Pathogenetic mechanisms of hematological abnormalities of patients with MYH9 mutations

Mutations of MYH9, the gene for non-muscle myosin heavy chain IIA (NMMHC-IIA), cause a complex clinical phenotype characterized by macrothrombocytopenia and granulocyte inclusion bodies, often associated with deafness, cataracts and/or glomerulonephritis. The pathogenetic mechanisms of these defects are either completely unknown or controversial. In particular, it is a matter of debate whether haploinsufficiency or a dominant-negative effect of mutant allele is responsible for hematological abnormalities. We investi-gated 11 patients from six pedigrees with different MYH9mutations. We evaluated NMMHC-IIA levels in plate-lets and granulocytes isolated from peripheral blood and in megakaryocytes (Mks) cultured from circulating progenitors. NMMHC-IIA distribution in Mks and granulocytes was also assessed. We demonstrated that all the investigated patients had a 50 % reduction of NMMHC-IIA expression in platelets and that a similar defect was present also in Mks. In subjects with R1933X and E1945X mutations, the whole NMMHC-IIA of platelets and Mks was wild-type. No NMMHC-IIA inclusions were observed at any time of Mk maturation. In granulo-cytes, the extent of NMMHC-IIA reduction in patients with respect to control cells was significantly greater than that measured in platelets and Mks, and we found that wild-type protein was sequestered within most of the NMMHC-IIA inclusions. Altogether these results indicate that haploinsufficiency of NMMHC-IIA in megakaryocytic lineage is the mechanism of macrothrombocytopenia consequent to MYH9 mutations

Contemporary update on neoadjuvant therapy for bladder cancer.

Administration of neoadjuvant chemotherapy preceding radical cystectomy in patients with bladder cancer remains a matter of debate. Results of prospective, randomized studies have demonstrated an overall absolute survival benefit of 5% at 5 years, provided cisplatin-based combination regimens are used. Owing to the perception of a modest survival benefit, the medical community has been slow to adopt the use of neoadjuvant chemotherapy. Other reasons for the underuse of neoadjuvant chemotherapy range from patient ineligibility to fear of delaying potentially curative surgery in nonresponders. Instead, several institutions have adopted an individualized, risk-adapted approach, in which the decision to administer chemotherapy is based on clinical stage and patient comorbidity profile. The development of new cytotoxic and targeted therapies, in particular immune checkpoint inhibitors, warrants well-designed prospective studies to test their efficacy alone or in combination in the neoadjuvant setting. Moving forward, genomic characterization of muscle-invasive bladder cancer could offer information that aids clinicians in selecting the appropriate chemotherapy regimen. Following neoadjuvant therapy, every effort should be made to ensure optimal surgery, as surgical margins and the number of removed lymph nodes are prognostic factors; thus, radical cystectomy and a meticulous extended pelvic lymph node dissection should be performed by expert surgeons