Idiopathic systemic capillary leak syndrome (Clarkson's disease): the Mayo clinic experience.

OBJECTIVE: To determine clinical features, natural history, and outcome of a well-defined cohort of 25 consecutive patients with idiopathic systemic capillary leak syndrome (SCLS) evaluated at a tertiary care center. PATIENTS AND METHODS: Records of patients diagnosed as having SCLS from November 1, 1981, through April 30, 2008, were reviewed. Descriptive statistics were used to analyze patient demographics, clinical features, complications, and therapeutic interventions. RESULTS: Of the 34 patients whose records were reviewed, 25 fulfilled all diagnostic criteria for SCLS. The median age at diagnosis of SCLS was 44 years. Median follow-up of surviving patients was 4.9 years, and median time to diagnosis from symptom onset was 1.1 years (interquartile range, 0.5-4.1 years). Flulike illness or myalgia was reported by 14 patients (56%) at onset of an acute attack of SCLS, and rhabdomyolysis developed in 9 patients (36%). Patients with a greater decrease in albumin level had a higher likelihood of developing rhabdomyolysis (p=.03). Monoclonal gammopathy, predominantly of the IgG-κ type, was found in 19 patients (76%). The progression rate to multiple myeloma was 0.7% per person-year of follow-up. The overall response rate to the different therapies was 76%, and 24% of patients sustained durable (>2 years) complete remission. The estimated 5-year overall survival rate was 76% (95% confidence interval, 59%-97%). CONCLUSION: Systemic capillary leak syndrome, a rare disease that occurs in those of middle age, is usually diagnosed after a considerable delay from onset of symptoms. The degree of albumin decrement during an attack correlates with development of rhabdomyolysis. A reduction in the frequency and/or the severity of attacks was seen in nearly three-fourths of patients who were offered empirical therapies. The rate of progression to multiple myeloma appears to be comparable to that of monoclonal gammopathy of undetermined significance.

Tumor suppressor p16 methylation in multiple myeloma: biological and clinical implications.

The biological and clinical implications of p16 gene methylation in multiple myeloma (MM) are still unclear despite previous studies. In this comprehensive study, using methylation-specific PCR (MS-PCR), we show that p16 methylation is relatively common and occurs in monoclonal gammopathy of undetermined significance (MGUS; n=17), smoldering multiple myeloma (SMM; n=40), and MM (n=522) at a prevalence of 24%, 28%, and 34%, respectively. However, p16 methylation does not appear to affect gene expression level. In a large cohort of patients with long-term follow-up information (n=439), there was no difference in overall survival between patients with or without p16 methylation. We also found no association between p16 methylation and the main cytogenetic categories, although it was more common among patients with 17p13.1 deletions (p53 locus), a genetic progression event in MM. In addition, p16 methylation has no apparent effect on the cycle because there was also no difference in the plasma cell labeling index (a direct measurement of proliferation) between patients with and without p16 methylation. Our results question a major role for p16 methylation in the oncogenesis of the PC neoplasm, and we now believe p16 methylation may be a marker for overall epigenetic changes associated with disease progression, with no obvious direct biological or clinical consequences.

Ectopic expression of VAV1 reveals an unexpected role in pancreatic cancer tumorigenesis.

Herein, we show that the hematopoietic-specific GEF VAV1 is ectopically expressed in primary pancreatic adenocarcinomas due to demethylation of the gene promoter. Interestingly, VAV1-positive tumors had a worse survival rate compared to VAV1-negative tumors. Surprisingly, even in the presence of oncogenic KRAS, VAV1 RNAi abrogates neoplastic cellular proliferation in vitro and in vivo, thus identifying Vav1 as a growth-stimulatory protein in this disease. Vav1 acts synergistically with the EGF receptor to stimulate pancreatic tumor cell proliferation. Mechanistically, the effects of Vav1 require its GEF activity and the activation of Rac1, PAK1, and NF-kappaB and involve cyclin D1 upregulation. Thus, the discovery of prooncogenic pathways regulated by Vav1 makes it an attractive target for therapeutic intervention.

The recurrent IgH translocations are highly associated with nonhyperdiploid variant multiple myeloma.

Aneuploid is ubiquitous in multiple myeloma (MM), and 4 cytogenetic subcategories are recognized: hypodiploid (associated with a shorter survival), pseudodiploid, hyperdiploid, and near-tetraploid MM. The hypodiploid, pseudodiploid, and near-tetraploid karyotypes can be referred to as the nonhyperdiploid MM. Immunoglobulin heavy-chain (IgH) translocations are seen in 60% of patients. We studied the relation between aneuploidy and IgH translocations in MM. Eighty patients with MM and abnormal metaphases were studied by means of interphase fluorescent in situ hybridization (FISH) to detect IgH translocations. We also studied a second cohort of 199 patients (Eastern Cooperative Oncology Group [ECOG]) for IgH translocations, chromosome 13 monosomy/deletions (Delta13), and ploidy by DNA content. Mayo Clinic patients with abnormal karyotypes and FISH-detected IgH translocation were more likely to be nonhyperdiploid (89% versus 39%, P <.0001). Remarkably, 88% of tested patients with hypodiploidy (16 of 18) and 90% of tested patients with tetraploidy (9 of 10) had an IgH translocation. ECOG patients with IgH translocations were more likely to have nonhyperdiploid MM by DNA content (68% versus 21%, P <.001). This association was seen predominantly in patients with recurrent chromosome partners to the IgH translocation (11q13, 4p16, and 16q23). The classification of MM into hyperdiploidy and nonhyperdiploidy is dictated largely by the recurrent (primary) IgH translocations in the latter.