tbuckley/cabot-search huggingface dataset:
Osimertinib activity in patients (pts) with leptomeningeal (LM) disease from non-small cell lung cancer (NSCLC): Updated results from BLOOM, a phase I study.
Authors: James Chih-Hsin Yang, Dong-Wan Kim, Sang-We Kim, Byoung Chul Cho, Jong-Seok Lee, Xin Ye, Xiaolu Yin, Zhenfan Yang, Haiyi Jiang, Myung-Ju Ahn
Journal: Journal of Clinical Oncology (2016)

9002 Background: LM disease is a severe type of NSCLC disease progression, associated with poor prognosis. Osimertinib (AZD9291) is an oral, potent, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) selective for activating (EGFRm) and T790M resistance mutations. We present updated data from a phase I study, BLOOM (NCT02228369), of osimertinib in pts with LM disease from EGFRm NSCLC. Methods: Pts with EGFRm advanced NSCLC who had progressed on prior EGFR-TKI therapy and LM disease confirmed by positive cerebrospinal fluid (CSF) cytology were enrolled. Pts were treated with osimertinib 160 mg, once daily. Response was assessed based on CSF cytology, intracranial (IC) imaging, and neurological examination. EGFRm DNA in CSF was determined by Droplet Digital PCR. Results: As of December 30, 2015, 20 pts were dosed, of whom 7 were dosed for ≤ 3 weeks. Maximum treatment duration was 37 weeks. Of 12 pts reaching a 12-week IC image assessment, 7 had radiological improvement, 2 had stable disease (SD) and 3 were not evaluable (NE). 12 pts reached 12-week neurological assessment: of 7 symptomatic pts, 3 improved, 1 had no change and 2 were NE. Of the 5 asymptomatic pts, 2 worsened and 3 remained asymptomatic. In 9 pts with pre-dose and Cycle 2 Day 1 CSF time point samples, 8 had EGFRm DNA copy decrease, with a >50% decrease in 5 pts, sustained over 4 months. Five pts withdrew from the study (1 extracranial [EC] only progressive disease [PD], 2 EC and CNS PD, 1 disease-related dysphagia, and 1 Gr 5 aspiration pneumonia). 5 pts had dose interruptions and 2 had dose reductions to 80 mg. The most common treatment-related AEs were skin reactions (n=15; 11 Gr 1, 4 Gr 2) and diarrhea (n=8; 5 Gr 1, 3 Gr 2). Gr 3 neutropenia was reported in 1 pt (recovered to Gr 2 after a 3 day dose interruption, dose resumed at 80 mg). Updated data will be available at presentation. Conclusions: Osimertinib at 160mg once daily demonstrates encouraging preliminary safety and activity in heavily pre-treated pts with LM disease from EGFR-mutant NSCLC. Further evaluation of osimertinib in this setting is warranted. Clinical trial information: NCT02228369.
Tuberculosis screening yield of asylum seekers in Europe
Authors: Wouter Arrazola de Oñate, Lilas Weber, Kristien Janssens, Maryse Wanlin, Annemie Forier, Sandrina Schol, Kathia van Egmond
Journal: European Respiratory Journal (2016)

With interest we read the research letter by de Vries et al . [1] describing the yield of screening asylum seekers from countries with a tuberculosis (TB) incidence of <50 per 100 000 population. Over an almost 4-year period (2011–September 2015), the Dutch TB prevention programme diagnosed 12 TB patients from these countries through active screening (including eight Syrians). The authors concluded the yield of this screening was low and could therefore be discontinued. In high income, low incidence countries foreign-born cases contribute significantly to TB epidemiology [2], while elimination was set as the objective [3]. Yield of tuberculosis entry screening of Syrian refugees in Belgium, 2015: migration is not a public health threat <http://ow.ly/xECn302fkS8>
Incidence of second malignancies among 10,919 patients over 20 years: Retrospective analysis of a community hospital cancer registry data.
Authors: S. Subramonia-Iyer, A. Singh, K. Katato
Journal: Journal of Clinical Oncology (2010)

e12026 Background: Diagnosis of a second cancer contributes significantly to subsequent morbidity and mortality in cancer survivors. The aim of this study is to ascertain the incidence and characteristics of second cancers among adult patients enrolled in the Hurley Medical Center cancer registry. Methods: The registry was searched for patients enrolled during 1988-2007, who were diagnosed with subsequent cancers. Incidence and survival was analysed. Results: Total follow up was for over 78,680 person-years. 700 patients (6.4%) had subsequent cancers over 20 years, compared to SEER results of 13.7% over 20 years. Further analyses were performed on 534 patients (76%) for whom detailed data was available. Incidence rate of second cancers was 0.6% per year of follow up. About 25 second cancers were diagnosed annually, making up 5% of the ∼550 new diagnoses, compared to 16% in SEER data. Median interval between the diagnoses of the two cancers was 32 months. Among second cancer sites, breast (20%), lung (17%) head and neck (7.5%), colorectal (7.1%) and prostate (6.9%) were most frequent. In comparison, commonest second sites described in the SEER report are: lung (17.3%), breast (16.4%), colon (11.1%), prostate (10%) and head and neck (4.8%). 242 (45.3%) of the patients were male, and 292 (54.7%) were female. Mean age at diagnosis of the first cancer was 62 years and second cancer was 65 years. Median survival duration was 82 months after first cancer and 33 months after the second. After a median of 10 years of follow up, 192 (36%) were alive. In the SEER analysis, 20% survived to 10 years. Analysis of causes of death showed that 41 were directly and 9 were indirectly related to the cancer. This information was unavailable for 258 patients (75%). Conclusions: Compared to SEER data, recorded incidences of second cancers are lower in our cancer registry, and survival proportion at 10 years is higher. Incomplete follow up due to out-migration of patients may have contributed to low incidence. Second cancers may be related to common risk factors and some are detectable by age-appropriate screening programs. Hence it is important to emphasize lifestyle modifications and cancer surveillance among cancer survivors. No significant financial relationships to disclose.
Diagnostic criteria for cryopyrin-associated periodic syndrome (CAPS)
Authors: Jasmin B Kuemmerle-Deschner, Seza Ozen, Pascal N Tyrrell, Isabelle Kone-Paut, Raphaela Goldbach-Mansky, Helen Lachmann, Norbert Blank, Hal M Hoffman, Elisabeth Weissbarth-Riedel, Boris Hugle, Tilmann Kallinich, Marco Gattorno, Ahmet Gul, Nienke Ter Haar, Marlen Oswald, Fatma Dedeoglu, Luca Cantarini, Susanne M Benseler
Journal: Annals of the Rheumatic Diseases (2016)

Cryopyrin-associated periodic syndrome (CAPS) is a rare, heterogeneous disease entity associated with NLRP3 gene mutations and increased interleukin-1 (IL-1) secretion. Early diagnosis and rapid initiation of IL-1 inhibition prevent organ damage. The aim of the study was to develop and validate diagnostic criteria for CAPS. An innovative process was followed including interdisciplinary team building, item generation: review of CAPS registries, systematic literature review, expert surveys, consensus conferences for item refinement, item reduction and weighting using 1000Minds decision software. Resulting CAPS criteria were tested in large cohorts of CAPS cases and controls using correspondence analysis. Diagnostic models were explored using sensitivity analyses. The international team included 16 experts. Systematic literature and registry review identified 33 CAPS-typical items; the consensus conferences reduced these to 14. 1000Minds exercises ranked variables based on importance for the diagnosis. Correspondence analysis determined variables consistently associated with the diagnosis of CAPS using 284 cases and 837 controls. Seven variables were significantly associated with CAPS (p&lt;0.001). The best diagnosis model included: Raised inflammatory markers (C-reactive protein/serum amyloid A) plus ≥two of six CAPS-typical symptoms: urticaria-like rash, cold-triggered episodes, sensorineural hearing loss, musculoskeletal symptoms, chronic aseptic meningitis and skeletal abnormalities. Sensitivity was 81%, specificity 94%. It performed well for all CAPS subtypes and regardless of NLRP3 mutation. The novel approach integrated traditional methods of evidence synthesis with expert consensus, web-based decision tools and innovative statistical methods and may serve as model for other rare diseases. These criteria will enable a rapid diagnosis for children and adults with CAPS.
Cytotoxicity of oncolytic herpes simplex virus vector on breast cancer stem cells.
Authors: J. Li, R. Liu, J. Wang, S. D. Rabkin
Journal: Journal of Clinical Oncology (2010)

e13637 Background: CD44+CD24−/low is an important marker of breast cancer stem cells, which underlies the incurable and relapse characteristics of breast cancer in clinic. A third-generation oncolytic herpes simplex virus (HSV) vector G47D is a novel agent for the treatment of many cancers. In this study, we investigate the cytotoxity of G47Δ on CD44+CD24−/low cells that were purified from the human SK-BR-3 cell line. Methods: Breast cancer cell line SK-BR-3 was cultured in suspension to generate primary mammospheres. After 10 days of culture, the proportion of CD44+CD24-/low cells from mammospheres was measured by flow cytometry. Then, the CD44+CD24-/low population were adherent cultured and infected with G47Δ of different multiplicities of infection (MOI). G47Δ-infected cells were detected with X-gal staining. Results: The proportion of CD44+CD24-/low cells in SK-BR-3 mammospheres was 95.3% +2.1% after 10 days of suspension culture. At day 9 of adherent culture, the proportion of CD44+CD24-/low cells was 90.2%+1.9%. G47Δ was highly cytotoxic for CD44+CD24-/low cells in vitro at both low MOIs (Table). X-gal staining showed the G47Δ infected cells. Conclusions: Recently constructed oncolytic HSV vector G47Δ was effective at killing breast cancer CD44+CD24-/low cells in vitro. The efficiency and specificity of this novel cancer therapy deserve further investigation and consideration of animal models and clinical studies. Percentage of CD44+CD24−/low SK-BR-3 cells killed by G47Δ MOI D1 D2 D3 D4 D5 D6 0.01 2 10 38 55 72 91 0.1 8 21 63 85 92 97 No significant financial relationships to disclose.
Mitotane pharmacodynamics in adrenocortical cancer in children and adults.
Authors: Stephen P. Ackland, Madhu Bala Garg, Lyndal Tacon, Catherine Johnson, Jennette Sakoff
Journal: Journal of Clinical Oncology (2014)

e13532 Background: Mitotane (DDD) is the only recognized effective systemic therapy for advanced adrenocortical carcinoma (ACC) (Tacon et al The Oncologist 2011). Intraadrenal metabolic transformation is essential for its therapeutic effects. Benefit depends on maintenance of adequate plasma drug levels >14μg/ml and toxicity occurs at >20μg/ml (Veytsman et al JCO 2009). The relationship between steady state plasma level and dose administered is variable, with up to 5-10 fold inter-patient variation. Methods: We established a therapeutic drug monitoring service for measuring plasma mitotane and two main metabolites simultaneously (HPLC: Garg et al J Chrom B 2011) in ACC patients. Results: We have conducted >450 mitotane levels on 74 patients (44F, 30M) from Australasia (med. age 50, range 11-81, 3 children). Mitotane starting dose varied from 1-8 g/day, with empirical recommendations provided to adjust dose and re-measure, which were variably followed. 42 patients (24F, 18M), including 3 children, achieved therapeutic range with a dose of 6.1±3.2 (mean±SD) g/day. It took adults 5.9±3.7 months of therapy to achieve therapeutic range while it took children 1.5 ± 0.1 months. 21 patients (14 females, 7 males), including all children recorded plasma levels in the toxic range. Conclusions: It takes a long and variable time (2-6 months) to achieve a therapeutic range of mitotane plasma level with current practice and some patients exceed the therapeutic range despite monitoring. Clearance is slow (weeks) probably due to the fat solubility of mitotane and metabolite DDE. A multi-site prospective clinical study is underway to define a TDM strategy to achieve ideal levels quickly, to determine the relationship between DDD and metabolite levels and toxicity. We will identify factors that account for variability in mitotane kinetics by correlating kinetic parameters with pre-treatment phenotypic factors.
Improvement In Renal Function In Newly Diagnosed Myeloma Improves Survival, but Still Remains Inferior to Those with Normal Renal Function
Authors: Shaji Kumar, Angela Dispenzieri, Martha Lacy, Suzanne R. Hayman, Francis Buadi, David Dingli, Kristen Detweiler-Short, John Lust, Steven Zeldenrust, Stephen Russell, Philip R. Greipp, Robert Kyle, Morie Gertz, Vincent Rajkumar
Journal: Blood (2010)
Diabetes diagnosis and care in sub-Saharan Africa: pooled analysis of individual data from 12 countries
Authors: Jennifer Manne-Goehler, Rifat Atun, Andrew Stokes, Alexander Goehler, Dismand Houinato, Corine Houehanou, Mohamed Msaidie Salimani Hambou, Benjamin Longo Mbenza, Eugène Sobngwi, Naby Balde, Joseph Kibachio Mwangi, Gladwell Gathecha, Paul Waweru Ngugi, C Stanford Wesseh, Albertino Damasceno, Nuno Lunet, Pascal Bovet, Demetre Labadarios, Khangelani Zuma, Mary Mayige, Gibson Kagaruki, Kaushik Ramaiya, Kokou Agoudavi, David Guwatudde, Silver K Bahendeka, Gerald Mutungi, Pascal Geldsetzer, Naomi S Levitt, Joshua A Salomon, John S Yudkin, Sebastian Vollmer, Till Bärnighausen
Journal: The Lancet Diabetes & Endocrinology (2016)
Radiofrequency ablation for the management of occluded biliary metal stents
Authors: Abdurrahman Kadayifci, Mustafa Atar, David Forcione, Brenna Casey, Peter Kelsey, William Brugge
Journal: Endoscopy (2016)

Background and study aim: Obstruction of biliary self-expandable metal stents (SEMSs) is seen frequently. Radiofrequency ablation (RFA) causes tissue necrosis. This study aimed to assess the efficacy of RFA for management of occluded SEMS. Patients and methods: Patients with biliary malignancy and treated for an occluded SEMS were retrospectively reviewed. The study group comprised patients treated with RFA using an Habib endoprobe inside the SEMS. The control group comprised patients treated only with insertion of a plastic stent into an occluded SEMS. The end points were; 90-day stent patency rate, time to stent reocclusion, 30-day mortality, and 3 - and 6-month survival rates. Results: During the 5-year study period 25 patients with an occluded SEMS underwent RFA and 25 patients underwent a plastic stent placement only. Both groups were matched for age and diagnosis. Immediate biliary drainage was restored in all patients. In the RFA group, the stenosis was ablated successfully in 14 patients (56 %); ablation failed in 11 and a plastic stent was then inserted into the SEMS for these. The control group had only placement of a plastic stent across the stenosis. Stent patency rate at 90 days was 56 % and 24 % in the RFA and control groups, respectively (P = 0.04). The mean stent patency time was significantly longer in the RFA group compared to the control group (119.5 vs. 65.3 days, P = 0.03). Conclusion: The application of RFA for occluded SEMS improves stent patency. RFA is an alternative treatment of tissue ingrowth in malignant biliary obstruction.
Pooled analysis of safety over time and link between adverse events and efficacy across combination dabrafenib and trametinib (D+T) registration trials.
Authors: Jean Jacques Grob, Keith Flaherty, Georgina V. Long, Paul D. Nathan, Dirk Schadendorf, Antoni Ribas, Caroline Robert, Stephen R. Lane, Carmen Mak, Philippe Legenne, Michael A. Davies
Journal: Journal of Clinical Oncology (2016)

9534 Background: Phase 2 (BRF113220 [NCT01072175]) and phase 3 (COMBI-d [NCT01584648], COMBI-v [NCT01597908]) trials of D+T have provided a large homogeneous dataset for evaluating these agents in patients (pts) with BRAFV600E/K–mutant melanoma. Previous pooled analyses demonstrated that the extent and duration of clinical benefit with D+T across studies is consistent with that of individual trials (ORR, 67%; median OS, 25.6 mo [95% CI, 23.1-34.3 mo]). Univariate, multivariate, and regression-tree analyses of pooled efficacy data determined baseline and post-baseline factors associated with response, progression, and long-term outcomes (eg, baseline LDH influenced OS ≥ 24 mo). Here, pooled safety data is described. Methods: The pooled population included randomized pts treated with D 150 mg BID + T 2 mg QD in BRF113220 (Part C; cutoff, Jan 2015), COMBI-d (cutoff, Jan 2015), and COMBI-v (cutoff, Mar 2015). AEs were graded per NCI CTCAE v4.0. Cox proportional hazards modeling was used to evaluate the prognostic value of pyrexia occurrence. Results: The pooled safety population included 614 pts treated with D+T in BRF113220 (n = 55), COMBI-d (n = 209), and COMBI-v (n = 350). With a median follow-up of 20.0 mo, the most frequent AEs ( ≥ 20% of pts) were pyrexia (57%), nausea (36%), fatigue (36%), chills (35%), diarrhea (34%), headache (32%), vomiting (30%), arthralgia (27%), hypertension (27%), rash (26%), and cough (23%). Hyperkeratosis, photosensitivity, and SCC/KA occurred in 7%, 4%, and 2% of pts, respectively. In pts receiving D+T for ≥ 24 mo (n = 165; 27%), AE incidence generally peaked within 6 mo of treatment initiation and declined thereafter (eg, pyrexia rate was 52% from 0-6 mo, 26% from 6-12 mo, 26% from 12-18 mo, and 22% from 18-24 mo). Pyrexia occurrence in all D+T pts did not predict response or progression. Conclusions: The safety profile of D+T across registration trials is consistent with individual study reports. With long-term treatment, the highest AE rates were observed within 6 mo of D+T initiation. Although common with D+T, occurrence of pyrexia during treatment did not predict response or progression. Additional pooled safety analyses will be presented. Clinical trial information: NCT01072175; NCT01584648; NCT01597908.
Comparison of Two Doses of Antithymocyte Globulin (ATG) in Reduced Intensity Conditioning (RIC) Allogeneic Hematopoietic Stem Cell Transplant (alloHSCT)
Authors: Hassan Issa, Amy S. Ruppert, Patrick Elder, Craig Hofmeister, Don M Benson, Sam Penza, Leslie A. Andritsos, Rebecca B. Klisovic, Sumithira Vasu, William Blum, Samantha M. Jaglowski, Steven M. Devine, Yvonne A Efebera
Journal: Blood (2015)
A plain radiograph in back pain
Authors: Joseph Dalby Sinnott, David C Howlett
Journal: BMJ (2016)

A 35 year old man presented to his general practitioner with lower back pain that was getting progressively worse. The pain was now severe enough to wake him in the night. What does the radiograph show (fig 1⇓) and what is the diagnosis?



Fig 1 

The radiograph shows multiple signs pointing to …
An immobilized liquid interface prevents device associated bacterial infection in vivo
Authors: Jiaxuan Chen, Caitlin Howell, Carolyn A. Haller, Madhukar S. Patel, Perla Ayala, Katherine A. Moravec, Erbin Dai, Liying Liu, Irini Sotiri, Michael Aizenberg, Joanna Aizenberg, Elliot L. Chaikof
Journal: Biomaterials (2016)
A Massive Retroperitoneal Mass With Leukocytosis
Authors: Kyle J. Van Arendonk, Jin He
Journal: JAMA Surgery (2016)

A man had worsening abdominal discomfort and a large recurrent umbilical hernia, early satiety but no nausea or vomiting, night sweats, and weight loss; examination revealed an umbilical hernia, palpable abdominal mass, and lower extremity edema. What is your diagnosis?
Polymorphisms of DNA repair and glutathione s-transferase genes and progression-free survival (PFS) in treated advanced esophageal cancer (EC) patients
Authors: G. Liu, W. Zhou, S. Park, S. Gurubhagavatula, B. Yeap, N. S. Nishioka, L. Su, J. C. Wain, T. J. Lynch, D. C. Christiani
Journal: Journal of Clinical Oncology (2004)

9564 Background: DNA repair capacity may influence the level of platinum-DNA adducts formed by platinum compounds. In turn, platinum compounds are metabolized by glutathione s-transferases (GSTs). We hypothesized that variant alleles of DNA repair genes and the presence of (or efficient) GST metabolic activity would be detrimental to the therapeutic functions of platinum. Methods: We evaluated PFS and genetic polymorphisms of GSTM1(deletion), GSTT1(deletion), GSTP1(Ile105Val), and the DNA repair genes, XPD (Asp312Asn, Lys751Gln) and XRCC1 (Arg399Gln), in 70 patients with locally advanced (Tany NanyM0–1a, 86%) or metastatic (Tany NanyM1b, 14%) EC treated with 2–4 cycles of platinum-based chemotherapy. Results: Median age was 64 (range: 37–88) years. 96% were male. 86% were adenocarcinomas. 97% had performance status ECOG 0 or 1. Median PFS was 16.3 months; by stage, median PFS were 23.0 mos (M0–1a) and 9.2 mos (M1b), respectively. Median follow-up was 23.6 months, while median overall survival was 30.1 months. Stage was not associated with any of the genotypes. After adjusting for stage (M0–1a versus M1b), the XPD751 Gln/Gln genotype was associated with shorter PFS (p=0.06, by Cox proportional hazards model, CPHM; see table), while the GSTM1-null genotype was associated with improved PFS (p=0.04 by CPHM). When combined, the XPD751 Gln/Gln + GSTM1 present genotypes had the shortest PFS (p=0.01 by CPHM). There were similar but non-significant trends (p>0.05) for the following polymorphisms: XPD Asp312Asn (Asn/Asn had shortest median PFS) and GSTT1-deletion (null genotype had longer median PFS). No polymorphisms were associated with overall survival. Conclusion: Genetic polymorphisms in XPD and GSTM1 may be important predictive factors of PFS in platinum-treated EC patients. No significant financial relationships to disclose.