tbuckley/cabot-search huggingface dataset:
Virtual population pharmacokinetic using physiologically based pharmacokinetic model for evaluating bioequivalence of oral lacidipine formulations in dogs
Authors: Bin Yang, Chunnuan Wu, Bin Ji, Mingrui Wu, Zhonggui He, Lei Shang, Jin Sun
Journal: Asian Journal of Pharmaceutical Sciences (2016)

The aim of the present study was to investigate virtual population pharmacokinetic using physiologically based pharmacokinetic (PBPK) model for evaluating bioequivalence of oral lacidipine formulations in dogs. The dissolution behaviors of three lacidipine formulations including one commercial product and two self-made amorphous solid dispersions (ASDs) capsules were determined in 0.07% Tween 80 media. A randomized 3-period crossover design in 6 healthy beagle dogs after oral administration of the three formulations at a single dose of 4 mg was conducted. The PBPK modeling was utilized for the virtual bioequivalence study. In vitro dissolution experiment showed that the dissolution behaviors of lacidipine amorphous solid dispersions (ASDs) capsules, which was respectively prepared by HPMC-E5 or Soluplus, as polymer displayed similar curves compared with the reference formulation in 0.07% Tween 80 media. In vivo pharmacokinetics experiments showed that three formulations had comparable maximum plasma drug concentration (Cmax ), and the time (Tmax ) to reach Cmax of lacidipine tablet, which was prepared by Soluplus, as polymer was slower than other two formulations in consistency with the in vitro dissolution rate. The 90% confidence interval (CI) for the Cmax , AUC0-24 h and AUC0-∞ of the ratio of the test drug to the referencedrug exceeded the acceptable bioequivalence (BE) limits (0.80-1.25). However, the 90% CI of the AUC0-24 h, AUC0-∞ and Cmax of the ratio of test to reference drug were within the BE limit, calculated using PBPK modeling when the virtual subjects reached 24 dogs. The results all demonstrated that virtual bioequivalence study can overcome the inequivalence caused by inter-subject variability of the 6 beagle dogs involved in in vivo experiments.
A Nomogram to Predict Distant Metastases After Multimodality Therapy for Patients With Localized Esophageal Cancer
Authors: Kazuki Sudo, Xuemei Wang, Lianchun Xiao, Roopma Wadhwa, Hironori Shiozaki, Elena Elimova, David C. Rice, Jeffrey H. Lee, Brian Weston, Manoop S. Bhutani, Adarsh Hiremath, Nikolaos Charalampakis, Ritsuko Komaki, Mariela A. Blum, Stephen G. Swisher, Dipen M. Maru, Heath D. Skinner, Jeana L. Garris, Jane E. Rogers, Wayne L. Hofstetter, Jaffer A. Ajani
Journal: Journal of the National Comprehensive Cancer Network (2016)

Background: Among patients with localized esophageal cancer (LEC), 35% or more develop distant metastases (DM) as first relapse, most in the first 24 months after local therapy. Implementation of novel strategies may be possible if DM can be predicted reliably. We hypothesized that clinical variables could help generate a DM nomogram. Patients and Methods: Patients with LEC who completed multimodality therapy were analyzed. Various statistical methods were used, including multivariate analysis to generate a nomogram. A concordance index (c-index) was established and validated using the bootstrap method. Results: Among 629 patients analyzed (356 trimodality/273 bimodality), 36% patients developed DM as first relapse. The median overall survival from DM was only 8.6 months (95% CI, 7.0–10.2). In a multivariate analysis, the variables associated with a higher risk for developing DM were poorly differentiated histology (hazard ratio [HR], 1.76; P<.0001), baseline T3/T4 primary (HR, 3.07; P=.0006), and baseline N+ LEC (HR, 2.01; P<.0001). Although variables associated with a lower risk for DM were age of 60 years or older (HR, 0.75; P=.04), squamous cell carcinoma (HR, 0.54; P=.013), and trimodality therapy (HR, 0.58; P=.0001), the bias-corrected c-index was 0.67 after 250 bootstrap resamples. Conclusions: Our nomogram identified patients with LEC who developed DM with a high probability. The model needs to be refined (tumor and blood biomarkers) and validated. This type of model will allow implementation of novel strategies in patients with LEC.
Mepolizumab in COPD with Eosinophilic Bronchitis: A Randomized Clinical Trial
Authors: Parameswaran K. Nair, Angira Dasgupta, Melanie Kjarsgaard, Dante Capaldi, Katherine Radford, Fernando P. Aleman, Grace Parraga, Paul M. O'Byrne
Journal: Journal of Allergy and Clinical Immunology (2016)
Abstract 225: The Mitochondria-localizing Peptide Bendavia Reduces Cardiac Injury By Targeting Cardiolipin
Authors: David A Brown, Mitchel Harris, Fatiha Moukdar, Hetal D Patel, Saame R Shaikh
Journal: Circulation Research (2013)

Bendavia is a cardioprotective mitochondria-targeting peptide that is currently being utilized in the EMBRACE-STEMI clinical trial for acute coronary syndromes (ACS). Across a variety of pre-clinical models examining ACS and heart failure, administration of Bendavia reduces infarction and coronary “no-reflow”, improves function, preserves mitochondrial energetics, and lowers ROS-dependent cell death. Despite the clear effects in mitigating reperfusion injury, Bendavia’s molecular targets and underlying mechanisms are not fully understood. The objective of these studies was to determine Bendavia’s molecular mechanism of action and pharmacokinetic profile. In diabetic animals, Bendavia treatment reversed the decline in 18:2 cardiolipin composition observed in diabetic heart. In vivo (i.v.) administration of 3H-Bendavia showed tissue distribution that correlated with tissue mitochondrial volume density. 3H-Bendavia levels in heart mitochondria peaked 1 hour after treatment, and by 24 hours there was no discernible 3H-Bendavia in the myocardium. Biologic processing of Bendavia results in two major metabolites, and neither of these metabolites showed cardioprotective efficacy, suggesting that the cardioprotection is unique to the intact, tetra-peptide. In isolated heart cells, 3H-Bendavia uptake was found to be independent of mitochondrial membrane potential, and respiratory studies revealed no discernible uncoupling activity. We then tested the hypothesis that Bendavia selectively targeted cardiolipin biophysical organization by synthesizing lipid vesicles of differing phospholipid composition. Fluorescence quenching and electrostatically sensitive probes revealed Bendavia preferentially associated with cardiolipin-enriched lipid vesicles. We modeled changes in inner membrane lipids during cardiac ischemia/reperfusion. Bendavia augmented membrane microviscosity in proportion to the cardiolipin content. As a number of disease states (heart failure, diabetes, ischemia/reperfusion) are characterized by low membrane microviscosity, Bendavia’s putative ability to restore the lipid microenvironment represents a novel paradigm for preserving tissue bioenergetics.
Renal cell carcinoma in the elderly: Is partial nephrectomy the right surgical option?
Authors: M. H. Hayn, N. J. Hellenthal, W. Underwood, H. L. Kim, T. Schwaab
Journal: Journal of Clinical Oncology (2010)

e15040 Background: Data are scarce on literature describing surgical outcomes in elderly patients undergoing treatment for renal cell carcinoma (RCC). The goals of this study were to determine overall- and cancer-specific survival, use of radical versus partial nephrectomy, and complication rates in elderly patients with RCC. Methods: 532 patients who underwent extirpative surgery for clinically diagnosed RCC between 1994 and 2009 were identified using a single-institution IRB-approved database. Of these patients, 127 (24%) were 75 years of age or older. These patients were further separated into groups based on surgical type and incidence of complications and were stratified by gender, tumor stage, and tumor grade. Preoperative and postoperative creatinine clearances and length of stay were compared among the groups. Cox proportional hazard modeling and Kaplan-Meier analyses were used to determine overall- and cancer-specific survival among the cohorts. Results: Older patients were more likely to undergo laparoscopic radical than partial nephrectomy than their younger counterparts (p=0.003), and had longer average hospital stays (4.0 versus 2.7 days, p<0.001). Older patients were 3.4 times more likely to experience an immediate (within 24 hours) complication (95% CI 1.37-8.30, p=0.008), and there was a trend toward a higher overall complication rate in elderly patients. Complication rates, however, were similar after radical or partial nephrectomy. Calculated creatinine clearance in the radical nephrectomy group (18.9 mL/min/m2) decreased more than in the partial nephrectomy group (8.0 mL/min/m2, p<0.0001). Despite this, there was no significant difference in overall or cancer-specific survival between younger and older patients. Median length of followup were 13.3 (0-135) and 19.2 (0-164) months for younger and older patients, respectively. Conclusions: Extirpative surgery is safe in elderly patients with RCC. The risk of immediate complications is increased in older than younger patients, but risk appears unrelated to type of surgery. Partial nephrectomy should be advocated when feasible in order to maintain renal function. No significant financial relationships to disclose.
Comparaison entre la cholédoco-duodénostomie guidée par échoendoscopie et l’hépatico-gastrostomie pour le traitement des sténoses biliaires associées à une sténose duodénale
Journal: Endoscopy (2016)

Le drainage endoscopique des sténoses biliaires néoplasiques est le traitement de première ligne. En cas d’obstruction duodénale associée, l’accès à la papille par CPRE est difficile. Dans ce cas, l’échoendoscopie permet un repérage des voies biliaires: l’abord se fait au niveau du canal hépatique à travers l’estomac (hépatico-gastrostomie [HG]) ou au niveau du cholédoque à travers le duodénum cholédoco-duodénostomie [CD]). Les deux méthodes ont montré un taux de réussite élevé tant au niveau technique que fonctionnel, des complications sévères ont cependant été rapportées (cholépéritoine). Le double drainage biliaire et duodénal a été rarement rapporté.
Phase I trial with a novel oral NF-κB/STAT3 inhibitor RTA 402 in patients with solid tumors and lymphoid malignancies
Authors: D. S. Hong, R. Kurzrock, J. G. Supko, D. P. Lawrence, J. J. Wheler, C. J. Meyer, J. W. Mier, M. Andreeff, G. I. Shapiro, B. J. Dezube
Journal: Journal of Clinical Oncology (2008)

3517 Background: RTA 402 (CDDO-Me) is a first-in-class antioxidant inflammation modulator with potent anticancer and anti- inflammatory activity. The drug suppresses ROS-mediated signaling through suppression of pro-inflammatory transcription factors NF-κB and STAT3 and induction of antioxidant/detoxification transcription factor Nrf2. Methods: The primary objectives of the study were to determine the DLT, MTD and phase II dose of RTA 402 in patients with advanced solid tumors or lymphoid malignancies; and to characterize the pharmacokinetics of RTA 402 given orally once daily for 21 days every 28 days. Dose escalation proceeded via an accelerated titration design. Results: RTA 402 was administered to 34 patients at 10 dose levels (5 to 1,300 mg/day). The MTD is 900 mg/day; DLT at 1,300 mg/day was asymptomatic Grade 3 LFT elevation, which resolved to ≤ Grade 1 upon dose reduction. 50% of all patients and 40% at MTD had no toxicities greater than Grade 1. The median biological half-life of RTA 402 was 33.1 h (range, 18–98 h), with volume of distribution suggesting extensive tissue uptake. Of 18 patients evaluable for efficacy, one Partial Response was observed in a patient with anaplastic thyroid cancer. A further 9 patients had stable disease, 6 of which lasted for 6–12 months (3 melanoma, 2 renal cell, 1 medullary thyroid). Suppression of NF-κB and STAT3, as well as downstream targets iNOS, cyclin D1, COX-2, and arginase, was observed in multiple biopsies at doses as low as 40 mg/day. TUNEL positivity was increased up to 6-fold, and the presence of macrophages was increased up to 10-fold. Consistent with dual NF-κB/STAT3 suppression, leukocytosis was observed in several patients with prolonged stable disease. Induction of Nrf2 was demonstrated in PBMCs by increases in NQO1 and gamma-GCS mRNA. Conclusions: The first-in-class antioxidant inflammation modulator RTA 402 is well tolerated up to 900 mg/day with prolonged exposure up to 12 months. Data indicate appropriate modulation of targets NF-κB, STAT3, and Nrf2 and suggest clinical benefit associated with this novel mechanism, including a PR and prolonged disease stabilization in several patients. Phase II trials have begun. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Reata Pharmaceuticals, Inc Reata Pharmaceuticals, Inc Reata Pharmaceuticals, Inc
Resistance trends among clinical isolates in China reported from CHINET surveillance of bacterial resistance, 2005–2014
Authors: F.-P. Hu, Y. Guo, D.-M. Zhu, F. Wang, X.-F. Jiang, Y.-C. Xu, X.-J. Zhang, C.-X. Zhang, P. Ji, Y. Xie, M. Kang, C.-Q. Wang, A.-M. Wang, Y.-H. Xu, J.-L. Shen, Z.-Y. Sun, Z.-J. Chen, Y.-X. Ni, J.-Y. Sun, Y.-Z. Chu, S.-F. Tian, Z.-D. Hu, J. Li, Y.-S. Yu, J. Lin, B. Shan, Y. Du, Y. Han, S. Guo, L.-H. Wei, L. Wu, H. Zhang, J. Kong, Y.-J. Hu, X.-M. Ai, C. Zhuo, D.-H. Su, Q. Yang, B. Jia, W. Huang
Journal: Clinical Microbiology and Infection (2016)

With the aim of gathering temporal trends on bacterial epidemiology and resistance from multiple laboratories in China, the CHINET surveillance system was organized in 2005. Antimicrobial susceptibility testing was carried out according to a unified protocol using the Kirby-Bauer method or automated systems. Results were analyzed according to Clinical and Laboratory Standards Institute (CLSI) 2014 definitions. Between 2005 and 2014, the number of bacterial isolates ranged between 22 774 and 84 572 annually. Rates of extended-spectrum β-lactamase production among Escherichia coli isolates were stable, between 51.7 and 55.8%. Resistance of E. coli and Klebsiella pneumoniae to amikacin, ciprofloxacin, piperacillin/tazobactam and cefoperazone/sulbactam decreased with time. Carbapenem resistance among K. pneumoniae isolates increased from 2.4 to 13.4%. Resistance of Pseudomonas aeruginosa strains against all of antimicrobial agents tested including imipenem and meropenem decreased with time. On the contrary, resistance of Acinetobacter baumannii strains to carbapenems increased from 31 to 66.7%. A marked decrease of methicillin resistance from 69% in 2005 to 44.6% in 2014 was observed for Staphylococcus aureus. Carbapenem resistance rates in K. pneumoniae and A. baumannii in China are high. Our results indicate the importance of bacterial surveillance studies.
Cerebrospinal fluid bombesin and calcitonin in patients with central nervous system metastases from small-cell lung cancer.
Authors: A G Pedersen, K L Becker, F Bach, R H Snider, A F Gazdar, P S Sorensen, P A Bunn, H H Hansen
Journal: Journal of Clinical Oncology (1986)

To determine whether levels of mammalian bombesin (MB) or calcitonin would be useful in detecting CNS metastases in patients with small-cell lung cancer (SCLC), we measured their concentrations in the CSF of 94 patients who underwent lumbar puncture for suspected CNS involvement. The MB concentration was significantly elevated in the 51 patients with definite CNS metastases as compared with the 30 patients without apparent CNS involvement (P less than .01). This significance was due to increased levels of MB in 18 patients with meningeal carcinomatosis. Whereas CSF MB was detectable (greater than 10 fmol/mL) in only 7% of patients without apparent CNS involvement, CSF MB was detectable in 21% with parenchymal CNS metastases and in 78% of those with meningeal carcinomatosis. Interestingly, 93% of patients having MB concentrations above 20 fmol/mL had meningeal metastases. The calcitonin concentration was significantly elevated in 42 patients with CNS metastases as compared with 27 patients without CNS involvement (P less than .01). Both the 15 patients with meningeal carcinomatosis and the 27 patients with only parenchymal metastases had significantly elevated levels of CSF calcitonin as compared with those without CNS metastases. Fifty-three percent of patients with meningeal carcinomatosis and 48% with parenchymal metastases had a CSF calcitonin level above 18 fmol/mL, whereas only 7% without apparent CNS metastases exceeded this level. Sixty-seven percent of all patients with CNS metastases had increased CSF levels of one of the two hormonal markers. Thus, in SCLC patients, an elevated CSF calcitonin strongly suggested CNS metastases and an elevated MB was very suggestive of the presence of meningeal carcinomatosis. However, only the latter observation seems of clinical importance due to the difficulties in establishing this diagnosis with current diagnostic measures.
A case of HLA-DR negative B-precursor acute lymphoblastic leukemia.
Authors: S Giotopoulou, E Dokou, M Tzoufi, N Kolaitis, G Vartholomatos
Journal: Journal of experimental & clinical cancer research (2003)

We present the case of a 9-year-old girl from northwestern Greece admitted to our Hospital because of malaise, low-grade fever, intermittent hip joint pain, anemia, leukopenia and thrombocytopenia. The examination of a bone marrow aspirate revealed the predominance of blast cells (97%) with FAB L1 morphology, immunopheno-typically positive for CD19 (95%), CD10 (95%), CD22 (95%), CD13 (82%), CD34 (95%) and CD38 (72%), with dim expression of CD45 and of the intracellular antigen terminal deoxynucleotidyl transferase (Tdt). Only 10% of the blasts expressed HLA-DR. Staining for CD2, CD3, CD5, CD7, CD20, CD23, CD33, CD14, CD15, AC133 and KOR-SA3544 was negative. Blast cells were lacking surface immunoglobulin expression and bcr/abl rearrangements were not detected. Cell cycle analysis revealed a diploid cell population. Karyotypic abnormalities were not identified. The lack of expression of HLA-DR and the presence of myeloid antigen CD13 indicated that it was a rare case of B-precursor ALL with aberrant immunophenotypic characteristics.
Predicting the pathology of post-BCG lesions
Authors: J. Blitstein, R. Macchia
Journal: Journal of Clinical Oncology (2006)

14573 Background: This study evaluated the accuracy of office cystoscopy and urinary cytology in predicting the histopathology of post-BCG bladder lesions. Methods: A retrospective chart review was performed of all patients who had received intravesical BCG at two Veteran Affairs Hospitals from July 1995 to July 2005. The initial pathology, the post-treatment cystoscopy findings, urinary cytology and post-BCG biopsy were correlated. Results: A total of 136 biopsies from 64 patients who had received 79 courses of BCG were reviewed. The mean time to the first repeat bladder biopsy and to the first recurrence was 8.8 months and 11.7 months, respectively. During the study, 83% of patients developed recurrence. Malignancy was confirmed in 61% of all biopsies. For all lesions, cytology alone had a sensitivity of 53.7%, specificity of 90.5%, PPV 85%, NPV 47%. The biopsy was positive in 84% of patients with visible papillary lesions and a negative cytology. Improved accuracy was seen in papillary lesions with a positive cytology; 94% positive biopsy. The bladder biopsy was positive in 91% of patients with erythema and a positive cytology in comparison to 9.5% of patients with erythema and a negative cytology. Conclusions: There is controversy regarding the necessity of obtaining transurethral biopsies of erythematous lesions in patients who have undergone intravesical BCG therapy. Combining the cystoscopic findings and the urine cytology increases the ability to delineate BCG effect from recurrence. This study suggests that patients with post-BCG erythematous patches and a negative cytology can avoid an unnecessary transurethral bladder biopsy. This study also demonstrates that most BCG failures occur after the traditionally believed 3-month evaluation. No significant financial relationships to disclose.
Responses to romidepsin by line of therapy in patients with relapsed/refractory (R/R) peripheral T-cell lymphoma (PTCL).
Authors: Francine M. Foss, Barbara Pro, H. Miles Prince, Lubomir Sokol, Matthew Greenwood, Dolores Caballero, Steven M. Horwitz, Bertrand Coiffier
Journal: Journal of Clinical Oncology (2014)

8563 Background: Most patients with PTCL, an aggressive form of non-Hodgkin lymphoma, experience R/R disease with few effective salvage treatments. Romidepsin is a histone deacetylase inhibitor approved by the US FDA for treatment of patients with PTCL who have received ≥ 1 prior therapy. Durable clinical responses (objective response rate [ORR] of 25% and median duration of response [DOR] of 28 mo; median follow up 22.3 mo) and tolerability with extended dosing have been reported. As heavily pretreated patients are especially challenging, responses to romidepsin by line of therapy were examined herein. Methods: Patients with PTCL (N = 130) who were R/R to ≥ 1 prior therapy received romidepsin 14 mg/m2on days 1, 8, and 15 every 28 days. The primary endpoint was confirmed/unconfirmed complete response (CR/CRu), and secondary endpoints included ORR (CR/CRu + partial responses) and DOR; progression-free and overall survival (PFS, OS) were also assessed. In this analysis, baseline characteristics, responses to therapy, and safety are examined for patients who received 1, 2, or ≥ 3 prior therapies. Results: Nearly all patients received chemotherapy in the first line, and patients with more lines of prior therapy were more likely to have prior radiation, monoclonal antibody or other immunotherapy or stem cell transplant. Response rates, DOR, and survival with romidepsin were not significantly different for patients with R/R PTCL who received 1, 2, or ≥ 3 prior therapies, though heavily pretreated patients discontinued due to adverse events (AEs) more frequently (Table). Conclusions: Romidepsin resulted in durable responses in patients with 1, 2, or ≥ 3 prior treatments for PTCL. These data support the use of romidepsin in the second line, particularly as patients with PTCL may receive a limited number of regimens due to age or comorbidities. Clinical trial information: NCT00426764. Prior therapies 1 (n = 38) 2 (n = 44) ≥ 3 (n = 48) ORR, n (%) 9 (24) 10 (23) 15 (31) CR/CRu 5 (13) 7 (16) 8 (17) DOR, median (range), mo NE (1.9-33.9) NE (< 0.1-56.3) 16.4 (< 0.1-37.3) PFS, median (range), mo 5.4 (0.4-35.5) 3.1 (0.3-57.9) 3.8 (0.3-38.9) OS, median (range), mo 18.2 (0.4-36.6) 9.4 (0.3-58.1) 9.2 (1.3-53.8) Discontinuation due to AEs, n (%) 6 (16) 6 (14) 12 (25) Abbreviation: NE, not estimable.