P450 3A activity and cyclosporine dosing in kidney and heart transplant recipients

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109917/1/cptclpt1994135.pd

Autoregression as a means of assessing the strength of seasonality in a time series

BACKGROUND: The study of the seasonal variation of disease is receiving increasing attention from health researchers. Available statistical tests for seasonality typically indicate the presence or absence of statistically significant seasonality but do not provide a meaningful measure of its strength. METHODS: We propose the coefficient of determination of the autoregressive regression model fitted to the data ([Image: see text]) as a measure for quantifying the strength of the seasonality. The performance of the proposed statistic is assessed through a simulation study and using two data sets known to demonstrate statistically significant seasonality: atrial fibrillation and asthma hospitalizations in Ontario, Canada. RESULTS: The simulation results showed the power of the [Image: see text] in adequately quantifying the strength of the seasonality of the simulated observations for all models. In the atrial fibrillation and asthma datasets, while the statistical tests such as Bartlett's Kolmogorov-Smirnov (BKS) and Fisher's Kappa support statistical evidence of seasonality for both, the [Image: see text] quantifies the strength of that seasonality. Corroborating the visual evidence that asthma is more conspicuously seasonal than atrial fibrillation, the calculated [Image: see text] for atrial fibrillation indicates a weak to moderate seasonality ([Image: see text] = 0.44, 0.28 and 0.45 for both genders, males and females respectively), whereas for asthma, it indicates a strong seasonality ([Image: see text] = 0.82, 0.78 and 0.82 for both genders, male and female respectively). CONCLUSIONS: For the purposes of health services research, evidence of the statistical presence of seasonality is insufficient to determine the etiologic, clinical and policy relevance of findings. Measurement of the strength of the seasonal effect, as can be determined using the [Image: see text] technique, is also important in order to provide a robust sense of seasonality

Concurrent whole brain radiotherapy and bortezomib for brain metastasis

Abstract Background Survival of patients with brain metastasis particularly from historically more radio-resistant malignancies remains dismal. A phase I study of concurrent bortezomib and whole brain radiotherapy was conducted to determine the tolerance and safety of this approach in patients with previously untreated brain metastasis. Methods A phase I dose escalation study evaluated the safety of bortezomib (0.9, 1.1, 1.3, 1.5, and 1.7 mg/m2) given on days 1, 4, 8 and 11 of whole brain radiotherapy. Patients with confirmed brain metastasis were recruited for participation. The primary endpoint was the dose-limiting toxicity, defined as any ≥ grade 3 non-hematologic toxicity or grade ≥ 4 hematologic toxicity from the start of treatment to one month post irradiation. Time-to-Event Continual Reassessment Method (TITE-CRM) was used to determine dose escalation. A companion study of brain diffusion tensor imaging MRI was conducted on a subset of patients to assess changes in the brain that might predict delayed cognitive effects. Results Twenty-four patients were recruited and completed the planned therapy. Patients with melanoma accounted for 83% of all participants. The bortezomib dose was escalated as planned to the highest dose of 1.7 mg/m2/dose. No grade 4/5 toxicities related to treatment were observed. Two patients had grade 3 dose-limiting toxicities (hyponatremia and encephalopathy). A partial or minor response was observed in 38% of patients. Bortezomib showed greater demyelination in hippocampus-associated white matter structures on MRI one month after radiotherapy compared to patients not treated with bortezomib (increase in radial diffusivity +16.8% versus 4.8%; p = 0.0023). Conclusions Concurrent bortezomib and whole brain irradiation for brain metastasis is well tolerated at one month follow-up, but MRI changes that have been shown to predict delayed cognitive function can be detected within one month of treatment.http://deepblue.lib.umich.edu/bitstream/2027.42/112849/1/13014_2013_Article_928.pd

Dysplasia in Barrett esophagus

BACKGROUND Dysplasia in Barrett esophagus is a premalignant condition that is associated with an increased risk of developing esophageal adenocarcinoma. Unfortunately, clinical investigation aimed at prevention of progression to malignant disease has been hampered by the variable prevalence of dysplasia reported in the literature. The objective of the current study was to more accurately determine the prevalence of dysplasia among individuals with Barrett esophagus who would be available for enrollment in a chemoprevention trial. METHODS The pathology archives of 3 institutions were reviewed over a 5-year period for all reports of diagnoses of Barrett esophagus. Surgical cases, malignancies, and duplicate or referral cases were excluded from the analysis. RESULTS A total of 790 cases of Barrett esophagus were identified. Of these, 37 (4.7%) were cases of low-grade dysplasia (LGD), and 20 (2.5%) were cases of high-grade dysplasia. The University of Michigan Medical Center (Ann Arbor, MI) diagnosed 18 cases of LGD, Henry Ford Hospital (Detroit, MI) diagnosed 15 cases of LGD, and Brigham and Women's Hospital (Boston, MA) diagnosed 4 cases of LGD in patients with Barrett esophagus over the 5-year study period. CONCLUSIONS The confirmed low prevalence of cases of LGD will affect the design of future clinical trials of chemopreventive interventions for Barrett esophagus. Cancer 2004. © 2004 American Cancer Society.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34387/1/20149_ftp.pd

How Much Pharyngeal Exposure Is “Normal”? Normative Data for Laryngopharyngeal Reflux Events Using Hypopharyngeal Multichannel Intraluminal Impedance (HMII)

Laryngopharyngeal reflux (LPR) can cause atypical symptoms, asthma, and pulmonary fibrosis. The aim of this study was to establish the normative data for LPR using hypopharyngeal multichannel intraluminal impedancepH (HMII)

Blocking TLR7- and TLR9-mediated IFN-α Production by Plasmacytoid Dendritic Cells Does Not Diminish Immune Activation in Early SIV Infection

Persistent production of type I interferon (IFN) by activated plasmacytoid dendritic cells (pDC) is a leading model to explain chronic immune activation in human immunodeficiency virus (HIV) infection but direct evidence for this is lacking. We used a dual antagonist of Toll-like receptor (TLR) 7 and TLR9 to selectively inhibit responses of pDC but not other mononuclear phagocytes to viral RNA prior to and for 8 weeks following pathogenic simian immunodeficiency virus (SIV) infection of rhesus macaques. We show that pDC are major but not exclusive producers of IFN-α that rapidly become unresponsive to virus stimulation following SIV infection, whereas myeloid DC gain the capacity to produce IFN-α, albeit at low levels. pDC mediate a marked but transient IFN-α response in lymph nodes during the acute phase that is blocked by administration of TLR7 and TLR9 antagonist without impacting pDC recruitment. TLR7 and TLR9 blockade did not impact virus load or the acute IFN-α response in plasma and had minimal effect on expression of IFN-stimulated genes in both blood and lymph node. TLR7 and TLR9 blockade did not prevent activation of memory CD4+ and CD8+ T cells in blood or lymph node but led to significant increases in proliferation of both subsets in blood following SIV infection. Our findings reveal that virus-mediated activation of pDC through TLR7 and TLR9 contributes to substantial but transient IFN-α production following pathogenic SIV infection. However, the data indicate that pDC activation and IFN-α production are unlikely to be major factors in driving immune activation in early infection. Based on these findings therapeutic strategies aimed at blocking pDC function and IFN-α production may not reduce HIV-associated immunopathology. © 2013 Kader et al

Recurrence and survival outcomes after anatomic segmentectomy versus lobectomy for clinical stage I non- Small-cell lung cancer: a propensity-matched analysis

Purpose: Although anatomic segmentectomy has been considered a compromised procedure by many surgeons, recent retrospective, single-institution series have demonstrated tumor recurrence and patient survival rates that approximate those achieved by lobectomy. The primary objective of this study was to use propensity score matching to compare outcomes after these anatomic resection approaches for stage I non-small-cell lung cancer. Patients and Methods: A retrospective data set including 392 segmentectomy patients and 800 lobectomy patients was used to identify matched segmentectomy and lobectomy cohorts (n = 312 patients per group) using a propensity score matching algorithm that accounted for confounding effects of preoperative patient variables. Primary outcome variables included freedom from recurrence and overall survival. Factors affecting survival were assessed by Cox regression analysis and Kaplan-Meier estimates. Results: Perioperative mortality was 1.2% in the segmentectomy group and 2.5% in the lobectomy group (P = .38). At a mean follow-up of 5.4 years, comparing segmentectomy with lobectomy, no differences were noted in locoregional (5.5% v 5.1%, respectively; P = 1.00), distant (14.8% v 11.6%, respectively; P = .29), or overall recurrence rates (20.2% v 16.7%, respectively; P = .30). Furthermore, when comparing segmentectomy with lobectomy, no significant differences were noted in 5-year freedom from recurrence (70% v 71%, respectively; P = .467) or 5-year survival (54% v 60%, respectively; P = .258). Segmentectomy was not found to be an independent predictor of recurrence (hazard ratio, 1.11; 95% CI, 0.87 to 1.40) or overall survival (hazard ratio, 1.17; 95% CI, 0.89 to 1.52). Conclusion: In this large propensity-matched comparison, lobectomy was associated with modestly increased freedom from recurrence and overall survival, but the differences were not statistically significant. These results will need further validation by prospective, randomized trials (eg, Cancer and Leukemia Group B 140503 trial)

Concurrent whole brain radiotherapy and bortezomib for brain metastasis

Background: Survival of patients with brain metastasis particularly from historically more radio-resistant malignancies remains dismal. A phase I study of concurrent bortezomib and whole brain radiotherapy was conducted to determine the tolerance and safety of this approach in patients with previously untreated brain metastasis.Methods: A phase I dose escalation study evaluated the safety of bortezomib (0.9, 1.1, 1.3, 1.5, and 1.7 mg/m2) given on days 1, 4, 8 and 11 of whole brain radiotherapy. Patients with confirmed brain metastasis were recruited for participation. The primary endpoint was the dose-limiting toxicity, defined as any ≥ grade 3 non-hematologic toxicity or grade ≥ 4 hematologic toxicity from the start of treatment to one month post irradiation. Time-to-Event Continual Reassessment Method (TITE-CRM) was used to determine dose escalation. A companion study of brain diffusion tensor imaging MRI was conducted on a subset of patients to assess changes in the brain that might predict delayed cognitive effects.Results: Twenty-four patients were recruited and completed the planned therapy. Patients with melanoma accounted for 83% of all participants. The bortezomib dose was escalated as planned to the highest dose of 1.7 mg/m2/dose. No grade 4/5 toxicities related to treatment were observed. Two patients had grade 3 dose-limiting toxicities (hyponatremia and encephalopathy). A partial or minor response was observed in 38% of patients. Bortezomib showed greater demyelination in hippocampus-associated white matter structures on MRI one month after radiotherapy compared to patients not treated with bortezomib (increase in radial diffusivity +16.8% versus 4.8%; p = 0.0023).Conclusions: Concurrent bortezomib and whole brain irradiation for brain metastasis is well tolerated at one month follow-up, but MRI changes that have been shown to predict delayed cognitive function can be detected within one month of treatment. © 2013 Lao et al.; licensee BioMed Central Ltd

Dose escalation of a curcuminoid formulation

BACKGROUND: Curcumin is the major yellow pigment extracted from turmeric, a commonly-used spice in India and Southeast Asia that has broad anticarcinogenic and cancer chemopreventive potential. However, few systematic studies of curcumin's pharmacology and toxicology in humans have been performed. METHODS: A dose escalation study was conducted to determine the maximum tolerated dose and safety of a single dose of standardized powder extract, uniformly milled curcumin (C(3 )Complex™, Sabinsa Corporation). Healthy volunteers were administered escalating doses from 500 to 12,000 mg. RESULTS: Seven of twenty-four subjects (30%) experienced only minimal toxicity that did not appear to be dose-related. No curcumin was detected in the serum of subjects administered 500, 1,000, 2,000, 4,000, 6,000 or 8,000 mg. Low levels of curcumin were detected in two subjects administered 10,000 or 12,000 mg. CONCLUSION: The tolerance of curcumin in high single oral doses appears to be excellent. Given that achieving systemic bioavailability of curcumin or its metabolites may not be essential for colorectal cancer chemoprevention, these findings warrant further investigation for its utility as a long-term chemopreventive agent

A double-blind, randomized, placebo-controlled trial of prostaglandin E 1 in liver transplantation

A double-blind placebo-controlled trial of intravenous prostaglandin PGE 1 (40 Μg/h) was conducted in adult orthotopic liver transplant recipients. Infusion was started intraoperatively and continued for up to 21 days. Patients were followed up for 180 days postoperatively. Among 172 patients eligible for treatment in the study, 160 could be evaluated (78 PGE 1 ; 82 placebo). Patient and graft survival were similar (PGE 1 : 16 deaths, 9 retransplantations [7 survivors]; controls: 15 deaths, 6 retransplantations [3 survivors]). In patients with surviving grafts, however, PGE 1 administration resulted in a 23% shorter mean duration of hospitalization following transplantation (PGE 1 : 24.4 days; controls: 31.8 days; P = .02) and 40% shorter length of time postoperatively in the intensive care unit (PGE 1 : 8.2 days; controls 13.7 days; P = .05). Reduced needs for renal support ( P = .03) or surgical intervention other than retransplantation ( P = .02) were also noted with PGE 1 use. Further, PGE 1 administration resulted in a trend toward improved survival rates in patients with mild renal impairment (preoperative serum creatinine 1.5 mg percent or greater; P = .08). Neither the incidence of acute cellular rejection nor of primary nonfunction was significantly different in the two groups. Phlebitis was the only complication that was more common during PGE 1 administration, (PGE 1 : 9; controls: 4). These results suggest that PGE 1 use in hepatic allograft recipients reduces morbidity and may result in sizable cost reductions. (H EPATOLOGY 1995;21:366–372.)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38409/1/1840210216_ftp.pd