T-cell therapies for T-cell lymphoma

T-cell lymphomas represent a subpopulation of non-Hodgkin lymphomas with poor outcomes when treated with conventional chemotherapy. A variety of novel agents have been introduced as new treatment strategies either as first-line treatment or in conjunction with chemotherapy. Immunotherapy has been demonstrated to be a promising area for new therapeutics, including monoclonal antibodies and adoptive cellular therapeutics. T-cell therapeutics have been shown to have significant success in the treatment of B-cell malignancies and are rapidly expanding as potential treatment options for other cancers including T-cell lymphomas. Although treating T-cell lymphomas with T-cell therapeutics has unique challenges, multiple targets are currently being studied both preclinically and in clinical trials.     

Epstein-Barr病毒相关淋巴瘤的研究进展

Epstein-Barr病毒（Epstein-Barr virus,EBV）是第1个被发现与人类肿瘤发生相关的病毒,且越来越多的数据表明其感染与某些淋巴瘤的发生发展、治疗及预后密切相关。近年来免疫治疗手段发展迅速,但EBV阳性淋巴瘤的治疗目前主要仍以放化疗为基础,结合抗病毒药物。因此,加强EBV及其相关淋巴瘤的研究,寻找有效预防或治疗EBV感染的方法,将有望改善EBV阳性淋巴瘤患者的预后。     

Radiation-associated loss of heterozygosity at the Znfn1a1 (Ikaros) locus on chromosome 11 in murine thymic lymphomas

Although information on the molecular pathways in radiation carcinogenesis is accumulating, the data are still relatively scanty. To find the tumor suppressor locus associated with radiation carcinogenesis, we determined the frequency and distribution of loss of heterozygosity (LOH) of X-ray-induced thymic lymphomas of B6C3F(1) mice using 58 microsatellite markers and compared the results with those for spontaneous lymphomas and N-ethylnitrosourea (ENU)-induced lymphomas. Based on the results, we describe a unique locus with frequent LOH in the centromeric region of chromosome 11 of X-ray-induced lymphomas. This locus has never been observed to be altered similarly in either ENU-induced or spontaneous lymphomas, suggesting radiation-specific molecular alteration. The LOH patterns of individual thymic lymphomas indicated that the common region of LOH was located within 1.6 cM between D11Mit62 and D11Mit204, a region syntenic to human chromosome 7p13. Linkage analysis revealed that the markers of the common LOH region were genetically linked to Ikaros (now known as Znfn1a1), a master gene of lymphopoiesis. Although the presence of radiation-associated LOH in other loci cannot be ruled out, these results suggest a novel molecular pathway in induction of thymic lymphomas by ionizing radiation.     

Progress in the treatment of non-Hodgkin's lymphomas

The authors analyze the progress achieved in the treatment of low-grade as well as of high-grade non-Hodgkin's lymphomas. The challenging task in the treatment of low-grade or indolent lymphomas still is to decide whether watchful waiting is sufficient or whether chemotherapy is necessary and how aggressive this treatment should be. Among the new chemotherapeutic agents the role of purine analogues should be emphasized, fludarabin is especially important in the treatment of chronic lymphocytic leukemia and follicular lymphoma, while pentostatin and cladribine have revolutionized the treatment of hairy cell leukemia. Treatment with monoclonal antibodies, radioimmunoconjugates as well as autologous or allogeneic stem cell transplantation are potential new therapeutic options in the treatment of low-grade non-Hodgkin's lymphomas. In the case of aggressive non-Hodgkin's lymphomas risk-adapted strategies help the choice between standard or more intensive treatment options. In patients with relapsed high-grade lymphomas stem cell transplantation is indicated. In patients with marginal zone lymphoma the combination of hyperCVAD protocol + stem cell transplantation greatly improves prognosis.     

Expression of the MDR1 and MRP genes in patients with lymphoma with primary bone marrow involvement

Expression of MDR1 and MRP genes in patients with low-grade and high-grade non-Hodgkin's lymphomas with primary bone marrow involvement before and after chemotherapy was investigated. The data demonstrate that overexpression of MDR1 and MRP genes in hematological malignancies elevates in patients after chemotherapy and correlates with poor clinic prognosis and more frequent recurrences of the malignancies.     

T-cell gamma/delta hepatosplenic lymphoma - prolonged remission induced by aggressive first line treatment

T-cell gamma/delta hepatosplenic lymphoma is a primary extranodal lymphoma, distinct from other T/LGL lymphomas. The clinical course is aggressive, and despite use of the multiagent chemotherapy and young age of the patients, the median survival is less than 1 year. Curability of this disease is still uncertain. We reported a case of the successful intensive treatment with splenectomy, chemotherapy a first line autologous stem cell transplant. High intensity cytarabine- platinum containing regimen (EDHAP) may overcome primary resistance to conventional alkylating agents.     

AKXD recombinant inbred strains: models for studying the molecular genetic basis of murine lymphomas.

We analyzed the lymphoma susceptibility of 13 AKXD recombinant inbred mouse strains derived from AKR/J, a highly lymphomatous strain, and DBA/2J, a weakly lymphomatous strain. Of the 13 strains used, 12 showed a high incidence of lymphoma development. However, the average age at onset of lymphoma varied considerably among the different AKXD strains, suggesting that they have segregated several loci that affect lymphoma susceptibility. A relatively unambiguous classification of lymphomas was made possible by using histopathology in addition to detailed molecular characterization of rearrangements in immunoglobulin heavy and kappa light genes and in T-cell receptor beta-chain genes. Among the 12 highly lymphomatous strains, only 2 were identified that, like the parental AKR/J strain, died primarily of T-cell lymphomas. Three strains died primarily of B-cell lymphomas, and one strain primarily of myeloid lymphomas. Six strains were susceptible to both T-cell and B-cell lymphomas. Thus, these strains have segregated genes that affect both lymphoma susceptibility and lymphoma type and should prove to be useful models for studying the molecular genetic basis of murine lymphomas.     

Immunotherapy in the treatment of lymphoma

Relapsed or refractory non-Hodgkin's lymphomas, especially diffuse large B-cell lymphoma as well as relapsed or refractory Hodgkin lymphomas are hard-to-treat diseases. Patients who do not respond to initial therapy or experience relapse are treated with salvage regimens, and if eligible for aggressive therapy, treatment is continued with high-dose chemotherapy and autologous stem cell transplantation. Current therapy options can cure substantial numbers of patients, however for some it is still an uncurable disease. Numerous new drugs and cell therapies are being investigated for the treatment of relapsed or refractory lymphomas. Different types of immunotherapy options have shown promising results, and some have already become the standard of care. Here, we review immunotherapy options for the treatment of lymphoma and discuss the results, positions, practical aspects, and future directions of different drugs and cellular therapies for the treatment of this disease.     

Value of prednimustine in treating non Hodgkin's lymphomas of favourable histological type

24 patients with non-Hodgkin's lymphomas of low-grade malignancy (stage III and IV) were treated either with a single drug (prednimustine) or with combination chemotherapy (cyclophosphamide, vincristine and prednisone). Response to therapy was similar in both groups. Prednimustine induced complete remission in 6 from 13 patients, while in that group treated with combination chemotherapy a complete remission was recorded in 4 from 11 patients. Both regimens were well tolerated. Therapy with prednimustin has an advantage in oral administration enabling it to be used in out-patient practice.     

Primary malignant non-Hodgkin's lymphoma of the breast: a study of seven cases and literature review

ABSTRACT: INTRODUCTION: Primary breast lymphoma is an uncommon disease with poor clinical outcome. Breast lymphomas present less than 0.5% of malignant breast neoplasms and 2.2% of extranodal lymphomas. This study investigated the clinicopathological features and optimal treatment of PBL. Case presentations Clinical records of seven Moroccan PBL patients, treated at the National Institute of Oncology, Rabat, Morocco, from 2002 to 2010, were reviewed. Six of the patients were women and one a man, with ages ranging from 32 to 76. Five patients had stage IE and two stage IIE. All of the patients were classified with DLBCL. Of seven patients, one received a mastectomy and three excision of the breast lesion. Axillary dissection was performed in three patients. Two patients received chemotherapy followed by radiotherapy, while four received chemotherapy alone. Complete remission (CR) following primary treatment for all patients with PBL except in two cases was obtained. In one patient, recurrence occurred. CONCLUSIONS: There is no consensus on the question of how to best treat PBL: Mastectomy offers no benefit in the treatment of PBL. The combined therapy approach, with chemotherapy and radiotherapy, is the most successful treatment. PBL is poorly represented in rituximab-containing trials in DLBCL patients; there is not much experience with this agent in breast DLBCL. Because of the high incidence of central nervous system (CNS) involvement in PBL patients, many authors strongly believe that patients with aggressive forms of PBL should receive CNS infiltration prophylaxis.     

Genetic bases of the repertoire of immunoglobulins in application to diagnostics of clonality of B-cell lymphoid populations

Molecular mechanisms underlying the formation of B-cell lymphomas in connection with processes associated with the maturation of B-lymphocytes are reviewed. The currently used diagnostic methods do not always distinguish lymphomas from reactive changes of the lymphoid tissue. The principle of the molecular genetic method of clonality detection in lymphocyte populations, technical problems, and the strategy of its application in clinical diagnostics of lymphomas are described in detail.     

Genetic bases of diversity of the repertoire of immunoglobulins in application to diagnostics of clonality of B-cell lymphoid populations

Molecular mechanisms underlying the formation of B-cell lymphomas in connection with processes associated with the maturation of B lymphocytes are reviewed. The currently used diagnostic methods do not always distinguish lymphomas from reactive changes of the lymphoid tissue. The principle of the molecular genetic method ofclonality detection in lymphocyte populations, technical problems, and the strategy of its application in clinical diagnostics of lymphomas are described in detail.     

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.     

Lack of ecotropic virus involvement in induction of lymphomas in DBA/2J mice by 7,12-dimethylbenz(a)anthracene.

DBA/2 mice carry a single endogenous ecotropic murine leukemia provirus, Emv-3, that is replication defective because of a single nucleotide substitution in codon 3 of p15gag. However, when weanling DBA/2 mice are treated percutaneously with 7,12-dimethylbenz(a)anthracene (DMBA), ecotropic virus replication is induced in almost all of the treated mice. Previous studies have shown that this induction results from DMBA-induced reverse mutations in codon 3 that allow efficient virus replication. In addition to ecotropic virus replication, DMBA also induces lymphomas in 100% of the treated mice. These results have raised the possibility that ecotropic virus replication is causally associated with the development of lymphomas in DBA/2 mice, perhaps via the insertional activation or mutation of cellular proto-oncogenes. To test this possibility, we compared lymphoma incidence after percutaneous DMBA treatment in DBA/2J-dv/dv mice, which carry two copies of Emv-3, with lymphoma incidence in DBA/2J-d+18J/d+18J mice, which lost both copies of Emv-3 by homologous recombination involving the long terminal repeat sequences. The results of this study conclusively demonstrated that Emv-3 is not causally associated with the development of DMBA-induced lymphomas in DBA/2J mice. Interestingly, histopathological and molecular analyses of the lymphomas indicated that the majority of the lymphomas in both strains of mice were of the B-cell lineage. This was unanticipated, since the majority of chemically induced lymphomas in other inbred strains are thymic lymphomas, presumably of the T-cell lineage. Thus, DBA/2 mice appear to present a unique model system for the investigation of chemically induced B-cell lymphomas in mice.     

The pathogenesis of diabetes mellitus. Possible usefulness of spontaneous hyperglycemic syndromes in animals.

Systematic studies of the patterns of anatomic distribution, pathways of probable spread, and prognosis of the malignant lymphomas have been greatly aided by the development of new histopathologic classifications and the introduction of more sophisticated and precise diagnostic techniques, such as lymphangiography and laparotomy with splenectomy and retroperitoneal node biopsy. Concomitantly, megavoltage radiotherapy apparatus has made total-lymphoid radiotherapy feasible and practical, and the availability of a widening spectrum of chemotherapeutic agents has ushered in a new era of combination chemotherapy. Collectively, these diagnostic and therapeutic advances have already begun to yield a dramatic improvement in the prognosis of Hodgkin''s disease and the other malignant lymphomas.     

The Use of Tumor Registry Data

The End Results Group, sponsored by the National Cancer Institute, coordinates a national cooperative program for evaluating the results of cancer therapy. Three central tumor registries (in California, Connecticut and Massachusetts) plus nine individual hospital registries (in university hospitals) are participating in the program.During the period 1940-59, there was an encouraging increase in five-year survival rates among patients with carcinomas and sarcomas (solid tumors). Preliminary data for 1955-59 suggest that the upward trend is leveling off. A smaller absolute increase in five-year survival rates occurred among patients with lymphomas and leukemia. These increases in patient survival rates coincided with more frequent use of surgical operation for solid tumors and more frequent use of chemotherapy for lymphomas and leukemia.     

Glucocorticoids in cancer therapy

Glucocorticoids are often included with other agents in cancer treatment although the mode of action is not clear. They are useful in the primary combination chemotherapy of both acute and chronic lymphocytic leukaemias, Hodgkins' and non-Hodgkin's lymphomas, multiple myeloma and breast cancer. Other uses for glucocorticoids in cancer patients include an anti-inflammatory action for the oedema of cranial and spinal metastases, a weak antihypercalcaemic effect and the ability to suppress tumour-related fever.     

Risk of second primary cancers after Hodgkin's disease by type of treatment: analysis of 2846 patients in the British National Lymphoma Investigation.

OBJECTIVE--To analyse the risk of second primary cancers during long term follow up of patients with Hodgkin''s disease. DESIGN--Cohort study. SETTING--The British National Lymphoma Investigation (a collaborative group of over 60 participating centres in Britain treating lymphomas). PATIENTS--2846 patients first treated for Hodgkin''s disease during 1970-87, for whom follow up was complete in 99.8%. MAIN OUTCOME MEASURES--Second primary cancers; uniform pathology reviews confirmed the diagnosis of Hodgkin''s disease and of second primary non-Hodgkin''s lymphomas. RESULTS--113 second primary cancers occurred. Relative risk of cancer other than Hodgkin''s disease was 2.7 (95% confidence interval 2.3 to 3.3) compared with the general population, with significant risk of leukaemia (16.0(9.1 to 26.0)); non-Hodgkin''s lymphoma (16.8(9.8 to 26.9)); and cancers of the colon (3.2 (1.4 to 6.2)), lung (3.8 (2.6 to 5.4)), bone (15.1 (1.8 to 54.7)), and thyroid (9.4 (1.1 to 33.9)). Absolute excess risk associated with treatment was greater for solid tumours than for leukaemia and lymphomas. Relative risk of leukaemia increased soon after treatment, reaching a peak after five to nine years. It was increased substantially after chemotherapy (27.9 (12.7 to 52.9)), combined treatment with radiotherapy and chemotherapy (21.5 (7.9 to 46.8)), and relative to number of courses of chemotherapy but was not significantly increased after radiotherapy (2.5 (0.1 to 14.1)). Relative risk of non-Hodgkin''s lymphoma increased in the first five years after treatment and remained high but showed no clear relation with type or extent of treatment. Relative risk of solid tumours was less raised initially but increased throughout follow up and for lung cancer 10 years or more after entry was 8.3 (4.0 to 15.3). The risk of solid tumours increased after treatments including radiotherapy and after chemotherapy alone. The risk after chemotherapy increased significantly with time since first treatment. CONCLUSION--The risk of solid cancer, not of leukaemia, is the major long term hazard of treatment for Hodgkin''s disease, and this seemed to apply after chemotherapy as well as after radiotherapy. These risks of second cancers are important in choice of treatment and in follow up of patients, but they are small compared with the great improvements in survival which have been brought about by modern therapeutic methods for Hodgkin''s disease.     

Primary retroperitoneal mucinous cystadenoma of borderline malignancy in a male patient. Case report and review of the literature

The spleen is an infrequent site for metastatic lesions, and solitary splenic metastases from squamous cell carcinoma of the esophagus are very rare: only 4 cases have been reported thus far. These lesions are whitish nodules that are macroscopically and radiologically similar to primary splenic lymphomas. We report a case of metachronous splenic metastases from esophageal cancer and multiple splenic abscesses, which developed nine months after apparently curative esophagectomy without adjuvant chemotherapy. The patient underwent splenectomy dissection followed by adjuvant chemotherapy, but liver and skin metastases developed, and the patient died 9 months later.