Enumeration of CD34+ blasts by immunohistochemistry in bone marrow biopsies from MDS patients may have significant impact on final WHO classification

The percentage of blasts cells in the bone marrow (BM) of MDS patients is one of the key parameters for MDS classification and for the differential diagnosis with acute myeloid leukemia (AML). Currently, the gold standard to determine the blast percentage is conventional cytomorphology. To assess the possible impact of blast cell enumeration in BM biopsies from MDS patients on the final WHO classification using CD34 immunohistochemistry (IHC) a total of 156 BM samples from MDS and MDS-AML patients were studied and compared to blast counts by cytomorphology (CM). Eighty-nine BM aspirates were also studied by flow cytometry (FCM). Percentages of CD34+ blasts by IHC were determined blindly by two hematopathologists. Automated CD34-cell count was performed in 25 cases. Good overall agreement was found for CM and FCM with respect to critical blast thresholds (5%, 10%, 20%) (p < 0.05). However, in 17% of patients, CD34+ blast counts by IHC were higher as compared to CM with possible impact on MDS subclassification. In 7 of 21 AML patients, diagnosis was established on BM histology, while the blast percentage by CM was below the AML threshold. The assessment of CD34+ cells by IHC showed high interobserver agreement (Spearman R 0.95, p < 0.01), while automated CD34 counts were not optimal due to interference with other cellular and stromal elements. BM histology including CD34 IHC improves the diagnostic accuracy in MDS and AML. The quantification of blast cells should be based on the integration of all three methods for reliable disease classification and risk assessment

The effect of biological heterogeneity on R-CHOP treatment outcome in diffuse large B-cell lymphoma across five international regions

Addressing the global burden of cancer, understanding its diverse biology, and promoting appropriate prevention and treatment strategies around the world has become a priority for the United Nations and International Atomic Energy Agency (IAEA), the WHO, and International Agency for Research on Cancer (IARC). The IAEA sponsored an international prospective cohort study to better understand biology, treatment response, and outcomes of diffuse large B-cell lymphoma (DLBCL) in low and middle-income countries across five UN-defined geographical regions. We report an analysis of biological variation in DLBCL across seven ethnic and environmentally diverse populations. In this cohort of 136 patients treated to a common protocol, we demonstrate significant biological differences between countries, characterized by a validated prognostic gene expression score (p < .0001), but International Prognostic Index (IPI)-adjusted survivals in all participating countries were similar. We conclude that DLBCL treatment outcomes in these populations can be benchmarked to international standards, despite biological heterogeneity

Identification of a patient cohort with relapsing diffuse large b-cell lymphoma with a low international prognostic index in pet/ct using a 2-gene (lmo2/tnfrsf9) scoring system

Treating patients with diffuse large Bcell lymphoma (DLBCL) remains a challenge, with a remission rate of 75% at 2 years from diagnosis. The International Prognostic Index (IPI) [1] and molecularcharacterization [2] are employed in the stratification and relapse prediction. Additionally, 18F-fluorodeoxyglucose positron emission tomography (PET) and computed tomography (CT) have now become part of standard care in differentiating metabolic activity of the disease from fibrosisor necrosis [3]. Early optimism that the speed of response to treatment, as indicated by an interim-PET (iPET) scan after 2?3 cycles of chemotherapy, might reliably predict cure has not been fulfilled [4].To investigate the role of both an interim and an end-treatment-PET (ePET) scan for the management of DLBCL in an international setting, at a time when PET centers were becoming established globally, the International Atomic Energy Agency (IAEA) sponsored a study across 7 countries in Europe, South Asia, Southeast Asia, and South America [5]. This study, the largest study to date, found that 34% of cases were iPET+ after 2 or 3 cycles of standard chemotherapy (R-CHOP), but 54% of the iPET+ cases became ePET?; and that these ?slow responders? had relatively good outcomes at 2 years (event-free survival, EFS: 86%). Notably, the study found that by combining a negative iPET scan with 2 clinical components of the IPI (normal LDH and good performance status), it was possible to identify a population, 35% of all cases, 98% of whom were disease free 2 years after diagnosis. By contrast, iPET+ cases that remained PET+ at the end of treatment had dismal outcomes. These findings raisethe important question of how to separate slow-responding iPET+ cases who are PET? at the end treatment, who are destined for good survival, from those who will fail to achieve a complete or stable remission by continuing standard therapy.Fil: Omidvar, Nader. Cardiff University; Reino UnidoFil: Tekin, Nilgun. Ankara Üniversitesi; TurquíaFil: Conget, Paulette. Universidad del Desarrollo; ChileFil: Bruna, Flavia Alejandra. Universidad del Desarrollo; Chile. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Timar, Botond. Semmelweis Egyetem; HungríaFil: Gagyi, Eva. Semmelweis Egyetem; HungríaFil: Basak, Ranjan. Tata Memorial Hospital; IndiaFil: Auewarakul, Chirayu. Mahidol University; TailandiaFil: Sritana, Narongrit. Mahidol University; TailandiaFil: Cerci, Juliano Julio. Department of Nuclear Medicine, Quanta Diagnóstico e Terapia; BrasilFil: DImamay, Mark Pierre. St Luke's Medical Centre; FilipinasFil: Gyorke, Tamas. Semmelweis University; HungríaFil: Redondo, Francisca. Fundación Arturo López Pérez; ChileFil: Nair, Reena. Tata Memorial Hospital; IndiaFil: Gorospe, Charity. St Luke's Medical Centre; FilipinasFil: Paez, DIana. International Atomic Energy Agency; AustriaFil: Fanti, Stefano. Universidad de Bologna; ItaliaFil: Ozdag, Hilal. Ankara Üniversitesi; TurquíaFil: Padua, Rose Ann. Université Paris Diderot - Paris 7; FranciaFil: Carr, Robert. Guy’s and St. Thomas’ Hospital; Reino Unid

Protocol for qRT-PCR analysis from formalin fixed paraffin embedded tissue sections from diffuse large b-cell lymphoma: Validation of the six-gene predictor score

As a part of an international study on the molecular analysis of Diffuse Large B-cell Lymphoma (DLBCL), a robust protocol for gene expression analysis from RNA extraction to qRT-PCR using Formalin Fixed Paraffin Embedded tissues was developed. Here a study was conducted to define a strategy to validate the previously reported 6-gene (LMO2, BCL6, FN1, CCND2, SCYA3 and BCL2) model as predictor of prognosis in DLBCL. To avoid variation, all samples were tested in a single centre and single platform. This study comprised 8 countries (Brazil, Chile, Hungary, India, Philippines, S. Korea, Thailand and Turkey). Using the Kaplan-Meier and log rank test on patients (n=162) and two mortality risk groups (with those above and below the mean representing high and low risk groups) confirmed that the 6-gene predictor score correlates significantly with overall survival (OS, p < 0.01) but not with event free survival (EFS, p=0.18). Adding the International Prognostic Index (IPI) shows that the 6-gene predictor score correlates significantly with high IPI scores for OS (p < 0.05), whereas those with low IPI scores show a trend not reaching significance (p=0.08). This study defined an effective and economical qRT-PCR strategy and validated the 6-gene score as a predictor of OS in an international setting.Fil: Tekin, Nilgun. Ankara University. Biotechology Institute; TurquíaFil: Omidvar, Nader. Cardiff University; Reino UnidoFil: Morris, Tim Peter. Clinical Trials Unit at University College. Medical Research Council; Reino UnidoFil: Conget, Paulette. Universidad del Desarrollo; ChileFil: Bruna, Flavia Alejandra. Universidad del Desarrollo; Chile. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Timar, Botond. Semmelweis University. Department of Pathology and Experimental Cancer Research; HungríaFil: Gagyi, Eva. Semmelweis University. Department of Pathology and Experimental Cancer Research; HungríaFil: Basak, Ranjan. Tata Memorial Hospital. Departments of Medical Oncology & Pathology; IndiaFil: Naik, Omkar. Tata Memorial Hospital. Departments of Medical Oncology & Pathology; IndiaFil: Auewarakul, Chirayu. Faculty of Medicine Sirira; Tailandia. Chulabhorn Cancer Centre; TailandiaFil: Sritana, Narongrit. Faculty of Medicine Sirira; Tailandia. Chulabhorn Cancer Centre; TailandiaFil: Levy, Debora. Chulabhorn Cancer Centre; Tailandia. Faculty of Medicine Sirira; TailandiaFil: Cerci, Juliano Julio. Department of Nuclear Medicine. Quanta - Diagnóstico e Terapia; BrasilFil: Bydlowski, Sergio Paulo. Universidade de Sao Paulo; BrasilFil: Pereira, Juliana. Universidade de Sao Paulo; BrasilFil: Dimamay, Mark Pierre. St. Lukes Medical. Research and Biotechnology Division; FilipinasFil: Natividad, Filipinas. St. Lukes Medical. Research and Biotechnology Division; FilipinasFil: Chung, June-Key. Seoul National University Hospital. Department of Nuclear Medicine; Corea del SurFil: Belder, Nevin. Ankara University. Biotechology Institute; TurquíaFil: Kuzu, Isinsu. Ankara University. Faculty of Medicina; TurquíaFil: Paez, Diana. International Atomic Energy Agency; AustriaFil: Dondi, Maurizio. International Atomic Energy Agency; AustriaFil: Carr, Robert. King’s College. Guy’s & St Thomas’ Hospital; Reino UnidoFil: Ozdag, Hilal. Ankara University. Faculty of Medicina; TurquíaFil: Padua, Rose Ann. Institut National de la Sante Et de la Recherche Médica; Francia. Université Paris-Diderot; Francia. Institut Universitaire d'Hématologie; Franci

PRDM1/BLIMP1 is commonly inactivated in anaplastic large T-cell lymphoma

Anaplastic large cell lymphoma (ALCL) is a mature T-cell lymphoma that can present as a systemic or primary cutaneous disease. Systemic ALCL represents 2% to 5% of adult lymphoma but up to 30% of all pediatric cases. Two subtypes of systemic ALCL are currently recognized on the basis of the presence of a translocation involving the anaplastic lymphoma kinase ALK gene. Despite considerable progress, several questions remain open regarding the pathogenesis of both ALCL subtypes. To investigate the molecular pathogenesis and to assess the relationship between the ALK(+) and ALK(-) ALCL subtypes, we performed a genome-wide DNA profiling using high-density, single nucleotide polymorphism arrays on a series of 64 cases and 7 cell lines. The commonest lesions were losses at 17p13 and at 6q21, encompassing the TP53 and PRDM1 genes, respectively. The latter gene, coding for BLIMP1, was inactivated by multiple mechanisms, more frequently, but not exclusively, in ALK(-)ALCL. In vitro and in vivo experiments showed that that PRDM1 is a tumor suppressor gene in ALCL models, likely acting as an antiapoptotic agent. Losses of TP53 and/or PRDM1 were present in 52% of ALK(-)ALCL, and in 29% of all ALCL cases with a clinical implication