SETD2 and histone H3 lysine 36 methylation deficiency in advanced systemic mastocytosis.

The molecular basis of advanced systemic mastocytosis (SM) is not fully understood and despite novel therapies the prognosis remains dismal. Exome sequencing of an index-patient with mast cell leukemia (MCL) uncovered biallelic loss-of-function mutations in the SETD2 histone methyltransferase gene. Copy-neutral loss-of-heterozygosity at 3p21.3 (where SETD2 maps) was subsequently found in SM patients and prompted us to undertake an in-depth analysis of SETD2 copy number, mutation status, transcript expression and methylation levels, as well as functional studies in the HMC-1 cell line and in a validation cohort of 57 additional cases with SM, including MCL, aggressive SM and indolent SM. Reduced or no SETD2 protein expression-and consequently, H3K36 trimethylation-was found in all cases and inversely correlated with disease aggressiveness. Proteasome inhibition rescued SETD2 expression and H3K36 trimethylation and resulted in marked accumulation of ubiquitinated SETD2 in SETD2-deficient patients but not in patients with near-normal SETD2 expression. Bortezomib and, to a lesser extent, AZD1775 alone or in combination with midostaurin induced apoptosis and reduced clonogenic growth of HMC-1 cells and of neoplastic mast cells from advanced SM patients. Our findings may have implications for prognostication of SM patients and for the development of improved treatment approaches in advanced SM.

Serum total tryptase level confirms itself as a more reliable marker of mast cells burden in mast cell leukaemia (aleukaemic variant).

Mast cell leukemia (MCL) is a very rare form of systemic mastocytosis (SM) with a short median survival of 6 months. We describe a case of a 65-year-old woman with aleukaemic variant of MCL with a very high serum total tryptase level of 2255 µg/L at diagnosis, which occurred following an episode of hypotensive shock. She fulfilled the diagnostic criteria of SM, with a bone marrow smear infiltration of 50-60% of atypical mast cells (MCs). She tested negative for the KIT D816V mutation, without any sign of organ damage (no B- or C-findings) and only few mediator-related symptoms. She was treated with antihistamine alone and then with imatinib for the appearance of anemia. She maintained stable tryptase level and a very indolent clinical course for twenty-two months; then, she suddenly progressed to acute MCL with a serum tryptase level up to 12960 µg/L. The patient died due to haemorrhagic diathesis twenty-four months after diagnosis. This clinical case maybe represents an example of the chronic form of mast cell leukemia, described as unpredictable disease, in which the serum total tryptase level has confirmed itself as a reliable marker of mast cells burden regardless of the presence of other signs or symptoms.

Extraperitoneal radical cystectomy and ureterocutaneostomy in octogenarians.

OBJECTIVES: Bladder cancer is the fourth more frequent tumour in men. Radical cystectomy is considered the standard treatment for muscle invasive bladder cancer (MIBC). However, its role in elderly patients is still debate. Management of MIBC in the elderly population is considered an important issue in urological practice for the continuous ageing of the European population. Aim of our study is to evaluate the feasibility and relatively morbidity and mortality of radical cystectomy in octogenarian patients affected by MIBC. METHODS: From 2005 to 2009, we performed in octogenarian patients (83-92 years), affected by MIBC, 30 radical cystectomy with mono or bilateral extraperitoneal terminal ureterocutaneostomy in regional anaesthesia (spinal anaesthesia). Pre-operative patients' characteristics were evaluated with the American Society Anaesthesiologists score (ASA); peri- and post-operative complications were also recorded. Patients were revaluated at 3-6-9 months post-operatively with physical examination, serum analysis and ultrasound kidney scan. RESULTS: Radical cystectomy was always performed, median surgical time was 100 min (range 80-120 min), median blood replacement was 750 ml, and the overall morbidity rate was 13%. One patient died post-operatively. Median hospital stay was 8 days (range 5-12 days). Twenty-nine patients were alive at 9 months of follow-up. CONCLUSION: Extraperitoneal radical cystectomy with ureterocutaneostomy could represent a feasible option, associated with a limited mortality and mobility, in the management of MIBC in octogenarian patients.

WT1 transcript amount discriminates secondary or reactive eosinophilia from idiopathic hypereosinophilic syndrome or chronic eosinophilic leukemia.

Idiopathic hypereosinophilic syndromes (HES) comprise a spectrum of indolent to aggressive diseases characterized by persistent hypereosinophilia. Hypereosinophilia can result from the presence of a defect in the hematopoietic stem cell giving rise to eosinophilia, it can be present in many myeloproliferative disorders or alternatively it may be a reactive form, secondary to many clinical conditions. The hybrid gene FIP1L1-PDGRFalpha was identified in a subset of patients presenting with HES or chronic eosinophilic leukemia (CEL). In spite of this, the majority of HES patients do not present detectable molecular lesions and for many of them the diagnosis is based on exclusion criteria and sometimes it remains doubt. In this study we explored the possibility to distinguish between HES/CEL and reactive hypereosinophilia based on WT1 transcript amount. For this purpose, 312 patients with hypereosinophilia were characterized at the molecular and cytogenetic level and analyzed for WT1 expression at diagnosis and during follow-up. This study clearly demonstrates that WT1 quantitative assessment allows to discriminate between HES/CEL and reactive eosinophilia and represents a useful tool for disease monitoring especially in the patients lacking a marker of clonality.

Nephro-ileal conduit subcutaneous stent: an alternative to percutaneous nephrostomy.

Nephrostomy has been the standard method of urinary diversion for chronic ureteral obstruction or when placement of ureteral stents has failed. We describe the first case of left kidney ileal conduit (Briker's urinary diversion) subcutaneous urinary by-pass. This method made the patient free from a second collecting bag without any significant complications. This method may improve the quality of life of patients with severe ureteral obstruction and ileal conduit.

C-erb-2 gene amplification and chromosomal anomalies in bladder cancer: preliminary results.

Studies recently suggested that different genetic factors are involved in the development and progression of bladder cancer. In this study, 30 consecutive patients affected by bladder neoplasm were evaluated in order to analyze the frequency of c-erb-2 gene amplification and chromosome 7, 9, 17 aneusomy using fluorescence in situ hybridization (FISH) technique. C-erb-2 gene amplification, chromosome 17 gain and aneusomy were respectively observed in 3.7% (1/27), in 47% (12/27) and in 74% (20/27) of examined tumors. Moreover, chromosome 7 and 9 aneusomy were detected in 74% (20/27) and in 72% (16/27) of specimens. A statistically significant correlation was observed between chromosome 17 aneusomy and tumor stage and grade (r: 0.642, p = 0.0001; r: 0.385, p = 0.04, respectively). In conclusion, we observed a low incidence of C-erb-2 gene amplification, while chromosome 17 aneusomy was confirmed as a marker of advanced and aggressive bladder cancer.

Gross hematuria 10 years after radical cystectomy: adenomatous polyp.

Patients undergoing radical cystectomy with an ileal neobladder need intensive follow-up due to the recent studies concerning the potential neoplastic transformation of the intestinal mucosa. We report a case of a gross hematuria due to a lesion that developed in an ileal orthotopic bladder 10 years after a nerve and seminal sparing radical cystectomy for transitional bladder cancer. We performed a transurethral resection of the lesion and histopathological evaluation revealed an adenomatous polyp. In our case transurethral resection of the adenoma seems to be a safe and conservative approach in the management of these lesions, however further follow-up is requested.