Cody Chiuzan

Combined preoperative mechanical bowel preparation with oral antibiotics significantly reduces surgical site infection, anastomotic leak, and ileus after colorectal surgery.

OBJECTIVES To clarify whether bowel preparation use or its individual components [mechanical bowel preparation (MBP)/oral antibiotics] impact specific outcomes after colorectal surgery. METHODS National Surgical Quality Improvement Program-targeted colectomy data initiated in 2012 capture information on the use/type of bowel preparation and colorectal-specific complications. For patients undergoing elective colorectal resection, the impact of preoperative MBP and antibiotics (MBP+/ABX+), MBP alone (MBP+/ABX-), and no bowel preparation (no-prep) on outcomes, particularly anastomotic leak, surgical site infection (SSI), and ileus, were evaluated using unadjusted/adjusted logistic regression analysis. RESULTS Of 8442 patients, 2296 (27.2%) had no-prep, 3822 (45.3%) MBP+/ABX-, and 2324 (27.5%) MBP+/ABX+. Baseline characteristics were similar; however, there were marginally more patients with prior sepsis, ascites, steroid use, bleeding disorders, and disseminated cancer in no-prep. MBP with or without antibiotics was associated with reduced ileus [MBP+/ABX+: odds ratio (OR) = 0.57, 95% confidence interval (CI): 0.48-0.68; MBP+/ABX-: OR = 0.78, 95% CI: 0.68-0.91] and SSI [MBP+/ABX+: OR = 0.39, 95% CI: 0.32-0.48; MBP+/ABX-: OR = 0.80, 95% CI: 0.69-0.93] versus no-prep. MBP+/ABX+ was also associated with lower anastomotic leak rate than no-prep [OR = 0.45 (95% CI: 0.32-0.64)]. On multivariable analysis, MBP with antibiotics, but not without, was independently associated with reduced anastomotic leak (OR = 0.57, 95% CI: 0.35-0.94), SSI (OR = 0.40, 95% CI: 0.31-0.53), and postoperative ileus (OR = 0.71, 95% CI: 0.56-0.90). CONCLUSIONS These data clarify the near 50-year debate whether bowel preparation improves outcomes after colorectal resection. MBP with oral antibiotics reduces by nearly half, SSI, anastomotic leak, and ileus, the most common and troublesome complications after colorectal surgery.

Survival of melanoma patients with brain metastases treated with ipilimumab and stereotactic radiosurgery

Historically, melanoma with brain metastases has a poor prognosis. In this retrospective medical record review, we report the outcome of patients with stage IV melanoma with brain metastases treated with ipilimumab and brain stereotactic radiosurgery (SRS). All patients with metastatic melanoma treated with ipilimumab from June 2010 to September 2012 were identified and stratified by presence (A) or absence (B) of brain metastases at the time of ipilimumab administration. All patients with brain metastases received SRS. Overall survival (OS) was defined as time from the date of stage IV diagnosis and the time of ipilimumab administration to death or last follow‐up. Survival curves were estimated using the Kaplan–Meier method, and Cox proportional hazards model was employed to compute the hazard ratios (HR). Results: Five out of 10 patients in Cohort A and 10 out of 21 patients in Cohort B died as of last follow‐up. In Cohort A, median number of lesions treated with SRS was 3. Median survivals from date of stage IV for Cohorts A and B were 29.3 and 33.1 months, respectively (HR = 0.93, P = 0.896). Median survival from cycle 1 ipilimumab was 16.5 and 24.5 months for Cohort A and B, respectively (HR = 1.05, P = 0.931). The 3‐year survival rates from the date of cycle one of ipilimumab administration for Cohort A and B were 50% (95% CI: 27–93%) and 39% (95% CI: 19–81%), respectively. Eight of 10 patients in Cohort A maintained a good PS. Survival of patients with melanoma brain metastases treated with ipilimumab combined with SRS may be comparable to patients without brain metastases.

Impact of Depressive Symptoms on Future Alcohol Use in Patients with Co-Occurring Bipolar Disorder and Alcohol Dependence: A Prospective Analysis in an 8-Week Randomized Controlled Trial of Acamprosate

BACKGROUND Bipolar disorders and alcohol use disorders commonly co-occur, yet little is known about the proximal impact of bipolar symptoms on alcohol use in patients with this comorbidity. The present study examined the impact of depressive symptoms and alcohol craving on proximal alcohol use in patients with co-occurring bipolar disorder and alcohol dependence. METHODS Data were collected during an 8-week randomized controlled trial of acamprosate for individuals with co-occurring bipolar disorder and alcohol dependence (n = 30). Depressive symptoms and alcohol craving were assessed biweekly using the Montgomery Asberg Depression Rating Scale (MADRS) and the Obsessive Compulsive Drinking Scale (OCDS), respectively. Daily alcohol use data were available via administration of the Time-line Follow-back interview at baseline and at subsequent weekly study visits. Correlational analyses and hidden Markov modeling were used to examine the prospective relationships between depressive symptoms, alcohol craving, and alcohol use. RESULTS Depressive symptoms and alcohol craving were significantly correlated with proximal (i.e., 1 week later) alcohol use across a variety of alcohol consumption summary measures. In hidden Markov models, depressive symptoms (OR = 1.3, 95% credible interval = [1.1, 1.5]) and alcohol craving (OR = 1.6, 95% credible interval = [1.4, 1.9]) significantly predicted transitioning from a light to a heavy drinking state, or remaining in a heavy drinking state. CONCLUSIONS The results from the present study suggest that depressive symptoms and alcohol craving increase proximal risk for alcohol use in individuals with co-occurring bipolar and alcohol use disorders.

G-CSF/anti-G-CSF antibody complexes drive the potent recovery and expansion of CD11b+Gr-1+ myeloid cells without compromising CD8+ T cell immune responses

BackgroundAdministration of recombinant G-CSF following cytoreductive therapy enhances the recovery of myeloid cells, minimizing the risk of opportunistic infection. Free G-CSF, however, is expensive, exhibits a short half-life, and has poor biological activity in vivo.MethodsWe evaluated whether the biological activity of G-CSF could be improved by pre-association with anti-G-CSF mAb prior to injection into mice.ResultsWe find that the efficacy of G-CSF therapy can be enhanced more than 100-fold by pre-association of G-CSF with an anti-G-CSF monoclonal antibody (mAb). Compared with G-CSF alone, administration of G-CSF/anti-G-CSF mAb complexes induced the potent expansion of CD11b+Gr-1+ myeloid cells in mice with or without concomitant cytoreductive treatment including radiation or chemotherapy. Despite driving the dramatic expansion of myeloid cells, in vivo antigen-specific CD8+ T cell immune responses were not compromised. Furthermore, injection of G-CSF/anti-G-CSF mAb complexes heightened protective immunity to bacterial infection. As a measure of clinical value, we also found that antibody complexes improved G-CSF biological activity much more significantly than pegylation.ConclusionsOur findings provide the first evidence that antibody cytokine complexes can effectively expand myeloid cells, and furthermore, that G-CSF/anti-G-CSF mAb complexes may provide an improved method for the administration of recombinant G-CSF.

The safety, efficacy, and durability of lung-volume reduction surgery: A 10-year experience.

OBJECTIVES The National Emphysema Treatment Trial (NETT) validated the efficacy of lung-volume reduction surgery (LVRS) in selected patients with emphysema; however, concerns about the safety and durability of the operation have limited its clinical application. We evaluated our experience with LVRS, for the time period since approval was given by the Centers for Medicare and Medicaid Services, with respect to surgical morbidity and mortality, early and late functional outcomes, and long-term survival. METHODS Retrospective analysis was performed on 91 patients for whom consent was obtained for bilateral LVRS at our institution between January 2004 and June 2014. Primary outcomes analyzed were 6-month surgical mortality and overall survival at 1, 2, and 5 years. Secondary outcomes (forced expiratory volume in 1 second [FEV1], residual volume, carbon monoxide diffusing capacity, a 6-minute walk test, exercise capacity, and a shortness-of-breath questionnaire) were analyzed for mean change from baseline at 1, 2, and 5 years after LVRS. RESULTS The 6-month surgical mortality rate was 0%. At the 1- and 5-year follow-up, 69% and 36% of the patients had an improvement in FEV1. The 1-, 2-, and 5-year FEV1 change in % predicted of the FEV1, compared with baseline after LVRS, respectively, was 11.1% (95% CI: 8.6%, 13.6%); 8.7% (95% CI: 6.1%, 11.4%); and 11.1% (95% CI: 7.1%, 15.0%); and the maximal workload (in watts [W]) had an average increase of: 10.7 W (95% CI: 6.9, 14.6); 7.6 W (95% CI: 2.8, 12.4); and 10.24 W (95% CI: 4.4, 16.1). Overall survival (95% CI) for the group was: 0.99 (95% CI: 0.96, 1.00) at 1 year; 0.97 (95% CI: 0.93, 1.00) at 2 years; and 0.78 (95% CI: 0.67, 0.89) at 5 years. CONCLUSIONS Given proper patient selection, LVRS is a safe operation. Early functional measurements are consistent with significant clinical benefit. Long-term results demonstrate that improvements can be durable. Surgical LVRS continues to represent the standard for lung-volume reduction therapy.

A likelihood-based approach for computing the operating characteristics of the 3+3 phase I clinical trial design with extensions to other A+B designs

Background In phase I clinical trials, the “3+3” algorithmic design has been unparalleled in its popularity. The statistical properties of the “3+3” design have been studied in the literature either in comparison with other methods or by deriving exact formulae of statistical quantities. However, there is still much to be known about its capabilities of describing and accounting for uncertainties in the observed data. Purpose The objective of this study is to provide a probabilistic support for analyzing the heuristic performance of the “3+3” design. The operating characteristics of the algorithm are computed under different hypotheses, levels of evidence, and true (or best guessed) toxicity rates. The dose-finding rules are further compared with those generated by the modified toxicity probability interval design and generalized for implementation in all “A+B” designs. Methods Our likelihood method is based on the evidential paradigm. Two hypotheses are chosen to correspond to two hypothesized dose-limiting toxicity rates, for example, H 1 —unsafe versus H 2 —acceptable. Given observed toxicities per dose, the likelihood-ratio is calculated and compared to a certain k threshold (level of evidence). Under various true toxicities, the probabilities of weak evidence, favoring H 1 and H 2 , were computed under four sets of hypotheses and several k thresholds. Results For scenarios where the midpoint of the two hypothesized dose-limiting toxicity rates is around 0.30, and for a threshold of k = 2, the “3+3” design has a reduced probability (≈0.50) of identifying unsafe doses, but high chances of identifying acceptable doses. For more extreme scenarios targeting a relatively high or relatively low dose-limiting toxicity rate, the “3+3” design has no probabilistic support, and therefore, it should not be used. In our comparisons, the likelihood method is in agreement with the modified toxicity probability interval design for the majority of the hypothesized scenarios. Even so, based on the evidential paradigm, a “3+3” design is often incapable of providing sufficient levels of evidence of acceptability for doses under reasonable scenarios. Limitations Given the small sample size per dose, the levels of evidence are limited in their ability to provide strong evidence favoring either of the hypotheses. Conclusion In many situations, the “3+3” design does not treat enough patients per dose to have confidence in correct dose selection and the safety of the selected/unselected doses. This likelihood method allows consistent inferences to be made at each dose level, and evidence to be quantified regardless of cohort size. The approach can be used in phase I studies for identifying acceptably safe doses, but also for defining stopping rules in other types of dose-finding designs.

Improving the Predictive Accuracy of Identifying Exudative Effusions

BACKGROUND Application of Lights criteria results in misclassification of some transudative effusions as exudative, particularly because of congestive heart failure (CHF). We sought to determine if the serum to pleural fluid albumin (SF-A) and serum to pleural fluid protein (SF-P) gradients increased the predictive accuracy to correctly identify exudative effusions. METHODS We retrospectively analyzed 1,153 consecutive patients who underwent a diagnostic thoracentesis at the Medical University South Carolina. Univariable logistic regression analyses were used to determine the statistical significance of pleural fluid tests that correctly identified exudative effusions. Tests with significant diagnostic accuracy were combined in multivariable logistic regression models, with calculation of areas under the curve (AUCs) to determine their predictive accuracy. The predictive capability of the best model was compared with Lights criteria and other test combinations. RESULTS Pleural fluid lactate dehydrogenase (LDH), SF-A gradient, and SF-P gradient had a significant effect on the probability of identifying exudative pleural effusions. When combined together in a multivariable logistic regression, LDH (OR, 14.09 [95% CI, 2.25-85.50]), SF-A gradient (OR, 7.16 [95% CI, 1.24-41.43]), and SF-P gradient (OR, 6.83 [95% CI, 1.56-27.88]) had an AUC of 0.92 (95% CI, 0.85-0.98). CONCLUSIONS Application of Lights criteria, not uncommonly, misclassifies CHF transudative effusions as exudates. In cases where no cause for an exudative effusion can be identified or CHF is suspected, the sequential application of the fluid LDH, followed by the SF-P and then the SF-A gradients, may assist in reclassifying pleural effusions as transudates.

Dose-finding designs for trials of molecularly targeted agents and immunotherapies

ABSTRACT Recently, there has been a surge of early phase trials of molecularly targeted agents (MTAs) and immunotherapies. These new therapies have different toxicity profiles compared to cytotoxic therapies. MTAs can benefit from new trial designs that allow inclusion of low-grade toxicities, late-onset toxicities, addition of an efficacy endpoint, and flexibility in the specification of a target toxicity probability. To study the degree of adoption of these methods, we conducted a Web of Science search of articles published between 2008 and 2014 that describe phase 1 oncology trials. Trials were categorized based on the dose-finding design used and the type of drug studied. Out of 1,712 dose-finding trials that met our criteria, 1,591 (92.9%) utilized a rule-based design, and 92 (5.4%; range 2.3% in 2009 to 9.7% in 2014) utilized a model-based or novel design. Over half of the trials tested an MTA or immunotherapy. Among the MTA and immunotherapy trials, 5.8% used model-based methods, compared to 3.9% and 8.3% of the chemotherapy or radiotherapy trials, respectively. While the percentage of trials using novel dose-finding designs has tripled since 2007, the adoption of these designs continues to remain low.

An adaptive dose-finding design based on both safety and immunologic responses in cancer clinical trials

ABSTRACT Dose-finding in cancer clinical trials has been dominated by algorithmic designs on the principle that the highest tolerable dose is also the most effective dose. This assumption no longer applies to the biologic treatments that are characterized by different toxicity and/or efficacy profiles to the extent that the best therapeutic dose might be well below any dose that produces serious toxicity. As such, we propose a two-stage design with focus on immunotherapy trials, incorporating both safety and efficacy information. The first stage establishes the safety profile of each dose, with escalation decisions based on likelihood principles. Continuous immunologic outcomes are used to evaluate the relative efficacy of the doses. The second stage employs an adaptive randomization to assign patients to doses showing higher efficacy. Safety is being continuously monitored throughout Stage 2, where some doses may be ‘closed’ due to unacceptable toxicity. The proposed design is compared to the modified toxicity probability interval (mTPI) design using percent dose allocation and estimation of outcomes under different scenarios. We show that by using an efficacy-driven adaptive randomization with safety constraints, the allocation distribution is skewed towards more efficacious doses, and thus limit the number of patients exposed to toxic or non-therapeutic doses. Supplementary materials for this article are available online.

Sample size considerations for clinical research studies in nuclear cardiology

Sample size calculation is an important element of research design that investigators need to consider in the planning stage of the study. Funding agencies and research review panels request a power analysis, for example, to determine the minimum number of subjects needed for an experiment to be informative. Calculating the right sample size is crucial to gaining accurate information and ensures that research resources are used efficiently and ethically. The simple question “How many subjects do I need?” does not always have a simple answer. Before calculating the sample size requirements, a researcher must address several aspects, such as purpose of the research (descriptive or comparative), type of samples (one or more groups), and data being collected (continuous or categorical). In this article, we describe some of the most frequent methods for calculating the sample size with examples from nuclear cardiology research, including for t tests, analysis of variance (ANOVA), non-parametric tests, correlation, Chi-squared tests, and survival analysis. For the ease of implementation, several examples are also illustrated via user-friendly free statistical software.