tbuckley/cabot-search huggingface dataset:
Prospective genomic/transcriptomic profiling of advanced pancreatic ductal adenocarcinoma (PDAC) for personalized therapy: Feasibility and preliminary results from the COMPASS study (NCT02750657).
Authors: Kyaw Lwin Aung, Sandra Fischer, Rob Denroche, Gun Ho Jang, Anna Dodd, Sean Creighton, Dianne Chadwick, Lee Timms, Grainne M. O'Kane, Hamzeh Albaba, Bernadette M. Southwood, Sangeet Ghai, Malcolm J. Moore, Jessica Miller, Faiyaz Notta, Julie Wilson, David W. Hedley, Neesha C. Dhani, Steven Gallinger, Jennifer J. Knox
Journal: Journal of Clinical Oncology (2017)

e15776 Background: Prospective characterization of advanced PDAC using whole genome sequencing (WGS) and whole transcriptome sequencing (WTS) may identify patients (pts) who will benefit from a personalized treatment strategy. The feasibility of this approach has not previously been established in PDAC. Methods: Advanced PDAC pts with ECOG PS 0-1 and accessible metastatic or primary tumors, were recruited. A fresh tumor sample for WGS and WTS was obtained by percutaneous biopsy and a reference whole blood sample for germline DNA analysis collected before starting 1 st line palliative chemotherapy. Tumor biospecimens were enriched by laser capture microdissection before genomic analysis. The primary endpoint was feasibility (to report WGS results within 56 days in 40 of the first 50 recruited pts.) with a plan to accrue 200 pts. Results: From Dec 2015 – Jan 2017, 42 pts with advanced PDAC safely underwent tumor biopsy (32 liver, 1 omentum, 1 adrenal, 8 primary tumor). Adequate tumor biospecimens were obtained in all but one pt. The median number of tissue cores was 5 (range 3-6). The median post-enrichment tumor cellularity was 77% (range 37-93). WGS was successful for all samples analyzed. In 41 of 42 pts (97.6%), WGS was feasible and results were reported within 56 days (Median 37 days; range 19 to 52 days) meeting the primary endpoint. Potentially actionable somatic genetic aberrations were found in 12 pts (29%) involving ARID1A (N = 4), PIK3CA (N = 1), PDGFRB (N = 1), ERBB4 (N = 1), ATM (N = 2), CDK4 (N = 1) and CDK6 (N = 2). One pt with a germline BRCA2 mutation and another with somatic DSBR mutation signature achieved partial response with FOLFIRINOX (FFX). WTS results were available for 35 pts (85%). Of those, 19 were evaluable for FFX response. Eight of 9 pts (88%) with ‘classic’ signature and 4 of 10 pts (40%) with ‘basal like’ signature had tumor shrinkage with FFX (P = 0.08). Conclusions: Prospective comprehensive genomic profiling of advanced PDAC is feasible with an acceptable turnaround time. Approximately 30% of advanced PDAC pts have targetable genomic signatures and aberrations. RNA signature may predict FFX response.
The impact of tertiary Gleason pattern 5 in the grade group system on recurrence following radical prostatectomy in patients with prostate cancer.
Authors: Masashi Kato, Toyonori Tsuzuki, Ryo Ishida, Tohru Kimura, Osamu Kamihira, Naoto Sassa, Momokazu Gotoh
Journal: Journal of Clinical Oncology (2018)

44 Background: The current ISUP/WHO grade group system classified the Gleason grade into five groups. Although presence of tertiary Gleason pattern 5 (tG5) reported to be related with unfavorable tumor characteristic, only a few data is available about influences on the grade group system of tG5 so far. In this study, we evaluated the effect of tG5 on recurrence following radical prostatectomy in patients with prostate cancer. Methods: We retrospectively evaluated 1,020 patients with prostate cancer who underwent radical prostatectomy without neoadjuvant therapy at the hospitals that the authors were affiliated with between 2005 and 2013. After excluding the patients with missing data or slides, 1000 patients were enrolled in this study. All prostatectomy specimen slides were reviewed by a single genitourinary pathologist according to ISUP 2014. Recurrence following radical prostatectomy was defined according to European Association of Urology guidelines. The endpoint was defined as an increase in PSA level. Results: Patient median age was 67 years (range 49–77 years). The median serum PSA was 6.9 ng/mL (range 0.4–82 ng/mL). The median follow-up period was 69 months (range 0.7–134 months). All the patients showed Group1:163 cases (16.3%), Group2: 436 (43.6%), Group 2 with tG5: 54 (5.4%), Group 3:121 (12.1%), Group 3 with tG5: 89 (8.9%), Group 4: 39 (3.9%), and Group 5: 98 (9.8%). PSA progression-free survival was significantly different among the five groups (Group1-5) (p = 0.0001). As concerning tG5, it showed significant difference between Group 2 and Group 2 with tG5 by using log rank test (p &lt; 0.0001). Similarly, there was significant difference between Group 3 and Group 3 with tG5 (p = 0.001). On the other hand, there was no difference between Group 2 with tG5 and Group 3 (p = 0.916), and in the same way, no difference between Group 3 with tG5 and Group 4 (p = 0.854). Conclusions: The Presence of tG5 on the grade group system increase PSA progression following radical prostatectomy in patients with prostate cancer. Especially, Group 2 and 3 showed upgrade by presence of tG5. Integrating tG5 into the grade group system will improve the accuracy of patient outcome predictions.
Effects of index client and geo-targeting on HIV case identification: an observational study
Authors: E Oladele, William Menson, O-O Badejo, E Onwasigwe, I Iyamu, A Olarinoye, C Agbakwuru, T Bruno, H Khamofu, E E Ezeanolue
Journal: The Lancet Global Health (2018)

BackgroundDespite huge investments in HIV prevention, treatment, and care in sub-Saharan Africa, fewer than one in 10 individuals knows their HIV status, and 40% of individuals living with HIV are not cognisant of their positive status. Efforts to improve and strengthen HIV service delivery, particularly in HIV testing, are necessary to increase efficiency in HIV case finding and optimise service delivery. Standard approaches to HIV testing have not been effective in addressing this gap. Our objective was to evaluate a targeted approach for HIV case identification in a PEPFAR-supported HIV programme in Nigeria.MethodsBetween October, 2016, and June, 2017, we implemented a strategy that included index client testing, geo-targeted HIV testing, and provider-initiated counselling and testing in 14 local government areas in Akwa Ibom, southern Nigeria. The tests were administered in conjunction with the conventional method of testing and were in line with the PEPFAR impact agenda. We estimated the number of individuals who needed to be tested by each method in order to meet a benchmark of 8000 new diagnoses per quarter. We described dispersion using median and IQR.FindingsConventional methods in the 14 local government areas required testing of 600 000 individuals (median 50 000 [IQR 741 000]) whereas using our targeted approach, we met 60% of the benchmark in each quarter by testing 214 000 individuals on average (median 14 000 [IQR 12 000]).InterpretationWe demonstrated that use of a targeted approach to HIV testing can increase the efficiency of case identification. This process can therefore help increase early initiation of treatment and retention of subjects diagnosed with HIV.FundingPEPFAR.
Phase I trial of the programmed death receptor 1 (PD-1) inhibitor, BI 754091, in patients (pts) with advanced solid tumors.
Authors: Melissa Lynne Johnson, Manish R. Patel, Lillian L. Siu, Mark Kozloff, Raid Aljumaily, Ulka N. Vaishampayan, Mabrouk M. Elgadi, Miaomiao Ge, Christine Duffy, Ralph Graeser, Sheetal Vinay Khedkar, Suzanne Fields Jones, Howard A. Burris
Journal: Journal of Clinical Oncology (2018)

212 Background: Tumors may achieve immune evasion by expressing PD ligand-1 (PDL-1) to bind to PD-1 expressed on activated T cells, initiating immunosuppressive signals within the tumor. Pro-inflammatory anti-tumor activity can be restored when this interaction is blocked by therapeutic PD-1 or PDL-1 inhibition. BI 754091 is a monoclonal IgG4Pro antibody directed against PD-1 that has demonstrated anti-tumor activity in vitro and in vivo. We present the results of the first in human study evaluating BI 754091 in patients with advanced solid tumors. Methods: Patients who had exhausted standard treatment (tx) options, including prior anti-PD-1 tx, were enrolled to receive BI 754091 IV every 3 weeks (Q3W) in one of 3 sequential dose escalation cohorts (80, 240 and 400 mg), 3 patients/cohort, to evaluate the safety and tolerability and establish the maximum-tolerated dose (MTD) or recommended Phase II Dose (RPIID). Additional anti-PD-1 naïve patients with select solid tumors are being enrolled in dose expansion to be treated with the selected RPIID. The objectives of the dose expansion cohort are to evaluate the safety, tolerability, PK and preliminary efficacy of the RPIID of BI 754091, in patients with advanced solid tumors. Results: 17 patients have enrolled to date, 9 patients in the dose escalation and 8 patients in the dose expansion cohorts. Both, safety and PK profile supported a RPIID of 240 mg. The most common all grade Treatment Related Adverse Events (TRAE) were fatigue 35% (6 patients), decreased appetite 18% (3 patients) and arthralgia 12% (2 patients). There were no dose-limiting toxicities, tx-related serious adverse events, or TRAEs ≥Grade 3 reported. To date, one patient (gastric cancer) has had a partial response, 8 had stable disease, and 8 patients continue on treatment. Additional efficacy data among patients in dose-expansion will be reported. Conclusions: BI 754091 is safe and well-tolerated across all dose levels tested for advanced solid tumors, with preliminary evidence of activity. A dose of 240 mg Q3W was selected for dose expansion and RPIID based upon the available safety and PK data. Clinical trial information: NCT02952248.
Depth of organ response in AL amyloidosis is associated with improved survival: grading the organ response criteria
Authors: Eli Muchtar, Angela Dispenzieri, Nelson Leung, Martha Q. Lacy, Francis K. Buadi, David Dingli, Martha Grogan, Suzanne R. Hayman, Prashant Kapoor, Yi Lisa Hwa, Amie Fonder, Miriam Hobbs, Rajshekhar Chakraborty, Wilson Gonsalves, Taxiarchis V. Kourelis, Rahma Warsame, Stephen Russell, John A. Lust, Yi Lin, Ronald S. Go, Steven Zeldenrust, Robert A. Kyle, S. Vincent Rajkumar, Shaji K. Kumar, Morie A. Gertz
Journal: Leukemia (2018)
Consultant contract has delivered expected benefits but at considerable expense, National Audit Office finds
Authors: Helen Jaques
Journal: BMJ (2013)

The 2003 consultant contract has fully or partly delivered the benefits expected by the Department of Health but has significantly increased costs to the NHS, concludes the National Audit Office (NAO).

To realise all the benefits set out in the original plan for the contract, hospital trusts should manage consultants better, such as through more effective job planning, it said.

The NAO conducted a web based census of all NHS acute foundation and non-foundation trusts (85% response rate) and all NHS consultants (28% response rate). The census sought to establish whether the expected benefits of the 2003 consultants contract had been realised and whether consultants were managed effectively and consistently across the NHS.

The NAO found that consultants’ participation in the workforce had risen as a result of the new contract. It …
Consultants should be supported to work up to retirement age, BMA says
Authors: Tom Moberly
Journal: BMJ (2016)

Consultants in their 50s should be allowed to reduce their responsibilities so that they can continue working in the health service up to retirement age, the BMA has said.

Delegates at the BMA’s annual UK consultants’ conference in London on 3 March passed a motion calling for the BMA to support consultants wanting to work up to and beyond retirement age.

“This conference …
Pulmonary vascular endothelium: the orchestra conductor in respiratory diseases
Authors: Alice Huertas, Christophe Guignabert, Joan A. Barberà, Peter Bärtsch, Jahar Bhattacharya, Sunita Bhattacharya, Maria R. Bonsignore, Laurence Dewachter, Anh Tuan Dinh-Xuan, Peter Dorfmüller, Mark T. Gladwin, Marc Humbert, Tom Kotsimbos, Theodoros Vassilakopoulos, Olivier Sanchez, Laurent Savale, Ugo Testa, Martin R. Wilkins
Journal: European Respiratory Journal (2018)

The European Respiratory Society (ERS) Research Seminar entitled “Pulmonary vascular endothelium: orchestra conductor in respiratory diseases - highlights from basic research to therapy” brought together international experts in dysfunctional pulmonary endothelium, from basic science to translational medicine, to discuss several important aspects in acute and chronic lung diseases. This review will briefly sum up the different topics of discussion from this meeting which was held in Paris, France on October 27–28, 2016. It is important to consider that this paper does not address all aspects of endothelial dysfunction but focuses on specific themes such as: 1) the complex role of the pulmonary endothelium in orchestrating the host response in both health and disease (acute lung injury, chronic obstructive pulmonary disease, high-altitude pulmonary oedema and pulmonary hypertension); and 2) the potential value of dysfunctional pulmonary endothelium as a target for innovative therapies.
Association of High Body Mass Index and Hepatocellular Carcinoma in Patients With Chronic Hepatitis B Virus Infection
Authors: Kyuwoong Kim, Seulggie Choi, Sang Min Park
Journal: JAMA Oncology (2018)

This analysis of population-level data examines evidence of the association between body mass index and development of hepatocellular carcinoma among men and women with chronic hepatitis B virus infection.
Interim results from PURE-01: A phase 2, open-label study of neoadjuvant pembrolizumab (pembro) before radical cystectomy for muscle-invasive urothelial bladder carcinoma (MIUC).
Authors: Andrea Necchi, Alberto Briganti, Daniele Raggi, Patrizia Giannatempo, Luigi Mariani, Antonella Messina, Andrea Anichini, Giuseppina Calareso, Flavio Crippa, Mario Catanzaro, Nicola Fossati, Giorgio Gandaglia, Andrea Salonia, Roberto Salvioni, Francesco Montorsi
Journal: Journal of Clinical Oncology (2018)

TPS533 Background: MIUC is an aggressive disease and &gt; 40% of patients (pts) will develop recurrence after radical cystectomy (RC). Despite cisplatin-based neoadjuvant chemotherapy yields Level 1 evidence, it is administered in a minority of pts worldwide. Pembro is an EMA and FDA-approved standard therapy for metastatic UC after platinum failure or for cisplatin-ineligible pts. Our hypothesis was that pembro, given neoadjuvantly, could downstage MIUC and reduce recurrence. Methods: PURE-01 (NCT02736266) is an open-label, single-arm, phase 2 study to evaluate the activity, medical and surgical safety, and immune modulatory effects of pembro administered as a short window-of-opportunity course of therapy preceding RC. Eligibility criteria included: T2-T4aN0 stage, and residual disease after transurethral resection of the bladder (TURB, surgical opinion, cystoscopy or radiological presence). The study includes cisplatin eligible- and ineligible pts. Pts receive 3 cycles of pembro 200mg 3 weekly before RC (planned &lt; 3 weeks of the last dose). Computed tomography (CT) scan, FDG-PET/CT scan, and bladder multiparametric magnetic resonance imaging (mpMRI) are done during screening and before RC. Radiologically non responders to pembro (per investigator decision; i.e., study failures) are given 3 additional courses of dose-dense MVAC chemotherapy. After RC, pts are managed according to local guidelines (adjuvant chemotherapy vs observation). Further anti PD-1/PD-L1 therapy will not be given post-operatively. Pathologic complete response (pT0) is the primary endpoint. All pts enrolled who receive at least 1 cycle of study drug will be included in the ITT analysis. The H 1 is pT0 ≥20% and H 0 pT0≤10%. In a 2-stage design, 90 pts overall will be accrued (80% power and a 2-sided test of significance at the 10% level). A first interim analysis for safety is planned after 18 patients enrolled and treated (by December 1 st , 2017). Activity results and early translational findings (immune-cell profiling) will be added, and may be regarded to as first data of preoperative immunotherapy before major surgery. Clinical trial information: NCT02736266.
Postgraduate certificate in medical education (PGCert Med Ed)
Authors: Ayeshea Zacharkiw
Journal: BMJ (2008)

The postgraduate certificate in medical education is a university affiliated qualification in medical education. It is worth 60 masters level credits and you can choose to add extra modules to achieve a postgraduate diploma (120 credits) or masters degree (180 credits).

It is aimed at doctors of all levels and other healthcare workers who have a teaching role; foundation year doctors are welcomed even if their experience of teaching is minimal.

You need not be involved in formal education to benefit from this course as it has some degree of flexibility to work around the type of teaching that you do in your practice; what you do need, however, is motivation to learn.

I started this certificate during my foundation year 2 job and have continued it into my current …
Abstract P5-22-21: Radioactive seed and targeted axillary dissection: A feasibility study
Authors: K Boulva, S Rodriguez-Qizilbash, L Guilarte, S Lazizi, A Robidoux, R Younan, E Patocskai
Journal: Cancer Research (2018)

Abstract Targeted axillary dissection (TAD) with a radioactive seed is a new and promising technique to evaluate the axillary status in post-neoadjuvant chemotherapy (NACT) node-positive breast cancer patients. This study aims to evaluate the feasibility of TAD with a radioactive seed in a Canadian setting. We conducted a retrospective observational study of a prospectively gathered database of patients having undergone TAD with a radioactive seed implanted in a proven metastatic axillary node, between 2015 and 2017 in our institution. An iodine-125 radioactive seed was implanted under ultrasound guidance by trained radiologists. Patients then underwent standard sentinel lymph node biopsy (SLNB) using technicium-99 and blue dye, as well as selective removal of the node containing the radioactive seed. Data was gathered from electronic medical records and chart review. Nine patients with a median age of 54 underwent TAD for unilateral breast cancer post-NACT between 2015 and 2017, three of which were "triple-negative". A median of 3 lymph nodes were removed, including that which contained the radioactive seed. Postoperative pathological evaluation showed 4 patients with positive nodes and 5 pathologic complete responses in the axilla. In all patients, the seed had been accurately positioned in a positive node (no false negatives). The seed also located a positive retropectoral node that would otherwise have been missed using standard dual tracer SLNB. No complications due to the use of the radioactive seed were encountered. All implanted seeds were identified and retrieved within the pathology specimen. In our experience, TAD with a radioactive seed combined to dual tracer SLNB is an accurate and safe method of evaluating the axillary lymph node status in post-NACT node positive breast cancer patients. Further studies with larger cohorts are warranted to ensure continued feasibility and reproducibility of our positive results. Citation Format: Boulva K, Rodriguez-Qizilbash S, Guilarte L, Lazizi S, Robidoux A, Younan R, Patocskai E. Radioactive seed and targeted axillary dissection: A feasibility study [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 P5-22-21.
Life Expectancy of Patients With Low-Normal Thyroid Function—Reply
Authors: Arjola Bano, Robin P. Peeters, Oscar H. Franco
Journal: JAMA Internal Medicine (2018)

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Oral retinoids and depression: reply from the authors
Authors: M. Le Moigne, J.-P. Fournier, C. Victorri-Vigneau, B. Dréno
Journal: British Journal of Dermatology (2018)

Linked Articles:Lehloenya and Jessop. Br J Dermatol 2018; 178:1223–1224. Vallerand and Patten. Br J Dermatol 2018; 178:305. Le Moigne et al. Br J Dermatol 2018; 178:278–280
CONTINUOUS LEFT ATRIAL PRESSURE AND INVASIVE HEMODYNAMIC MONITORING VIA STEERABLE GUIDE CATHETER TO OPTIMIZE TRANSCATHETER MITRAL VALVE REPAIR WITH MITRACLIP NT SYSTEM
Authors: Gilbert Hin-Lung Tang, Lawrence Ong, Ryan Kaple, Basel Ramlawi, Tanya Dutta, Syed Zaid, Hasan Ahmad, Robert Kalimi, Cenap Undemir, Asaad Khan, Matias Yudi, Adnan Nadir, Farhan Majeed, Omar A. Ali, Jeffrey Skiles, Joanne Bennett, Chandra Bhim, Martin Cohen, Steven Lansman, Samin K. Sharma, Annapoorna Subhash Kini
Journal: Journal of the American College of Cardiology (2018)
Key HLA‐DRB1‐DQB1 haplotypes and role of the BTNL2 gene for response to a hepatitis B vaccine
Authors: Nao Nishida, Masaya Sugiyama, Hiromi Sawai, Sohji Nishina, Aiko Sakai, Jun Ohashi, Seik‐Soon Khor, Keisuke Kakisaka, Takayo Tsuchiura, Keisuke Hino, Ryo Sumazaki, Yasuhiro Takikawa, Kazumoto Murata, Tatsuo Kanda, Osamu Yokosuka, Katsushi Tokunaga, Masashi Mizokami
Journal: Hepatology (2018)

Approximately 5‐10% of individuals who are vaccinated with a hepatitis B (HB) vaccine designed based on the hepatitis B virus (HBV) genotype C fail to acquire protective levels of antibodies. Here, host genetic factors behind low immune response to this HB vaccine were investigated by a genome‐wide association study (GWAS) and Human Leukocyte Antigen (HLA) association tests. The GWAS and HLA association tests were carried out using a total of 1,193 Japanese individuals including 107 low responders, 351 intermediate responders, and 735 high responders. Classical HLA class II alleles were statistically imputed using the genome‐wide SNP typing data. The GWAS identified independent associations of HLA‐DRB1‐DQB1 , HLA‐DPB1 and BTNL2 genes with immune response to a HB vaccine designed based on the HBV genotype C. Five HLA‐DRB1‐DQB1 haplotypes and two DPB1 alleles showed significant associations with response to the HB vaccine in a comparison of three groups of 1,193 HB vaccinated individuals. When frequencies of DRB1‐DQB1 haplotypes and DPB1 alleles were compared between low immune responders and HBV patients, significant associations were identified for three DRB1‐DQB1 haplotypes, and no association was identified for any of the DPB1 alleles. In contrast, no association was identified for DRB1‐DQB1 haplotypes and DPB1 alleles in a comparison between high immune responders and healthy individuals. Conclusion: The findings in this study clearly show the importance of HLA‐DR‐DQ (i.e., recognition of a vaccine related HB surface antigen (HBsAg) by specific DR‐DQ haplotypes) and BTNL2 molecules (i.e., high immune response to HB vaccine) for response to a HB vaccine designed based on the HBV genotype C. (H epatology 2018).