Clinical value of ALK and CD30 expression in mature systemic T cell lymphomas: analysis from the Czech Lymphoma Study Group database (NIHIL).

Mature T cell lymphomas (MTCLs) have worse prognosis, and in contrast to B cell lymphomas, there is no universal marker like CD20 with exception of ALK and CD30, which are present in proportion of MTCL only. Up to now, ALK is traditionally associated with good prognosis in ALCLs, and there are some evidences that CD30-positive T cell or B cell lymphomas have better prognosis. In our retrospective, population-based analysis, we analyzed the real clinical value of ALK and CD30 in the most frequent MTCL subtypes. Between 2000 and 2017, we identified 732 patients with newly diagnosed ALCL, AITL, or PTCL-NOS. Among them, 207 ALCL patients were with known ALK, whereas 61 AITL and 238 PTCL-NOS with known CD30 expression. There were 69/207 (33.3%) ALK + ALCLs, who displayed better 5-year PFS (65.6% vs. 36.2%) (p .001) and 5-year OS (71.5% vs. 45.9%) (p .002) compared to ALK - ; ALK + patients were significantly younger (median 48 vs. 60 years; p < 0.001). For patients ≥ 60 years, 5-year PFS (38.5% vs. 31.2%) and 5-year OS (38.5% vs. 39.6%) were similar between ALK + vs. ALK - patients. For AITL and PTCL-NOS, there were 44/61 (72.1%) and 120/238 (50.4%) CD30 + samples, and difference in CD30 expression was significant (p .02). AITL patients had 5-year OS of 43.8% vs. 55.7% (p 0.848) and 5-year PFS of 36.7% vs. 29.4% (p .624) for CD30 + vs. CD30 - patients, whereas PTCL-NOS had 5-year OS of 35.7% vs. 34.3% (p .318) and 5-year PFS of 29.3% vs. 22.5% (p.114) for CD30 + vs. CD30 - cases. We conclude that ALK in ALCLs (≥ 60 years) and CD30 expression in PCTL-NOS and AITL have only limited prognostic value.

Lymphomas and acute abdomen - a set of case reports.

Surgical treatment of gastrointestinal solid tumors is the basic method with a curative potential. However, the first-line treatment modalities in lymphomas are systemic oncology therapy (chemotherapy, immunotherapy and hematopoietic stem cell transplantation), radiotherapy or their combination. Surgery in lymphomas is predominantly associated with acute disease and dominantly, surgery is still used mainly in diagnosing lymphomas. Acute abdomen associated with lymphoma can be divided into 3 groups: bleeding, obstruction and perforation of GIT due to lymphoma. All these conditions might be caused by both gastrointestinal (extranodal) lymphomas or advanced nodal lymphomas that directly infiltrate or compress gastrointestinal tract (GIT) as well. Perforation is also often associated with the effect of systemic chemotherapy administration. When treating acute abdomen conditions caused by lymphomas, multidisciplinary cooperation with all participating experts is necessary. From the surgical point of view, minimizing the risk of postoperative complications is crucial to ensure the possibility of early systemic oncological treatment administration.

[Novel Findings in Follicular Lymphoma Pathogenesis and the Concepts of Targeted Therapy]. / Nové poznatky o patogenezi folikulárního lymfomu a koncepty cílené lécby.

The molecular pathogenesis of follicular lymphoma (FL) was partially revealed by the discovery of BCL2 translocations to the region encoding the immunoglobulin heavy chain, which accompany the vast majority of cases. This aberration leads to the ectopic and constitutive expression of anti-apoptotic BCL2 protein in B-cells. Nevertheless, the aberration alone is not sufficient for FL development, which suggests necessity of further genetic aberrations acquisition for neoplastic transformation to FL. Their discovery has been enabled by recent progress in the field of massive parallel sequencing (next generation sequencing), which revealed high number of genetic aberrations connected with onset and progression of FL. The occurrence of many of these aberrations in the early stages of the disease, and the fact that they are shared by the majority of patients with FL, fundamentally changed our former understanding of the disease onset. Furthermore, in a large fraction of patients, FL undergoes histological transformation to a more aggressive lymphoma, which is also associated with specific genetic alterations. In this review, we summarize the current knowledge of molecular pathways connected with FL biology and discuss their role in the context of normal B-cell development. Understanding of FL biology is essential for the development of new targeted therapies and the stratification of patients, and potentially also for the selection of treatment for specific patients who share the same genetic aberrations.Key words: follicular lymphoma - mutation - aberration - apoptosis - epigenetic regulators - microRNA This research was carried out under the project CEITEC 2020 (LQ1601) with financial support from the Ministry of Education, Youth and Sports of the Czech Republic under the National Sustain ability Programme II. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 28. 1. 2017Accepted: 5. 3. 2017.

[The Importance of MicroRNA Deregulation in the Molecular Pathogenesis and Histological Transformation of Follicular Lymphoma]. / Význam deregulace mikroRNA v molekulární patogenezi a histologické transformaci folikulárního lymfomu.

BACKGROUND: Molecular pathogenesis of follicular lymphoma (FL) is characterized by substantial dysregulation of epigenetic regulators. Many cases of FL are associated with the aberrant expression of non-coding regulatory RNAs, namely microRNAs (miRNA). Here we studied changes in miRNA expression and their association with histological transformation of FL to diffuse large B-cell lymphoma (DLBCL). MATERIAL AND METHODS: To identify changes in miRNA levels during FL transformation we performed a global expression analysis of 377 miRNAs in 16 samples (8 pairs) from FL patients vs. transformed FL (tFL) (TLDA miRNA cards; Thermo Fisher Scientific). The association of miRNA expression with clinical-biological characteristics and target proteins were further analyzed in a cohort of 89 FL patients. RESULTS: The miRNA expression profiling of paired FL-tFL samples revealed statistically significant changes in the expression of five miRNAs (p < 0.05). Four of them were down-regulated and one was up-regulated in tFL compared to FL. Lower levels of one of these miRNA were also associated with higher proliferation rate of FL cells (Ki-67 > 20%), higher FLIPI score ( 3) and shorter overall survival of FL patients. Furthermore, we found that this miRNA regulates the levels of FOXP1 protein in FL. The patients with high-level FOXP1 expression (> 70% positive cells) had significantly shorter overall survival in comparison to those with low-level FOXP1 expression (< 30% positive cells). Moreover, FOXP1 protein levels were higher in most tFL samples compared to FL before transformation. CONCLUSION: We found miRNAs associated with the transformation of FL to a more aggressive DLBCL, and described that one of them could serve as a prognostic marker. We found that reduced expression of this tFL-associated miRNA results in increased levels of FOXP1 protein and we assume that the increased activity of FOXP1 proto-oncogene contributes to the histological transformation of FL.Key words: follicular lymphoma - microRNA - histological transformation This work was supported by Czech Ministry of Health registration No. 16-29622A. All rights reserved. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 5. 3. 2017Accepted: 26. 3. 2017.

[Staging and Treatment Response Evaluation in Malignant Lymphomas - Czech Lymphoma Study Group Recommendations According to Criteria Revised in 2014 (Lugano Classification)]. / Hodnocení klinického stadia a lécebné odpovedi u maligních lymfomu - doporucení Kooperativní lymfomové skupiny na základe revidovaných kritérií z roku 2014 (Luganská klasifikace).

BACKGROUND: Recent advances in the use of the imaging modalities, especially PET/CT, and their utilization for determining clinical stage (CS) and assessment treatment response (TR) in malignant lymphomas, along with development of prognostic tools and new treatment modalities, formed the basis for the revised criteria for evaluating CS and TR (published as the Lugano classification, 2014). MATERIALS AND METHODS: The authors summarize the new Lugano recommendations (published in 2014) and the changes from the criteria published in 2007. Moreover, discussion of the changes places emphasis on practical use. The practicality of the Lugano classification, 2014 was the subject of consensus meeting at the annual meeting of the Cooperative Lymphoma Study Group (CLSG) in March 2015. This study reports the final consensus. The CLSG recommends use of the Lugano classification, 2014, but recommends some modifications. CONCLUSIONS: Standardization of the criteria used to determine CS and TR in malignant lymphomas has led to improvements in initial staging and assessment of TR. The criteria are helpful for unifying response assessment in clinical trials and simplify the work of regulatory agencies (e.g., the EMA and the Czech State Institute for Drug Control) when registering new drugs. It also allows evaluation of treatment outcomes outside clinical trials, for example within the CLSG prospective registry of patients with newly diagnosed lymphoma. KEY WORDS: malignant lymphoma - computed tomography - positron emission tomography - staging - treatment responseThis work was supported by the grant Prvouk P27/2012 of the Third Faculty of Medicine, Charles University in Prague and by the grant of the Czech Lymphoma Study Group No. NT12193-5/2011.The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 24. 1. 2016Accepted: 16. 2. 2016.

Outcomes of 167 healthy sibling donors after peripheral blood stem cell mobilization with G-CSF 16µg/kg/day: efficacy and safety.

Mobilization of peripheral blood stem cells (PBSC) using the granulocyte colony-stimulating factor (G-CSF) has enabled the collection even from older donors and those with comorbidities. Several clinical parameters have been reported to predict the success of PBSC mobilization. The aim of our study was to evaluate the safety of PBSC donation in a cohort of 167 sibling donors after mobilization with G-CSF 16 µg/kg/day for 5 days during short- and long term follow-up and to analyse the efficacy, toxicity and factors influencing CD34+ mobilization capacity. All 167 sibling donors completed the established mobilization protocol. The median yield was 7.9x106 CD34 cells/kg per recipient weight. The optimal target dose of CD34 cells ≥ 4.0x106/kg was achieved in 140 donors (84%). Only in 4 donors (2%) was the CD34+ yield < 2x106/kg. No major toxicities occured.Factors associated with higher PBSC yields included age 51/µL (p 45.5 x 109/L (p = 0.003). Comorbidity score, performance status and donor weight did not significantly influence PBSC yields. Long-term follow-up was possible in 60% (101/167) of the donors. The median length of follow-up from PBSC donation was 11.9 years. Most of these donors reported good or very good general health (91%), and no hematological malignancies were observed.The mobilization of PBSC in sibling donors with G-CSF 16 µg/kg/day is an effective and safe procedure with no significant short- and long-term toxicities.

[Vitamin D during cancer treatment]. / Vitamin D pri lécbe nádorového onemocnení.

Recent knowledge on vitamin D has shown that its active form not only regulates calcium and phosphate metabolism but also has significant antimitotic and cell differentiation effects. It can inhibit proliferation, angiogenesis and metastatic potential in cancer tissue. Insufficient vitamin D plasma levels are found in 20- 60% of cancer patients at dia-gnosis. By many authors, vitamin D deficiency is associated with higher aggressivity of tumor and shorter survival of patients. Even in the absence of clinical studies showing benefit of supplementation on outcome, clear recommendations are currently available for treatment of vitamin D deficiency. Owing to the high prevalence of vitamin D insufficiency in cancer patients and significant risks of its further decrease after antitumor therapy, it should become standard of care to examine 25- hydroxyvitamin D serum levels and correct vitamin D insufficiency in cancer patients.

[The role of radiotherapy in the treatment of malignant lymphomas - recommendations of the Czech Lymphoma Study Group]. / Postavení radioterapie v lécbe maligních lymfomu - doporucení Kooperativní lymfomové skupiny.

BACKGROUND: Indication of radiotherapy in lymphoma treatment is an important strategic decision requiring comprehensive expertise. It also calls for a better definition of the position of radiotherapy in clinical practice. DESIGN: This position paper represents a consensus between hematooncologists and radiation oncologists on the role of RT in treatment of different histological types and stages of malignant lymphomas. The discussion was underway within professional societies of both specializations (Czech Lymphoma Study Group for the hematooncologists and the Society of Radiation Oncology, Biology and Physics for the radiation oncologists). RESULTS: The consensus presented here was reached in early 2012 and draws on evidence-based medicine and clinical practice. Besides defining the role of radiotherapy in lymphoma treatment, this paper also gives specific recommendations on total doses of radiotherapy in lymphoma treatment. CONCLUSION: These recommendations will supplement 7th edition of "Diagnostic and treatment guidelines in patients with malignant lymphoma" scheduled for publication in 2013.

Circulating free DNA and its potential in the diagnostics and therapy of malignant lymphoma.

BACKGROUND: Malignant lymphomas represent a highly heterogeneous group of tumors with varied clinical behavior - from indolent to very aggressive forms with survival in the order of months. From the very beginning, these diseases are considered systemic, often occurring in several anatomical locations simultaneously. However, diagnosis and exact classification are usually inferred from a bio-psy of a single pathological lymph node or infiltrate, even though clinical experience shows that the bio-logical behavior of lymphoma is not necessarily identical across anatomical locations. In an effort to address this issue as well as the problem of bio-psy of not easily accessible compartments, circulating free DNA (cfDNA), which contains circulating tumor DNA (ctDNA) released from dead tumor cells, has been extensively studied in recent years. This DNA is easily accessible from liquid bio-psies such as blood or other patient's bodily fluids. PURPOSE: This article summarizes current scientific knowledge on cfDNA and ctDNA, particularly in the context of malignant lymphoma, and foreshadows its potential future uses. CONCLUSION: Detection and analysis of cfDNA represents a new approach that can lead to future improvements in all phases of lymphoma treatment from diagnostics to minimal residual disease monitoring.

Outcome in patients with diffuse large B-cell lymphoma who relapse after autologous stem cell transplantation and receive active therapy. A retrospective analysis of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

Autologous hematopoietic stem cell transplantation (auto-HSCT) is the standard of care for patients with diffuse large B-cell lymphoma (DLBCL) who relapse/progress after first line chemoimmunotherapy. Long-term outcome of those who relapse after transplant is poor. We present the results of a retrospective study of 256 adult patients reported to the EBMT registry with DLBCL who relapsed after auto-HSCT performed between 2003 and 2013, and who received active salvage strategies. One hundred and fifty-four (60%) were male; median age was 53 years. Median time to relapse was 7 months, 65% relapsed during the first year. Overall response rate after salvage therapy was 46%. Median follow-up after first salvage therapy was 40 months (IQR 23-63 months). Overall survival (OS) at 3 years was 27% (95% CI 22-33). OS at 3 years of patients relapsing longer than 1 year after auto-HSCT was 41% (95% CI 31-53) compared with 20% (95% CI 14-24) in those who relapsed in less than 1 year. Eighty-two patients (32%) had a second HSCT, an allogeneic HSCT (allo-HSCT) in 69 cases, at a median time of 6.5 months after relapse. OS at 3 years after allo-HSCT was 36% (95% CI 25-51). In conclusion, the prognosis of patients with DLBCL that relapse after auto-HSCT is dismal. Patients who relapse in less than 1 year remain an unmet need, and should be considered for CAR T cell therapy or clinical trials. Patients who relapse after 1 year can be rescued with salvage therapies and a second HSCT. These results provide a benchmark to compare data of new prospective studies.

[Invasive aspergillosis in hematooncological patients: advantages and disadvantages of various diagnostic methods, treatment options and financial costs of therapy]. / Invazivní aspergilové infekce u hematoonkologických nemocných: význam jednotlivých diagnostických metod, lécebných postupu a nástin financní nárocnosti lécby.

BACKGROUND: Invasive aspergillosis (IA) is a leading invasive fungal infection in hematooncological patients. The aim of this study was to analyse the incidence, diagnostic procedures and treatment of IA in hematooncological department in large hospital in the Czech Republic. PATIENTS AND METHODS: A retrospective analysis of medical and laboratory records from patients hospitalised in our department with proven/probable IA between January 2000 and December 2006 was performed. RESULTS: 52 cases of IA in 51 patients were identified (17.3% proven IA/82.7% probable IA). Number of IA cases notably increased during study period (1 case of IA in 2000 vs 21 cases of IA in 2006) and majority of them was of nosocomial origin (61.5%). Pulmonary aspergillosis was diagnosed in 46 cases (88.5%). Patients treated for acute leukemia or undergoing allogeneic stem cell transplantation represent the group at the highest risk of IA (in total 52% of cases). Fever and signs of pulmonary involvement were the most common clinical signs of infection (presented in 92.3% and 69.2 cases respectively). Conventional diagnostic methods including autopsy were able to diagnose only 15 cases of IA (28.8%). In all other cases (71.2%) the diagnosis was done by detection of galactomannan (GM) in serum. Introduction of GM monitoring enabled erlier initiation of antifungal treatment by 4 days. Initial therapy of IA led to the treatment response (partial and complete) in 18 (34.6%) of infections--the highest percentage of response has been seen in voriconazole monotherapy group (42%) and when combination of voriconazole and caspofungin has been used (83%). Salvage therapy was initiated due to the failure of initial treatment in 21 (40.3%) of cases. Patients were treated mostly with combination ofvoriconazole and caspofungin and/or monotherapy with voriconazole has been used with treatment response 55% and 50% respectively. Introduction of new antifungal drugs together with increased number of patients with IA led to the marked increase of total costs spent on treatment of IA per year--from 11,5 thousands CZK in 2000 to 6,2 millions CZK in 2006. CONCLUSIONS: IA is the most frequent cause of infection-related mortality in patients with haematological malignancies. Routine use of non-culture base methods in diagnosis of IA together with treatment using new, effective antifungals can improve prognosis of patients with this life threatening infection.