Amit K. Chowdhry

Double-blind, randomized, controlled, crossover trial of pregabalin for neurogenic claudication

Objectives: To test the effects of pregabalin on the induction of neurogenic claudication. Methods: This study was a randomized, double-blind, active placebo-controlled, 2-period, crossover trial. Twenty-nine subjects were randomized to receive pregabalin followed by active placebo (i.e., diphenhydramine) or active placebo followed by pregabalin. Each treatment period lasted 10 days, including a 2-step titration. Periods were separated by a 10-day washout period, including a 3-day taper phase after the first period. The primary outcome variable was the time to first moderate pain symptom (Numeric Rating Scale score ≥4) during a 15-minute treadmill test (Tfirst). Secondary outcome measures included pain intensity at rest, pain intensity at the end of the treadmill test, distance walked, and validated self-report measures of pain and functional limitation including the Roland-Morris Disability Questionnaire, modified Brief Pain Inventory–Short Form, Oswestry Disability Index, and Swiss Spinal Stenosis Questionnaire. Results: No significant difference was found between pregabalin and active placebo for the time to first moderate pain symptom (difference in median Tfirst = −1.08 [95% confidence interval −2.25 to 0.08], p = 0.61). In addition, none of the secondary outcome measures of pain or functional limitation were significantly improved by pregabalin compared with active placebo. Conclusions: Pregabalin was not more effective than active placebo in reducing painful symptoms or functional limitations in patients with neurogenic claudication associated with lumbar spinal stenosis. Classification of evidence: This study provides Class I evidence that for patients with neurogenic claudication, compared with diphenhydramine, pregabalin does not increase the time to moderate pain during a treadmill test.

Stereotactic Body Radiotherapy for Lung Metastases from Colorectal Cancer: Prognostic Factors for Disease Control and Survival

Objectives: To evaluate disease control and survival after stereotactic body radiotherapy (SBRT) for lung metastases from colorectal cancer and to identify prognostic factors after treatment. Methods: Patients with metastatic colorectal cancer to the lungs treated with SBRT from 2002 to 2013 were identified from a prospectively maintained database. Patients may have received prior systemic therapy, radiotherapy to nonthoracic sites and/or resection of thoracic and/or nonthoracic metastases. Endpoints were timed from end of SBRT and included overall survival (OS), progression-free survival, distant metastases-free survival, and local failure-free survival. Univariate and multivariate analysis using Cox proportional hazard modeling was used to identify prognostic factors. Results: Sixty-five patients were identified. Before SBRT, 69.2% and 33.8% of patients received systemic therapy and lung-directed local therapy, respectively, for metastatic disease. At the time of SBRT, 64.6% had lung-only involvement. Median survivals were: OS of 20.3 months (95% confidence intervals [CI], 15.9-27.0 mo), progression-free survival of 5.7 months (95% CI, 3.2-7.0 mo), distant metastases-free survival of 5.8 months (95% CI, 3.2-7.6 mo), and local failure-free survival of 15.4 months (95% CI, 8.5-21.1 mo). Nearly all (98%) patients developed distant progression. Extra lung and liver involvement at the time of initial metastases (hazard ratios [HR] 2.10) and extra lung involvement at SBRT (HR 2.67) were the only independent predictors of OS. Net gross target volume of >14.1 mL (HR 2.49) was the only independent predictor of local failure-free survival. Conclusions: Reasonable survival and local control can be achieved with SBRT. We identified several prognostic factors testable in future prospective trials that may help improve patient selection.

Cross-sectional area for the calculation of carotid artery stenosis on computed tomographic angiography.

OBJECTIVE The use of cross-sectional area (CSA) measurements obtained from computed tomographic angiography (CTA) for the calculation of carotid artery stenosis has been suggested but not yet validated in a large population. The objective of this study was to determine whether CTA-derived CSA measurements were able to predict carotid stenosis with a level of confidence similar to CTA-derived diameter measurements, using Strandness criteria applied to carotid duplex ultrasound (CDUS) as a surrogate for true stenosis. METHODS A retrospective review was conducted to identify patients who underwent both CDUS and CTA between 2000 and 2009. Percent stenosis was calculated using the North American Symptomatic Carotid Endarterectomy Trial (NASCET) formula with diameter measurements and again with CSA measurements. A nonparametric correlation coefficient was calculated to detect correlation between the two groups. Two-dimensional receiver-operating characteristic curves with corresponding area under the curve (AUC) statistics were generated for >50% stenosis and >80% stenosis. Three-dimensional receiver-operating characteristic plots with corresponding volume under the surface (VUS) statistics were generated to measure the comparative accuracy of diameter-based and CSA-based stenosis for <50%, 50%-79%, and >80% stenosis. RESULTS A total of 575 vessels in 313 patients were included in the study. Spearmans correlation coefficient between diameter and CSA-derived stenosis was ρ = 0.938 (95% confidence interval [CI], 0.927-0.947; P < .0001). For diameter-derived stenosis, AUC was 0.905 (95% CI, 0.878-0.932; P < .0001) for >50% stenosis and 0.950 (95% CI, 0.928-0.972; P < .0001) for 80%-99% stenosis. For CSA-derived percent stenosis, the AUC was 0.908 (95% CI, 0.882-0.935; P < .0001) for >50% stenosis and 0.935 (95% CI, 0.908-0.961; P < .0001) for 80%-99%. The nonparametric estimate for VUS in the diameter-based stenosis group was 0.761, whereas in the CSA-based group, the VUS was 0.735. The difference between VUS was 0.026 (95% CI, -0.022 and 0.077; P = .318). CONCLUSIONS These data support the use of CTA as an accurate method of calculating carotid artery stenosis based on agreement with Strandness criteria applied to CDUS velocities. When additional imaging beyond CDUS is necessary, we report no significant difference between diameter and CSA measurements obtained from CTA for preoperative evaluation of carotid disease.

A Randomized, Double-blind, Placebo-Controlled Crossover Trial of Oxymorphone Hydrochloride and Propoxyphene/Acetaminophen Combination for the Treatment of Neurogenic Claudication Associated With Lumbar Spinal Stenosis

Study Design. Randomized, double-blind, placebo-controlled, single-dose crossover study. Objective. To test the analgesic efficacy of oxymorphone hydrochloride (OH) and propoxyphene/acetaminophen (PA) for patients with neurogenic claudication associated with lumbar spinal stenosis. Summary of Background Data. Although opioids are often prescribed for neurogenic claudication, no randomized controlled studies support their efficacy for this condition. Patients with neurogenic claudication are generally excluded from clinical trials or included with patients who have nonspecific chronic low back pain, yielding a heterogeneous study population with very different pathophysiologies and clinical presentations. Methods. Participants received a single dose of each of the 3 treatments in random order. Treatments were separated by at least 3-day washout periods. The primary outcome variable was the time to first treadmill walking–induced moderate pain (≥4 out of 10 on a Numeric Rating Scale) (Tfirst) assessed 90 minutes after treatment administration. Secondary outcome measures included patient global assessment of low back pain, Roland-Morris Disability Questionnaire, Modified Brief Pain Inventory-Short Form, Oswestry Disability Index, and Swiss Spinal Stenosis Questionnaire. Results. The study was prematurely terminated because of the removal of PA from the US market. Twenty-four patients were randomized; 21 completed all 3 treatment periods. There were no significant differences among the treatment groups with respect to the median Tfirst (OH—placebo: median [98.3% confidence limits] =−0.25 min [−6.54, 5.00]; PA—placebo: 0.02 min [−7.65, 4.90]; OH—PA: −0.27 min [−5.56, 6.66]). Conclusion This trial failed to demonstrate a benefit of OH or PA in patients experiencing neurogenic claudication. Considering the potential negative side effects of chronic opioid use, additional research is necessary to evaluate the efficacy of sustained opioid treatment specifically for neurogenic claudication. Level of Evidence: 2

Meta‐analysis with missing study‐level sample variance data

We consider a study-level meta-analysis with a normally distributed outcome variable and possibly unequal study-level variances, where the object of inference is the difference in means between a treatment and control group. A common complication in such an analysis is missing sample variances for some studies. A frequently used approach is to impute the weighted (by sample size) mean of the observed variances (mean imputation). Another approach is to include only those studies with variances reported (complete case analysis). Both mean imputation and complete case analysis are only valid under the missing-completely-at-random assumption, and even then the inverse variance weights produced are not necessarily optimal. We propose a multiple imputation method employing gamma meta-regression to impute the missing sample variances. Our method takes advantage of study-level covariates that may be used to provide information about the missing data. Through simulation studies, we show that multiple imputation, when the imputation model is correctly specified, is superior to competing methods in terms of confidence interval coverage probability and type I error probability when testing a specified group difference. Finally, we describe a similar approach to handling missing variances in cross-over studies. Copyright

Complications From Computed Tomography–Guided Core Needle Biopsy for Patients Receiving Stereotactic Body Radiation Therapy for Early-Stage Lesions of the Lung

BACKGROUND Obtaining a tissue diagnosis has traditionally been standard practice before initiating therapy for early-stage non-small-cell lung cancer (NSCLC). In several recent studies from Europe and Asia, a substantial proportion of patients have received stereotactic body radiation therapy (SBRT) based only on the imaging characteristics of the suspicious lesion. The underlying assumption is that the risk of percutaneous needle biopsy may outweigh the benefits in a population that generally has underlying pulmonary dysfunction and other medical comorbidity. Nevertheless, there is limited information regarding biopsy-related complication rates in high-risk patients with early-stage NSCLC who are treated with SBRT. MATERIALS AND METHODS This was a retrospective review of outcomes after biopsy in patients treated with SBRT. Complications of percutaneous core needle biopsy were analyzed in relation to patient and tumor characteristics. Each biopsy event was analyzed independently for patients with multiple biopsies. RESULTS A total of 112 percutaneous biopsies were performed in 103 patients. Pneumothorax of any degree was observed in 40 patients (35%) (95% CI, 27%-45%), and 12 patients (10.7%) had a clinically significant pneumothorax requiring chest tube placement (95% CI, 6%-18%). The time to first fraction of SBRT was not different in patients who had a pneumothorax or placement of a chest tube. On multivariate analysis, age, performance status, smoking history, pack-years of smoking, chronic obstructive pulmonary disease history, and forced expiratory volume in the first second of expiration were not statistically significantly associated with chest tube placement. CONCLUSION Computed tomography-guided needle biopsy in a primarily medically inoperable patient population is safe, with an acceptable degree of complications.

A population-based study of prognosis and survival in patients with second primary thyroid cancer after Hodgkin lymphoma

Abstract Hodgkin lymphoma (HL) survivors are at increased risk of thyroid cancer (TC). We sought to determine whether increased risks of high-risk pathology or mortality are seen with thyroid cancer after HL (HL-TC) compared with first primary thyroid cancer (TC-1). From the Surveillance, Epidemiology and End Results (SEER) registry, we compared patient and tumor characteristics as well as survival outcomes between HL-TC and TC-1 and fit a multivariable Cox model to assess for a possible association between HL history and overall survival after TC. Among 139,297 TC-1 and 174 HL-TC patients, history of HL was not associated with anaplastic or sarcoma TC. Multivariable analyzes showed that history of HL was not associated with a difference in risk of death after TC (hazard ratio: 0.96, 95% confidence interval: (0.81, 1.13), p = .61). Despite a significantly increased risk of TC among HL survivors, prior HL is not associated with more aggressive pathologic subtypes or worse prognosis.

Predictive multivariate regression to increase the specificity of carotid duplex ultrasound for high-grade stenosis in asymptomatic patients.

BACKGROUND Carotid duplex ultrasound (CDUS) is commonly used to screen for carotid artery stenosis. Specificities of CDUS criteria however are lower than sensitivities, potentially resulting in false-positive examinations with subsequent unnecessary imaging or surgery. Our objective was to establish a multivariate logistic regression to increase the specificity of CDUS for high-grade (≥70%) stenosis. METHODS A retrospective review collected CDUS velocities and radiographic measurements from patients who underwent both CDUS and computed tomography angiography (CTA). After stratification with standard CDUS criteria, a logistic regression was created using peak systolic velocity (PSV), end diastolic velocity (EDV), and PSV ratio (PSV of internal carotid artery [ICA]/PSV of common carotid artery [CCA]) as predictor variables. A receiver operating characteristic curve was generated to test the models predictive ability. A cutoff probability for unequivocal high-grade stenosis was chosen based on optimal specificity. The regression model was applied to patients with equivocal high-grade stenosis. Probabilities for detection of high-grade stenosis were calculated. Descriptive statistics were generated to quantify the accuracy of the model. RESULTS A total of 244 vessels were included. Standardized velocity criteria for ≥70% stenosis yielded a sensitivity of 90.6% (95% confidence interval [CI], 82.3-95.6%), specificity of 63.5% (95% CI, 55.4-70.5%), positive predictive value (PPV) of 57.0% (95% CI, 48.8-65.5%), and negative predictive value (NPV) of 92.7% (95% CI, 85.8-96.5%). Regression analysis produced a model for predicting the probability of high-grade stenosis defined as probability = logit(-1) (-4.97 + [0.00938 × PSV] + [0.0135 × EDV] + [0.103 × PSV ICA/CCA ratio]). A cutoff probability of 0.65 for high-grade stenosis yielded a sensitivity of 54.7% (95% CI, 43.9-65.0%), specificity of 94.3% (95% CI, 89.3-97.2%), PPV of 83.9% (95% CI, 71.6-91.9%), and NPV of 79.3% (95% CI, 72.8-84.5%). A cutoff PSV of 400 cm/sec was chosen for unequivocal stenosis of ≥70%. A total of 94 patients were found to meet criteria for high-grade stenosis (PSV ≥ 230 cm/sec) but fall short of criteria for unequivocal high-grade stenosis (PSV < 400 cm/sec). Application of the regression model resulted in identification of 15 patients with probability ≥0.65 for high-grade stenosis and 79 patients with probability <0.65. This resulted in a 16% potential reduction in CTA scans. CONCLUSIONS Our regression model provides increased specificity of CDUS for high-grade stenosis in patients who have met initial highly sensitive screening criteria. Application of this model may limit the need for additional imaging and increase the threshold for operative intervention in asymptomatic patients with equivocal high-grade carotid stenosis.

Long-term CT surveillance after primary lung cancer treatment captures events in all risk groups

In the article “ Risk Stratification for Second Primary Lung Cancer ” by Han et al . (1), the authors address the problem of selective screening of lung cancer survivors by creating a competing-risk prognostic model to determine the probability of a secondary primary lung cancer (SPLC).

Survival implications of staging lymphadenectomy for non-endometrioid endometrial cancers

PURPOSE To determine, in patients with non-endometrioid endometrial carcinoma, 1) survival benefit associated with pelvic lymphadenectomy (LND), 2) survival benefit for para-aortic lymphadenectomy performed in addition to pelvic lymphadenectomy, and 3) association between number of lymph nodes removed and survival. METHODS Patients with clinical stage I serous carcinoma, clear cell carcinoma, or carcinosarcoma who underwent hysterectomy from 2010 to 2013 were identified from the National Cancer Database. Hazard ratio (HR) for death was assessed using propensity score-weighted multivariable Cox regression models. Subgroup analyses assessed for differences in risk of death among histologic subtypes. RESULTS 7250 patients met study criteria. 930 (13%) did not undergo LND; 2177 (30%) underwent pelvic LND alone; 4143 (57%) underwent pelvic+para-aortic LND. On propensity score-weighted analysis, pelvic LND was associated with decreased risk of death (HR=0.65, 95% CI: 0.59-0.71) compared to no LND. Pelvic+para-aortic LND was associated with decreased risk of death (HR=0.85, 95% CI: 0.79-0.91) compared to pelvic LND for patients with serous carcinoma. Removal of >15 nodes was independently associated with decreased HR for death (HR=0.86, 95% CI: 0.77-0.96); this association persisted when analysis was limited to patients with node-positive disease (HR=0.78, 95% CI: 0.63-0.95). CONCLUSIONS LND is associated with survival benefit in patients with non-endometrioid endometrial cancers. Addition of para-aortic LND to pelvic LND may be most beneficial for patients with serous carcinoma. Systematic lymphadenectomy may be associated with survival benefit through detection and microscopic cytoreduction of occult disease.