Clinical experience with alpha-particle emitting 211At: treatment of recurrent brain tumor patients with 211At-labeled chimeric antitenascin monoclonal antibody 81C6.

alpha-Particle-emitting radionuclides, such as (211)At, with a 7.2-h half-life, may be optimally suited for the molecularly targeted radiotherapy of strategically sensitive tumor sites, such as those in the central nervous system. Because of the much shorter range and more potent cytotoxicity of alpha-particles than of beta-particles, (211)At-labeled agents may be ideal for the eradication of tumor cells remaining after surgical debulking of malignant brain tumors. The main goal of this study was to investigate the feasibility and safety of this approach in patients with recurrent malignant brain tumors. METHODS: Chimeric antitenascin monoclonal antibody 81C6 (ch81C6) (10 mg) was labeled with 71-347 MBq of (211)At by use of N-succinimidyl 3-[(211)At]astatobenzoate. Eighteen patients were treated with (211)At-labeled ch81C6 ((211)At-ch81C6) administered into a surgically created resection cavity (SCRC) and then with salvage chemotherapy. Serial gamma-camera imaging and blood sampling over 24 h were performed. RESULTS: A total of 96.7% +/- 3.6% (mean +/- SD) of (211)At decays occurred in the SCRC, and the mean blood-pool percentage injected dose was < or = 0.3. No patient experienced dose-limiting toxicity, and the maximum tolerated dose was not identified. Six patients experienced grade 2 neurotoxicity within 6 wk of (211)At-ch81C6 administration; this neurotoxicity resolved fully in all but 1 patient. No toxicities of grade 3 or higher were attributable to the treatment. No patient required repeat surgery for radionecrosis. The median survival times for all patients, those with glioblastoma multiforme, and those with anaplastic astrocytoma or oligodendroglioma were 54, 52, and 116 wk, respectively. CONCLUSION: This study provides proof of concept for regional targeted radiotherapy with (211)At-labeled molecules in oncology. Specifically, the regional administration of (211)At-ch81C6 is feasible, safe, and associated with a promising antitumor benefit in patients with malignant central nervous system tumors.     

Enhanced chondrogenesis and Wnt signaling in PTH-treated fractures.

Studies have shown that systemic PTH treatment enhanced the rate of bone repair in rodent models. However, the mechanisms through which PTH affects bone repair have not been elucidated. In these studies we show that PTH primarily enhanced the earliest stages of endochondral bone repair by increasing chondrocyte recruitment and rate of differentiation. In coordination with these cellular events, we observed an increased level of canonical Wnt-signaling in PTH-treated bones at multiple time-points across the time-course of fracture repair, supporting the conclusion that PTH responses are at least in part mediated through Wnt signaling. INTRODUCTION: Since FDA approval of PTH [PTH(1-34); Forteo] as a treatment for osteoporosis, there has been interest in its use in other musculoskeletal conditions. Fracture repair is one area in which PTH may have a significant clinical impact. Multiple animal studies have shown that systemic PTH treatment of healing fractures increased both callus volume and return of mechanical competence in models of fracture healing. Whereas the potential for PTH has been established, the mechanism(s) by which PTH produces these effects remain elusive. MATERIALS AND METHODS: Closed femoral fractures were generated in 8-wk-old male C57Bl/6 mice followed by daily systemic injections of either saline (control) or 30 microg/kg PTH(1-34) for 14 days after fracture. Bones were harvested at days 2, 3, 5, 7, 10, 14, 21, and 28 after fracture and analyzed at the tissue level by radiography and histomorphometry and at the molecular and biochemical levels level by RNase protection assay (RPA), real-time PCR, and Western blot analysis. RESULTS: Quantitative muCT analysis showed that PTH treatment induced a larger callus cross-sectional area, length, and total volume compared with controls. Molecular analysis of the expression of extracellular matrix genes associated with chondrogenesis and osteogenesis showed that PTH treated fractures displayed a 3-fold greater increase in chondrogenesis relative to osteogenesis over the course of the repair process. In addition, chondrocyte hypertrophy occurred earlier in the PTH-treated callus tissues. Analysis of the expression of potential mediators of PTH actions showed that PTH treatment significantly induced the expression of Wnts 4, 5a, 5b, and 10b and increased levels of unphosphorylated, nuclear localized beta-catenin protein, a central feature of canonical Wnt signaling. CONCLUSIONS: These results showed that the PTH-mediated enhancement of fracture repair is primarily associated with an amplification of chondrocyte recruitment and maturation in the early fracture callus. Associated with these cellular effects, we observed an increase in canonical Wnt signaling supporting the conclusion that PTH effects on bone repair are mediated at least in part through the activation of Wnt-signaling pathways.     

Pretransplant survival is shorter in HIV-positive than HIV-negative subjects with end-stage liver disease.

Despite improved survival after liver transplantation (OLTX) in HIV-positive individuals treated with highly active antiretroviral therapy (HAART), some transplant candidates do not survive to OLTX. To determine if pretransplant outcome is related to severity of liver disease and/or HIV infection, we prospectively evaluated 58 consecutive HIV-positive candidates seen at a single center from 1997-2002. Of the 58, 15 (25.9%) were transplanted, whereas 21 (36.2%) died before OLTX, a median one month of evaluation, with more than half of those (12 of 21, 57.1%) dying from infection. By contrast, of 1,359 HIV-negative candidates, 860 (63.3%) were transplanted, whereas 211 (15.5%) died before OLTX (P < 0.001). The cumulative survival following initial evaluation was significantly shorter among HIV-positive than HIV-negative candidates (880 vs. 1,427 days, P = 0.035, Breslow) but was not related to the initial pretransplant MELD score (16 vs. 15), INR (1.5 vs. 1.5), creatinine (1.3 vs. 1.3 mg/dL), or total bilirubin (6.6 vs. 5.7 mg/dL), respectively, all P > 0.05. Among untransplanted HIV-positive candidates, the 21 who died did not differ from the 22 surviving in initial MELD (15 vs. 13), CD4 (230 vs. 327/microL), HIV load (both < 400 copies/mL), HAART intolerance (10/21, 47.6% vs. 10/22, 45.4%), or HCV infection (16/21, 76.2% vs. 16/22, 72.3%), all P > 0.05. Further, the 21 did not differ from the 15 transplanted in pre-OLTX CD4, HIV load, or MELD score, all P > 0.05. In conclusion, pretransplant survival appears shorter in HIV-positive OLTX candidates and is unrelated to severity of liver or HIV disease. Further study is warranted to determine risk factors for poorer pretransplant outcomes.     

Retrospective review of the preoperative biliary and gastrointestinal evaluation for gastric bypass surgery

BACKGROUND: The purpose of this study was to analyze the frequency and results of preoperative biliary and gastrointestinal (GI) evaluation of patients undergoing Roux-en-Y gastric bypass (RYGB). METHODS: Retrospective review of the preoperative evaluation of 144 consecutive RYGB patients. RESULTS: Cholecystectomy had already been performed in 43 (30%) patients; 22% of those patients with an intact gallbladder had cholelithiasis. Ten patients (7%) had an upper GI x-ray (UGI), and 94 patients (65%) had an esophagogastroduodenoscopy (EGD). Abnormalities were found in 40% of the UGIs and 84% of the EGDs. A total of 96 patients (67%) were tested for Helicobacter pylori; 11% were positive. Twenty-one patients (15%) underwent preoperative colonoscopy; 48% were abnormal, but most of the abnormalities were not clinically significant. Three patients had barium enema x-ray, which was normal in all cases. CONCLUSIONS: The preoperative biliary and GI evaluation of bariatric surgery patients should include a routine ultrasound of the gallbladder. Routine preoperative EGD will detect a significant number of abnormalities that should be treated, but should rarely alter the bariatric surgical procedure or result in denial of bariatric surgery. Many abnormalities will be asymptomatic. Patients should be routinely screened for H. pylori and, if positive, treated before bariatric surgery. Lower GI evaluation should be performed selectively based on the patient's symptoms, physical findings, and guidelines for colorectal cancer and polyp screening.     

Hemiballismus from a parietal stroke in a Parkinson patient.

Stroke-induced hemiballismus (HB) has been reported to improve motor function in people with Parkinson's disease (PD). We report on a patient who developed HB from a parietal infarct. The HB was improved by very low-dose clozapine but the HB did not improve the parkinsonism. This suggests that HB itself, whether from a lesion in the subthalamic nucleus or elsewhere, is not what improves motor function in PD; instead, the physiological function of the damaged structure is the determining factor.     

A preliminary study comparing sleep restriction and relaxation treatments for insomnia in older adults

This study compared Sleep Restriction Therapy (SRT) and Relaxation Therapy (RLT) as treatments for insomnia in a sample of community-residing elderly (mean age, 69.7 years). SRT subjects (n = 10) and RLT subjects (n = 12) reported information about their sleep twice daily to a telephone recording machine for 2 weeks of baseline, 4 weeks of treatment, and 2 weeks at 3-month follow-up. Results showed sleep latency and waking after sleep onset were significantly reduced for both treatment groups under active treatment. Predictable reductions in time in bed and improved sleep efficiency reported during active treatment by SRT subjects were still apparent at 3-month follow-up; no corresponding changes were found for RLT. In both groups, increased total sleep time was reported at follow-up; the improvement for SRT subjects was approximately twice that seen in RLT. These findings, at this early stage in the development of behavioral treatments for insomnia in older adults, encourage further study.     

Implications of the revised surveillance definition: AIDS among New York City drug users.

The Centers for Disease Control (CDC) has proposed revising the AIDS surveillance definition to include any HIV-seropositive person with a CD4 cell count of less than 200 cells per microliter. Based on a study of persons receiving treatment for HIV infection, this new definition would lead to an estimated 50% increase in the number of persons recognized as living with AIDS. Among 440 HIV-seropositive research subjects recruited from drug treatment programs and through street outreach in New York City, 59 met this definition, yet only 25% of those had been reported to the New York City AIDS registry. The new definition, if combined with HIV and T-cell testing at drug treatment and street outreach programs, could thus yield very large increases in the number of injecting drug users meeting the new surveillance definition of AIDS.     

Matching Adolescents Who Abuse Drugs to Treatment

This “matching” study attempts to determine characteristics of adolescent drug abuse patients that may determine whether an inpatient or an outpatient treatment setting will be more effective or more suitable for meeting the needs of the patient. Compared to short-term inpatient treatment, long-term outpatient treatment was shown to have significantly greater effect in reducing substance use/abuse for patients who had relatively more severe social lifestyle problems, family problems, and employment problems. Outpatient treatment even showed a trend toward a significantly better outcome for patients with more severe psychiatric problems.     

Choroidal lesions in patients with AIDS.

Seven cases of bilateral, scattered, yellow-white choroidal lesions have been seen in AIDS patients since January 1988. One resulted from presumed extension of cryptococcal meningitis into the optic nerve and choroid. All the remaining six patients had pneumocystis pneumonia at some time during the course of the disease and were receiving aerosolised pentamidine therapy. None died quickly of disseminated Pneumocystis carinii infection, unlike previously reported patients. Mycobacterial infection was also present in five of these six patients. The differential diagnosis of this entity in AIDS patients is discussed.