Rony Schaffel

Low prevalence of the JAK2V617F in patients with ischemic stroke or cerebral venous thrombosis.

Quebec platelet disorder (QPD) is an autosomal dominant bleeding disorder associated with increased risks for bleeding and the expression and storage of urokinase plasminogen activator (u-PA) in platelets, despite normal u-PA in plasma (reviewed in [1]). In the recent article on QPD published in this journal [1], QPD was proposed to result from defective u-PA regulation by megakaryocytes. However, the levels of u-PA in other QPD cells and urine have not been reported. Individuals with QPD are at increased risk of experiencing bleeding following hemostatic challenges, and approximately 50% experience episodic, spontaneous hematuria, which is associated with higher levels of platelet u-PA [2]. As urine normally contains significant amounts of u-PA (40–80 mg/ml) [3], we investigated whether individuals with QPD have an increased urinary u-PA as a potential contributor to their urinary tract bleeding.

PKC-beta II expression has prognostic impact in nodal diffuse large B-cell lymphoma.

Recent studies of gene expression and immunohistochemistry have shown that protein kinase C-beta II (PKC-beta II) might have prognostic significance in patients with diffuse large B-cell lymphoma (DLBCL). We sought to determine the prognostic significance of the expression of PKC-beta II in patients with nodal DLBCL. Formalin-fixed, paraffin-embedded tissues were stained with a monoclonal antibody to PKC-beta II protein. A total of 125 patients were studied; 83 patients (66%) were in the low-risk International Prognostic Index (IPI) group. Forty-eight patients (38%) were positive for PKC-beta II. Complete remission was obtained in 70%, and was not influenced by the PKC-beta II status (67 vs 71%). The 5-year event-free survival (EFS) was worse in high-risk patients (14 vs 58%, P<0.001) and in those with PKC-beta II positivity (36 vs 49%, P=0.054). In low-risk IPI patients, PKC-beta II expression was related to a worse 5-year overall survival (OS) (60 vs 76%, P=0.033) and a worse 5-year EFS (48 vs 66%, P=0.014). In a Cox regression analysis for EFS, both PKC-beta II expression (hazard ratio=1.68, P=0.037) and the IPI (HR=3.07, P<0.001) were independent poor prognostic factors. PKC-beta II (HR=1.72, P=0.046) and the IPI (HR=5.16, P<0.001) were also independent poor prognostic factors for the OS. PKC-beta II expression, along with the IPI, were associated with a worse EFS and OS in patients with nodal DLBCL specially in low-risk IPI patients.

Thiabendazole for the Treatment of Strongyloidiasis in Patients with Hematologic Malignancies

A total of 21 patients with hematologic malignancies were given thiabendazole for treatment of strongyloidiasis. Fifteen patients were cured. Since there were no relapses, it is unlikely that maintenance therapy has a role in the management of strongyloidiasis in this population of patients.

Evaluation of intra- and interobserver agreement and its clinical significance for scoring bcl-2 immunohistochemical expression in diffuse large B-cell lymphoma

Immunohistochemistry (IHC) has become an essential part of diagnosis and clinical research in lymphomas. There is considerable heterogeneity, however, in IHC findings regarding expression rate and positivity cut‐offs, which creates a degree of uncertainty that has prevented its incorporation for prognostic purposes. The purpose of the present study was to assess intra‐ and interobserver agreement in scoring bcl‐2 expression on IHC. The study materials were 81 diffuse large B‐cell lymphomas. Slides were processed in the same laboratory, and were analyzed independently and in a blinded manner by four pathologists twice, at least 1 month apart. The positivity rates ranged from 31% to 41% in the first evaluation, and from 30% to 43% in the second evaluation. The two analyses by the same pathologist gave concordant results in 88–93% of cases (κ = 0.71–0.83). Complete agreement among all observers varied from 72% to 79%. The experience of the observer did not influence intra‐observer concordance. Cooperative analysis of discordant slides led to consensus in all cases. The variation observed in scoring bcl‐2 expression is acceptable for use in lymphoma diagnosis and classification. The use of IHC stratification, however, for clinical decisions regarding treatment will require standardization and centralized consensus review, and must await the results of ongoing prospective trials.

Molecular responses at 3 and 6 months after switching to a second-generation tyrosine kinase inhibitor are complementary and predictive of long-term outcomes in patients with chronic myeloid leukemia who fail imatinib

Abstract Early molecular response (MR) defined by BCR–ABLIS levels has prognostic impact in chronic myeloid leukemia (CML). MR was evaluated at 3 and 6 months after switching to nilotinib or dasatinib in 115 patients with resistance to imatinib. Three groups were delineated at 3 months (< 1%, 1–10% or > 10% BCR–ABLIS levels) with different outcomes at 3 years regarding major molecular response (MMR, 91%, 47%, 22%, p < 0.001), failure-free survival (FFS), progression-free survival (PFS, 96%, 89% and 78%, p = 0.05) and overall survival (OS). After 6 months, patients with MR < 1% had higher 3-year MMR (83% vs. 16%, p < 0.001), FFS, PFS (94% vs. 84%, p = 0.05) and OS. Four patients had 3-month and 6-month MR > 10% and < 1%, respectively (3-year FFS 50%). Thirteen had 3-month and 6-month MR < 10% and ≥ 1%, respectively (3-year FFS 38%). These findings confirm the strong predictive value of 3-month and 6-month BCR–ABLIS levels in imatinib-resistant patients.

Risk factors for unsuccessful peripheral blood stem cell harvesting using granulocyte-colony stimulating factor mobilization in patients with multiple myeloma

The aim of this study was to determine factors that influence unsuccessful peripheral blood stem cell (PBSC) harvesting in patients with multiple myeloma (MM). Retrospective data of 186 MM patients who received G-CSF as mobilization were analyzed. Patients with successful harvest were compared with those who failed (using 2 definitions of failure <2 and <4 CD34 cells×10(6)/mm(3)). The groups were compared regarding age, gender, body weight, baseline platelet count, receipt of radiotherapy, number of prior chemotherapy regimens, PBSC count before collection, processed and collected volume, collect replace, number of sessions and final number of PBSC collected. By multivariate analysis, a baseline platelet count <161,000 cells/mm(3) was associated with PBSC harvest lower than 2×10(6)/kg, and age >58 years was related to PBSC harvest lower than 4×10(6)/kg CD34 cells/kg. Patients with these parameters should not receive mobilization protocols with G-CSF alone. Alternative protocols should be tested in this high risk harvest failure population.

Leucemia Linfoblástica Aguda Filadélfia positiva

O cromossomo Filadelfia (Ph1) e a alteracao citogenetica mais comum da Leucemia Linfoblastica Aguda do adulto (LLA). Esta alteracao citogenetica predomina nos adultos com mais de 50 anos e na LLA de origem na celula B, principalmente CD10 positiva. O diagnostico requer a analise citogenetica e a pesquisa do mRNA do gene BCR-ABL no sangue periferico ou na medula ossea. A LLA Ph1 apresenta uma sobrevida global em cinco anos inferior a 20% quando tratada com protocolos para LLA. Os poucos casos de cura ocorrem nos pacientes submetidos ao transplante alogenico de medula ossea (TMO). A adicao do imatinibe a quimioterapia resultou em melhora na taxa de remissao completa, maior taxa de remissao molecular completa, maior numero de pacientes aptos para realizar o TMO, uma maior sobrevida livre de eventos e maior sobrevida global, embora o tempo de seguimento seja ainda muito curto. Entretanto, a taxa de recaidas e o aparecimento de mutacoes do BCR-ABL resistentes ao imatinibe ainda sao preocupantes. No futuro, novos inibidores de tirosina quinase poderao ser incorporados ao tratamento da LLA Ph1.

Comparative study on the mechanism of bradykinin potentiation induced by bradykinin-potentiating peptide 9a, enalaprilat and kinin-potentiating peptide

The action of a kinin-potentiating peptide (KPP) obtained from tryptic digestion of human serum proteins was compared with that of bradykinin-potentiating peptide 9a (BPP9a; obtained from snake venom) and enalaprilat (a synthetic inhibitor of angiotensin-converting enzyme; ACE) as a means of understanding the mechanism of action of KPP on smooth muscle. KPP potentiated bradykinin-induced contractile effects in guinea-pig ileum and rat uterus, but not the bradykinin-induced relaxation of pre-contracted ileum, whereas BPP9a and enalaprilat potentiated both bradykinin effects. The receptor mediating both the contraction and the relaxation elicited by bradykinin in the ileum was found to be of the B2 type. KPP retained its potentiating effect in the presence of enalaprilat in the guinea-pig ileum and rat uterus, whereas the potentiation evoked by BPP9a was abolished. Enalaprilat inhibited the activity of purified ACE, whereas KPP was completely devoid of such an effect. The potentiating effect of KPP, but not that of BPP9a or enalaprilat, was blocked by compounds that inhibit phospholipase A2 and lipoxygenase activity but not by inhibitors of cyclo-oxygenase or phosphodiesterases. The results suggest that the potentiating effect of KPP (i) does not involve inhibition of ACE; (ii) is not due to an increased affinity of the receptor for bradykinin, and (iii) probably involves post-receptor events linked to phospholipase A2 and to the lipoxygenase pathway.

Diagnosis and treatment of chronic lymphocytic leukemia: recommendations from the Brazilian Group of Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia is characterized by clonal proliferation and progressive accumulation of B-cell lymphocytes that typically express CD19+, CD5+ and CD23+. The lymphocytes usually infiltrate the bone marrow, peripheral blood, lymph nodes, and spleen. The diagnosis is established by immunophenotyping circulating B-lymphocytes, and prognosis is defined by two staging systems (Rai and Binet) established by physical examination and blood counts, as well as by several biological and genetic markers. In this update, we present the recommendations from the Brazilian Group of Chronic Lymphocytic Leukemia for the diagnosis and treatment of chronic lymphocytic leukemia. The following recommendations are based on an extensive literature review with the aim of contributing to more uniform patient care in Brazil and possibly in other countries with a similar social–economic profile.

Early molecular response ≤1% has strong prognostic impact for CML patients that switch to second-line therapy with BCR-ABL1 ≤10% and no major molecular response

(FILO). British Journal of Haematology, 179, 439–448. Leleu, X., Soumerai, J., Roccaro, A., Hatjiharissi, E., Hunter, Z.R., Manning, R., Ciccarelli, B.T., Sacco, A., Ioakimidis, L., Adamia, S., Moreau, A.S., Patterson, C.J., Ghobrial, I.M. & Treon, S.P. (2009) Increased incidence of transformation and myelodysplasia/acute leukemia in patients with Waldenstrom macroglobulinemia treated with nucleoside analogs. Journal of Clinical Oncology, 27, 250–255. Lin, P., Mansoor, A., Bueso-Ramos, C., Hao, S., Lai, R. & Medeiros, L.J. (2003) Diffuse large B-cell lymphoma occurring in patients with lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia. Clinicopathologic features of 12 cases. American Journal of Clinical Pathology, 120, 246– 253. Lionakis, M.S., Dunleavy, K., Roschewski, M., Widemann, B.C., Butman, J.A., Schmitz, R., Yang, Y., Cole, D.E., Melani, C., Higham, C.S., Desai, J.V., Ceribelli, M., Chen, L., Thomas, C.J., Little, R.F., Gea-Banacloche, J., Bhaumik, S., Stetler-Stevenson, M., Pittaluga, S., Jaffe, E.S., Heiss, J., Lucas, N., Steinberg, S.M., Staudt, L.M. & Wilson, W.H. (2017) Inhibition of B cell receptor signaling by ibrutinib in primary CNS lymphoma. Cancer Cell, 31, e835. Swerdlow, S.H., Campo, E., Pileri, S.A., Harris, N.L., Stein, H., Siebert, R., Advani, R., Ghielmini, M., Salles, G.A., Zelenetz, A.D. & Jaffe, E.S. (2016) The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood, 127, 2375–2390. Talaulikar, D., Tam, C.S., Joshua, D., Ho, J.P., Szer, J., Quach, H., Spencer, A., Harrison, S., Mollee, P., Roberts, A.W., Horvath, N., Lee, C., Zannettino, A., Brown, R., Augustson, B., Jaksic, W., Gibson, J., Kalff, A., Johnston, A., Trotman, J., Kalro, A., Grigoriadis, G., Ward, C. & Prince, H.M. (2017) Treatment of patients with Waldenstrom macroglobulinaemia: clinical practice guidelines from the Myeloma Foundation of Australia Medical and Scientific Advisory Group. Internal Medicine Journal, 47, 35–49. Treon, S.P., Tripsas, C.K., Meid, K., Warren, D., Varma, G., Green, R., Argyropoulos, K.V., Yang, G., Cao, Y., Xu, L., Patterson, C.J., Rodig, S., Zehnder, J.L., Aster, J.C., Harris, N.L., Kanan, S., Ghobrial, I., Castillo, J.J., Laubach, J.P., Hunter, Z.R., Salman, Z., Li, J., Cheng, M., Clow, F., Graef, T., Palomba, M.L. & Advani, R.H. (2015) Ibrutinib in previously treated Waldenstrom’s macroglobulinemia. New England Journal of Medicine, 372, 1430–1440. Wilson, W.H., Young, R.M., Schmitz, R., Yang, Y., Pittaluga, S., Wright, G., Lih, C.J., Williams, P.M., Shaffer, A.L., Gerecitano, J., de Vos, S., Goy, A., Kenkre, V.P., Barr, P.M., Blum, K.A., Shustov, A., Advani, R., Fowler, N.H., Vose, J.M., Elstrom, R.L., Habermann, T.M., Barrientos, J.C., McGreivy, J., Fardis, M., Chang, B.Y., Clow, F., Munneke, B., Moussa, D., Beaupre, D.M. & Staudt, L.M. (2015) Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nature Medicine, 21, 922–926.