Long-Term Survival After Alcohol Septal Ablation for Hypertrophic Obstructive Cardiomyopathy: A 16-Year Experience.

BACKGROUND: Alcohol septal ablation (ASA) is an accepted treatment for medically refractory hypertrophic obstructive cardiomyopathy (HOCM). The procedural and medium-term outcomes have been reassuring. The iatrogenic targeted septal infarction has raised theoretical concerns about risk of arrhythmia and long-term survival. In this study, we describe the long-term survival in a large cohort of patients from a single referral center and the iterative improvement in procedural technique since its inception. METHODS: This cohort includes 580 consecutive patients who underwent 664 ASA procedures between the years 1999 and 2015. Procedural details and outcomes are described. Long-term survival is compared with expected survival of demographically similar controls. RESULTS: Fifty-four percent were women and 85% were Caucasian. At the time of ablation, mean age was 57 ± 15 years, septal thickness was 2.1 ± 0.5 cm, and left ventricular outflow tract (LVOT) gradient was 72 ± 40 mm Hg at rest and 102 ± 58 mm Hg with Valsalva provocation. Mean follow-up was 8.0 ± 4.3 years. LVOT gradient reduction >50% was achieved in 94% of patients with reduction in New York Heart Association functional class scores and increase in exercise treadmill duration. Procedural mortality was 0.9%. Over the 16-year period, survival estimates at 1, 5, 10, and 15 years were 98%, 92%, 84%, and 81%, respectively, which are comparable to demographically similar controls. The standardized mortality ratio was 0.84 (95% confidence interval, 0.66-1.06); P=.09. CONCLUSIONS: ASA appears to be a safe and effective treatment for symptomatic HOCM refractory to medical therapy with long-term survival comparable to a demographically similar United States population.

Thrombin contributes to cancer immune evasion via proteolysis of platelet-bound GARP to activate LTGF-ß.

Cancer-associated thrombocytosis and high concentrations of circulating transforming growth factor-ß1 (TGF-ß1) are frequently observed in patients with progressive cancers. Using genetic and pharmacological approaches, we show a direct link between thrombin catalytic activity and release of mature TGF-ß1 from platelets. We found that thrombin cleaves glycoprotein A repetitions predominant (GARP), a cell surface docking receptor for latent TGF-ß1 (LTGF-ß1) on platelets, resulting in liberation of active TGF-ß1 from the GARP-LTGF-ß1 complex. Furthermore, systemic inhibition of thrombin obliterates TGF-ß1 maturation in platelet releasate and rewires the tumor microenvironment toward favorable antitumor immunity, which translates into efficient cancer control either alone or in combination with programmed cell death 1-based immune checkpoint blockade therapy. Last, we demonstrate that soluble GARP and GARP-LTGF-ß1 complex are present in the circulation of patients with cancer. Together, our data reveal a mechanism of cancer immune evasion that involves thrombin-mediated GARP cleavage and the subsequent TGF-ß1 release from platelets. We propose that blockade of GARP cleavage is a valuable therapeutic strategy to overcome cancer's resistance to immunotherapy.

Clinical, demographic, and laboratory characteristics of children with nephrolithiasis.

While the incidence of pediatric kidney stones appears to be increasing, little is known about the demographic, clinical, laboratory, imaging, and management variables in this patient population. We sought to describe various characteristics of our stone-forming pediatric population. To that end, we retrospectively reviewed the charts of pediatric patients with nephrolithiasis confirmed by imaging. Data were collected on multiple variables from each patient and analyzed for trends. For body mass index (BMI) controls, data from the general pediatrics population similar to our nephrolithiasis population were used. Data on 155 pediatric nephrolithiasis patients were analyzed. Of the 54 calculi available for analysis, 98 % were calcium based. Low urine volume, elevated supersaturation of calcium phosphate, elevated supersaturation of calcium oxalate, and hypercalciuria were the most commonly identified abnormalities on analysis of 24-h urine collections. Our stone-forming population did not have a higher BMI than our general pediatrics population, making it unlikely that obesity is a risk factor for nephrolithiasis in children. More girls presented with their first stone during adolescence, suggesting a role for reproductive hormones contributing to stone risk, while boys tended to present more commonly at a younger age, though this did not reach statistical significance. These intriguing findings warrant further investigation.

Evaluation for intra-abdominal injury in children after blunt torso trauma: can we reduce unnecessary abdominal computed tomography by utilizing a clinical prediction model?

BACKGROUND: Blunt trauma is a leading cause of morbidity and mortality in children. Despite the potential for malignancy, increased cost, limited small bowel injury detection sensitivity, and the low incidence of injury requiring operative intervention, the use of computed tomographic (CT) scan in pediatric blunt trauma evaluation remains common. Previous studies suggest that a clinical model using examination and laboratory data may help predict intra-abdominal injuries (IAIs) and potentially limit unnecessary CT scans in children. METHODS: A retrospective chart review of all blunt "trauma alerts" for patients younger than 16 years during an 18-month period was performed at a Level I trauma center. Clinical factors, which might predict blunt IAI (hemodynamics, abdominal examination, serology, and plain radiographs), and potential limitations to performing a reliable abdominal examination (altered mental status, young age) were reviewed. A previously defined clinical prediction model based on six high-risk clinical variables for blunt IAI (hypotension, abnormal abdominal examination, elevated aspartate aminotransferase, elevated amylase, low hematocrit, and heme-positive urinalysis) was applied to each patient. RESULTS: Of the 125 "trauma alert" patients who sustained blunt trauma during the study period, 97 underwent abdominal CT scan, with only 15 identified as IAI. Our prediction rule would have identified 16 of 17 patients with IAI (SE, 94%) as high-risk and missed only 1 patient (grade I spleen laceration, which did not require operation) (negative predictive value, 99%). Of the 83 patients with no risk factors for IAI based on the prediction rule, 54 underwent a negative abdominal CT scan. Of these 54 patients, only 22 had a potential limitation to a reliable abdominal examination. Application of our prediction rule could have prevented unnecessary CT scan in at least 32 patients (33%) during an 18-month period. CONCLUSION: Use of a prediction model based on high-risk variables for IAI may decrease cost and radiation exposure by reducing the number of abdominal CT scans in children being evaluated for blunt abdominal trauma.

Low-dose weekly platinum-based chemoradiation for advanced head and neck cancer.

OBJECTIVES/HYPOTHESIS: The optimal concurrent chemoradiotherapy regimen for definitive treatment of locoregionally advanced head and neck cancer remains to be determined. The present investigation reports toxicities, disease control, patterns of failure, and survival outcomes in a large mature cohort of patients treated with low-dose weekly platinum-based concurrent chemoradiotherapy. STUDY DESIGN: Retrospective single-institution series. METHODS: Toxicity and outcome data for locoregionally advanced head and neck cancer patients treated with low-dose weekly platinum-based chemotherapy concurrent with standard fractionation radiotherapy were retrospectively collected and analyzed from a clinical database. Survival analysis methods, including Kaplan-Meier estimation and competing risks analysis, were used to assess locoregional disease control, freedom from failure, and overall survival. RESULTS: Ninety-six patients were eligible for the present analysis. Nearly all patients had American Joint Committee on Cancer clinical stage III to IVB disease (99%). Severe acute toxicities included grade 3 mucositis (61%), grade 3/4 nausea (27%/1%), and grade 3 neutropenia (8%). Thirty-seven patients (38%) required hospitalization for a median of 7 days (range, 1-121). Ninety-two percent of patients completed the fully prescribed course of radiotherapy, and 87% completed >or=6 cycles of chemotherapy. At a median survivor follow-up of 40 months (range, 8-68), 47% of patients were without evidence of disease recurrence. The estimated 4-year freedom from failure and overall survival were 48% and 58%, respectively. Initial site(s) of disease failure were locoregional for 22 patients, locoregional and distant (five patients), and distant only (14 patients). CONCLUSIONS: Weekly low-dose platinum-based chemotherapy with full-dose daily radiotherapy is a tolerable alternative regimen for locoregionally advanced head and neck cancers, with comparable efficacy and patterns of failure to alternative regimens.