tbuckley/cabot-search huggingface dataset:
Evans syndrome secondary to undiagnosed chronic lymphocytic leukemia in a patient with unexplained bleeding
Authors: Christopher B. Hergott, Olga Pozdnyakova
Journal: American Journal of Hematology (2018)

A 60-year-old man reported worsening fatigue and multiple recent episodes of epistaxis to his physician. He denied any personal or family history of hematologic disorders. Physical examination was notable only for mild pallor. Examination of a peripheral blood smear (Image 1) revealed numerous small, atypical lymphocytes and “smudge” cells (black arrowhead), abundant spherocytes (black arrow), reticulocytes (gray arrow), and few platelets. The patient's coagulation values were normal, but a complete blood count revealed lymphocytosis (WBC of 52 130/µL; 83% lymphocytes), macrocytic anemia (Hgb 7.1 g/dL; MCV 110 fL), and thrombocytopenia (56 000/µL). Flow cytometry identified a predominant, monotypic population of aberrant B cells expressing CD19, CD20(dim), CD5, and CD23, thus confirming a diagnosis of chronic lymphocytic leukemia (CLL). Elevated lactate dehydrogenase (730 IU/L), reticulocytosis (9.4%), and a positive direct antiglobulin test subsequently verified ongoing hemolysis. Peripheral blood smear (1000× magnification) displaying small lymphoid cells with “soccer ball” chromatin and including occasional “smudge” cells (black arrowhead), suggestive of chronic lymphocytic leukemia, along with markedly frequent spherocytes (black arrow) and reticulocytes (gray arrow), collectively indicative of hemolytic anemia. Note also the reduced frequency of visible platelets The patient was diagnosed with combined autoimmune hemolytic anemia and thrombocytopenia—also known as Evans syndrome—secondary to CLL. Autoimmune cytopenias afflict 5%-15% of CLL patients and can provoke potentially dangerous bleeding events.1 Fatigue, pallor, and unexplained bleeding comprise the most common presenting symptoms, often manifesting before any neoplasm is recognized.2 Despite the risks of these complications, autoimmune cytopenias are associated with a more favorable prognosis than cytopenias due to extensive bone marrow infiltration by CLL,3 underscoring the importance of swift evaluation of leukemia-associated hematologic abnormalities. This case highlights the singular utility of early blood smear examination in diagnosing and directing appropriate therapy for CLL-associated autoimmune phenomena. Treatment strategies for Evans syndrome include corticosteroids, intravenous immunoglobulin, rituximab, splenectomy, and a variety of chemotherapeutic regimens.4 This patient began a trial of prednisone and was referred to oncology to consider future management of his leukemia. Nothing to report.
Editor’s Choice: The craft and meaning of work
Authors: Tom Moberly
Journal: BMJ (2016)

Alongside the fulfilment of caring for other people, for a long time much of the enjoyment of a career in medicine came from the satisfaction of learning, practising, and refining a craft and the camaraderie of team working. But, as Kathy Oxtoby has described, expanding bureaucracy, increasing pressure on time, and more …
How to fail an interview
Authors: Caroline Elton
Journal: BMJ (2012)

Several years ago a journalist came to see me for some careers counselling because he was repeatedly shortlisted for jobs but failing at the interview stage. As you would hope with somebody in his profession, he had a great way with words, and one phrase of his in particular—catastrophic candour—stuck in my mind long after he had completed the careers counselling. What he was referring to with this term was his tendency in interviews (and actually in other situations as well) to share the contents of his head with all and sundry, rather than being more judicious in deciding what he would say to a given group of people. So, for example, in a previous interview, when asked why he wanted to work on a particular publication, he found himself saying that the salary was high and this would help with the family budget, given that his previous wife was proving expensive …
Lessons from the class of 1970: male school leaver entrants to medical school versus male graduate entrants and women
Authors: Alison M Leak, Toby J L Humphrey
Journal: BMJ (2012)

Do men who went straight to medical school from secondary school differ in their contribution to medicine from male graduate entrants and women? <b>Alison Leak and Toby Humphrey</b> review the evidence from a qualitative survey of a 1970 London medical school cohort
Prehospital Blood Product Transfusion and Combat Injury Survival—Reply
Authors: Stacy A. Shackelford, Deborah J. del Junco
Journal: JAMA (2018)

In Reply Although a retrospective study cannot rule out unmeasured confounding, we respectfully disagree with Dr David and colleagues that the reported between-group mortality difference "may be related to the quality of prehospital resuscitation rather than prehospital transfusion."
BMA will oppose army-style conscription of doctors to NHS
Authors: Abi Rimmer
Journal: BMJ (2017)

The BMA has rejected the health secretary’s plan to require UK trained doctors to work in the NHS for four years and will oppose any move to impose a minimum period of NHS employment on doctors.

In October last year England’s health secretary, Jeremy Hunt, announced plans to require doctors to work in the NHS for at least four years after qualification unless they repaid …
Simultaneous multiple interaction T-cell engaging (SMITE) bispecific antibodies overcome bispecific T-cell engager (BiTE) resistance via CD28 co-stimulation
Authors: Colin E. Correnti, George S. Laszlo, Willem J. de van der Schueren, Colin D. Godwin, Ashok Bandaranayake, Melanie A. Busch, Chelsea J. Gudgeon, Olivia M. Bates, James M. Olson, Christopher Mehlin, Roland B. Walter
Journal: Leukemia (2018)
Association of E-Cigarette Use With Smoking Cessation Among Smokers Who Plan to Quit After a Hospitalization
Authors: Nancy A. Rigotti, Yuchiao Chang, Hilary A. Tindle, Sara M. Kalkhoran, Douglas E. Levy, Susan Regan, Jennifer H.K. Kelley, Esa M. Davis, Daniel E. Singer
Journal: Annals of Internal Medicine (2018)

Many smokers report using e-cigarettes to help them quit smoking, but whether e-cigarettes aid cessation efforts is uncertain.To determine whether e-cigarette use after hospital discharge is associated with subsequent tobacco abstinence among smokers who plan to quit and are advised to use evidence-based treatment.Secondary data analysis of a randomized controlled trial. (ClinicalTrials.gov: NCT01714323 [parent trial]).3 hospitals.1357 hospitalized adult cigarette smokers who planned to stop smoking, received tobacco cessation counseling in the hospital, and were randomly assigned at discharge to a tobacco treatment recommendation (control) or free tobacco treatment (intervention).Self-reported e-cigarette use (exposure) was assessed 1 and 3 months after discharge; biochemically validated tobacco abstinence (outcome) was assessed 6 months after discharge.Twenty-eight percent of participants used an e-cigarette within 3 months after discharge. In an analysis of 237 propensity score-matched pairs, e-cigarette users were less likely than nonusers to abstain from tobacco use at 6 months (10.1% vs. 26.6%; risk difference, -16.5% [95% CI, -23.3% to -9.6%]). The association between e-cigarette use and quitting varied between intervention patients, who were given easy access to conventional treatment (7.7% vs. 29.8%; risk difference, -22.1% [CI, -32.3% to -11.9%]), and control patients, who received only treatment recommendations (12.0% vs. 24.1%; risk difference, -12.0% [CI, -21.2% to 2.9%]) (P for interaction = 0.143).Patients self-selected e-cigarette use. Unmeasured confounding is possible in an observational study.During 3 months after hospital discharge, more than a quarter of smokers attempting to quit used e-cigarettes, mostly to aid cessation, but few used them regularly. This pattern of use was associated with less tobacco abstinence at 6 months than among smokers who did not use e-cigarettes. Additional study is needed to determine whether regular use of e-cigarettes aids or hinders smoking cessation.National Heart, Lung, and Blood Institute.
Clinical features, management and outcomes of paediatric central nervous system tumours disseminated and nondisseminated at presentation: a fourteen-year experience
Authors: Matthew Kirkman, Kim Phipps, Kristian Aquilina
Journal: Neuro-Oncology (2018)

It is unusual for paediatric central nervous system (CNS) tumours to be disseminated at presentation, and literature on the clinical features, management and outcomes of this specific group is scarce. Surgical management decisions can be challenging, particularly in the presence of hydrocephalus. We present our experience in managing paediatric CNS tumours disseminated and nondisseminated at presentation over fourteen years. Retrospective review of prospectively-collected data on children presenting to our tertiary centre between 2003 and 2016 inclusive. We identified 53 patients with CNS tumour dissemination at presentation (M:F=34:19, median age=3.8 years, range=7 days-15.6 years) and 308 without dissemination (M:F=161:147, median age=5.8 years, range=1 day-16.9 years). Five tumour groups were studied: medulloblastoma (disseminated n=29/nondisseminated n=74), other primitive neuroectodermal tumour (n=8/n=17), atypical teratoid rhabdoid tumour (n=8/n=22), pilocytic astrocytoma (n=6/n=138), and ependymoma (n=2/n=57). Median follow-up in survivors was not significantly different between those with (64.0 months, range=5.2–152.0 months) and those without disease dissemination at presentation (74.5 months, range=4.7–170.1 months; P>0.05). Dissemination status at presentation significantly impacted survival, risk of recurrence, rates of complete resection of the operated lesion, chance of proceeding to palliative care as an early management strategy, surgical complication rate, and risk of requiring CSF diversion (all Ps<0.05). Differences between the five tumour groups were evident. No factors to predict the need for permanent CSF diversion following temporary external ventricular drainage were identified on multivariate analysis, and there was no clear superiority of either ventriculoperitoneal shunt or endoscopic third ventriculostomy as a permanent CSF diversion procedure. Tumour type and dissemination status at initial presentation significantly affect outcomes across a range of measures. The management of hydrocephalus in patients with CNS tumours is challenging, and further prospective studies are required to identify the optimal CSF diversion strategy or strategies in this population.
PROGNOSTIC IMPLICATION OF PERFUSION DEFECT ON CONTRAST STRESS ECHOCARDIOGRAPHY AFTER PERCUTANEOUS CORONARY INTERVENTION
Authors: In-Cheol Kim, Hyungseop Kim, Sang-Wookng Choi, Han-Jun Bae, Seung-Woon Jun, Yun-Kyeong Cho, Hyoung-Seob Park, Hyuck-Jun Yoon, Chang-Wook Nam, Seongwook Han, Seung-Ho Hur, Yoon-Nyun Kim, Kwon-Bae Kim
Journal: Journal of the American College of Cardiology (2018)
Could someone please explain the different NHS pay bands, how one qualifies for a particular band, and how overtime is paid?
Authors: Simon Eccles
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>
Nut Oral Immunotherapy (NOIT) Using Two or More Nuts Successfully Desensitizes Most Patients
Authors: Dena M. Pence, Richard L. Wasserman, Robert W. Sugerman, Qurat Ul Ain Kamili, Angela R. Hague, Joanna G. Rolen, Morley Herbert
Journal: Journal of Allergy and Clinical Immunology (2018)
Exacerbation of Murine Experimental Autoimmune Myositis by Toll‐Like Receptor 7/8
Authors: Clara Sciorati, Antonella Monno, Maria Giulia Doglio, Elena Rigamonti, Dana P. Ascherman, Angelo A. Manfredi, Patrizia Rovere‐Querini
Journal: Arthritis & Rheumatology (2018)

Toll-like receptor 7 (TLR-7), TLR-8, and interferon (IFN)-induced genes are expressed in patients with idiopathic inflammatory myositis. This study was undertaken to investigate whether their activation influences the natural history of the disease.Experimental autoimmune myositis was induced in mice by injection of the amino-terminal portion of the murine histidyl-transfer RNA synthetase (HisRS). Disease was compared in the presence or the absence of the TLR-7/8 agonist R-848 in wild-type mice and in mice that fail to express the IFNα/β receptor (IFNα/βR-null mice).Experimental autoimmune myositis induced by a single intramuscular immunization with HisRS spontaneously abated after 7-8 weeks. In contrast, levels of anti-HisRS autoantibodies, endomysial/perimysial leukocyte infiltration, and myofiber regeneration persisted at the end of the follow-up period (22 weeks after immunization) in mice immunized with HisRS in the presence of R-848. Myofiber major histocompatibility complex (MHC) class I molecules were detectable only in mice immunized with both HisRS and R-848. MHC up-regulation occurred early and in muscles that were not directly injected with HisRS. Muscle MHC expression paralleled with leukocyte infiltration. MHC class I molecules were selectively up-regulated in myotubes challenged with R-848 in vitro. Type I IFN was necessary for the prolonged autoantibody response and for the spreading of the autoimmune response, as demonstrated using IFNα/βR-null mice. Muscle infiltration was maintained in the injected muscle up to the end of the follow-up period.TLR-7/8 activation is necessary to induce and maintain a systemic autoimmune response targeting the skeletal muscle. This experimental autoimmune myositis model reproduces many characteristics of human idiopathic inflammatory myopathies and may represent a tool for preclinical studies.
Staffing turnover effect of fellowship-trained surgical specialists on oncologic outcomes in community cancer center.
Authors: Jan Franko, Soren Kraemer, Charles David Goldman, Daniela Frankova, Shankar Raman
Journal: Journal of Clinical Oncology (2018)

187 Background: Contemporary health care is delivered in highly interdependent team-based environment. Transitions in surgeon complement may be associated with a disturbance of workflow, especially in smaller-sized community cancer centers. Herein we examined the impact of two surgical oncologists turnover in our cancer center. Methods: Survival outcomes of all cases of esophageal, gastric, rectal and pancreatic adenocarcinoma treated in the index cancer center (n = 1,445) were compared to then-contemporary standard derived from Iowa-SEER registry, 2001-2015 (n = 12,617). Period before and after changeover of surgeons was compared using descriptive statistics and regression model. Results: Substantial reduction of annually referred (101.8±9.2 versus 60.5±0.7 case per year, p = 0.026) and operative cases (37.0±4.5 versus 17.5±3.5 cases per year, p = 0.027) was seen during fully-staffed versus on-boarding periods at the index hospital. At the state level, there was no fluctuation of annually referred cases (898.0±19.8 versus 910.5±35.6 cases per year, p = 0.384) and minimal decrease in operated cases (366.2±18.0 versus 335.0±24.1 cases per year, p = 0.020) in early versus late period. New surgical team was able to improve upon survival of resectable esophageal cancer patients in the index hospital and maintain survival of other complex GI malignancies as compared to geographically relevant standard of Iowa-SEER registry. Survival regression model on all 5,795 non-metastatic cases with available data, adjusted for age, stage and primary disease site, demonstrated that being treated in the index hospital did not result is inferior survival comparing early and late period (HR = 1.060, p = 0.237). Conclusions: Loss of surgical cancer specialists was associated with profound &amp; significant loss of referrals to the index cancer center, and likely outmigration of patients from the community seeking advanced care. Quick restoration of surgical services may reinstate overall efficacy of care for resectable cancer cases without negative survival effect.
A phase 2 and biomarker study of sorafenib combined with FOLFOX in patients with advanced hepatocellular carcinoma (HCC).
Authors: Lipika Goyal, Hui Zheng, Thomas Adam Abrams, Rebecca A. Miksad, Andrea J. Bullock, Jill N. Allen, Matthew B. Yurgelun, Susan Sheehan, Patricia Lynch, Anthony James Afflitto, Caroline Dinicola, Jordan Robert Maurer, Stephanie Reyes, Michelle Knowles, Aralee Galway, Jeffrey W. Clark, Emilie Birnbaum, Anna Khachatryan, Gabriel Dan Duda, Andrew X. Zhu
Journal: Journal of Clinical Oncology (2018)

270 Background: Sorafenib is the standard first line treatment for advanced HCC and showed a median time to progression (TTP) of 5.5 months and an overall response rate (ORR) of 2% in the phase III SHARP trial. FOLFOX has shown modest activity in HCC with a progression free survival (PFS) of 2.9 months and ORR of 8% in a phase III trial. In this single-arm, multicenter phase 2 and biomarker study, sorafenib plus FOLFOX was evaluated in the first line treatment of advanced HCC. Methods: Patients with histologically proven advanced HCC, Child Pugh A liver function, and no prior systemic therapies received sorafenib 400mg orally twice daily during a 2-week lead-in, followed by concurrent modified FOLFOX (5-FUCI 1200mg/m2/day for 46 hours and LV 400mg/m2 bolus, Oxaliplatin 85mg/m2) on day 1 and 15 of each 28-day cycle. The primary endpoint was TTP, calculated from date of study entry to date of radiological or clinical disease progression. Serial plasma anti-angiogenic and anti-inflammatory biomarkers were evaluated. Results: The study enrolled 40 patients with advanced HCC: median age, 65 years; male 85%; Child Pugh A5, 70%; BCLC stage C, 95%; HCC etiology, HCV 40%, HBV 13%, alcohol 13%. Grade 3/4 adverse events were notable for AST (23%), ALT (15%), bilirubin (10%), diarrhea (10%), anemia (10%), hypertension (5%), hand-foot syndrome (5%), and thrombocytopenia (5%). Dose reductions for sorafenib and FOLFOX were done in 73% and 65% of patients, respectively. The median TTP was 8.8 months (95%CI, 6.5-11.2). The ORR was 18%, and the stable disease rate was 55%. Among 36 patients with a baseline AFP ≥ 5 ng/mL, 10 (28%) had a ≥ 50% drop in AFP. Low baseline plasma levels of sVEGFR1, VEGF-C, and bFGF and high levels of s-cMET and IL-12 tended to associate with longer TTP (p &lt; 0.10). Decreased s-cMET at day 15 and decreased s-cMET and IL-2 at day 43 were associated with longer TTP (p &lt; 0.05). Conclusions: Sorafenib+FOLFOX demonstrated encouraging clinical efficacy with moderate toxicity in the first line treatment of advanced HCC. Initial biomarker evaluation suggested a correlation between TTP and baseline angiogenic markers as well as changes in IL-2 and s-cMET. Complete biomarker analysis will be presented at the meeting. Clinical trial information: NCT01775501.
ProBio II: An adaptive and randomized multi-arm biomarker driven phase 2 study in men with castrate resistant prostate cancer (CRPC).
Authors: Henrik Gronberg, Martin Eklund, Johan Lindberg, Anders Ullén, Anders Bjartell, Ove Andren, David Robinson, Ingela Franck Lissbrant, Gunilla Enblad, Olof Stahl, Camilla Thellenberg
Journal: Journal of Clinical Oncology (2018)

TPS397 Background: Castrate-resistant prostate cancer (CRPC) affects around 3,000 men in Sweden every year. New drugs are available but they have moderate effect, low response rates, are expensive, and lack predictive treatment markers. This will lead to an unsustainable situation for prostate cancer care. Our hypothesis is that treatment decisions based on molecular profiling will significantly increase the response rate at 3 months compared to current clinical care, translating into improved progression free and overall survival. The vast majority of CRPC metastasize to the bone, with low success rate in obtaining sufficient material. Therefore, we will sequence circulating tumor DNA (ctDNA) being present at high levels in plasma. Methods: ProBio-II is an adaptive, multi-arm, open-label, multiple assignment randomized biomarker driven phase 2 trial in men with CRPC . Men (n=750) will be randomized to receive either standard of care (following Swedish national guidelines) or treatment with Enzalutamide, Abiraterone, PARP inhibitors, RA-223, Cabazitaxel, or immune modulators based on molecular subtypes. The molecular subtypes are defined as tumor properties or mutations in certain genes/pathways including: Microsatellite instability; Androgen receptor alterations; DNA-repair deficiency; TP53 inactivation; PTEN inactivation etc. The molecular subtypes will be identified by ctDNA profiling. A specially designed ctDNA profile for CRPC has been developed by our group to detect: mutations, amplifications and genomic rearrangements in the androgen receptor (AR); mutations, genomic rearrangements and amplifications/deletions in 300 key genes involved in prostate cancer; and microsatellite instable and hypermutated cancers. ProBio-II’s design is novel and inspired by successful studies as I-SPY (breast cancer) and the NCI-MATCH trial (metastatic cancer). Novel aspects of the study design includes using prior probability of treatment response; re-randomization of non-responders; and adaptive design. The ProBio II study will start recruiting patients in Sweden in Q1 2018 and recruit patients during a 18 month period. All major oncology departments in Sweden will participate.
Oncogenic activation of JAK3-STAT signaling confers clinical sensitivity to PRN371, a novel selective and potent JAK3 inhibitor, in natural killer/T-cell lymphoma
Authors: M. -L. Nairismägi, M. E. Gerritsen, Z. M. Li, G. C. Wijaya, B. K. H. Chia, Y. Laurensia, J. Q. Lim, K. W. Yeoh, X. S. Yao, W. L. Pang, A. Bisconte, R. J. Hill, J. M. Bradshaw, D. Huang, T. L. L. Song, C. C. Y. Ng, V. Rajasegaran, T. Tang, Q. Q. Tang, X. J. Xia, T. B. Kang, B. T. Teh, S. T. Lim, C. K. Ong, J. Tan
Journal: Leukemia (2018)

Aberrant activation of the JAK3-STAT signaling pathway is a characteristic feature of many hematological malignancies. In particular, hyperactivity of this cascade has been observed in natural killer/T-cell lymphoma (NKTL) cases. Although the first-in-class JAK3 inhibitor tofacitinib blocks JAK3 activity in NKTL both in vitro and in vivo, its clinical utilization in cancer therapy has been limited by the pan-JAK inhibition activity. To improve the therapeutic efficacy of JAK3 inhibition in NKTL, we have developed a highly selective and durable JAK3 inhibitor PRN371 that potently inhibits JAK3 activity over the other JAK family members JAK1, JAK2, and TYK2. PRN371 effectively suppresses NKTL cell proliferation and induces apoptosis through abrogation of the JAK3-STAT signaling. Moreover, the activity of PRN371 has a more durable inhibition on JAK3 compared to tofacitinib in vitro, leading to significant tumor growth inhibition in a NKTL xenograft model harboring JAK3 activating mutation. These findings provide a novel therapeutic approach for the treatment of NKTL.