tbuckley/cabot-search huggingface dataset:
Effect of the proton pump inhibitor esomeprazole on the oral absorption and pharmacokinetics of nilotinib
Authors: N. J. Gallagher, D. Fischer, E. Demirhan, W. Zhou, G. Golor, H. Schran, O. Yin
Journal: Journal of Clinical Oncology (2009)

7053 Background: Nilotinib, a highly selective and potent BCR-ABL tyrosine kinase inhibitor, is approved for the treatment of CML-CP and CML-AP patients resistant or intolerant to prior therapy including imatinib. The solubility of nilotinib is pH dependent, with lower solubility at higher pH. We evaluated whether esomeprazole, a potent proton pump inhibitor (PPI) that can significantly increase gastric pH, could affect the oral absorption and pharmacokinetics of nilotinib in healthy subjects. Methods: Twenty-two subjects (6 F, 16M, age range 18–64 years) were enrolled to receive nilotinib alone or in the presence of steady-state esomeprazole during two treatment periods. Nilotinib was given as a single oral 400 mg dose on days 1 and 13, and esomeprazole 40 mg once-daily on day 8 through day 13. Serial blood samples were collected up to 72 hours after nilotinib dosing for determination of nilotinib serum concentrations by a validated liquid chromatography-tandem mass spectrometry assay. Gastric pH was monitored in all subjects at baseline (prior to nilotinib and esomeprazole dosing), before and during the first 4 hrs of esomeprazole steady state dosing (fifth dose on Day 12). Results: When coadministered with esomeprazole, nilotinib C max was decreased by 27% (397±89 vs 303±157ng/mL) and AUC 0-∞ decreased by 34% (11515±6140 vs 7164±3752ng*hr/mL) respectively. The median time to reach nilotinib C max was slightly prolonged from 4.0 hrs to 6.0 hrs, but its elimination half-life was not altered (17.3±10.7 vs 15.9±6.6 hrs). Median gastric pH was increased from 0.8 at baseline to 2.0 at pre-dose, and to 3.9, 5.8, 5.5, and 5.7 at 1, 2, 3, and 4 hrs after esomeprazole dosing. Administration of nilotinib alone or in combination with esomeprazole was generally well tolerated in the study subjects. Conclusions: The study results demonstrate a modest reduction in the rate and extent of nilotinib absorption when co-administered with esomeprazole. Such an effect is unlikely to cause a significant clinical consequence for nilotinib therapy, and thus nilotinib can be used with esomeprazole or other PPIs without the risk of substantial decrease in nilotinib systemic exposure. [Table: see text]
Differentiating Among Proposed Mechanisms for Tumor Promotion in Mouse Skin With the Use of the Multievent Model for Cancer
Authors: K C Chu, C C Brown, R E Tarone, W Y Tan
Journal: JNCI Journal of the National Cancer Institute (1987)

Numerous mechanisms for tumor promotion in mouse skin have been recently proposed. These include the multistage, genetic view of Slaga, Furstenberger, and Marks; the multistage, genetic and/or epigenetic view of Parkinson; and the two-stage view of Yuspa and Hennings. With the use of the multievent model, a mathematical model for cancer that can incorporate cell proliferation phenomena, these tumor promotion mechanisms were modeled mathematically. It was found that the models had different predictions about the incidence of papillomas in initiator-promoter-initiator experiments and the incidence of carcinomas in initiator-promoter experiments with varying periods of tumor promotion. Upon analysis, existing data were shown to be in agreement with the Yuspa and Hennings two-stage model. The analysis also supported the view, formulated by Scribner and co-workers, that different types of initiated cells were created, some capable of transformation to carcinomas and some not. Phenomena determined by use of benign tumors as the end point may need to be demonstrated with the use of the carcinoma as the end point, prior to the acceptance of these phenomena being applicable to the human carcinogenic process.
Phase Ii Trial of Metronomic Oral Vinorelbine As First-Line Treatment in Elderly Patients with Advanced Non-Small Cell Lung Cancer (Move Trial)
Authors: A. Camerini, C. Puccetti, S. Donati, C. Valsuani, M.C. Petrella, G. Tartarelli, P. Puccinelli, D. Amoroso
Journal: Annals of Oncology (2014)
Phase III study of BCOP v CHOP in unfavorable categories of malignant lymphoma: a Southeastern Cancer Study Group trial.
Authors: R A Gams, M Rainey, M Dandy, A A Bartolucci, H Silberman, G Omura
Journal: Journal of Clinical Oncology (1985)

A total of 296 evaluable patients with unfavorable categories of malignant lymphoma were randomly assigned treatment with cyclophosphamide, vincristine, and prednisone plus BCNU (BCOP) or doxorubicin (CHOP). In diffuse histiocytic (DH) lymphoma, CHOP produced superior complete (54% v 34%) and total (70% v 46%) response rates. Among the responders to either therapy, no differences were seen in duration of response or survival times. Median duration of response has not been reached with follow-up in excess of 50 months. In categories of lymphoma other than DH (including small-cell, mixed, and nodular histiocytic lymphomas), complete (27% v 29%) and total (48% v 54%) responses were similar for BCOP and CHOP, as were durations of response and survival. These data suggest that BCOP and CHOP are equivalent regimens for other categories of malignant lymphomas. CHOP appears preferable for diffuse large-cell categories, since it resulted in greater overall survival in patients with DH lymphoma; this was due to a significantly greater response rate, since patients with DH lymphoma who did respond to BCOP maintained their response and survived as long as did the CHOP responders.
Strategies to Prevent Cholera Introduction during International Personnel Deployments: A Computational Modeling Analysis Based on the 2010 Haiti Outbreak
Authors: Joseph A. Lewnard, Marina Antillón, Gregg Gonsalves, Alice M. Miller, Albert I. Ko, Virginia E. Pitzer
Journal: PLoS Medicine (2016)

Introduction of Vibrio cholerae to Haiti during the deployment of United Nations (UN) peacekeepers in 2010 resulted in one of the largest cholera epidemics of the modern era. Following the outbreak, a UN-commissioned independent panel recommended three pre-deployment intervention strategies to minimize the risk of cholera introduction in future peacekeeping operations: screening for V. cholerae carriage, administering prophylactic antimicrobial chemotherapies, or immunizing with oral cholera vaccines. However, uncertainty regarding the effectiveness of these approaches has forestalled their implementation by the UN. We assessed how the interventions would have impacted the likelihood of the Haiti cholera epidemic.We developed a stochastic model for cholera importation and transmission, fitted to reported cases during the first weeks of the 2010 outbreak in Haiti. Using this model, we estimated that diagnostic screening reduces the probability of cases occurring by 82% (95% credible interval: 75%, 85%); however, false-positive test outcomes may hamper this approach. Antimicrobial chemoprophylaxis at time of departure and oral cholera vaccination reduce the probability of cases by 50% (41%, 57%) and by up to 61% (58%, 63%), respectively. Chemoprophylaxis beginning 1 wk before departure confers a 91% (78%, 96%) reduction independently, and up to a 98% reduction (94%, 99%) if coupled with vaccination. These results are not sensitive to assumptions about the background cholera incidence rate in the endemic troop-sending country. Further research is needed to (1) validate the sensitivity and specificity of rapid test approaches for detecting asymptomatic carriage, (2) compare prophylactic efficacy across antimicrobial regimens, and (3) quantify the impact of oral cholera vaccine on transmission from asymptomatic carriers.Screening, chemoprophylaxis, and vaccination are all effective strategies to prevent cholera introduction during large-scale personnel deployments such as that precipitating the 2010 Haiti outbreak. Antimicrobial chemoprophylaxis was estimated to provide the greatest protection at the lowest cost among the approaches recently evaluated by the UN.
구연 : 그랜드볼룸 ; 만성 B형 간염에서 entecavir에 대한 조기 치료반응 예측인자로서 HBsAg titer의 의미 (초)
Authors: 송준창, 김종엽, 김여명, 정숙향, 김진욱
Journal: Clinical and Molecular Hepatology (2010)
Results of Surgery in 88 Consecutive Cases of Extrahepatic Biliary Atresia
Authors: Edward R Howard, Janet McClement, Marie Driver, Alex P Mowat
Journal: Journal of the Royal Society of Medicine (1982)

Of 88 cases of extrahepatic biliary atresia, satisfactory bile flow has been established in 46% of the patients who have undergone portoenterostomies and in 25% of patients with hepaticojejunostomies. Histological analysis of the extrahepatic biliary tissue has not shown a consistent correlation with outcome of operation, except that the patients with one or two large residual ducts lined with columnar epithelium have a better chance of developing bile flow. Cholangitis developed in 43% of the cases, and co-trimoxazole was not shown to have any beneficial effect in a small prospective trial in 18 patients. Severe haemorrhage from oesophageal varices has occurred in 4 jaundice-free survivors. Seventeen patients are now over 3 years of age and thriving but many show persistent elevation of liver enzymes.
Calcification Outcome in Renal Disease (CORD) - A prospective epidemiological multinational study: Importance of changes in aortic stiffness on outcome in dialysis patients
Authors: F. Verbeke, Jean-Marie Krzesinski, P. Rensma, Knut Aasarod, B. Wikstrom, E. Honkanen, P. B. Jensen, A. Willernsem, M. Rasmussen
Journal: Journal of the American Society of Nephrology (2007)
Asthma phenotypes associated with vocal cord/laryngeal dysfunction
Authors: Peter Holmes, Kathy Low, Kenneth K. Lau, Marcus Crossett, Paul M. Leong, Kais Hamza, Garun Hamilton, Philip G. Bardin
Journal: European Respiratory Journal (2012)

Aim:  To identify asthma phenotypes in patients with refractory and non-refractory asthma in whom inappropriate vocal cord closure and laryngeal dysfunction (LD) may occur (Low  et al , AJRCCM, 2011).   Methods:  We evaluated 57 patients with mild to moderate non-refractory asthma (N=31) or refractory asthma (N=26). Dynamic 320 slice computerised tomography (CT) of larynx was done and a validated algorithm was used to accurately measure vocal cord lateral diameter during inspiration and expiration. Excessive narrowing of the airways was diagnosed if a predetermined lower limit of normal was exceeded. The asthma groups were compared by semi-supervised cluster analysis to identify asthma phenotypes associated with laryngeal dysfunction.   Results:  Overall vocal cord diameter was reduced below the lower limit of normal in 26 of 57 cases (46%). There was no relationship with asthma severity (LD) in refractory asthma: 12/26 (46%) versus non-refractory 14/31 (45%). Laryngeal dysfunction was associated with increased age (P   1. age > 40 years, female, bronchodilator response   2. age > 40 years, bronchodilator response   30kgs / m 2 ;  3. female, bronchodilator response   30kgs / m 2 .   Conclusion:  Our results indicate that vocal cord behaviour is abnormal in asthma, irrespective of severity. However, laryngeal dysfunction may often be associated with particular patient phenotypes and contribute to their overall symptomatic burden of disease.
Clinical behavior of a cohort of patients with triple negative breast cancer
Authors: R. Villalobos, G. Hernández, M. Martinez-Prieto
Journal: Journal of Clinical Oncology (2008)

11576 Background: In recent times, there have been publications on the clinical characteristics of breast cancer that is negative for ER, PR and Her2, triple negative BC, but its behavior patterns are not clear We present the descriptive analysis of a cohort of triple negative patients at our hospital. Methods: 37 of 43 files for pts with triple negative breast cancer were available for evaluation from Jul 2007 to Jan 2008. Determination for ER, PR and Her2 was done through IHQ and were stratified by clinical characteristics and disease evolution. Results: Median age was 50.1 years range 30 to 83, 22 were postmenopausal we had one male in our population. Stages were as follows I one, IIA 6, IIB 6, IIIA 3, IIIB 6, IIIC 6, IV. Histologically 57% were grade III, 77% were p53 positive. 13 patients were treated with neoadjuvant CT, 4 of which had a CR, 5 had a PR, and 4 had PD. After a 79-month follow-up, 17 pts (46%) recurred and 3 progressed. At the end of follow- up, 17 pts (46%) are alive with no evidence of recurrence 21% had a recurrence and 21% more are dead. Main site of relapse was systemic in 13 pts (76.4%) and local in 4 pts after a median DFS of 24.2 months range 1 to 68. An important consideration is that for pts alive without relapse follow-up time is 15 months only. One of these pts was stage I, 7stage II, 8 stage III and one stage IV. With regard to line of CT received on relapse, 19 pts were on 1st line and 12 pts on 2nd line, 5 pts third, 4 pts fourth, 4 pts fifth and 2 pts sixth. Conclusions: The results of this analysis show a high percentage of recurrences in this group of patients, greater histologic degree as well as a high percentage of expression of p53. By the small number of patients it is not possible to determine other factors predictive and prognoses, but a greater pursuit and greater increase of our sample will allow us to reach better conclusions. No significant financial relationships to disclose.
HER2 and EGFR status in pancreatic ductal adenocarcinomas (PDACs) and lymph node metastases
Authors: J. Luettges, D. Schuldt, K. Richter, K. Peters, G. Kloppel
Journal: Journal of Clinical Oncology (2004)

4246 Background: The use of monoclonal antibody therapies against growth factor receptors as treatment for malignant tumours is on the increase. The potential usefulness of such therapies may be determined by assessment of the expression level of the receptor. Inter-study variation in the levels of the HER2 and EGFR receptors has been seen in PDACs. This study seeks to evaluate the expression rate of these receptors in metastatic PDACs, with regard to the possible use of monoclonal antibody therapies such as trastuzumab (Herceptin) in treating these tumours. Methods: 28 PDACs and their associated lymph node metastases underwent immunohistochemical staining for HER2 (CB11 antibody, Ventana) and EGFR (E30 antibody, Merck). HER2 gene amplification was also assessed by chromogenic in situ hybridisation (CISH, Zytomed). The percentage of cells in each sample that stained positive for HER2 was also analysed in a second series of 104 primaries only. Results: HER2 overexpression was seen in 28% of PDACs; 3+ overexpression was demonstrated in 10% of primary tumours and 21% of metastatic tumours. 28% of primary and metastatic tumours displayed HER2 gene amplification by CISH. EGFR was overexpressed in 50% of primaries and 28% of metastases. All lesions tumours classed as pancreatic intraepithelial neoplasia (PanIN, n=23) were negative for HER2 and EGFR, with the exception of three PanIN3 lesions that overexpressed HER2. 87% of samples had less than 50% of cells staining positive for HER2. Conclusions: The rate of HER2 overexpression in PDACs appears to be lower than previously reported. This suggests that these tumours are less suitable for treatment with HER2 antibody therapies such as trastuzumab. However, the high rate of EGFR overexpression indicates that this may be a promising therapeutic target in PDACs. No significant financial relationships to disclose.
Predicting clinical outcome through gene expression profiling in stage III melanoma
Authors: T. John, M. A. Black, T. Toro, C. A. Gedye, I. D. Davis, D. Leader, P. Guilford, J. S. Cebon
Journal: Journal of Clinical Oncology (2007)

8502 Background: Melanoma patients with clinically involved regional lymph nodes (Stage IIIB&amp;C) represent a prognostically heterogeneous population. Current prognostic factors cannot distinguish the 30% of patients who will achieve long term survival from those who will relapse early. We hypothesized that gene expression profiling could identify these different prognostic groups and provide a greater understanding of the genetic mechanisms involved. Methods: Lymph node sections from 29 patients with Stage IIIB &amp; IIIC melanoma and divergent clinical outcome as defined by time to tumor progression (TTP), including 16 poor (TTP&lt;6 months) and 13 good (TTP&gt;28 months) prognosis patients, were subjected to molecular profiling using spotted oligonucleotide arrays containing 30,888 probes as an initial test set. The differentially expressed genes were determined using a Wilcoxon-Mann-Whitney t-test with the false discovery rate controlling method of Benjamini-Hochberg and validated using quantitative real-time RT-PCR. Using logistic regression, a predictive score algorithm was developed based on the 15 genes for which the correlation between the two platforms was the strongest. The score was then applied to two independent validation sets of 10 and 14 patient samples. Results: Supervised analysis using differentially expressed genes was able to distinguish the two prognostic groups in the test set. The score correlated directly with clinical outcome, with higher scores associated with improved TTP. When the score was then applied to two independent sets of Stage III melanoma patient samples, it predicted clinical outcome accurately in 90% of samples. Conclusions: Stage IIIB and IIIC melanoma can be prognostically sub-classified according to the expression of 15 genes. To our knowledge this is the first study focused on Stage III disease using ex vivo patient samples. These results are encouraging and this genetic signature is currently being validated on a larger cohort. This method will allow appropriate stratification of stage III melanoma patients in adjuvant clinical trials, ameliorating the inherent biological heterogeneity that can confound these studies. [Table: see text]
Fixed dose rate (FDR) gemcitabine (G) and capecitabine (C) in patients with advanced and/or metastatic cancer: phase I trial
Authors: D. Santini, B. Vincenzi, V. Virzì, A. La Cesa, G. Schiavon, V. Leoni, S. Gasparro, C. Grilli, A. Calvieri, G. Tonini
Journal: Journal of Clinical Oncology (2006)

12016 Background: Combination of C and G has been demonstrated to be well tolerated, with apparent efficacy in patients with advanced cancers. To determine the toxicity of C plus Fixed Dose Rate (FDR) G in metastatic cancer patients, a phase I trial was conducted. Methods: This is an open-label, single-center, dose-escalating phase I study. C was administered orally according to the standard 21-day schedule: bid in equal doses (650 mg/m 2 bid) for 14 days every 21 days. G was administered at a FDR of 10 mg/m 2 per min in escalating durations of infusion on days 1 and 8 every 21 days. The doses of G explored were 600, 700, 800 mg/m 2 infused at FDR in 60, 70 and 80 minutes, respectively. 15 pts (10 female, 5 male), aged 37–70 yr (median 66) with a variety of advanced solid tumors have been treated (11 peri-ampullary cancers, 3 colorectal cancers and 1 ovarian cancer). The FDR G dose was escalated when 3 patients in a cohort had completed two cycles of treatment without experiencing dose-limiting toxicities (DLT). The MTD was defined as the dose level at which no more than one of nine patients experienced a DLT. Results: No DLT occurred at doses of 600 and 700 mg/m 2 in any of the 3 patients included at each level. At 800 mg/m 2 , 1 of 9 patients experienced DLT (neutropenia grade 4 with fever). The non-haematological toxicities have been generally mild or moderate in all patients (grade 2 stomatitis: 4 patients; grade 2 fatigue: 3 patients; grade 2 nausea/vomiting: 2 patients). 2 patients showed one episode of grade 4 neutropenia spontaneously regressed in 3 days. 2 patients showed one episode of grade 2 thrombocytopenia. The recommended dose for further studies is C bid in equal doses (650 mg/m 2 bid) for 14 days (28 doses) plus FDR G at 800 mg/m 2 infused in 80 minutes on days 1 and 8 every 21 days. Other patients with periampullary carcinoma are being evaluated at the same dose level, with an ongoing evaluation of cumulative (all cycles) toxicity and efficacy. In terms of response, we have observed 2 PR and 3 SD in the 6 pancreatic cancer patients evaluated for response after the first 3 cycles. Conclusions: C plus FDR G combination seems to be a feasible and safety approach which has demonstrated promising clinical activity. No significant financial relationships to disclose.
Squamous cell carcinoma of the anal canal at the Queen Elizabeth Hospital: A local experience
Authors: T. J. Price, J. Zakaria, D. Rodda, P. Hewett, N. Rieger, J. Stephens, K. Pittman, K. Patterson, M. Borg
Journal: Journal of Clinical Oncology (2005)

6126 Background: Abdominal-perineal resection (APR) with or without chemo radiation (CRT) was a standard treatment for squamous cell carcinoma of anal canal. Subsequently a series of clinical trials have clearly demonstrated that CRT as primary treatment results in improvement in local regional control, colostomy free survival and disease-free survival. The aims of this study are to determine what is the local practice and outcomes in a single centre. Methods: All patients with squamous cell carcinoma of the anus treated in TQEH over 6-year period (1998–2004) were identified. A standardised chemoradiotherapy protocol was used - 36 Gy in 20 fractions to the pelvis using a 3–4 field technique followed by a dose of 14.4 -18.0 Gy, in 8–10 fractions, to macroscopic disease (primary and nodes) combined with mitomycin C/CVI 5fluorouracil. Baseline data were collected prospectively. Results: A total of 35 patients were reviewed during the study period: 14 men and 21 women with a median age of 64 years. After diagnosis 77% of patients had chemo radiotherapy as first line treatment. 23% local recurrence rates were found and all had salvage abdominal-perineal resection. The 3 and 5 year overall survival for all patients was 75% & 53%. For patients undergoing primary CRT, the 3 and 5 year disease free survival (DFS) was 62% & 53%. The median survival has not been reached. For patients undergoing primary surgery - 3 year DFS is 62%. The median survival for those patients undergoing salvage surgery was 41.5 months, with a 3 year DFS of 50%. One patient with local recurrence subsequently underwent hepatic resection for an isolated metastasis 10 months out from diagnosis and is disease free 5 months post resection. CRT was generally well tolerated although there was one unexplained death at the completion of CRT. Conclusions: This series demonstrates combined chemo radiotherapy is used as first line treatment in the majority of patients with similar outcomes to those reported in other trials. Furthermore this series confirms that salvage surgery achieves prolonged survival. Despite these results, nearly 50% of patients still die of this disease by 5 years and further research assessing the impact of newer chemotherapy agents or targeted drugs is warranted. No significant financial relationships to disclose.