Incidence, risk factors, and outcome of asymptomatic central nervous system involvement in adult patients with acute myeloid leukemia.

Examination of central nervous system (CNS) involvement is not routine diagnostic practice in adult patients with acute myeloid leukemia (AML). Therefore, many asymptomatic patients with CNS involvement might go undetected. The effect of CNS involvement on the AML disease course is not well defined, with conflicting results regarding clinical outcome. This study aimed to determine the incidence of asymptomatic CNS involvement in AML estimated by multiparametric flow cytometry of cerebrospinal fluid (MFC-CSF) at diagnosis, the related potential risk factors, and prognosis. In total, 645 patients with de novo AML were screened; 183 (28.4%) of them fulfilled institutional practice for MFC-CSF analysis based on presence of CNS symptoms and/or clinical features. CNS symptoms and signs were observed in 8/183 (4.4%) patients, but most patients (175/183, 95.6%) were asymptomatic. In the asymptomatic group, 73/175 (41.7%) patients had positive or suspicious cerebrospinal fluid (CSF) findings categorized as CNS positive (CNSpos) and 102/175 (58.3%) had normal CNS findings categorized as CNS negative (CNSneg). The presence of leukemic blasts was confirmed in 81/183 (44.3%) patients; the total incidence of CNS involvement in the whole AML group was 12.6% (81/645). Compared with asymptomatic patients with CNSneg, those with CNSpos had a significantly higher frequency of lymphadenopathy, white blood cell count ≥30 × 109/L, presence of the monocytic phenotype, and a high percentage of bone marrow (BM) blasts. The multivariate logistic regression model identified monocytic phenotype (p = 0.047) and high percentage of BM blasts (p = 0.042) as predictors for CNSpos. CNSpos did not affect overall survival in patients with AML. There was a higher incidence of CNS involvement in asymptomatic adult patients with de novo AML, emphasizing possible undervalued rates of CNS disease at diagnosis. Prospective studies should determine whether diagnostic lumbar puncture for MFC-CSF analysis and CNS prophylaxis could contribute to better selection and prognosis in this patient population.

The WHO diagnostic criteria for polycythemia vera-role of red cell mass versus hemoglobin/hematocrit level and morphology.

Regarding diagnosis of polycythemia vera (PV), discussion persists about hemoglobin (Hb) and/or hematocrit (Hct) threshold values as surrogate markers for red cell mass (RCM) and the diagnostic impact of bone marrow (BM) morphology. We performed a retrospective study on 290 patients with PV (151 males, 139 females; median age 65 years) presenting with characteristic BM features (initial biopsies, centralized evaluation) and endogenous erythroid colony (EEC) formations. This cohort included (1) a group of 229 patients when following the 2008 versus 256 patients diagnosed according to the 2016 World Health Organization (WHO) guidelines, all presented with increased RCM; (2) masked PV patients with low Hb (n = 143)/Hct (n = 45) recruited from the 2008 WHO cohort; (3) a cohort of 17 PV patients with elevated diagnostic Hb/Hct levels but low RCM; and (4) nine PV patients with increased RCM, opposing low Hb/Hct values. All patients were treated according to current PV guidelines (phlebotomies 87%, hydroxyurea 79%, and acetylsalicylic acid 87%). Applying the 2016 WHO criteria significantly increased concordance between RCM and Hb values compared with the 2008 WHO criteria (90 vs. 43% in males and 83 vs. 64% in females). Further analysis of the WHO 2016 PV cohort revealed that increased RCM is associated with increased Hb/Hct (93.8/94.6%). Our study supports and extends the diagnostic impact of the 2016 revised WHO classification for PV by highlighting the importance of characteristic BM findings and implies that Hb/Hct threshold values may be used as surrogate markers for RCM measurements.

BCL2 positive and BCL6 negative diffuse large B cell lymphoma patients benefit from R-CHOP therapy irrespective of germinal and non germinal center B cell like subtypes.

PURPOSE: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

A single institution experience on 314 newly diagnosed advanced Hodgkin lymphoma patients: the role of ABVD in daily practice.

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.

Can pharmacogenetics impact the therapeutic effect of cytarabine and anthracyclines in adult acute myeloid leukaemia patients?: A Serbian experience.

Background: Cytarabine-anthracycline-based induction chemotherapy remains the standard of care for remission induction among patients with newly diagnosed acute myeloid leukaemia (AML). There are remarkable differences in therapy response among AML patients. This fact could be partly explained by the patients' genetic variability related to the metabolic paths of cytarabine and anthracyclines. This study aims to evaluate the effect of variants in pharmacogenes SLC29A1, DCK, ABCB1, GSTM1, and GSTT1, as well as laboratory and AML-related parameters on clinical outcomes in adult AML patients. Methods: A total of 100 AML patients were included in the study. Pharmacogenetic variants SLC29A1 rs9394992, DCK rs12648166, ABCB1 rs2032582, and GSTM1 and GSTT1 gene deletions were detected by methodology based on PCR, fragment analysis and direct sequencing. The methods of descriptive and analytic statistics were used. Survival analysis was done using the Kaplan-Meier method using the Log-Rank test. Results: This is the first study of adult AML pharmacogenetics in the Serbian population. Clinical outcomes in our cohort of AML patients were not impacted by analysed variants in SLC29A1, DCK, ABCB1 and GSTT1, and GSTM1 genes, independently or in combinations. Achievement of complete remission was identified as an independent prognostic indicator of clinical outcome. Conclusions: The population-specific genomic profile has to be considered in pharmacogenetics. Since the data on AML pharmacogenetics in European populations is limited, our results contribute to knowledge in this field and strongly indicate that a high-throughput approach must be applied to find particular pharmacogenetic markers of AML in the European population.

Prognostic significance of Bcl-2, tumor-associated macrophages, and total neoplastic and inflammatory lymph node involvement in advanced stage classical Hodgkin's lymphoma.

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 advanced stage 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.

Hodgkin's lymphoma relapse in the uterine cervix 15 years after the initial cure.

Uterine cervix is an uncommon site for the presentation of Hodgkin's lymphoma. We describe a 62-year-old woman who developed an unusual relapse of classical Hodgkin's lymphoma, a nodular sclerosis subtype, in the uterine cervix, with propagation to the vaginal wall. She relapsed 15 years after achieving a complete remission of Hodgkin's lymphoma, initially in clinical stage IVB. This late relapse of the Hodgkin's lymphoma was in the clinical stage IEB and the treatment was initiated according to ABVD regimen. After the second course, lethal outcome ensued due to progression of the renal failure, which ensued in the meantime, probably as an adverse effect of the previous therapy.

The predictive value of morphological findings in early diagnosis of acute myeloid leukemia with recurrent cytogenetic abnormalities.

This study explores cytomorphologic features and their predictive role for early identification of acute myeloid leukemia (AML) with morphological distinctive recurrent cytogenetic abnormalities (RCA): t(15;17), t(8;21) and inv(16)/t(16;16). We retrospectively evaluated 396 de novo AML cases, diagnosed and treated at single institution, between 2013-2017. Specific cytomorphologic features suggesting distinctive AML-RCA were revealed at diagnosis in 62 (15.65%) patients, including AML with t(15;17) in 41 (66.13%), t(8;21) in 13 (20.97%) and inv(16)/t(16;16) in 8 (12.90%). Final diagnoses of AML-RCA according to WHO integrated diagnostic criteria were established in 66 (16.66%) cases, including AML with t(15;17) 40 (60.60%), t(8;21) 17 (25.76%), and inv(16)/t(16;16) 9 (13.64%). Discordance between cytomorphological and other integrated criteria was detected as missed/wrong-call in 0/1 for t(15;17), 6/2 for t(8;21) and 2/1 for inv(16)/t(16;16). The cytomorphological accuracy was 97.56% (40/41) for t(15;17), 57.89% (11/19) for t(8;21) and 70% (7/10) for inv (16)/t(16;16). Positive/negative predictive values of cytomorphological evaluation were: 97.56%/100% for t(15;17); 84.62%/88.68% for t(8;21); 87.50%/96.65% for inv(16)/t(16;16). Sensitivity/specificity were: 100%/96.15% for t(15;17); 64.10%/95.92% for t(8;21); 77.78%/98.25% for inv(16)/t(16;16). We confirmed that morphology is still a highly relevant evaluation method in diagnosing several common AML-RCAs before completing cytogenetic and molecular studies, enabling early detection, particularly of AML with t(15;17).

The expression of Ki-67 and Bcl-2 in Hodgkin's lymphoma: correlation with the International Prognostic Score and bulky disease: a study by the Serbian Lymphoma Study Group (SLG).

The prognosis of Hodgkin's lymphoma has been improved over last 10 yr due to identification of prognostic parameters. These factors may predict the clinical outcome and therefore may have influence on the selection of appropriate treatment. In a cohort of 40 patients with Hodgkin's lymphoma of nodular sclerosis subtype, treated with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) regimen, we analyzed prognostic relevance of the expression of Ki-67 and Bcl-2 at diagnosis as well as other clinical parameters: International Prognostic Score, bulky disease, tissue eosinophilia, and high erythrocyte sedimentation rate. Significance was tested according to response rate and overall survival. Patients with a high proliferative fraction (Ki-67 > 50%) had worse overall survival compared with those with low proliferation, 56% vs 91%. There was a correlation between Ki-67 positivity and the achievement of complete remission. Cox's multivariate model revealed that Ki-67 positivity at threshold of 50% was a significant independent prognostic factor. The Bcl-2 expression in less than 50% of tumor cells was detected in 65.5% of patients, and in a majority of cases it was associated with complete remission. Patients with high IPS had more progressive disease and shorter survival. Bulky disease, tissue eosinophilia, and high erythrocyte sedimentation rate had no significant influence on complete remission and survival. However, there was a marked divergence in survival curves after 4 yr follow-up for each of these parameters. Patients with high Ki-67, IPS > 3, bulky disease, tissue eosinophilia, and high sedimentation rate are at a higher risk of treatment failure and relapse and therefore might be eligible for other aggressive therapeutic approach.

Prognostic value of lymphocyte/monocyte ratio in advanced Hodgkin lymphoma: correlation with International Prognostic Score and tumor associated macrophages.

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.

Extramedullary plasmacytoma of the tongue base: a rare presentation of head and neck plasmacytoma.

INTRODUCTION: Special entities like solitary bone plasmocytoma (SBP) or extramedullary plasmacytoma (EMP) can be found in a less than 5% of patients with plasma cell disorders. EMP of the tongue represents very rare localization of the head and neck plasmacytoma. CASE REPORT: We report a case of 78-years-old woman who developed EMP of the tongue base detected by the magnetic resonance imaging (MRI) of the head and neck region. Immunohistochemical profile of the tumor tissue biopsy (CD38, IgG, kappa positivity) indicated diagnosis of EMP. The diagnosis was established with additional staging which confirmed the absence of other manifestation of the disease. The patient was treated with 40 Gy of radiotherapy in 20 doses resulting in the achievement of the complete remission of the disease. This case was discussed with the reference to the literature. CONCLUSION: EMP of the tongue base is a very rare entity of plasma cell dyscrasias. Appropriate irradiation results in the achievement of a long-term remission and a potential cure of the disease.

ABVD as the treatment option in advanced Hodgkin's lymphoma patients older than 45 years.

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 (p < 0.05). The complete remission rate was significantly lower in elderly patients and in patients with an IPS ≥ 3 (p < 0.05, p < 0.05, respectively). Elderly patients had significantly shorter event-free survival (p < 0.01) and overall survival (p < 0.01) compared to patients of 45-60 year. Extranodal disease, an IPS ≥ 3, bulky disease, an ESR > 50 and the presence of a large mediastinal tumour mass didn't have an influence on survival (p > 0.05). The multivariate Cox regression analysis identified the age of >60 year as an independent prognostic factor. The prospective clinical trials seem to be needed for defining the optimal therapeutic approach in elderly patients.

The number of lymphoma-associated macrophages in tumor tissue is an independent prognostic factor in patients with follicular lymphoma.

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 with <10 LAM/HPF. Multivariate analysis indicated that IF LAM/HPF ≥ 10 and Eastern Cooperative Oncology Group performance status >1 are independent prognostic factors for a poor outcome.

The prognostic relevance of tumor associated macrophages in advanced stage classical Hodgkin lymphoma.

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 with >25% 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, IPS >2, 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.

Simultaneous presentation of hairy cell leukemia and metastatic signet ring carcinoma of the stomach diagnosed by bone marrow biopsy.

Hairy cell leukemia (HCL) is a rare chronic B-cell disorder with an increased risk of second tumors. The relative risk of second cancers reported in various series of HCL patients ranged from 0.95 to 4.33, but simultaneous presentation of HCL and other epithelial malignancies is very rare. To our knowledge, we present the first case of the coexistence of signet ring carcinoma of the stomach and HCL. We report a case of the simultaneous presentation of HCL and metastasis of the primary signet ring cell carcinoma of the stomach to the bone marrow and skin. A bone marrow biopsy was performed on a patient with pancytopenia. A histologic examination with immunostaining of the bone marrow specimen showed the presence of signet ring carcinoma cells in addition to HCL. As a consequence, our patient underwent further diagnostic procedures including endo-gastro-duodenoscopy with biopsy of gastric tumor mass, which established the diagnosis of gastric signet ring cell carcinoma.

A case of primary peripheral T-cell type non-Hodgkin lymphoma originating in the iris--clinicopathological findings.

BACKGROUND: The ocular adnexal region is the primary localization of extranodal lymphoma in 5% to 15% of all Non-Hodgkin lymphoma. Intraocular lymphoma of T-cell origin is extremely rare and such sites of infiltration have been rarely observed in clinical examination. CASE REPORT: We presented a 56-year-old man with iris infiltration by primary intraocular peripheral T-cell lymphoma. The patient was in clinical stage I BE and the treatment was initiated according to cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone (CHOP) regimen. When the second course of the therapy was scheduled, the patient developed central nervous system lymphoma infiltration. Although De Angelis regimen was used, 3 months after the diagnosis was established, lethal outcome ensued due to disease progression. CONCLUSION: According to our experience we can conclude that further therapeutical approach to patients with primary intraocular T-cell lymphoma requires modification of conventional treatment regimens. The lower median survival in these patients suggests that the disease may be of more aggressive course.

Isolated myeloid sarcoma of the gastrointestinal tract.

Myeloid sarcoma (MS) is a rare disease that presents as an extramedullary tumor of myeloid cells. Most patients subsequently develop acute myelogenous leukemia (AML), and their prognosis is poor. Here, we report the case of a 28-year-old woman with a primary isolated myeloid sarcoma which originated in the gastrointestinal (GI) tract. Two months after initial presentation, bone marrow tests led to a diagnosis of AML. This case is noteworthy because GI tract infiltration with leukemic cells is very rare, and it is even more rare as an occurrence preceding the development of systemic leukemia.

[Diagnosis and the treatment of primary amyloidosis].

BACKGROUND: Primary amyloidosis belongs to a group of monoclonal plasma cell disorders, characterized by extracellular deposition of immunoglobulin light chain fibrils in various tissues and subsequent multiorgan dysfunction. CASE REPORT: We present a 51-year-old female with 2-years history of fatigue on exertion, oedema of face, abdomen and legs, bone pain and obstipation. After diagnostic procedures such as electrophoresis and immunoelectrophoresis of serum and urine proteins, immunohistohemical staining of bone marrow biopsy specimens and Congo red staining of rectal biopsy specimens, the patient received misdiagnosis of multiple myeloma and was referred to our hospital for further treatment. We reevaluated and complemented diagnostic procedures (ehocardiosonography and biopsy of subcutaneaus tissue with Congo red staining), and established diagnosis of primary amyloidosis. The therapy had started with intravenous (i.v.) melphalan and dexamethasone (totally eight cycles) and continued with peroral melphalan and i.v. dexamethasone. Stabilization of the disease was achieved after 35 months of the treatment. CONCLUSION: The case of this rare and often fatal disease emphasizes significance of early diagnosis and, consequently, initiation of specific therapies which are indispensable to improve the disease prognosis.