Pharmacobiological Approach for the Clinical Development of Ruxolitinib in Myeloproliferative Neoplasms

Ruxolitinib, a JAK1 and JAK2 inhibitor drug, has recently been approved for the treatment of patients with high- or intermediate-risk myelofibrosis with symptomatic splenomegaly. Ruxolitinib is the first clinically useful targeted therapy in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). The aim of this paper is to indicate pharmacobiological aspects of ruxolitinib within the potential context of MPNs. Pharmacobiological assessments, in addition to knowledge of the risk profile for ruxolitinib in MPNs, are required. We propose hypotheses based on our experience in a splenectomized MPN patient with hyperproliferative bone marrow and moderate fibrosis receiving ruxolitinib. We believe that a true clinical development approach for this drug should include pharmacobiological assessments for ruxolitinib in addition to the disease risk profile of MPNs.PubMedWoSScopu

Co-Expression Of T(15;17) And T(8;21) In A Case Of Acute Promyelocytic Leukemia: Review Of The Literature

Additional chromosomal abnormalities in acute myelogenous leukemia have been identified as one of the most important prognostic factors. Favorable chromosomal changes such as t(8;21), inv(16), and t(15;17) are associated with higher rates of complete remission and event-free survival. Translocation (15;17) characterizes acute promyelocytic leukemia (APL) (French-American-British class M3) in almost all patients. Secondary chromosomal abnormalities are also present in approximately 23%-29% of patients with newly diagnosed APL. The prognostic implications of t(8;21) and other secondary cytogenetic aberrations in APL are reviewed here. We present a 47-year-old woman diagnosed with APL whose initial cytogenetic analysis included both t(8;21) and t(15;17). The initial induction chemotherapy included 3 days of idarubicin (12 mg/m2/day) and daily all-trans retinoic acid (ATRA; 45 mg/m2/day). At the sixth week of treatment, a control bone marrow biopsy was found to be normocellular, t(15;17) bcr3 and t(8;21) were negative, and t(15;17) bcr1 fusion transcripts were reduced from 5007 (1.78525699%) copies per 1 µg RNA to 40 (0.00062020%) with real-time quantitative polymerase chain reaction. Consolidation with 4 days of idarubicin (5 mg/m2/day), ATRA (45 mg/m2/day for 15 days), and cytarabine (1 g/m2/day for 4 days) was then started. However, the patient became pancytopenic and had neutropenic fever after consolidation treatment. Unfortunately, she died 3 months after the time of APL diagnosis, due to acute respiratory distress syndrome-like respiratory problems and multiorgan dysfunction requiring respiratory support and hemodialysis. , Conflict of interest:None declared.PubMedWo

Unusual Extramedullary Recurrence And Renal Relapse Despite Complete Chimerysm After Allografting In Ph+ All

Extramedullary recurrences with or without bone marrow involvement are reported in up to a half of leukemic relapses after bone marrow transplantation. Extramedullary relapse of acute lymphoblastic leukemia (ALL) in the kidney after allogeneic stem cell transplantation (allo-SCT) is rare. We herein, report an additional case with extramedullary recurrences and renal relapse after first-allografting for Ph+-acute lymphoblastic leukemia. He had no evidence of leukemia in his marrow demonstrating 98% full-donor chimerism while he had ALL relapse in his kidney.WoSScopu

Allografting for Bosutinib, Imatinib, Nilotinib, Dasatinib, and Interferon Resistant Chronic Myeloid Leukemia without ABL Kinase Mutation

The current treatment of chronic phase chronic myeloid leukemia (CML) consists of oral tyrosine kinase inhibitors (TKIs). However, high-risk CML may present with an aggressive course which may result in blastic crisis or a "difficult-to-manage" state with available treatments. The aim of this paper is to report a patient with complicated CML resistant to treatment and progressed despite the administration of bosutinib, imatinib mesylate, nilotinib, dasatinib, interferon alpha 2a, cytotoxic chemotherapy, and allogeneic hematopoietic stem cell transplantation. The striking point of this case story is that no Abl kinase domain mutation against TKIs has been detected during this very complicated disease course of CML. Meanwhile, challenging cases will always be present despite the hope and progress in CML in the TKI era

Local Renin-Angiotensin System in Normal Hematopoietic and Multiple Myeloma-Related Progenitor Cells

Objective: The prominent functions of the local renin-angiotensin system (RAS) in primitive hematopoiesis further support the hypothesis that local autocrine bone marrow RAS could also be active in neoplastic hematopoiesis. The aim of this study is to examine critical RAS elements in normal CD34+ hematopoietic stem cells and multiple myeloma (MM)-related progenitor cells., Materials and Methods: The study group comprised the total bone marrow cells (CBM) of 10 hematologically normal people, the CD34+ stem cell samples (CD34+CBM) of 9 healthy donors for allogeneic peripheral stem cell transplantation, and the CD34+ stem cell samples (CD34+MM) of 9 MM patients undergoing autologous peripheral stem cell transplantation. We searched for the gene expression of the major RAS components in healthy hematopoietic cells and myeloma cells by quantitative real-time polymerase chain reaction analysis., Results: RENIN, angiotensinogen (ANGTS), and angiotensin converting enzyme-I (ACE I) mRNA expression levels of CBM were significantly higher than those in myeloma patients (p=0.03, p=0.002, and p=0.0008, respectively). Moreover, RENIN and ANGTS mRNA expression levels were significantly higher in CD34+ stem cell samples of healthy allogeneic donors compared to those in myeloma patients (p=0.001 and p=0.01). However, ACE I expression levels were similar in CD34+CBM and CD34+MM hematopoietic cells (p=0.89)., Conclusion: Although found to be lower than in the CBM and CD34+CBM hematopoietic cells, the local RAS components were also expressed in CD34+MM hematopoietic cells. This point should be kept in mind while focusing on the immunobiology of MM and the processing of autologous cells during the formation of transplantation treatment protocols.PubMedWoSScopu

The Prognosis Of Adult Burkitt’S Cell Leukemia In Real-Life Clinical Practice

Objective: Many studies reported an improved prognosis in patients with Burkitt’s lymphoma obviating the need of stem cell transplantation. However, prognosis of the advanced disease [i.e. Burkitt’s cell leukemia (BCL)] has not been reported with current treatment modalities except for a few prospective trials. The aim of this study is to compare the prognoses of BCL patients with similarly treated and nontransplanted patients with other types of acute lymphoblastic leukemia (ALL) and with ALL patients that underwent allogeneic stem cell transplantation (ASCT) in their first remissions. Materials and Methods: In this retrospective analysis, BCL patients aged between 16 and 63 who were admitted between 2000 and 2014 to the hospitals of Hacettepe or Gazi University and were treated with intensive therapies aimed at cure were included. All ALL patients who were treated with a similar protocol not including transplantation during the same period (NT-ALL group) and all ALL patients who underwent ASCT in the first complete remission during the same period (T-ALL group) served as control groups. Results: The central nervous system or extramedullary involvement rates, lactate dehydrogenase levels, and white blood cell counts at diagnosis were higher in the BCL group than the NT-ALL group and these differences were significant. BCL patients had disease-free survival (DFS) durations comparable with the T-ALL cohort but NT-ALL patients had significantly shorter DFS durations. Both cumulative relapse incidence and cumulative nonrelapse mortality were higher in NT-ALL patients compared to the T-ALL group and BCL patients. Conclusion: DFS in BCL patients treated with a widely accepted modern regimen, R-HyperCVAD, is comparable to results in other ALL patients receiving allogeneic transplantation. Our results are in agreement with a few prospective noncomparative studies suggesting no further need for stem cell transplantation in BCL.PubMedWoSScopu

Expression Profiles Of The Individual Genes Corresponding To The Genes Generated By Cytotoxicity Experiments With Bortezomib In Multiple Myeloma

Objective: Multiple myeloma (MM) is currently incurable due to refractory disease relapse even under novel anti-myeloma treatment. In silico studies are effective for key decision making during clinicopathological battles against the chronic course of MM. The aim of this present in silico study was to identify individual genes whose expression profiles match that of the one generated by cytotoxicity experiments for bortezomib. Materials and Methods: We used an in silico literature mining approach to identify potential biomarkers by creating a summarized set of metadata derived from relevant information. The E-MTAB-783 dataset containing expression data from 789 cancer cell lines including 8 myeloma cell lines with drug screening data from the Wellcome Trust Sanger Institute database obtained from ArrayExpress was “Robust Multi-array analysis” normalized using GeneSpring v.12.5. Drug toxicity data were obtained from the Genomics of Drug Sensitivity in Cancer project. In order to identify individual genes whose expression profiles matched that of the one generated by cytotoxicity experiments for bortezomib, we used a linear regression-based approach, where we searched for statistically significant correlations between gene expression values and IC50 data. The intersections of the genes were identified in 8 cell lines and used for further analysis. Results: Our linear regression model identified 73 genes and some genes expression levels were found to very closely correlated with bortezomib IC50 values. When all 73 genes were used in a hierarchical cluster analysis, two major clusters of cells representing relatively sensitive and resistant cells could be identified. Pathway and molecular function analysis of all the significant genes was also investigated, as well as the genes involved in pathways. Conclusion: The findings of our present in silico study could be important not only for the understanding of the genomics of MM but also for the better arrangement of the targeted anti-myeloma therapies, such as bortezomib.PubMedWoSScopu

Hacettepe Dahiliye Ders Kitabı 2

Ondokuzuncu yüzyılın tıp literatürü, korku filmi gibidir. Hekimlerin, ellerine geçirdikleri her şeyi, akıllarına gelen her yöntemi tedavi için kullandıkları görülür. Bilgiye değil, kulaktan dolma duyumlara dayanan, “içten doğma” uydurma fikirlerle hastaların yelken kürek tedavi edilmeye çalışıldığı bir dönemdir. Litrelerce kan alınır, barsaklar yüksek basınçlı lavmanlarla delik deşik edilir, hastalar buzlu sulara yatırılıp uzuvlar gangren olana dek dondurulur, dondurmak işe yaramazsa kaynar kazanlara sokulur, deriyi kabartan bitkisel merhemlerle epidermis eritilir, terkibi ikinci kez asla tutturulamayan envai çeşit bitkisel karışımlarla organlar iflas ettirilirdi. Yirminci yüzyılın başında, modern tıbbın kurucusu sayılan Dr. William Osler öncelikle bu “palavra tıbba” rest çekmiş, yeni bir çağı aralamıştır. Çağdaşı olan bazı hünerli hekimlerle birlikte, önümüze gelen her hastayı, elimize geçirdiğimiz her şeyle, bu şekilde rastgele tedavi edemeyiz, öncelikle hastalıkları tanımamız gerekir diyerek, tıbbın önceliğini tanıya yöneltmişler, kendilerine kadar olan eski devirlerden miras iki ilaç (digoksin ve morfin) dışındaki tüm o ilkel tedavi yöntemlerini reddetmişlerdir. Akıldışı eski tedavileri reddederek, yerine henüz yeni bir tedavi seçenekleri de olmadığından; yalnızca (doğru) tanı koymaya çalışan ve hastanın prognozunu tayin etmeye odaklanmış, tepkisel ve aslında bir bakıma muhafazakar yeni bir tıbbı başlatmışlardır. Tıp eğitimini de bu doğrultuda değiştirip, çalakalem ilaç ve tedavi veren hekimler yerine; hastanın hastalığını kavramaya çalışan, doğru tanı koyan hekimler yetiştirmeye yönelmişlerdir. Tıp eğitimindeki “hasta başı vizitler” bizzat Dr. William Osler tarafından başlatılmıştır. Bu ekol, 1900’ların başında cesur bir kararla, neyi tedavi ettiğini bilmeyen eski hekimlik pratiğini kapatıp, öncelikle hastalıkları kavramaya, hastalarına titizlikle isabetli bir tanı koymaya odaklanmıştır. Bu devir, tıbbın rönesansı sayılır. Kuruluşundan itibaren çağdaşı modern tıp dünyasının bir takipçisi ve aktörü olan Hacettepe Tıp Fakültesi; hünerli hekimler, iyi klinisyenler yetiştirmeyi amaçlamıştır. Prof. Dr. Şeref Zileli’nin kurucusu olduğu İç Hastalıkları Anabilim Dalımız, mezuniyet öncesi tıp eğitiminde yatay ve dikey entegrasyon modeliyle klinik eğitim aşamasında, öğrencilerimize “dahiliye nosyonu” kazandırmayı hedeflemiştir. Dahiliye nosyonu, hastaya saçından tırnağına bir bütün olarak bakabilmeyi; hastanın sorunlarını rasyonel bir klinik denklem haline getirebilmeyi; semptomlarından başlayıp, fizik muayene ve isabetli tetkik seçimiyle en doğru tanıyı koyabilmeyi ve hastaya en az zarar verecek en uygun tedaviyi planlayabilmeyi gerektirir. Mezuniyet öncesi İç Hastalıkları Klinik Eğitim programımızın öğrenim hedefleriyle, içeriği ve ulusal çekirdek müfredatımız gözetilerek hazırlanan bu kitap; İç Hastalıkları, Kardiyoloji, Göğüs Hastalıkları, İnfeksiyon Hastalıkları ve Klinik Mikrobiyoloji anabilim dallarımız öğretim üyelerinin ortaklaşa titiz bir çalışmasıdır