tbuckley/cabot-search huggingface dataset:
SARC023: Phase I/II trial of ganetespib in combination with sirolimus for refractory sarcomas and malignant peripheral nerve sheath tumors (MPNST).
Authors: AeRang Kim, Denise K. Reinke, Karen Cichowski, John Peter Perentesis, Pamela Wolters, Staci Martin, Eva Dombi, Seth M. Steinberg, Brigitte C. Widemann
Journal: Journal of Clinical Oncology (2014)

TPS10603 Background: Combination treatments of Hsp90 inhibitors with the mTOR inhibitor rapamycin produce dramatic tumor shrinkage in a genetically engineered MPNST mouse model of human MPNST (DeRaedt et al. Cancer Cell 2011). Previously, targeted agents have not resulted in substantial tumor regression in these models. Ganetespib is a potent small molecule inhibitor of Hsp90 that enhances endoplasmic reticulum stress with a favorable safety profile and promising activity in a variety of cancers. Sirolimus is a commercially available mTOR inhibitor, which has been tolerated in combination with multiple cytotoxic and targeted agents. These agents have also demonstrated activity in a variety of pre-clinical bone and soft tissue sarcoma models. Methods: SARC023 is a multi-institutional SARC sponsored, Department of Defense funded open label phase I/II trial of ganetespib in combination with sirolimus in patients with refractory sarcoma including MPNST (NCT02008877). The primary objective of the phase I component is to determine the safety, tolerability, and recommended dose of this combination. Eligibility includes individuals ≥ 18 years of age with unresectable or metastatic MPNST who have progressed after ≥1 prior regimens of chemotherapy. The Phase I component is also open to patients with other refractory or relapsed sarcomas. Ganetespib is administered intravenously over one hour on days 1, 8, and 15 every 28 days. Sirolimus is administered orally once daily continuously (28 days = 1 cycle). Patients receive treatment until disease progression or unacceptable toxicity for a maximum of 13 cycles. Upon determination of the recommended dosing, the phase II primary objective will be to determine the clinical benefit rate (CR, PR, or stable disease ≥ 4 months using WHO criteria) of this combination for patients with refractory MPNST. Secondary objectives include determination of the pharmacokinetic profile, correlative studies evaluating pharmacodynamic parameters of Hsp and mTOR inhibition in tumor tissue and peripheral blood mononuclear cells, patient reported pain outcomes, and measurement of tumor size changes using volumetric MRI analysis. Clinical trial information: NCT02008877.
A Randomized Controlled Trial in Routine Clinical Practice Comparing Acceptance and Commitment Therapy with Cognitive Behavioral Therapy for the Treatment of Major Depressive Disorder
Authors: Jacqueline G.L. A-Tjak, Nexhmedin Morina, Maurice Topper, Paul M.G. Emmelkamp
Journal: Psychotherapy and Psychosomatics (2018)

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; Since current therapies for depression are effective but not for all patients alike, we need to further improve available treatments. Existing research suggests that acceptance and commitment therapy (ACT) may effectively treat major depressive disorder (MDD). We compared ACT with cognitive behavioral therapy (CBT) for depression, testing the hypothesis that CBT would outperform ACT. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; We conducted a randomized controlled trial with 82 patients suffering from MDD. Data were collected before and after treatment and at the 6-month follow-up, assessing diagnosis, symptom levels of depression, and quality of life. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; After treatment, the rates of remission from depression were 75 and 80% for the ACT and CBT conditions, respectively. Patients in both conditions further reported significant and large reductions in depressive symptoms and improvement in quality of life from before to after treatment as well as at the follow-up. Our findings indicated no significant differences between the two intervention groups. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; Our results indicate that CBT is not more effective in treating depression than ACT. Further research is needed to investigate whether ACT and CBT work differently for different groups of patients with depression.
Atezolizumab (MPDL3280A) Monotherapy for Patients With Metastatic Urothelial Cancer
Authors: Daniel P. Petrylak, Thomas Powles, Joaquim Bellmunt, Fadi Braiteh, Yohann Loriot, Rafael Morales-Barrera, Howard A. Burris, Joseph W. Kim, Beiying Ding, Constanze Kaiser, Marcella Fassò, Carol O’Hear, Nicholas J. Vogelzang
Journal: JAMA Oncology (2018)

Atezolizumab (anti-programmed death ligand 1) has demonstrated safety and activity in advanced and metastatic urothelial carcinoma, but its long-term clinical profile remains unknown.To report long-term clinical outcomes with atezolizumab therapy for patients with metastatic urothelial carcinoma.Patients were enrolled in an expansion cohort of an ongoing, open-label, phase 1 study. Median follow-up was 37.8 months (range, >0.7 to 44.4 months). Enrollment occurred between March 2013 and August 2015 at US and European academic medical centers. Eligible patients had measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1, Eastern Cooperative Oncology Group performance status 0 to 1, and a representative tumor sample. Programmed death ligand 1 expression on immune cells was assessed (VENTANA SP142 assay).Atezolizumab was given intravenously every 3 weeks until unacceptable toxic effects, protocol nonadherence, or loss of clinical benefit.Primary outcome was safety. Secondary outcomes included objective response rate, duration of response, and progression-free survival. Response and overall survival were assessed in key baseline subgroups.Ninety-five patients were evaluable (72 [76%] male; median age, 66 years [range, 36-89 years]). Forty-five (47%) received atezolizumab as third-line therapy or greater. Nine patients (9%) had a grade 3 to 4 treatment-related adverse event, mostly within the first treatment year; no serious related adverse events were observed thereafter. One patient (1%) discontinued treatment due to a related event. No treatment-related deaths occurred. Responses occurred in 26% (95% CI, 18%-36%) of patients. Median duration of response was 22.1 months (range, 2.8 to >41.0 months), and median progression-free survival was 2.7 months (95% CI, 1.4-4.3 months). Median overall survival was 10.1 months (95% CI, 7.3-17.0 months); 3-year OS rate was 27% (95% CI, 17%-36%). Response occurred in 40% (95% CI, 26%-55%; n = 40) and 11% (95% CI, 4%-25%; n = 44) of patients with programmed death ligand 1 expression of at least 5% tumor-infiltrating immune cells (IC2/3) or less than 5% (IC0/1), respectively. Median overall survival in patients with IC2/3 and IC0/1 was 14.6 months (95% CI, 9.0 months to not estimable) and 7.6 months (95% CI, 4.7 to 13.9 months), respectively.Atezolizumab remained well tolerated and provided durable clinical benefit to a heavily pretreated metastatic urothelial carcinoma population in this long-term study.clinicaltrials.gov Identifier: NCT01375842.
Abstract P4-11-04: Talking about risk in the context of GEomic profiling tests (TARGET)
Authors: LJ Fallowfield, VA Jenkins
Journal: Cancer Research (2018)

Abstract Background: Risk of recurrence scores from genomic profiling tests such as OncotypeDX® and EndoPredict® are being used increasingly with other clinico-pathologic features to help determine the likely benefit of adjuvant chemotherapy in early stage breast cancer. Decision-making requires the balancing of likely absolute benefits in terms of preventing recurrence versus the treatment related side effects. Health literacy and numeracy skills in the general population are often poor thus explaining risk and uncertainty can be confusing especially when set against a backdrop of fear and anxiety. As clinicians are facing more of these types of conversations with their patients we developed an educational program to help when discussing genomic test results. Methods: The development of the educational package followed discussions with key clinicians who routinely used genomic profiling tests, clinician-scientists and a review of the risk literature. We mapped out the difficulties they encountered when explaining high, intermediate and low risk test results together with the added challenges faced when communicating with patients with different personality and socio-educational characteristics. As clinicians and their patients may both have a measurable intolerance to uncertainty this may contribute irrespective of the recurrence score (RS) to seemingly irrational decisions about treatment. We rehearsed simulated patients (actors) experienced in improvisation to create different characters and filmed unscripted genomic test result consultations with cancer clinicians. This process proved successful in previous educational initiatives aimed at improving communication about clinical trials. (Jenkins et al 2006; Fallowfield et al 2012). Results: The educational package comprises an interview with Professor Mitch Dowsett explaining the science behind gene expression profiling tests, a lecture on the psychology of risk with group exercises and strategies on how to communicate together with 5 filmed scenarios with a timecoded facilitator handbook. The scenarios depicted are based on real clinical situations and demonstrate some of the issues discussing RS with low risk patients who nevertheless wish to have chemotherapy as well as high risk patients who are averse to chemotherapy. Conclusion: Discussions about the logic and rationale behind different treatment recommendations for breast cancer have become increasingly complex. Clinicians need an increased repertoire of communication skills to explain risks and benefits. We are now evaluating the efficacy of TARGET prior to training facilitators to roll the program out. Citation Format: Fallowfield LJ, Jenkins VA. Talking about risk in the context of GEomic profiling tests (TARGET) [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 P4-11-04.
Pamela Hardy: the pre-hospital specialist
Authors: Anne Gulland
Journal: BMJ (2018)

Having grown up in Nottingham, Pamela Hardy is now an emergency care consultant in the north of Scotland. Her “life’s too short” attitude has led to a hugely varied career and meant she has done things she never thought possible.

I went to a comprehensive school on a council estate in Nottingham where it wasn’t really “the thing” to go to university. I was planning to do midwifery training when someone suggested I do medicine. I was relatively bright at school but worked hard because I was bullied. I didn’t get in first time round and had to re-sit my A levels. When I got my results, I ran down the road after my dad, who was on his way to work as a mechanic, to tell him that I was going to medical school. I’ve always had incredible support from my parents and family.

After initial training in paediatrics I moved back to Nottingham and started doing a mixture of adult and paediatric emergency. It was during this time that pre-hospital care was developing. Like so many people who got involved in the specialty in …
Differentiation of Recurrent/Residual Glioma From Radiation Necrosis Using Semi Quantitative 99mTc MDM (Bis-Methionine-DTPA) Brain SPECT/CT and Dynamic Susceptibility Contrast-Enhanced MR Perfusion
Authors: Nisha Rani, Baljinder Singh, Narendra Kumar, Paramjit Singh, Puja Panwar Hazari, Harpreet Singh, Ganesh Kumar, Bishan Radotra, Mukesh Kumar, Anish Bhattacharya, Rajnish Sharma, Adarsh Kohli, Rajesh Chhabra, Sunil Kumar Gupta, Anil Kumar Mishra
Journal: Clinical Nuclear Medicine (2018)

Purpose In this study, 99m Tc MDM (bis-methionine-DTPA) SPECT was used for the detection and differentiation of recurrent/residual glioma from radiation necrosis and the results were compared with dynamic susceptibility contrast-enhanced (DSCE)-MRI and clinical findings. Materials and Methods Twenty-eight patients (18 men and 10 women; mean ± SD age, 41.4 ± 15.03 years) with histologically proven glioma (grade IV, 14; grade III, 7; grade II, 7) who were planned for postsurgical standard radio/chemo therapy were recruited prospectively. All the patients underwent technetium 99m Tc MDM SPECT/CT and DSCE-MRI imaging at 6 months after surgery/radio-chemotherapy, 9 of 28 patients also underwent SPECT imaging at 1 to 2 weeks after surgery. Results 99m Tc MDM SPECT/CT analysis demonstrated significantly higher target to nontarget (T/NT) ratio of the radiotracer in tumor recurrence than in radiation necrosis (3.59 ± 1.70 vs 1.16 ± 0.42). Likewise, the normalized cerebral blood volume (nCBV) values in patients with tumor recurrence were also significantly higher than in radiation necrosis (5.16 ± 2.30 vs 1.63 ± 0.94). A positive correlation (rho = 0.823, P &lt; 0.0001) between T/NT ratios and nCBV was observed. The cutoff T/NT ratios and nCBV values estimated by receiver operating characteristic analysis were greater than 1.50 (area under the curve, 0.944 ± 0.34) and greater than 2.12 (area under the curve, 0.931 ± 0.39), respectively. Combining the results of 99m Tc MDM SPECT/CT, DSCE-MRI, and clinical findings, diagnosis of recurrent/residual glioma or radiation necrosis was made in 18 and 10 patients, respectively. Sensitivity and specificity of 2 techniques were comparable, that is, 92.0%: 78.6% for MDM SPECT/CT and of 92.0%: 71.4% for DSCE-MRI, respectively. Conclusion Thus, combining MDM SPECT with DSCE MRI may provide an accurate method for differentiation of tumor recurrence from radiation-induced necrosis in glioma patients.
What are the subspecialties of psychiatry?
Authors: Rahul Rao
Journal: BMJ (2004)

Got a career or related problem that needs answering? Can't find the right person to point you in the right direction? Log on to the Advice Zone ([www.bmjcareers.com/advicezone][1]) 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. [1]: http://www.bmjcareers.com/advicezone
AKT1-MEDIATED SKELETAL MUSCLE GROWTH PROMOTES ANGIOGENESIS BY ENHANCING HEME OXYGENASE-1 EXPRESSION IN SURROUNDING ENDOTHELIAL CELLS
Authors: Yasuhiro Izumiya, Yoshiro Onoue, Shinsuke Hanatani, Kenichi Tsujita
Journal: Journal of the American College of Cardiology (2018)
Glucocorticoids Inhibit Oncogenic RUNX1-ETO in Acute Myeloid Leukemia with Chromosome Translocation t(8;21)
Authors: Lianghao Lu, Yefei Wen, Yuan Yao, Fengju Chen, Guohui Wang, Fangrui Wu, Jingyu Wu, Padmini Narayanan, Michele Redell, Qianxing Mo, Yongcheng Song
Journal: Theranostics (2018)

Acute myeloid leukemia (AML) is a major blood cancer with poor prognosis.New therapies are needed to target oncogene-driven leukemia stem cells, which account for relapse and resistance.Chromosome translocation t(8;21), which produces RUNX1-ETO (R-E) fusion oncoprotein, is found in ~13% AML.R-E dominance negatively inhibits global gene expression regulated by RUNX1, a master transcription factor for hematopoiesis, causing increased self-renewal and blocked cell differentiation of hematopoietic progenitor cells, and eventually leukemia initiation.Methods: Connectivity-Map followed by biological activity testing were used to identify candidate compounds that can inhibit R-E-mediated gene transcription.Molecular mechanistic studies were also performed.Results: Glucocorticoid drugs, such as betamethasone and dexamethasone, were found to exhibit potent and selective in vitro and in vivo activities against R-E leukemia, as well as strong synergy when combined with chemotherapeutics.Microarray analysis showed that treatment with glucocorticoids significantly inhibited R-E's activity and reactivated that of RUNX1.Such gene expression changes caused differentiation and apoptosis of R-E leukemia cells.Our studies also show a possible molecular mechanism for the targeted therapy.Upon treatment with a glucocorticoid drug, more glucocorticoid receptor (GR) was translocated into the nucleus and bound to DNA, including promoters of RUNX1 target genes.GR was found to associate with RUNX1, but not R-E.This interaction increased binding of RUNX1 to DNA and reduced that of R-E, shifting to a RUNX1 dominance.Conclusion: Glucocorticoid drugs represent a targeted therapy for AML with chromosome translocation t(8:21).Given their high activity, favorable human pharmacokinetics as well as synergy with chemotherapeutics, glucocorticoids could be clinically useful to treat R-E AML.
NEW-ONSET ATRIAL FIBRILLATION IS ASSOCIATED WITH INCREASED MORTALITY IN CRITICALLY ILL PATIENTS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Napatt Kanjanahattakij, Pattara Rattanawong, Parasuram Krishnamoorthy, Benjamin Horn, Pakawat Chongsathidkiet, Veronica Garvia, Putthapiban Prapaipan, Natee Sirinvaravong, Vincent Figueredo
Journal: Journal of the American College of Cardiology (2018)
Incidence of cephalosporin‐induced anaphylaxis and clinical efficacy of screening intradermal tests with cephalosporins: A large multicenter retrospective cohort study
Authors: M.‐S. Yang, D.Y. Kang, B. Seo, H. J. Park, S.‐Y. Park, M.‐Y. Kim, K. H. Park, S.‐M. Koo, Y.‐H. Nam, S. Kim, J.‐W. Jung, T.‐B. Kim, G. C. Jang, H.‐J. Yang, Y.‐M. Ahn, J.‐W. Park, H.‐R. Kang
Journal: Allergy (2018)

Few studies have investigated the incidence of anaphylaxis induced by individual or structurally similar cephalosporins. The aims of the study were to assess the incidence of cephalosporin-induced anaphylaxis and evaluate the clinical efficacy of screening skin tests.In this retrospective cohort study, we obtained information on total cephalosporin use and cephalosporin-induced anaphylaxis in intravenous cephalosporin recipients in 12 general hospitals between 2013 and 2015. Cephalosporins were divided into 4 groups according to similar side-chain structures. The incidence of cephalosporin-induced anaphylaxis was assessed for each cephalosporin, cephalosporin generation, and side-chain group. To verify the efficacy of screening intradermal tests (IDT) with cephalosporin, the 12 hospitals were assigned to the intervention or control group depending on whether they performed screening IDT before the administration of cephalosporins.We identified 76 cases of cephalosporin-induced anaphylaxis with 1 123 345 exposures to intravenous cephalosporins (6.8 per 100 000 exposures), and the incidence of fatal anaphylaxis by cephalosporin was 0.1 cases per 100 000 exposures. The highest incidences of anaphylaxis occurred in the ceftizoxime (13.0 cases per 100 000 exposures) and side-chain group 1 (cefepime, cefotaxime, ceftizoxime, ceftriaxone, and cefuroxime; 9.3 per 100 000). There was no case of anaphylaxis induced by cefoxitin, cefmetazole, cefminox, and cefotiam. The clinical effectiveness of routine screening IDT was not significant (P = .06).The incidence of cephalosporin-induced anaphylaxis differed according to individual drugs and side-chain structure. Screening IDT showed no clinical efficacy at a population level.
MODERN-DAY PREVALENCE OF THE FREDRICKSON-LEVY-LEES DYSLIPIDEMIAS: MORE COMMON THAN YOU THINK
Authors: Vasanth Sathiyakumar, Jihwan Park, Peter Toth, Mariana Lazo, Renato Quispe, Eliseo Guallar, Roger Blumenthal, Steven Jones, Seth Martin
Journal: Journal of the American College of Cardiology (2018)
Trust in the GMC to lay down the law on beliefs
Authors: Rob Finch
Journal: BMJ (2008)

With the controversial Human Fertilisation and Embryology Bill up for debate in the coming weeks and the arrest of several Muslim doctors in connection with terrorist attacks in Glasgow last year, the personal beliefs of doctors are never far away from headline news. And yet it would be an impossible task to separate the practice of medicine from doctors’ personal beliefs. Even the earliest professional medical ethical code—the Hippocratic oath—had religious overtones. Its opening line was a pledge to not one, but four, deities of the classical Greek pantheon.

Despite these difficulties, the General Medical Council has attempted to spell out the separation of belief and medicine as far as it can in its latest guidance. “Personal Beliefs and Medical Practice” faces up to the reality that both doctors and patients bring particular viewpoints to every consultation, but it aims not to be overly proscriptive on how every situation should be judged.

Instead it places the onus on doctors to be above reproach by putting patients first. It says: “Some doctors’ personal beliefs may give rise to concerns about carrying out or recommending particular procedures for patients. While we do not impose unnecessary restrictions on doctors, we expect them to be prepared to set aside their personal beliefs where this is necessary in order to provide care.”

Jane O’Brien, head of standards and ethics at the GMC, says: “We’re not an inspectorate so we’re not going round looking for trouble, so it will be dependent on information or complaints we receive.

“We’re not saying that any deviation from the guidance won’t result in action. These are the principles we want doctors to adhere to. If somebody is constantly forcing patients to pray with them …
Noninvasive Assessment of Hemodynamic Status in HeartWare Left Ventricular Assist Device Patients
Authors: Simone Frea, Paolo Centofanti, Stefano Pidello, Francesca Giordana, Virginia Bovolo, Andrea Baronetto, Beatrice Franco, Marco Matteo Cingolani, Matteo Attisani, Mara Morello, Serena Bergerone, Mauro Rinaldi, Fiorenzo Gaita
Journal: JACC. Cardiovascular imaging (2018)
Phase Ib Study of Glasdegib, a Hedgehog Pathway Inhibitor, in Combination with Standard Chemotherapy in Patients with AML or High-Risk MDS
Authors: Michael R. Savona, Daniel A. Pollyea, Wendy Stock, Vivian G. Oehler, Mark A. Schroeder, Jeffrey Lancet, James McCloskey, Hagop M. Kantarjian, Weidong Wendy Ma, M. Naveed Shaik, A. Douglas Laird, Mirjana Zeremski, Ashleigh O'Connell, Geoffrey Chan, Jorge E. Cortes
Journal: Clinical Cancer Research (2018)

Abstract Purpose: This open-label, multicenter, dose-finding, phase Ib study (NCT01546038) evaluated the safety, pharmacokinetics, pharmacodynamics, and clinical activity of the novel Hedgehog pathway Smoothened inhibitor glasdegib (PF-04449913) in patients (N = 52) with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS). Experimental Design: Glasdegib 100 or 200 mg was administered orally, once daily in 28-day cycles, in combination with low-dose cytarabine (arm A) or decitabine (arm B) to newly diagnosed patients considered not suitable for standard induction chemotherapy, and in combination with cytarabine/daunorubicin (arm C) to fit patients. The study followed a standard 3+3 dose-escalation design. The primary endpoint was dose-limiting toxicity (DLT). Ten additional patients were enrolled in expansion cohorts of arms A (n = 23) and C (n = 22) to confirm the recommended phase II dose (RP2D). Results: No DLTs were observed in arms A and B; 1 DLT (grade 4 neuropathy) occurred in arm C. The most common treatment-related nonhematologic adverse events were mostly grades 1 and 2 in all arms. Muscle spasms, dysgeusia, and alopecia were generally mild. Overall, 16 patients (31%) achieved a complete remission (CR)/CR with incomplete blood count recovery. Note that 100 mg daily was selected as the RP2D for glasdegib in combination with standard chemotherapies in the absence of an estimated MTD in this setting. Conclusions: Treatment with glasdegib in combination with standard chemotherapy was generally well-tolerated and consistent with prior findings, warranting further evaluation of glasdegib-based combinations in patients with AML or high-risk MDS. Clin Cancer Res; 24(10); 2294–303. ©2018 AACR.