Browsing by Subject "Clinical Research"

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Are all commonly prescribed antipsychotics associated with increased mortality in reased mortality in elderly male veterans with dementia?
(2010-12) Rossom, Rebecca Clare, M.D.
Objective: Estimate mortality risk associated with individual commonly-prescribed antipsychotics. Design: 5-year retrospective cohort study. Setting: Veterans national health care data. Participants: Predominantly male, 65 years or older with a diagnosis of dementia and no other known indication for an antipsychotic. Subjects who received an antipsychotic were compared to controls selected randomly from veterans with similar dates of dementia diagnosis and time elapsed from diagnosis to the start of antipsychotic therapy. Exposed and control cohorts were matched by their date of dementia diagnosis and time elapsed from diagnosis to the start of antipsychotic therapy. Measurements: Mortality during incident antipsychotic use. Results: Subjects who were exposed to haloperidol (n=2217), olanzapine (n=3384), quetiapine (n=4277) or risperidone (n=8249) had more co-morbidities than control cohorts. During the first 30 days, there was a significant increase in mortality in subgroups prescribed a daily dose of haloperidol>1mg (hazard ratio (HR) = 3.2, 95% confidence interval (CI): 2.2-4.5, p<0.0001), olanzapine>2.5 mg (HR=1.5, 95%CI: 1.1-2.0, p=0.01) or risperidone>1mg (HR=1.6, 95%CI: 1.1-2.2, p=0.01) adjusted for demographic, co-morbidity and medication history using Cox regression analyses. Increased mortality was not seen when quetiapine >50 mg (HR=1.2, 95%CI: 0.7-1.8, p=0.5) was prescribed, and there was no increased mortality associated with a dose iii <50 mg (HR=0.7, 95%CI 0.5 to 1.0, p=0.03). No antipsychotic was associated with increased mortality after the first 30 days. Conclusions: Commonly prescribed doses of haloperidol, olanzapine and risperidone, but not quetiapine, were associated with a short-term increase in mortality. Further investigations are warranted to determine causality and identify patient characteristics and antipsychotic dosage regimens that are not associated with an increased risk of mortality in elderly patients with dementia.
Conditional survival after surgical treatment of Melanoma: an analysis of the surveillance, epidemiology, and end results database.
(2011-02) Rueth, Natasha M. MD.
Introduction: Survival curves following surgical treatment of cutaneous melanoma are heavily influenced by early deaths. Therefore, survival estimates may be misleading for long-term cancer survivors. We examined whether conditional survival (CS) is more accurate in predicting long-term melanoma survival. Methods: We used the Surveillance Epidemiology and End-Results database (1992- 2005) to identify patients who underwent surgical treatment for melanoma. We included patients with T2-T4 disease and with known nodal status. Patients were stratified into low-risk (T2-3N0M0) and high-risk (T4N0M0 or T2-4N1-3M0) categories. We defined CS as time-specific estimates conditioned on living to a certain point in follow-up, and calculated 10 year cancer-specific survival curves conditioned on annual survival. We adjusted for potential confounders using a Cox proportional hazards regression model (α=0.05). Results: 8,647 patients met inclusion criteria (low-risk, 5987 [69.2%]; high-risk, 2660 [30.8%]). At diagnosis, low-risk patients had a significantly better 10-year survival rate (low-risk, 79.6%; high-risk, 41.2%; p<0.001). On CS analysis, survival differences remained until 8 years after treatment, after which 10-year cancer-specific survival rates were no longer significantly different (p=0.51) for low-risk (95.4%) and high-risk (91.7%) groups. Multivariate analysis demonstrated that age, gender, location, and remained until 8 years after treatment, after which 10-year cancer-specific survival rates were no longer significantly different (p=0.51) for low-risk (95.4%) and high-risk (91.7%) groups. Multivariate analysis demonstrated that age, gender, location, and remained until 8 years after treatment, after which 10-year cancer-specific survival rates were no longer significantly different (p=0.51) for low-risk (95.4%) and high-risk (91.7%) groups. Multivariate analysis demonstrated that age, gender, location, and ulceration (initial predictors of survival) were no longer predictive after 8 years of survival. Conclusions: For patients who survive 8 years after surgical treatment of melanoma, CS data become discordant with traditionally used estimates. Our findings have important implications for patient counseling, as high-risk melanoma survivors may require no more intensive surveillance than low-risk survivors 8 years after treatment.
Determination of the Minimum Number of Lymph Nodes to Examine in Esophagectomy Specimens to Maximize Survival in Patients with Esophageal Carcinoma: Data from the Surveillance Epidemiology and End Results Database
(2009-12) Groth, Shawn Spencer
Objective: We used a population-based cancer registry to examine the association between lymph node counts and survival in order to determine the minimum number of lymph nodes that should be examined as part of esophageal resection. Methods: Using the Surveillance Epidemiology and End Results (SEER) database, we identified patients who underwent esophagectomy for invasive esophageal carcinoma from 1988 through 2005 and who had a known number of lymph nodes examined pathologically. After stratifying patients into groups (0, 1 to 11, 12 to 29, and 30 or more lymph nodes examined) based on a recursive partitioning analysis, we assessed the association between lymph nodes counts and survival using the Kaplan-Meier method. To adjust for potential confounding covariates, we used a Cox proportional hazards regression model. Results: Of the patients in the SEER database with esophageal cancer, 4,882 met our inclusion criteria. We noted a significant difference between the lymph node groups with regards to unadjusted overall (p < 0.0001) and cancer-specific survival (p = 0.004). After adjusting for geographical location (cancer registry), patient factors, tumor characteristics, and timing of radiation therapy, we noted a significant difference between the lymph node groups with regards to overall and cancer-specific survival. As compared with patients who had no lymph node evaluation, only patients who had more than 12 lymph nodes examined had a significant improvement in survival. Patients who had 30 or more lymph nodes examined had significantly better survival rates than the other groups. Conclusion: In order to maximize overall and cancer-specific survival, esophageal cancer patients should have at least 30 lymph nodes examined pathologically as part of esophageal resection.
Donors with group B KIR haplotypes improve relapse-free survival after unrelated hematopoietic cell transplantation for acute myelogenous leukemia
(2009-11) Cooley, Sarah Anne
Survival after unrelated donor (URD) hematopoietic cell transplantation (HCT) for Acute Myeloid Leukemia (AML) is limited by toxicity and relapse. Killer-cell immunoglobulin-like receptors (KIR) control NK cell alloreactivity after HCT. Hypothesizing that donor KIR genotype (A/A: 2 A KIR haplotypes; B/x: ≥ 1 B haplotype) would affect outcomes, we genotyped donors and recipients from 448 URD transplantations for AML. Three year overall survival was significantly higher after transplantation from a KIR B/x donor (31% [95% CI: 26-36] vs. 20% [95% CI: 13-27]; p = 0.007). Multivariate analysis demonstrated a 30% better relative risk of relapse-free survival with B/x vs. A/A donors (RR 0.70 [95% CI 0.55-0.88]; p=.002). B/x donors were associated with more chronic GVHD (RR 1.51 [95% CI 1.01-2.18]; p=.03), but not more acute GVHD, relapse or treatment-related mortality. This analysis demonstrates that HCT from unrelated donors with KIR B haplotypes confers significant survival benefit for patients with AML.
Evaluation of traditional and novel measures of cardiac fucntion to detect anthracycline induced cardiotoxicity in survivors of childhood cancer
(2011-06) Dietz, Andrew Charles
Background: Cardiovascular disease is the leading non-cancer cause of death among survivors of childhood cancer. Ejection fraction (EF) and fractional shortening (FS) are common echocardiographic measures of cardiac function. Newer analysis modalities, including radial displacement, may provide additional information about pre-clinical disease such as regional myocardial dysfunction. Methods: We compared mean radial displacement, EF, and FS among adult survivors of childhood cancer exposed to ≥ 250 mg/m2 of anthracyclines to age, sexmatched healthy controls. Survivors with a history of cardiac directed radiation, diabetes, or heart disease were excluded. Results: There were no differences in gender (35% male vs. 35% male, p=1.0) or current age (28.4 years (range18-50) vs. 28.7 years (range 18-50), p=0.94) between survivors and controls, respectively. Among survivors mean age at diagnosis was 12.5 (range 1-20) years, mean survival time 16 (range 5-30) years, and mean anthracycline exposure was 420 (range 300-645) mg/m2. FS (35.5% vs. 39.6%, p < 0.01) and radial displacement (5.6 mm vs. 6.7 mm, p = 0.02) were significantly lower in cancer survivors as compared to controls. EF showed a trend towards being lower in survivors versus controls (55.4% vs. 59.7%, p = 0.057). All echocardiographic measures were inversely related with dose of anthracyclines, though radial displacement was no longer significantly correlated with antrhacycline dose after controlling for survival time (p = 0.07) while EF remained correlated (p = 0.003). Conclusions: Novel and traditional measures of radial displacement, FS, and EF are lower in childhood cancer survivors in long-term follow-up compared to controls. Novel measures may add new information, but the potential clinical utility remains undetermined and requires further longitudinal study.
De novo IBD after solid organ transplant: case series and risk factor analysis.
(2012-06) Shepela, Christopher J.
Background: Diarrhea is a frequent complication of solid organ transplant (SOT) with significant morbidity. Potential causes include infections and medications, but there is increasing recognition of de novo inflammatory bowel disease (IBD) as a cause in this population. The aim of this study was to evaluate the incidence of de novo IBD in SOT recipients and identify any potential risk factors for its development. Methods: We conducted a retrospective, single center study of all patients receiving a solid organ transplant between 1988 and 2007. A diagnosis of de novo IBD was made based on clinical symptoms, exclusion of all other causes, and endoscopic and histologic criteria. Risk factor analysis was performed using a case-control design for liver transplant recipients. Results: During this time period 23 cases of de novo IBD were identified among 6270 transplant recipients: liver (16), kidney (5), lung (1) and pancreas (1). Of the 16 liver transplants, 8 were performed for PSC or AIH. De novo IBD type was UC in 12, Crohn’s disease in 9 and indeterminate in 2.The mean lag time between transplant and IBD diagnosis was 63.7 (10.4-240.5) months. The annual incidence for this cohort was 18.5 per 100,000. Among liver recipients, the annual incidence was much higher at 100 per 100,000 vs. 5.8 per 100,000 in the non-liver organ recipients. Neither CMV mismatch OR 1.55 (0.43-5.58), acute CMV infection OR 0.87 (0.25-3.07) nor tacrolimus exposure OR 5.26(0.55-50.022) could be confirmed as modifiable risk factors for developing IBD. Novel risk factors of personal or family history of autoimmunity, lymphopenia, and rejection episodes were not statistically significant. Conclusion: De novo IBD occurs in liver transplant recipients at a rate 5x higher than the general population and over 17x higher than other SOT recipients. Previously identified risk factors could not be confirmed. Since patients diagnosed with de novo IBD require additional medications beyond their transplant immunosuppression for treatment, recognition of this entity has important clinical implications.
An optimized classification system of acute kidney injury for predicting the short-term mortality after open heart surgery; comparison of current classification systems.
(2010-05) Afshinnia, Farsad
Epidemiologic studies need a unique operational definition of acute kidney injury (AKI) to compare outcomes. We aimed to compare prognostic value of change in serum creatinine with classification systems of AKI to predict 30day mortality after heart surgery. From VA database, 27410 eligible patients with stable baseline kidney function who had heart surgery from 1999 to 2005 were selected. There was a graded increase in mortality from stage A to stage C of all systems. Adjusted 30day mortality odds ratio starts to increase significantly after an acute rise ≥ 0.3 mg/dL of creatinine in CKD stages 1 and 2, and after 0.6 mg/dL increase in CKD stage 3. Area under ROC curve of change of creatinine from baseline was significantly higher than those of classification systems (P<0.001). In conclusion, compared to continuous increase of creatinine, classification systems of AKI misestimate mortality risk by collapsing predictive, clinically important data into categories.
Pancreatectomy and autologous islet transplantation: a study of long-trem outcomes.
(2010-08) Carlson, Annelisa M.
Abstract summary not availavle.
A phase II trial of carboplatin and docetaxel followed by radiotherapy given in a “Sandwich” method for stage III, IV, and recurrent endometrial cancer.
(2010-10) Geller, Melissa Ann MD
Purpose: To determine feasibility and efficacy of administering docetaxel and carboplatin chemotherapy followed by pelvic radiotherapy and then consolidation chemotherapy in patients with advanced or recurrent endometrial cancer. Patients and Methods: Patients with surgically staged III-IV (excluding IIIA from positive cytology alone) endometrial cancer or biopsy confirmed recurrent disease were eligible. Treatment consisted of 3 cycles of docetaxel (75mg/m2) and carboplatin (AUC 6) on a q21 day schedule followed by involved field irradiation (45Gy) ± brachytherapy and 3 additional cycles of docetaxel and carboplatin. Kaplan-Meier (KM) methods estimated overall survival (OS) and progression free survival (PFS). Results: Forty-two patients enrolled, 7 did not complete therapy. 95% (39/41) had primary disease. Median age = 58 years (range: 21-81). 78% (32/41) = endometrioid histology. Stages=10 IIIA, 21 IIIC, 1 IVA, 7 IVB, (recurrent=1 IC, 1 IIA). There were 23 non-hematologic and 14 grade 3 and 16 grade 4 hematologic toxicities. Five patients died following treatment with a median follow-up of 16.1 months (range: 5-51). KM estimates and 95% confidence intervals for OS at 1 year were=94.4% (79.5-98.6), at 2 years 90.9% (74.2-97.0)), and at 3 years 79.6% (45.4-93.6). Of the 39 with primary disease, 9 progressed or died within 3 years of study enrollment. KM estimates and 95% confidence intervals for PFS at 1 year were 85.7% (69.0-93.8), at 2 years 75.6% (56.8-87.1), and at 3 years=68.0% (44.6-83.2). Conclusions: “Sandwiching” radiation between chemotherapy for advanced or recurrent endometrial cancer merits further development based on the reported PFS and OS.
Prognostic factors associated with periodontal treatment response in pregnant women
(2014-08) Naik, Amruta, B.D.S.
The goal of the present study is to determine if certain baseline clinical, serological parameters and patient characteristics can predict initial response to non-surgical periodontal therapy in pregnant women with chronic periodontitis. We studied associations between periodontal treatment response and certain baseline demographic, clinical and serological characteristics and measures. The response to periodontal treatment was defined as full-mouth mean change from baseline to 29-32 weeks gestation using three periodontal measures: Clinical attachment level (CAL), probing depth (PD) and percentage of sites with bleeding on probing (BOP). Baseline endotoxin and CRP levels were significantly associated with gain in CAL. The findings of the present study suggest that baseline patient characteristics such as race; serum measures such as CRP, endotoxins and antibodies to T. denticola; and periodontal measures such as PD, play a significant role in predicting the gain in CAL after periodontal treatment in pregnant women with chronic periodontitis.
Safety and Efficacy of two dietary supplements, Immuno-Viva™ and Immune Lift™ used as Free Radical Scavengers in Healthy Subjects.
(2009-11) Hammer, Timothy John
Chronic vascular disease among other things is linked to systemic stress, production of free radicals, and a reduced antioxidant defense that may ultimately lead to tissue damage and related cardiovascular complications. Administration of dietary supplements with antioxidant properties have shown to be beneficial in protecting against free radical effects. Immuno-Viva™, a blend of cold pressed pure, black raspberry and black cumin seed oils meeting FDA DSHEA Regulations, has shown significant free radical scavenging properties in preliminary animal studies; however, supportive evidence using controlled clinical trials are not yet available. Immune Lift™, a powder product from the cold press procedure containing black raspberry and black cumin, has not been studied extensively. The components of the two products are generally accepted as safe food ingredients or have been evaluated in animal models; however, no safety data on the final product formulations are available. The primary aim of this study is to examine product safety in respect to maintained normal liver and kidney functions in healthy participants. Levels of ALT, AST and creatinine were measured. Secondary aims included evaluating possible effects of these oils on free radical levels immune response mechanisms. Total blood counts and lymphocyte fractions as well as malondialdehyde in urine were measured. The study involved 30 participants consuming 3 teaspoons (15 g) of Immuno-Viva™ daily for one month, and an additional 2 tablets of Immune Lift™ for one additional month. Measurements and blood sampling was conducted on days 0, 30 and 60. The design is pre and post oil effects. The hypothesis is that Immuno-Viva™ and Immune Lift™ will have no adverse effects on normal liver and kidney functions and support the immune response mechanisms to control free radical effects.
Severe peripheral artery disease: new observations from a community-based Minnesota Registry.
(2010-06) Keo, Hak Hong
This study assessed whether time serves as a previously undefined predictor of both limb and patient survival in individuals with acute limb ischemia (ALI) and critical limb ischemia (CLI). Patients with ALI or CLI referred to a single metropolitan tertiary care hospital were consecutively entered into the prospective “FReedom from Ischemic Events: New Dimensions for Survival” (FRIENDS) registry. Demographics, key time segments and short-term outcomes were evaluated for all patients. Key time segments were reported as median and interquartile range (IQR). Myocardial infarction (MI), stroke, amputation and all-cause mortality were collected at one month. From 2/07 through 12/09, 206 patients (75 ALI, 131 CLI) were enrolled in the FRIENDS registry. The median age was 76 (64, 84) years and 58% were male patients. Median time from symptom onset to admission was 19.2 hours (7.2, 79.2) for ALI and 59 days (24, 124) for CLI patients. Length of stay was 7.0 days (4.3, 10.4) for ALI and 6.1 days (3.1, 10.7) for CLI patients. Minor and major amputation was performed during the index hospitalization in 10 (13%) of patients with ALI and 34 (26%) of those with CLI. In ALI patients, amputation was significantly associated with increased duration of ischemia (P=0.015 for trend), but this trend was not observed in CLI patients. One month after discharge, a longer duration of ischemia was significantly associated with an increase in the quadruple endpoint of nonfatal MI, stroke, amputation or death in patients with ALI (P=0.007 for trend). No such association was observed in individuals with CLI. Amputation-free survival at one month was 78.7% and 71.8% for patients with ALI and CLI, respectively. In conclusion, these data suggest that expedited admission and treatment for ALI is associated with lower rates of in-hospital amputation and morbidity and mortality at one month. There was no association between the duration of ischemia and morbidity and mortality among the CLI patients. These data clarify a high incidence of ALI amongst patients with severe PAD; verify that length of stay remains long and major adverse outcomes remain common even within the first month of a severe PAD admission. Future research might investigate the biological mechanisms and processes of care that could link the long referral times and high rates of vascular ischemic events.
Structural and functional brain abnormalities in children with fetal alcohol spectrum disorders (FASD)
(2011-05) Wozniak, Jeffrey Robert
Over the past five years, Diffusion Tensor Imaging (DTI) has begun to provide new evidence about the effects of prenatal alcohol exposure on white matter development. DTI, which examines microstructural tissue integrity, is more sensitive to subtle white matter abnormalities than traditional volumetric MRI methods. Thus far, the available DTI data suggest that white matter microstructural abnormalities fall on a continuum of severity in Fetal Alcohol Spectrum Disorder (FASD). Abnormalities are prominent in the corpus callosum, but also evident in major anterior-posterior fiber bundles, corticospinal tracts, and cerebellum. These subtle abnormalities are correlated with neurocognitive deficits, especially in processing speed, non-verbal ability, and executive functioning. The two studies presented here provide evidence of microstructural anomalies in the brains of children who were prenatally exposed to alcohol and demonstrate that those anomalies are associated with disruptions in functional brain connectivity. The majority of the patients in these two investigations were children who did not meet full criteria for Fetal Alcohol Syndrome (FAS). Thus, these data provide evidence that there are genuine consequences of moderate alcohol consumption during pregnancy even in the absence of the full syndrome. Ultimately, these types of sensitive brain measures may serve as indices of change in future longitudinal studies and in studies of interventions for FASD.
Survival outcomes after contralateral prophylactic mastectomy: a decision analysis
(2014-07) Portschy, Pamela Rochelle, MD.
Background: Contralateral prophylactic mastectomy (CPM) rates have significantly increased in recent years and may reflect an exaggerated perceived benefit from the procedure. The objective of this study was to evaluate the magnitude of the survival benefit of CPM for women with unilateral breast cancer. Methods: We developed a Markov model to simulate survival outcomes after CPM and no CPM among women with stage I or II breast cancer without a BRCA mutation. Probabilities for developing contralateral breast cancer (CBC), dying from CBC, dying from primary breast cancer, and age-specific mortality rates were estimated from published studies. We estimated life expectancy (LE) gain, 20-year overall survival, and disease-free survival with each intervention strategy among cohorts of women defined by age, estrogen receptor (ER) status, and stage of cancer.Results: Predicted LE gain from CPM ranged from 0.13 to 0.59 years for women with stage I breast cancer and 0.08 to 0.29 years for those with stage II breast cancer. Absolute 20-year survival differences ranged from 0.56% to 0.94% for women with stage I breast cancer and 0.36% to 0.61% for women with stage II breast cancer. CPM was more beneficial among younger women, stage I, and ER-negative breast cancer. Sensitivity analyses yielded a maximum 20-year survival difference with CPM of only 1.45%. Conclusion: The absolute 20-year survival benefit from CPM was less than 1% among all age, ER status, and cancer stage groups. Estimates of LE gains and survival differences derived from decision models may provide more realistic expectations of CPM.

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