Hungarian experience with non-Hodgkin's lymphoma in childhood

Between 1990 and 2004, 230 children with non-Hodgkin's lymphoma (NHL) were treated according to the Berlin-Frankfurt-Münster (BFM) protocols (NHL-BFM-90 and -95) in Hungary. The aim of the present study was to summarize our experience with these protocols, to assess the survival rates and to compare the Hungarian data with the international results. The male-to-female ratio was 2.59:1, the mean age at the time of diagnosis was 10 years and 1 month. Ninety-one children had lymphoblastic/T-NHL (LB/T-NHL), 108 B-NHL and 31 anaplastic large cell lymphoma (ALCL). Twenty-eight patients had relapse after a mean time of 13 months from the time of the initial diagnosis. In the above mentioned period, 16 children underwent autologous stem-cell transplantation. Nine patients with B-NHL got anti-CD20 immunotherapy. The five-year overall survival (OS) of our patients is 77.8%+/-3%, the event-free survival (EFS) is 75.1%+/-3%. The 5-year OS and EFS rates were not statistically different in the three histology groups (OS: 71.6%+/-5%, 82.7%+/-4% and 80.3%+/-7%; EFS: 68.7%+/-5%, 81.1%+/-4% and 73.9%+/-8% in LB/T-NHL, B-NHL and ALCL, respectively). We can conclude that non-Hodgkin's lymphoma has a quite good prognosis among the malignant pediatric diseases. The cure rate is over 75%. The Hungarian results are comparable with other international data. In the last five years the mortality during induction was reduced from 10% to 2% and the OS is about 10% better than it was before. In case of relapse or residual disease, therapeutic results can be improved with stem-cell transplantation with or without immunotherapy.     

COX-2和Survivin在B细胞非霍奇金淋巴瘤中的表达及意义

目的:探讨COX-2和Survivin在B细胞非霍奇全淋巴瘤(B-NHL)中的表达及临床意义.方法:采用免疫组化SP法检测43例B-NHL和10例良性淋巴结病变组织中COX-2和Survivin的表达.结果:COX-2和Survivin在B-NHL中的阳性表达率分别为55.8%(24/43)和69.8%(30/43),与对照组相比差异具有显著性(P＜0.05.Ⅲ/Ⅳ期B-NHL患者COX-2蛋白的表述要高于Ⅰ/Ⅱ期患者(P＜0.05).Survivin的表达与B-NHL的组织病理学等级和国际预后指数(IPL)具有相关性(P＜0.05).Spearman相关分析表明COX-2的表达与Survivin的表达呈正相关(r=1.000,P=0.030).结论:COX-2和Survivin在B-NHL中表达上调以及两者之间的阳性表达密切相关,表明COX-2和Survivin在B-NHL的发生和发展中具有协同作用.     

Caspase-independent killing of Burkitt lymphoma cell lines by rituximab

Caspase-independent cell death may have a critical role to play in the therapeutic destruction of tumours. Recently it has been suggested that one of the mechanisms by which rituximab, a therapeutic anti-CD20 antibody, kills B cells is caspase-independent. In this study we show that rituximab can induce death in a variety of Burkitt lymphoma derived cell lines. Rituximab-treated cells show leakage of adenylate kinase, surface expression of phosphatidylserine, upregulation of the cellular stress protein HSP70, phosphorylation of the survival protein Akt, and depolarisation of the mitochondrial membrane but no loss of cytochrome c or apoptosis inducing factor. Caspase inhibitors do not block these events. In support of these data there is no cleavage of caspases 3, 8 and 9, poly(ADP-ribose) polymerase, BH3 interacting domain death agonist or genomic DNA. Morphologically, cells show nuclear enlargement and cytoplasmic vacuolisation. Triggering of receptor mediated death in CD95 responsive lines results in “classical” apoptosis indicating that the internal machinery necessary for apoptosis is intact in these lines. The results suggest that rituximab can kill human B cells via a caspase-independent form of programmed cell death that shares features of apoptosis and necrosis. This pathway may be relevant to the clinical efficacy of rituximab.     

ONC201 induces cell death in pediatric non-Hodgkin's lymphoma cells

ONC201/TIC10 is a small molecule initially discovered by its ability to coordinately induce and activate the TRAIL pathway selectively in tumor cells and has recently entered clinical trials in adult advanced cancers. The anti-tumor activity of ONC201 has previously been demonstrated in several preclinical models of cancer, including refractory solid tumors and a transgenic lymphoma mouse model. Based on the need for new safe and effective therapies in pediatric non-Hodgkin''s lymphoma (NHL) and the non-toxic preclinical profile of ONC201, we investigated the in vitro efficacy of ONC201 in non-Hodgkin''s lymphoma (NHL) cell lines to evaluate its therapeutic potential for this disease. ONC201 caused a dose-dependent reduction in the cell viability of NHL cell lines that resulted from induction of apoptosis. As expected from prior observations, induction of TRAIL and its receptor DR5 was also observed in these cell lines. Furthermore, dual induction of TRAIL and DR5 appeared to drive the observed apoptosis and TRAIL expression was correlated linearly with sub-G1 DNA content, suggesting its potential role as a biomarker of tumor response to ONC201-treated lymphoma cells. We further investigated combinations of ONC201 with approved chemotherapeutic agents used to treat lymphoma. ONC201 exhibited synergy in combination with the anti-metabolic agent cytarabine in vitro, in addition to cooperating with other therapies. Together these findings indicate that ONC201 is an effective TRAIL pathway-inducer as a monoagent that can be combined with chemotherapy to enhance therapeutic responses in pediatric NHL.     

Initial experience with treatment of human B cell lymphoma with anti-CD19 monoclonal antibody

Summary Six patients with progressive B cell non-Hodgkin's lymphoma have been treated with an IgG2a mouse monoclonal antibody (mAb) against the B cell differentiation antigen CD19, with total doses varying from 225 mg to 1000 mg. Free mAb was detected in the serum after doses of 15–30 mg. After the mAb infusions the number of circulating tumour cells was temporarily reduced, but in some cases antibody-coated cells remained in the circulation for several days. mAb penetrated to extravascular tumour sites; in general higher doses were required to saturate cells in the lymph nodes than to sensitize tumour cells in the bone marrow. mAb doses of up to 250 mg were given i.v. over 4 h without major toxicity. One patient twice achieved a partial remission after two periods of mAb treatment with an 8-month interval; the second remission lasted for 9 months. One patient showed a minor response. None of the patients made antibodies against the mouse immunoglobulin. Serum immunoglobulin levels were followed as a measure of the function of the normal B cell compartment; no significant changes were seen up to 6 months after mAb treatment.Supported by the Dutch Cancer Society (grant NKI 84-14)     

Cutaneous manifestations in non-Hodgkin's lymphoma

OBJECTIVE: To examine and subtype cutaneous lymphoma specimens for diagnosis. STUDY DESIGN: Aspiration smears from skin lesions and lymph nodes diagnosed as non-Hodgkin's lymphoma (NHL) on cytology in 6 cases over a period of 1 year were reviewed. Two were follow-up cases of nodal lymphoma and were receiving chemotherapy, during which they developed skin lesions. In 4, the patients had cutaneous lesions as a presenting manifestation. Cytologic findings were correlated with histologic and hematologic findings and immunocytochemical markers for subtyping. RESULTS: Patients ranged from 14 to 50 years, with equal sex ratio. All presented with 0.5-5 cm multiple nodular, ulcerated and fungating skin lesions at various body sites. The aspirate was satisfactory in all cases. Cytologically, all cases were diagnosed as NHL. They were then immunocytochemistry subtyped as various lymphomas. CONCLUSION: Cutaneous lymphoma should always be considered in the presence of predominantly atypical lymphoid cells in smears from nodular and fungating skin lesions, even in the absence of a definitive clinical diagnosis.     

Cytomorphologic characteristics of non-Hodgkin's lymphoma

The cytologic samples of 84 non-Hodgkin's lymphomas, classified according to the Rappaport system, were reviewed, with particular attention to the cell pattern, the size of the cells and other morphologic characteristics. The analysis revealed that: (1) the subgroups of malignant lymphoma in the Rappaport classification display a heterogeneous cytologic picture; (2) cytology cannot make the differentiation between nodular and diffuse non-Hodgkin's malignant lymphomas; and (3) reliable cytologic classification is possible only in certain cases of well-differentiated lymphocytic and diffuse histiocytic lymphomas. Well-differentiated lymphocytic lymphoma is characterized by a uniform cell picture consisting of mature lymphocytes, prolymphocytes or centrocytes up to 12 micron in size, by the presence of paraimmunoblasts and by the absence of reticulum cells. The diffuse histiocytic lymphoma contains over 48% centroblasts or over 8% immunoblasts or multinucleated giant blast cells.     

Management of localized non-Hodgkin's lymphoma

Non-Hodgkin''s lymphomas (NHLs) are a heterogeneous group of disorders that vary widely in response to therapy. In Canada the modified Rappaport classification is used to categorize NHL. To facilitate the reporting and comparison of treatment results all cases should also be categorized in the terminology of the National Cancer Institute''s working formulation. The choice of therapy should be guided by specific prognostic factors: stage and bulk of the disease, patient''s age, presence of systemic symptoms and histologic subtype. Of these, the last appears to be the most important. Radiotherapy (RT) is the treatment of choice in localized low-grade lymphomas with favourable prognoses, while bimodal therapy (RT and chemotherapy [CT]) is warranted in presentations with unfavourable prognoses. Regional irradiation alone is indicated in intermediate-grade lymphomas with good prognoses (i.e., pathological stage I or II or clinical stage IA or IIA localized disease of small bulk in young patients). All other patients require CT followed by RT. The results of CT alone are encouraging but remain experimental. Aggressive therapy with multidrug regimens that include central nervous system prophylaxis is the foundation for successful treatment of high-grade NHL such as lymphoblastic lymphoma and diffuse small-noncleaved-cell lymphomas. Low-dose RT should be given to sites of bulky disease.     

Impaired response to influenza vaccine associated with persistent memory B cell depletion in non-Hodgkin's lymphoma patients treated with rituximab-containing regimens

Influenza vaccination is generally recommended for non-Hodgkin's lymphoma (NHL) patients, but no data are available about the activity of this vaccine after treatment with rituximab-containing regimens. We evaluated the humoral response to the trivalent seasonal influenza vaccine in a group of NHL patients in complete remission for ≥6 mo (median, 29 mo) after treatment with rituximab-containing regimens (n = 31) compared with age-matched healthy subjects (n = 34). B cell populations and incidence of influenza-like illness were also evaluated. For each viral strain, the response was significantly lower in patients compared with controls and was particularly poor in patients treated with fludarabine-based regimens. In the patient group, the response to vaccination did not fulfill the immunogenic criteria based on the European Committee for Medicinal Products for Human Use requirements. Among the patients, CD27(+) memory B cells were significantly reduced, and their reduction correlated with serum IgM levels and vaccine response. Episodes of influenza-like illness were recorded only in patients. These results showed that NHL patients treated with rituximab-containing regimens have persisting perturbations of B cell compartments and Ig synthesis and may be at particular risk for infection, even in long-standing complete remission.     

CD40-activated B cell cancer vaccine improves second clinical remission and survival in privately owned dogs with non-Hodgkin's lymphoma

Cell-based active immunotherapy for cancer is a promising novel strategy, with the first dendritic cell (DC) vaccine achieving regulatory approval for clinical use last year. Manufacturing remains arduous, especially for DC vaccines, and the prospect of using cell-based immunotherapy in the adjuvant setting or in combination with chemotherapy remains largely untested. Here, we used a comparative oncology approach to test the safety and potential efficacy of tumor RNA-loaded, CD40-activated B cells in privately owned dogs presenting with non-Hodgkin's lymphoma (NHL), a clinical scenario that represents not only a major problem in veterinary medicine but also a bona fide spontaneous animal model for the human condition. When administered to NHL dogs in remission after induction chemotherapy, CD40-B cells electroporated ex vivo with autologous tumor RNA safely stimulated immunity in vivo. Although chemotherapy plus CD40-B vaccination did not improve time-to-progression or lymphoma-specific survival compared to dogs treated with chemotherapy alone, vaccination potentiated the effects of salvage therapy and improved the rate of durable second remissions as well as subsequent lymphoma-specific survival following salvage therapy. Several of these relapsed dogs are now long-term survivors and free of disease for more than a year. Overall, these clinical and immunological results suggest that cell-based CD40 cancer vaccination is safe and synergizes with chemotherapy to improve clinical outcome in canine NHL. More broadly, our findings underscore the unique value of clinical investigations in tumor-bearing companion animals.     

Ultrasonic diagnosis of non-Hodgkin's lymphoma]

Analyzes the results of ultrasonic examinations of 111 patients with various forms of non-Hodgkin's lymphomas. Reviews ultrasonic semeiotics of non-Hodgkin's lymphadenopathy of the abdominal cavity and retroperitoneal space and of extranodal variants of lymphoma course (with involvement of the spleen and stomach). Suggests the most safe method for precision diagnostic aspiration biopsy of the spleen monitored by ultrasound. The author considers ultrasonic examination to be a valuable method for the diagnosis of non-Hodgkin's lymphomas; it is economic, rapid, safe, permits a simultaneous assessment of the status of many organs and systems. The results of ultrasonic examinations should be assessed in complex with the results of other diagnostic methods. Ultrasonic examination should be considered as a method of choice for monitoring patients with diagnosed non-Hodgkin's lymphoma.     

Rituximab induced hypoglycemia in non-Hodgkin's lymphoma

Background

Patients with aero-digestive malignancy will often require a feeding gastrostomy during their treatment to maintain their nutritional status. These are usually placed percutaneously using an endoscopic technique.

Case presentation

A fifty-six year old male underwent placement of a percutaneous gastrostomy (PEG) prior to commencement of his treatment for an oral squamous cell carcinoma. The treatment for this was locally curative. However, he developed a metastasis at the site of his PEG tube. This was excised en-bloc with the anterior gastric and abdominal walls.

Conclusion

Tumour implantation into wounds has been previously reported. In this case the direct trauma of passing the PEG tube through the oropharynx led to implantation of cells in the anterior abdominal wall. In these cases laparoscopic placement may be more beneficial to avoid this problem.     

Antibody therapy of non-Hodgkin's B-cell lymphoma

Engineering antibodies with reduced immunogenicity and enhanced effector functions, and selecting antigen targets with the appropriate specificity, density, and/or functionality, have contributed to the recent clinical successes in using unconjugated "naked" antibody therapies of B-cell lymphoma (rituximab) and breast carcinoma (Herceptin). The non-overlapping toxicities of naked antibodies and chemotherapy, together with their potential synergy, which is based on unique and complementary mechanisms of action, have contributed to the creation of new standards of care in cancer therapy and management. Clinical trial results supporting these concepts are presented. Furthermore, the exquisite specificity of antibodies renders them ideal vehicles for selective delivery of toxic payloads such as drugs or radionuclides. Although successful in therapy of hematological cancers (Zevalin, Mylotarg), the broader application of these technologies to carcinomas still remains to be proven in clinical testing. Engineering of antibody constructs with optimal blood clearance and tumor-targeting kinetics, and selecting the radionuclide that may deliver sufficient radiation energy to kill the more radio-resistant carcinomas, are discussed. With the advent of genomics and proteomics, new membrane-associated tumor antigens are being discovered and will provide novel targets for future antibody therapy of cancer.     

Reconstitution of the adult B cell repertoire after treatment with rituximab

B cells play diverse and fundamental roles in the pathogenesis of autoimmune diseases. Consequently, therapeutic targeting of B cells is gaining prominence in our clinical armamentarium for an ever expanding array of autoimmune and neoplastic disorders. Therefore, it is of great importance to understand the mechanism of action of B cell depletion. Given that the ideal consequence of B cell depletion would be the subsequent re-establishment of immunologic tolerance, a detailed analysis of the properties of the emerging repertoire will be required. The results presented by Rouzière and coworkers in their study of rheumatoid arthritis patients shed some light on this question and are discussed in this commentary.     

Primary non-Hodgkin's lymphoma of the breast: a case report

Extranodal non-Hodgkin's lymphoma (NHL) of the breast is a rare entity. It represents 0.04-1.1% of malignant tumors of the breast. 1.7-2.2% of extranodal lymphomas and 0.7% of all NHL. However, primary NHL (PNHL) is the most frequent hematopojetic tumor of the breast. CASE: A 23-year-old woman presented with a mass in the left breast for 3 months followed by enlarged left axillary lymph nodes. Mammography showed a diffuse increase in the density of the left breast. Other investigations were unremarkable. Both fine needle aspiration cytology (FNAC) and histopathology were diagnostic of NHL. Immunohistochemistry was confirmatory of NHL, diffuse large cell type, of B-cell lineage. CONCLUSION: Primary and secondary lymphomas of the breast, though rare, should be considered in the differential diagnosis of breast malignancies. PNHL of the breast is usually right sided, but this patient had left breast involvement. Diagnosis by FNAC was successful as the cytologic picture is similar to that of any other lymphoid or extranodal NHL. When histopathology and immunohistopathology are conclusive, FNAC, supplemented by immunocytochemistry, can be applied as a simple, reliable and cost-effective tool in the early diagnosis of breast lymphomas.     

Safety of rituximab in the treatment of B cell malignancies: implications for rheumatoid arthritis

The chimeric anti-CD20 monoclonal antibody rituximab has been used extensively in the treatment of B cell malignancies, and more recently it has emerged as a potential treatment for rheumatoid arthritis (RA), via selective B lymphocyte depletion. Experience in oncology shows that rituximab is well tolerated in a variety of settings, with mild-to-moderate infusion related reactions following the first infusion being the most common adverse event. Current data suggest that the safety profile of rituximab in patients with RA is similar to that in oncology, but that the adverse events are less frequent and less severe in patients with RA.