tbuckley/cabot-search huggingface dataset:
Allogeneic hematopoietic stem cell transplant overcomes the adverse survival effect of very high risk and unfavorable karyotype in myelofibrosis
Authors: Ayalew Tefferi, Daniel K. Partain, Jeanne M. Palmer, James L. Slack, Vivek Roy, William J. Hogan, Mark L. Litzow, Rhett P. Ketterling, Mrinal M. Patnaik
Journal: American Journal of Hematology (2018)

Abstract The prognostic importance of genetic information in primary myelofibrosis (PMF) was recently highlighted in a study of over 1000 cytogenetically‐annotated patients; 5‐year survival rates were 8% for very high risk (VHR), 27% “unfavorable” and 45% “favorable” karyotype. The current study addresses the practice‐relevant question of whether or not allogeneic hematopoietic stem cell transplant (HCT) can overcome the detrimental survival effect of VHR or unfavorable karyotype. The study included 67 patients with PMF or secondary MF who received HCT at the Mayo Clinic and in whom pretransplant cytogenetic information was available. Dynamic international prognostic scoring system (DIPSS) risk distribution was 13% high, 66% intermediate‐2 and 21% intermediate‐1. Cytogenetic risk distribution was 11% VHR, 34% unfavorable and 55% favorable. At median post‐HCT follow‐up of 60 months for living patients (range 34‐170), 28 (42%) deaths were recorded. Five‐year survival was 62% and was not affected by VHR or unfavorable karyotype ( P = .68). The salutary effect of HCT in patients with VHR or unfavorable karyotype was also apparent during analysis of a combined dataset that included a nontransplant cohort of 383 patients with PMF; multivariable analysis of the combined dataset ( n = 450) resulted in HRs (95% CI) of 2.4 (1.6‐3.6) for absence of transplant, 3.3 (2.2‐4.8) for VHR karyotype, 1.6 (1.2‐2.1) for unfavorable karyotype, 2.9 (2.0‐4.2) for DIPSS high and 1.7 (1.4‐2.2) for DIPSS intermediate‐2. These observations were further confirmed by analysis of more stringently matched case‐control subset cohorts and provide the evidence for the therapeutic preference of HCT in cytogenetically high risk patients with MF.
A survival analysis of a prospective multicenter observational study of surgical palliation in patients treated for malignant gastric outlet obstruction caused by incurable advanced gastric cancer.
Authors: Masanori Terashima, Kazumasa Fujitani, Masahiko Ando, Kentaro Sakamaki, Ryohei Kawabata, Yuichi Ito, Takaki Yoshikawa, Masato Kondo, Yasuhiro Kodera, Masahide Kaji, Yoshio Oka, Hiroshi Imamura, Junji Kawada, Akinori Takagane, Hideaki Shimada, Yutaka Tanizawa, Takeharu Yamanaka, Satoshi Morita, Motoki Ninomiya, Kazuhiro Yoshida
Journal: Journal of Clinical Oncology (2018)

113 Background: We previously reported that surgical palliation maintained patients’ quality of life (QOL) while improving the solid food intake with an acceptable surgical safety in patients with malignant gastric outlet obstruction (GOO) caused by advanced gastric cancer. To elucidate the impact of the improvement in the QOL on the survival, we performed a survival analysis according to the changes in the QOL. Methods: Eligibility criteria included (1) no or liquids-only oral intake, (2) aged ≥20 , (3) surgically fit, (4) ECOG PS of 0-2, and (5) written informed consent. Patients underwent either palliative gastrectomy or gastrojejunostomy. Validated QOL instruments (EORTC QLQ-STO22 and EuroQol-5D) assessed the QOL at baseline, 2 weeks, 1 month, and 3 months following surgical palliation, and postoperative improvement in the oral intake was also evaluated. Univariate and multivariate survival analyses were performed according to baseline characteristics and changes in QOL 2 weeks, 1 month, and 3 months after the operation. Results: The median survival time in the 104 patients was 11.30 months. In the univariate analysis, the survival was significantly better in the patients who received gastrectomy, received adjuvant chemotherapy, had a better PS, and had a worse baseline EQ5D score. Changes in the QOL scores had no marked impact on the survival at 2 weeks and 1 month after operation. However, in patients with an improved or stable EQ5D score at 3 months post-surgery, the survival was significantly better (p = 0.0043). An improved oral intake on the GOO score system (GOOSS) had a positive impact on the survival. A multivariate analysis in the patients survived more than 3 months after the operation revealed that adjuvant chemotherapy, a better baseline PS, a worse baseline EQ5D, an improved or stable EQ5D score, and an improved oral intake on the GOOSS at 3 months after surgical palliation were independent prognostic factors. Conclusions: In patients who received surgical palliation for malignant GOO caused by advanced gastric cancer, an improved oral intake and QOL score at 3 months after operation predicted a good survival. Clinical trial information: 000023494.
T-cell Homing Therapy for Reducing Regulatory T Cells and Preserving Effector T-cell Function in Large Solid Tumors
Authors: Jiemiao Hu, Chuang Sun, Chantale Bernatchez, Xueqing Xia, Patrick Hwu, Gianpietro Dotti, Shulin Li
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Infused autologous tumor-infiltrating lymphocytes (TIL) and tumor-targeted chimeric antigen receptor (CAR) T cells typically surround malignant lesions or penetrate small tumor nodules but fail to penetrate large solid tumors, significantly compromising their antitumor impact. Strategies to overcome this primary challenge are largely required. Experimental Design: We tested the effects of IL12 plus doxorubicin on T-cell penetration and efficacy in solid tumors in a murine lung cancer model, a murine breast carcinoma lung metastasis model, and two human xenograft tumor models bearing large tumors (&amp;gt;10 mm). Results: Intriguingly, this simple approach increased the numbers, the distribution, and the depth of penetration of infused CD8+ T cells in these tumors, including both TILs and CAR T cells. This combined treatment halted tumor progression and significantly extended survival time. Studies of the underlying mechanism revealed multiple effects. First, the combined treatment maintained the high ratios of immune-stimulatory receptors to immune-inhibitory receptors on infiltrated CD8+ T cells, reduced the accumulation of immunosuppressive regulatory T cells, and enhanced the numbers of T-bet+ effector T cells in the tumors. Second, doxorubicin induced chemokines CXCL9 and CXCL10, which may attract NKG2D+CD8+ T cells to tumors, and this effect was boosted by IL12-induced IFNγ accumulation in tumors, promoting the penetration of NKG2D+CD8+ T cells. Conclusions: The deep penetration of infused T cells associated with combined IL12 plus doxorubicin yielded striking therapeutic effects in murine and human xenograft solid tumors. This approach might broaden the application of T-cell therapy to a wider range of solid tumors. Clin Cancer Res; 24(12); 2920–34. ©2018 AACR. See related commentary by Berraondo et al., p. 2716
Applied basic surgical sciences for the IMRCS OSCE course
Authors: Abeyna Jones
Journal: BMJ (2010)

The Intercollegiate Basic Surgical Examinations Committee (representing the three royal colleges of surgeons in the United Kingdom) has recently made a very significant change to the format of the intercollegiate membership of the Royal College of Surgeons (IMRCS) examination. Parts 1 and 2 (applied basic sciences and clinical problem solving), which comprised the written component of the old format, have now been replaced by part A, which is made up of two papers—applied basic sciences and clinical surgery—to be done at the same sitting. The candidate is required to pass both papers individually and at the same sitting.

Part 3 of the old format (comprising three separate components: oral examination followed by the clinicals and communication skills) has been replaced by the new part B objective structured clinical examination (OSCE). Although part 3 of the old MRCS examination is still available for those who have passed their written components under the old system, it is being phased out and will cease altogether in the autumn of 2010.

In conforming to the altered format of the new examination, candidates will need to adopt a different approach when studying and preparing for the part B OSCE exams from that which might have been appropriate to the old part …
I have just come back from work after a day of being bullied. I cannot carry on like this any longer and I feel I need help. Could you suggest anything?
Authors: Dan Saunders
Journal: BMJ (2005)

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>
O009 MIR-146A an important key player in bone metabolism
Authors: V Saferding, M Hofmann, JS Brunner, MF Militaru, A Puchner, S Hayer, M Timmen, R Stange, JS Smolen, S Blüml
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> Micro RNAs (miRNAs) play a crucial role in the regulation of bone metabolism. MiR-146a, an important anti-inflammatory miRNA, was found to negatively impact osteogenesis and bone regeneration <i>in vitro</i>, by controlling the differentiation of mesenchymal stem cells. But to date the role of miR-146a in bone remodelling, its influence on bone stability and development of osteoporosis is not known. <h3>Objectives</h3> The objective of this project is the analysis of the role of miR-146a in bone metabolism. <h3>Methods</h3> Systemic bone, tibiae and femur, of wt and miR-146a deficient animals was assessed histologically and via µCT analysis, over a period of 3 to 18 months of age. Serum cytokine levels were analysed by Elisa. MRNA expression levels in bone were analysed by qPCR. To induce osteoporosis, ovariectomy (OVX) induced bone loss was performed. <h3>Results</h3> When we analysed bone volume of long bones histologically as well as with µCT analysis we detected significantly increased trabecular bone mass in miR-146a deficient compared to wt animals, starting at an age of 6 months. However, cortical thickness of systemic bones from miR-146a knock out animals was significantly reduced compared to control mice. Analysis of serum in aged miR-146a deficient animals displayed elevated activity of bone resorbing osteoclasts as amounts of CTX I in miR-146a<sup>-/-</sup> mice were significantly increased compared to wt animals. Q-PCR analysis of important osteoclast as well as osteoblast marker genes in bones <i>ex vivo</i> displayed elevated expression of signature molecules of both cell types in aged miR-146a deficient mice, suggesting a regulatory role of miR-146a in both osteoclasts as well as osteoblasts. When we induced osteoporosis using the OVX disease model, histological analysis of long bones showed significant trabecular bone loss in ovariectomized wt mice. In contrast, we detected no trabecular bone loss in ovariectomized miR-146a knock out animals, suggesting that loss of miR-146a deficiency protects bone loss induced by oestrogen deficiency. <h3>Conclusions</h3> MiR-146a seems to control bone turnover and miR-146a deficient mice accrue bone over time. Moreover this miRNA has a negative influence on bone loss occurring during oestrogen loss induced osteoporosis. Therefore miR-146a could be possibly used as a therapeutic target in the treatment of osteoporosis. <h3>Disclosure of interest</h3> None declared
Doctors must stop stigmatising mental health, says BMA
Authors: Abi Rimmer
Journal: BMJ (2017)

The BMA will create a national campaign to eliminate mental health stigma among doctors, after a vote at its annual representative meeting.

On 28 June delegates at the meeting in Bournemouth voted in favour of the motion, which also stated that parity between physical and mental health would be achieved only if “the stigma against mental health problems among medical professionals is addressed.”

Ryan …
Long Non-coding MIR205HG Depletes Hsa-miR-590-3p Leading to Unrestrained Proliferation in Head and Neck Squamous Cell Carcinoma
Authors: Silvia Di Agostino, Fabio Valenti, Andrea Sacconi, Giulia Fontemaggi, Matteo Pallocca, Claudio Pulito, Federica Ganci, Paola Muti, Sabrina Strano, Giovanni Blandino
Journal: Theranostics (2018)

Over 70% of head & neck squamous cell carcinoma (HNSCC) patients carry TP53 oncogenic mutations.Here we studied the role of specific tumor-derived mutant p53 proteins in the aberrant transcription of long non-coding (lnc) MIR205HG gene in head and neck cancer cells.Methods: To understand the role of lncMIR205HG, that we showed to be transcriptionally regulated by mutant p53 in HNSCC, we have employed siRNA and shRNA in CAL27 and FaDu HNSCC cell lines to suppress p53 gene expression in ChIP assays and RT-qPCR.We validated our findings in a cohort of 522 HNSCC patients from The Cancer Genome Atlas Data Portal (TCGA).We further evaluated our results in 63 HNSCC tumor samples collected at our institute, 32 of which were characterized by mutated TP53 (missense mutations) while 31 were characterized by wild-type TP53.Results: Maturation of pre-MIR205HG transcript produces two non-coding RNAs, lncMIR205HG and hsa-miR-205-5p.Down-regulation of lncMIR205HG expression significantly reduced cell proliferation, cell migration and clonogenic activity of head and neck cancer cells.Expression of MIR205HG was significantly increased in HNSCC with mutated TP53 when compared with matched non-tumoral tissues.Furthermore, MIR205HG expression levels were significantly higher in tumoral samples with mutant p53 than in tumoral tissues expressing wild-type p53.Mechanistically, MIR205HG depletes endogenous miR-590-3p leading to increased cyclin B, cdk1, and YAP protein expression.Conclusions: Taken together, these findings identify a transcriptional and post-transcriptional molecular network that includes mutant p53 protein, lncMIR205HG, YAP, and other proliferation-related genes, which are enriched in HNSCC patients with poor prognosis.
Adoption of Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer
Authors: Andrea Cercek, Campbell S.D. Roxburgh, Paul Strombom, J. Joshua Smith, Larissa K.F. Temple, Garrett M. Nash, Jose G. Guillem, Philip B. Paty, Rona Yaeger, Zsofia K. Stadler, Kenneth Seier, Mithat Gonen, Neil H. Segal, Diane L. Reidy, Anna Varghese, Jinru Shia, Efsevia Vakiani, Abraham J. Wu, Christopher H. Crane, Marc J. Gollub, Julio Garcia-Aguilar, Leonard B. Saltz, Martin R. Weiser
Journal: JAMA Oncology (2018)

<h3>Importance</h3> Treatment of locally advanced rectal (LARC) cancer involves chemoradiation, surgery, and chemotherapy. The concept of total neoadjuvant therapy (TNT), in which chemoradiation and chemotherapy are administered prior to surgery, has been developed to optimize delivery of effective systemic therapy aimed at micrometastases. <h3>Objective</h3> To compare the traditional approach of preoperative chemoradiation (chemoRT) followed by postoperative adjuvant chemotherapy with the more recent TNT approach for LARC. <h3>Design, Setting, and Participants</h3> A retrospective cohort analysis using Memorial Sloan Kettering Cancer Center (MSK) records from 2009 to 2015 was carried out. A total of 811 patients who presented with LARC (T3/4 or node-positive) were identified. <h3>Exposures</h3> Of the 811 patients, 320 received chemoRT with planned adjuvant chemotherapy and 308 received TNT (induction fluorouracil- and oxaliplatin-based chemotherapy followed by chemoRT). <h3>Main Outcomes and Measures</h3> Treatment and outcome data for the 2 cohorts were compared. Dosing and completion of prescribed chemotherapy were assessed on the subset of patients who received all therapy at MSK. <h3>Results</h3> Of the 628 patients overall, 373 (59%) were men and 255 (41%) were women, with a mean (SD) age of 56.7 (12.9) years. Of the 308 patients in the TNT cohort, 181 (49%) were men and 127 (49%) were women. Of the 320 patients in the chemoRT with planned adjuvant chemotherapy cohort, 192 (60%) were men and 128 (40%) were women. Patients in the TNT cohort received greater percentages of the planned oxaliplatin and fluorouracil prescribed dose than those in the chemoRT with planned adjuvant chemotherapy cohort. The complete response (CR) rate, including both pathologic CR (pCR) in those who underwent surgery and sustained clinical CR (cCR) for at least 12 months posttreatment in those who did not undergo surgery, was 36% in the TNT cohort compared with 21% in the chemoRT with planned adjuvant chemotherapy cohort. <h3>Conclusions and Relevance</h3> Our findings provide additional support for the National Comprehensive Cancer Network (NCCN) guidelines that categorize TNT as a viable treatment strategy for rectal cancer. Our data suggest that TNT facilitates delivery of planned systemic therapy. Long-term follow-up will determine if this finding translates into improved survival. In addition, given its high CR rate, TNT may facilitate nonoperative treatment strategies aimed at organ preservation.
RIGHT HEART MALADAPTIVE PHENOTYPES AND PREDICTION OF RIGHT HEART FAILURE FOLLOWING CONTINUOUS-FLOW LEFT VENTRICULAR ASSIST DEVICE IMPLANTATION
Authors: Marie Aymami, Francois Haddad, Myriam Amsallem, Matthew Wheeler, Kegan Moneghetti, Jackson Adams, Jean-Philippe Verhoye, Karim Sallam, Y. Woo, Richard-Tien Ha, Dipanjan Banerjee
Journal: Journal of the American College of Cardiology (2018)
Emerging value of multigene panels for germline testing in patients with neuroendocrine tumors.
Authors: Julia Whitman, Brandon Shih, Amie Blanco, Salina Chan, Alan Paciorek, Jacqueline Desjardin, Mallika Sachdev Dhawan, Li Zhang, Emily Bergsland
Journal: Journal of Clinical Oncology (2018)

226 Background: Neuroendocrine tumors (NETs) are known to be associated with hereditary syndromes stemming from MEN1, VHL, SDH or TSC mutations. Recent data suggest that additional germline mutations may be relevant, implying a role of germline testing with multigene panels. We examined genetic counseling (GC) referral and testing patterns, test results, and their changes over time in NET patients (pts). Methods: Retrospective chart review was conducted in 236 NET pts referred to UCSF Cancer Genetics and Prevention Program 2004-2017. Univariate logistic models were used to assess relationship between binary outcome and covariate. STATA was used for analysis and statistical significance was based on p &lt; 0.05. Results: 139 referred pts (59%) followed up with GC. Pts with &gt;1 family members diagnosed with cancer were more likely to attend GC [OR=2.75, p=0.010]. Among 107 pts tested, small bowel NETs were less associated with testing than pancreatic NETs [OR=0.15, p=0.001]. Single-gene tests were routine until 2015, when panels up to 130 genes became standard. Overall, 31 pts (29% of 107 tested) had a pathogenic/likely pathogenic (P/LP) result. There was no significant difference between single and multi-gene tests in identifying P/LP mutations (likely due to changes in threshold for testing over time), but greater diversity in P/LP mutations was noted with larger panels. Functional tumors showed lower rate of P/LP mutations than non-functional [OR=0.17, p=0.037]. Conclusions: Only 59% of referred pts followed up with GC, suggesting significant barriers to testing exist. Of those tested, 29% harbored a P/LP mutation. Germline mutations not traditionally associated with NETs were identified, highlighting the potential importance of larger panels to detect rare mutations. [Table: see text]
Cancer-associated fibroblasts enhance tumor <sup>18</sup>F-FDG uptake and contribute to the intratumor heterogeneity of PET-CT
Authors: Chengfang Shangguan, Guifang Gan, Jieying Zhang, Jinliang Wu, Ying Miao, Miao Zhang, Biao Li, Jun Mi
Journal: Theranostics (2018)

Purpose: Elevated glucose uptake is a hallmark of cancer.Fluorodeoxyglucose (FDG) uptake was believed to indicate the aggressiveness of tumors and the standardized uptake value (SUV) is a well-known measurement for FDG uptake in positron emission tomography-computed tomography (PET/CT).However, the SUV is variable due to the heterogeneity of tumors.Methods: 126 patients with colorectal cancer underwent 18 F-FDG PET/CT scanning before surgery between Jan 2011 and April 2016.Cancer-associated fibroblast (CAF) densities were calculated with the inForm Advanced image analysis software and were comparatively analyzed between patients with high and low maximum SUV (SUVmax-high and SUVmax-low).Glucose uptake was evaluated in induced and isolated CAFs and CAF-cocultured colon cancer HCT116 cells.Moreover, micro-PET/CT was performed on xenografted tumors and autoradiography was performed in the AOM/DSS induced colon cancer model.Results: CAFs were glycolytic, evidenced by glucose uptake and upregulated HK2 expression.Compared to non-activated fibroblasts (NAFs), CAFs were more dependent on glucose and sensitive to a glycolysis inhibitor.CAFs increased the SUVmax in xenograft tumors and spontaneous colon cancers.Moreover, multivariate analysis revealed that the SUVmax was only associated with tumor size among conventional parameters in colon cancer patients (126 cases, p = 0.009).Besides tumor size, the CAF density was the critical factor associated with SUVmax and outcome, which was 2.27 ± 0.74 and 1.68 ± 0.45 in the SUVmax-high and the SUVmax-low groups, respectively (p = 0.014).Conclusion: CAFs promote tumor progression and increase SUVmax of 18 F-FDG, suggesting CAFs lead to the intratumor heterogeneity of the SUV and the SUVmax is a prognostic marker for cancer patients.
Junior doctors must have say in changes to training, says BMA
Authors: Abi Rimmer
Journal: BMJ (2014)

Junior doctors must have a say in any reorganisation of training, the co-chairs of the BMA’s Junior Doctors Committee have said.

Speaking at the BMA Junior Doctors Conference on Saturday, co-chairs Kitty Mohan and Andrew Collier warned against the training reforms proposed by David Greenaway’s Shape of Training review.1

Mohan said, “We must also ensure that the concerns of junior doctors are not …
Interindividual Differences in Caffeine Metabolism and Factors Driving Caffeine Consumption
Authors: Astrid Nehlig
Journal: Pharmacological Reviews (2018)

Most individuals adjust their caffeine intake according to the objective and subjective effects induced by the methylxanthine. However, to reach the desired effects, the quantity of caffeine consumed varies largely among individuals. It has been known for decades that the metabolism, clearance, and pharmacokinetics of caffeine is affected by many factors such as age, sex and hormones, liver disease, obesity, smoking, and diet. Caffeine also interacts with many medications. All these factors will be reviewed in the present document and discussed in light of the most recent data concerning the genetic variability affecting caffeine levels and effects at the pharmacokinetic and pharmacodynamic levels that both critically drive the level of caffeine consumption. The pharmacokinetics of caffeine are highly variable among individuals due to a polymorphism at the level of the CYP1A2 isoform of cytochrome P450, which metabolizes 95% of the caffeine ingested. Moreover there is a polymorphism at the level of another critical enzyme, <i>N</i>-acetyltransferase 2. At the pharmacodynamic level, there are several polymorphisms at the main brain target of caffeine, the adenosine A2A receptor or ADORA2. Genetic studies, including genome-wide association studies, identified several loci critically involved in caffeine consumption and its consequences on sleep, anxiety, and potentially in neurodegenerative and psychiatric diseases. We start reaching a better picture on how a multiplicity of biologic mechanisms seems to drive the levels of caffeine consumption, although much more knowledge is still required to understand caffeine consumption and effects on body functions.