longitudinal changes in donation in both sexes, yet donation was stable in the highest two population income quartiles in women but only in the highest income quartile in men. In both sexes, living related donations declined, irrespective of income. In conclusion, living donation declined in men but remained stable in women between 2005 and 2015, and income appeared to have a greater effect on living donation in men.
Vascular surgery specialty launches in 2013
Authors: Helen Jaques
Journal: BMJ (2013)

A vascular surgery specialty is being launched this summer to allow trainees to gain more specialist experience than is currently possible through surgical training programmes.

The Vascular Society of Great Britain and Ireland has secured parliamentary approval for the new specialty and its dedicated training programme. The society has campaigned for 10 years for vascular surgery to be a specialty separate from general surgery.

At present, prospective vascular surgeons complete core training in surgery and then the general surgery specialty training programme …
Abstract ES4-3: Can we improve treatment tailoring in advanced HER2+ breast cancer?
Authors: MJ Piccart
Journal: Cancer Research (2018)

Abstract In the 1980s the importance of HER2 signalling to the aberrant behaviour of certain breast cancer cells was recognized for the first time. The intervening 3 decades have seen an immense international translational and clinical research effort that at first identified a hitherto unknown subtype of breast cancer – HER2-positive breast cancer - and then went on to entirely transform the natural history of this aggressive disease. For women with metastatic HER2-positive breast cancer, this has meant in practical terms a doubling of median overall survival and 5-year survival rate. First with the advent of trastuzumab, followed closely by lapatinib, pertuzumab and T-DM1, the lives of thousands of women have been made both longer and better. Nevertheless, metastatic HER2-positive breast cancer remains an incurable disease and new therapeutic options are needed. Additionally, the rapid changes in treatment standards 5 years ago have left unanswered numerous questions, including about the “real-life” benefit of pertuzumab and T-DM1 since both the CLEOPATRA and EMILIA trials were conducted on populations that no longer exist in practice. Furthermore, despite significant research efforts with translational research and new imaging techniques, in both the advanced and early settings, no predictive biomarkers has been clinically validated to help decision making for this patient population and therefore a more refined approach to treatment tailoring remains beyond our reach. Finally, better understanding of resistance to currently existing anti-HER2 agents and of the role played by the microenvironment (e.g. immune system) and of interconnected signalling pathways (e.g. PI3K-mTOR-AKT) is at the core of clinical trials exploring new drugs and new regimens, including the combination of anti-HER2 agents and anti-PD-1/PDL-1, PI3K inhibitors and CDK 4/6 inhibitors, as well as new host of pan-HER inhibitors, drug antibody conjugates and bi-specific antibodies which may in coming years further push the boundaries of what we can do for our patients. Citation Format: Piccart MJ. Can we improve treatment tailoring in advanced HER2+ breast cancer? [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr ES4-3.
The Metastatic Prostate Cancer project (MPCproject): Translational genomics through direct patient engagement.
Authors: Stephanie Anne Mullane, Corrie Painter, Michael Dunphy, Elana Anastasio, Tania Simoncelli, Kristen Zarrelli, Anthony Philippakis, Rana R. McKay, Toni K. Choueiri, Todd Golub, Eric Lander, Nikhil Wagle, Eliezer Mendel Van Allen
Journal: Journal of Clinical Oncology (2018)

279 Background: While there has been substantial advancement in the genomic understanding of metastatic prostate cancer (MPC), there is still much to be discovered. Additional progress is dependent upon obtaining a large amount of clinically-annotated genomic data. Therefore, we piloted a direct-to-patient nationwide research initiative where patients can contribute their medical records and biospecimens to accelerate research ( mpcproject.org ). Methods: In collaboration with patients and advocacy groups, we have developed a website ( mpcproject.org ). Participants are asked to complete a 17-question survey about their experiences with prostate cancer and an electronic informed consent. All participants receive a saliva kit for germline DNA and blood kit for circulating tumor DNA (ctDNA). Additionally, medical records are collected and archived tissue samples are requested if available. Ultra low pass whole genome sequencing (ULP-WGS) and whole exome sequencing (WES) are performed on the whole blood samples. WES is performed on saliva samples. Genomic, clinical, and patient-reported data will be shared widely with the research community. Aggregate study results will be reported to patients. Results: As of October 2017, 12 pilot patients aged 47-74 from 7 states, provided informed consent. 7 saliva kits, 4 blood kits, and 2 medical records were received. 4 patients were diagnosed with de novo metastatic disease, 8 reported a family history of breast and/or prostate cancer, 6 reported a secondary malignancy. All blood kits were submitted for ULP-WGS and WES. Updated genomic, clinical, and patient-reported data will be presented. Conclusions: We have provided preliminary evidence that partnering directly with MPC patients enabled the remote collection of saliva and blood samples, medical records, and patient-reported data. At the conclusion of the pilot phase, the MPC Project will open enrollment for all men with metastatic and advanced prostate cancer in the US and Canada.
Response to Comment on Russell-Jones et al. Diabetes Care 2017;40:943–950. Comment on Bowering et al. Diabetes Care 2017;40:951–957
Authors: Bruce W. Bode, Keith Bowering, David Russell-Jones
Journal: Diabetes Care (2018)

We appreciate the relevant comments raised by Wu et al. (1) regarding the challenges faced by clinicians in safely achieving postprandial, and overall, glycemic control for patients with diabetes in the face of individual needs and physiological variation (including varying rates of gastric emptying/gastroparesis). Increasing awareness and understanding of factors affecting the complex physiology of postprandial glucose regulation, together with an understanding of the clinical pharmacological profile, are key in guiding appropriate dosing and timing of any mealtime insulin therapy. In the onset 1 and 2 trials, both mealtime (0–2 min before the meal) and postmeal dosing (20 min after the start of a meal investigated in onset 1) of fast-acting insulin aspart (faster aspart) demonstrated noninferior overall glycemic control compared with mealtime conventional insulin aspart. Importantly, no statistically significant differences in the overall rates of hypoglycemia were found in these trials …
The FALCON trial: Impact of <sup>18</sup>F-fluciclovine PET/CT on clinical management choices for men with biochemically recurrent prostate cancer.
Authors: Eugene Jueren Teoh, David M. Bottomley, Andrew Scarsbrook, Heather Payne, Asim Afaq, Jamshed Bomanji, Nick Van As, Sue Chua, Peter Hoskin, Anthony Chambers, Gary J. Cook, Victoria S. Warbey, Albert Chau, Penelope Ward, Matthew P. Miller, Daniel J. Stevens, Lynn Wilson, Fergus V. Gleeson
Journal: Journal of Clinical Oncology (2018)

165 Background: Detection of the extent of local recurrence and of metastases in biochemical recurrence (BCR) of prostate cancer facilitates selection of appropriate treatment. The FALCON trial (NCT02578940) assessed the impact of 18 F-fluciclovine PET/CT on the clinical management of men with BCR of prostate cancer following initial radical therapy. Methods: Men being considered for curative-intent salvage therapy following first BCR were recruited at 6 UK sites. Management plans were documented prior to and following 18 F-fluciclovine PET/CT imaging. Post-scan changes to treatment modality such as salvage radiotherapy [RT] to systemic therapy were classed as ‘major’, while changes within a modality (e.g. modified RT fields) were classed as ‘other’. A pre-planned interim analysis of the first 85 patients was conducted; recruitment was to be stopped for efficacy if the number of treatment changes was &gt; 45 (52.9%; 97.5% CI: 40.3–62.3%), or for futility if ≤ 8 (9.4%, 97.5% CI: 3.6–18.9%). Results: The 85 enrolled patients were a mean 4.8 y post-initial diagnosis, with a median age of 67 y and median PSA of 0.63ng/mL. Twelve (14.1%) had a Gleason score ≤ 6, 60 (70.6%) had a score of 7 and 13 (15.3%) had a score ≥ 8. Most (56; 65.9%) had previously undergone radical prostatectomy (RP), with 27 having received RT (± other therapy). The majority of those imaged (52; 61.2%) had a change in management (CIM) post-scan (Table). Recruitment was subsequently stopped as the pre-specified condition defining overwhelming efficacy was met. Conclusions: This prospective trial shows 18 F-fluciclovine PET/CT has substantial impact on clinical decisions for men with a first BCR of prostate cancer after curative-intent primary therapy. Clinical trial information: NCT02578940. [Table: see text]
I would like to work on a range of non-clinical projects such as sitting on boards/panels or working for organisations in an advisory capacity. Do you have any ideas where these type of positions are advertised?
Authors: Sabina Dosani
Journal: BMJ (2007)

Have a career or related problem that needs answering? Can9t find the right person to point you in the right direction? Log on to the Advice Zone for reliable medical careers advice. You can post a question or see if one of our 300 advisers has already answered a similar question. Here is a selection of questions and answers posted on the site. <b>www.bmjcareers.com/advicezone</b>
HEMS helicopter crew course
Authors: Rachel Hawes
Journal: BMJ (2010)

As prehospital emergency medicine develops as a specialty, there are calls to standardise training, develop minimum acceptable standards, and standardise operating procedures via evidence based clinical guidelines across the United Kingdom. The HEMS helicopter crew course is an intensive three week university accredited course that aims to cover the aspects of aviation, prehospital emergency medicine, and multiagency working required for health professionals to function at a high standard in this high pressure environment.

This course is for any doctor, paramedic, or nurse who is experienced in prehospital care and is about to start a post with a UK based air ambulance service. The current national guidelines1 suggest that a minimum level of experience for doctors wishing to perform prehospital anaesthesia is equivalent to the acute care common stem programme (six months’ emergency medicine, six months’ medicine, and 12 months’ anaesthesia and critical care), and the course directors advise that …
Interview and travel expenses
Authors: Turab Syed
Journal: BMJ (2004)

When shortlisted for interviews ring human resources to confirm that you are attending. Most hospitals provide overnight accommodation in hospital or pay for it outside (see web extra). Keep all the receipts of the travelling (expenses for rail travel, food, drink, etc) and claim from human resources. (Do not forget to get receipts for any parking at or travel to airports, which can be reimbursed as well.) Here is a …