tbuckley/cabot-search huggingface dataset:
NHS England consultation on London calls for changes to GP training and redesign of workforce
Authors: Abi Rimmer
Journal: BMJ (2013)

NHS England has called for “growth and redesign” of the general practice workforce in London and for training of GPs to better reflect the future needs of the city’s patients.

In a consultation document NHS England said that the capital faced a shortage of new GPs, with a high number of GPs approaching retirement.1 The document was developed in partnership with the Royal College of General Practitioners, the National Association of Primary Care, Londonwide Local Medical Committees, and other organisations.

NHS England said that a “city-wide approach” was …
CHOOSING CARDIOLOGY: CAREER CHOICE AND GENDER INFLUENCE PROFESSIONAL DEVELOPMENT NEEDS AND PERCEPTIONS OF THE CARDIOLOGY FIELD AMONG INTERNAL MEDICINE TRAINEES
Authors: Pamela S. Douglas, Anne Rzeszut, C. Noel Bairey Merz, Claire Duvernoy, Sandra Lewis, Mary Walsh, Linda Gillam
Journal: Journal of the American College of Cardiology (2018)
An open-label phase 1/2a study to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of TRC253, an androgen receptor antagonist, in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Dana E. Rathkopf, Mansoor N. Saleh, Frank Yung-Chin Tsai, Lee S. Rosen, Bonne J. Adams, Lilian Liu, Charles P. Theuer, James L. Freddo, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2018)

TPS403 Background: Resistance to AR-targeted therapy is a challenge in the treatment of mCRPC. Single amino acid mutations of the AR ligand binding domain may mediate resistance to second generation AR inhibitors, including enzalutamide (Rathkopf, Annals of Oncology 2017). Development of potent antagonists of wild-type (WT) AR as well as mutated AR is a priority. TRC253 is an orally available, high-affinity, small molecule antagonist of AR with inhibitory activity against WT AR as well as mutated variants. TRC253 blocks AR nuclear translocation and AR binding to DNA and antagonizes transcription. TRC253 does not have agonist activity toward WT or mutated ARs. Methods: This phase 1/2a study of TRC253 in patients with mCRPC will be conducted in two parts: dose-escalation (part 1) and dose-expansion (part 2). Objectives include assessment of safety, selection of a phase 2 dose, and to evaluate PSA response at week 12. Secondary objectives include the evaluation of the extent of receptor occupancy (FDHT PET) and anti-tumor effects of TRC253. Toxicity and efficacy assessments will be determined using NCI-CTCAE and PCWG3 criteria. Dose escalation will begin with single-patient cohorts. Cohorts will be expanded to 3 patients when pre-defined grades of drug-related toxicity occur. TRC253 doses in part 1 are 40 mg, 80 mg, 160 mg, 240 mg, 320 mg, and 400 mg. The DLT evaluation period will be the first 28 days of continuous daily dosing. Six patients have been enrolled to Part 1 to date. Part 2 will consist of two cohorts of up to 30 patients each. Cohort 1 (AR F876L mutation positive) and cohort 2 (AR F876L mutation negative) will receive TRC253 at the RP2D. Circulating tumor DNA will be analyzed in plasma samples to test for AR mutations. In Part 1 patients must have received ≥ 2 prior therapies. Part 2 patients must have demonstrated acquired resistance to enzalutamide or apalutamide. Descriptive statistics will be used to summarize patient characteristics, safety, efficacy, PK, and immunologic biomarkers. Clinical trial information: NCT02987829.
Autologous tumor lysate-pulsed dendritic cell vaccination therapy after resection of stage IIA (T2N0, T3N0) esophageal cancer: An analysis of immunological responses.
Authors: Yasuyoshi Sato, Koichi Yagi, Kazuhiko Mori, Hirokazu Matsushita, Kazuhiro Kakimi, Yasuyuki Seto
Journal: Journal of Clinical Oncology (2018)

96 Background: Immunotherapy using active immunization of tumor associated antigens has been expected to improve the prognosis of malignant tumor patients. We conducted phase I trial to investigate safety and efficacy of autologous tumor lysate-pulsed dendritic cell (DC) vaccination therapy after resection for esophageal cancer. We already reported the clinical results for enrolled 11 patients. All patients completed the protocol therapy and no treatment-related adverse events more than grade 3 was observed (primary endpoint), and recurrence rate within 2 years was 18% (n = 2). In this study, we further analyzed the immune responses in vaccinated patients. Methods: Patients with stage IIA (T2N0 or T3N0, UICC TNM classification 6 th edition) esophageal cancer after curative (R0) resection were eligible. Tumor lysate we used for DC vaccines potentially contains mutated proteins (neoantigens) derived from somatic mutations. Patients received DC vaccines (more than 5.0×10 6 cells) 6 times every 2 weeks. We evaluated neutrophil-to-lymphocyte ratio (NLR) in each patient from CRF data. We identified candidate neoantigens by next generation sequencing and MHC class I binding prediction algorism. We screened the immune responses against those neoantigens using HLA transgenic mice and healthy human PBMCs. Results: Absolute lymphocyte counts, absolute neutrophil counts and NLR were not specifically different between patients with or without recurrence. For specific immune responses, we observed the reactivity in 6 out of 59 candidate neoepitopes identified from two patients in HLA transgenic mouse system. Two out of 6 peptides displayed reactivity in human healthy PBMCs. Conclusions: We analyzed immune responses to predicted candidate neoantigens. We are now investigating immune landscape in the tumor using RNA sequencing data and its relevance to the antigen responses. Clinical trial information: UMIN000002837.
Abstract 18159: A Functional Variant for Atrial Fibrillation Affects PITX2c Expression by Interacting With TFAP2a
Authors: Jiangchuan Ye, Nathan R Tucker, Elena Dolmatova, Patrick T Ellinor
Journal: Circulation (2015)

Background: To date, 17 loci associated with atrial fibrillation (AF) have been identified, and there are 4 regions at 4q25 around PITX2 gene strongly associated with AF. However, the functional variants at all known AF loci remain elusive. Methods and Results: Among the 4 AF loci at 4q25, we focused on one associated region of ~84 kb extending from Chr4: 111,520,926 to 111,604,727 that includes the PITX2 gene itself (defined as all SNPs with r 2 &gt; 0.6 from the sentinel SNP rs1448818). To identify potential functional variants , we analyzed DNase hypersensitivity, histone modification and mammalian conservation from ENCODE and Roadmap Epigenomics Project. Additionally, cap analysis of gene expression (CAGE) data was also investigated. We identified 13 candidate regions, 5 of which showed enhancer activity in zebrafish skeletal muscle and heart. Using luciferase assays in a mouse atrial cell line (HL-1), we then identified one SNP (rs2595104) in which the T risk allele was associated with 31% decreased activity compared to the G non-risk allele (p = 0.007). rs2595104 lies ~10 kb upstream of PITX2c transcriptional start site and is in high linkage disequilibrium (LD) (r 2 = 0.67) with rs1448818. In silico investigation of rs2595104 using UniPROBE and HaploReg database revealed differential binding of each allele to activating enhancer binding protein 2 alpha (TFAP2a). Electrophoretic mobility shift assays showed that TFAP2a bound robustly to the non-risk G allele at rs2595104 but not to the risk T allele. Chromatin immunopricipitation followed by allele-specific qPCR in human embryonic stem cell-derived cardiomyocytes (hESC-CM) further suggested that TFAP2a was preferentially recruited to the non-risk G allele at rs2595104 in an AF-relevant cell type. hESC-CMs with homozygous deletion of rs2595104-containing enhancer using CRSPR-Cas9 expressed less PITX2c (35 ± 6%, p = 0.036), compared to the wild-type hESC-CMs. Finally, mutating the G allele at rs2595104 to T allele by CRSPR-Cas9 led to 21% reduction in PITX2c level in hESC-CMs (p = 0.027). Conclusion: We have found that the AF-associated SNP rs2595104 alters PITX2c expression via interaction with TFAP2a. Such a pathway may ultimately contribute to AF susceptibility at the PITX2 locus.
Overstretched doctors must be encouraged to seek help, GMC says
Authors: Abi Rimmer
Journal: BMJ (2016)

NHS organisations should do more to recognise the intense pressures on the medical profession and make it more acceptable for people to seek help when they are struggling, the General Medical Council (GMC) has said.

The recommendation is part of a report, Medical professionalism matters , published by the GMC on Tuesday 6 December.1

The report’s findings were based on a series of events held by the GMC that explored the challenges facing the …
Complement activation in hidradenitis suppurativa: a new pathway of pathogenesis?
Authors: T. Kanni, O. Zenker, M. Habel, N. Riedemann, E.J. Giamarellos-Bourboulis
Journal: British Journal of Dermatology (2018)

Despite the heavy purulence observed in hidradenitis suppurativa (HS), the kinetics of complement anaphylatoxins acting to prime chemotaxis of neutrophils has not been studied.To explore complement activation in HS.Circulating concentrations of complement factor C5a, as well as of membrane attack complex C5b-9, were determined in the plasma of 54 treatment-naïve patients and of 14 healthy controls, as well as in the pus of seven patients. Results were correlated with Hurley stage and International Hidradenitis Suppurativa Severity Score. Peripheral blood mononuclear cells (PBMCs) were isolated from seven patients with Hurley stage III HS and seven healthy volunteers and stimulated in the presence of 25% of plasma for the production of tumour necrosis factor-α (TNF-α).Circulating C5a and C5b-9 were significantly greater in patient than in control plasma; however, concentrations in pus were very low. Circulating C5a levels exceeding 28 ng mL-1 were associated with a specificity > 90% with the occurrence of HS. Circulating levels of C5a and C5b-9 were greater in patients with more severe HS. PBMCs of patients produced high concentrations of TNF-α only when growth medium was enriched with patient plasma; this was reversed with the addition of the C5a blocker IFX-1.Systemic complement activation occurs in HS and may be used as a surrogate biomarker of HS. C5a stimulates overproduction of TNF-α and may be a future therapeutic target.
What would be a good question to ask the panel at the end of an interview for a specialist registrar post?
Authors: Carl Gray
Journal: BMJ (2004)

<i>Got 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 (www.bmjcareers.com/advicezone) 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.</i>
Phase 1b/2 study of tivozanib in patients with advanced inoperable hepatocellular carcinoma.
Authors: Sunyoung S. Lee, Austin Miller, Smitha S. Krishnamurthi, Bassam N. Estfan, Andrea Frazer, Chong Wang, Renuka V. Iyer
Journal: Journal of Clinical Oncology (2018)

364 Background: Sorafenib has been the only FDA-approved medication for inoperable HCC (iHCC) as first line. Agents with better tolerability and potential to improve progression-free-survival (PFS) are needed. Tivozanib (TIVO) is an inhibitor of vascular endothelial growth factor (VEGF) tyrosine kinase, inhibiting angiogenesis critical in HCC. Methods: This is a phase 1b/2 study with HCC patients (pts) having a measurable disease, Child-Pugh class A, and no prior systemic therapy. Phase 1b portion followed a modified 3 + 3 design; phase 2 portion was a two-stage, single arm, un-blinded study. Adverse events were categorized based on CTCAE, and tumor imaging was assessed per RECIST. Results: At 3 centers with IRB approval, 21 eligible pts were enrolled. In phase 1b, 8 pts were enrolled at a starting dose of 1mg once daily q21days with one week off. Upon escalation to 1.5mg, two pts had dose limiting toxicities (DLTs, grade 3 mucositis and hypertension) and came off study without completing the DLT period. The dose of TIVO was de-escalated to 1 mg, and the accrual of remaining patients to phase 2 portion occurred at 1 mg. In a total of 19 pts, median follow up was 16.9 months (mo). The primary endpoint of median PFS was 5.5 mo. Partial response (PR) was seen in 4/19 (21%) and stable disease (SD) in 8/19 (42%): disease control rate was 63%. Overall survival (OS) at 6 and 12 mo was 58% and 25%. Median OS was 7.5 mo. Three pts have remained on TIVO for &gt; 2 years. Viral loads of hepatitis B and C remained stable during the study. Adverse events (AEs) related to TIVO included grade 3 fatigue (15.7%), decreased appetite (5.3%), pulmonary embolism (5.3%), hand-foot syndrome (5.3%), elevated LFT (10.5%), and grade 4 hypertension (5.3%). Conclusions: TIVO is tolerable at 1 mg in iHCC. In few pts, TIVO had deep and durable responses. Biomarker driven studies of TIVO in the context of immunotherapy are warranted. Acknowledgment: We appreciate support from NCCN. Clinical trial information: NCT01835223.
BIODEGRADABLE POLYMERDRUG ELUTING STENTS VERSUS DURABLE POLYMER DRUG ELUTING STENTS FOR PERCUTANEOUS CORONARY INTERVENTION: A PROPENSITY SCORE MATCHED ANALYSIS
Authors: Amos Levi, Uri Landes, Tamir Bental, Abid Assali, Hana Vaknin Assa, Eli Lev, Ran Kornowski
Journal: Journal of the American College of Cardiology (2018)
Abstract P4-02-13: Can background parenchymal enhancement (BPE) predict the chance of multicentric/ bilateral breast cancer on staging breast MRI?
Authors: APA Benveniste, LO Ebuoma, A Jonna, K Sam, FJ Severs, A Roark, KA Sepulveda, O-P Tamara, EE Sedgwick
Journal: Cancer Research (2018)

Abstract Purpose: Can background parenchymal enhancement (BPE) predict the chance of multicentric/ bilateral breast cancer on staging Breast MRI? Materials and Methods: Retrospective review of women diagnosed with breast cancer who underwent a breast MRI for staging of disease was performed at a single institution from October 2012 to September 2015. Results: Breast MRI for staging was done for 435 patients diagnosed with breast cancer. Ages ranging from 24 to 86 years old (median, 52 years); sizes ranging from 0.5 to 13.5 cm (mean, 3.5 cm). 29 patients (7 %) had biopsy-proven second tumors in the same breast but different quadrant as the primary tumor or in the contralateral breast. From the 435 patients, 304 had minimal/ mild BPE and 103 had moderate/marked BPE (28 missing). Of the patients with an invasive primary cancer and a second tumor in the same breast but different quadrant as the primary tumor or in the contralateral breast, 12 of 29 patients had discordance in subtypes between the primary and secondary tumors (41%) and 17 of 29 had concordance in the subtypes between the primary and secondary tumors (59%). 6.3% (19 out 304) of patients with minimal/ mild BPE had multicentric /bilateral disease and 9.7% (10 out 103) of patients with moderate/ marked BPE had multicentric/ bilateral breast cancer. Conclusion: 435 patients with recent diagnosis of breast cancer who underwent staging breast MRI for diagnosis of additional sites of disease, 7% was diagnosed with an additional site of cancer. From these group of patients, approximately 6% had other site of disease among patients who had minimal/ mild BPE in the breast MRI versus 10% of patients with moderate/marked BPE. BPE may play a role in the setting of multicentric/ bilateral breast cancer. Citation Format: Benveniste APA, Ebuoma LO, Jonna A, Sam K, Severs Jr. FJ, Roark A, Sepulveda KA, Tamara O-P, Sedgwick EE. Can background parenchymal enhancement (BPE) predict the chance of multicentric/ bilateral breast cancer on staging breast MRI? [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 P4-02-13.
Implications of Higher Than Expected Prevalence of Fetal Alcohol Spectrum Disorders
Authors: Shannon Lange, Jürgen Rehm, Svetlana Popova
Journal: JAMA (2018)

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CHARACTERIZATION OF THE OBESITY-HEART FAILURE WITH PRESERVED EJECTION FRACTION PHENOTYPE USING A MULTIMODAL IMAGING APPROACH
Authors: Anupam Kumar, Bilal Ansari, Jessica Kim, Maheswara Reddy Koppula, Sowmya Gaddam, Jagan M.R. Vanjarapu, Dheera Tamvada, Scott Akers, Julio Chirinos
Journal: Journal of the American College of Cardiology (2018)
A phase II trial of risk-adapted treatment for muscle invasive bladder cancer after neoadjuvant accelerated MVAC.
Authors: Daniel M. Geynisman, Philip Abbosh, Matthew R. Zibelman, Rebecca Feldman, David James McConkey, Noah M. Hahn, Trinity Bivalacqua, Edouard John Trabulsi, Costas D. Lallas, Jean H. Hoffman-Censits, Rosalia Viterbo, Eric M. Horwitz, Thomas M. Churilla, R. Katherine Alpaugh, Richard E. Greenberg, Marc C. Smaldone, Robert Uzzo, David Chen, Alexander Kutikov, Elizabeth R. Plimack
Journal: Journal of Clinical Oncology (2018)

TPS537 Background: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by cystectomy (Cx) or chemoradiation (CRT) is the standard of care for urothelial carcinoma (UC) pts with muscle invasive bladder cancer (MIBC). Both Cx and CRT carry potential short and long-term toxicity and quality of life implications. Recent work has shown that mutations in DNA damage repair/response genes are predictive of pathologic downstaging after NAC at the time of Cx, with those pts achieving pT0 disease demonstrating excellent long-term survival (Van Allen et al. Cancer Discov. 2014; Plimack et al. Eur Urol. 2015; Liu et al. JAMA Oncol. 2016; Teo et al. CCR. 2017). Sparing pts Cx or CRT after NAC without compromising oncologic outcomes would improve quality of life and decrease morbidity. Methods: A phase II, parallel arm, multi-institutional clinical trial (NCT02710734) is being conducted to evaluate a risk-adapted approach to treatment of MIBC. Pts with cT2-T3N0M0 UC of the bladder, ECOG PS 0-1 and CrCl≥50 mL/min, undergo NAC with accelerated methotrexate, vinblastine, doxorubicin, and cisplatin. Simultaneously, the pre-NAC TURBT specimen is submitted for deep sequencing to identify variants in a panel of cancer-relevant genes (Caris Life Sciences, Phoenix, AZ). Those with an alteration in ATM, RB1, FANCC or ERCC2 and no clinical evidence of disease by restaging TUR and imaging post-NAC will begin a pre-defined active surveillance regimen that includes urinary cytological, cystoscopic, and radiographic evaluations. The remaining pts will undergo bladder-directed therapy at the discretion of the pt and clinician applying either intravesical therapy ( &lt; cT2 post-NAC), CRT or Cx (≤cT2 post-NAC) or Cx (≥cT3 post-NAC). The primary objective is metastasis-free survival (MFS) at 2 years for all enrolled and evaluable pts. The trial has a non-inferiority design with a 14% margin between risk-adapted treatment (MFS = 78%) and standard-of-care (MFS = 64%) with a sample size of 70 pts, 82% power and a type I error of 0.045. Key secondary and translational objectives: assess the rate of UC recurrence in active surveillance pts; validate biomarkers of response to NAC; evaluate urinary biomarkers consistent with persistent UC. Clinical trial information: NCT02710734.
A phase 3, open-label, randomized study of nivolumab plus ipilimumab or standard of care (SOC) versus SOC alone in patients (pts) with previously untreated unresectable or metastatic urothelial carcinoma (mUC; CheckMate 901).
Authors: Matt D. Galsky, Thomas Powles, Shengting Li, Delphine Hennicken, Guru Sonpavde
Journal: Journal of Clinical Oncology (2018)

TPS539 Background: Cisplatin-containing regimens have been SOC for mUC for nearly 40 years, but durable responses are rare with such treatments. Furthermore, a large proportion of pts with unresectable/mUC are ineligible for cisplatin therapy. Treatment approaches conferring longer-term disease control and extending to broader mUC pt populations are urgently needed. Recently, the programmed death-1 (PD-1) inhibitor, nivolumab, induced durable responses in pts with unresectable/mUC progressing despite platinum-based chemotherapy, and nivolumab combined with ipilimumab (a CTLA-4 inhibitor) demonstrated acceptable safety and clinical activity. This phase 3 study will evaluate nivolumab + ipilimumab and nivolumab + SOC vs SOC in previously untreated pts with unresectable/mUC (NCT03036098). Methods: Key inclusion criteria: cisplatin-eligible and -ineligible pts with measurable disease, no prior systemic chemotherapy for unresectable/mUC, and evaluable tumor biopsy. Key exclusion criteria: active brain metastases, autoimmune disease, and prior treatment with drugs specifically targeting T-cell co-stimulation or checkpoint pathways. Cisplatin-eligible and -ineligible pts will be randomized 1:1 to arm A (nivolumab 1 mg/kg + ipilimumab 3 mg/kg every 3 weeks up to 4 doses, followed by nivolumab 480 mg every 4 weeks until disease progression or unacceptable toxicity) or arm B (gemcitabine-cisplatin or gemcitabine-carboplatin for up to 6 cycles). Additional cisplatin-eligible pts will be randomized to arm C (nivolumab 360 mg + gemcitabine-cisplatin every 3 weeks for up to 6 cycles, followed by nivolumab 480 mg) or arm D (gemcitabine-cisplatin for up to 6 cycles). Stratification factors: PD-1 ligand 1 status, cisplatin eligibility, and liver metastasis. Co-primary endpoints: overall and progression-free survival (OS and PFS) by blinded independent review committee (BIRC) in cisplatin-ineligible pts receiving nivolumab + ipilimumab vs SOC, and PFS by BIRC in cisplatin-eligible pts receiving nivolumab + SOC vs SOC. Enrollment began March 2017 with a target of 897 pts. Clinical trial information: NCT03036098.
THIRTY-DAY READMISSION AFTER LEFT VENTRICULAR ASSIST DEVICE IN THE UNITED STATES
Authors: Ahmed Almustafa, Fahad Alqahtani, Sami Aljohani, Almoutassim Trabulsi, Mohamad Alkhouli, David Campsey, Marco Caccamo, Christopher Bianco, George Sokos
Journal: Journal of the American College of Cardiology (2018)