tbuckley/cabot-search huggingface dataset:
HapB3 and the deep intronic variant c.1129-5923 C&gt;G of the dihydropyrimidine dehydrogenase gene (DPYD) to predict toxicity in stage III colon cancer (CC) patients (pts) (NCCTG Alliance N0147).
Authors: Adam M Lee, Qian Shi, Steven R. Alberts, Daniel J. Sargent, Frank A. Sinicrope, Jeffrey L. Berenberg, Richard M. Goldberg, Robert B. Diasio
Journal: Journal of Clinical Oncology (2015)

508 Background: Severe adverse events (AEs) to 5-fluorouracil (5-FU) constitute a major dilemma in CC treatment. We recently demonstrated that specific deleterious DPYD variants in the coding region were highly predictive of grade &gt;3 (G3+) AEs in stage III CC pts receiving adjuvant 5-FU based combination chemotherapy [Lee et al. JNCI. In press]. Other studies have suggested potential associations between AEs and non-coding DPYD variants: a novel haplotype (HapB3) containing three intronic variants (c.483+18 G&gt;A, c.680+139 G&gt;A, and c.959-51 T&gt;C), one synonymous variant (c.1236 G&gt;A, E412E), and a deep intronic variant (c.1129-5923 C&gt;G) that affects pre-mRNA splicing. However, these studies included a diversity of cancer types, stages and treatments. The findings require further evaluation in a refined population. Methods: A total of 2,134 Caucasian stage III CC pts without DPYD*2A, D949V, and I560S variants from NCCTG N0147 trial who received adjuvant FOLFOX or FOLFIRI +/- cetuximab were genotyped by multiplexed single-base extension assays on the Sequenom MassARRAY. G3+ AEs were recorded (CTCAE v3) and classified as common to 5-FU treatment (5FU-AEs). Logistic regressions were used to assess the univariate and multivariate associations. Results: Analyzed pts displayed the following characteristics: 54.3% male, median age 59 [19-85], proficient MMR 87.5%, PS-0 76.5%, + irinotecan 8.5%, and + cetuximab 46.5%. Pts carrying c.1129-5923 C&gt;G were significantly associated with higher risk of G3+ 5FU-AEs (Odds Ratio [OR]=1.539, 95% confidence interval [CI]=1.001 – 2.367, p=0.049). Only marginal association was observed for one of the HapB3 variants, c.1236 G&gt;A (p=0.058). A linearly increasing risk of G3+ 5FU-AEs was identified for HapB3, comparing pts with no, one or &gt;1 variant present (unadjusted OR=1.539, 95% CI=1.001 – 2.367, p=0.041; adjusted OR=1.198, 95% CI=0.998-1.437, p=0.052). Conclusions: In the largest study to date, c.1129-5923 C&gt;G and HapB3 were predictive of 5FU-AE risk in stage III CC patients without DPYD*2A, D949V, and I560S variants receiving 5-FU-based combination chemotherapy.
Late-breaking abstract: Moxifloxacin (MXF) vs amoxicillin/clavulanic acid (AMC) in acute exacerbations of COPD (AECOPD): Results of a large clinical trial with a novel endpoint
Authors: Robert Wilson, Antonio Anzueto, Marc Miravitlles, Pierre Arvis, Jeff Alder, Daniel Haverstock, Mila Trajanovic, Sanjay Sethi
Journal: European Respiratory Journal (2011)

Introduction: Evidence-based therapy of AECB/COPD is limited by a lack of appropriate trials. MAESTRAL compares antibiotic therapies for AECOPDs in patients with moderate-to-severe disease at risk of poor outcomes.

Method: This was a multiregional, prospective, randomised, double-blind study of patients ≥60 years, FEV1<60% predicted, with an Anthonisen type 1 exacerbation and ≥2 exacerbations in the last year. Patients were stratified by systemic steroid use and received MXF 400 mg PO qd (5 days) or AMC 875/125 mg PO bd (7 days). The primary endpoint was clinical failure 8 weeks post-therapy (PP) and the study was powered for superiority (ITT).

Results: At 8-weeks post-therapy MXF was non-inferior to AMC (Table). In microbiologically confirmed AECOPD, MXF resulted in lower clinical failure and higher bacterial eradication (Table). Steroid-treated patients had worse outcomes overall; this effect was lower for MXF vs AMC. Clinical cure at 8 weeks post-therapy was significantly higher in MXF patients with eradication vs persistence at EOT (P<0.0001) but not in AMC patients (P=0.149) (Table).

![Figure][1] 



Conclusion: Both drugs had good efficacy. At the 8-week endpoint, MXF was superior to AMC in microbiologically confirmed AECOPD. Bacterial eradication and clinical success were strongly correlated. The results may help physicians optimise antibiotic therapy in moderate-to-severe AECOPD.

 [1]: pending:yes
Abstract 13805: Imaging Mass Spectrometry with Focus Microwave Treatment Reveals Heterogeneity in Directional Glucose Fluxes in and Around Ischemic Myocardium
Authors: Yoshinori Katsumata, Yuki Sugiura, Kurara Honda, Mayumi Kajimura, keiichi Fukuda, Motoaki Sano, Makoto Suematsu
Journal: Circulation (2014)

Introduction: Matrix-assisted laser desorption/ionization (MALDI)-imaging-mass spectrometry (MS) combined with a focused microwave irradiation for rapidly fixing tissue metabolism allowed us to quantify and visualize many metabolites within heart tissues in a region-specific manner. Hypothesis: We assessed the hypothesis that these techniques are applicable to visualization of regional changes in glucose metabolism of murine heart exposed to coronary ischemia. Methods and Results: Heart-focused microwave irradiation (FMW) was found to be an optimal method to minimize postmortem changes in metabolites induced by ischemia as compared with traditional ways of sacrifice. After 10 min of myocardial ischemia by LAD ligation, quantitative imaging of various metabolites on the same section showed the highest levels of lactate, succinate, NADH in the ischemic core. Distribution of these metabolites was demarcated to that of ATP. Imaging of distinct metabolic fluxes from 13C6-glucose on the same section revealed th...
Abstract 12338: N-Terminal Probrain Natriuretic Peptide is a Strong Predictor of Long-Term Mortality in Patients With Severe Sepsis and Septic Shock. Data From the Albumin Italian Outcome Sepsis Study
Authors: Serge Masson, Pietro Caironi, Caterina Fanizza, Tarcisio Vago, Sara Carrer, Anselmo Caricato, Paola Fassini, Marilena Romero, Gianni Tognoni, Luciano Gattinoni, Roberto Latini
Journal: Circulation (2014)

Background: Myocardial depression is a common finding in severe sepsis, related to hemodynamic, metabolic and structural abnormalities. It is associated with increased morbidity and mortality. Although no pathogenic treatment is available, circulating biomarkers may be helpful for clinical management and early stratification of risk. Aims: To evaluate the clinical utility of circulating biomarkers of myocardial stress and injury in a large, representative cohort of patients with severe sepsis. Methods: Blood samples were collected 1, 2 and 7 days after enrolment in 995 patients with severe sepsis or septic shock enrolled in the multicenter Albumin Italian Outcome Sepsis (ALBIOS) trial (NCT00707122). N-terminal proBNP (NT-proBNP) and high sensitivity cardiac troponin T (hs-cTnT) were measured in a central laboratory with an electrochemiluminescent assay (Roche Diagnostics). We evaluated the relations between biomarker concentrations, clinical characteristics, 90-day mortality, and the effect of randomized ...
Correlation of body mass index with toxicity and survival in locoregionally advanced head and neck cancer patients treated with induction chemotherapy and concurrent chemoradiotherapy
Authors: A. K. Jain, J. K. Salama, K. M. Stenson, E. Blair, E. E. Cohen, M. Witt, D. J. Haraf, E. E. Vokes
Journal: Journal of Clinical Oncology (2009)

6074 Background: Concurrent chemoradiotherapy (CRT) offers high functional organ preservation rates for locoregionally advanced head and neck cancer (LRAHNC) patients, but is associated with significant acute and chronic speech and swallowing toxicity. Recently, body mass index (BMI) has been suggested as a predictor of head and neck cancer patient outcome. In this analysis we sought to determine the impact of BMI on survival and toxicity outcomes in LRAHNC patients treated with CRT. Methods: 220 LRAHNC patients were treated on a multiinstitutional protocol consisting of induction carboplatin and paclitaxel followed by CRT. CRT was delivered for 4–5 cycles; each 14-day cycle consisted of 5 days concurrent paclitaxel, continuous infusion 5-FU, hydroxyurea, and 1.5 Gy twice daily radiation followed by 9 days without any treatment. Each patient's pre-treatment BMI was classified as overweight (BMI &gt;= 25) or non-overweight (BMI &lt; 25). As an independent variable, BMI was analyzed as a predictor of IndCT or CRT toxicity, locoregional control, and overall survival. BMI was analyzed as categorical variable, and also a continuous variable in a multivariate proportional hazards model. Results: There was no association between BMI and IndCT toxicity. During CRT overweight patients had significantly lower rates (24/103 vs 42/112) of grade 3 or higher neutropenia (p = 0.027), mucositis (p = 0.05), dermatitis (p = 0.028) and higher rates of anorexia (p = 0.05). Overweight patients had 12% long term PEG tube rate, compared to 34% of non-overweight patients (p &lt; 0.001). On pooled survival analysis, patients with BMI &gt; 25 had significantly better overall survival outcomes (mean 81.2 months, 95% CI 75.1–87.3 months) than patients with BMI &lt; 25 (median 58.2 months; mean 56.5 months, 95% CI 49.6–63.3 months) (log-rank p &lt; 0.001). Conclusions: Our data suggest patients with pre-treatment BMI &gt; 25 experience lower rates of toxicity commonly associated with chemoradiation, and have a significantly better prognosis than patients with BMI &lt; 25. Although the mechanism of BMI as an independent predictor of outcomes is unclear, we are continuing to explore mechanisms underlying this association. No significant financial relationships to disclose.
Pharmacokinetic characteristics of ethambutol hydrochloride depending on the way of administration
Authors: Mykhailo Kuzhko, Nataliia Gulchuk, Miroslava Klimenko, Lubomir Protsyk, Oksana Avramchuk
Journal: European Respiratory Journal (2014)

Background.  Drug concentration may vary depending on the route of administration. Low plasma/tissue concentration leads to ineffective TB treatment and resistance development. We studiedpharmacokinetic properties of ethambutol hydrochloride (E) depending on the mode of administration.   Methods.  In a comparative pharmacokinetic study 12 patients with newly diagnosed pulmonary TB formed a homogeneous group and received E (10% sol.) in a single dose of 1600 mg intravenously (iv). A few days later all patients received E in tablets in a single dose 1600 mg, orally.   Results.  1 hour (h) after iv infusion mean serum concentration of E was significantly higher (3,2±0,2 mcg/ml), than after oral use (1,5±0,1 mcg/ml), p 0.05); in 3 h it was 1,0±0,1 and 2,8±0,4 mcg/ml, respectively, (p   Conclusion.  Maximum concentration of E after iv administration 2.5 times exceeds it while taking the drug orally.
Interim Guidelines for Pregnant Women During a Zika Virus Outbreak — United States, 2016
Authors: Emily E. Petersen, J. Erin Staples, Dana Meaney-Delman,, Marc Fischer, Sascha R. Ellington, William M. Callaghan, Denise J. Jamieson
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

CDC has developed interim guidelines for health care providers in the United States caring for pregnant women during a Zika virus outbreak. These guidelines include recommendations for pregnant women considering travel to an area with Zika virus transmission and recommendations for screening, testing, and management of pregnant returning travelers. Updates on areas with ongoing Zika virus transmission are available online (http://wwwnc.cdc.gov/travel/notices/). Health care providers should ask all pregnant women about recent travel. Pregnant women with a history of travel to an area with Zika virus transmission and who report two or more symptoms consistent with Zika virus disease (acute onset of fever, maculopapular rash, arthralgia, or conjunctivitis) during or within 2 weeks of travel, or who have ultrasound findings of fetal microcephaly or intracranial calcifications, should be tested for Zika virus infection in consultation with their state or local health department. Testing is not indicated for women without a travel history to an area with Zika virus transmission. In pregnant women with laboratory evidence of Zika virus infection, serial ultrasound examination should be considered to monitor fetal growth and anatomy and referral to a maternal-fetal medicine or infectious disease specialist with expertise in pregnancy management is recommended. There is no specific antiviral treatment for Zika virus; supportive care is recommended.
Intravenous vinorelbine (NVBiv) on D1 and oral vinorelbine (NVBo) on D8 in combination with carboplatin (CBDCA) as first-line treatment in advanced non-small lung cancer (NSCLC) patients: Results of a prospective study in nonselected population.
Authors: J. Skrickova, L. Babickova, M. Tomiskova, B. Kadlec
Journal: Journal of Clinical Oncology (2010)

e18061 Background: In the Czech Republic approximately 65% of patients with NSCLC have advanced disease at the time of diagnosis. For this group of patients, the standard therapy is a double agent platinum-based chemotherapy. Most patients who receive first-line chemotherapy experience disease progression within 3 to 6 months of initiating therapy and the median survival time observed is 8 to 10 months. In this situation, there is a need to find a therapeutic regimen with an administration as simple as possible and the most favorable toxicity profile. The purpose of this trial was to evaluate the activity and feasibility of CBDCA together with NVBiv and NVBo. Methods: Patients with advanced NSCLC received NVBiv 25 mg/m2 on D1 and NVBo 60 mg/m2 on D8 combined with CBDCA AUC5 on D1 every three weeks. In stage III, chemotherapy was followed by external radiotherapy. Response was assessed by imaging techniques after 4-6 weeks of treatment and was confirmed one month later by chest X-ray and/or CT scanning. Results: 153 patients were treated: 121 men (79%) and 32 women (21%), median age 65 years. ECOG performance status at inclusion was 0 in 34 patients, 1 in 107 and 2 in 12 patients. Most patients had stage IIIB 66 (43%) and stage IV NSCLC 82 (54%). Adenocarcinoma was confirmed in 33 patients (22%), squamous-cell carcinoma in 94 (61%) and other in 26 (17%). Complete response was confirmed in 1 patient, partial response in 74 (49%), stable disease in 50 (33%), 27 (18%) patients progressed and 1 was not evaluated. Major toxicities (Grade 3-4) were neutropenia in 33 (21.6%), leucopenia in 13 (10.6%), anemia in 4 (2.3%), and thrombocytopenia in 1 (0.7%) patients. Febrile neutropenia was observed in 2 (1.4%) patients. With a median follow-up period of 0.87 year, the median survival is 14.8 months and the progression-free survival 10.6 months. Conclusions: In this group of 153 non-selected patients with advanced NSCLC treated with NVB-CBDCA in first line, switching from NVBiv to NVBo allows a more convenient and well tolerated treatment with evidence of high antitumour activity. No significant financial relationships to disclose.
Neoadjuvant bevacizumab and anthracycline–taxane-based chemotherapry in 686 triple-negative primary breast cancers: Seconday endpoint analysis of the GeparQuinto study (GBG 44).
Authors: B. Gerber, H. Eidtmann, M. Rezai, P. A. Fasching, H. Tesch, H. Eggemann, I. Schrader, K. Kittel, C. A. Hanusch, R. Kreienberg, C. Solbach, C. Jackisch, G. Kunz, J. U. Blohmer, J. B. Huober, M. Hauschild, S. Loibl, V. Nekljudova, M. Untch, G. Von Minckwitz
Journal: Journal of Clinical Oncology (2011)

1006 Background: The addition of bevacizumab (Bev) to EC-docetaxel chemotherapy (CT) did not improve pathological complete response (pCR) rates in unselected patients (P) with HER2 negative breast cancers (von Minckwitz G et al, San Antonio 2010). Secondary aim of GeparQuinto was to determine pCR rates in patients with triple-negative breast cancer (TNBC) exclusively. Methods: P with untreated TNBC (ER and PgR <10% and HER2 IHC score 0/1 or FISH negative; detected locally) were included in GeparQuinto if they had T1c-T4d tumors and showed no increased cardiac or bleeding risks. P were randomized to receive 4 cycles EC (90/600 mg/m²) q3w followed by 4 cycles docetaxel (100mg/m²) with or without Bev 15mg/kg q3w added to CT cycles. P not clinically responding to EC ± Bev were considered as treatment failures and entered another part of the protocol. P were a stratified subset of the 1948 participants of the HER2 negative part of GeparQuinto. Results: In total 684 P with TNBC were randomized to EC-D (N=345) and EC-D+Bev (N=339). Median tumor size was 35 / 35 [-Bev / +Bev] mm (clinically) and 28.5 / 28 mm (sonographically); 15.7% / 16.0% had T3-4a-d, 1.2% / 1.5% bilateral, 13.3% / 12.7% multifocal, and 5.8% / 6.5% multicentric disease, 97.1% / 97.9% had non-lobular, 71.6% / 69.6% grade 3, 57.2% / 58.0% node-positive. 32.9% / 28.7% discontinued treatment, 20.7% / 12.3% due to no response after 4xEC. Additional 4.7% continued CT but stopped Bev. pCR rate % (ypT0, ypN0; primary endpoint) was 27.8 / 36.4 (p=0.021). Rate of P with ypT0/is was 36.5 / 44.6 (p=0.04) and ypT0/is ypN0 was 32.7 / 40.1 (p=0.059). If pCRs in non-responding P were included, ypT0,ypN0 rates raised to 28.7 / 38.2; ypT0/is ypN0 rates to 33.9% / 41.9%. If only P with ER=0%, PgR=0% were considered, ypT0 ypN0 was 32.3% / 40.1%. Bev treatment (p=0.013), age (p=0.021), cT (p=0.042) and grade (p=0.004) were independent predictors for pCR in multivariate logistic regression analysis. Breast conservation was achieved in 75.2% / 71.5% (p=0.39). Conclusions: The effect of Bev on pCR in the GeparQuinto study was restricted exclusively to patients with TNBC. Long term follow-up has to be awaited.
Occurrence of Tumors in Wild House Mice
Authors: Howard B. Andervont, Thelma B. Dunn
Journal: JNCI Journal of the National Cancer Institute (1962)

The occurrence of spontaneous tumors in wild house mice (Mus musculus) raised in captivity is recorded. All tumors included herein were visible on gross examination. A total of 225 mice was necropsied, of which 98, or 43.5 percent, had developed tumors. A total of 121 tumors was found, of which 44, or 36 percent, were in 107 mice from 2 to 24 months of age, and 77, or 64 percent, were in 118 mice from 25 to 33 months of age. Incidences of the most frequent tumors found were: pulmonary, 21 percent; reticulum-cell (type B), 10 percent; granulosa-cell of ovary, 5 percent; hepatomas, 5 percent; hemangioendotheliomas, 4 percent. Ninety-nine breeding females showed a mammary-tumor incidence of 6 percent; no mammary tumors were found in 72 nonbreeding females. Only 2 unquestionable lymphocytic neoplasms were found. One arose subcutaneously in the dorsal cervical region, and the other was in the thymus gland and was spreading beyond the capsule.
Dose-finding study by continuous reassessment method (CRM) for topotecan (TT) in combination with ifosfamide (IF) as a second-line therapy for pediatric solid cancer: Preliminary report of phase I/II study.
Authors: H. Kawamoto, M. Saito, T. Kimura, A. Ogawa, Y. Ishida, T. Taga, H. Mugishima, A. Makimoto
Journal: Journal of Clinical Oncology (2010)

9546 Background: TT has already become a key drug for recurrent pediatric solid cancer especially in combination with cyclophosphamide (CY). The combination of TT and IF (TI) could be more effective because most recurrent cases are more sensitive to IF than CY. We conducted a dose-finding trial of TI as a second-line therapy with pharmacokinetic study. Methods: Pediatric recurrent solid cancer only with previous chemotherapy no more than 20 cycles is eligible. IF, fixed to 1.2g/m2/day, and TT, 0.6 (level 0), 0.75 (starting dose, level 1), 0.9 (level 2), 1.1 (level 3) mg/m2/day, were administered on days 1-5 with prophylactic use of G- CSF every 21 days. We defined the maximum tolerated dose (MTD) as the closest dose level to dose-limiting toxicity (DLT) occurrence rate of 30% and set target rate (recommended dose [RD]) at 20% by CRM estimation. Results: Safety profile of the first 11 pts resulted in termination of the phase I part. All 4 DLTs occurred on level 1 and included platelet transfusions twice/cycle (3/4), red blood cell transfusion (2/4), and prolonged febrile neutropenia (1/4). Occurrence rates of DLT estimated by CRM are 14.1% (0/5 pts), 41.8% (4/6 pts) in the level 0 and level 1, respectively (Table) at study termination. We determined RD is level 0 and MTD was level 1. No severe nonhematological toxicity was reported except for temporary nausea and anorexia. Pharmacokinetic studies indicated that IF administered on the schedule used in this study did not alter TP disposition as reported regarding concurrent use of CY. Responses were reported in 1PR /4 rhabdomyosarcoma, 1PR /1 hepatoblastoma. Conclusions: CRM could function to determine RD efficiently with minimum number of pts. IF, in combination with TT, appeared slightly more toxic than the equivalent dose of CY. This current trial is now continued as early phase II for assessment of efficacy. Level 0 Level 1 Level 2 Level 3 Expected probability of DLT occurrence rate before trial 5% 10% 30% 50% Pts DLT occurred/Pts treated 0/5 4/6 0/0 0/0 DLT occurrence rate 14.1% 41.8% 85.7% 94.7% Probability of more than 30% DLT occurrence rate 1.1% 73.4% 98.9% 99.7% No significant financial relationships to disclose.
Mutations in CTNNA1 cause butterfly-shaped pigment dystrophy and perturbed retinal pigment epithelium integrity
Authors: Nicole T M Saksens, Mark P Krebs, Frederieke E Schoenmaker-Koller, Wanda Hicks, Minzhong Yu, Lanying Shi, Lucy Rowe, Gayle B Collin, Jeremy R Charette, Stef J Letteboer, Kornelia Neveling, Tamara W van Moorsel, Sleiman Abu-Ltaif, Elfride De Baere, Sophie Walraedt, Sandro Banfi, Francesca Simonelli, Frans P M Cremers, Camiel J F Boon, Ronald Roepman, Bart P Leroy, Neal S Peachey, Carel B Hoyng, Patsy M Nishina, Anneke I den Hollander
Journal: Nature Genetics (2015)
Autofluorescence and narrow band imaging videobronchoscopy in detection of premalignant bronchial lesions
Authors: Bojan Zaric, Branislav Perin, Svetlana Jovanovic, Evica Budisin, Goran Stojanovic, Nensi Lalic, Milan Antonic
Journal: European Respiratory Journal (2011)

Background: The search for most efficient bronchoscopic imaging tool in detection of early lung cancer is still active. The major aim of this study was to determine sensitivity, specificity, positive (PPV) and negative predictive value (NPV) of each technique and their combination in detection of premalignant bronchial lesions.

Patients and methods: Ninety six patients were enrolled in the study. Major indications were: radiological suspicion for lung cancer, surveillance of patients after surgery, evaluation of known malignancy, positive sputum cytology and prolonged cough. Lesions were classified as visually positive if pathological fluorescence was observed under AFI or, dotted, tortuous and abrupt ending blood vessels were identified under NBI. Squamous metaplasia, mild, moderate or severe dysplasia and CIS were regarded as histologically positive lesion were.

Results: Sensitivity, specificity, PPV and NPV of WLB in detection of premalignant lesions were 26.5%,63.9%,34.4% and54.9% respectively, corresponding values for AFI were 52%,79.6%,64.6% and69.9% respectively, for NBI were 66%, 84.6%, 75.4%, 77.7%, respectively, while corresponding values for combination of NBI and AFI were 86.1%, 86.6%, 84.6%, and88% respectively. Combination of NBI and AFI significantly improves sensitivity when compared to each individual technique (p<0.001). When specificity is of concern combination of techniques improves specificity of WLB (p<0.001), specificity of AFI (p=0.03) but it has no significant influence on specificity of NBI (p=0.53).

Conclusion: Combination of NBI and AFI in detection of premalignant bronchial lesions increases both sensitivity and specificity of each technique.