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Over the years, a rising incidence of liver cirrhosis and lymphoma has been observed. Therefore, the risk of having cirrhosis as a comorbidity increases, thus challenging treatment approaches as data on the management of these patients is lacking. We performed a systematic review to summarize papers that analyzed patients with liver cirrhosis that occurred before and/or concomitantly to lymphoma. We identified 153 papers (230 patients) through Pubmed and/or Embase search. Publications comprised predominantly of case reports and/or case series. Most patients had HCV-related cirrhosis (62.6%), and aggressive lymphoma histology (59.6%). Data on liver status was available in 55.7% of all patients, with 46.1% having decompensated liver cirrhosis. These patients experienced more often treatment reductions and/or modifications, treatment side effects, and inferior survival than those with compensated cirrhosis (median 18 months vs. median not reached). Dose reductions and/or treatment modifications primarily due to concomitant liver disease were common. Moreover, liver toxicity was observed in 33.6% of patients with provided information on treatment side effects, ranging from mild toxicity to liver failure with fatal outcomes. Again, despite treatment modification/reduction, patients with decompensated liver cirrhosis developed hepatic toxicity more frequently than patients with compensated liver disease. Although patients suffering from cirrhosis and lymphoma can tolerate standard chemoimmunotherapy, a cautious multidisciplinary approach is needed to evaluate the risks and benefits.

Background and Aim: Based on advances in the diagnosis, classification, and management of diffuse large B-cell lymphoma (DLBCL), a number of new prognostic models have been proposed. The aim of this study was to review and compare different prognostic models of DLBCL based on the statistical methods used to evaluate the performance of each model, as well as to analyze the possible limitations of the methods. Methods and Results: A literature search identified 46 articles that proposed 55 different prognostic models for DLBCL by combining different clinical, laboratory, and other para-meters of prognostic significance. In addition, six studies used nomograms, which avoid risk categorization, to create prognostic models. Only a minority of studies assessed discrimination and/or calibration to compare existing models built upon different statistical methods in the process of development of a new prognostic model. All models based on nomograms reported the c-index as a measure of discrimination. There was no uniform evaluation of the performance in other prognostic models. We compared these models of DLBCL by calculat-ing differences and ratios of 3-year overall survival probabilities between the high-and the low-risk groups. We found that the highest and lowest ratio between low-and high-risk groups was 6 and 1.31, respectively, while the difference between these groups was 18.9% and 100%, respectively. However, these studies had limited duration of follow-up and the number of patients ranged from 71 to 335. Conclusion: There is no universal statistical instrument that could facilitate a comparison of prognostic models in DLBCL. However, when developing a prognostic model, it is recom-mended to report its discrimination and calibration in order to facilitate comparisons between different models. Furthermore, prognostic models based on nomograms are becoming more appealing owing to individualized disease-related risk estimations. However, they have not been validated yet in other study populations.

The Follicular Lymphoma International Prognostic Index (FLIPI) is widely used for risk stratification of patients with follicular lymphoma (FL). Motivated by evolvement in treatment modalities, several prognostic models for FL have been proposed recently. This systematic review aimed to identify available prognostic models for newly diagnosed FL and discuss their potential limitations. A total of ten studies fulfilled the inclusion criteria. Different clinical, laboratory, radiological, and histopathological findings were combined in prognostic models. The majority of studies developed models from clinical trial cohorts, and most lacked validation in populations treated with current treatment options. Although the FLIPI is the most widely used model for prognostication in FL patients, current prognostic models, including FLIPI, are rarely used in clinical practice for treatment decision-making. Future studies should validate the existing, or develop new prognostic models, to identify which of the current standard treatment options benefit high-risk FL patients the most.

The prognostic value of the International Prognostic Index (IPI) has been re-evaluated in the rituximab-treated diffuse large B cell lymphoma (DLBCL) patients. Accordingly, National Comprehensive Cancer Network-IPI (NCCN-IPI) has been introduced to estimate prognosis of DLBCL patients. However, comorbidities that frequently affect elderly DLBCL patients were not analyzed. The aim of this study was to evaluate the prognostic significance of comorbidities using Charlson Comorbidity Index (CCI) in 962 DLBCL patients. According to CCI, majority of patients (73.6%) did not have any comorbidity, while high CCI (≥ 2) was observed in 71/962 (7.4%) patients, and in 55/426 (12.9%) of the elderly patients aged ≥ 60 years. When the CCI was analyzed in a multivariate model along with the NCCN-IPI parameters, it stood out as a threefold independent risk factor of a lethal outcome. Also, we have developed a novel comorbidity-NCCN-IPI (cNCCN-IPI) by adding additional 3 points if the patient had a CCI ≥ 2. Four risk groups emerged with the following patient distribution in low, low-intermediate, high-intermediate, and high group: 3.4, 34.3, 49.4, and 12.5%, respectively. The prognostic value of the new cNCCN-IPI was 2.1% improved compared to that of the IPI, and 1.3% improved compared to that of the NCCN-IPI (p

Autologous stem cell transplant with high-dose chemotherapy is considered to be an effective treatment strategy for outcome improvement in lymphoma patients, especially those with refractory and relapsed disease. Despite the feasibility and efficacy of autologous stem cell transplant, patients with lymphoma still face the risk for relapse, mostly patients who have adverse prognostic features. Salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant is recognized as the most effective strategy for relapsed or refractory Hodgkin lymphoma or aggressive non-Hodgkin lymphoma improving their response rate. First line therapy is ABVD (Hodgkin lymphoma patients), R-CHOP or R-CHOP-like regimens while salvage regimens such as DHAP, ESHAP, ICE represent the standard of care for relapsed/refractory lymphoma patients. Before autologous stem cell transplant, standard condition regimens are BEAM or CBV.

Over the last decade, several prognostic models have been proposed for primary central nervous system lymphoma (PCNSL), but consensus on the optimal model for these patients is absent or lacking. This study aims to review available prognostic models for PCNSL and discuss their prognostic features. A comprehensive literature search performed in Pubmed/Embase identified ten studies with a variable number of analysed patients (range 32–3453), which proposed 12 prognostic models. Age and performance status were the most important prognostic factors in PCNSL and an integral part of the majority of the proposed models. However, there is no universally accepted prognostic model for PCNSL owning to a number of limitations such as a small number of patients, limited samples obtained for genetic analysis, retrospective nature of studies, single centre studies, and lack of validation. Future multicentre studies are necessary to determine the optimal prognostic model for PCNSL by combining different prognostic markers of significance.

Prognostic significance of immune microenvironment has been emphasized using the most advanced analysis, with consecutive attempts to reveal prognostic impact of this findings. The aim of this study was to compare and define prognostic significance of clinical parameters, microvessel density (MVD) in tumour tissue and expression of CD44s as adhesive molecule on tumour cells in diffuse large B cell lymphoma-DLBCL, primary central nervous system DLBCL-CNS DLBCL and follicular lymphoma-FL. A total of 202 histopathological samples (115 DLBCL/65 FL/22 CNS DLBCL) were evaluated. Overall response (complete/partial remission) was achieved in 81.3 % DLBCL patients, 81.8 % primary CNS DLBCL and 92.3 % FL. Absolute lymphocyte count-ALC/Absolute monocyte count-AMC2.6 in DLBCL and ALC/AMC ≥ 4.7 in FL were associated with better event-free survival (EFS) and overall survival (OS) (p 0.05). In DLBCL, MVD 42 blood vessels/0.36 mm(2) correlated with primary resistant disease (p 0.0001), poorer EFS and OS (p = 0.014). High CD44s expression in FL correlated with inferior EFS and OS (p 0.01). In DLBCL, multivariate Cox regression analysis showed that ALC/AMC was independent parameter that affected OS (HR 3.27, 95 % CI 1.51-7.09, p = 0.003) along with the NCCN-IPI (HR 1.39, 95 % CI 1.08-1.79, p = 0.01). Furthermore, in FL, ALC/AMC mostly influenced OS (HR 5.21, 95 % CI 1.17-23.21, p = 0.03), followed with the FLIPI (HR 3.98, 95 % CI 1.06-14.95, p = 0.041). In DLBCL and FL, ALC/AMC is simple and robust tool that is, with current prognostic scores, able to define long-term survival and identify patients with inferior outcome. The introduction of immunochemotherapy might altered the prognostic significance of microenvionmental biomarkers (MVD and CD44s).

Consideration of comorbidity, disability, and frailty represents a significant part of the treatment of elderly multiple myeloma (MM) patients. The aim of study was to analyze the effect of the Charlson Comorbidity Index (CCI) and scale of Instrumental Activities of Daily Living (IADL) on the course of disease.The study included 110 newly diagnosed MM patients older than 65 years of age. According to the CCI most patients had at least 1 comorbidity (CCI score of 1) and most of them (51 of 110 patients; 46.4%) had an age-adjusted CCI (aaCCI) score of 5 to 6. Most of our patients were capable of performing routine daily activities (IADL ≥ 6). Patients were treated with thalidomide- and bortezomib- based combinations, or with conventional chemotherapy.International Staging System (ISS) score 3 correlated with high scores of CCI or aaCCI (R = 0.314, P.003; R = .317, P.002, respectively), and lower IADL (R = 0.259, P.007). The probability of adverse events was 70% greater for CCI score ≥ 2 (odds ratio [OR], 1.72); 28% for aaCCI ≥ 5 (OR, 1.28) and 22% higher for IADL3 (OR, 2.25). The patients with a CCI score of 0 to 1 had significantly longer overall survival (OS; log rank, 6.538; P.011). The patients with aaCCI ≥ 5 had significantly shorter OS (log rank, 4.209; P.040), and the patients with IADL3 had significantly longer OS (log rank, 6.62; P.001). In the proposed model, aaCCI ≥ 5 and IADL3 scores had a major effect on the OS (χ(2), 8.46; P = .037).CCI, aaCCI, and IADL scale are clinical parameters of prognostic significance. A proposed model for a personalized treatment approach is based on variables such as scores for aaCCI ≥ 5 and IADL3.

Background/Aim. Follicular lymphoma (FL) is a B-cell tumor usually with indolent clinical course, yet in some cases the course of the disease can be very aggressive. The aim of the re-search was to determine distribution of patients into prognostic groups based on the International Prognostic Index (IPI) and Folicular Lymphoma International Prognostic Index (FLIPI) criteria, as well as to determine the importance of classifying patients into the prognostic groups, since this could potentially have the influence on selection of the treatment modality. Methods. The retrospective study was performed on 257 patients with follicular lymphoma diagnosed between January 2000 and April 2011. Results. Based on the IPI score, 153 (59.53%) patients had low risk, 57 (22.18%) low intermediate risk, 15 (5.84%) high intermediate risk, 9 (3.50%) high risk, whereas the classification of 23 patients diagnosed with FL remained with unknown risk according to the IPI. Based on the FLIPI prognostic index, 113 (43.97%) patients had low risk, 70 (27.24%) intermediate risk and 51 (19.84%) high risk, whereas the classification of 23 (8.95%) patients remained unknown. On the basis of the FLIPI 2 prognostic index, 48 (18.68%) patients had low risk, 145 (56.42%) intermediate risk and 41 (15.95%) high risk. The classification into prognostic groups for 23 (8.95%) patients remained unknown. According to the IPI, FLIPI and FLIPI 2 there were the patients that required treatment in all the risk groups. Conclusion. The FLIPI and FLIPI 2 effectively identify patients at high risk, thus helping in treatment decision for each single patient.

Background/Aim. The widely accepted Follicular Lymphoma International Prognostic Index (FLIPI) divides patients into three risk groups based on the score of adverse prognostic factors. The estimated 5-year survival in patients with a high FLIPI score is around 50%. The aim of this study was to analyse the prognostic value of clinical and laboratory parameters that are not included in the FLIPI and the New Prognostic Index for Follicular Lymphoma developed by the International Follicular Lymphoma Prognostic Factor Project (FLIPI2) indices, in follicular lymphoma (FL) patients with a high FLIPI score and high tumor burden. Methods. The retrospective analysis included 57 newly diagnosed patients with FL, a high FLIPI score and a high tumor burden. All the patients were diagnosed and treated between April 2000 and June 2007 at the Clinic for Hematology, Clinical Center of Serbia, Belgrade. Results. The patients with a histological grade > 1, erythrocyte sedimentation rate (ESR) ? 45 mm/h and hypoalbuminemia had a significantly worse overall survival (p = 0.015; p = 0.001; p = 0.008, respectively), while there was a tendency toward worse overall survival in the patients with an Eastern Cooperative Oncology Group (ECOG) > 1 (p = 0.075). Multivariate Cox regression analysis identified a histological grade > 1, ESR ? 45 mm/h and hypoalbuminemia as independent risk factors for a poor outcome. Based on a cumulative score of unfavourable prognostic factors, patients who had 0 or 1 unfavourable factors had a significantly better 5-year overall survival compared to patients with 2 or 3 risk factors (75% vs 24.1%, p = 0.000). Conclusion. The obtained results suggest that from the examined prognostic parameters histological grade > 1, ESR ? 45 mm/h and hypoalbuminemia can contribute in defining patients who need more aggressive initial treatment approach, if two or three of these parameters are present on presentation.

Introduction Vitamin D has a role in cellular differentiation, proliferation, apoptosis, and angiogenesis and therefore is studied as a prognostic factor in cancer. The aim of our study was to assess the prevalence and significance of 25(OH)D deficiency in patients with lymphoid malignancies. Methodology Between January 2014 and June 2016 at the Clinic for Hematology, Clinical Center of Serbia, Belgrade, the pretreatment serum level of 25(OH)D was determined in 133 (62 women/71 men, median age 58 (18-84) years) previously untreated patients with lymphoid malignancy using a chemiluminescent immunoassay. From their medical records, we noted the age, clinical stage, Eastern Cooperative Oncology Group Performance Scale (ECOG PS), nutritional status using the Nutritional Risk Score 2002 (NRS2002), the time of year, comorbidity index, progression, and progression-free survival (PFS) for a median of 20 (1-32) months. The optimal cutoff point for prediction of outcome was determined using the Maximally Selected Rank Statistics. Results There were 37 (27.8%) patients with the severe 25(OH)D deficiency lt = 25 nmol/l, 80 (60.2%) with 25(OH)D deficiency 25-50 nmol/l, and 16 (12%) with 25(OH)D insufficiency 50-75 nmol/l. None of the patients had the desired normal level. There were significant differences between groups in regard to ECOG PS, NRS2002, type of lymphoma, and progression. The severely 25(OH)D-deficient patients had a shorter mean time until progression (P = 0.018). Cox regression analysis showed that 25(OH)D lt 19.6 nmol/l remained the only significant parameter for PFS (HR = 2.921; 95% CI 1.307-6.529). Conclusion The prevalence of 25(OH)D deficiency in the analyzed group of patients with lymphoid malignancies is high and greater in malnourished individuals. Patients with pretreatment serum 25(OH)D lt 19.6 nmol/l had a significantly shorter PFS.

The purpose of this study was to evaluate the clinical characteristics, prognostic factors, therapy and outcomes of patients with very late relapse (5 years) of Hodgkin's lymphoma (HL).We retrospectively reviewed the database of all relapsed patients with HL treated between 1999 and 2009 and compared the clinical characteristics and survival of patients who relapsed before and after 5 years of follow up.Among the group of 102 patients with relapsed HL 16 (15.68%) patients had very late relapse of disease. Median time to very late relapse was 86 months (range 61- 199). On relapse most of these patients (11; 68.5%) were in advanced clinical stage. Eleven (68.75%) patients with very late relapse were treated with high dose chemotherapy and autologous stem cell transplantation (ASCT). Second complete response was achieved in 13 (81.25%) patients. At a median follow up of 4.5 years after therapy, 13 (81.25%) patients are still alive (10 without disease and 3 with disease), while 3 patients died (2 from HL, and 1 from brain tumor). There was no significant difference between patients with very late relapse and patients who relapse earlier in terms of initial clinical parameters. Median overall survival of patients with very late relapse was significantly longer than in patients with earlier relapse (p=0.001), but survival calculated from the time оf relapse was not significantly different between these two groups of patients (p=0.83).An open question that remains is whether high dose therapy and ASCT is necessary in most patients with very late relapse of disease. Individualization of therapy in patients with very late relapse of HL is mandatory, tailored on risk factors and comorbidities.

Based on the results of clinical trials, there is no global consensus on the optimal first-line therapy for patients with advanced Hodgkin lymphoma (HL) with both ABVD and BEACOPP currently being used. However, the results of clinical trials are usually better than those in daily practice. We thus describe here our experience on 314 advanced classical HL patients treated with ABVD at the Clinical Center of Serbia and associated centers between 1997 and 2008. The median follow-up for all patients was 91 months; the estimated 5-yr event-free survival was 62% and the 5-yr overall survival (OS) 76%. Multivariate Cox regression analysis revealed that patients with IPS ≥ 3 and extranodal disease involving more than one site have a poorer outcome. The data presented here show on overall improvement in outcome as compared to more previous data and illustrate the problems of treating advanced stage HL outside the setting of a clinical trial.

Background: Primary testicular lymphoma (PTL) is a rare and highly aggressive extranodal non-Hodgkin's lymphoma. Patients and Methods: We evaluated the clinical and histopathological features and outcomes of 10 PTL patients treated in the period of 2003-2013 with multimodal therapy (rituximab, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), intrathecal prophylaxis, irradiation of the contralateral testis) following orchiectomy. Results: Complete remission was achieved in 8 patients after first-line therapy while 2 patients had disease progression. The median follow-up duration was 30 months (range 6-110 months). Relapse occurred in 3 patients. 1 patient relapsed in the contralateral testis, while the other 2 patients relapsed to the skin and the central nervous system (CNS), respectively. The time to relapse was 2, 8, and 9 months. Patients with disease progression and relapse received ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin) as salvage treatment, except for 1 patient who was treated with palliative radiotherapy. After second-line therapy, only 1 patient had a short partial remission of 2 months. The median overall survival was 48 months, and the mean progression-free survival was 36 months (the median was not reached). Conclusions: We evaluated 10 patients with PTL treated with rituximab plus CHOP, prophylactic intrathecal chemotherapy, and prophylactic irradiation of the contralateral testis, resulting in good outcome and low incidence of relapse in the contralateral testis; however, the benefit of intrathecal chemotherapy is not yet confirmed.

The Follicular Lymphoma International Prognostic Index (FLIPI) is widely used in the identification of risk groups among follicular lymphoma (FL) patients. The aim of the present study was to evaluate the prognostic value of FLIPI combined with the Charlson comorbidity index (CCI) and histological grade of lymphoma. 224 newly diagnosed FL patients (median age 56 years) treated with immunochemotherapy were retrospectively analysed. Low FLIPI had 21.0 % of patients, intermediate 28.1 % and high 46.9 %. 50.9 % of patients had no comorbidities. Only 7.1 % of patients had a high CCI score (≥2), while 25.9 % of patients were histological grade 3. Parameters that influenced overall survival were evaluated using Cox regression analysis, in which CCI, FLIPI and histological grade (p

Lymphoma patients are at increased risk of thromboembolic events but thromboprophylaxis in these patients is largely underused. We sought to develop and validate a simple model, based on individual clinical and laboratory patient characteristics that would designate lymphoma patients at risk for thromboembolic event. The study population included 1,820 lymphoma patients who were treated in the Lymphoma Departments at the Clinics of Hematology, Clinical Center of Serbia and Clinical Center Kragujevac. The model was developed using data from a derivation cohort (n = 1,236), and further assessed in the validation cohort (n = 584). Sixty-five patients (5.3%) in the derivation cohort and 34 (5.8%) patients in the validation cohort developed thromboembolic events. The variables independently associated with risk for thromboembolism were: previous venous and/or arterial events, mediastinal involvement, BMI30 kg/m(2) , reduced mobility, extranodal localization, development of neutropenia and hemoglobin level 100g/L. Based on the risk model score, the population was divided into the following risk categories: low (score 0-1), intermediate (score 2-3), and high (score3). For patients classified at risk (intermediate and high-risk scores), the model produced negative predictive value of 98.5%, positive predictive value of 25.1%, sensitivity of 75.4%, and specificity of 87.5%. A high-risk score had positive predictive value of 65.2%. The diagnostic performance measures retained similar values in the validation cohort. Developed prognostic Thrombosis Lymphoma - ThroLy score is more specific for lymphoma patients than any other available score targeting thrombosis in cancer patients. Am. J. Hematol. 91:1014-1019, 2016. © 2016 Wiley Periodicals, Inc.

Introduction There are few prediction tools for estimating the risk of thrombosis but they are based on studies performed on hospitalized medical patients without cancer or on hospitalized neutropenic cancer patients without special consideration to lymphoma patients. Aim Aim of our study was to determine incidence of thromboembolic (TE) events in patients with non Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL) and chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL) who were hospitalized to the lymphoma department in the Clinic of hematology, Clinical Center Serbia, Belgrade and Clinic of hematology, Clinical Center Kragujevac. Also, we assessed 2 predictive models (Padua and Khorana score) and create new model for the identification of lymphoma patients at risk for thromboembolism. Materials and Methods We reviewed all medical records of patients with with NHL, HL and CLL/SLL diagnosed and treated at two previously mentioned institution between January 2006 and December 2014. Results The study population included 1820 eligible lymphoma patients. Of all the patients included in the study, 99 (5.4%) developed at least one TE during a follow-up period of 3 months from the end of therapy. In the final multivariate analysis, the following variables were independently associated with risk of TE: previous VTE and/or arterial events, reduced mobility (ECOG 2-4), obesity (BMI >30 kg/m 2 ), extranodal localization, mediastinum involvement, development of neutropenia during therapy and hemoglobin level less than 100g/L. Subsequently, we assigned points for the risk model based on the regression coefficients obtained from the final model and developed Thrombosis Lymphoma (ThroLy) score consisting of all significant variables from the multivariate analysis. The Throly score was arrived at by assigning 2 points for all parameters with an OR >5 in multivariate regression analyses (e.g., previous VTE and arterial events, mediastinum involvement, and BMI) and 1 point for rest all other significant variables. Finally, population were divided into 3 risk categories for TE based on the score from the risk model: low (score 0-1), intermediate (score 2-3) and high (score >3). High risk score had a positive predictive value (probability of TE in those designated high risk) of 65.2%. Conclusions Significance of our investigation is development of score that help phisicians to recruit lymphoma patients at risk for development of thromboembolic complications. Also, we can say that our score is dynamic allowing us to change approach during different phase of therapy and is not limited to outpatient settings or with some complicated laboratory analysis.

We studied the prognostic significance of the absolute lymphocyte/monocyte count ratio (ALC/AMC), its contribution to the prognostic value of the International Prognostic Score (IPS), and evaluated if ALC/AMC could serve as a proxy for the frequency of CD68 + tumor-associated macrophages (TAMs) in 101 patients with advanced Hodgkin lymphoma (HL). The receiver operating characteristic (ROC) curve identified best cut-off values of 2.0 for ALC/AMC and 25% for CD68 + TAM. Patients with ALC/AMC 2, IPS 2 and 25% CD68 + TAM had an inferior overall survival (OS) and event-free survival (EFS). Spearman's test also uncovered a significant correlation between the ALC/AMC and TAM. Multivariate analysis identified ALC/AMC 2, IPS 2 and 25% CD68 + TAM as poor prognostic factors of OS and EFS. After evaluating ALC/AMC and IPS, we stratified patients into three progressively-worse-outcome groups (low-risk: 0 risk factors; intermediate: 1 risk factor; high: 2 risk factors). Our study encourages the combination of ALC/AMC with IPS, for refining risk prediction in advanced HL patients.

Background: Although Hodgkin’s lymphoma (HL) is a curable cancer, current treatment strategies based on risk stratification and response modulation are not precise enough. The predictive power of biological and morphological parameters is controversial, with prognostic models not reaching wide acceptance. Patients and Methods: We analyzed the prognostic relevance of 8 parameters in 85 advancedstage classical HL patients, in order to determine whether tissue-based variables could add prognostic value to standard clinical parameters, thus contributing to better risk stratification at presentation. Results: Univariate analysis confirmed 5 indicators of shorter overall survival (OS): Bcl-2 overexpression; increased CD68+ tumor-associated macrophages (TAM); international prognostic score (IPS) > 2; bulky disease; and total lymph node involvement (TLNI) with regard to neoplastic and inflammatory cells. Apart from TLNI, these parameters influenced lower event-free survival (EFS). Multivariate analysis identified 5 independent factors for OS: Bcl-2 overexpression; increased CD68+ TAM; TLNI; IPS > 2; and bulky disease. Increased CD68+ TAM, IPS > 2, and bulky disease affected the EFS. Utilizing the cumulative score of unfavorable prognostic factors for OS, we designed a prognostic model stratifying patients into 4 risk groups (with 0–1, 2, 3, or 4–5 factors), each with progressively reduced OS (p < 0.001). Conclusion: Our findings support the combination of tissue-based variables with clinical parameters at diagnosis, identifying patients who are at higher risk of poor outcome.

The aim of this study was to evaluate the prognostic significance of international prognostic index (IPI), mantle cell lymphoma IPI (MIPI), simplified MIPI (sMIPI), and MIPI biological (MIPIb), as well as their correlation with immunophenotype, clinical characteristics, and overall survival (OS), in a selected group of 54 patients with advanced-stage mantle cell lymphoma (MCL), treated uniformly with CHOP. Seventeen patients had IV clinical stage (CS), while other 37 had leukemic phase at presentation. Diffuse type of marrow infiltration was verified in 68.5% and nodular in remainder patients. Extranodal localization (25.9%) included bowel (20.4%), pleural effusion, sinus, and palpebral infiltration. All of analyzed patients expressed typical MCL immunophenotypic profile: CD19(+)CD20(+)CD22(+)CD5(+)Cyclin-D1(+)FMC7(+)CD79b(+)smIg(+)CD38(+/-)CD23(-)CD10(-). Median OS of the whole group was 23 months, without significant differences between IV CS and leukemic phase patients. Thirty-two patients (59.3%) responded to initial treatment, 9 (16.7%) with complete and 23 (42.6%) with partial remission. Negative prognostic influence on OS had high IPI (P0.01), high sMIPI (P0.001), MIPI (P0.01), MIPIb (P0.01), extranodal localization (P0.01), and diffuse marrow infiltration (P0.01). Testing between randomly selected groups showed that patients with lower proportion of CD5(+) cells (80%) correlated with cytological blastoid variant and had shorter survival comparing with the group with higher proportion of CD5(+) cells (80%) (P0.01). Using univariate Cox regression, we proved that IPI, sMIPI, MIPI, and MIPIb had an independent predictive importance (P0.01) for OS in uniformly treated advanced MCL patients, although sMIPI prognostic significance was the highest (P0.001).

A 60-year-old woman with no previous history of chronic disease or malignancy presented with intense back and left leg pain and sleep disturbances. The patient had been treated unsuccessfully for the past 6 months with analgetics. Magnetic resonance imaging showed a soft tissue tumor in the L5-S1 region that involved the spinal canal, and a pathohistological analysis of the tumor specimen confirmed the presence of non-Hodgkin, diffuse large B cell lymphoma. After the diagnosis was confirmed, malaise, nausea, and vomiting developed. Multislice computed tomography of the endocranium showed focal infiltration of the hypothalamus and lateral ventricle; dissemination of a systemic lymphoma was excluded. Therapy was initiated as per the De Angelis protocol. After intravenous and intrathecal administration of metotrexate, the patient developed signs of central diabetes insipidus, which responded to therapy with an antidiuretic hormone analog. Despite the obvious infiltration of the hypothalamus, we cannot exclude an idiosyncratic effect of methotrexate on the central diabetes insipidus.

Cardiac involvement by non-Hodgkin's lymphoma is not uncommon, however rarely diagnosed during life due to nonspecific clinical presentation. We report a case of secondary cardiac lymphoma in patient who presented with new-onset atrial fibrillation. Cardiac lymphoma was in a form of bulky right atrial mass, infiltrating the atrial septum and cavo-atrial junction with concomitant mild pericardial effusion. In the present case, we illustrate complementary role of transthoracic, transesophageal echocardiography and multislice CT scan with three-dimensional reconstruction, in detection and evaluation of secondary cardiac tumor. Usefulness of echocardiography to follow up the effects of chemotherapy is also shown. (Echocardiography 2010;27:332-336)

Nehockinski limfomi danas predstavljaju kamen temeljac savremenoj onkohematologiji, s obzirom na mogucnost visokog procenta njihovog izlecenja. Najcesca podgrupa limfoma su DBKL koji su kod oko 30% bolesnika izlecivi primenom konvencionalne terapije, dok su FL neizlecivi ukoliko se lece samo konvencionalnom terapijom. Istina je da se kod bolesnika sa FL terapijski odgovor postize brzo, ali recidivi se gotovo po pravilu desavaju i bolesnike je u svakom sledecem recidivu sve teze leciti. Sredinom devedestih godina napravljeno je prvo monoklonsko antitelo u lecenju malignih bolesti, i to najpre za recidive ili refraktarne FL. Ovo anti CD20 monoklonsko antitelo, rituksimab, predstavlja krucijalan napredak u lecenju limfoma, jer je primenom kombinoivane imunohemioterapije izlecenje DBKL poraslo na oko 60%, a poslednje studije ukazuju na mogucnost dugotrajnih remisija i PFS za FL, sto moze biti ekvivalent izlecenju i ove podgrupe limfoma. U toku su brojne studije kojima se vrse uporedne analize za primenu ritoksimaba i kod drugih podtipova limfoma kao sto je limfom marginalne zone, mantle celijski limfom, Hockinova bolest, a uvode se indikacije i za pojedine sistemske bolesti vezivnog tkiva, kao sto je reumatoidni artritis.

The aim of the study was to evaluate retrospectively clinical course of 27 patients with primary central nervous system lymphoma (PCNSL) diagnosed and treated by different surgical approaches. Initial therapy-diagnostic approach included surgery with total tumour reduction (TTR) performed in 12 patients (44.4%), while partial reduction and biopsy were performed in 8 (29.7%) and 7 (25.9%) patients, respectively. All patients were treated with chemotherapy based on high-dose methotrexate (HD-MTX) with/without whole-brain radiotherapy (WBRT).The median overall survival (OS) and event-free survival were 37 and 31 months, respectively, with overall response rate of 74%. The patients who underwent an open surgery with TTR had significantly longer OS (median not reached), comparing with partial tumour reduction or biopsy only (Log-Rank χ(2) 6.08, p = 0.014) when median OS was 23 months. In patients with performance status according to Eastern Cooperative Oncology Group (ECOG PS) ≥ 3, OS was 23 months, contrary to ECOG PS 1-2 when median was not reached. The International Extranodal Lymphoma Study Group score (low, intermediate and high) also influenced OS between three risk groups (Log-Rank χ(2) 12.5, p = 0.002).The treatment of PCNSL still remains doubtful, however possible benefit from the TTR followed with HD-MTX with/without WBRT should be reconsidered.

Despite major advances in the treatment of diffuse large B cell lymphoma (DLBCL), approximately one third of the patients progress or die, suggesting the existence of additional oncogenic events. The purpose of this study was to evaluate the prognostic value of the "Hans classifier", and BCL2 and MYC protein expression and gene alterations in DLBCL patients treated with CHOP or R-CHOP chemotherapy over a 5-year period. Furthermore, we tried to correlate these parameters with the International Prognostic Index (IPI).The immunohistochemical (IHC) expression of CD10, BCL6, MUM1 and BCL2 on paraffin-embedded formalin-fixed tumor samples from 103 centroblastic DLBCLs was analyzed. IHC expression of MYC and fluorescence in situ hybridization (FISH) for MYC and BCL2 gene alterations was performed on 67 samples using the tissue microarray (TMA) method.The Hans algorithm was not predictive of survival in both therapy groups. No significant difference in BCL2 and MYC alterations or MYC protein expression in relation to complete response (CR), event-free survival (EFS) and overall survival (OS) was observed in our study. High IPI correlated significantly with poor outcome and it was identified as independent prognostic factor for OS and EFS (both p=0.000). The 5-year OS was 61% in the R-CHOP compared to 38% in the CHOP group (p=0.007). Rituximab significantly improved the OS in the BCL2 positive (60 vs 29%, p=0.008), and the BCL6 negative (73 vs 25%, p=0.001) cases.IPI is an independent prognosticator for DL-BCL patients and the addition of rituximab significantly improved survival. Furthermore, patients with BCL2+ and BCL6-DLBCL benefited from R-CHOP.

We herein present the case of a 55-year-old woman with a previous history of malignancies – uterine adenocarcinoma, basal cell carcinoma (which occurred twice consecutively), recurrent respiratory infections due to common variable immunodeficiency (CVID), and systemic granulomatous disease diagnosed at a later age. The patient suffered from diffuse large B cell lymphoma (DLBCL), which was successfully treated with R-CHOP chemotherapy, and continued with immunoglobulin supplementation. The patient was free of lymphoma and infectious complications for over 20 months despite her persistent immunodeficiency, but eventually developed colorectal adenocarcinoma. To the best of our knowledge, this is the first reported case of CVID associated with multiple solid tumours and DLBCL.

Orbital and ocular andexal Mucosa-Associated Lymphoid Tissue Lymphoma (MALT) or ocular adnexal MALT lymphoma (OAML) is the most common of all eye non-Hodgkin lymphomas. Autoimmune inflammatory disorders and chronic infections are important etiological factors and CD5 and CD43 (sialophorin) tumor markers are significant negative prognostic factors. Disease signs and symptoms can occur a long time before diagnosis. Varieties of treatment options are available. The aim of this retrospective analysis was to compare the efficiency of different treatment options and to investigate disease outcome. Twenty OAML patients, diagnosed in the Clinic of Hematology, Clinical Centre of Serbia, between 2003 and 2013, were enrolled. In most cases, OAML developed in the eighth decade with greater incidence in the male population. Median age was 67.5 years. The median period between the appearance of local signs and symptoms and diagnosis was 7 months. The dominant sign at presentation was swelling of involved tissue (40%). The most common was orbital involvement (55%). All patients had localized disease. Observed laboratory parameters on presentation showed low disease activity. Sialophorin prognostic significance was not registered. Our patients were initially treated differently but there was no significant difference in progression-free survival (PFS) due to initial treatment option (p = 0.2957). Median PFS was 22 months (3-89), and 5-year PFS was 60%. Median overall survival (OS) was 43 months (1-105) and 5-year OS 95%. Eight patients (40%) relapsed and one patient died due to non-hematological complications. In our experience, most modern induction treatment options appear to result in the same, favorable outcome.

The existence of a potential primary central nervous system lymphoma-specific genomic signature that differs from the systemic form of diffuse large B cell lymphoma (DLBCL) has been suggested, but is still controversial. We investigated 19 patients with primary DLBCL of central nervous system (DLBCL CNS) using the TruSeq Amplicon Cancer Panel (TSACP) for 48 cancer-related genes. Next generation sequencing (NGS) analyses have revealed that over 80% of potentially protein-changing mutations were located in eight genes (CTNNB1, PIK3CA, PTEN, ATM, KRAS, PTPN11, TP53 and JAK3), pointing to the potential role of these genes in lymphomagenesis. TP53 was the only gene harboring mutations in all 19 patients. In addition, the presence of mutated TP53 and ATM genes correlated with a higher total number of mutations in other analyzed genes. Furthermore, the presence of mutated ATM correlated with poorer event-free survival (EFS) (p = 0.036). The presence of the mutated SMO gene correlated with earlier disease relapse (p = 0.023), inferior event-free survival (p = 0.011) and overall survival (OS) (p = 0.017), while mutations in the PTEN gene were associated with inferior OS (p = 0.048). Our findings suggest that the TP53 and ATM genes could be involved in the molecular pathophysiology of primary DLBCL CNS, whereas mutations in the PTEN and SMO genes could affect survival regardless of the initial treatment approach.

Angiogenesis in solid tumors is important for tumor growth, invasion, and metastasis. However, angiogenesis plays also an important role in hematological malignancies. We have analyzed the expression of vascular endothelial growth factor (VEGF) in the leukemic blast cells and microvessel density (MVD) in the bone marrow biopsy samples of the patients with acute lymphoblastic leukemia (ALL). Bone marrow MVD of the patients with ALL was significantly higher compared with normal controls and complete remission (P0.001), but slightly lower than in patients with relapsed ALL (P0.05). The bone marrow blast VEGF expression was significantly higher in newly diagnosed ALL patients, with predominant strong VEGF expression as compared with complete remission patients (who had negative or weak VEGF expression) (P0.05), whereas initial values were slightly lower than in relapsed patients. There was a strong positive correlation between VEGF expression and MVD at presentation of ALL. Stronger expression of VEGF on blast cells indicates shorter overall survival in ALL. Furthermore, initial values of MVD had positive correlation with overall survival and leukemia-free survival (P=0.024 and P=0.017, respectively). Our data suggest that increased angiogenesis (confirmed by immunohistochemical expression of VEGF in leukemic blasts), and MVD may play an important role in the pathophysiology of ALL with prognostic implications. Thus, targeting VEGF pathway may bring the new approach for ALL treatment-using antiangiogenic drugs and tyrosine kinase inhibitors in combination with standard chemotherapy regimens.

The clinical course of patients with follicular lymphoma is variable from a slowly progressive disease to a progressive disease with a survival time of approximately 1 year. Many prognostic models have been suggested to identify high-risk patients. Recent gene profiling analysis showed that the clinical behavior of follicular lymphoma is determined by the properties of the nonmalignant tumor microenvironment. We investigated the role of lymphoma-associated macrophages (LAMs) in tumor tissue in patients with newly diagnosed follicular lymphoma. The LAM was determined immunohistochemically in lymph node tissue sections by anti-CD68 PG-M1 and analyzed through high-power field (HPF) magnification intrafollicularly (IF) and extrafollicularly. In our study, the patients who had an IF LAM count equal to or more than 10/HPF had significantly shorter overall survival (P=0.018) and 3 years of progression-free survival (P=0.034) compared with patients with10 LAM/HPF. Multivariate analysis indicated that IF LAM/HPF ≥ 10 and Eastern Cooperative Oncology Group performance status1 are independent prognostic factors for a poor outcome.

Advanced age is considered an unfavourable prognostic factor for Hodgkin's lymphoma (HL). The optimal treatment for these patients is not yet defined, especially for the advanced stages. We analysed the outcome and prognostic relevance of patient and disease characteristics in 46 advanced stage HL patients who were older than 45 years, treated with ABVD. Elderly patients (60 year) had a significantly higher rate of comorbidities (p0.05). The complete remission rate was significantly lower in elderly patients and in patients with an IPS ≥ 3 (p0.05, p0.05, respectively). Elderly patients had significantly shorter event-free survival (p0.01) and overall survival (p0.01) compared to patients of 45-60 year. Extranodal disease, an IPS ≥ 3, bulky disease, an ESR50 and the presence of a large mediastinal tumour mass didn't have an influence on survival (p0.05). The multivariate Cox regression analysis identified the age of60 year as an independent prognostic factor. The prospective clinical trials seem to be needed for defining the optimal therapeutic approach in elderly patients.

Although the treatment of Hodgkin lymphoma (HL) has been improved, distinguishing reliable prognostic biomarkers could better stratify patients for more effective treatment. We analyzed the prognostic relevance of CD68+ tumor-associated macrophages (TAMs) by immunohistochemical analysis at diagnosis and standard clinical parameters in 52 ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine)-treated patients with advanced stage classical HL (cHL). Patients with25% CD68+ TAMs compared to those with ≤25% had worse 5-year overall survival (45% vs. 77%, log-rank p = 0.019) and showed a trend toward shorter 5-year event-free survival (51% vs. 71%, log-rank p = 0.19). Additionally, no significant correlation with selected clinical features was found. Significantly shorter 5-year overall survival was associated with International Prognostic Score (IPS)2, bulky disease, elevated erythrocyte sedimentation rate (log-rank test, p = 0.003, p = 0.049, p = 0.007, respectively). In multivariate analysis, increased CD68+TAMs, IPS2, and bulky disease were identified as independent prognostic factors for overall survival (Cox multivariate model, p = 0.006, p = 0.007, p = 0.013, respectively). Tumor-associated macrophages represent a potential prognostic biomarker which could contribute to better risk stratification of patients with cHL.

Plasmablastic lymphoma (PBL) has initially been described as a rapidly progressive and almost invariably fatal diffuse large-cell lymphoma with plasmablastic features, exclusively involving the jaw and oral mucosa in HIV-positive patients. Although its clinical features may help in differential diagnosis, an extra-oral localization in a patient without HIV makes it more difficult to suspect clinically. We describe a very rare case of gastric PBL primarily involving stomach in a middle age man without an HIV infection. A biopsy was performed and its findings revealed a diffuse, monomorphous proliferation of the tumor cells with features of immunoblasts, MUM-1, EMA, and lambda light chains positive. Serology was negative for the human immunodeficiency virus (HIV), HBsAg, and hepatitis C virus infection. The patient started treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy, but unfortunately died before the second cycle was given. To our knowledge, this is the second case of gastric PBL presented in HIV-negative patients. The findings in this case suggest that PBL should be included in the differential diagnosis of gastrointestinal tumors.

Aim: The aim of this study was to evaluate nutritional status at the presentation of lymphoma as predictor for therapy outcome. Methods: We have analised 115 pts, m- 59/ f- 56, with newly diagnosed lymphoproliferative disorders( Jan 2012-mar 2014.) with curable modality of therapy. Pts with paliative treatment were excluded. We have analised influence of their nutritional status on therapy outcome:complete remission (CR), partial remission (PR), very good partial remission (VGPR), early death (ED), early relaps (ER) and stable dissease (SD) or progressive dissease (PD). Alse we have calculated risk according age, clinical stage and agressivnes of primary dissease. According to ECOG PS we divided pts in two groups:ECOG PS less than 2, and 2 and more. Nutritional status was screenined using NRS2002 (nutritional assement proposed by ESPEN) and MNA (“mini nutritional assesment”). We also had information about infiltration of gastrointestinal tract (GIT). Results: We had 95 pts with agressive lymphoma and 20 pts with indolent lymphoma. Median age was 60,5 (23-85)years, ECOG PS 0-1 47pts vs. 68 pts with ECOG PS 2 and more. We has 38pts in CS less than III and 77 pts with CS III and more. Median weight loss was 8,3(0-33)%, median BMI was 24,3 (16,7-38,6)kg/m2. Median percentage of weight loss per month was 2,7 (0-10)% . We have divided pts in two groups with loss until 3% per month or over 3% per month. As outcome of therapy 91pts achieved CR, VGPR or PR as favorable outcome and 24 pts had ED, ER, SD or PD. According NRS2002 we had two groups less than 3 vs. 4 and more. For MNA 11 and more vs. less than11. Binary logistic model for outcome previously explaned was significant (Wald 33,7, p Conclusions: Besides ECOG PS nutritional assesment can be predictor for therapy outcome in lymphoma pts. MNA screening was better predictor than NRS2002. Implementation of nutritional assesment in initial staging for pts with limforpoliferative dissease can reveal patients that need nutritional suport along with treatment. Study has limitation for implementing comorbidity indexes in model and larger group can be more conclusive. Disclosure: All authors have declared no conflicts of interest.