Primary effusion lymphoma in two HIV-negative patients successfully treated with pleurodesis as first-line therapy.

Primary effusion lymphoma (PEL) is a rare non-Hodgkin's lymphoma (NHL) mostly occurring in HIV-positive patients. It is characterized by the development of effusion in one or more body cavities, with no tumor masses and a positive human herpes virus-8 (HHV8) status. It has a poor survival profile and no optimal treatment is yet defined. We report two HIV-negative, HHV8-positive patients with PEL of the pleural cavity who achieved a durable remission after pleurodesis with bleomycin and no systemic therapy. We also perform a review of the relevant literature regarding the clinical data, treatment, and survival of PEL in HIV-negative patients.

Coexistence of Behcet's disease and chronic myelomonocyte leukemia with trisomy 8: a case report and review of the literature.

Behçet's disease (BD) is a multisystem inflammatory vasculitis of unknown etiology and pathogenesis. Coexistence of BD along with hematological malignancies is extremely rare. We describe a patient diagnosed with BD and chronic myelomonocytic leukaemia (CMML) with trisomy 8. This case suggests that trisomy 8 may be involved in the concurrent manifestation of myelodysplastic syndrome (MDS) and BD with gastrointestinal ulcers.

High serum levels of B-lymphocyte stimulator are associated with clinical-pathological features and outcome in classical Hodgkin lymphoma.

B-lymphocyte stimulator (BLyS) acts as survival factor for B lymphocytes. As Hodgkin and Reed-Sternberg (HRS) cells express receptors through which BLyS promotes their growth and chemotherapy resistance, we investgated whether this molecule was increased in sera from patients with classical Hodgkin lymphoma (cHL) and whether it correlates with clinical-pathological features and outcomes. Enzyme-linked immunosorbent assay was used to measure soluble BLyS (sBLyS) in sera from 87 patients and 33 donors; higher levels were detected in patients (mean +/- standard error 4493.9 +/- 264.9 pg/ml vs. 2687.0 +/- 200.9 pg/ml; P < 0.0001). Levels above the median value (4242.0 pg/ml) were associated with age > or = 45 years (P = 0.042), advanced stages of disease (P = 0.005), systemic symptoms (P = 0.014) and extranodal involvement (P = 0.009). Five-year failure-free survival (FFS) of patients with sBLyS below or equal to median levels was 88.6% as compared to 65.1% of those with levels above the median (P = 0.009). Statistical analyses confirmed the prognostic significance of sBLyS (P = 0.046). When patients were analysed according to variables associated with high levels, sBLyS showed an independent predictive power in terms of FFS. Our findings support the involvement of BLyS in cHL pathogenesis. The association between high serum levels and an inferior FFS indicates that sBLyS is a possible prognostic predictor with a potential significance as a therapeutic target.

Rituximab monotherapy is highly effective in splenic marginal zone lymphoma.

Splenectomy has traditionally been considered as a standard first line treatment for splenic marginal zone lymphoma (SMZL) conferring a survival advantage over chemotherapy. However it carries significant complications, especially in elderly patients. The purpose of this retrospective study was to report our experience on the efficacy of Rituximab as first line treatment in 16 consecutive SMZL patients, diagnosed in our department. The diagnosis was established using standard criteria. Patients' median age was 57 years (range, 48-78). Prior to treatment initiation all patients had splenomegaly, nine had anemia, five lymphocytosis, five neutropenia and six thrombocytopenia. Rituximab was administered at a dose of 375 mg/m2/week for 6 consecutive weeks. The overall response rate was 100%. After treatment, all patients had a complete resolution of splenomegaly along with restoration of their blood counts. Eleven patients (69%) achieved a CR, three (19%) unconfirmed CR and two (12%) a PR. Among the complete responders seven patients had also a molecular remission. The median time to clinical response was 3 weeks (range, 2-6). Rituximab maintenance was given to 12 patients. Eleven of them had no evidence of disease progression after a median follow-up time of 28.5 months (range, 14-36), while two out of four patients who did not receive maintenance, relapsed 7 and 24 months after the completion of induction treatment. Median follow-up time for the entire series was 29.5 months (range, 15-81). No deaths were recorded during the follow-up period. Therapy was well tolerated. The present study demonstrates that rituximab is an effective treatment for SMZL and could be considered as a substitute or alternative to splenectomy.

FLT3 overexpression in acute promyelocytic leukemia patients without detectable FLT3-ITD or codon 835-836 mutations: a pilot study.

BACKGROUND: Activating mutations of the FLT3 receptor tyrosine kinase are common in acute promyelocytic leukemia (APL) but have uncertain prognostic significance. Information regarding FLT3 expression levels in APL without FLT3 mutations is lacking. MATERIALS AND METHODS: Using RT-PCR, mutation analysis of the FLT3 gene, regarding internal tandem duplications (ITDs) and codon 835-836 point mutations, was performed and real-time PCR was carried out to determine the level of FLT3 expression in 11 APL patients at diagnosis and 5 in haematological remission with molecularly detectable disease. RESULTS: High levels of FLT3 transcript, at least a 10-fold increase compared to the normal controls, were found at diagnosis in all 3 mutated cases and in 2 patients without detectable FLT3 mutations. CONCLUSION: FLT3 overexpression can be documented in patients without FLT3 mutations. These patients might benefit from treatment using specific FLT3 tyrosine kinase inhibitors. Larger studies are needed to evaluate the clinical and biological significance of FLT3 overexpression in the absence of FLT3 mutations.

Angiogenesis in Hodgkin's lymphoma: a morphometric approach in 286 patients with prognostic implications.

The significance of angiogenesis in Hodgkin's lymphoma (HL) is not well defined. The aim of this study was to evaluate various morphometric characteristics of microvessels in lymph node sections of 286 patients with HL at diagnosis and investigate their relationship with clinicopathologic parameters and prognosis. Microvessel density (MVD), total vascular area (TVA) and several size- and shape-related microvascular parameters were quantitated--after anti-CD34 immunohistochemical staining--in the region of most intense vascularization, using image analysis. An increase in microvessel caliber parameters (area, perimeter, major and minor axis length) and a decrease in MVD were noted with increasing stage. An inverse relationship was recorded between MVD and the number of involved sites (NIS) and LDH. In univariate analysis, overall disease-specific survival was adversely affected by MVD and TVA, whereas inferior failure-free survival (FFS) was associated with the presence of more flattened vessel sections. Multivariate analysis disclosed that the extent of angiogenesis (MVD/TVA), age and the NIS independently affected overall survival. Accordingly, FFS was independently linked to the shape of microvessels and albumin levels or the NIS. In conclusion, our data support the view that angiogenesis in HL provides independent prognostic information, requiring the concomitant evaluation of quantitative and qualitative aspects of microvascular network.

Breast cancer following curative chemotherapy for non-Hodgkin's lymphoma and the effect of drug resistance proteins to the final outcome. A retrospective study.

PURPOSE: To investigate the overall survival (OS) of patients developing breast cancer (BC) after curative chemotherapy for non-Hodgkin's lymphoma (NHL) and to evaluate the possible effect on the patients' outcome of the expression of drug resistance-related proteins (P-glycoprotein-Pgp, multidrug resistance-associated protein-MRP, and multidrug resistance-related vault lung resistance protein-LRP) in BC issue. STUDY GROUP: 25 female patients (median age 60 years, range 37-70) who developed BC after chemotherapy for high/intermediate grade B-cell NHL, treated with CHOP and achieving complete remission (CR). This group was further subdivided in subgroups A and B, according to the time interval between NHL and BC development ( 24 months, respectively). A matched-pair group of de novo BC patients formed the control group. BC tissue was immuno-histochemically stained for Pgp, MRP and LRP. RESULTS: The median interval between NHL diagnosis and BC development was 26 months (range 9-49). In both groups 14 patients had tumor grade II; 16 were negative for steroid receptors; 17 overexpressed c-erbB-2; 14 were stage IIIA/B, and 11 stage IV. CMF or CNF (mitoxantrone instead of doxorubicin) were given for BC. Early progression was noticed in all study group patients for which second-line chemotherapy was instituted. There was a better response for stage IV patients in the control versus the study group (p=0.07). More prolonged OS was demonstrate for patients with stage III in the control group (median 51 months) and in subgroup B (median 47 months) than in subgroup A (median 16 months; p=0.00012), as well as for patients with advanced disease (p=0.0045). Development of BC < 24 months after NHL resulted in reduced OS (p=0.017). No difference was noticed in the expression of drug resistance proteins between the study and control group or between subgroups A and B. CONCLUSION: BC developing shortly after a CR to NHL is an aggressive disease variant with minimal potential for response to conventional chemotherapy. Analysis of Pgp, MRP and LRP failed to demonstrate significant difference between the study and control group, although indications exist that drug resistance mechanisms might be part of the aggressive disease phenotype, contributing to the poor outcome.

beta(2)-microglobulin in Hodgkin's lymphoma: prognostic significance in patients treated with ABVD or equivalent regimens.

PURPOSE: Serum beta-2 microglobulin (sbeta(2)m) is an established prognostic factor for several lymphoproliferative disorders. Because its significance in Hodgkin's lymphoma (HL) is controversial, we determined sbeta(2)m levels in pretreatment serum samples of patients with HL in order to elucidate its prognostic value in this condition. PATIENTS AND METHODS: Pretreatment sbeta(2)m levels were determined in 379 HL patients who were treated with ABVD or equivalent regimens with or without radiotherapy (RT), using a radioimmunoassay (upper normal limit 2.4 mg/l). Sbeta(2)m levels were correlated with several clinical and laboratory parameters. RESULTS: Elevated sbeta(2)m levels were detected in 138/379 (36%) patients and correlated with all clinical and laboratory baseline features except gender, lung involvement and mediastinal bulk. They also correlated with serum soluble CD30 and interleukin-10 levels. The 8-year failure-free survival (FFS) was 78 -/+ 4% for patients with normal versus 65 -/+ 7% for patients with elevated sbeta(2)m levels (p=0.003). The corresponding rates among early-stage patients were 83 -/+ 53% versus 71 -/+ 9% (p=0.003), while for advanced stages they were 70 -/+ 6% versus 64 -/+ 8% (p=0.54). In multivariate analysis of the whole patient population elevation of sbeta(2)m levels was not predictive of FFS, but it was strongly predictive among early-stage patients. The 8-year overall survival (OS) rates were 91 -/+ 3% for patients with normal versus 59 -/+ 11% (p <0,0001) for patients with elevated sbeta(2)m levels, while unrelated mortality at 8 years was 1 -/+ 1% versus 27 -/+ 12% (p<0.0001). CONCLUSION: Our data suggest that sbeta(2)m levels may be a potent prognostic factor for FFS in patients with early stage HL treated with ABVD and equivalent regimens. Their effect on OS is confounded by the higher unrelated mortality in patients with elevated baseline sbeta(2)m levels, probably due to the strong association between sbeta(2)m and older age.

Octreotide neutralizes dexamethasone antitumor actions on P388 murine lymphocytic leukemia in vivo.

PURPOSE: A wide variety of human malignancies, including lymphoproliferative neoplasms, express somatistatin (SS) receptors (SS-R). SS induces apoptosis and exerts pronounced antiproliferative effects on various human tumors cell lines, human xenografts, and animal tumors including P388 lymphocytic leukemia. In patients with thymoma the combination of octreotide (OCT) with corticosteroids improves the overall response rate. It has been reported that SS can increase glucocorticoid activity. Hereby, we studied the in vitro and in vivo activity of the SS analogue OCT and of the glucocorticoid dexamethasone (DEX) alone or in combination against the murine P388 lymphocytic leukemia. MATERIALS AND METHODS: Cultures of P388 lymphocytic leukemia and BDF(1) male mice implanted with P388 cells where used for the in vitro an in vivo evaluation of the antileukemic activity of SS and DEX. RESULTS: OCT induced a moderate and DEX a satisfactory cytostatic effect in vitro. OCT produced borderline antileukemic effect when administered on days 1-5 while DEX was effective in all schemes and routes of administration. However, none of the combination schemes exerted any anti-leukemic activity both in vitro and in vivo. CONCLUSION: Since both SS and glucocorticoids exert direct (via receptors) and indirect antitumor actions (regulation of growth factor activity) on several cell lines, in vitro and in vivo, it becomes obvious that further in vitro studies shall provide the molecular evidence for the signal transduction pathways which are involved in the interactions of such important anticancer drugs. Based on the results of the present study, the simultaneous use of these drugs in clinical practice should be carefully considered.

Breast cancer after curative chemotherapy in non-Hodgkin's lymphoma: examination of the role of drug resistance and retrospective comparison to the outcome of de novo breast cancer.

We examined the outcome of patients who developed breast cancer after curative chemotherapy (CHOP) for aggressive non-Hodgkin's lymphoma (NHL) in comparison to the outcome of a retrospectively selected matched-pair group of patients with de novo breast cancer, and evaluated the role of drug resistance-related protein (MDR, MRP, LRP) expression in breast cancer tissue. Twenty-two patients presented with breast cancer (BC) in complete remission after CHOP for NHL. The median age was 62 (49-70) years, each had high/intermediate grade B-cell NHL treated with 6 courses of CHOP, and were in complete remission. These patients were compared to a matched-pair group of de novo BC patients selected from our database over the same time period. Breast cancer tissue was stained by immunohistochemistry for drug resistance proteins LRP, MRP, and MDR. Breast cancer developed after a median of 26 (9-49) months of NHL diagnosis; breast tumor grades 1-2 were seen in 12, and grade 3 in 10 patients; 15 were negative and 7 weakly positive for estrogen and progesterone receptors. Twelve patients were stage IIIA/B, and 10 stage IV and were treated with conventional chemotherapy regimens. All progressed early in liver (n=13), brain (n=9), lung (n=6), bone (n=8), lymph nodes (n=7) and soft tissue (n=5), and received second-line chemotherapy with mitomycin-C + vinblastine or taxanes. The overall survival was 11.8 (6-26) months (p<0.01). Time from NHL to breast cancer development was 19 (14-27) months in patients with positive drug resistance proteins (group A), and 37 (26-56) months in patients with 1 or 2 positive resistance proteins (group B) (p<0.001). In patients with stage IIIA/B disease, there was no difference between the examined and control matched-pair group in median TTP, but there was in overall survival (OS) (23 vs 36 months, p=0.029). In advanced disease, there were more responders in the control vs the examined group (p=0.07). Patients in the control matched-pair group had more prolonged OS when compared to group A patients who developed BC in <24 months from NHL to BC (p=0.017). We conclude that breast cancer developing shortly after a complete response in NHL, is an aggressive disease variant with minimal potential for response to conventional chemotherapy. Analysis of drug resistance mechanisms concerning MDR, MRP and LRP indicates that most of these patients have BC that overexpress these proteins leading to the suggestion that these mechanisms might be a part of the aggressive disease phenotype and partially explain the poor outcome.

Retinoblastoma gene product and P21 (WAF1, CIP1) protein expression in non Hodgkin's lymphomas: a multivariate survival analysis.

We evaluated immunohistochemically the expression of two negative regulators of the cell cycle, namely retinoblastoma gene product (pRb) and WAF1/Cip1 gene product (p21), in paraffin sections from 93 patients with non-Hodgkin's lymphomas (NHL) and related it to clinicopathological parameters, proliferative fraction, p53 expression and survival. Patients were followed until death (n=33) or for an average of 52 months (60-160). Rb labelling index (LI) increased with malignancy grade and proliferative activity but was unrelated to other clinicopathological parameters. In 33% of cases, especially those of the aggressive groups, we observed diminished pRb expression (i.e. low pRb/Ki-67 ratio). p21 expression on the other hand correlated only with histological grade, Rb LI and p53 LI. In multivariate analysis, Rb LI was a negative predictor of disease-free survival but was linked to a higher probability of complete response. However, diminished pRb expression as well as p21 expression were not statistically significant prognostic indicators. Our results suggest that pRb as a cell cycle related molecule may play an important role in determining prognosis and therapeutic response in NHL patients.

Primary lung involvement in Waldenström's macroglobulinaemia: report of two cases and review of the literature.

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.

Serum interleukin-10 levels are an independent prognostic factor for patients with Hodgkin's lymphoma.

BACKGROUND AND OBJECTIVES: Interleukin-10 (IL-10) is a pleiotropic cytokine which increases bcl-2 levels and protects cells from steroid or doxorubicin-induced apoptosis. Hodgkin and Reed-Sternberg (HRS) cells bear functional IL-10 receptors. Thus serum IL-10 (sIL-10) might inhibit apoptosis in HRS cells, which could occur as a result of either chemotherapy or the crippled immunoglobulin genes. DESIGN AND METHODS: We determined sIL-10 levels in 122 patients with Hodgkin's lymphoma (HL), treated with ABVD or equivalent regimens with or without radiotherapy, and correlated them with presenting clinical and laboratory features, as well as failure-free survival (FFS) and overall survival. RESULTS: Elevated sIL-10 levels ( > or = 10 pg/mL) were detected in 55 patients (45%), and were correlated with advanced stage and elevated serum b2-microglobulin levels. At 7 years FFS was 85% vs. 63% for patients with normal vs. elevated sIL-10 levels, respectively (p=0.01); overall survival was 97% vs. 73% (p=0.005). Multivariate analysis with Cox's proportional hazards model demonstrated that elevated sIL-10 levels were the strongest independent predictor of FFS, and were also associated with inferior overall survival. INTERPRETATION AND CONCLUSIONS: We conclude that sIL-10 levels are elevated in 45% of patients with HL, and are associated with inferior FFS and overall survival, independently of other established prognostic factors.

Evaluation of DNA topoisomerase IIalpha expression provides independent prognostic information in non-Hodgkin's lymphomas.

AIMS: In view of the dual role that DNA topoisomerase IIa (TopoIIa) plays as a cell proliferation marker and as a possible indicator of chemosensitivity, we investigated its expression in non-Hodgkin's lymphomas (NHL) in relation to conventional clinicopathological parameters, cell proliferation (as defined by Ki67 immunoreactivity), response to therapy and patient outcome. METHODS AND RESULTS: Formalin-fixed paraffin-embedded tissues from 153 patients with NHL were immunohistochemically stained for TopoIIalpha. Patients were followed up until death (n = 63) or for an average of 68 months (median 64 months, n = 90). The percentage of TopoIIalpha positive cells (TopoIIalpha LI) increased with grade (P < 0.001), extranodal location (P = 0.05) and Ki67 LI (P = 0.01, r = 0.673). In most cases (58%), Ki67 LI exceeded TopoIIalpha LI (TopoIIalpha/Ki67 < 1), especially within the indolent group (P < 0.001). TopoIIalphaLI, Ki67LI and TopoIIalpha/Ki67 ratio were all adversely related to overall survival in univariate analysis, though their significance was not maintained after adjustment for grade. In multivariate analysis high TopoIIalpha/Ki67 ratio and high TopoIIalpha LI independently predicted shortened overall and post-relapse survival, respectively. Most importantly, low TopoIIalpha/Ki67 ratio was the only independent predictor of diminished disease-free survival. However, there was no relationship between TopoIIalpha expression and response. CONCLUSIONS: Our results suggest that evaluation of TopoIIalpha expression and TopoIIalpha/Ki67 ratio as cell proliferation markers provides independent prognostic information in relation to post-relapse and overall survival. Furthermore, TopoIIalpha/Ki67 ratio appears to play a key role in the identification of patients prone to early relapse.

Campath-1H (anti-CD52) monoclonal antibody therapy in lymphoproliferative disorders.

Campath-1H is a humanized monoclonal antibody targeted against the CDw52 membrane antigen of lymphocytes, which causes complement and antibody-dependent cell-mediated cytotoxicity. Campath-1H has been used in B-chronic lymphocytic leukemia (B-CLL), T-prolymphocytic leukemia (T-PLL), and low-grade non-Hodgkin's lymphoma (LGNHL). Campath-1H is administered intravenously thrice weekly for up to 12 wk, at an initial dose of 3 mg, escalated to 10 and 30 mg. The responses (complete [CR] and partial [PR]) obtained in untreated B-CLL patients are of the order of 90%. In previously treated B-CLL patients, responses are of the order of approximately 40%, with 2-4% CRs. Responses are more prominent in the blood and bone marrow compared to the lymph nodes. The median duration of response is 9-12 mo. Because of the antibody's higher activity on circulating lymphocytes, it has been used for in vivo purging of residual disease in B-CLL, followed by autologous stem-cell transplantation. In heavily pretreated advanced stage LGNHL, response is achieved only in 14% of cases with B-phenotype; a 50% response rate is noted in mycosis fungoides. In T-PLL, the CR rate is approximately 60%. Promising results have been reported in a small number of patients with refractory autoimmune thrombocytopenia of lymphoproliferative disorders. The main complications of Campath-1H treatment are caused by tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 release, usually during the first intravenous infusion, and include fever, rigor, nausea, vomiting, and hypotension responsive to steroids. These side effects are usually less severe with subsequent infusions and can be prevented by paracetamol and antihistamines. Immunosupression resulting from normal B- and T-lymphocyte depletion is frequent, resulting in an increased risk for opportunistic infections. More clinical trials in a larger number of patients are necessary to determine the exact role and indications of Campath-1H in lymphoproliferative disorders.

Waldenström's macroglobulinemia: clinical course and prognostic factors in 60 patients. Experience from a single hematology unit.

Waldenström's macroglobulinemia (WM) is a lymphoplasmacytic lymphoma characterized by the presence in patients' serum of an IgM monoclonal component. We report on our experience with 60 WM patients, focusing on their clinical findings, response to treatment, and the possible identification of prognostic factors. Of these patients, 70% presented with fatigue, and lymphadenopathy was observed in 22%, splenomegaly in 18%, hepatomegaly in 13%, and extranodal site of involvement in 6%. Bleeding tendency was seen in 17%, infections in 17%, hyperviscosity syndrome in 12%, and cardiac failure in 25% of the patients. The median of IgM levels was 30 g/l with hypoalbuminemia in 20% of cases, hypogammaglobulinemia in 27%, polyclonal hypergammaglobulinemia in 15%, kappa light-chain restriction in 78%, and Bence-Jones proteinuria in 54%. Anemia was frequent (85%), followed by leukocytosis (18%), lymphocytosis (12%), leukopenia (10%), and thrombocytopenia (10%). Cryoglobulinemia and autoimmune hemolytic anemia were encountered in 5%. In all cases but two, bone marrow was involved. Of 50 patients initially treated with intermittent oral chlorambucil, 46 (92%) responded. Median overall survival was 108 months. Factors associated with adverse prognosis were age > or =65 years (p=0.06), presence of lymphadenopathy (p=0.06), bone marrow infiltration > or =50% (p=0.007), international prognostic index (IPI) > or =3 (p=0.0001), and Morel's scoring system (p=0.04). Concluding, we found in this series of WM patients that chlorambucil is an effective treatment and that the parameters of age, lymphadenopathy, percentage of bone marrow infiltration, IPI, and Morel's scoring system carry prognostic significance.