Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic disorder with increased mortality and morbidity resulting from intravascular hemolysis. Eculizumab, a monoclonal antibody against the complement protein 5, stops the intravascular hemolysis in PNH. We evaluated 79 consecutive patients treated with eculizumab in Leeds between May 2002 and July 2010. The survival of patients treated with eculizumab was not different from age- and sex-matched normal controls (P = .46) but was significantly better than 30 similar patients managed before eculizumab (P = .030). Three patients on eculizumab, all over 50 years old, died of causes unrelated to PNH. Twenty-one patients (27%) had a thrombosis before starting eculizumab (5.6 events per 100 patient-years) compared with 2 thromboses on eculizumab (0.8 events per 100 patient-years; P < .001). Twenty-one patients with no previous thrombosis discontinued warfarin on eculizumab with no thrombotic sequelae. Forty of 61 (66%) patients on eculizumab for more than 12 months achieved transfusion independence. The 12-month mean transfusion requirement reduced from 19.3 units before eculizumab to 5.0 units in the most recent 12 months on eculizumab (P < .001). Eculizumab dramatically alters the natural course of PNH, reducing symptoms and disease complications as well as improving survival to a similar level to that of the general population.

Key Points• Acquired pathogenic mutations in SAMHD1 are found in up to 11% of relapsed/refractory patients with CLL. • SAMHD1 is mobilized to sites of DNA damage.SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase and a nuclease that restricts HIV-1 in noncycling cells. Germ-line mutations in SAMHD1 have been described in patients with Aicardi-Goutières syndrome (AGS), a congenital autoimmune disease. In a previous longitudinal whole genome sequencing study of chronic lymphocytic leukemia (CLL), we revealed a SAMHD1 mutation as a potential founding event. Here, we describe an AGS patient carrying a pathogenic germ-line SAMHD1 mutation who developed CLL at 24 years of age. Using clinical trial samples, we show that acquired SAMHD1 mutations are associated with high variant allele frequency and reduced SAMHD1 expression and occur in 11% of relapsed/refractory CLL patients. We provide evidence that SAMHD1 regulates cell proliferation and survival and engages in specific protein interactions in response to DNA damage. We propose that SAMHD1 may have a function in DNA repair and that the presence of SAMHD1 mutations in CLL promotes leukemia development. (Blood. 2014;123(7):1021-1031)

Genetic and epigenetic changes in the von Hippel-Lindau (VHL) tumor suppressor gene are common in sporadic conventional renal cell carcinoma (cRCC). Further insight into the clinical significance of these changes may lead to increased biological understanding and identification of subgroups of patients differing prognostically or who may benefit from specific targeted treatments. We have comprehensively examined the VHL status in tissue samples from 115 patients undergoing nephrectomy, including 96 with sporadic cRCC. In patients with cRCC, loss of heterozygosity was found in 78.4%, mutation in 71%, and promoter methylation in 20.4% of samples. Multiplex ligation-dependent probe amplification identified intragenic copy number changes in several samples including two which were otherwise thought to be VHLnoninvolved. Overall, evidence of biallelic inactivation was found in 74.2% of patients with cRCC. Many of the mutations were novel and approximately two-thirds were potentially truncating. Examination of these and other published findings confirmed mutation hotspots affecting codons 117 and 164, and revealed a common region of mutation in codons 60 to 78. Gender-specific differences in methylation and mutation were seen, although not quite achieving statistical significance (P = 0.068 and 0.11), and a possible association between methylation and polymorphism was identified. No significant differences were seen between VHL subgroups with regard to clinicopathologic features including stage, grade, tumor size, cancer-free and overall survival, with the exception of a significant association between loss of heterozygosity and grade, although a possible trend for survival differences based on mutation location was apparent.

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Purpose: This study aimed to carry out a comprehensive analysis of genetic and epigenetic changes of the von Hippel Lindau (VHL) gene in patients with conventional (clear cell) renal cell carcinoma and to determine their significance relative to clinicopathologic characteristics and outcome. Experimental Design: The VHL status in 86 conventional renal cell carcinomas was determined by mutation detection, loss of heterozygosity (LOH), and promoter methylation analysis, extending our original cohort to a total of 177 patients. Data were analyzed to investigate potential relationships between VHL changes, clinical parameters, and outcome. Results: LOH was found in 89.2%, mutation in 74.6%, and methylation in 31.3% of evaluable tumors; evidence of biallelic inactivation (LOH and mutation or methylation alone) was found in 86.0% whereas no involvement of VHL was found in only 3.4% of samples. Several associations were suggested, including those between LOH and grade, nodal status and necrosis, mutation and sex, and methylation and grade. Biallelic inactivation may be associated with better overall survival compared with patients with no VHL involvement, although small sample numbers in the latter group severely limit this analysis, which requires independent confirmation. Conclusions: This study reports one of the highest proportions of conventional renal cell carcinoma with VHL changes, and suggests possible relationships between VHL status and clinical variables. The data suggest that VHL defects may define conventional renal cell carcinomas but the clinical significance of specific VHL alterations will only be clarified by the determination of their biological effect at the protein level rather than through genetic or epigenetic analysis alone. ( The incidence of renal cancer is increasing and currently accounts for ∼2% to 3% of cancers worldwide, with around 210,000 new cases diagnosed annually (GLOBOCAN 2002). 6 Patients often present late with advanced or unresectable disease, and up to 30% of patients relapse after potentially curative surgery. Metastatic renal cancer is associated with a 5-year survival rate of ∼10% (1, 2). Traditional treatments, such as interferon and interleukin, only have response rates of 15% to 20% but more recently, therapies such as the tyrosine kinase inhibitors sunitinib and sorafenib (3) have shown response rates and survival benefits.The von Hippel Lindau (VHL) tumor suppressor gene on chromosome 3p plays a central role in the development of the conventional (clear cell) histologic subtype of renal cell carcinoma. Identified in patients with familial VHL disease, an autosomal dominant cancer syndrome associated with the development of a number of tumors including conventional renal cell carcinoma (4), VHL has also been shown to be important in sporadic conventional renal cell carcinomas, with a large number of studies reporting potential loss of VHL function as a result of allele loss, mutation, and promoter methylation (5-47). In one of the most comprehensive studie...