Nucleotide sequence of the BK virus DNA segment encoding small t antigen.

The nucleotide sequence from 0.64 to 0.53 map units in the BK virus genome coding for the small t protein has been determined. There is only one open reading frame that can code for a polypeptide of 172 amino acids, the putative small t protein. Beyond this segment, multiple termination codons are present in all three reading frames. There is considerable nucleotide and amino acid sequence homology between this region of BK virus and the analogous region of simian virus 40, especially in the proximal portion from 0.64 to 0.60 map units which is most likely common to the small t and large T BK virus proteins. A comparison of the conserved sequences within the early papovavirus genes both confirms the evolutionary relationship between these viruses and suggests the amino acid composition of the regions required for T antigen functions.     

Inter‐Institutional Pathology Consultation: The Importance of Breast Pathology Subspecialization in a Setting of Tertiary Cancer Center

Inter‐institutional pathology consultation (IPC) has shown to be significant in patient care. The purpose of the study was to evaluate the impact of IPC for breast biopsies in our institution. A total of 502 consecutive consult cases of breast core needle biopsies were reviewed. The original pathology reports from the referring institutions and our reports were compared for all cases. All cases were reviewed by specialized breast pathologists. Discordance was divided into minor and major based on the impact on patient care. We reviewed the subsequent excisional biopsy for all discordant cases. Discordance was seen in 104 (20.7%) cases; 40 (8%) had a major discordance and 64 (13%) had a minor discordance. Subsequent surgical excision was available for 25 (62.5%) cases with major discordance and for 13 (20.3%) with minor discordance. Our interpretation changed management in 15 (3%) patients, while 25 (5%) had a potential of management change. The cases with major discordance could be subcategorized into five groups, malignant 5 (12.5%), premalignant 16 (40%), biomarkers 10 (25%), fibroepithelial lesions 6 (15%), and others 3 (7.5%). Our findings support the value of IPC review in decreasing the likelihood of diagnostic errors that may lead to significant impact on patient care. It is necessary that outside pathology material in the referral settings been reviewed by a specialized breast pathologist.     

Natural Course of Nonmalignant Partial Portal Vein Thrombosis in Cirrhotic Patients

Background/Aim:

Portal vein thrombosis (PVT) has a high incidence in patients with liver cirrhosis and determines a poor prognosis of hepatic disease. The aim of our study was to define the natural course of partial PVT in cirrhotic patients, including survival and decompensation rates.

Patients and Methods:

We performed a prospective, cohort study, in a tertiary referral center. There were 22 cirrhotic patients with partial nonmalignant PVT, without anticoagulant treatment, who were followed-up between January 2011 and October 2013. All patients were evaluated by Doppler abdominal ultrasound and computed tomography. Kaplan–Meier method was used to determine the difference in clinical events between the study subgroups.

Results:

After a mean follow-up period of 20.22 months, partial PVT improved in 5 (22.73%), was stable in 11 (50%), and worsened in 6 (27.27%) patients. Hepatic decompensation rate at 6 and 18 months was higher in patients with worsened PVT than in those with stable/improved PVT (50% vs. 25%, P < 0.0001 and 100% vs. 56.25%, P < 0.0001, respectively). The survival rate at 6 months was 66.66% in worsened PVT group vs. 81.25% (P = 0.005) in stable/improved group, and 16.66% vs. 81.25% (P < 0.0001) at 18 months, respectively. Multivariate analysis showed that Model of End-Life Disease was the independent predictor of hepatic decompensation [hazard ratio (HR) 1.42; 95% confidence interval (CI): 1.08−1.87, P = 0.012] and survival (HR 1.76; 95% CI: 1.06−2.92, P = 0.028).

Conclusions:

Nonmalignant partial PVT remained stable/improved in over half of cirrhotic patients and aggravated in more than one fourth in whom it negatively influenced the survival and decompensation rates.     

Characteristics and outcomes of diffuse large B-cell lymphoma presenting in leukaemic phase

Diffuse large B‐cell lymphoma (DLBCL) occasionally presents with circulating malignant cells. The clinical characteristics and long‐term outcomes of these patients have not been described. Twenty‐nine newly diagnosed DLBCL presenting in leukaemic phase were identified between 1996 and 2010, at two institutions. Median age was 48 years, and patients presented with leucocytosis, high lactate dehydrogenase levels, B symptoms, and high International Prognostic Index score. Extra nodal site involvement was observed in all patients and affected the bone marrow (100%), spleen (62%), pleura/lung (41%), liver (21%), bone (17%), bowels (7%) and cerebrospinal fluid (14%). Blood lymphomatous cells co‐expressed CD19, CD20, CD22, CD38, CD45, HLA‐DR and FMC7 in >90%, and kappa or lambda light chain restriction in >50%. Ninety per cent received rituximab and anthracycline‐based chemotherapy. Overall, remission was complete in 54% and partial in 31%; 15% had resistant disease. Median follow‐up was 47 months; 13 (45%) patients remain alive in complete remission. Median progression‐free and overall survivals were 11·5 and 46·7 months, respectively. In summary, patients with DLBCL in leukaemic phase present with high tumour burden and frequent involvement of extra nodal sites. In this uncommon DLBCL subgroup, anthracycline‐based regimens with rituximab are associated with early morbidity and mortality, but yield approximately 50% 4‐year survival.     

Panobinostat (LBH589)-induced acetylation of tubulin impairs megakaryocyte maturation and platelet formation

Drug-induced thrombocytopenia often results from dysregulation of normal megakaryocytopoiesis. In this study, we investigated the mechanisms responsible for thrombocytopenia associated with the use of Panobinostat (LBH589), a histone deacetylase inhibitor with promising anti-cancer activities. The effects of LBH589 were tested on the cellular and molecular aspects of megakaryocytopoiesis by utilizing an ex vivo system in which mature megakaryocytes (MK) and platelets were generated from human primary CD34(+) cells. We demonstrated that LBH589 did not affect MK proliferation or lineage commitment but inhibited MK maturation and platelet formation. Although LBH589 treatment of primary MK resulted in hyperacetylation of histones, it did not interfere with the expression of genes that play important roles during megakaryocytopoiesis. Instead, we found that LBH589 induced post-translational modifications of tubulin, a nonhistone protein that is the major component of the microtubule cytoskeleton. We then demonstrated that LBH589 treatment induced hyperacetylation of tubulin and alteration of microtubule dynamics and organization required for proper MK maturation and platelet formation. This study provides new insights into the mechanisms underlying LBH589-induced thrombocytopenia and provides a rationale for using tubulin as a target for selective histone deacetylase inhibitor therapies to treat thrombocytosis in patients with myeloproliferative neoplasms.