tbuckley/cabot-search huggingface dataset:
Improving efficacy of PD-1 blockade in unresponsive lymphoma tumors with in situ vaccination through induction of a highly efficient cross-presenting dendritic cell subset.
Authors: Linda Hammerich, Maxime Dhainaut, Thomas A. Davis, Tibor Keler, Andres M. Salazar, Brian D. Brown, Joshua Brody
Journal: Journal of Clinical Oncology (2018)

76 Background: Low-grade non-Hodgkin’s B-cell lymphomas are generally incurable; preliminary results with anti-PD-1 therapy have yielded low response rates. Tumoral DC infiltration correlates with efficacy of checkpoint blockade and tumor-targeted vaccines represent promising, novel treatment strategies to induce anti-tumor T cells. Methods: A20 lymphoma-bearing mice were treated with a PD-1 blocking antibody with an in situ vaccine (ISV) consisting of intratumoral injections of FMS-like tyrosine kinase-3 ligand (Flt3L), local irradiation (XRT) of the tumor and intratumoral injections of the TLR3 agonist poly-ICLC (pIC). Results: Untreated lymphoma tumors contained very low numbers of DC and treatment with anti-PD1 alone did not induce tumor regression or increase survival. Flt3L treatment resulted in a dramatic increase of IRF8+TLR3+ DC at the tumor site, the draining lymph node and the spleen. XRT of A20 cells induced activation of Flt3L-treated splenic DC in vitro and local XRT of the tumor in vivo induced expression of CD103 on infiltrating TLR3+ DC. Local XRT also enhanced uptake of dying tumor cells by DC. Interestingly, tumor antigens were taken up mainly by CD103+ DC and not CD103- subtypes. CD103+ expression distinguishes a subset of migratory cross-presenting DC. Accordingly, CD103+ DC isolated from the tumor induced proliferation of tumor-specific CD8+ T cells more efficiently than CD103- subsets. The combination of Flt3L with XRT and pIC induced tumor-reactive, IFNg-producing T cells, but delayed tumor growth and improved survival only in 40% of mice. ISV also increased expression of PD-L1 on tumor cells and tumor infiltrating DC. Consistently, combination of ISV with PD-1 blockade led to complete tumor regression and increased long-term survival in the majority of mice. PD-1 blockade also increased the number of tumor-reactive T cells and depletion of CD8+ T cells abrogated the anti-tumor effect. Conclusions: In situ vaccination can improve efficacy of anti-PD-1 in checkpoint-unresponsive lymphoma tumors through induction of a cross-presenting DC subset leading to long-term regression of established lymphoma tumors.
SHORT-TERM REPRODUCIBILITY OF CARDIOPULMONARY EXERCISE TEST PARAMETERS IN PATIENTS WITH LEFT VENTRICULAR ASSISTIVE DEVICE
Authors: Miguel Alvarez Villela, Kalil Salkey, Thiru Chinnadurai, Mounica Yanamandala, Jooyoung Shin, Ileana Pina, Ulrich Jorde, Snehal Patel
Journal: Journal of the American College of Cardiology (2018)
Prognostic value of chromogranin-a (CGA) compared to circulating tumor cells (CTCs) in metastatic castration resistant prostate cancer (mCRPC).
Authors: Karthik Giridhar, Cristobal T. Sanhueza, David W. Hillman, Hassan Alkhateeb, Rachel Carlson, Winston Tan, Fernando Quevedo, Lance C. Pagliaro, Brian Addis Costello, Manish Kohli
Journal: Journal of Clinical Oncology (2018)

249 Background: Serum CGA has been identified as a candidate prognostic biomarker for mCRPC. In a two cohort study, we compared the prognostic value of serum CGA with a validated CTC assay. Methods: In the discovery cohort (DC), blood samples were collected from 256 men with mCRPC. In an independent validation cohort (VC), 92 men with mCRPC were enrolled in a biospecimen collection study. In both cohorts, men receiving proton pump inhibitors and those with non-castrate levels of testosterone ( &gt; 50ng/dl) were excluded. Serum CGA was measured in a homogeneous automated immunofluorescent assay using time-resolved amplified cryptate emission. In the VC, CTC enumeration was performed using the FDA cleared CELLSEARCH CTC test prior to treatment with abiraterone acetate/ prednisone. Cox proportional hazard regression and Kaplan-Meier analysis were performed for associations with elevated CGA (above reference range), unfavorable (≥ 5) CTCs, and overall survival (OS). Results: In the DC, 200 men were eligible for analysis. The median age was 72 years (yrs), 81/200 pts had a Gleason score (GS) ≥ 8, 34/200 had an elevated CGA. At a median follow up of 2.2 yrs, 156/200 were deceased. In the subset of men with GS ≥ 8, elevated CGA was associated with shorter OS [hazard ratio (HR) 2.19, p = 0.017]. In the VC, 71 men were eligible for analysis. The median age was 71 yrs, 36/71 tumors were GS ≥ 8, 31/71 pts had an elevated CGA, 26/66 had unfavorable CTCs (≥ 5). At a median follow up of 1.8 yrs, 31/71 were deceased. Elevated CGA (HR 1.91, p = 0.043) and unfavorable CTC counts (HR 2.97, p = 0.0012) were adversely associated with OS. In the high GS group, both CTCs and CGA had the same area under the curve (AUC) of 0.72. Pts with elevated CTC and CGA had the poorest OS (HR 3.76, p = 0.008). Conclusions: Elevated serum CGA was negatively associated with OS in men with mCRPC. Serum CGA represents a prognostic biomarker that may complement CTC enumeration. Clinical trial information: NCT#01953640.
MRD(微小残存病変)反応の遅延により,小児期のT細胞ALL(急性リンパ性白血病)の全体的および部分的な再発リスクが明らかになる: AIEOP-BFM-ALL 2000試験の成績
Authors: Schrappe Martin, Valsecchi Maria Grazia, R Bartram Claus, Schrauder Andre, Panzer-Gruemayer Renate, Moericke Anja, Parasole Rosanna, Zimmermann Martin, Dworzak Michael, Buldini Barbara, Reiter Alfred, Basso Giuseppe, Klingebiel Thomas, Messina Chiara, Ratei Richard, Cazzaniga Giovanni, Koehler Rolf, Locatelli Franco, W Schaefer Beat, Arico Maurizio, Welte Karl, J M Van Dongen Jacques, Gadner Helmut, Biondi Andrea, Conter Valentino
Journal: Blood (2011)
Abstract P1-07-15: Withdrawn
Authors: C Desmedt, M Fornili, C Poncet, F Clatot, A Orenti, P Boracchi, A Di Leo, G Viale, E de Azambuja, C Sotiriou, J Crown, PA Francis, H Bonnefoi, M Piccart, E Biganzoli
Journal: Cancer Research (2018)

Abstract This abstract was withdrawn by the authors.
Diploma in practical dermatology (DPD)
Authors: Stephen Kell
Journal: BMJ (2005)

General practitioners (GPs) who would like to increase their practical knowledge or skills in dermatology. It's ideal for anyone who wants to learn in a supportive, interactive, and enjoyable environment and has other work commitments.⇓



2003-4. I felt it was important to do it at that stage as I was in the process of trying to establish a local GP with a special interest service.

I'd been a clinical assistant in dermatology for three years and wanted to improve my …
Diabetes and Hypertension in India
Authors: Pascal Geldsetzer, Jennifer Manne-Goehler, Michaela Theilmann, Justine I. Davies, Ashish Awasthi, Sebastian Vollmer, Lindsay M. Jaacks, Till Bärnighausen, Rifat Atun
Journal: JAMA Internal Medicine (2018)

Understanding how diabetes and hypertension prevalence varies within a country as large as India is essential for targeting of prevention, screening, and treatment services. However, to our knowledge there has been no prior nationally representative study of these conditions to guide the design of effective policies.To determine the prevalence of diabetes and hypertension in India, and its variation by state, rural vs urban location, and individual-level sociodemographic characteristics.This was a cross-sectional, nationally representative, population-based study carried out between 2012 and 2014. A total of 1 320 555 adults 18 years or older with plasma glucose (PG) and blood pressure (BP) measurements were included in the analysis.State, rural vs urban location, age, sex, household wealth quintile, education, and marital status.Diabetes (PG level ≥126 mg/dL if the participant had fasted or ≥200 mg/dL if the participant had not fasted) and hypertension (systolic BP≥140 mm Hg or diastolic BP≥90 mm Hg).Of the 1 320 555 adults, 701 408 (53.1%) were women. The crude prevalence of diabetes and hypertension was 7.5% (95% CI, 7.3%-7.7%) and 25.3% (95% CI, 25.0%-25.6%), respectively. Notably, hypertension was common even among younger age groups (eg, 18-25 years: 12.1%; 95% CI, 11.8%-12.5%). Being in the richest household wealth quintile compared with being in the poorest quintile was associated with only a modestly higher probability of diabetes (rural: 2.81 percentage points; 95% CI, 2.53-3.08 and urban: 3.47 percentage points; 95% CI, 3.03-3.91) and hypertension (rural: 4.15 percentage points; 95% CI, 3.68-4.61 and urban: 3.01 percentage points; 95% CI, 2.38-3.65). The differences in the probability of both conditions by educational category were generally small (≤2 percentage points). Among states, the crude prevalence of diabetes and hypertension varied from 3.2% (95% CI, 2.7%-3.7%) to 19.9% (95% CI, 17.6%-22.3%), and 18.0% (95% CI, 16.6%-19.5%) to 41.6% (95% CI, 37.8%-45.5%), respectively.Diabetes and hypertension prevalence is high in middle and old age across all geographical areas and sociodemographic groups in India, and hypertension prevalence among young adults is higher than previously thought. Evidence on the variations in prevalence by state, age group, and rural vs urban location is critical to effectively target diabetes and hypertension prevention, screening, and treatment programs to those most in need.
Update in Pulmonary Vascular Disease 2016 and 2017
Authors: Evan L. Brittain, Thennapan Thennapan, Bradley A. Maron, Stephen Y. Chan, Eric D. Austin, Edda Spiekerkoetter, Harm J. Bogaard, Christophe Guignabert, Roxane Paulin, Roberto F. Machado, Paul B. Yu
Journal: American Journal of Respiratory and Critical Care Medicine (2018)
BMA urges action to make general practice a more attractive career
Authors: Abi Rimmer
Journal: BMJ (2013)

The BMA has told NHS England that “urgent action” must be taken to make general practice a more attractive career if the government wants to achieve its aim of increasing the GP workforce.

In its response to NHS England’s consultation on the future of general practice,1 the BMA told the body that it was “imperative” to strengthen the existing GP trainee contract as …
<i>Editor’s Choice</i>A useful anachronism
Authors: Tom Moberly
Journal: BMJ (2016)

What does “first do no harm” mean for an overstretched doctor working in an under-resourced health service?

Does it mean protecting patients from potentially harmful government policies, as when junior doctors withdrew their provision of emergency care to protect patients from unsafe service provision in the future?

Does it mean providing preventive treatments to broad groups of …
Radiation therapy and immune-related side effects in patients treated with PD-1 inhibitors.
Authors: Nadine Abdallah, Suketu Nagin Patel, Misako Nagasaka, Seongho Kim, Harold E. Kim, Ammar Sukari
Journal: Journal of Clinical Oncology (2018)

207 Background: Checkpoint inhibitors exert their antitumor effects by producing a heightened immune state, and inadvertently give rise to immune-mediated toxicities, including pneumonitis and hypothyroidism. We investigated whether these side effects were more common in patients who were treated with both PD-1 inhibitors and radiation. Methods: Our institution’s pharmacy database was used to collect data on patients who received ≥ 1 dose of PD-1 inhibitors, with or without radiation before August 31, 2016. Adverse effects of hypothyroidism, and pneumonitis were recorded and graded based on CTCAEv4. A logistic regression analysis was performed between radiation and hypothyroidism among patients with Hodgkin’s lymphoma (HL) and head and neck squamous cell carcinoma (HNSCC) and between radiation therapy (RT) and pneumonitis in lung cancer patients. Results: 231 patients received at least one dose of PD-1 inhibitors prior to data cut-off. Median age was 65 (24-92). There were 125 patients (54%) with lung cancer, 18 (8%) with HL and 9 (4%) with HNSCC. 115 patients received radiation. HL and HNSCC patients had higher odds to experience hypothyroidism (adjusted p = 0.023) but this did not seem to be due to RT exposure [HR:0.156, 95% CI 0.008-1.122, p = 0.110]. Lung cancer patients with thoracic radiation had higher odds to experience pneumonitis [HR:2.206, 95% CI 0.451-15.931] although this was not statistically significant (p = 0.358). Conclusions: There was no association between RT and hypothyroidism. Our results suggested a possible increased risk of pneumonitis with thoracic radiation among lung cancer patients treated with PD-1 inhibitors, although statistically insignificant. Larger prospective studies are needed to further delineate this effect.
ENDOSCOPIC INJECTION OF ALPHA-CYANOACRYLATE MONOMER (A-CA) FOR A THORACIC ENDOVASCULAR REPAIR (TEVAR) WITH A STENT GRAFT FOR AN AORTOESOPHAGEAL FISTULA
Authors: Katsuki Matsumiya, Shuzo Nishihara, Hiroyuki Miyagami
Journal: Journal of the American College of Cardiology (2018)
James B Richardson: persuaded NICE to recommend stem cell therapy for cartilage repair
Authors: Penny Warren
Journal: BMJ (2018)

In October 2017 the man affectionately known to his team simply as “Prof” delivered a momentous announcement at the 11th annual Oswestry Cartilage Symposium. After more than 20 years of trials and research, the National Institute for Health and Care Excellence (NICE) had finally approved the autologous chondrocyte implantation (ACI) procedure for articular cartilage defect.

ACI involves taking chondrocytes from healthy cartilage, culturing them in the laboratory, and then transplanting them into a damaged area of cartilage. It was developed by Richardson’s team at the Robert Jones and Agnes Hunt Orthopaedic Hospital (RJAH) in Oswestry.

Sally Roberts, a longstanding colleague, says that Richardson’s ability to see a project through was key: “James was an optimist and an enthusiast. He saw the bigger picture. And if he believed in something he would chase it and follow it through.”

Richardson was born near Inverness in 1955. He went …
Up to 40% of new consultant posts in England have fewer than 2.5 SPAs
Authors: Helen Jaques
Journal: BMJ (2012)

At least a third and possibly as many as 40% of new consultants appointed in England between September 2010 and September 2011 took up posts with fewer than 2.5 supporting professional activities (SPAs) a week, a BMJ Careers investigation has found. 

SPAs are designed to allow consultants time outside their clinical care duties for teaching, training, education, continuing professional development, audit, appraisal, research, clinical management, clinical governance, and service development. 

This time is important for improving the quality and efficiency of healthcare, so it is disappointing that some trusts don’t seem to be making SPAs a priority in new posts, said Ian Wilson, deputy chairman of the BMA’s Central Consultants and Specialists Committee.

“The BMA has always argued that SPA time needs to be matched …
Abstract P3-15-05: Early breast cancer in the elderly: characteristics, therapy, and long-term outcome
Authors: O Gal, Y Ishai, A Sulkes, T Shochat, R Yerushalmi
Journal: Cancer Research (2018)

Abstract Objective: The number of older adults diagnosed with breast cancer is increasing. However, data on breast cancer characteristics, treatment, and survival in elderly women are sparse. Methods: The database of a tertiary cancer center was searched for all women aged &amp;gt;65 years who were diagnosed with early breast cancer in 2004-2007. Patients were divided into two age groups: 65-75 years and &amp;gt;75 years. Data on tumor, treatment and outcome parameters were compared. Results: The cohort included 390 patients. The older group underwent more mastectomies but less axillary surgery or adjuvant systemic therapy. Median overall survival (OS) was 9.5 years in the older group and not reached in the younger group; the 8 year disease-free survival rates were 85% and 88%, respectively (p=0.27). Both age and tumor subtype had an effect on OS and recurrence rates (p&amp;lt;0.001 for OS; p=0.16 for recurrence). The worst outcome was noted in women aged &amp;gt;75 years with triple-negative (TN) disease. Conclusion: Treatment approach was different between both age groups, despite similar tumor characteristics. TN subtype presented as the most aggressive disease in both age groups. Physicians should be alert to these findings and select treatment on a case-by-case basis. Citation Format: Gal O, Ishai Y, Sulkes A, Shochat T, Yerushalmi R. Early breast cancer in the elderly: characteristics, therapy, and long-term outcome [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 P3-15-05.
Clinical and biomechanical outcomes of rehabilitation targeting intersegmental control in athletic groin pain: prospective cohort of 205 patients
Authors: Enda King, Andrew Franklyn-Miller, Chris Richter, Eamon O’Reilly, Mark Doolan, Kieran Moran, Siobhan Strike, Éanna Falvey
Journal: British Journal of Sports Medicine (2018)

Clinical assessments and rehabilitation in athletic groin pain (AGP) have focused on specific anatomical structures and uniplanar impairments rather than whole body movement.To examine the effectiveness of rehabilitation that targeted intersegmental control in patients with AGP and to investigate post rehabilitation changes in cutting biomechanics.Two hundred and five patients with AGP were rehabilitated focusing on clinical assessment of intersegmental control, linear running and change of direction mechanics in this prospective case series. Hip and Groin Outcome Score (HAGOS) was the primary outcome measure. Secondary measures included pain-free return to play rates and times, pain provocation on squeeze tests and three-dimensional (3D) biomechanical analysis during a 110° cutting manoeuvre.Following rehabilitation, patients demonstrated clinically relevant improvements in HAGOS scores (effect size (ES): 0.6-1.7). 73% of patients returned to play pain-free at a mean of 9.9 weeks (±3.5). Squeeze test values also improved (ES: 0.49-0.68). Repeat 3D analysis of the cutting movement demonstrated reductions in ipsilateral trunk side flexion (ES: 0.79) and increased pelvic rotation in the direction of travel (ES: 0.76). Changes to variables associated with improved cutting performance: greater centre of mass translation in the direction of travel relative to centre of pressure (ES: 0.4), reduced knee flexion angle (ES: 0.3) and increased ankle plantar flexor moment (ES: 0.48) were also noted.Rehabilitation focused on intersegmental control was associated with improved HAGOS scores, high rates of pain-free return to sporting participation and biomechanical changes associated with improved cutting performance across a range of anatomical diagnoses seen in AGP.
Put patients first⇓
Authors: Nicola Sharp
Journal: BMJ (2004)

Dear Dr Carter, Dr Doorman, and Dr Millstone, I wish to resign from my post as salaried partner at Murkton Moor Health Centre. 

Justin Peters reread the letter then threw it in the waste paper bin. He turned to the computer and started again, Dear Giles, I'm sorry but I... 

Giles Millstone walked in and looked over at the computer screen. “Typing your own letters?” he asked. “The secretary is very slow.”

“It's something personal,” said Justin and pressed delete.

“I wasn't going to read it,” said Giles. “I've come to tell you that I've decided to work full time again.”

“I suppose that's good news,” said Justin. “Does Penelope mind?”

“I don't know,” said Giles.

“Is she coming to Dr Carter's leaving do tonight?”

“Probably not.”

“Have you two sorted out your problems yet?”

“Not exactly.”

The door opened, and Dr Burney entered. He was wearing a red and green golfing sweater and a black and white checked cap. Giles and Justin stared at him.

“You're too early for Dr Carter's leaving do,” said Justin. “We're meeting at the Central Hotel at seven o'clock.”

“I am the solution to all your problems,” said Dr Burney.

“I very much doubt it,” said Giles. …
Post-chemotherapy PD-L1 expression correlates with clinical outcomes in Japanese bladder cancer patients treated with total cystectomy.
Authors: Yasuhiro Hashimoto, Daisuke Noro, Shingo Hatakeyama, Takahiro Yoneyama, Takuya Koie, Toshiaki Kawaguchi, Chikara Ohyama
Journal: Journal of Clinical Oncology (2018)

416 Background: Programmed cell death ligand-1 (PD-L1) is a key target molecule of immunotherapy that is frequently overexpressed in bladder cancer. In the present study, we examined whether PD-L1 expression is associated with clinical outcomes in bladder cancer patients. Methods: We enrolled 102 bladder cancer patients treated with cystectomy at the Aomori Prefectural Hospital between April 2004 and May 2014. We conducted an immunohistochemical examination of PD-L1 expression using the SP142 assay. PD-L1 expression was scored at three diagnostic levels (0/1/2). Results: Of the 102 patients, 82 were men (81.0%) and 20 were women (19.0%) (mean age 60 years, range 43-84 years). Sixty-six patients (64.8%) had previously undergone neoadjuvant chemotherapy [neoadjuvant (+) group]. During the mean observation period of 54.5 months, 42 patients had recurring disease (41.1%) and 34 died (33.3%). The 5-year cause-specific survival (CSS) rate was 66.6%; the 5-year disease-free survival (DFS) rate was 59.7%. In the neoadjuvant (+) group, the 5-year DFS rate was 65.0% for PD-L1 (-) patients and 31.7% for PD-L1 (+) patients (log-rank p = 0.006). In the neoadjuvant (+) groups, the 5-year CSS rate was 69.6% for PD-L1 (-) patients and 48.1% for PD-L1 (+) patients. Differences in CSS and DFS rates between PD-L1 (-) and PD-L1 (+) patients in both treatment groups were statistically significant (log-rank p = 0.006 and 0.039, respectively.) Conclusions: Despite the small study size, our data suggest that post-chemotherapy PD-L1 expression is associated with poor prognosis in patients receiving neoadjuvant chemotherapy who had previously undergone cystectomy.
RISK OF MYOCARDIAL INFARCTION AND COMPOSITE VASCULAR EVENTS IN PATIENTS WITH HERPES ZOSTER: 2007-2014 UNITED STATES CLAIMS DATA ANALYSIS
Authors: Brandon Patterson, Debora A. Rausch, Debra E. Irwin, Michael Liang, Songkai Yan, Barbara Yawn
Journal: Journal of the American College of Cardiology (2018)