BCNU wafer placement with temozolomide (TMZ) in the immediate postoperative period after tumor resection followed by radiation therapy with TMZ in patients with newly diagnosed high grade glioma: final results of a prospective, multi-institutional, phase II trial.

Temozolomide (TMZ) and BCNU have demonstrated anti-glioma synergism in preclinical models. We report final data from a prospective, multi-institutional study of BCNU wafers and early TMZ followed by radiation therapy with TMZ in patients with newly diagnosed malignant glioma. 65 patients were consented in 4 institutions, and 46 patients (43 GBM, 3 AA) were eligible for analysis. After resection and BCNU wafer placement, TMZ began on day four postoperatively. Radiation and TMZ (RT/TMZ) were then administered, followed by monthly TMZ at 200 mg/m2 for the first 26 patients, which was reduced to 150 mg/m2 for the remaining 20 patients. Non-hematologic toxicities were minimal. Nine of 27 patients (33 %) who received 200 mg/m2 TMZ, but only 1 of 20 (5 %) who received 150 mg/m2, experienced grade 3/4 thrombocytopenia. Median progression free survival (PFS) and overall survival (OS) period was 8.5 and 18 months, respectively. The 1-year OS rate was 76 %, which is a significant improvement compared with the historical control 1-year OS rate of 59 % (p = 0.023). However, there was no difference in 1-year OS compared with standard RT/TMZ (p = 0.12) or BCNU wafer followed by RT/TMZ (p = 0.87) in post hoc analyses. Early post-operative TMZ can be safely administered with BCNU wafers following resection of malignant glioma at the 150 mg/m2 dose level. Although there was an OS benefit compared to historical control, there was no indication of benefit for BCNU wafers and early TMZ in addition to standard RT/TMZ or early TMZ in addition to regimens of BCNU wafers followed by RT/TMZ.

Incidence and predictors of late complete heart block after alcohol septal ablation treatment of hypertrophic obstructive cardiomyopathy.

OBJECTIVES: This study was designed to identify the incidence of late complete heart block (CHB) first identified at least 48 hours post alcohol septal ablation (ASA). BACKGROUND: Septal reduction with ASA is a therapeutic option for patients with symptomatic hypertrophic obstructive cardiomyopathy (HCM). CHB, resulting from the septal infarct, is a known complication with a reported incidence of 9-22%. The incidence of CHB more than 48 hours post-procedure is unknown. METHODS: Consecutive patients who underwent ASA were analyzed and clinical characteristics associated with late CHB were assessed. Late CHB was defined as first identification of CHB more than 48 hours after ASA. RESULTS: From 2002-2013, 145 subjects underwent 168 ASA procedures and were followed for a mean of 3.2 +/- 2.3 years. The incidence of late CHB was 8.9% (15/168 ASA procedures). Heart block occurred from 48 hours to 3-years post-procedure. In a multivariable model, patients with any CHB were more likely to have had multiple ASA procedures (OR 4.14; 95% CI: 1.24, 13.9; P < 0.05) and high resting and provoked left ventricular outflow tract (LVOT) gradient assessed by catheterization (OR per 10 mmHg gradient 1.14; 95% CI: 1.0, 1.20; P < 0.05). After multivariable adjustment, only a high provokable LVOT gradient remained an independent predictor of late CHB (OR per 10 mmHg gradient 1.14 [95% CI 1.02-1.29]). CONCLUSIONS: Late CHB is a common complication of ASA for treatment of symptomatic HCM. Post-discharge electrocardiographic surveillance for atrioventricular conduction disease should be considered after ASA, especially for those with a high provokable LVOT gradient.

Kinesin velocity increases with the number of motors pulling against viscoelastic drag.

Although the properties of single kinesin molecular motors are well understood, it is not clear whether multiple motors pulling a single vesicle in a cell cooperate or interfere with one another. To learn how small numbers of motors interact, microtubule gliding assays were carried out with full-length Drosophila kinesin in a novel motility medium containing xanthan, a stiff, water-soluble polysaccharide. At 2 mg/ml xanthan, the zero-shear viscosity of this medium is 1,000 times the viscosity of water, similar to cellular viscosity. To mimic the rheological drag force on the motors when attached to a vesicle in a cell, we attached a 2 microm bead to one end of the microtubule (MT). During gliding assays in our novel medium, the moving bead exerted a drag force of 4-15 pN on the kinesins pulling the MT. The velocity of MTs with an attached bead increased with MT length and with kinesin concentration. The increase with MT length arose because the number of motors is directly proportional to MT length. Our results show that small numbers of kinesins cooperate constructively when pulling against a viscoelastic drag. In the absence of a bead but still in the viscous medium, MT velocity was independent of MT length and kinesin concentration because the thin MT, like a snake moving through grass, was able to move between xanthan molecules with little resistance. A minimal shared-load model in which the number of motors is proportional to MT length fits the observed dependence of gliding velocity on MT length and kinesin concentration.