tbuckley/cabot-search huggingface dataset:
Homologous repair deficiency in <i>VHL</i>-mutated clear cell renal cell carcinoma.
Authors: Patrick Glen Pilie, Lijun Zhou, Christine B Peterson, Yang Peng, Guang Peng, Eric Jonasch
Journal: Journal of Clinical Oncology (2018)

585 Background: Clear cell renal cell carcinoma (ccRCC) displays genomic instability across all tumor stages, indicative of increased replicative stress and defects in DNA damage response (DDR) pathways including homologous repair (HR); however ccRCC does not display mutations in canonical DDR genes and advanced ccRCC is not traditionally sensitive to DNA damaging agents. We hypothesized that biallelic VHL loss is sufficient to cause HR deficiency (HRD) and that early stage ccRCC is more likely to display HRD than late stage disease. Methods: We performed whole-exome (WES) sequencing of 15 small ccRCC tumors to assess for mutational burden, mutational signature, and cancer-related driver gene mutations. We performed in silico genomic, transcriptomic, and proteomic analysis of tumors in KIRC TCGA to assess for HRD. Finally, we assessed HR efficiency as a product of biallelic VHL loss in engineered cell line models. Results: 15/15 early stage ccRCC had VHL mutations, approximately 100 additional mutations per tumor, but no common mutations found in KIRC TCGA. In silico analysis showed 67% of KIRC TCGA displayed HRD gene signature, and was significantly higher in stage I disease (p = 2.21e-08). Patients with VHL-mutated tumors are more commonly HRD than HR intact (HRI) (p = 0.03), with frameshift/nonsense variants in VHL more likely to result in HRD than missense variants (p = 0.02). Multivariate analysis showed HRD predicted for better overall survival compared to HRI (p &lt; 0.0001). Proteomic analysis of KIRC TCGA revealed HRI samples had significantly higher protein expression of Rad51 and RAPTOR when compared to HRD samples. Lastly, etoposide-treated MEF Vhl -/- cell lines displayed reduced HR efficiency when compared to Vhl intact controls. Conclusions: Biallelic loss of VHL is sufficient to cause HRD. HRD gene signature predicts for significantly better OS in ccRCC patients, and early stage ccRCC is more likely to be HRD. mTOR/PI3K signaling pathway proteins are differentially expressed in HRI patient samples from TCGA compared to HRD, suggesting a possible role for these oncogenes driving a HRI phenotype. Treatment strategies combining PARP inhibitors with PI3K/mTOR inhibitors should be tested in advanced VHL-mutated ccRCC.
Environmental allergens induce allergic inflammation through proteolytic maturation of IL-33
Authors: Corinne Cayrol, Anais Duval, Pauline Schmitt, Stephane Roga, Mylène Camus, Alexandre Stella, Odile Burlet-Schiltz, Anne Gonzalez-de-Peredo, Jean-Philippe Girard
Journal: Nature Immunology (2018)
Medical training should be more flexible, recommends Future Forum
Authors: Helen Jaques
Journal: BMJ (2012)

The medical training pathway needs to be more flexible to allow junior doctors to switch specialties during training, develop their skills by working in other disciplines, and take up academic fellowships or international posts, the NHS Future Forum has said in its report on education and training. 

The forum also recommends that properly constructed jobs with educational opportunities should be made available for doctors who do not wish to take up consultant or general practitioner posts on receiving their certificate of completion of training, something the BMA has warned could lead to a “subconsultant” grade.

On the topic of general practice, the Future Forum suggests that generalism should be fostered as a career choice for doctors and …
Bioactive polydimethylsiloxane surface for optimal human mesenchymal stem cell sheet culture
Authors: Zichen Qian, David Ross, Wenkai Jia, Qi Xing, Feng Zhao
Journal: Bioactive Materials (2018)

Human mesenchymal stem cell (hMSC) sheets hold great potential in engineering three-dimensional (3D) completely biological tissues for diverse applications. Conventional cell sheet culturing methods employing thermoresponsive surfaces are cost ineffective, and rely heavily on available facilities. In this study, a cost-effective method of layer-by-layer grafting was utilized for covalently binding a homogenous collagen I layer on a commonly used polydimethylsiloxane (PDMS) substrate surface in order to improve its cell adhesion as well as the uniformity of the resulting hMSC cell sheet. Results showed that a homogenous collagen I layer was obtained via this grafting method, which improved hMSC adhesion and attachment through reliable collagen I binding sites. By utilizing this low-cost method, a uniform hMSC sheet was generated. This technology potentially allows for mass production of hMSC sheets to fulfill the demand of thick hMSC constructs for tissue engineering and biomanufacturing applications.
CHRONIC OBSTRUCTIVE PULMONARY DISEASE IS ASSOCIATED WITH WORSE MORTALITY, INCREASED LENGTH OF STAY AND INCREASED HOSPITAL COSTS IN PATIENTS WITH ATRIAL FIBRILLATION: A NATIONWIDE STUDY
Authors: Shawn Lee, Farid Gholitabar, May Bakir, Syed Ahsan, Seyed Hamed Hosseini Dehkordi, Carlos Gongora, Alejandro Lemor, Davendra Mehta
Journal: Journal of the American College of Cardiology (2018)
Effect of the tumor-shed antigen CA125 on humoral immune responses of IgG1, IgG3, and IgM-type antibodies.
Authors: J Bradford Kline
Journal: Journal of Clinical Oncology (2018)

15 Background: Human cancers employ a number of mechanisms to evade host immune responses. Here we report the effects of CA125 on suppressing humoral immune responses of naturally occurring and therapeutic antibodies (Abs). These data stem from prespecified subgroup analysis of a Ph3 trial testing farletuzumab, a monoclonal Ab (mAb) to folate receptor alpha, plus standard-of-care carboplatin-taxane (CT) chemotherapy in patients with recurrent platinum-sensitive ovarian cancer. Patients with low CA125 serum levels treated with farletuzumab plus CT demonstrated improvements in PFS (HR 0.49, p = 0.0028) and OS (HR 0.44, p = 0.0108) compared to placebo plus CT. Farletuzumab utilizes Ab-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) with the aim to kill target bound tumor cells. These functions were analyzed in patient samples to determine if CA125 negatively impacts mAb-mediated humoral responses. Methods: Molecular and cell based assays tested the effects of CA125 on humoral immune activity mediated by mAbs on ovarian cancer patient serum samples. Results: Here we show that CA125 inhibits ADCC and CDC by directly binding to a subset of mAbs and perturbing engagement with Fc-γ activating receptors CD16a and CD32a and the C1q complement initiating protein. The effects occur via CA125 binding to the mAb variable domain, which alters the structure of the CH2 motif leading to suppressed binding by CD16a/CD32a and C1q. The lack of inhibition by the high affinity CD64a Fc-γ receptor as well as lack of FcRn inhibition suggests a conformational change occurs within the CH2 motif that perturbs the binding of low affinity CD16a, CD32a and C1q proteins. The effect appears to involve a subset of Abs composed of IgG1, IgG3 and IgM isotypes. Conclusions: CA125 has an immunosuppressive effect on Ab-mediated humor immunity in a subset of tested Abs of varied isotypes including IgG1, IgG3, and IgM. The effects have implications in monitoring therapeutic mAbs that may be negatively affected by CA125 binding as well as potential implications for identifying patients who may be at risk for developing certain types of cancer, including ovarian.
Sarcomatoid renal cell carcinoma: Does stage impact survival?
Authors: Kyle A Blum, Renzo DiNatale, Alejandro Sanchez, Nirmal T John, Eden Axler, Mazyar Ghanaat, Mahyar Kashan, Maria Becerra, Paul Russo, Jonathan Coleman, Satish Tickoo, A. Ari Hakimi
Journal: Journal of Clinical Oncology (2018)

693 Background: Sarcomatoid differentiation is associated with poor clinical outcomes and is present in approximately 4% of patients with renal cell carcinoma (sRCC). However, limited studies have evaluated the impact of sarcomatoid differentiation among patients, especially with lower stage pT1−2 disease. Methods: This study evaluated 3,850 patients with RCC who underwent partial or radical nephrectomy between 2000−2017. Patients were divided into four groups for analysis: pT1−2NxMx RCC without sarcomatoid features, pT1−2NxMx sRCC, pT3−4 RCC without sarcomatoid features and pT3−4 sRCC. Clinicopathological outcomes including sex, race, age, primary histology, lymph node involvement and margin status were compared between groups using Chi−squared and T-tests. Overall survival rates were analyzed by constructing Kaplan−Meier curves, p−values were calculated using log−rank tests and fitting Cox proportional hazards models for adjusted analyses. Results: Among 3,850 cases, 168 (4.4%) sRCC patients were identified. Of these, 33 (19.6%) were pT1−2. The mean overall follow up time was 59.9 months. When comparing CSS between groups, survival was poorer in patients with sarcomatoid features regardless of pT stage (p &lt; 0.0001). Of note, CSS was worse in sRCC pT1−2 patients compared to non−sarcomatoid pT3−4 patients. Overall survival (OS) results were similar, with sarcomatoid tumors having worse estimates on survival analysis (p &lt; 0.0001). Conclusions: Patients with pT1−2 sRCC demonstrated worse CSS when compared to pT1-2 and pT3−T4 RCC without sarcomatoid features, regardless of primary histology. Sarcomatoid differentiation in low−stage disease may be a marker of poor oncologic outcomes requiring more vigilant surveillance and possible inclusion in adjuvant therapy trials. Our next step, which is currently ongoing, is to pursue a multi−institutional collaborative effort and establish a larger cohort of sRCC for analysis.
Only one in 10 CCGs in latest wave have been authorised without conditions
Authors: Helen Jaques
Journal: BMJ (2013)

Only six of the 62 clinical commissioning groups in the third wave of authorisation by the NHS Commissioning Board have been signed off without any conditions.

Fifty one CCGs have been authorised with conditions, having failed to meet all 119 criteria in the six domains for authorisation set out by the board. A further five—Eastbourne, Hailsham and Seaford; Newham; …
CARDIO-ANKLE VASCULAR INDEX AS A PREDICTOR OF CARDIOVASCULAR EVENTS AND ALL-CAUSE MORTALITY IN METABOLIC SYNDROME PATIENTS
Authors: Thosaphol Limpijankit, Prin Vathesatogkit, Dujrudee Matchariyakul, Teerapat Yingchoncharoen, Hathaichon Boonhat, Piyamitr Sritara
Journal: Journal of the American College of Cardiology (2018)
Number of “subconsultant” posts has almost quadrupled in four years
Authors: Caroline White
Journal: BMJ (2012)

The number of “subconsultant” posts being advertised and accepted has almost quadrupled over the past four years in England, suggests a workforce survey from the Royal College of Physicians.

The fourth annual rolling survey of holders of the Certificate of Completion of Training (CCT), which this year had a 50% response rate among the 441 doctors contacted, shows that the proportion of newly qualified consultants gaining substantive posts rose by more than 6% to reach 62% in 2012.

But the overall number of those obtaining these posts was lower than that of previous years, with an increase in the average number of job applications matched by a concomitant fall in the offers of consultant posts across all specialties.

The highest rejection …
What are the questions usually asked in interviews for senior house officer jobs?
Authors: Trevor Pickersgill
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>
Prognostic Role of p16 in Nonoropharyngeal Head and Neck Cancer
Authors: Alex K Bryant, Elena J Sojourner, Lucas K Vitzthum, Kaveh Zakeri, Hanjie Shen, Cammie Nguyen, James D Murphy, Joseph A Califano, Ezra E W Cohen, Loren K Mell
Journal: JNCI Journal of the National Cancer Institute (2018)

Previous studies have reported conflicting information regarding the prognostic role of p16 in nonoropharyngeal head and neck squamous cell carcinoma (HNSCC). Using the US Veterans Affairs database, we analyzed 1448 patients with locoregionally advanced HNSCC and known p16 status diagnosed between 2005 and 2015 and treated with surgery, radiotherapy, or chemoradiotherapy. Tumor p16 status was determined through manual review of pathology reports of primary tumor specimens. Oropharyngeal (n = 1061) or nonoropharyngeal (n = 387; hypopharyngeal, laryngeal, or oral cavity) tumor site was determined from tumor registry data and manually reviewed for accuracy. We used multivariable Cox regression to analyze the effect of p16 status on overall survival (OS), cancer-specific survival (CSS), and competing mortality (CM) for oropharyngeal or nonoropharyngeal tumor sites. All statistical tests were two-sided. In multivariable models adjusting for treatment, stage, age, comorbidity, and body mass index, patients with p16-positive tumors had improved OS, CSS, and CM compared with patients with p16-negative tumors in both oropharyngeal (OS: hazard ratio [HR] = 0.53, 95% confidence interval [CI] = 0.40 to 0.71, P < .001; CSS: HR = 0.50, 95% CI = 0.35 to 0.73, P < .001; CM: HR = 0.59, 95% CI = 0.38 to 0.93, P = .02) and nonoropharyngeal primary sites (OS: HR = 0.41, 95% CI = 0.25 to 0.69, P < .001; CSS: HR = 0.37, 95% CI = 0.18 to 0.77, P = .008; CM: HR = 0.46, 95% CI = 0.23 to 0.95, P = .04). The prognostic impact of p16 status did not statistically significantly differ by primary tumor site for OS, CSS, or CM (Pinteraction > .05). Our findings support the hypothesis that p16 has a similar prognostic role in both nonoropharyngeal and oropharyngeal cancer. Consideration should be given to increased testing for p16 in laryngeal, hypopharyngeal, and oral cavity primaries.
Clinical implementation of a comprehensive targeted amplicon sequencing system for the patients with gastrointestinal cancer as a real world evidence in Japan.
Authors: Hideyuki Hayashi, Shigeki Tanishima, Ryo Mori, Yasunobu Okamura, Emmy Yanagita, Ryosuke Matsuoka, Toraji Amano, Ichiro Kinoshita, Yoshito Komatsu, Hirotoshi Akita, Hiroshi Nishihara
Journal: Journal of Clinical Oncology (2018)

329 Background: Clinical implementation of genome sequencing is recently prevailing in the treatment for cancer. We have launched an in-house clinical sequencing system to perform exhaustive targeted exome sequencing for patients with all types of cancer, as an outpatient service. We have analyzed the clinical utility of this system for patients with gastrointestinal cancer to elucidate real world evidence. Methods: Genomic DNA was extracted from tumor tissues and peripheral blood sera of 86 patients with different types of gastrointestinal cancer, from April 2016 to April 2017. The top five types of primary cancer were colorectal (34%), pancreas (28%), stomach (13%), biliary tract (12%), and esophagus (8%). We performed a targeted amplicon exome sequencing for 160 cancer-related genes. The sequencing data was analyzed using an original bioinformatics pipeline within three days, and we identified cancer-specific somatic gene alterations such as SNV (Single Nucleotide Variation), Ins (Insertion)/Del (Deletion), and CNV (Copy Number Variation). The primary endpoints were the detection rates of potential actionable and druggable genes. The secondary endpoints were the detection rates of incidental germline variants and the period from initial visit to elucidation of the results to the patients. Results: Actionable and druggable gene alterations were detected in 97% (83/86) and 65% (56/86) of the subjects, respectively. Actionable gene alterations were frequently detected in TP53 (64/86), KRAS (38/86), APC (25/86), ARID1A (11/86), and FBXW7 (10/86). Druggable gene alterations were detected in ARID1A (11/86), and FBXW7 (10/86), BRAF (7/86), BRCA1/2 (6/86), and EGFR (4/86). Incidental germline variants were detected only in 6% (5/86) of all the patients. The median period of examination was 30 days (10-78 days). Seven out of the 86 patients (8%) were treated with therapeutic agents, based on the results of our clinical sequencing. Conclusions: Our clinical sequencing system provided a large number of cancer patients with clinically valuable genomic information available in selecting anticancer drugs within about a month.
Quality of Life During Treatment With Chemohormonal Therapy: Analysis of E3805 Chemohormonal Androgen Ablation Randomized Trial in Prostate Cancer
Authors: Alicia K. Morgans, Yu-Hui Chen, Christopher J. Sweeney, David F. Jarrard, Elizabeth R. Plimack, Benjamin A. Gartrell, Michael A. Carducci, Maha Hussain, Jorge A. Garcia, David Cella, Robert S. DiPaola, Linda J. Patrick-Miller
Journal: Journal of Clinical Oncology (2018)

Purpose Chemohormonal therapy with docetaxel and androgen deprivation therapy (ADT+D) for metastatic hormone-sensitive prostate cancer improves overall survival as compared with androgen deprivation therapy (ADT) alone. We compared the quality of life (QOL) between patients with metastatic hormone-sensitive prostate cancer who were treated with ADT+D and those who were treated with ADT alone. Methods Men were randomly assigned to ADT+ D (six cycles) or to ADT alone. QOL was assessed by Functional Assessment of Cancer Therapy-Prostate (FACT-P), FACT-Taxane, Functional Assessment of Chronic Illness Therapy-Fatigue, and the Brief Pain Inventory at baseline and at 3, 6, 9, and 12 months. The Wilcoxon signed rank test was used to examine changes over time. Mixed-effect models compared the QOL between arms at each time point. Results Seven hundred ninety men were randomly assigned (ADT+D [n = 397] and ADT[ n = 393]) and completed FACT-P (90% at baseline, 86% at 3 months, 83% at 6 months, 78% at 9 months, and 77% at 12 months). ADT+D patients reported a statistically significant decline in FACT-P at 3 months ( P < .001) but FACT-P did not differ significantly between baseline and 12 months ( P = .38). ADT+D FACT-P scores were significantly lower at 3 months ( P = .02) but significantly higher at 12 months ( P = .04) when compared with ADT FACT-P scores. Differences did not exceed the minimal clinically important difference at any time point. ADT+D patients reported significantly lower Functional Assessment of Chronic Illness Therapy-Fatigue scores at 3 months than did ADT patients ( P < .001). Over time, both arms reported significantly poorer FACT-Taxane scores ( P < .001) when compared with baseline. Brief Pain Inventory scores were similar between arms. Conclusion Although ADT+D was associated with statistically worse QOL at 3 months, QOL was better at 12 months for ADT+D patients than for ADT patients. Both arms reported a similar minimally changed QOL over time, suggesting that ADT+D is not associated with a greater long-term negative impact on QOL.
Shingles Occurs in Only 0.5% of Myeloma Patients on Any Dose of Antiviral Prophylaxis
Authors: Jacqueline Chu, Syed Basir Hussaini, Nidhi Sharma, Nita Williams, Don M Benson, Ashley E Rosko, Yvonne A Efebera, Craig C Hofmeister
Journal: Blood (2017)
VinCaP: A phase II trial of vinflunine chemotherapy in locally-advanced and metastatic carcinoma of the penis (CRUK/12/021).
Authors: Lisa M. Pickering, Holly Tovey, Tony Elliott, Stephanie M. Burnett, Amit Bahl, Peter Kirkbride, Anita Mitra, Alastair H Thomson, Naveen Vasudev, Rachel Slade, Lucy Tregellas, Bruno Morgan, Alison Hassall, Emma Hall, Steve Nicholson
Journal: Journal of Clinical Oncology (2018)

547 Background: Platinum-based combination chemotherapy regimens are used in the treatment of carcinoma of the penis, but toxicity limits their value for patients with metastatic disease. This trial aims to define both the toxicity and the rate of disease control for the non-platinum cytotoxic agent Vinflunine. Methods: A phase II single-arm trial was designed to demonstrate a clinical benefit rate of at least 40% and to exclude a rate of less than 15% (p0 = 0.15, p1 = 0.40, α = 0.05, β = 0.80, Fleming-A’hern exact design). 22 evaluable patients were required. Key eligibility criteria included measurable, histologically-proven squamous cell carcinoma of the penis staged as M1; or M0, Tx, N3; or M0, Tx, N2 and deemed inoperable by multidisciplinary team; or M0, T4 any N. Patients were required to have ECOG performance status of 0, 1 or 2 and adequate hepatic and renal function. Treatment comprised four 21-day cycles of vinflunine (320mg/m 2 ) with RECIST v1.1 restaging following cycle 4 (response primary endpoint). Patients deemed to be benefitting from treatment were permitted to continue vinflunine at the discretion of the treating clinician until progression or unacceptable toxicity. Results: 25 patients were recruited from 8 UK centres between June 2014 and May 2017. Median age was 68 years; 19 patients had metastatic (M1) disease. All patients have completed trial treatment and primary endpoint assessment. Data cleaning for the primary analysis is currently in progress, with the snapshot for the primary analysis due in October 2017 and primary analysis to be presented to the trial oversight committees in November 2017. Conclusions: It is hoped that single-agent vinflunine will be associated with a favourable toxicity profile combined with meaningful clinical responses. The results will be available for presentation at the meeting. Clinical trial information: NCT02057913.
Bevacizumab for progressive glioblastoma multiforme: a case of treading the tightrope
Authors: Paulina Majewska, Krishnaswamy Madhavan, George Sioftanos
Journal: Neuro-Oncology (2018)

Until March 2013, Bevacizumab had been funded through the National Cancer Drugs Fund (CDF) for the treatment of recurrent/progressive Glioblastoma multiforme (GBM). Although the CDF concluded at the time that there was insufficient evidence around the effectiveness of the Bevacizumab on overall survival and quality of life, there is evidence that a small number of individual patients may significantly benefit from it. We present a case of a 40-year old man with GBM (IDH-1 wild-type, MGMT <10% methylated) who, following surgical debulking, was treated as per the Stupp regime. 2 months after completing adjuvant Temozolamide, he developed clinical and radiological progression. He was commenced on Bevacizumab and Irinotecan, which at the time was funded through the CDF. Following 4 cycles of treatment, his symptoms resolved, and at minimum, good partial radiological response was achieved. After 34 cycles the Irinotecan was stopped due to debilitating diarrhoea. After 44 cycles, the Bevacizumab was suspended for 4 weeks because the patient developed a perianal abscess and fistula, which were treated surgically with incision, drainage, and Seton insertion. At this point, discussions with the patient regarding stopping Bevacizumab were held, and his choice was to continue despite the risks. To date (March 2017) he has received 101 cycles of Bevacizumab, equating to 4 years of treatment, with no evidence of radiological or clinical progression. He has developed mild hypertension, for which he has declined antihypertensive treatment. His perianal fistula has completely healed. To our knowledge, this patient is one of the longest survivors on Bevacizumab given at progression. This case has posed, and still poses, important questions in relation to patient choice and risk-benefit conversations; in particular relating to the potential risks of protracted treatment vs its benefit, and the possibility of “drug holidays”.