tbuckley/cabot-search huggingface dataset:
Outcomes of immunotherapy in advanced melanoma in relation to age.
Authors: Krishna Prasad Joshi, Dinesh Atwal, Rahul Ravilla, Jun Tao, Joseph Su, Issam Makhoul, Laura Fulper Hutchins, Fade A. Mahmoud
Journal: Journal of Clinical Oncology (2018)

187 Background: Older age is a risk feature in melanoma. Elderly are more likely to have immunosenescence, which could help melanoma cells escape immune surveillance. Hence, there is a belief that elderly people cannot mount a potent immune response to checkpoint inhibitors (CPI) to fully eliminate melanoma. The objective of the study was to investigate age-related differences in the time to progression (TTP), overall survival (OS), and immunotherapy related adverse events (irAEs) among patients with metastatic melanoma who received CPI. Methods: We retrospectively identified patients with stage IV melanoma who received at least 1 dose of ipilimumab, pembrolizumab, nivolumab, or combined ipilimumab and nivolumab. Demographics, pathologic, and clinical characteristics were obtained. Immune-related response criteria were utilized to define responses. Results: Sixty patients were included; 29 were less than 65 years old and 31 were 65 years or older. No significant differences, when adjusted for gender, type of melanoma and presence of brain metastasis, in TTP [HR 0.79; 95% CI (0.371.70); p = 0.46] and OS [Hazard ratio (HR) 0.75; 95% CI (0.31-1.82); P = 0.491] was observed between the &lt; 65 and ≥65 year-old groups who received CPI for metastatic melanoma. Overall irAEs in two groups was comparable with 62% in the younger patients and 45% in the older patients (P = 0.19). Thirty responders had a median age of 66.9 (54.3-73.3 years old) and 30 non-responders had a median age of 62.7 (54-69.1 years old). Non-responders, regardless of age, were more likely to have BRAF mutated melanomas (53.3% vs. 27.6%; P = 0.04) and less likely to have irAEs (40% vs. 66.7%; P = 0.04) than responders. Conclusions: No difference in TTP, OS or irAEs was observed between the elderly and the young patients who received CPI for metastatic melanoma. In general, responders had higher irAEs and less BRAF mutated melanomas than non-responders.
Some unanswered questions about NICE
Authors: Simon J Ellis
Journal: Journal of the Royal Society of Medicine (1999)

The stated aims of the National Institute of Clinical Excellence are 'to improve standards of patient care, and to reduce inequities in access to innovative treatment'2. So much for the stated aims: NICE is about rationing3. Since the inception of state-organized healthcare, there has been a dialectical tension between the expectations of patients, the aspirations of healthcare professionals and the public purse. Explicitly, or more commonly implicitly, this has meant rationing. Politicians talk of setting priorities, but for rational decision-making one has to follow the advice of Marcus Aurelius: 'look things in the face and know them for what they are'4.
Efficacy of Epratuzumab, an Anti‐<scp>CD</scp>22 Monoclonal IgG Antibody, in Systemic Lupus Erythematosus Patients With Associated Sjögren's Syndrome
Authors: Jacques‐Eric Gottenberg, Thomas Dörner, Hendrika Bootsma, Valérie Devauchelle‐Pensec, Simon J. Bowman, Xavier Mariette, Holger Bartz, Marga Oortgiesen, Anthony Shock, Willem Koetse, Catrinel Galateanu, Sabine Bongardt, William A. Wegener, David M. Goldenberg, Guy Meno‐Tetang, Gordana Kosutic, Caroline Gordon
Journal: Arthritis & Rheumatology (2018)

Objective EMBODY 1 (ClinicalTrials.gov identifier: NCT 01262365) and EMBODY 2 (ClinicalTrials.gov identifier: NCT 01261793) investigated the efficacy and safety of epratuzumab, a CD 22‐targeted humanized monoclonal IgG antibody, in patients with systemic lupus erythematosus ( SLE ). The studies showed no significant difference from placebo in primary or secondary clinical outcome measures but did demonstrate B cell–specific immunologic activity. The aim of this post hoc analysis was to determine whether epratuzumab had a different clinical efficacy profile in SLE patients with versus those without an associated diagnosis of Sjögren's syndrome (SS). Methods The efficacy and safety of epratuzumab were compared between 2 patient subpopulations randomized in EMBODY 1 and 2: SLE patients with and those without a diagnosis of associated SS . British Isles Lupus Assessment Group ( BILAG ) total score, BILAG ‐based Combined Lupus Assessment ( BICLA ) clinical response to treatment, biologic markers (including B cells, IgG, IgM, and IgA), and safety were assessed. Results A total of 1,584 patients were randomized in the EMBODY 1 and EMBODY 2 trials; 113 patients were anti‐ SSA positive and had a diagnosis of associated SS , and 1,375 patients (86.8%) had no diagnosis of associated SS (918 patients were randomized to receive epratuzumab and 457 to receive placebo). For patients with associated SS , but not those without associated SS , a higher proportion of patients receiving epratuzumab achieved a BICLA response and a reduction from baseline in BILAG total score. B cell reduction was faster in patients with associated SS . The sensitivity of B cells to epratuzumab as measured by the mean concentration producing 50% of the maximum B cell count depletion was lower for patients with associated SS (9.5 μg/ml) versus the total EMBODY population (87.1 μg/ml). No difference in the frequency of adverse events in those receiving placebo was reported. Conclusion Patients with SLE and associated SS treated with epratuzumab showed improvement in SLE disease activity, which was associated with bioactivity, such as decreases in B cell number and IgM level.
A translational effort to identify prognostic and predictive biomarkers in pancreatic cancer among RBM3-regulated genes.
Authors: Sofie Olsson Hau, Emelie Karnevi, Sebastian Lundgren, Bo Li, Seodhna Lynch, Jacob Elebro, Margareta Heby, Bjorn Nodin, Jakob Eberhard, Mathias Uhlen, Bruce Moran, William M. Gallagher, Karin Jirstrom
Journal: Journal of Clinical Oncology (2018)

305 Background: Pancreatic cancer has a dismal prognosis and clinical protocols are still lacking predictive biomarkers. RNA-binding motif protein 3 (RBM3) has emerged as a promising biomarker in several solid cancers, including pancreatic cancer. High RBM3 expression in human tumors has been associated with good response to chemotherapy, as well as to confer increased chemosensitivity in vitro. The aim of this study was to identify RBM3-regulated genes in pancreatic cells in vitro, and further interrogate their potential utility as prognostic and predictive biomarkers in a translational setting. Methods: Next generation RNA-sequencing was applied to compare gene expression between MIAPaCa-2 cells with siRNA-downregulated RBM3 and control cells. Single genes with the strongest association to RBM3 were further selected by gene set enrichment analysis, and their prognostic value in pancreatic cancer was examined in The Cancer Genome Atlas (TCGA). The most promising biomarker candidates with well-validated antibodies were then analyzed by immunohistochemistry in tissue microarrays with tumors from a consecutive, retrospective cohort of 175 patients with periampullary and pancreatic adenocarcinoma. Results: MIAPaCa-2 cells with downregulated RBM3 displayed 21 differentially expressed genes (p &lt; 0.01). One of the top downregulated genes was PDS cohesion associated factor A (PDS5A) encoding a protein involved in sister chromatid cohesion. PDS5A protein expression was reduced in siRBM3-treated MIAPaCa-2 cells compared to control cells. High PDS5A mRNA expression was significantly associated with a reduced survival in pancreatic cancer in the TCGA (n = 176, p = 0.026). High PDS5A protein expression in the separate cohort was significantly associated with a poor prognosis but predictive of improved response to adjuvant chemotherapy in KRAS-mutated, but not wild-type, pancreatobiliary-type tumors (p for interaction = 0.043). Conclusions: Here, we provide the first report of the expression of PDS5A in pancreatic and periampullary cancer, suggesting its potential utility as a prognostic and predictive biomarker. Further studies to unravel the underlying mechanisms are encouraged.
Evaluation of prostate cancer risk in men with PSA &lt; 1.5.
Authors: Whitney N. Stanton, E. David Crawford, Paul Arangua, John Hoenemeyer, Francisco G. La Rosa, Adrie van Bokhoven, M. Scott Lucia, Wendy Poage, Priya N. Werahera
Journal: Journal of Clinical Oncology (2018)

64 Background: Prostate Specific Antigen (PSA) screening remains controversial primarily because of over detection and treatment. There is an unmet clinical need to identify patients at increased risk for high-grade (HG – Gleason Score ≥7) prostate cancer (PCa) since PSA has low sensitivity. Combining PSA with well-validated prostate cancer biomarkers (PCM) can improve risk assessment. We investigated the performance of three PCMs (phi – prostate health index, 4KScore, and SelectMDx) on patients with PSA levels &lt; 1.5 ng/mL that represent a “safe zone” where risk of any PCa is rare Methods: 652 men were screened for PCa during the annual Prostate Cancer Awareness Week at the University of Colorado Hospital. This study was supported by Prostate Condition Education Council and the Schramm Foundation. phi is evaluated using p2PSA, total PSA, and free PSA in serum. Phi &lt; 52.7 suggests absence of HG PCa. 4KScore incorporates four kallikrein protein biomarkers: total PSA, free PSA, intact PSA, human kallikrein protein, and clinical information. A 4KScore &lt; 20% suggests absence of HG PCa. The SelectMDx post-DRE urine test measures mRNA levels of the homeobox C6 and distal-less homeobox 1 biomarkers. SelectMDx score of 0% indicates absence of HG PCa. Results: No patients with a PSA &lt; 1.5 had SelectMDx &gt; 0% and/or phi &gt; 52.7. One patient had a 4KScore of 27%, indicating a risk for HG PCa. For patients with PSA between 1.5-3.99, 2.9% (4/135), 7.4% (4/54), and 2.3% (2/85) had positive phi, 4KScore, and SelectMDx results, respectively. Conclusions: Men with PSA &lt;1.5 ng/mL are at very low risk for HG PCa. Men with PSA between 1.5-3.99 with positive PCM results may be referred for further evaluation. [Table: see text]
Implementation of a Structured Diabetes Consultation Model to Facilitate a Person-Centered Approach: Results From a Nationwide Dutch Study
Authors: Guy E H M Rutten, Heidi A van Vugt, Inge de Weerdt, Eelco de Koning
Journal: Diabetes Care (2018)

We assessed both from a patient and provider perspective the usefulness and added value of a consultation model that facilitates person-centered diabetes care.The model consists of 1) inventory of disease and patient-related factors; 2) setting personal goals; 3) choosing treatment; and 4) determination of required care. It was implemented in 47 general practices and 6 hospital outpatient clinics. Providers were trained, and patients were recommended to prepare their visit. All filled out a questionnaire after every consultation. Differences between primary and secondary care practices and between physician-led and nurse-led consultations were analyzed.Seventy-four physicians and thirty-one nurses participated, reporting on 1,366 consultations with type 2 diabetes patients. According to providers, the model was applicable in 72.4% (nurses 79.3% vs. physicians 68.5%, P < 0.001). Physicians more often had a consultation time <25 min (80.4% vs. 56.9%, P < 0.001). According to providers, two of three patients spoke more than half of the consultation time (outpatient clinics 75.2% vs. general practices 66.6%, P = 0.002; nurses 73.2% vs. physicians 64.4%, P = 0.001). Providers stated that person-related factors often determined treatment goals. Almost all patients (94.4%) reported that they made shared decisions; they felt more involved than before (with physicians 45.1% vs. with nurses 33.6%, P < 0.001) and rated the consultation 8.6 of 10. After physician-led consultations, 52.5% reported that the consultation was better than before (nurse visit 33.7%, P < 0.001).A consultation model to facilitate person-centered care seems well applicable and results in more patient involvement, including shared decision making, and is appreciated by a substantial number of patients.
T cell autoreactivity directed toward CD1c itself rather than toward carried self lipids
Authors: Kwok S. Wun, Josephine F. Reijneveld, Tan-Yun Cheng, Kristin Ladell, Adam P. Uldrich, Jérôme Le Nours, Kelly L. Miners, James E. McLaren, Emma J. Grant, Oscar L. Haigh, Thomas S. Watkins, Sara Suliman, Sarah Iwany, Judith Jimenez, Roger Calderon, Kattya L. Tamara, Segundo R. Leon, Megan B. Murray, Jacob A. Mayfield, John D. Altman, Anthony W. Purcell, John J. Miles, Dale I. Godfrey, Stephanie Gras, David A. Price, Ildiko Van Rhijn, D. Branch Moody, Jamie Rossjohn
Journal: Nature Immunology (2018)
THREE-YEAR OUTCOMES IN ‘REAL-WORLD’ PATIENTS TREATED WITH A THIN-STRUT, PLATINUM-CHROMIUM, EVEROLIMUS-ELUTING STENT IN THE PROMUS ELEMENT PLUS U.S. POST-APPROVAL STUDY (PE-PLUS PAS)
Authors: David E. Kandzari, Jeffrey Chambers, Stilianos Efstratiadis, Matthew Wolff, Steve Lin, Anthony White, Stephen McIntyre, Michael Kelberman, William Berg, Alan Moak, Sandeep Dube, Thomas Christen, Keith Dawkins
Journal: Journal of the American College of Cardiology (2017)
Haemodynamics to predict outcome in pulmonary hypertension due to left heart disease: a meta-analysis
Authors: Sergio Caravita, Céline Dewachter, Davide Soranna, Sandy Carolino D'Araujo, Amina Khaldi, Antonella Zambon, Gianfranco Parati, Antoine Bondue, Jean-Luc Vachiéry
Journal: European Respiratory Journal (2018)

Pulmonary hypertension (PH) is a common complication of left heart disease (LHD), as the result of a "passive" increase of left atrial pressure (LAP), leading to isolated post-capillary PH [1–3]. Several haemodynamic parameters have been proposed to identify a more severe phenotype of PH-LHD, for which the increase in pulmonary artery pressure cannot be accounted for by the increase in LAP, and described as combined post-capillary PH with a pre-capillary component, or CpcPH [1–3]. The latter haemodynamic phenotype may potentially expose patients to a higher risk of right ventricular failure and a poorer outcome [4, 5]. However, since the last World Symposium in 2013, how to define the pre-capillary component in PH-LHD has been a matter of debate, as pathophysiological arguments have been suggested to potentially contrast with clinical and prognostic evidences [1]. PVR, DPG, PAC are all associated with survival in pulmonary hypertension due to left heart disease <http://ow.ly/R8sF30ieHSQ> The authors would like to thank Irene Lang, Christian Gerges and Mario Gerges (Division of Cardiology, Department of Internal Medicine II, General Hospital Vienna (AKH-Wien), Medical University of Vienna, Vienna, Austria) for having provided their own data, otherwise not available for this meta-analysis.
Phase I study of defactinib combined with pembrolizumab and gemcitabine in patients with advanced cancer.
Authors: Andrea Wang-Gillam, A. Craig Lockhart, Benjamin R. Tan, Rama Suresh, Kian-Huat Lim, Lee Ratner, David G. DeNardo
Journal: Journal of Clinical Oncology (2018)

2561 Background: Focal adhesion kinase (FAK) is consistently hyperactivated in multiple tumor types including pancreatic ductal adenocarcinoma (PDAC). Our preclinical work showed that FAK and PD-1 inhibitors elicit significant tumor regression, and a maximal response is achieved by combining FAK and PD-1 inhibitors with gemcitabine, suggesting the need for a cytotoxic agent to bolster antigen presentation (Jiang H et al, Nature Medicine 2016). Methods: Eligible patients are being treated according to the dose escalation schema (Table 1). A 3+3 design is being used. The study has an expansion portion for PDAC patients at the recommended phase 2 dose (RP2D). The primary endpoint is to determine the RP2D. Secondary endpoints include safety, toxicity, objective response rate, progression-free survival and overall survival. The exploratory endpoints include developing a molecular and immune profile for treatment response. Results: The dose escalation cohort has been completed with a total of 20 patients with refractory solid tumors. The common treatment-related adverse events included nausea (50%), vomiting (40%), diarrhea (35%), anorexia (30%), fever (25%), and myalgia (25%). No DLTs were observed, therefore the Level 5 dose was deemed to be the RP2D. Among the 15 patients evaluable for treatment response, 1 (7%) partial response, 8 (53%) stable disease and 6 (40%) disease progression were observed. The median time on treatment was 132 days for all evaluable patients, and 127 days in the 8 PDAC patients with the longest time on treatment being 290 days. Partial response was seen in a patient with PDAC who progressed on gemcitabine and nab-paclitaxel. Paired biopsies in PDAC patients showed increased proliferating CD8+ T cells and decreased macrophages with treatment. Conclusions: The combination regimen is well tolerated. Dose Level 5 is the RP2D dose. The expansion cohort (PDAC only) is ongoing. Efficacy and correlative data is forthcoming. Clinical trial information: 02546531.Dose escalation schema. Dose Level Defactinib D1-21 (BID) Pembrolizumab D1 Gemcitabine D1, 8 Level 1 (starting dose) 200 mg 200 mg - Level 2 400 mg 200 mg - Level 3 400 mg 200 mg 500 mg/m2 Level 4 400 mg 200 mg 750 mg/m2 Level 5 400 mg 200 mg 1,000 mg/m2
What level of income can I expect if a UK practice says it is “well above average” or “very profitable”?
Authors: Steve McCabe
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>
Docetaxel with or without ramucirumab after immune checkpoint inhibition in platinum-refractory metastatic urothelial carcinoma (mUC): Prespecified subgroup analysis from the phase 3 RANGE trial.
Authors: Alexandra Drakaki, Conor J Kirby, Michiel Simon Van Der Heijden, Daniel Peter Petrylak, Thomas Powles, Kim N. Chi, Aude Flechon, Andrea Necchi, Lajos Geczi, Jae-Lyun Lee, Georgios Gakis, Sergio Bracarda, Simon Chowdhury, Chia-Chi Lin, Daniel Keizman, Ulka N. Vaishampayan, Astra M. Liepa, Annamaria Zimmermann, Katherine M Bell-McGuinn, Daniel E. Castellano
Journal: Journal of Clinical Oncology (2018)

434 Background: Immune checkpoint inhibitors (ICI) targeting PD-1/PD-L1 have shown objective response rates (ORR) of 15-21% in PD-L1 unselected patients (pts) with platinum-refractory mUC. Overall results of RANGE, a randomized, double-blinded phase 3 trial comparing ramucirumab and docetaxel (R+D) to placebo and docetaxel (P+D) in pts with platinum-refractory mUC demonstrated an ORR of 24.5% to R+D and a statistically significant improvement in progression free survival (PFS; median 4.07 vs 2.76 mo; HR 0.757). Here we present a pre-specified subgroup analysis of pts who received a prior ICI. Methods: RANGE enrolled pts with progressive mUC during or after platinum-based chemotherapy. Additional prior treatment with one ICI was permitted. Pts were randomized (1:1) to receive D 75 mg/m 2 up to 10 cycles with R 10 mg/kg or P on day 1 of a 21-day cycle until disease progression or other discontinuation criteria. Primary endpoint, investigator-assessed PFS, was analyzed in the first 437 randomized pts. Secondary endpoints included overall survival, objective response, and safety. Radiographic assessment occurred every 6 weeks. Results: Thirty three of the 437 pts (8%) in the PFS population received a prior ICI. The majority (91%) received the ICI immediately following platinum and immediately prior to RANGE. Most pts received atezolizumab (55%) or pembrolizumab (36%); ORR to prior ICI was 6% and the majority (67%) had progressive disease as best response. Median duration of the ICI was 3.5 mo (IQR 1.6-5.2). Disease sites at entry onto RANGE included lymph node (79%), lung (48%), liver (39%) and bone (18%). At data cutoff, responses were achieved by 5/14 (35.7%) on R+D, compared to 2/19 (10.5%) on P+D. Responses to R+D were independent of disease site. Of pts with liver metastases, 3/8 responded to R+D compared to 0/5 on P+D. Overall, median PFS was 5.29 mo on R+D and 2.76 mo on P+D (HR 0.920). The frequency of grade ≥3 adverse events was similar between arms. Conclusions: Acknowledging limitations of sample size, R+D showed higher ORR than P+D in pts who had progressed on platinum and ICI therapy, including those with liver metastases. Clinical trial information: NCT02426125.
Pilot study of moderately-hypofractionated intensity-modulated radiation therapy over 3 weeks for localized prostate cancer.
Authors: Kiyonao Nakamura, Haruo Inokuchi, Itaru Ikeda, Tomomi Kamba, Takahiro Inoue, Toshinari Yamasaki, Takashi Kobayashi, Osamu Ogawa, Takashi Mizowaki
Journal: Journal of Clinical Oncology (2018)

8 Background: The purpose of this trial was to prospectively evaluate the short-term outcomes of moderately hypofractionated intensity-modulated radiation therapy (MH-IMRT) for localized prostate cancer. Methods: In November 2013, we started a pilot study of MH-IMRT for prostate cancer. Eligible patients were 50 to 80 years old and had D’Amico’s low- or intermediate-risk disease. Fifty-four Gy in 15 fractions (3.6 Gy per fraction), in which the equivalent total dose in 2-Gy fractions to prostate cancer was estimated about 78 Gy, were delivered over 3 weeks using image-guided IMRT based on daily cone beam CT without intraprostatic fiducial markers. Neoadjuvant androgen deprivation therapy was given 4 to 8 months before the start of IMRT. The primary endpoint was incidence rates of acute toxicities, and the secondary endpoints were incidence rates of late toxicities at 2 years and biochemical relapse free survival (BRFS) at 2 years. Acute toxicities were evaluated based on the Common Terminology Criteria for Adverse Events version 4.0 criteria. Late toxicities were evaluated based on RTOG/EORTC Late Radiation Morbidity Scoring Schema. Biochemical relapse was defined according to the Phoenix definition (absolute nadir + 2 ng/ml). The planned sample size was 25 patients. Results: Twenty-five patients were enrolled in this trial. Twenty-four patients were treated with MH-IMRT, and 1 patient was treated with conventionally fractionated IMRT because his small intestine was close to the target. The median age in the cohort was 71 years old, and median follow-up period was 31 months (range 24-42). Four patients (17%) had low- and 20 (83%) had intermediate-risk disease. No grade ≥3 acute toxicity was observed and the incidence rates of grade 2 acute genitourinary and gastrointestinal toxicities were 21% and 4%, respectively. So far no grade ≥2 late toxicity has been observed and the 2-year BRFS is 95.8%. Transient PSA elevation over 0.4 ng/ml was observed in 11 patients (46%) and in 5 patients (21%) PSA rose ≥1.0 ng/ml above nadir. Conclusions: Sort-term outcome of MH-IMRT delivering 54 Gy in 15 fractions over 3 weeks for prostate cancer was comparable to that of conventionally fractionated IMRT. Clinical trial information: UMIN000012057.