Mild hyperthermia with magnetic resonance- guided high intensity focused ultrasound combined with salvage chemoradiation for recurrent rectal cancer.

INTRODUCTION: Pelvic recurrences from rectal cancer present a challenging clinical scenario. Hyperthermia represents an innovative treatment option in combination with concurrent chemoradiation to enhance therapeutic effect. We provide the initial results of a prospective single center feasibility study (NCT02528175) for patients undergoing rectal cancer retreatment using concurrent chemoradiation and mild hyperthermia with MR-guided high intensity focused ultrasound (MR-HIFU). METHODS: All patients were deemed ineligible for salvage surgery and were evaluated in a multidisciplinary fashion with a surgical oncologist, radiation oncologist and medical oncologist. Radiation was delivered to a dose of 30.6 Gy in 1.8 Gy per fraction with concurrent capecitabine. MR-HIFU was delivered on days 1, 8 and 15 of concurrent chemoradiation. Our primary objective was feasibility and toxicity. RESULTS: Six patients (total 11 screened) were treated with concurrent chemoradiation and mild hyperthermia with MR-HIFU. Tumor size varied between 3.1-16.6 cm. Patients spent an average of 228 min in the MRI suite and sonication with the external transducer lasted an average of 35 min. There were no complications on the day of the MR-HIFU procedure and all acute toxicities (no grade >/=3 toxicities) resolved after completion of treatment. There were no late grade >/=3 toxicities. CONCLUSION: Mild hyperthermia with MR-HIFU, in combination with concurrent chemoradiation for appropriately selected patients, is safe for localized pelvic recurrences from rectal cancer. The potential for MR-HIFU to be applied in the recurrent setting in rectal cancer treatment requires further technical development and prospective evaluation.

Short QT in a cohort of 1.7 million persons: prevalence, correlates, and prognosis.

BACKGROUND: Short QT syndrome (QTc ≤ 300 ms) is a novel hereditary channelopathy linked to syncope, paroxysmal atrial fibrillation, and sudden cardiac death. However, its epidemiological features remain unsettled. OBJECTIVES: (1) To assess the prevalence of short QT in a large population-based sample; (2) to evaluate its demographic and clinical correlates and; (3) to determine its prognosis. METHODS: A database of 6.4 million electrocardiograms (ECGs) obtained between 1995 and 2008 among 1.7 million persons was used. An internal, population-based method for heart rate correction (QTcreg ) was used and all ECGs with QTcreg ≤300 ms were manually validated. Linked health plan databases were used for covariate and survival ascertainment. RESULTS: Of 6,387,070 ECGs, 1086 had an ECG with machine-read QTcreg ≤300 ms. Only 4% (45/1086) were validated yielding a prevalence of 0.7 per 100,000 or 1 of 141,935 ECGs. At the person level, the overall prevalence of QTcreg ≤300 ms was 2.7 per 100,000 or 1 of 37,335. The factors independently and significantly associated with validated QTcreg ≤300 ms were age over 65 years, Black race, prior history of ventricular dysrhythmias, chronic obstructive pulmonary disease, ST-T abnormalities, ischemia, bigeminy pattern, and digitalis effect. After 8.3 years of median follow-up and relative to normal QTcreg , validated QTcreg ≤300 ms was associated after multivariate adjustment with a 2.6-fold (95% confidence interval [CI] = 1.9-3.7) increased risk of death. CONCLUSION: QTcreg ≤300 ms was extraordinarily rare and was associated with significant ECG abnormalities and reduced survival.

Validation of a population-based method to assess drug-induced alterations in the QT interval: a self-controlled crossover study.

PURPOSE: The purpose of this study was to ascertain, in the context of an integrated health care delivery system, the association between a comprehensive list of drugs known to have potential QT liability and QT prolongation or shortening. METHODS: By using a self-controlled crossover study with 59 467 subjects, we ascertained intra-individual change in log-linear regression-corrected QT (QTcreg ) during the period between 1995 and mid-2008 for 90 drugs while adjusting for age, gender, race/ethnicity, comorbid conditions, number of electrocardiograms (ECGs), and time between pre-ECG and post-ECG. The proportion of users of each drug-developing incident long QT was also estimated. RESULTS: Two drugs (nicardipine and levalbuterol) had no statistically significant intra-individual QTcreg shortening effects, 10 drugs had no statistically significant prolonging effect, and 78 (87%) of the drugs had statistically significant intra-individual mean QTcreg lengthening effects, ranging from 7.6 ms for aripiprazole to 25.2 ms for amiodarone. Three drugs were associated with mean QTcreg prolongation of 20 ms or greater: amiodarone (antiarrhythmic), terfenadine (antihistaminic), and quinidine (antiarrhythmic); whereas 11 drugs were associated with mean QTcreg prolongation of 15 ms or greater but less than 20 ms: trimipramine (tricyclic antidepressant), clomipramine (tricyclic antidepressant), disopyramide (antiarrhythmic), chlorpromazine (antipsychotic), sotalol (beta blocker), itraconazole (antifungal), phenylpropanolamine (decongestant/anorectic), fenfluramine (appetite suppressant), midodrine (antihypotensive), digoxin (cardiac glycoside/antiarrhythmic), and procainamide (antiarrhythmic). CONCLUSIONS: QT prolonging effects were common and varied in strength. Our results lend support to past Food and Drug Administration regulatory actions and support the role for ongoing surveillance of drug-induced QT prolongation.

Development and application of an algorithm for statin-induced myopathy based on electronic health record-derived structured elements.

Objective: Considering the non-specific nature of muscle symptoms, studies of statin-induced myopathy (SIM) in electronic health records require accurate algortihms that can reliably identify true statin-related cases. However, prior algorithms have been constructed in study populations that preclude broad applicability. Here we developed and validated an algorithm that accurately defines SIM from electronic health records using structured data elements and conducted a study of determinants of SIM after applying the algorithm. Materials and Methods: We used electronic records from an integrated health care delivery system (including comprehensive pharmacy dispensing records) and defined SIM as elevated creatine kinase (CK) ≥4 x upper limit of normal. A diverse cohort of participants receiving a variety of statin regimens met the criteria for study inclusion. Results: We identified multiple conditions strongly associated with elevated CK independent of statin use. A 2-step algorithm was developed using these all-cause conditions as secondary causes (step 1) along with evidence of a statin regimen change (step 2). We identified 1,262 algorithm-derived statin-induced elevated CK cases. Gold standard SIM cases determined from manual chart reviews on a random subset of the all-cause elevated CK cases were used to validate the algorithm, which had a 76% sensitivity and 77% specificity for detecting the most certain cases. Pravastatin use was associated with a 2.18 odds (95% confidence interval 1.39-3.40, P=0.0007) for statin-induced CK elevation compared to lovastatin use after adjusting for dose and other factors. Conclusions: We have produced an efficient, easy-to-apply methodological tool that can improve the quality of future research on statin-induced myopathy.

Cytoreductive stereotactic body radiotherapy (SBRT) and combination SBRT with immune checkpoint inhibitors in metastatic renal cell carcinoma.

INTRODUCTION: Preclinical evidence demonstrates the immunogenic potential of stereotactic body radiotherapy (SBRT). There is growing interest in investigating this interplay with the immune system in metastatic renal cell carcinoma (mRCC). Cytoreduction with SBRT and combination therapy with SBRT and checkpoint inhibitor immuno-oncology agents (IO) are two potential therapeutic strategies in mRCC. In this review, we summarize the current clinical evidence for the use of cytoreductive SBRT to primary kidney and combination SBRT with IO. METHODS: A literature review for articles and abstracts published between January 2000 and March 2020 was conducted through the PubMed, the American Society of Clinical Oncology (ASCO), and the American Society of Radiation Oncology (ASTRO) databases. Evaluation of studies followed the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) criteria. RESULTS: A total of three articles for cytoreductive SBRT and one article and three abstracts for combination SBRT and IO in mRCC met inclusion criteria for this review. Evidence for SBRT to primary kidney is limited by small series and pilot studies. Outcomes vary widely due to small patient numbers and study heterogeneity. Local control ranges from 85-100% and one- and two-year overall survival ranges from 38-71% and 19-53%, respectively. Combination SBRT and IO are tolerable for patients with early data, suggesting grade 3-4 adverse event rates of 0-24%. Long-term survival data is not yet available. CONCLUSIONS: Cytoreductive SBRT and combination SBRT with IO therapy represent promising treatment strategies in mRCC. The evidence for clinical benefit is currently limited and requires further study with well-designed, randomized controlled trials.

A Comparison of Radiation Techniques in Patients Treated With Concurrent Chemoradiation for Stage III Non-Small Cell Lung Cancer.

PURPOSE: The standard of care in management of patients with good performance status and unresectable stage III non-small cell lung cancer (NSCLC) therapy is concurrent chemoradiation. Newer techniques such as intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) are replacing 3-dimensional conformal radiation (3DCRT) despite low-quality evidence of improved outcomes. We used population-based data to examine survival outcomes by radiation technique. METHODS AND MATERIALS: A population-based retrospective cohort of patients with stage III NSCLC treated with concurrent chemoradiation from 2009 to 2017 in Ontario were identified. The primary outcome was a comparison of overall survival among 3DCRT, IMRT, and VMAT, calculated using the Kaplan-Meier method and compared using log-rank test. Cox regression was used to investigate effect of radiation type on overall survival adjusted for other covariates. RESULTS: A total of 3872 patients were treated with 3DCRT (n = 1178), IMRT (n = 1847), or VMAT (n = 847). A decline in 3DCRT and increase in VMAT use were observed over time. Median survival in months was 21.2 (95% confidence interval [CI], 20.0-22.8) for 3DCRT, 23.9 (95% CI, 22.3-25.6) for IMRT, and 24.9 (95% CI, 22.5-27.4) for VMAT, but these differences were not statistically significant (P = .06). CONCLUSIONS: Our study demonstrates that survival is not compromised in patients receiving IMRT or VMAT (compared with 3DCRT). Thus, given the potential dosimetric advantages associated with these techniques, VMAT and IMRT are recommended for the management of patients with stage III NSCLC.

Overall and chemotherapy-free survival following stereotactic body radiation therapy for abdominopelvic oligometastases.

INTRODUCTION: Limited data establish the efficacy and safety of SBRT in the abdominopelvic (AP) space, where SBRT delivery is challenging due to the proximity of radiosensitive luminal gastrointestinal (GI) organs. The aim of this study was to assess clinical outcomes in patients with AP OM treated with SBRT. METHODS: Eligible patients were those with OM (defined as metastases in ≤3 total sites) in the AP space (excluding liver) treated with SBRT. Descriptive statistics and Kaplan-Meier estimates of (LC), progression-free survival (PFS), overall survival (OS) and chemotherapy-free survival (CFS) were performed. RESULTS: Fifty-one patients with 58 AP OM received SBRT between 2011 and 2015. Median follow-up was 21.9 months. All SBRT treatments were delivered in 5 fractions with a median dose of 35 Gy (25-40 Gy). Progression post-SBRT occurred in 38/51 patients (75%), with a median PFS of 4.9 months (95% CI: 2.5-7.5), and 2-year PFS of 29%. Rates of 2-and 4-year LC were 74% and 69%, respectively. Median OS was 42.6 months (95% CI: 31-55). Oligometastatic progression occurred in 21/38 patients, and of those, 48% (10/21) received further SBRT. Resulting 2- and 4-year CFS were 47% and 37%, respectively (median 15.1 months). Nineteen patients (37%) experienced a grade 1 or 2 acute toxicity. One grade 3 (acute) toxicity was observed. No grade 4 or 5 toxicities were detected. CONCLUSIONS: SBRT to AP OM was associated with sustained LC, excellent OS and minimal toxicity. The use of SBRT allowed for prolonged CFS and the salvage of limited-burden distant failures.

Fragmented QRS on a 12-lead ECG: a predictor of mortality and cardiac events in patients with coronary artery disease.

BACKGROUND: Fragmented QRS (fQRS) on a 12-lead electrocardiogram (ECG) is associated with myocardial scar in patients with coronary artery disease (CAD). OBJECTIVE: We postulated that fQRS is a predictor of cardiac events and mortality in patients who have known CAD or who are being evaluated for CAD. METHODS: The cardiac events (myocardial infarction, need for revascularization, or cardiac death) and all-cause mortality were retrospectively reviewed in 998 patients (mean age 65.5 +/- 11.9 years, male 967) who underwent nuclear stress test. The fQRS on a 12-lead ECG included various RSR' patterns (> or =1 R' prime or notching of S wave or R wave) without typical bundle branch block in 2 contiguous leads corresponding to a major coronary artery territory. RESULTS: All-cause mortality (93 [34.1%] vs 188 [25.9%]) and cardiac event rate (135 [49.5%] vs 200 [27.6%]) were higher in the fQRS group compared with the non-fQRS group during a mean follow-up of 57 +/- 23 months. A Kaplan-Meier survival analysis revealed significantly lower event-free survival for cardiac events (P <.001) and all-cause mortality (P = .02). Multivariate Cox regression analysis revealed that significant fQRS was an independent significant predictor for cardiac events but not for all-cause mortality. The Kaplan-Meier survival analysis showed no significant difference between fQRS and Q waves groups for cardiac events (P = .48) and all-cause mortality (P = .08). CONCLUSION: The fQRS is an independent predictor of cardiac events in patients with CAD. It is associated with significantly lower event-free survival for a cardiac event on long-term follow-up.

Nonutilization of Statins in a Community-based Population with a History of Coronary Revascularization.

PURPOSE: Statin therapy has been reported to reduce the incidence of vascular events in patients with atherosclerosis, but adherence to statins may be suboptimal. The aims of this study were to quantify the rate of statin use among individuals with a history of coronary revascularization in a large, integrated health care system and to determine which demographic characteristics and clinical factors are associated with statin use. METHODS: This was a retrospective cohort study using database programming and chart review. The study included adult members of Kaiser Permanente Northern California with a history of coronary revascularization. The study outcome was off-statin status, defined as a ≥1-year gap between filled prescriptions. The predictor variables included age, race, body mass index, dyslipidemia, liver disease, kidney disease, and history of statin allergy. Multivariable logistic regression was used to quantify the associations between the predictor variables and statin status. A chart review of a randomly selected subset was performed to identify reasons why individuals were not taking statins. FINDINGS: The study population included 17,869 Kaiser Permanente Northern California members, of which 18.3% had off-statin status. The following variables were associated with off-statin status: statin allergy (odds ratio [OR] = 2.18; 95% CI, 1.89-2.52), end-stage renal disease (OR = 1.55; 95% CI, 1.26-1.91), liver disease (OR = 1.44; 95% CI, 1.08-1.93), African-American race (OR = 1.55 vs white; 95% CI, 1.32-1.81), and Latino race (OR = 1.18; 95% CI, 1.05-1.33). The chart review found that off-statin status typically reflects patient (79%) rather than provider (21%) preference. IMPLICATIONS: A significant minority of patients with a history of coronary revascularization are not taking statins. Off-statin status is associated with kidney disease, liver disease, African-American race, and Latino race. At an individual level, off-statin status was usually driven by patient preference, due to minor or undefined reasons. These findings may be useful in guiding strategies to increase statin use in individuals with atherosclerosis.

Usefulness of fragmented QRS on a 12-lead electrocardiogram in acute coronary syndrome for predicting mortality.

Electrocardiographic signs of a non-ST elevation myocardial infarction (NSTEMI) are nonspecific, and therefore the diagnosis of NSTEMI during acute coronary syndromes (ACS) depends mainly on cardiac biomarker levels. Fragmented QRS (fQRS) represents myocardial conduction abnormalities due to myocardial infarction (MI) scars in patients with coronary artery disease. However, the time of appearance of fQRS during ACS has not been investigated. It was postulated that in patients with ACS, fQRS on 12-lead electrocardiography occurs within 48 hours of presentation with NSTEMI as well as ST elevation MI and that fQRS predicts mortality. Serial electrocardiograms from 896 patients with ACS (mean age 62 +/- 11 years, 98% men) who underwent cardiac catheterization were studied. Four hundred forty-one patients had MIs, including 337 patients with NSTEMIs, and 455 patients had unstable angina (the control group). Serial electrocardiograms were obtained every 6 to 8 hours during the first 24 hours after the diagnosis of MI and the next day (<48 hours). Fragmented QRS on 12-lead electrocardiography was defined by the presence of single or multiple notches in the R or S wave, without a typical bundle branch block, in > or =2 contiguous leads in 1 of the major coronary artery territories. Fragmented QRS developed in 224 patients (51%) in the MI group and only 17 (3.7%) in the control group (p <0.001). New Q waves developed in 122 (28%), 76 (23%), and 2 (0.4%) patients in the MI, NSTEMI, and control groups, respectively. The sensitivity values of fQRS for ST elevation MI and NSTEMI were 55% and 50%, respectively. The specificity of fQRS was 96%. Kaplan-Meier survival analysis revealed that patients with fQRS had significantly decreased times to death compared to those without fQRS. Fragmented QRS, T-wave inversion, and ST depression were independent predictors of mortality during a mean follow-up period of 34 +/- 16 months. In conclusion, fQRS on 12-lead electrocardiography is a moderately sensitive but highly specific sign for ST elevation MI and NSTEMI. Fragmented QRS is an independent predictor of mortality in patients with ACS.

Fragmented wide QRS on a 12-lead ECG: a sign of myocardial scar and poor prognosis.

BACKGROUND: Fragmented QRS (duration <120 ms) on a 12-lead ECG represents myocardial scar in patients with coronary artery disease. However, the significance of fragmented QRS has not been defined in the presence of a wide QRS (wQRS; duration >or=120 ms). We postulate that fragmented wQRS (f-wQRS) due to bundle branch block, premature ventricular complexes, or paced rhythms (f-pQRS) signify myocardial scar and higher mortality. METHODS AND RESULTS: Patients who underwent cardiac evaluation with nuclear stress imaging or cardiac catheterization and had wQRS (bundle branch block, premature ventricular complex, or pQRS) were studied. f-wQRS was defined by the presence of >2 notches on the R wave or the S wave and had to be present in >or=2 contiguous inferior (II, III, aVF), lateral (I, aVL, V(6)) or anterior (V(1) to V(5)) leads. ECG analyses of 879 patients (age, 66.7+/-11.4 years; male, 97%; mean follow-up, 29+/-18 months) with bundle branch block (n=310), premature ventricular complex (n=301), and pQRS (n=268) revealed f-wQRS in 415 (47.2%) patients. Myocardial scar was present in 440 (50%) patients. The sensitivity, specificity, positive predictive value, and negative predictive value of f-wQRS for myocardial scar were 86.8%, 92.5%, 92.0%, and 87.5%, respectively. The sensitivity and specificity for diagnosing myocardial scar were 88.6% and 94.4%, 81.4% and 88.4%, and 89.8% and 95.7% for f-bundle branch block, f-premature ventricular complex, and f-pQRS, respectively. f-wQRS was associated with mortality after adjusting for age, ejection fraction, and diabetes (P=0.017). CONCLUSIONS: f-wQRS on a standard 12-lead ECG is a moderately sensitive and highly specific sign for myocardial scar in patients with known or suspected coronary artery disease. f-wQRS is also an independent predictor of mortality.