The prognostic role of post-induction FDG-PET in patients with follicular lymphoma: a subset analysis from the FOLL05 trial of the Fondazione Italiana Linfomi (FIL)

Background[¹⁸F]fluorodeoxyglucose-positron emission tomography (PET) is emerging as a strong diagnostic and prognostic tool in follicular lymphoma (FL) patients.Patients and methodsIn a subset analysis of the FOLL05 trial (NCT00774826), we investigated the prognostic role of post-induction PET (PI-PET) scan. Patients were eligible to this study if they had a PI-PET scan carried out within 3 months from the end of induction immunochemotherapy. Progression-free survival (PFS) was the primary study end point.ResultsA total of 202 patients were eligible and analysed for this study. The median age was 55 years (range 33–75). Overall, PI-PET was defined as positive in 49 (24%) patients. Conventional response assessment with CT scan was substantially modified by PET: 15% (22/145) of patients considered as having a complete response (CR) after CT were considered as having partial response (PR) after PI-PET and 53% (30/57) patients considered as having a PR after CT were considered as a CR after PI-PET. With a median follow-up of 34 months, the 3-year PFS was 66% and 35%, respectively, for patients with negative and positive PI-PET (P < 0.001). At multivariate analysis, PI-PET (hazard ratio 2.57, 95% confidence interval 1.52–4.34, P < 0.001) was independent of conventional response, FLIPI and treatment arm. Also, the prognostic role of PI-PET was maintained within each FLIPI risk group.ConclusionsIn FL patients, PI-PET substantially modifies response assessment and is strongly predictive for the risk of progression. PET should be considered in further updates of response criteria.     

Progress and promise in the treatment of indolent lymphomas

In the era of conventional alkylating agent-based chemotherapy, advanced stage indolent lymphoma has been considered incurable. The failure of our traditional therapies to cure these patients, coupled with the indolent course of the disease and the elderly population affected, has fostered a nihilistic attitude about the treatment of these diseases. Twenty years ago, in the absence of interesting alternatives to alkylating agents, judicious use and reuse of alkylators was perhaps the best we could do. There are now many reasons for optimism and excitement in the treatment of these diseases, including the availability of promising agents such as interferon-alpha, the nucleoside analogues, and rituximab. Radioimmunotherapy will also likely play a role in future therapy programs. Allogeneic stem cell transplantation is a high-risk approach that is not an option for all patients, but it has the potential to cure patients, even in the setting of relapse. Mini-allogeneic transplantation may permit an approach to allogeneic transplantation that is better tolerated than standard transplant strategies. In addition to these therapy options, biological insights have provided new options for monitoring patients. Molecular monitoring (polymerase chain reaction for bcl-2) is a stringent measure of short-term treatment efficacy, and one that correlates with durability of remission, i.e., it is a surrogate marker by which to judge treatment efficacy. There used to be a limited number of conventional treatment approaches, which consistently failed. The pendulum has swung. There are now many promising new options. It is time to plan and conduct trials that are geared for success.     

Fludarabine, cyclophosphamide, and rituximab in patients with advanced, untreated, indolent B-cell nonfollicular lymphomas: phase 2 study of the Italian Lymphoma Foundation

BACKGROUND:

Indolent nonfollicular non‐Hodgkin B‐cell lymphomas (INFLs) are clonal mature B‐cell proliferations for which treatment has not been defined to date.

METHODS:

In this phase 2 study of patients with advanced INFL, the authors evaluated the efficacy and safety of first‐line rituximab, fludarabine, and cyclophosphamide (FCR) as induction immunochemotherapy (rituximab 375 mg/m² intravenously on day 1 of each cycle and on days 1 and 14 of cycles 4 and 5; fludarabine 25 mg/m² intravenously on days 2‐4, cyclophosphamide 250 mg/m² intravenously on Days 2‐4) every 28 days for 6 cycles followed by a maintenance phase with 4 infusions of rituximab (375 mg/m² intravenously on day 1) every 2 months for responders.

RESULTS:

Forty‐seven patients were enrolled. Among 46 evaluable patients (28 men; median age, 59 years), 19 were diagnosed with lymphoplasmacytic lymphoma, 21 were diagnosed with small lymphocytic lymphoma, and 6 were diagnosed with nodal marginal zone lymphoma. The overall response rate after maintenance was 89.1% with a 67.4% complete remission (CR) rate (CR/unconfirmed CR) and a 21.7% partial response rate. After a median follow‐up of 40.9 months, the failure‐free survival and progression‐free survival rates both were 90.1%, and the overall survival rate was 97.4%. The main toxicity was hematologic, and related grade 3 and 4 neutropenia was observed in 55.3% of patients.

CONCLUSIONS:

FCR induction therapy followed by a short maintenance phase is a highly effective regimen with acceptable toxicity. Cancer 2012. © 2011 American Cancer Society.     

The role of mitoxantrone in the treatment of indolent lymphomas

With the introduction of newer therapeutic approaches, survival in indolent non-Hodgkin's lymphoma (NHL) appears to be improving. Mitoxantrone (Novantrone; Serono, Inc.; Rockland, MA, http://www.seronousa.com), an anthracenedione with low cardiotoxic potential, has demonstrated activity in indolent NHL in combination with fludarabine (Fludara; Berlex Laboratories; Wayne, NJ, http://www.berlex.com) and other agents. In a Southwest Oncology Group trial (SWOG 9501), treatment with fludarabine and mitoxantrone (FM) induced a complete remission (CR) rate of 44% and a partial remission (PR) rate of 50% in untreated patients. The estimated 4-year progression-free survival (PFS) rate was 38%. In a multicenter Italian trial comparing the efficacy of FM with that of cyclophosphamide, doxorubicin (Adriamycin; Bedford Laboratories; Bedford, OH, http://www.bedfordlabs.com), vincristine (Oncovin; Eli Lilly and Company; Indianapolis, IN, http://www.lilly.com), and prednisone (Deltasone; Pfizer Pharmaceuticals; New York, NY, http://www.pfizer.com), CHOP, followed by rituximab (Rituxan; Genentech, Inc.; South San Francisco, CA, http://www.gene.com) for patients with incomplete clinical or molecular responses, the CR and molecular response rates were significantly higher in the FM arm, but the PFS and overall survival (OS) rates did not differ between the two arms. However, FM was also significantly less toxic than CHOP. The administration of rituximab following chemotherapy resulted in higher clinical and molecular response rates in both arms. In a separate trial, FM plus dexamethasone (Decadron; Merck and Co., Inc.; Whitehouse Station, NJ, http://www.merck.com), FND, plus concurrent rituximab produced a CR rate of 92%. In a randomized German study, patients with indolent lymphomas received FM plus cyclophosphamide (FCM) or FCM with rituximab. PFS and OS times were significantly better for patients who received combined chemoimmunotherapy. Mitoxantrone-based regimens are highly active and well tolerated in patients with both relapsed and previously untreated indolent lymphomas. The addition of rituximab appears to increase the activity of the FM, FND, and FCM regimens. Although the results of the Italian multicenter study support the superiority of FM over CHOP in terms of clinical and molecular responses and tolerability, additional studies using rituximab in combination with both of these regimens should be attempted to determine the possible further benefit of both in the management of indolent lymphoma. Because cure remains elusive in patients with indolent lymphoma, maximum prolongation of PFS with minimal toxicity and maximum preservation of quality of life should remain central goals of treatment.     

注射用盐酸苯达莫司汀单药治疗利妥昔单抗耐药的B细胞惰性淋巴瘤

  目的  观察注射用盐酸苯达莫司汀单药治疗利妥昔单抗耐药的B细胞惰性淋巴瘤临床疗效及安全性。   方法  25例利妥昔单抗治疗失败的B细胞惰性淋巴瘤患者,接受苯达莫司汀单药化疗（120 mg/m2,d1、2,每21天为1个周期）,评价其近期疗效、无进展生存期与不良反应。   结果  全组25例患者,共计化疗122个周期,中位5个周期。治疗2个周期后均可评价疗效,其中完全缓解（CR/CRu）6例,部分缓解（PR）13例,稳定（SD）3例,进展（PD）3例,总有效率（ORR）为76%,临床受益率（CBR）为88%。截至随访结束,13例患者出现PFS终点事件,中位疗效持续时间（DOR）8个月,中位无进展生存期（PFS）9个月。各亚组间无进展生存期的关系,主要与骨髓受累、血清LDH水平升高有关,差异有统计学意义（P < 0.05）。常见不良反应为骨髓抑制、胃肠道反应和感染,2例患者出现皮疹,1例患者用药5个周期后发生胃癌。   结论  注射用盐酸苯达莫司汀单药治疗利妥昔单抗耐药的B细胞惰性淋巴瘤可提高疗效,且耐受性良好。      

Clinical experience with lenalidomide alone or in combination with rituximab in indolent B-cell and mantle cell lymphomas

Lenalidomide is an oral immunomodulatory drug with significant activity in indolent B-cell and mantle cell lymphomas. Lenalidomide has a manageable safety profile whether administered as a single agent or in combination with rituximab. The combination of lenalidomide with rituximab, known as the ‘R²’ regimen, enhances efficacy over what has been shown with monotherapy and has demonstrated activity in patients considered resistant to rituximab. Tolerability of these regimens has been consistent among studies. Asymptomatic neutropenia is the most common grade 3/4 adverse event, typically managed by dose interruption, followed by dose reduction once neutrophils have recovered. Nonhematologic toxicities (e.g. fatigue) are generally low-grade, manageable with concomitant treatment, and/or lenalidomide dose modification. More frequent with R², immune-related symptoms such as rash and tumor flare are important to recognize as lenalidomide-associated treatment effects in patients with lymphoma who require supportive care and potential dose modifications. Severe tumor flare reactions with painful lymphadenopathy are not typically observed outside of chronic lymphocytic leukemia/small lymphocytic lymphoma. Venous thromboembolism is uncommon in lymphomas, though prophylaxis is recommended. The general safety profile, differences between lenalidomide monotherapy and R² treatment, and optimal strategies for managing adverse events are discussed here.     

Effective treatment of indolent non-hodgkin's lymphomas with mitoxantrone, chlorambucil and prednisone

Since indolent non-Hodgkin's lymphomas (NHL) represent about 35% of all malignant lymphomas and mainly affect elderly patients, availability of a conventional chemotherapy regimen with high efficacy and low toxicity is of clinical importance. Patients and Methods: We retrospectively analysed 13 patients with advanced indolent NHL who were treated with 6-9 cycles of MCP: mitoxantrone 8 mg/m2 (days 1 and 2), chlorambucil 3 x 3 mg/m2 (days 1-5) and prednisone 25 mg (days 1-5) every 4 weeks. Results: The overall response was 84% (61% complete response, 23% partial response), 1 patient had stable disease and 1 patient experienced progressive disease. Median time to progression was 37 months (95% CI: 20-53) and the median survival has not yet been reached. The main toxicity (66%) was neutropenia (WHO grade III). There was no hair loss and no cardial or neurologic adverse event. Conclusion: In summary, MCP is an effective and well tolerated chemotherapy regimen and is probably an alternative to the more toxic CHOP regimen, especially in older patients.     

Treatment of indolent B-Cell nonfollicular lymphomas: final results of the LL01 randomized trial of the Gruppo Italiano per lo Studio dei Linfomi.

PURPOSE: To evaluate the effect of epirubicin on therapeutic response and survival in patients with indolent nonfollicular B-cell lymphomas (INFL) treated with pulsed high-dose chlorambucil. PATIENTS AND METHODS: A total of 170 untreated patients with advanced/active INFL were randomly assigned to receive either eight cycles of high-dose chlorambucil (15 mg/m2/d) plus prednisone (100 mg/d) for 5 days (HD-CHL-P; arm A) or eight cycles of HD-CHL-P plus epirubicin 60 mg/m2 intravenous on day 1 (arm B). The responding patients were randomly assigned to either maintenance therapy with interferon alfa (IFNalpha-2a; 3 MU, three times weekly) for 12 months or observation. RESULTS: There were 160 assessable patients (82 males, 78 females; median age, 63 years; range, 33 to 77 years); 77 patients were assigned to arm A, and 83 were assigned to arm B. Induction therapy led to 47 complete responses (CRs; 29.4%) and 68 partial responses (PRs; 42.5%), with no significant difference between the two arms (60 CR + PR in arm A [77.9%] and 55 CR + PR in arm B [66.3%]; P =.07). After a median follow-up of 38 months (range, 2 to 103 months), there was no between-group difference in overall survival (OS; P =.45), failure-free survival (P =.07), or progression-free survival (PFS; P =.5). Eighty-eight patients were randomly assigned to either IFNalpha-2a (n = 43) or observation (n = 45), without any difference in 3-year PFS (44% and 42%, respectively). Univariate analysis showed that OS was influenced by age, anemia, serum lactate dehydrogenase levels, and International Prognostic Index distribution; multivariate analysis identified age and anemia as having influence on OS. CONCLUSION: HD-CHL-P treatment outcome in INFL patients was good (50% 3-year PFS, minimal toxicity, and low costs); epirubicin did not add any advantage. One-year IFNalpha maintenance treatment did not prolong response duration.     

Incidence of gastric B-cell lymphomas: a population-based study in Germany.

BACKGROUND: While the clinical and experimental knowledge concerning gastric lymphomas is increasing, there is a scarcity of epidemiological data. PATIENTS AND METHODS: A population-based sample of patients in Franconia and Saarland in Germany was collected from a clinical trial, hospital archives and a cancer registry. RESULTS: Over a period of 3 years, 94 patients with primary gastric lymphoma were recorded out of a total population of 3.5 million. The standardised incidence rates in Saarland and Franconia were 0.7 and 0.8 cases per 100 000, respectively. Patients were predominantly from higher age groups (mean age 62.1 years) and the incidence in men was slightly more than in women (P <0.03). The distribution of histological subtypes in Franconia was as follows: marginal zone B-cell lymphomas (MZBL), 58%; diffuse large-cell B-cell lymphoma (DLBL), 33%; and mixed forms, 9%. Helicobacter pylori could be detected histologically in 84% of all cases, 95% of MZBL cases and 68% of DLBL cases. CONCLUSIONS: Incidence rates of gastric lymphoma in Germany were similar to that in other European countries, except England, where rates are lower. The subtype-specific differences of H. pylori infection rates could be due to differences in carcinogenesis or to secondary changes during malignant transformation.     

The role of dose size in a chemotherapy regimen (ProMECE-CytaBOM) for the first-line treatment of large B-cell lymphomas: a randomized trial by the Gruppo Italiano Studio Linfomi (GISL).

BACKGROUND: It is still unclear the actual contribute of dose intensity (DI), dose size (DS) and dose density (DD) in the conventional chemotherapy of large, B-cell non-Hodgkin lymphomas. METHODS: A prospective, randomized trial compared the cyclic schedule of ProMECE-CytaBOM chemotherapy (cyc-PC, 6 cycles) with a modified version of it, which administered the same drugs sequentially (seq-PC), with the same planned cumulative DI and an 83% DD, within the same time frame (113 days), but with three times higher DS of all the drugs except vincristine. RESULTS: Fifty-six patients received cyc-PC and 52 seq-PC. The actual mean cumulative DI was 0.79 +/- 0.15 with cyc-PC, 0.78 +/- 0.17 with seq-PC. Response was complete in 59% and 52%, partial in 20% and 21%, null in 5% and 6%, respectively. There were four toxic deaths (two per arm). Relapses occurred in 36% and 37%, respectively. Toxicity was similar in both arms. Overall, failure-free, progression-free and disease-free survival (median follow-up: 54 months) were statistically indifferent. CONCLUSIONS: The very similar DI actually delivered in both arm seems to be the main common determinant of the indifferent results recorded. Increasing DS--at least within the limits clinically attainable without stem cell rescue--does not improve results.     

Comparison on therapeutic effects of RFT and RCTVP regimen in the treatment of patients with indolent B-cell lymphoma in China

To compare the efficacy and safety of RFT (retuximab, fludarabine, pirarubicin) with RCTVP (retuximab, cyclophophamide, pirarubicin, vindesine and prednisone) in 248 indolent B-cell non-Hodgkin's lymphoma (NHL) patients. Two hundred and forty-eight patients with indolent B-cell NHL were treated with combined chemotherapy, including RFT and RCTVP, from January 2002 to December 2010 in Tianjin Cancer Hospital. The rate of response, toxicity and long-term survival for the two regimens were analyzed retrospectively. For the previously untreated patients, overall response rate for RFT arm and RCTVP arm was 71.7 and 70.6%, and complete response rate was 47.5 and 54.9%, respectively (P?>?0.05). For the refractory and relapsed patients, overall response (OR) rate and complete response (CR) rate were significantly improved in the RFT arm versus the RCTVP arm (P?相似文献   

Long term results of a randomized study performed by Intergruppo Italiano Linfomi comparing Mini-CEOP vs P-VEBEC in elderly patients with diffuse large B-cell lymphoma

The Intergruppo Italiano Linfomi started, in 1996, a randomized trial for the initial treatment of elderly patients (older than 65 years) with Diffuse Large B-Cell Lymphoma (B-DLCL) comparing 6 courses of Mini-CEOP vs 8 weeks of P-VEBEC chemotherapy. Study objectives were survival, response and Quality of Life (QoL). Two hundred and thirty-two patients were evaluable for final analysis. Complete Response (CR) and Overall Response Rates (ORR) were 54% vs 66% (p = 0.107) and 90% vs 78% (p = 0.021) for P-VEBEC and Mini-CEOP, respectively. With a median follow-up of 72 months, the 5-year Overall Survival (OS), Relapse Free Survival (RFS), and Failure Free Survival (FFS) were 32%, 52%, and 21%, respectively. Subjects achieving a CR showed improvement of QoL regardless of treatment arm. Both Mini-CEOP and P-VEBEC determined a similar outcome for elderly patients with B-DLCL, with a third of patients alive after more than 6 years of follow-up. Both regimens can be considered equally for combination treatment with anti-CD20 monoclonal antibody.     

Phase II study of bendamustine in combination with rituximab as first-line treatment in patients 80 years or older with aggressive B-cell lymphomas

BackgroundRituximab plus combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is widely recommended for the treatment of aggressive B-cell lymphomas. However, there is very little information regarding the management of elderly patients.Patients and methodsWe initiated a phase II study of first-line treatment with rituximab and bendamustine in elderly patients (≥80 years) with aggressive B-cell lymphomas who were not eligible for R-CHOP or who did not agree to aggressive treatment. The treatment decision on eligibility for R-CHOP was left to discretion of the physicians.ResultsFourteen patients with a median age of 85 years (range 80–95 years) were included. The age-adjusted international prognostic index was zero in five patients, one in three patients, and two in six patients. Thirteen patients were assessable for response. Seven patients (54%) had a complete response, two (15%) a partial response, and four (31%) progressive disease. The median overall survival was 7.7 months, and the median progression-free survival 7.7 months; however, six patients (43%) were alive without disease at 20–72 months from the start of treatment. Major toxicity was neutropenia (17% grade 3 and 6% grade 4). All other grade 3 and 4 hematotoxicities and non-hematological toxic effects ranged between 2% and 11%ConclusionsBecause of its efficacy and low toxicity, bendamustine in combination with rituximab may be an alternative treatment for aggressive lymphomas in old patients not eligible for R-CHOP. These results, however, need to be confirmed in larger studies.     

Expansion of effector T cells associated with decreased PD-1 expression in patients with indolent B cell lymphomas and chronic lymphocytic leukemia

In patients with chronic lymphocytic leukemia (CLL), numbers of CD8 + CD45RA +/- CD27- effector T cells are expanded. We investigated whether this expansion is also present in other B cell malignancies and the possible mechanism underlying these changes. Whereas an increase in total CD4+and CD8+ T cell numbers was found only in CLL, numbers of CD4+ and CD8+ effector T cells were significantly increased in both CLL and indolent lymphoma, but not aggressive lymphoma and myeloma. Interestingly, PD-1 expression was decreased on effector T cells and inversely correlated with effector T cell numbers, suggesting a functional role for PD-1 in regulating T cell homeostasis. In vitro experiments revealed impaired up-regulation of PD-1 upon T cell activation in the presence of malignant but also healthy B cells. Our data suggest that in CLL and indolent lymphoma, the malignant B cells affect PD-1 expression on effector T cells, resulting in an expansion of these subsets.     

Rituximab for the treatment of diffuse large B-cell lymphomas

For more than 25 years, the combination of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) was considered the gold standard for the treatment of aggressive lymphomas, 90% of which are diffuse, large B-cell lymphomas (DLBCLs). Attempts to improve results by more intensive chemotherapy regimens, including high-dose chemotherapy approaches necessitating stem-cell support, have not convincingly shown improved outcome of DLBCL. The chimeric monoclonal antibody rituximab, which binds to the CD20 antigen expressed on normal B cells and the malignant cells of more than 90% of DLBCLs, and mediates lysis of these cells by direct induction of apoptosis, activation of complement- and antibody-dependent cellular cytotoxicity in vitro, is an attractive candidate for the treatment of B-cell lymphomas. Initial studies in follicular lymphoma demonstrated its efficacy as a single agent or in combination with chemotherapy without adding relevant toxicity. After the demonstration of rituximab single-agent activity in DLBCL, a pivotal trial in elderly patients demonstrated that combining rituximab with eight applications of CHOP significantly improved complete remission, event-free and overall survival rates when compared with CHOP alone. These positive results have meanwhile been confirmed by two additional randomized trials in elderly patients and have been extended to young patients with good-prognosis DLBCL by a fourth trial. While not yet formally established in young, poor-prognosis patients, rituximab in combination with CHOP has become accepted worldwide as the new standard for the treatment of DLBCL. Questions remain concerning the optimal dosage and schedule of rituximab for DLBCL, as well as the optimal chemotherapy regimen partner for rituximab. Rituximab is the first monoclonal antibody to consistently improve survival rates of patients with a malignant disease. Its excellent efficacy in combination with cytotoxic chemotherapy, together with its favorable toxicity profile, establishes rituximab as an indispensable component of modern standard immunochemotherapy of DLBCL.     

Hepatitis C virus infection and B-cell non-Hodgkin's lymphomas: more than a simple association

Several studies have reported that the prevalence of the hepatitis C virus (HCV) infection is significantly overrepresented in patients affected by non-Hodgkin's lymphoma (NHL), thus suggesting that besides the well-established link with essential mixed cryoglobulinemia, a possible role for HCV is determining the development of at least some types of B-cell NHL. Such an association, however, seems to be limited to geographic areas where the presence of HCV is more relevant or endemic. According to a multistep pathogenetic model based on a large series of clinical, immunological, histological, and molecular evidences, an HCV antigen-driven polyclonal B-cell lymphoproliferation could be the initial phase of a process leading, in a variable time, into a true clonal disease. Particular genetic and environmental backgrounds could play a role in the development of a malignant phenotype, while specific HCV genotypes do not seem to be relevant in this setting. Hepatitis C virus correlated with NHL often shows some distinctive clinicopathological features, such as older age, liver damage, presence of monoclonal gammopathy (often with no clinically relevant cryoglobulinemic and/or rheumatoid activity), increased rate of autoimmune disorders, extranodal localizations, and restricted histological subtypes. Overall, the clinical outcome of HCV-positive NHL does not seem to be different from that of NHL patients without HCV infection. However, the evidence of a significant hepatic injury may predict a worse prognosis in these subjects.     

Hepatitis B infection in patients with lymphomas.

This paper reviewed the clinical characteristics and treatment outcome of 484 lymphoma patients with known hepatitis B status. Comparisons were made between the hepatitis B surface antigen positive and negative patients. Also, the effect of treatment for lymphomas, including cytotoxic chemotherapy, in the hepatitis B antigen positive patients were analysed. The hepatitis B status was determined in 484 Chinese lymphoma patients at the time of initial diagnosis. Hepatic complications occurring during therapy for lymphomas were analysed. Although our lymphoma patients had a similar prevalence of hepatitis B markers of 42 per cent, they had a strikingly higher positive rate of 22 per cent for hepatitis B surface antigen and a relatively lower positive rate of 20 per cent for antibody, as compared to the respective figures of 9.5 per cent and 33 per cent in the control population. The hepatitis B surface antigen positive patients were younger than the negative patients but their treatment outcomes were similar despite the higher incidence of hepatic complications (21 per cent) in the hepatitis B surface antigen positive patients during therapy for lymphomas. None of the clinical parameters analysed appeared to be useful in predicting the development of these complications which included fatal liver failure (5.7 per cent), icteric hepatitis (5.7 per cent) and anicteric hepatitis (9.5 per cent). The high prevalence of hepatitis B surface antigen in our lymphoma patients may be related to the immunosuppressive effect of lymphomas. There is no definite evidence to suggest that hepatitis B infection has an aetiological or promoting role in the pathogenesis of lymphomas. Hepatitis B infection has contributed to the high incidence of hepatic complications during therapy for lymphomas and possible ways of prevention need to be investigated.     

Mast cell heterogeneity in B-cell non-Hodgkin's lymphomas: an ultrastructural study

Mast cells (MC) are critical for a number of pathological conditions, including acute and chronic inflammation and tumor angiogenesis. We have previously demonstrated that in B-cell non-Hodgkin's lymphoma (B-NHL) angiogenesis is correlated with total methachromatic and tryptase-positive MC and that both counts increase in step with the increase in malignancy, whereas the role of MC in malignant lymph nodes is not fully clear. An extensive ultrastructural study has been made of representative samples of 30 B-NHL and 10 benign lymphadenopathies. A heterogeneous population of MC characterized by the presence of granules with a semilunar aspect and containing scrolls was observed. The former are the expression of a slow but progressive release of angiogenic factors due to chronic, progressive stimulation of MC degranulation, while the latter contain tryptase, an angiogenic factor. These two ultrastructural data confirm the important role played by MC in the angiogenesis associated with progression in B-NHL.     

Prognostic factors in primary cutaneous large B-cell lymphomas: a European multicenter study.

PURPOSE: Most primary cutaneous B-cell lymphomas have an excellent prognosis. However, primary cutaneous large B-cell lymphomas (PCLBCLs) of the leg have been recognized as a distinct entity with a poorer prognosis in the European Organization for Research and Treatment of Cancer (EORTC) classification. This distinction on the basis of site has been debated. Our aim was to identify independent prognostic factors in a large European multicenter series of PCLBCL. PATIENTS AND METHODS: The clinical and histologic data of 145 patients with PCLBCL were evaluated. According to the EORTC classification, 48 patients had a PCLBCL of the leg and 97 had a primary cutaneous follicle center-cell lymphoma (PCFCCL). Data from both groups were compared. Univariate and multivariate analyses of specific survival were performed using a Cox proportional hazards model. RESULTS: Compared with PCFCCL, PCLBCL-leg were characterized by an older age of onset, a more recent history of skin lesions, a more frequent predominance of tumor cells with round nuclei and positive bcl-2 staining, and a poorer 5-year disease-specific survival rate (52% v 94%; P <.0001). Univariate survival analysis in the entire study group showed that older age, a more recent onset of skin lesions, the location on the leg, multiple skin lesions, and the round-cell morphology were significantly related to death. In multivariate analysis, the round-cell morphology (P <.0001), the location on the leg (P =.002), and multiple skin lesions (P =.01) remained independent prognostic factors. The round-cell morphology was an adverse prognostic factor both in PCLBCL-leg and in PCFCCL, whereas multiple skin lesions were associated with a poor prognosis only in patients with PCLBCL-leg. CONCLUSION: With site, morphology, and number of tumors taken into account, guidelines for the management of PCLBCL are presented.