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The article discusses the treatment of splenic marginal zone lymphoma (SMZL) and the lack of randomized trials, highlighting the use of rituximab infusions for the treatment. It examines the bone marrow for complete response (CR), the impact of rituximab on the disease progression, and the overall survival (OS) rate.

The article presents two case studies related to no evidence of splenic disease in patients with splenic marginal zone lymphoma (SMZL) undergoing splenectomy for autoimmune hemolytic anemia after monotherapy with rituximab. Topics include the first case was a 56 year-old male diagnosed with SMZL in September 2012, and the second case of a 60-year old woman first diagnosed with SMZL in May 2010 after she presented with abdominal pain and early satiety.

Splenic marginal zone lymphoma (SMZL) is a rare chronic B-cell lymphoproliferative disorder recognized as a distinct entity in the World Health Organization (WHO) classification. SMZL usually runs an indolent clinical course with a median survival of more than 10 years. However, in a proportion of patients (10-20%) SMZL behaves more aggressively, with a median survival of less than 4 years. Many efforts are ongoing to establish commonly accepted prognostic factors as a guide to therapy for this disorder. Data on the treatment of SMZL come from reported retrospective series including relatively limited numbers of patients. Despite these limitations, much progress has recently been made in the management of patients with SMZL. The oldest and most commonly used first-line therapeutic modality is splenectomy, which offers rapid alleviation of splenomegaly-related symptoms along with an improvement of cytopenias in the majority of patients, with a median PFS of 5 years. However, SMZL is a systemic disease, and splenectomy is not carried out with eradicative intent. Furthermore, splenectomy is a major surgical procedure with significant morbidity or even mortality, especially in older patients. Chemotherapy has only moderate activity in this form of MZL. Recent data suggest that rituximab is a very effective therapy with minimal toxicity and could replace splenectomy as first-line treatment. The overall response rate is > 90%, with almost half of responses being complete, while the 5-year progression-free survival is approximately 70%. The combination of rituximab with chemotherapy requires further evaluation. Based on the current data, splenectomy could be abandoned as first-line treatment for patients with SMZL. [ABSTRACT FROM AUTHOR]

Monoclonal B-cell lymphocytosis (MBL) is a premalignant condition characterized by the presence of less than 5000/μL circulating clonal B cells in otherwise healthy individuals. Three subcategories have been identified according to the immunophenotypic features: CLL-like, CD5(+) atypical, and CD5(-) MBL. CLL-like MBL is by far the most frequent and best studied category and further divided in low-count [LC] and high-count [HC] MBL, based on a cutoff value of 500/μL clonal B cells. LC-MBL typically remains stable and probably does not represent a truly premalignant condition, but rather an age-related immune senescence. On the other hand, HC-MBL is closely related to CLL-Rai0, bearing similar immunogenetic profile, and is associated with an annual risk of progression to CLL requiring therapy at a rate of 1.1%. Currently there are no reproducible factors for evaluating the risk of progression to CLL. CD5(-) MBL is characterized by an immunophenotype consistent with marginal zone origin and displays many similarities with marginal zone lymphomas (MZL),mainly the splenic MZL.Thecutoff value of 5000/μL clonal B cells cannot probably be applied in CD5(-) MBL, requiring a new definition to describe those cases. [ABSTRACT FROM AUTHOR]

The optimal treatment approach for patients with mantle cell lymphoma (MCL) is not well defined. Intensive therapeutic regimens result in high response rates and prolonged progression-free survival but at the expense of significant toxicity. We report here our results of the administration of rituximab plus chlorambucil (R-Chl) as first line treatment in patients with MCL. Twenty consecutively diagnosed patients were treated with this combination in which an induction and a maintenance arm were included. During induction, rituximab was administered at a dose of 375 mg/m2 on day 1, while chlorambucil was given afterward at a dose of 10 mg/day for 10 consecutive days for eight cycles and then as a single agent for an additional four cycles. Maintenance consisted of rituximab administration every 2 months for 1 year. Most patients had indolent disease features such as a low mantle-cell international prognostic index (MIPI) score. The overall response rate was 95% (90% CR, 5% PR). Among patients in CR, 78% presented a molecular remission. The 3-year progression-free survival was 89%. There were no serious side effects. These results show that the R-Chl combination could be an effective therapeutic option as first line treatment in MCL, especially for patients with indolent disease characteristics. [ABSTRACT FROM AUTHOR]

Kikuchi-Fujimoto disease is a form of reactive lymphadenopathy, which was firstly described in Japan, but is uncommon in the Western world. We retrospectively reviewed the medical records of nine cases of adult or adolescent Kikuchi’s disease diagnosed in a single Haematology Unit in Athens, Greece between 1990 and 2006. The median age of the patients was 25 years (14–40) and 8/9 were females. All patients presented with cervical lymphadenopathy sparing the supraclavicular fossa; one had associated axillary lymphadenopathy, seven had fever and two were asymptomatic. The median duration of lymphadenopathy before presentation was 30 days (10–45). Just palpable splenomegaly was recorded in three patients. The median value of the maximal lymph node diameter was 2 cm (1–5) and only 1/9 had nodes >2 cm in their largest diameter. Lymphadenopathy was tender in two patients; hard nodes were observed in three patients. The median leukocyte count was 4.7 × 109/l (2.2–4.9) with a normal differential in 7/9 patients. No infectious agent could be demonstrated. One patient had clinical and laboratory evidence of primary antiphospholipid syndrome (APLS). In conclusion, Kikuchi’s disease represents a rare but important diagnostic possibility for patients presenting with lymphadenopathy in Greece and other western countries. In this setting, autoimmune disorders, mainly lupus and APLS, should be considered and excluded by the appropriate laboratory work-up. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented concerning the treatment for the extranodal marginal zone lymphoma (ENMZL) of mucosaassociated lymphoid tissue (MALT).

In the present study, we assessed the clinical and pathological data of 76 patients with the diagnosis of non-gastric extranodal marginal zone B-cell lymphoma. The most commonly affected sites were salivary glands, skin, ocular adnexa, lung, intestine and Waldeyer's ring. Ann Arbor stage I disease was present in 39 patients (51%), stage II in 10 (13%) and stage IV in 27 (36%). In 17 cases (21%), the lymphoma presented at multiple mucosal sites. Lymph node and bone marrow involvement were present in 21% and 16%, respectively. Most cases were in the low or low-intermediate risk group. Treatment was heterogeneous and included chlorambucil in 59% either alone or in combination with other agents. Complete and partial remission was achieved in 79% and 7%, respectively, with an overall response rate of 86%. The 5- and 10-year overall survival and cause-specific survival rates were 94%, 82% and 95%, 91%, respectively. The 5- and 10-year progression free survival was 56% and 41%, respectively. The only feature associated with inferior outcome was disease localisation to the lung. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article regarding the toxicity in patients with relapsed hairy cell leukemia who are treated with rituximab.

Assesses different treatment strategies for indolent lymphomas. Use of chemotherapy based treatment when the patient develops constitutional symptoms or symptoms related to tumor burden; Treatment of elderly patients with oral alkylating agents; Production of superior progression free survival rates by adding rituximab to conventional chemotherapy.

The standard CHOP regimen may cure 30-40% of patients with advanced aggressive non-Hodgkin's lymphoma (ANHL). Mitoxantrone is an anthracenedione, which is active in NHL and its toxicity profile may be more favorable than doxorubicin with respect to alopecia, mucositis and cardiotoxicity. This study was designed to compare the effectiveness of an escalated dose of mitoxantrone with that of standard doxorubicin, used in the CHOP regimen in patients with ANHL. One hundred and forty three eligible patients with ANHL were randomized to receive 6 cycles of either CHOP (n = 71) or intensified CNOP (iCNOP) (n = 72), with mitoxantrone 20 mg/m², i.v., d.1 instead of doxorubicin. Complete responders (CR) were again randomized either to receive interferon-α (IFN-α) maintenance (3 MU t.i.w., s.c.) or not. The CR rate was 70 vs. 76% for iCNOP and CHOP (p = 0.45), and the overall response rate was 81 vs. 83%, respectively (p = 0.71). The 5-year failure free survival (FFS) was 48 and 50% in the iCNOP and CHOP arm, respectively (p = 0.45), and the 5-year overall survival (OS) was 61 vs. 64% (p = 0.56). IFN-α did not prolong relapse free survival (p = 0.91). iCNOP produced less alopecia (p = 0.001) but more febrile episodes (p = 0.04) than CHOP, while requiring more frequent G-CSF support (p = 0.01). Two cases of acute myelogenous leukemia (AML) were recorded, both in the iCNOP arm (p = 0.14). In conclusion, iCNOP was equally effective to CHOP in patients with ANHL, producing more leukopenia and febrile episodes, but less alopecia. The development of two cases of secondary AML in the iCNOP arm is of concern. [ABSTRACT FROM AUTHOR]

In this article the author views on dealing with primary mediastinal large B-cell lymphoma (PMLNCL). The author views that positron emission tomography-computed tomography (PET-CT) is used in Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma (DLBCL). The author also views that there is no convincing evidence for the use of interim PET-CT in PMLBCL.

The article discusses research which was conducted to determine the validity of the simplified risk stratification/ prognostic score of the Splenic Marginal Zone Lymphoma Working Group in patients with splenic marginal zone lymphoma. Researchers evaluated 177 patients with a median age of 65. They found that the working group's prognositic system was valid.

The article offers information on Mucosa associated lymphoid tissue (MALT) lymphoma for all non-Hodgkin Lymphomas. It mentions the acquisition of cytogenetic abnormalities confers a survival advantage to a clonal B cell population and also mentions the association of other chronic infections and autoimmune disorders with MALT lymphoma pathogenesis.

Nodal marginal zone lymphoma (NMZL) is one of the three well-recognized entities within the broad category of marginal zone lymphoma, representing approximately 10% of the cases in this group. Patients typically present with nodal disease, usually at advanced stages, and a thorough work-up and staging are necessary in order to exclude occult extranodal involvement. NMZL shares many similarities with splenic marginal zone (SMZL) and mucosa-associated lymphoid tissue (MALT) lymphomas, such as cytology, immunophenotype, genetic abnormalities and maybe even a common cell of origin: a post-germinal memory B-cell. NMZL is characterized by an indolent course, but its prognosis is generally considered less favorable than that of SMZL and MALT lymphoma, with reported 5-year overall survival rates ranging between 55% and 89%. Therapeutic recommendations for NMZL are derived from small retrospective series or studies on larger cohorts of indolent lymphomas, which include a limited number of patients with NMZL. For localized disease, radiotherapy appears to be the treatment of choice, while rituximab-containing therapy is recommended for advanced stage disease. Due to the rarity of NMZL it is very difficult to perform prospective trials, and an international collaborative effort is necessary in order to better understand the biological features and provide evidence-based treatment recommendations. [ABSTRACT FROM AUTHOR]

A number of studies have looked into the pathophysiological role of angiogenesis in CLL, but the results have often been inconsistent. We aimed to gain direct insight into the angiogenic process in lymph nodes involved by CLL, focusing on proangiogenic cytokines and microvessel morphometry. The tissue levels of VEGF, Th-2 cytokines IL-6 and IL-8, IL-8 receptor CXCR2, and tyrosine p-STAT-3/SOCS-3 axis modulating cytokine expression were evaluated immunohistochemically in 62 CLL/SLL cases. Microvascular characteristics were evaluated by image analysis. Results were analyzed with regard to clinicopathological characteristics. Proliferation centers (PCs) were less well vascularised compared to non-PC areas. IL-8 and CXCR2 expression was distinctly uncommon as opposed to IL-6, VEGF and SOCS-3, which were detected in the vast majority of cases. The latter twomolecule expressions weremore pronounced in the PCs in ∼40%of the cases. p-STAT-3 immunoreactivity was recorded in 66.67% of the cases with a predilection for PCs. Microvessel morphometry was unrelated to proangiogenic cytokines, p-STAT-3, SOCS-3, or survival. Microvascular caliber and VEGF expression were higher in Binet stage A, whereasIL-6 expression was higher in stage C. VEGF and p-STAT-3 exerted a favorable effect on progression, which remained significant in multivariate analysis, thereby constituting potential outcome predictors in CLL patients. [ABSTRACT FROM AUTHOR]

Autoimmune hemolytic anemia and thrombocytopenia (AIHA/AITP) frequently complicate the course of non-Hodgkin lymphomas, especially low-grade, but they are very rarely observed in Hodgkin lymphoma (HL). Consequently the frequency and the profile of patients with HL-associated AIHA/AITP have not been well defined. Among 1029 patients with HL diagnosed between 1990 and 2010, two cases of AIHA (0.19%) and three of AITP (0.29%) were identified at the presentation of disease. These patients were significantly older, and more frequently had features of advanced disease and non-nodular sclerosing histology, compared to the majority of patients, who did not have autoimmune cytopenias at diagnosis. ABVD combination chemotherapy (doxorubicin, bleomycin, vinblastine, dacarbazine) provided effective control of HL and the autoimmune condition as well. During approximately 6600 person-years of follow-up for the remaining 1024 patients, seven (0.7%) patients developed autoimmune cytopenias (three AITP, three AIHA, one autoimmune pancytopenia) for a 10- and 15-year actuarial incidence of 0.95% and 1.40%, respectively. Their features did not differ compared to the general population of adult HL. In this large series of consecutive, unselected patients, those who presented with autoimmune cytopenias had a particular demographic and disease-related profile. In contrast, patients developing autoimmune cytopenias during follow-up did not appear to differ significantly from those who did not. [ABSTRACT FROM AUTHOR]

Summary: The expression patterns and prognostic significance of sterile alpha motif and HD domain‐containing protein 1 (SAMHD1) protein in the neoplastic Hodgkin and Reed Sternberg (HRS) cells of Hodgkin lymphoma (HL) were investigated in a cohort of 154 patients with HL treated with standard regimens. SAMHD1 expression was assessed by immunohistochemistry using diagnostic lymph node biopsies obtained prior to treatment. Using an arbitrary 20% cut‐off, SAMHD1 was positive in HRS cells of 48/154 (31·2%) patients. SAMHD1 expression was not associated with clinicopathologic parameters, such as age, gender, stage or histologic subtype. In 125 patients with a median follow‐up of 90 months (7–401 months), SAMHD1 expression in HRS cells significantly correlated with inferior freedom from progression (FFP) (P = 0·025), disease‐specific survival (DSS) (P = 0·013) and overall survival (OS) (P = 0·01). Importantly, in multivariate models together with disease stage, histology subtype and type of treatment as covariates, SAMHD1 expression retained an independent significant association with unfavourable FFP (P = 0·005) as well as DSS (P = 0·022) and OS (P = 0·018). These findings uncover the significance of a novel, adverse prognostic factor in HL that may have therapeutic implications since SAMHD1 inhibitors are now available for clinical use. [ABSTRACT FROM AUTHOR]

PET/CT was not performed prior to surgery but the localized nature of the lesion was confirmed by the negative post-surgery PET/CT after the complete resection of the lesion, which had been transformed to anaplastic large cell lymphoma (ALK-negative). It is important to note that there were no other patients within the two cohorts of pediatric and adult cHL patients with 9 and 410 relapsed/refractory cases respectively, in whom a surgery-only approach was applied and failed. At least 70-80% of the patients with Hodgkin lymphoma (HL) can be cured with first-line therapy with the improvement of staging methods and the introduction of increasingly effective chemotherapy regimens during the last 50 years [[1]]. [Extracted from the article]

Abstract Cellular senescence is a stress response mechanism ensuring homeostasis. Its temporal activation during embryonic development or normal adult life is linked with beneficial properties. In contrast, persistent (chronic) senescence seems to exert detrimental effects fostering aging and age-related disorders, such as cancer. Due to the lack of a reliable marker able to detect senescence in vivo , its precise impact in age-related diseases is to a large extent still undetermined. A novel reagent termed GL13 (SenTraGorTM) that we developed, allowing senescence recognition in any type of biological material, emerges as a powerful tool to study the phenomenon of senescence in vivo. Exploiting the advantages of this novel methodological approach, scientists will be able to detect and connect senescence with aggressive behavior in human malignancies, such as tolerance to chemotherapy in classical Hodgkin Lymphoma and Langerhans Cell Histiocytosis. The latter depicts the importance of developing the new and rapidly expanding field of senotherapeutic agents targeting and driving to cell death senescent cells. We discuss in detail the current progress of this exciting area of senotherapeutics and suggest its future perspectives and applications. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cell (HSC) mobilization involves cleavage of ligands between HSC and niche components. However, there are scarce data regarding the role of bone cells in human HSC mobilization. We studied biochemical markers of bone metabolism and angiogenic cytokines during HSC mobilization in 46 patients' sera with lymphoma and multiple myeloma, by ELISA. Significant changes between pre-mobilization and collection samples were found: (1) Bone alkaline phosphatase (BALP) increased, indicating augmentation of bone formation; (2) Receptor activator of Nf-κB ligand/osteoprotegerin ratio (RANKL/OPG) increased, showing osteoclastic differentiation and survival; however, there was no evidence of increased osteoclastic activity; and (3) Angiopoietin-1/Angiopoietin-2 ratio (ANGP-1/ANGP-2) decreased, consistent with vessel destabilization. Poor mobilizers had significantly higher carboxy-terminal telopeptide of collagen type I (CTX) and lower ANGP-1 at pre-mobilization samples, compared to good ones. CTX, amino-terminal telopeptide of collagen type I (NTX) and ANGP-1 pre-mobilization levels correlated significantly with circulating CD34+ peak cell counts. Our results indicate that bone formation and vessel destabilization are the two major events during human HSC mobilization. Osteoblasts seem to be the orchestrating cells, while osteoclasts are stimulated but not fully active. Moreover, ANGP-1, CTX and NTX may serve as predictors of poor mobilization. [ABSTRACT FROM AUTHOR]

Expression of thioredoxin-1 (TXN) and CXCL9 is not restricted to THRLBCL macrophages, but may be observed in histiocytes and neoplastic (HRS) cells of EBV + mixed cellularity (MC) classical Hodgkin lymphoma (cHL) and nodular lymphocyte predominant HL. We aimed to validate and extend the above observations in 174 cHL patients evaluating the immunohistochemical expression of TXN, CXCL9 and IFN-γ. HRS-cell CXCL9 expression was higher in latent membrane protein-1 (LMP1)+, MC and Stage IV. TXN and CXCL9 expression by cHL histiocytes was more frequent in LMP1+, MC and older patients (only for CXCL9). TXN expression by HRS cells (≥80%) was independently associated with better failure-free survival. In conclusion, markers of TCHRLBCL histiocytes (TXN, CXCL9), as well as IFN-γ are also expressed by histiocyte subsets and neoplastic cells of cHL. The expression of some of them is more prominent in EBV + MC, but not restricted to this subtype. The prognostic implication of TXN needs further evaluation. [ABSTRACT FROM AUTHOR]

The article focuses on the bone marrow mesenchymal stem/stromal cells (BM-MSCs) in the disease progression of B-cell lymphoma. It discusses the anti-apoptotic and chemotactic effect of malignant bone marrow (BM) and healthy donor (HD) derived BM-MSC, determination of MSC's incidence related bone marrow mononuclear cell (BMMC) fraction with the help of colony forming unit-fibroblast (CFU-F) assay.

The article features commentaries on the paper presented by Van Grotel and others on the treatment of pediatric nodular lymphocyte predominant Hodgkin's lymphoma (NLPHL), with only chemotherapy without alkylating agents. While positively commenting on the work, further investigation of the results with the addition of rituximab to the standard anthracycline-based chemotherapy is recommended. NLPHL is considered an indolent disease, and less toxic treatment even in cases of multiple relapses.

E2F-1 is the best-described member of the E2F family of transcriptional factors and is particularly interesting in view of its often opposing roles. Our purpose was to examine the immunohistochemical expression of E2F-1 in Hodgkin lymphoma (HL) and to correlate it with proliferation and apoptosis of the tumor, clinicopathological parameters and patient outcome, as well as with expression of the downstream molecules p53 and p21. The median percentage of E2F-1-expressing Hodgkin Reed-Sternberg (HRS) cells was 80.2%. A significant positive correlation was found between expression of E2F-1 and p53 ( p = 0.034). Following stratification of our cases, within the group harboring functional p53, a statistically significant inverse correlation was identified between E2F-1 and Topo IIa ( p = 0.019). E2F-1 is up-regulated in the context of HL and its expression is inversely associated with proliferation. It seems that functional p53 can modulate the relationship between E2F-1 expression and tumor kinetics in HL. [ABSTRACT FROM AUTHOR]

The role of latent Epstein-Barr virus (EBV) infection in the pathogenesis of low-grade B cell non-Hodgkin lymphoma (B-NHL) has not been studied. We therefore investigated the incidence of latent EBV infection in a group of patients with leukemic low-grade B-NHL, as well as the incidence of viral latent membrane protein 1 (LMP1) oncoprotein expression in the same patient group. Furthermore, in an attempt to elucidate the role of this viral oncoprotein in non-EBV-related lymphomas, we correlated the expression of LMP1 with the level of oxidative stress, a parameter related to apoptosis. In the present study we detected lower levels of oxidative stress in the sera of LMP1-positive patients. This possibly implies an anti-apoptotic role of this viral oncoprotein in low-grade B cell lymphomas. However, LMP1 expression status did not affect expression of the major anti-apoptotic gene BCL-2. [ABSTRACT FROM AUTHOR]

We have analyzed the immunohistochemical expression of a wide range of molecules along with the proliferation rate separately in the proliferation centers (PCs) and in the rest of the tumor area, in lymph node or spleen sections of patients with chronic lymphocytic leukemia (CLL). Fas, FasL and c-FLIP were observed both within and outside the PCs in all cases. However, only the difference in FasL expression between the PCs and the non-PC areas attained statistical significance. Median survivin expression in the PCs was higher compared to the non-PC areas. Cleaved caspase 3 was expressed at very low levels both within and outside PCs, while BCL-2 protein was expressed at high levels in all cases in both tumor compartments. Multivariate analysis demonstrated that concurrent overexpression of Fas/FasL/c-FLIP in the PCs was correlated with worse outcome for progression-free survival as well as for overall survival. [ABSTRACT FROM AUTHOR]

The biological and clinical significance of a clonal B-cell lymphocytosis with an immunophenotype consistent with marginal-zone origin (CBL-MZ) is poorly understood. We retrospectively evaluated 102 such cases with no clinical evidence to suggest a concurrent MZ lymphoma. Immunophenotyping revealed a clonal B-cell population with Matutes score ≤2 in all cases; 19/102 were weakly CD5 positive and all 35 cases tested expressed CD49d. Bone marrow biopsy exhibited mostly mixed patterns of small B-lymphocytic infiltration. A total of 48/66 (72.7%) cases had an abnormal karyotype. Immunogenetics revealed overusage of the IGHV4-34 gene and somatic hypermutation in 71/79 (89.8%) IGHV-IGHD-IGHJ gene rearrangements. With a median follow-up of 5 years, 85 cases remain stable (group A), whereas 17 cases (group B) progressed, of whom 15 developed splenomegaly. The clonal B-cell count, degree of marrow infiltration, immunophenotypic, or immunogenetic findings at diagnosis did not distinguish between the 2 groups. However, deletions of chromosome 7q were confined to group A and complex karyotypes were more frequent in group B. Although CBL-MZ may antedate SMZL/SLLU, most cases remain stable over time. These cases, not readily classifiable within the World Heath Organization classification, raise the possibility that CBL-MZ should be considered as a new provisional entity within the spectrum of clonal MZ disorders. [ABSTRACT FROM AUTHOR]

BLyS is involved in CLL biology and its low soluble serum levels related to a shorter time to first treatment (TFT). TACI is a BLyS receptor and can be shed from cells' surface and circulate in soluble form (sTACI). We investigated the impact of serum BLyS and sTACI levels at diagnosis in CLL patients and their relationship with disease parameters and patients' outcome. Serum BLyS was determined in 73 patients, while sTACI in 60. Frozen sera drawn at diagnosis were tested by ELISA. sTACI concentrations correlated with BLyS (P = -0.000021), b2-microglobulin (P = 0.005), anemia (P = -0.03), thrombocytopenia (P = 0.04), Binet stage (P = 0.02), and free light chains ratio (P = 0.0003). Soluble BLyS levels below median and sTACI values above median were related to shorter TFT (P = 0.0003 and 0.007). During a ten-year followup, sTACI levels, but not BLyS, correlated with survival (P = 0.048). In conclusion, we confirmed the prognostic significance of soluble BLyS levels with regard to TFT in CLL patients, and, more importantly, we showed for the first time that sTACI is a powerful prognostic marker, related to parameters of disease activity and staging and, more importantly, to TFT and OS. [ABSTRACT FROM AUTHOR]

The article presents a study which examines the effect of treatment with granulocyte colony-stimulating factor (G-CSF) on leukemic transformation in 92 patients with myelodysplastic syndromes (MDS) treated in two hematology units in Athens, Greece from 1996 to 2005. Medical records of the patients were reviewed and bone marrow biopsies were reevaluated. The results showed considerably lower in patients treated with G-CSF.

Background/Aims: Disease-related anemia in chronic lymphocytic leukemia (CLL) occurs when the obvious causes are excluded while its pathogenesis is still obscure. We investigated its underlying mechanisms in 56 untreated patients with CLL. Methods: Bone marrow (BM) lymphocytic infiltration was estimated in trephine biopsies. Serum erythropoietin (EPO) and tumor necrosis factor-α (TNF-α) levels were measured by ELISA. The potential of BM CD34+ to differentiate into erythroid cells was evaluated by methylcellulose-based assays and in liquid cultures supplemented with EPO, SCF, IL-3 ± TNF-α. The response of erythroid precursors to EPO ± TNF-α was assessed by detecting activated key proteins of EPO-EPO receptor signalling pathway using Western Blot and EMSA. Results: Bone marrow lymphocytic infiltration was not exclusively responsible for disease-related anemia and CD34+ cells were intrinsically capable of generating erythroid precursors. Also, no deficiency of serum erythropoietin (EPO) or defective intracellular response of erythroid precursors to EPO ± TNF-α stimulation was observed. Serum TNF-α levels were found increased in anemic CLL patients and TNF-α appeared to directly inhibit the erythroid development in early stages of erythropoiesis. Conclusion: We concluded that CLL-related anemia was not due to intrinsic defects of erythroid precursors, but might result from the direct suppressive effect of TNF-α on the erythroid production. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Hepcidin is a 25-aminoacid cysteine-rich iron regulating peptide. Increased hepcidin concentrations lead to iron sequestration in macrophages, contributing to the pathogenesis of anaemia of chronic disease whereas decreased hepcidin is observed in iron deficiency and primary iron overload diseases such as hereditary hemochromatosis. Hepcidin quantification in human blood or urine may provide further insights for the pathogenesis of disorders of iron homeostasis and might prove a valuable tool for clinicians for the differential diagnosis of anaemia. This study describes a specific and non-operator demanding immunoassay for hepcidin quantification in human sera. Methods and Findings: An ELISA assay was developed for measuring hepcidin serum concentration using a recombinant hepcidin25-His peptide and a polyclonal antibody against this peptide, which was able to identify native hepcidin. The ELISA assay had a detection range of 10-1500 mg/L and a detection limit of 5.4 mg/L. The intra- and interassay coefficients of variance ranged from 8-15% and 5-16%, respectively. Mean linearity and recovery were 101% and 107%, respectively. Mean hepcidin levels were significantly lower in 7 patients with juvenile hemochromatosis (12.8 μg/L) and 10 patients with iron deficiency anemia (15.7 μg/L) and higher in 7 patients with Hodgkin lymphoma (116.7 μg/L) compared to 32 age-matched healthy controls (42.7 μg/L). Conclusions: We describe a new simple ELISA assay for measuring hepcidin in human serum with sufficient accuracy and reproducibility. [ABSTRACT FROM AUTHOR]

• PMLBCL rarely extends to extranodal subdiaphragmatic (ES) sites at diagnosis. • Among 455 patients, 32 (7%) had such localization at baseline. • Kidney, liver, and adrenals were most frequently involved. • ES site involvement had not independent prognostic impact beyond that of stage IV. [ABSTRACT FROM AUTHOR]

The prognostic value of baseline serum free light chain ratio (sFLCR) was investigated in 94 multiple myeloma (MM) patients. sFLCR was calculated as κ/ λ or λ/ κ, depending on the patients’ dominating monoclonal light chain. Median baseline sFLCR was 3·57 in κ-MM patients, 45·09 in λ-MM. ‘High’ sFLCR (≥ the observed median value for κ- and λ-MM respectively) correlated with elevated serum creatinine and lactate dehydrogenase, extensive marrow infiltration and light chain type MM. The 5-year disease-specific survival was 82% and 30% in patients with sFLCR lower than and equal or greater than the median, respectively ( P = 0·0001). sFLCR was an independent prognostic factor. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the prognostic role of pretreatment serum levels of soluble CD30 (sCD30) in patients with advanced stage classical Hodgkin's lymphoma (cHL) treated with adriamycin, bleomycin, vinblastine, and dacarbazine or equivalent regimens. Methods: We identified 321 previously untreated patients with cHL who presented to the participating centers between 1985 and 2002, and had serum samples available for the determination of sCD30 levels. Results: With a median follow-up of 72 months, the actuarial 5-year overall survival was 82%, and failure-free survival (FFS) was 71%. The median serum level of sCD30 was 65 U/mL (range: 1–2230), and was significantly higher ( P < 0.0001) when compared with a group of 113 healthy controls (4 U/mL, range: 0–20). Increasing level of sCD30 was associated with a continuous worsening of FFS and OS, and patients with sCD30 ≥200 U/mL had a 5-year FFS of 39%. With multivariate analysis, sCD30, Ann Arbor stage, and lactic acid dehydrogenase were significant independent factors in terms of FFS. The association of the above-mentioned three independent prognostic variables could discriminate 22% of patients with 5-year FFS of 40%. Conclusions: Our data confirm the independent prognostic role of sCD30 in identifying the patients with high risk of treatment failure, and show that its association with other variables can recognize patients with FFS considerably lower than 50%. [ABSTRACT FROM AUTHOR]

Primary cutaneous marginal zone lymphoma (PCMZL) is an indolent disease. Treatment options include excision, local irradiation, interferon- α or chemotherapy. We present two patients with PCMZL and multiple skin lesions successfully treated with intralesional administration of the anti-CD20 monoclonal antibody rituximab. The first presented with four red skin lesions and the second with two. Biopsy of the largest lesion revealed marginal zone B-cell lymphoma in both patients. There was no evidence of systemic involvement in either patient. Both patients were treated with intralesional rituximab for 18 consecutive weeks. Skin lesions gradually regressed. Apart from mild local pain during the injection, no other adverse effects were observed. In conclusion, rituximab can be safely administered intralesionally in patients with PCMZL and can produce disease remission. [ABSTRACT FROM AUTHOR]

Abstract: We report two patients, who developed dilated cardiomyopathy and subsequent congestive heart failure after treatment with amphotericin B (AmB). The echocardiographic findings and the symptoms of heart failure resolved after the discontinuation of the drug. The clinical data from our cases and two similar cases reported in the literature suggest that the presence of other factors predisposing to cardiac dysfunction may facilitate the occurrence of this rare side effect. [Copyright &y& Elsevier]

NSC290205 (A) is an hybrid synthetic antineoplastic ester that is a combination of ad-lactam derivative of androsterone and an alkylating derivative ofN,N-bis(2-chloroethyl)aniline. We tested NSC290205 for synergistic antileukaemic activity with adriamycin (ADR), (i)in vitroagainst the human lymphoid leukaemia cell lines: CCRF-CEM, MOLT-4, and RPMI-8226, (ii)in vivoagainst P388 lymphocytic and L1210 lymphoid murine leukaemias (at incipient and advanced phase). Our results indicated significant cytostatic and cytotoxic synergy of NSC290205 and ADRin vitro. We further examined these resultsin vivoby replacing cyclophosphamide in the standard CHOP (cyclophosphamide, hydroxydaunomycin, Oncovin, prednisone) regimen with NSC290205 (AHOP) and comparing the efficiency of these two regimensin vivo. Although treatment of P388 and L1210 with cyclophosphamide or NSC290205 alone yielded equivalent results, AHOP produced a clear benefit for survival compared with CHOP against advanced leukaemias, confirming thein vitroobservations [higher percentage increase in median lifespan of treated animals over the untreated (control): 188% and 239% in L1210, 308% and 353% in P388,P < 0·01, for CHOP and AHOP respectively]. AHOP also proved to be more genotoxic and cytostatic than CHOP, inducing higher sister chromatid exchange levels and cell division delays on P388 cellsin vivo. NSC290205 showed superior antineoplastic potential against lymphoid leukaemia and significant synergy with ADR, producing an excellent therapeutic outcome. [ABSTRACT FROM AUTHOR]

Recent data have suggested that rituximab is an active agent for the treatment of Waldenstrom's macroglobulinemia (WM). However, the patients that are more likely to benefit have not been clearly defined. In order to address this question we evaluated 52 patients who were treated with single-agent rituximab in the context of prospective studies. Several clinical and laboratory variables were assessed for their correlation with response and time to progression. Twenty-three (44%) patients achieved a partial response after treatment with rituximab. Previously untreated and pretreated patients had the same probability for response. Higher response rates were noted in patients with serum monoclonal protein < 40 g/l, with serum albumin &ges; 35 g/l and with kappa light chain. The median time to progression for all patients was 13.8 months. A multivariate analysis indicated that elevated serum monoclonal protein levels and low serum albumin were the dominant variables associated with shorter progression. Presence of two, one or none of these adverse prognostic factors was associated with time to progression of 3.6 months, 11 months and more than 40 months, respectively. We conclude that rituximab is an effective treatment modality for patients with WM. Patients with both low levels of monoclonal protein and normal albumin are the best candidates for treatment with standard dose rituximab. [ABSTRACT FROM AUTHOR]

Elevated pretreatment serum interleukin-10 (IL-10) is associated with inferior progression-free survival (PFS) in patients with Hodgkin's disease (HD) treated with ABVD or equivalent regimens. Therefore, we explored the association of serum IL-10 with presenting features and PFS in HD patients treated only by radiotherapy (RT) with curative intent. Eligible patients were previously untreated, had biopsy-proven HD, were older than 16 years, HIV-negative, and had unthawed pretreatment serum. Serum IL-10 levels were measured with ELISA and were considered high if &ges; 10 pg/ml. We identified 69 patients with median age of 34 years (range 16 - 74), of who 52% were males, and 3% had B-symptoms. Ann Arbor Stage was I in 35%, II in 58%, and III in 7% of the patients. Histology was lymphocyte predominance in 26%, and classical HD in 74% of the patients. Serum IL-10 was elevated in 35% of the patients. After a median follow-up of 67 months for survivors, the 5-year PFS of patients with high vs. normal serum IL-10 was 50% vs. 81% (all patients, P  = 0.006), and 43% vs. 77% for the subset with classical HD ( P  = 0.008). Multivariate analysis revealed that high serum IL-10 and β 2 -microglobulin were independently associated with inferior PFS. Patients with none, 1, or 2 adverse features comprised 57%, 36%, and 7% of the population, and their 5-year PFS was 80%, 63%, and 0%, respectively ( P  < 0.0001). In conclusion, high serum IL-10 is independently associated with inferior PFS in patients with HD treated with RT. [ABSTRACT FROM AUTHOR]

Purpose: To present our long-term experience regarding the use of chemotherapy plus low-dose involved-field radiotherapy (IFRT) for clinical Stage I-IIA Hodgkin''s lymphoma.Methods and materials: We analyzed the data of 368 patients. Of these, 66 received mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) and 302 received doxorubicin (or epirubicin), bleomycin, vinblastine, and dacarbazine [A(E)BVD]. Patients with complete remission or very good partial remission were scheduled for low-dose IFRT (≤3200 cGy).Results: The 10-year failure-free survival (FFS) and overall survival (OS) rate was 85% and 86%, respectively. A(E)BVD-treated patients had superior 10-year FFS and OS rates compared with MOPP-treated patients (87% vs. 75%, p = 0.009; and 93% vs. 71%, p = 0.0004, respectively). Only 10 of 41 relapses had any infield (irradiated) component. Of the complete responders/very good partial responders treated with low-dose IFRT, those who received <2800 cGy had inferior FFS but similar OS as those who received 2800–3200 cGy. Adverse prognostic factors for FFS included age ≥45 years, leukocytosis ≥10 × 109/L, and extranodal extension. Secondary acute leukemia developed after MOPP with or without salvage therapy (n = 6) or after ABVD plus salvage therapy (n = 2). None of the nine secondary solid tumors developed within the RT fields.Conclusion: IFRT at a dose of 2800–3000 cGy is highly effective in clinical Stage I-IIA HL patients who achieved a complete response or very good partial response with A(E)BVD. The long-term toxicity with respect to secondary malignancies appears to be acceptable. [Copyright &y& Elsevier]

ATLL is etiologically associated with HTLV-I retrovirus. A population of 10 to 20 million worldwide is estimated to be infected by the virus, but only 1 - 4% develop ATLL during a 70-year lifespan. The latency period is more than 30 years. The aim of this study was to report two cases of ATLL in Greek patients with the concomitant study of their family members. A 55-year-old woman and a 59-year-old man presented with leucocytosis and lymphocytosis. Both were asymptomatic and physical examination was unremarkable except for minimal lymphadenopathy in the second patient. In both patients blood smears showed small-to-medium-sized, multilobulated lymphocytes, with different degrees of nuclear irregularity. Immunophenotypic study was as follows: CD2 + (97%), CD3 + (95%), CD5 + (95%), CD3/CD4 + (93%), CD3/CD25 + (84%), CD7 - /CD4 + (89%) CD2 + /HLA-DR + (53%), TCRaβ + (96%) and CD7-(7%). Bone marrow biopsy revealed a normal cellularity with dyserythropoiesis and scattered small lymphocytes (CD4 + on immunostaining) Serum HTLV I and II antibodies were positive. T-cell receptor γ-chain rearrangement was positive in blood lymphocytes by PCR. Cytogenetic analysis showed complex karyotypic abnormalities. DNA analysis by PCR demonstrated the integration of the HTLV-1 DNA in the DNA of the neoplastic T cells. Both patients rapidly developed acute type ATLL. In the first patient multiple subcutaneous nodules on the palmar surface of both hands were also observed. She received deoxycoformycin, which was stopped because of autoimmune hemolytic anemia. Corticosteroid treatment was initiated, with gradual improvement. She suffered from recurrent opportunistic infections. She is currently under interferon and zidovudine therapy with stable blood parameters. Chemotherapy was administered to the other patient with > 50% initial response. Both patients' families were tested for serum anti HTLV-I antibodies and their mates were found to be positive; they also had detectable viral DNA by PCR analysis while asymptomatic, with no abnormal clinical findings and normal white blood cell count and morphology. In conclusion, the two aforementioned patients are the first fully documented ATLL patients described in Greece. Investigation for HTLV-I antibodies should be mandatory in all patients with T-cell lymphoproliferative disorders. [ABSTRACT FROM AUTHOR]

Kyrtsonis M-C, Vassilakopoulos TP, Siakantaris MP, Kokoris SI, Gribabis DA, Dimopoulou MN, Angelopoulou MK, Pangalis GA. Serum syndecan-1, basic fibroblast growth factor and osteoprotegerin in myeloma patients at diagnosis and during the course of the disease. Eur J Haematol 2004: 72: 252–258. © Blackwell Munksgaard 2004. Neovascularisation and bone resorption are related to myeloma disease activity. To investigate the possible prognostic importance of serum syndecan-1, basic fibroblast growth factor (bFGF) and osteoprotegerin (OPG) levels, the relationship between them, with parameters of disease activity and the effect of treatment on their levels. Twenty-seven patients were studied from diagnosis and an additional five from remission, for a median follow-up of 40 months. Twenty-three patients received chemotherapy plus bisphosphonates and nine only bisphosphonates. Sera from 11 healthy individuals (HI) were used as controls. Cytokines were determined by commercially available enzyme-linked immunosorbent assays (ELISA) kits. In HI, median syndecan-1 was 40 ng/mL (28–75), bFGF 8 pg/mL (7–30), OPG 35 pg/mL (4–100). Pretreatment median serum syndecan-1 was 177.5 ng/mL (34–3500), bFGF 11.5 pg/mL (8–65) and OPG 100 pg/mL (4–1000). Pretreatment syndecan-1, bFGF and OPG serum levels were increased in patients compared with HI ( P = 0.001, 0.03 and 0.01, respectively). Syndecan-1 and bFGF levels were correlated with stage ( P = 0.004 and 0.03, respectively). Both syndecan-1 and OPG levels were correlated with β2M ( P = 0.04 and 0.01, respectively). Patients with elevated syndecan-1 and bFGF serum levels had shorter survival than patients with normal levels ( P = 0.01 and 0.05, respectively). After chemotherapy syndecan-1 and OPG levels were found to be decreased in responders and syndecan-1 level was reduced in patients receiving bisphosphonates alone. Pretreatment syndecan-1, bFGF and OPG levels were found to be increased at diagnosis. Syndecan-1 and OPG fluctuated according to MM activity. Elevated serum syndecan-1 and bFGF levels predicted short survival. [ABSTRACT FROM AUTHOR]

Summary. Bone marrow angiogenesis has recently been implicated in the pathophysiology and course of various haematological malignancies. Little is known, however, about the significance of this phenomenon in hairy cell leukaemia (HCL). We evaluated various morphometric characteristics of microvessels, highlighted by means of anti-CD34 immunohistochemistry, in the bone marrow of 44 patients with typical HCL, before and after treatment with interferon-α (IFN-α). Overall, bone marrow from 103 HCL patients and 20 controls was examined. Microvessel density (MVD) and several size- and shape-related parameters were quantified in the region of most intense vascularization using image analysis. MVD, size-related parameters and the percentage of branching microvessels were higher in HCL than in controls. Likewise, perimeter counts were higher in partial/non-responders than in complete responders. Achievement of complete response was accompanied by smaller calibre microvessels. IFN-α induced a decrease in MVD and branching values in cases with diffuse marrow involvement. In univariate analysis, progression-free survival was adversely affected by MVD, branching and major axis length. Multivariate analysis indicated that MVD/branching independently affected progression-free survival and the likelihood of complete response. Our data suggest that the generation of bone marrow microvessels indicated an increased risk of progression and IFN-α treatment failure in HCL. Furthermore, the prognostic significance of angiogenesis requires the concomitant assessment of MVD and the complexity of the microvascular network. [ABSTRACT FROM AUTHOR]

Abstract: Objectives : To investigate the prognosis of patients with Hodgkin's lymphoma (HL) who relapse following a complete remission (CR) achieved by chemotherapy with or without radiotherapy (CT±RT), and to identify prognostic factors for freedom from second progression (FF 2 P). Methods : We analyzed the prognostic significance of the initial CT regimen (4 vs. 7–8 drugs), treatment-free interval (TFI), and demographic, clinical, and laboratory factors at the time of relapse and diagnosis, in 113 patients with HL, who relapsed after a CR achieved by CT±RT. Results : Conventional salvage CT±RT was administered in 107 patients, while six received RT only. The 5-yr FF 2 P was 24%, while the 10-yr survival after relapse (O 2 S) was 39% and was not afffected by the initial CT regimen. Multivariate analysis revealed that extranodal disease at relapse ( P <0.001), TFI<6 month ( P <0.001), >=5 involved sites at diagnosis ( P =0.04) and anemia at relapse ( P =0.03) were independent predictors of FF 2 P. 55% of patients had 0 or 1 of these adverse prognostic factors. The 5-yr FF 2 P of patients with 0, 1 or 2 adverse factors was 58%, 34% and 5% ( P <0.0001). The corresponding rates for 10-yr O 2 S were 68%, 51% and 25%, respectively ( P =0.002). Conclusions: Our data confirmed the significance of TFI and extranodal relapse and demonstrated a potential role for anemia at relapse and number of involved sites at diagnosis, for the prognosis of patients with HL relapsing after CT±RT. The combination of these prognostic factors defines a sizeable subgroup of patients with favorable outcome following conventional salvage therapy. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To describe the clinical, immunophenotypic and molecular features, as well as the clinical course of patients with unusual presentation of mantle cell lymphoma (MCL) purely located to the spleen. Patients and methods: We describe seven patients presented with splenomegaly and a leukemic picture without lymphadenopathy, fulfilling the diagnostic criteria of MCL. In addition to clinical and pathologic features, patients were studied with respect to surface immunophenotype, including adhesion molecule profile, immunohistochemical expression of cyclin-D1 and bcl-1 rearrangement by polymerase chain reaction. Results: Four patients were male and three female. The median palpable spleen size was 15 cm. A preliminary diagnosis of MCL was made, based on blood cell morphology and immunophenotype. All patients underwent splenectomy for therapeutic purposes. Studies done in blood and splenic lymphocytes revealed the following: 7/7 patients were CD19/CD5, CD20 and CD38 positive; CD10 negative and 6/7 CD23 negative. The adhesion molecule expression pattern was consistent in all patients: L-Selectin and CD11c were negative, CD11α and CD18 weakly positive and CD54 strongly positive. The median spleen weight was 1775 g. Histology disclosed a cytologic and architectural pattern consistent with MCL. Cyclin-D1 was positive in 6/6 studied patients. Bcl-1 rearrangement was found in 5/7 patients. Splenectomy was applied as the sole treatment and was beneficial in all patients, with median blood values as following: prior to splenectomy, Ht 29.5%, platelets 110 × 109 /l, lymphoma cells 5.0 × 109 /L, and at 6 months post-splenectomy, Ht 43%, platelets 311 × 109 /l and lymphoma cells 3.0 × 109 /L. Of the seven patients, two developed progressive disease 11 and 26 months post-splenectomy. The remaining five are in improving clinical and hematological condition without chemotherapy at a median follow... [ABSTRACT FROM AUTHOR]

Pulmonary involvement in Waldenström’s macroglobulinaemia (WM) occurs in 3–5% of cases, but lung involvement without bone marrow infiltration is extremely rare. We report 2 patients who presented with bilateral consolidations on chest X-ray and non-specific symptoms and were treated for a long period of time for pulmonary infections until the diagnosis was made by open lung biopsy. Both patients presented high monoclonal IgM in the serum and one also had blood lymphoplasmacytosis. Trephine bone biopsy and bone marrow smears were normal and there was no other site of involvement. Along with the presentation of our patients, we review the literature, discuss some of the possible underlying mechanisms and raise the attention of clinicians to this rare manifestation of the disease.Copyright © 2001 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]