tbuckley/cabot-search huggingface dataset:
A phase I study of CPI-0610, a bromodomain and extra terminal protein (BET) inhibitor in patients with relapsed or refractory lymphoma
Authors: K.A. Blum, J. Abramson, M. Maris, I. Flinn, A. Goy, J. Mertz, R. Sims, F. Garner, A. Senderowicz, A. Younes
Journal: Annals of Oncology (2018)

Background: NF-kB has been found to be constitutively activated in many lymphomas, such as diffuse large B-cell lymphomas (DLBCL), particularly the ABC subgroup. In preclinical studies, CPI-0610, a BET specific small molecule inhibitor, results in downregulation of NF-κB signaling activity, accompanied by loss of viability of ABC-DLBCL cell lines. Here we report the results from the first-in human Phase 1 study of CPI-0610 in patients with relapsed or refractory lymphomas (NCT01949883). Methods: Eligible patients were those whose lymphoma had progressed and for whom no effective therapies are available. Doses (mg) of 6 12, 24, 48, 80, 120, 170, 230, 300 (capsules) and 125 and 225 (tablets) administered orally QD on a 14 day on, 7 days off schedule were evaluated. The primary objective was to determine the maximum tolerated dose (MTD) and key secondary objectives were to determine the pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of CPI-0610. Results: 64 patients were enrolled (56% DLBCL) with a median of 4 prior lines of therapy. MTD for this trial was 225 mg QD tablets. Ten patients were treated at MTD with only 1 DLT (thrombocytopenia). The most frequent treatment related adverse events were thrombocytopenia (45%), fatigue (34%), nausea (27%) decreased appetite (27%) and anemia (25%). Thrombocytopenia, a class effect for all BET inhibitors, was dose limiting however, is was reversible (<1 week) and not cumulative. Five patients had an objective response; 2 CRs (1 T-cell/histocyte-rich DLBCL, 1 ABC-DLBCL), 3 PRs (1 follicular lymphoma, 2 ABC-DLBCL) and 5 patients had prolonged (> 6 months) SD. Three of the responses and 1 of the prolonged SD were in patients with ABC-DLBCL. PK was dose-proportional with Cmax reached after 3 hours and a half-life of 16 hours. PD analysis of BET target genes demonstrated dose dependent decreases in IL8 and CCR1 mRNA between 2-8 hours post dose. Conclusions: CPI-0610 is a well-tolerated, oral BET inhibitor that has demonstrated anti-tumor activity in advanced lymphoma patients. Clinical trial identification: NCT01949883 Legal entity responsible for the study: Constellation Pharmaceuticals Funding: Constellation Pharmaceuticals Disclosure: J. Mertz, R. Sims: Constellation Pharma employee. F. Garner: Radius stock, Constellation Pharma employee. A. Senderowicz: Constellation Pharma employee, on the BOD of Puma Pharmaceuticals. All other authors have declared no conflicts of interest.
Effect of pectasol-c modified citrus pectin (P-MCP) treatment (tx) on PSA dynamics in non-metastatic biochemically relapsed prostate cancer (BRPC) patients (pts): Results of a prospective phase II study.
Authors: Daniel Keizman, Moshe A. Frenkel, Avivit Peer, Eli Rosenbaum, David Margel, David Leonid Sarid, Victoria Neiman, Maya Gottfried, Natalie Maimon, Ilan Leibovitch, Hadas Dresler, Isaac Eliaz
Journal: Journal of Clinical Oncology (2018)

14 Background: 30% of pts with localized PC will have a biochemical relapse post local tx. The optimal tx of these pts remains elusive. While androgen deprivation therapy is effective in reducing PSA level, its long-term benefit on survival remain undefined, and it is associated with significant cumulative toxicities.Thus, evaluation of new non-toxic compounds in this pt population is warranted. P-MCP is a competitive inhibitor of galectin-3, a carbohydrate-binding protein, which is known to be involved in cancer pathogenesis. Pre-clinical and clinical data suggest that P-MCP is active in PC. We aimed to evaluate the safety and PSA dynamics of tx with P-MCP in pts with BRPC. Methods: Pts with non-castrate non-metastatic BRPC were enrolled in a prospective phase 2 study of tx with oral P-MCP, at 4.8 grams X 3/day for 6 months (mos). Pts that did not progress clinically, biochemically (PSA), and radiologically, at 6 mos, were treated for subsequent 12 mos. Sample size provided 85% power to assess a decrease in PSA progression rate from 80% (natural history) to 40% (P-MCP tx) at 6 mos. Results: The study was initiated in June 2013. 35 pts were enrolled. Median age was 74 years. Treatment of the primary tumor consisted of surgery in 11% (n = 4), radiation in 69% (n = 24), and both in 20% (n = 7). No pt had tx related grade 3/4 toxicity. One patient withdrew his consent after 1 mos. Of the 34 pts analyzed, 18% (n = 6) had grade 1 toxicity. 62% (n = 21) had a stabilization/decrease of PSA, and negative scans, at 6 mos, and entered the second 12 mos tx phase. A stabilization or improvement (increase) of PSA doubling time was noted in 79% (n = 27) of pts. Disease progression at 6 mos was noted in 38% (n = 13: PSA only 29%, n = 10; PSA and scans 9%, n = 3). Conclusions: The present study suggests a potential benefit of P-MCP tx on progression of BRPC. P-MCP tx is safe. Clinical trial information: NCT01681823.
Abstract P6-15-04: Characterization of tumor infiltrating lymphocytes and its association response in breast cancer
Authors: M Galvez, C Castaneda, V Villegas
Journal: Cancer Research (2018)

Abstract Background: The magnitude of tumor infiltrating lymphocytes (TIL) is a predictor of good prognosis in the context of neoadyuvant chemotherapy (NAC) in breast cancer, and is expressed in the capacity to achieve a pathological complete response (pCR) and therefore to obtain a major survival. The characteristics of TIL are influenced of different clinical and pathological features as well as its predictive value. The goal of this study is to define the different associations between level of stromal (sTIL) and interstitial (iTIL) tumor infiltrating lymphocytes and pathological and clinical feature of breast cancer. Methods: The level of TIL was analyzed in 483 patients diagnosed with breast cancer of the Instituto Nacional de Enfermedades Neoplasicas from 2003 to 2014. We evaluate patient characteristics such as age, clinical stage, histological subtype and grade, clinical T, N and M, presence of estrogen (ER) and progesterone (PgR) receptors, HER-2 expression and molecular subtype as well as pathological response. Results: We found a positive association between sTIL and iTIL proportion and histological grade (G1-2 vs G3, p&amp;lt;0.05 and p&amp;lt;0.05 respectively), hormone receptor (ER- vs ER+PgR- vs ER+PgR+, p&amp;lt;0.05 and p=0.001 respectively), molecular subtype (Luminal A vs Luminal B vs HER2 vs Triple Negative (TN), p&amp;lt;0.05 and p=0.002 respectively), clinical N (positive vs negative, p=0.006 and p&amp;lt;0.05 respectively). Also we found association between sTIL with lymph nodes after surgery (negative vs positive, p=0.028) and pathological response (pCR vs &amp;lt;pCR, p=0.018), there was no association between sTIL and iTIL with age, histological subtype, clinical T and M. Conclusions: The level of tumor infiltrating lymphocytes are affected by different clinical and pathological features, they are present in both lobular and ductal breast cancer without significant difference; higher level of TIL are associated with high histological grade, ER-, TNBC and high clinical N to diagnosis; and specially sTIL are associated with to achieve a negative lymph node after NAC and obtain a pathological complete response. Citation Format: Galvez M, Castaneda C, Villegas V. Characterization of tumor infiltrating lymphocytes and its association response in breast cancer [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 P6-15-04.
Nearly 25 000 doctors have successfully revalidated
Authors: Abi Rimmer
Journal: BMJ (2013)

Nearly 25 000 doctors have had their licences to practise renewed in the first year of revalidation.

According to figures from the General Medical Council (GMC), since 2 December 2012 24 550 doctors across England, Scotland, Wales, and Northern Ireland have had their licence to practise renewed following the revalidation process. Every doctor registered with a licence to practise in the UK is legally required to show the GMC that they are fit to practise, usually once …
Abstract P1-01-16: Detection of disseminated tumor cells in DCIS patients impacts local recurrence
Authors: VP Walter, F-A Taran, M Wallwiener, SY Brucker, AD Hartkopf
Journal: Cancer Research (2018)

Abstract Background Recently it was shown that tumor cell dissemination is an early event in breast cancer progression (Hosseini et al., Nature 2016). This has been backed up by an assessment of over 100,000 patients with in situ carcinoma (DCIS), where some patients developed distant metastases and died from breast cancer without presenting with local invasive recurrence (Narod et al., JAMA Oncology 2015). We therefore analyzed the presence and clinical impact of disseminated tumor cells (DTC) in the bone marrow (BM) of DCIS patients. Methods BM aspirates were collected from patients undergoing surgery for primary DCIS at Tuebingen University Hospital between 2001 and 2016. Exclusion criteria were presence of invasive breast cancer, bilateral or metastatic disease as well as other malignancies in their history. DTC were identified by immunocytochemistry using the A45-B/B3 anti-pancytokeratin antibody. Results 627 patients were included. Median follow-up was 49 months. 72 (11%) had detectable DTC. The detection of DTC was not significantly associated with lymph node positivity (3/479, Fisher's exact test: p=0.307) or tumor size (median 30mm, Wilcoxon test: p=0.952). In 33 (5%) women, a disease recurrence was observed. Of 31 local recurrences 19 were invasive. 7 Patients developed distant metastases, four without an invasive recurrence beforehand. 14 patients died during follow-up. The detection of at least 2 DTC per 1.5x106 mononuclear BM cells was significantly associated with a lower local recurrence free survival (log-rank: p=0.023) whereas there was no significant difference in distant disease free survival (p=0.315) and overall survival (p=0.083). Discussion For the first time, we were able to show that DTC-detection in DCIS patients is associated with local recurrence. The number of distant metastases in women without invasive local recurrence detected in this cohort was comparable to earlier findings at different centers. This study warrants further investigations concerning evolutionary relationship between primary tumor, minimal residual disease, local recurrence and clinically detectable macrometastases. Citation Format: Walter VP, Taran F-A, Wallwiener M, Brucker SY, Hartkopf AD. Detection of disseminated tumor cells in DCIS patients impacts local recurrence [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 P1-01-16.
Size of commissioning organisation has no effect on performance
Authors: Helen Jaques
Journal: BMJ (2012)

The size of a commissioning organisation has no effect on its performance once population factors are taken into account, a study in the January issue of the British Journal of General Practice has shown ( Br J Gen Pract 2012;62:28-29, doi:10.3399/bjgp12X616364).

Concerns have been raised during the creation …
THE PROGNOSTIC ABILITY OF LAYER-SPECIFIC STRAIN BY 2-DIMENSIONAL SPECKLE TRACKING ECHOCARDIOGRAPHY IN STABLE ANGINA PECTORIS
Authors: Christoffer Hagemann, Søren Hoffmann, Rikke Andersen, Philip Brainin, Thomas Fritz-Hansen, Flemming Javier Olsen, Peter Jørgensen, Jan Jensen, Tor Biering-Sørensen
Journal: Journal of the American College of Cardiology (2018)
Efficacy of programmed death 1 (PD-1) and programmed death 1 ligand (PD-L1) inhibitors in patients with <i>FGFR</i> mutations and gene fusions: Results from a data analysis of an ongoing phase 2 study of erdafitinib (JNJ-42756493) in patients (pts) with advanced urothelial cancer (UC).
Authors: Arlene O. Siefker-Radtke, Andrea Necchi, Eli Rosenbaum, Stephane Culine, Earle Frederick Burgess, Peter H. O'Donnell, Scott T. Tagawa, Yousef Zakharia, Anne OHagan, Anjali Narayan Avadhani, Bob Zhong, Ademi E. Santiago-Walker, Tito Roccia, Yohann Loriot
Journal: Journal of Clinical Oncology (2018)

450 Background: FGFR3 mutations appear to be enriched in luminal 1 UC, which have low expression of markers associated with an immune response, including CD8-T-effector gene expression levels. Objective response rate (ORR) to PD-1 and PD-L1 inhibitors in luminal 1 tumors appear lower (10-19%) than in infiltrated luminal 2 and basal 3 tumors (ORR 31-34%). This suggests FGFR3 mutations occur within a group of tumors less likely to benefit from immune checkpoint inhibition (ICI). Here we describe outcomes of a subgroup of pts with FGFR2/3 mutations and gene fusions, previously treated with PD-1/PD-L1 inhibitors and included in an ongoing erdafitinib phase 2 study. Methods: Patients who had received prior immunotherapy for advanced UC were selected from those enrolled on BLC2001, an ongoing phase 2, open-label study of the pan-FGFR inhibitor erdafitinib in subjects with advanced UC with specific FGFR2/3 gene alterations (NCT02365597). We explored investigator-reported clinical outcomes including ORR and median time to progression (TTP) of pts treated with ICI preceding erdafitinib therapy. Results: 28/203 pts had previously received anti PD-1 or anti PD-L1 treatment. In this subgroup, the median age was 67.0 y; 82% were male, 79% had an ECOG score ≤1, 36% had liver metastases, and 93% had ≥2 prior lines of systemic therapy. The response rate to anti PD-1/PD-L1 agents was 3.6% (95% CI, 0.1%-18.3%) with one partial response. Median TTP was 3.4 mo (range 2-15 mo; 95% CI, 2.3-4.9). Conclusions: In this post-hoc analysis, FGFR mutations and gene fusions seem to select for a group of pts less likely to respond to immune checkpoint inhibition. Although caution is needed due to the retrospective nature of the data, the presence of these alterations may reflect an unmet need with currently approved agents. This finding highlights the need for FGFR alteration testing and an effective FGFR-targeted therapy. Clinical trial information: NCT02365597.
Abstract P3-05-20: A study on amount, localization and immune phenotype of tumor-infiltrating lymphocytes in different subtypes of breast cancer
Authors: SL Popovska, PD Dimitrova, TB Dineva
Journal: Cancer Research (2018)

Abstract Objective: The aim of the study was to investigate the localization, amount and type of lymphocytic infiltrate, found in different molecular subtypes of breast cancer (BC). Methods: Retrospectively, 100 cases of invasive BC were analyzed and immunohistochemicaly (IHC) stratified in four subtypes (Luminal A and Luminal B-like, HER2-positive, and triple negative (TN). The percentage of stromal areas occupied by tumor-infiltrating lymphocytes (TILs) was assessed for H&amp;E slides. The samples were IHC-stained for CD3, CD4, CD8, CD20 and FoxP3. The immunophenotyped lymphocytes - intratumoural and stromal, were separately counted, semi-quantitatively graded and further analyzed. Results: A total of 10% of all tumors were lymphocyte-predominant BC. Intratumoral and stromal TILs were predominantly CD3+T-lymphocytes. High counts of all subtypes TILs - intratumoral and stromal, were most common for TNBC and HER2-positive BC. In TNBC, the intratumoral CD3+TILs are significantly related to CD8+ (p=0.002) and FoxP3+ phenotype (p=0.010). In HER2 BC, the intratumoral and stromal CD3+ TILs were significantly related to FoxP3+ phenotype (p = 0,035 and p= 0.011, respectively). Conclusion:CD3+T-cell mediated immunity, especially the one related to CD8+ and FoxP3+ lymphocytes was the leading one in antitumor response in BC, and high count of intratumoral and stromal lymphocytes predominated in TN and HER2-positive BC. Key words: Breast cancer, tumor-infiltrating lymphocytes, CD3, CD4, CD8, CD20, FoxP3. Citation Format: Popovska SL, Dimitrova PD, Dineva TB. A study on amount, localization and immune phenotype of tumor-infiltrating lymphocytes in different subtypes of breast cancer [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 P3-05-20.
PD-L1 in tumor microenvironment mediates resistance to oncolytic immunotherapy
Authors: Dmitriy Zamarin, Jacob M. Ricca, Svetlana Sadekova, Anton Oseledchyk, Ying Yu, Wendy M. Blumenschein, Jerelyn Wong, Mathieu Gigoux, Taha Merghoub, Jedd D. Wolchok
Journal: Journal of Clinical Investigation (2018)

Intralesional therapy with oncolytic viruses (OVs) leads to the activation of local and systemic immune pathways, which may present targets for further combinatorial therapies. Here, we used human tumor histocultures as well as syngeneic tumor models treated with Newcastle disease virus (NDV) to identify a range of immune targets upregulated with OV treatment. Despite tumor infiltration of effector T lymphocytes in response to NDV, there was ongoing inhibition through programmed death ligand 1 (PD-L1), acting as a mechanism of early and late adaptive immune resistance to the type I IFN response and T cell infiltration, respectively. Systemic therapeutic targeting of programmed cell death receptor 1 (PD-1) or PD-L1 in combination with intratumoral NDV resulted in the rejection of both treated and distant tumors. These findings have implications for the timing of PD-1/PD-L1 blockade in conjunction with OV therapy and highlight the importance of understanding the adaptive mechanisms of immune resistance to specific OVs for the rational design of combinatorial approaches using these agents.
THE CLINICAL SIGNIFICANCE OF TYPE 2 MYOCARDIAL INFARCTION ON OUTCOME AND MAJOR ADVERSE CARDIOVASCULAR EVENTS IN DIABETIC KETOACIDOSIS AND HYPEROSMOLAR HYPERGLYCEMIC STATE PATIENTS
Authors: Abdulwahab Hritani, Gregory Schleis, Tara Zehrer, Indrajit Choudhuri, Khawaja Afzal Ammar, Rama Hritani, Susan Olet, M. Fuad Jan
Journal: Journal of the American College of Cardiology (2018)
PLASMA NEUTROPHIL GELATINASE-ASSOCIATED LIPOCALIN IS ASSOCIATED WITH ACUTE KIDNEY INJURY AND CLINICAL OUTCOMES IN NEONATES UNDERGOING CARDIOPULMONARY BYPASS
Authors: Luke Schroeder, Jason Buckley, Renee Martin, Robert E. Stroud, Elizabeth K. Nadeau, Ryan W. Barrs, Eric Graham
Journal: Journal of the American College of Cardiology (2018)
Incidence and prevalence of rosacea: a systematic review and meta-analysis
Authors: L. Gether, L.K. Overgaard, A. Egeberg, J.P. Thyssen
Journal: British Journal of Dermatology (2018)

The exact prevalence and incidence of rosacea remain unknown, although it is a common condition associated with severe noncutaneous diseases. To perform a systematic review of the published literature to examine the global incidence and prevalence of rosacea. A systematic review of population‐based and dermatological outpatient studies reporting the incidence and/or prevalence of rosacea was performed using three electronic medical databases: PubMed, Embase and Web of Science. Data were extracted and a proportion meta‐analysis was performed to obtain pooled proportions. In total 32 studies were included examining a total of 41 populations with 26 519 836 individuals. Twenty‐two populations were from Europe, three from Africa, four from Asia, nine from North America and three from South America. The pooled proportion of individuals with rosacea was 5·46% [95% confidence interval (CI) 4·91–6·04] in the general population and 2·39% (95% CI 1·56–3·39) among dermatological outpatients. Self‐reported rosacea gave higher prevalence estimates than rosacea diagnosed by clinical examination, suggesting a low specificity of questionnaires based on symptoms. Rosacea affected both women (5·41%, 95% CI 3·85–7·23) and men (3·90%, 95% CI 3·04–4·87), and mostly those aged 45–60 years. We estimated the global prevalence of rosacea based on published data and found that 5·46% of the adult population is affected. However, the prevalence of rosacea depended on the diagnostic method, with higher estimates in questionnaire studies of rosacea symptoms and lower estimates in health registries with International Classification of Diseases codes.
Recruitment problems in emergency medicine: symptom of a bigger problem in medical careers?
Authors: Steven Alderson, Sveta Alladi
Journal: BMJ (2014)

<b>Steven Alderson</b> and <b>Sveta Alladi</b> spent a year working at Health Education England as national medical director’s clinical fellows, focusing on the issues of recruitment to emergency medicine, acute medicine, and general practice. Here they consider whether the recruitment issues seen in these specialties represent a “canary in the mine” for all branches of medical training
Centralization of radical cystectomy for bladder cancer in a universal healthcare system: Early results from a Canadian academic center.
Authors: Jan Krzysztof Rudzinski, Niels Jacobsen, Sunita Ghosh, Scott A. North, Naveen S. Basappa, Michael Paul Kolinsky, Eric Estey, Adrian S Fairey
Journal: Journal of Clinical Oncology (2018)

516 Background: Radical cystectomy for bladder cancer is a complex surgical oncology procedure. Centralization of this procedure to high volume, fellowship-trained surgeons may improve clinical outcomes. Our objective was to compare outcomes of radical cystectomy before and after centralization of care. Methods: A retrospective analysis of data from the University of Alberta Radical Cystectomy Database was performed. Eligible subjects were those with histologically proven urothelial carcinoma of the bladder (cTanyN1-3M0) undergoing curative intent surgery. Patients were classified into pre-centralization era (1994-2007; N = 523) and post-centralization era (2013-present; N = 134) cohorts for analyses. Pre-centralization era patients were treated by 1 of 11 urologic surgeons at 2 academic teaching hospitals. Post-centralization era patients were treated by 1 of 2 fellowship-trained urologic oncologists at 1 academic teaching hospital. Outcomes were overall survival, 90-day mortality rate, positive surgical margin (R1) resection rate, total number of lymph nodes evaluated, and 90-day blood product transfusion rate. The Kaplan-Meier method and multivariable regression analyses were used to analyze survival outcomes. Statistical tests were two-sided (p≤0.05). Results: The median follow-up duration in the pre- and post-centralization era was 33 months and 16 months, respectively. The predicted 2-year overall survival rate was 62% in the pre-centralization era and 84% in the post-centralization era (Log rank P = 0.0007; multivariable HR 0.40, 95% CI 0.24 to 0.68, P &lt; 0.0001). Treatment in the post-centralization era was associated with lower 90-day mortality (6.3% versus 1.5%, multivariable OR 0.23, 95% CI 0.06 to 0.99, P = 0.049), R1 resection (13.0% versus 1.5%; multivariable OR 0.07, 95% CI 0.01 to 0.51, P = 0.009), and 90-day blood product transfusion (59% versus 6%, P &lt; 0.0001) as well as higher total number of lymph nodes evaluated (7 versus 30 lymph nodes, P &lt; 0.0001). Conclusions: Surgical treatment in the post-centralization era was associated with superior survival, cancer control, and perioperative outcomes.