Salvage external beam radiotherapy of retinal capillary hemangiomas secondary to von Hippel-Lindau disease: visual and anatomic outcomes

OBJECTIVE: To examine the visual and anatomic outcomes of patients with retinal capillary hemangiomas secondary to von Hippel-Lindau (VHL) disease treated with globe-salvaging fractionated external beam radiotherapy (EBRT) after progression of hemangiomas despite initial therapy. DESIGN: Retrospective noncomparative consecutive case series. PARTICIPANTS: Review of medical records of 5 patients with retinal capillary hemangiomas secondary to VHL disease. INTERVENTION: External beam radiotherapy delivered to a total dose of 2160 cGy given over 12 daily fractions. MAIN OUTCOME MEASURES: Data on visual acuity and tumor size were collected at baseline, 1, 3, 6, and 12 months after EBRT, and at final follow-up, using echography, fundus photographs, and clinical examination. RESULTS: Six eyes of 5 patients were treated. Mean follow-up was 28.3 months (range, 6-51). Mean baseline visual acuity was 20/70. Mean visual acuity at last follow-up was 20/45 (range, 20/25-20/60). Tumor volume reduction was 27.5 mm(3) (range, 0.9-109.6 mm(3)). Mean percentage reduction in tumor volume was 39.6% (range, 3.3%-71.1%). CONCLUSIONS: External beam radiotherapy is a useful option in the treatment of retinal hemangiomas secondary to VHL disease that progress despite standard therapy. External beam radiotherapy leads to improvement in visual acuity, reduction in tumor volume, and stabilization of retinal detachment in most patients treated.     

Emergency management program operational responses to weapons of mass destruction: Veterans Health Administration, 2001-2004

BACKGROUND: Despite the recognition of chemical emergencies, terrorist events, and ongoing threats, little practical guidance exists for healthcare facilities. METHODS: An approach and materials developed by the Veterans Health Administration in a five-element program over the last 2 years to enhance the existing emergency management program is outlined. Nine steps to the development of a comprehensive all-hazards, emergency plan and program, with auditing and improvement tools are offered. RESULTS: Cognitive aids for clinical use are available on-line and in hard copy. A hazard assessment modeled patients as emission sources documenting the operations strategies under which level C personal protective equipment will protect healthcare workers. The development of this response program appears to support a broader, long-standing VHA approach to problem solving. This involves bringing together individual talented field staff, representing specific skills, geographic regions, and work styles; investing in face-to-face consensus development; and developing programs with extensive internal peer-review ("field-based," "bottom-up and top-down," and external reviews). CONCLUSIONS: Comprehensive and effective programs can be constructed at low cost with reasonable speed within large systems with a public mandate, leading to responsible use of public funds internally, and as models for private sector programs. It is the long-term operational cost implications, under budget constraints in health care, which often present the true challenge.     

Safety of anthrax vaccine: an expanded review and evaluation of adverse events reported to the Vaccine Adverse Event Reporting System (VAERS)

PURPOSE: To assess the safety of a licensed anthrax vaccine (AVA) given to more than 500,000 US military personnel, through review and medical evaluation of adverse events (AEs) reported to the Vaccine Adverse Event Reporting System (VAERS). METHODS: AEs were summarized by person, vaccine lot, type, frequency and impact. A Delphic approach was used to tentatively assess causality in an effort to detect serious AEs (SAEs) or other medically important AEs (OMIAEs) possibly attributable to AVA. RESULTS: The Anthrax Vaccine Expert Committee (AVEC) reviewed 1841 reports describing 3991 AEs (9.4 reports/10,000 doses of AVA) that were submitted to VAERS from 1Q1998 through 4Q2001. One hundred forty-seven reports described an SAE or OMIAE, of which 26 were tentatively rated as possible, probable or certain consequences of vaccination (injection-site reaction [12], 'anaphylactic-like reaction' [5] and eight other systemic AEs [1-2 each]). CONCLUSIONS: This review produced no evidence for an unusual rate of any SAE or OMIAE attributable to AVA. It supported an earlier impression that AVA may cause significant local inflammation and should be administered over the deltoid rather than the triceps to avoid direct or compression injury to the ulnar nerve. The subjects of VAERS reports tended to be older than all recipients of AVA. Females generally had and/or reported AEs more often than males, but transient articular reactions were surprisingly more common in males. Variations in the frequency or severity (as judged by hospitalization and/or loss of duty) of reported AEs did not suggest a significant problem with (1) a particular lot of AVA, (2) recurrent AEs after multiple doses or (3) vaccination of persons with a concomitant illness or those given other vaccines or medications.     

Lymph node metastases in patients with cutaneous melanoma: improvements in diagnosis by signal-enhanced color Doppler sonography

The purpose of the study was to evaluate whether signal-enhanced color Doppler sonography (CDS) is superior to native CDS in detection of characteristic vascularity patterns that are important for the differentiation between benign and malignant lymphadenopathy in patients with cutaneous melanomas. Twenty-two melanoma patients presenting with 24 structures suspicious for metastases in B-Mode sonography were examined using native and signal-enhanced CDS in a prospective two-center study. Presumptive sonographic diagnoses were compared with results of histopathological and follow-up examinations. Signal-enhanced CDS gave additional information about vascularization of lymph node metastases and reactive lymph nodes, which was indicative for the differential diagnosis in 12 of 24 examinations. For lymph node metastases, signal enhancement improved the visualization of accessory peripheral vessels in four of 10 examinations. Concerning reactive lymph nodes, hilar vessels in part with branching to the lymph node periphery could be better identified after application of the contrast enhancer in eight of 13 examinations. Signal-enhanced CDS is demonstrated as an important additional diagnostic tool for improved differentiation between malignant and reactive lymph nodes and may be of special value in preventing unnecessary lymphadenectomy in small reactive lymph nodes.     

Autologous bone marrow transplantation for marginal zone non-Hodgkin's lymphoma

The marginal zone non-Hodgkin's lymphomas are a recently defined group of related low-grade B cell malignancies whose natural history is heterogeneous. The optimal therapy is often unclear, particularly for the subset of patients with disseminated disease that behaves aggressively. We have retrospectively analyzed the outcomes of 11 patients with chemosensitive but disseminated marginal zone lymphomas who underwent uniform conditioning with cyclophosphamide and total body irradiation followed by bone marrow transplantation (BMT) with anti-B cell monoclonal antibody-purged autologous bone marrow between January 1994 and September 1999. All patients had stage IV disease and received multiple chemotherapy regimens prior to autologous BMT. Only 36% were in complete remission at the time of bone marrow harvest, and 36% had overt bone marrow infiltration at that time. Two treatment-related deaths occurred between 100 days and 6 months. Three patients relapsed and died of disease. One patient developed and died of myelodysplasia. Five patients remain in continuous complete remission at a median follow-up of 52 months (45%). The median progression-free survival for these patients was 56 months, with median overall survival 58 months. The only significant predictor of disease-free and overall survival was age at the time of transplant; no patient under 45 at the time of transplant has relapsed or died of any cause (P = 0.003). Outcomes of autologous BMT in patients with disseminated marginal zone NHL are similar to those in follicular NHL, and suggest that certain patients may experience prolonged disease-free survival.     

Promoter Hypermethylation Frequency and BRAF Mutations Distinguish Hereditary Non-Polyposis Colon Cancer from Sporadic MSI-H Colon Cancer

BACKGROUND: Colorectal cancers resulting from defective DNA mismatch repair can occur in both hereditary non-polyposis colon cancer (HNPCC) and in the sporadic setting. They are characterised by a high level of microsatellite instability (MSI-H) and superficially resemble each other in that they are frequently located in the proximal colon and share features such as circumscribed tumour margins and tumour-infiltrating lymphocytes. However, significant differences can be demonstrated at the molecular level including widespread promoter hypermethylation and BRAF -activating mutations which occur significantly less often in HNPCC. AIMS: In this study, we sought to determine whether the presence of widespread promoter hypermethylation and BRAF mutations would exclude HNPCC. MATERIALS AND METHODS: We investigated the methylation status of four methylated in tumour markers (MINTs 1,2,12 and 31), and the promoter regions of 5 genes hMLH1, HPP1, MGMT, p16INK4A and p14ARF, in 21 sporadic MSI-H colorectal cancers and compared these with 18 cancers from HNPCC patients. The methylation status of CpG islands were determined by either methylation specific PCR (MSP) or combined bisulfite restricton analysis (COBRA). In addition we considered the BRAF mutation status of 18 HNPCC tumours and 19 sporadic MSI-H cancers which had been previously determined by RFLP analysis and confirmatory sequencing. RESULTS: Methylation of the promoter regions in target genes occurred less frequently within the HNPCC tumours (27% of analyses), compared with the sporadic MSI-H tumours (59% of analyses) (P < 0.001). Methylation of MINTs 1, 2, 12 and 31 occurred in 4% of analyses for HNPCC tumours contrasted with 73% for sporadic MSI-H tumours (P < 0.001). BRAF mutations were detected in 74% of sporadic tumours but none of the HNPCC cancers tested. CONCLUSIONS: The total number of genes and MINTs methylated in HNPCC was lower than in MSI-H colorectal tumours. No HNPCC tumour showed evidence of widespread promoter hypermethylation or BRAF mutation suggesting this feature could be used as a discriminator between familial and sporadic cases.     

APC promoter hypermethylation contributes to the loss of APC expression in colorectal cancers with allelic loss on 5q

INTRODUCTION: Germ-line mutations of the APC gene are associated with familial adenomatous polyposis, and somatic mutations occur frequently in sporadic colorectal cancer. However, to abrogate APC function, both alleles must be inactivated. Recently, it has been demonstrated that epigenetic modification of the APC promoter influences APC silencing. Here we examined the influence of APC methylation on APC expression in tumors with and without LOH at the APC locus. MATERIAL AND METHODS: 137 sporadic colorectal cancer specimens were investigated for LOH at the 5q locus. The methylation status of the APC promoter was determined by methylation-specific PCR. APC expression was performed by immunohistochemistry. RESULTS: Expression was reduced or lost in 110 of 137 (80%) tumors and LOH at 5q was found in 13 of 132 (10%) tumors. There was no difference in 5q LOH between tumors with or without intact APC expression. Vice versa, there was no difference in the APC expression in tumors with 5q LOH. Aberrant APC promoter methylation was detected in 33 of 118 (28%) tumors investigated. Of the tumors with 5q LOH for which methylation data were available, 4 of 11 (36%) were methylated versus 28 of 105 (27%) of those without LOH. No difference in methylation was observed in tumors without 5q LOH and normal APC expression and those without 5q LOH and reduced or missing APC expression. Importantly, none of the tumors with 5q LOH and normal APC staining were aberrantly methylated, whereas 50% of the cancers with LOH at 5q and reduced or absent staining were hypermethylated. CONCLUSIONS: This report suggests that tumors with 5q LOH and reduced APC expression are more frequently hypermethylated at the APC promoter compared to those tumors with 5q LOH and normal APC expression. The association among APC promoter methylation status, 5q LOH, and reduced or lost APC expression suggests that de novo methylation plays an important role as a "second hit" in silencing APC expression in colorectal neoplasia.