Increased Risk of Diabetes after Definitive Radiotherapy in Patients with Indolent Gastroduodenal Lymphoma.

PURPOSE: This study aimed to evaluate the effect of radiotherapy (RT) on the risk of diabetes by assessing hemoglobin A1c (HbA1c) levels in patients with gastroduodenal indolent lymphoma. MATERIALS AND METHODS: This retrospective study included patients with stage I extranodal marginal zone lymphoma of the mucosa-associated lymphoid tissue or follicular lymphoma of the gastroduodenal region who were treated with Helicobacter pylori eradication and/or RT between 2000 and 2019 in our institution. Of total 79 patients with HbA1c test, 17 patients received RT (RT group), while 62 patients did not receive RT (control group). A diabetes-associated event (DAE) was defined as a ≥ 0.5% increase in HbA1c levels from baseline, and diabetes event (DE) were defined as HbA1c level of ≥ 6.5%. RESULTS: During the median follow-up of 49 months, no local failure occurred after RT and no patients died of lymphoma. The RT group had significantly higher risk for DAEs on univariable analysis (hazard ratio [HR], 4.18; 95% confidence interval [CI], 1.64 to 10.66; p < 0.01) and multivariable analysis (HR, 3.68; 95% CI, 1.42 to 9.56; p=0.01). Further, the DE risk was significantly higher in the RT group than in the control group (HR, 4.32; 95% CI, 1.08 to 17.30; p=0.04) and in patients with increased baseline HbA1c levels (HR, 35.83; 95% CI, 2.80 to 459.19; p=0.01). On multivariable analysis, RT significantly increased the risk of DEs (HR, 4.55; 95% CI, 1.08 to 19.19; p=0.04), even after adjusting baseline HbA1c level (HR, 40.97; 95% CI, 3.06 to 548.01; p=0.01). CONCLUSION: Patients who received RT for gastroduodenal indolent lymphoma had an increased risk of diabetes compared to those who did not.

Prognostic impact of trisomy 21 in follicular lymphoma.

The chromosomal abnormalities associated with follicular lymphoma (FL) prognosis are not fully elucidated. Here, we evaluated the pattern of chromosomal abnormalities in FL, and clarified the correlations between the cytogenetic features and clinical outcome. Cytogenetic analysis was performed using standard methods of Giemsa-banding at diagnosis for 201 FL patients admitted to our hospitals between 2001 and 2013. The identified chromosomal abnormalities were: t(14;18)(q32;q21) (59·2%), +X (17·9%), del(6)(q)/-6 (16·9%), +7 (14·4%), abnormality of 1q12-21/1q (12·9%), del(13)(q)/-13 (11·9%), abnormality of 3q27 (10·4%), abnormality of 10q22-24 (10·0%), +12/dup(12)(q) (10·0%), abnormality of 1p21-22/1p (9·0%), +18 (9·0%), del(17)(p)/-17 (5·0%), and a complex karyotype (54·7%). Patients with trisomy 21 had a significantly shorter progression-free survival (P = 0·00171) and overall survival (OS) (P < 0·001) than those without trisomy 21; additionally, patients with trisomy 21 in the rituximab-treated cohort also had a significantly shorter OS (P = 0·000428). Multivariate analysis identified trisomy 21 as an independent risk factor in our cohorts with or without t(14;18) (P = 0·015). In conclusion, the presence of trisomy 21 was an independent risk factor for in FL. Chromosomal analysis of FL patients at diagnosis can provide useful information about their expected survival.

Primary meningococcal arthritis as a presentation of nodal marginal zone lymphoma.

A 68-year-old man presented with a 4-day history of worsening knee and arm pain. On examination, there was erythema and swelling of the left knee and both wrists. Joint aspiration grew Neisseria meningitidis Blood tests showed an unusually high total protein level (100 g/L) and an IgM kappa paraprotein band of 45 g/L on protein electrophoresis. CT showed widespread lymphadenopathy, hepatosplenomegaly and multilevel thoracic vertebral collapse. A bone marrow biopsy revealed a lymphoplasmacytic infiltrate and a lymph node biopsy showed features of nodal marginal zone lymphoma with plasmacytic differentiation.

Pathways towards indolent B-cell lymphoma - Etiology and therapeutic strategies.

Although patients with indolent B-cell lymphomas have a relatively good survival rate, conventional chemotherapy is not curative. Disease courses are typically characterized by multiple relapses and progressively shorter response duration with subsequent lines of therapy. There has been an explosion of innovative targeted agents in the past years. This review discusses current knowledge on the etiology of indolent B-cell lymphomas with respect to the role of micro-organisms, auto-immune diseases, and deregulated pathways caused by mutations. In particular, knowledge on the mutational landscape of indolent B-cell lymphomas has strongly increased in recent years and harbors great promise for more accurate decision making in the current wide range of therapeutic options. Despite this promise, only in chronic lymphocytic leukemia the detection of TP53 mutations and/or del17p currently have a direct effect on treatment decisions. Nevertheless, it is expected that in the near future the role of genetic testing will increase for prediction of response to targeted treatment as well as for more accurate prediction of prognosis in indolent B-cell lymphomas.

Mycoplasmal cerebral vasculopathy in a lymphoma patient: presumptive evidence of Mycoplasma pneumoniae microvascular endothelial cell invasion in a brain biopsy.

A 73-year-old man had episodic encephalopathy, ataxia and neuropathy. Symptoms largely resolved but adenopathy later lead to the diagnosis of a low-grade follicular lymphoma. The neurological symptoms soon recurred with new pontine calcifications identified by computed tomography. Brain biopsy revealed microvascular endothelial cell nuclear changes. Electron microscopy identified small polymorphic bacteria without a cell wall and with terminal and attachment organelles within endothelial cells and clustered in some microvascular lumina. Immunostaining was positive for Mycoplasma pneumoniae and convalescent serum enzyme immunoassay was positive for M. pneumoniae IgG. The patient again recovered and he was neurologically stable 33 months after the initial episode. The ultrastructural findings of the bacterial cells are distinctive of some mycoplasmal species when compared to other small bacteria. Mycoplasma-like organisms are reported in four autopsied patients who had chronic encephalopathy, movement disorders, and some of the same light- and electron-microscopic findings in the brain as our patient. Direct neuroinvasion by Mycoplasma species has been suggested, while anatomic observations in our patient and in the four autopsy cases show microvascular invasion but not parenchymal invasion. Most mycoplasmal encephalitis may be immune-mediated. The frequency of neurovascular invasion is not known. It may be rare and it may persist.

Nocardia exalbida brain abscess in a patient with follicular lymphoma.

Nocardial brain abscess is a rare but severe complication in patients with malignancy. Nocardia exalbida was isolated in Japan and characterized within the genus Nocardia. We present the first report of N. exalbida brain abscess in a 63-year-old male patient with follicular lymphoma. He developed abnormal neurological findings during follicular lymphoma treatment, brain CT revealed ring-enhancing, multiloculated lesions, and N. exalbida was detected by aspiration of the lesion. He was successfully treated with trimethoprime-sulfamethoxazole (TMP-SMX) and meropenem without craniotomy or repeat aspirations. It should be noted that such an infection can occur in patients treated with conventional chemotherapy against malignant lymphoma.

Pathophysiological aspects of memory B-cell development.

B cells follow two functionally distinct pathways of development: a classical germinal center (GC) T-dependent pathway in which diversification and maturation generate a slow, but virtually unlimited high-affinity response to cognate antigens; and a marginal zone (MZ) T-independent pathway providing a first line of 'innate-like' defense against specific pathogens. Cells populating these two distinct locations are the normal counterparts of two clinically important pathological entities, follicular lymphoma (FL) and MZ lymphoma (MZL). FL and MZ represent paradigms of two rising concepts of lymphomagenesis, protracted preclinical and antigen-driven lymphoproliferation, respectively. Integrating the mechanisms and functions of MZ and GC B cells and the distinctive features of their pathological counterparts should provide essential clues to the understanding of their malignant development, and should offer new insights into the design of effective treatments for B-cell lymphomas.

Radiation therapy for localized low-grade non-Hodgkin's lymphomas.

The most common low grade B-cell non-Hodgkin's lymphomas are follicular lymphomas, and extranodal marginal zone lymphomas, also known as mucosa-associated lymphoid tissue (MALT) lymphomas. Localized presentations of follicular lymphoma occur in 20-30% of cases, while for MALT lymphomas, stage I-II disease presentations occur in 70-90%. These are radiation-sensitive lymphomas. Following moderate dose local radiation treatment (30-35 Gy) for these stage I and II low grade lymphomas, the clinical results indicate long-term local control and possible cure. While local control is achieved with minimal morbidity with involved-field radiation therapy, a significant proportion of patients relapse with systemic disease outside of radiation fields. For follicular lymphoma, this occurs in approximately 50% of patients after 15 years, and for non-gastric MALT lymphoma, 30-40% after 10 years. Although patients with relapsed systemic disease are not curable with chemotherapy, the disease often behaves in an indolent fashion and prolonged survival is observed. For gastric MALT lymphomas, radiation therapy is indicated in patients whose lymphoma did not respond to Helicobacter pylori eradication therapy, or in gastric lymphoma not related to this microorganism. The subject of causative agents responsible for non-gastric MALT lymphomas is under active study and the identification of putative microorganisms will lead to improved treatment strategies for these unusual lymphomas, similar to the success in gastric lymphomas over the last decade.

A unique EBV-negative low-grade lymphoma line (WSU-FSCCL) exhibiting both t(14;18) and t(8;11).

A new human B-cell line, WSU-FSCCL, was established from the peripheral blood of a patient with low-grade follicular small cleaved cell lymphoma in leukemic phase. Both the fresh lymphoma cells and the established cell line exhibit t(14;18)(q32;q21) and t(8;11)(q24;q21) chromosomal translocations, 6q-, 1p+, and +i(1q). PCR analysis confirmed the juxtaposition of the major breakpoint-cluster region of bcl-2 with immunoglobulin heavy chain (JH) gene rearrangements. Southern analysis demonstrated that the 8q24 breakpoint was 5' of c-myc exon 1. The new line grows as a single-cell suspension with a doubling time of approximately 26 hours. It expresses cytoplasmic and cell surface IgM-kappa and reacts with monoclonal antibodies to B-cell antigens. Cells are negative for T-cell and myeloid/monocyte antigens as well as for Epstein-Barr virus nuclear antigen (EBNA). DNA histogram generated by flow cytometry indicated a near diploid stemline. While t(14;18) is common in follicular lymphomas, the t(8;11) is unusual in lymphomas, although it does involve a region frequently aberrant on chromosome 8. The rearrangement of c-myc may have conferred an aggressive clinical behavior seen in the terminal phase of the disease. The role of 11q21 remains undetermined.

Lymphoma cell line (FL-18) and Epstein-Barr virus-carrying cell line (FL-18-EB) obtained from a patient with follicular lymphoma: monoclonal derivation and different properties.

A novel cell line, FL-18, was established from the pleural effusion of a patient with follicular small cleaved cell lymphoma. At the same time, an Epstein-Barr virus (EBV) nuclear antigen (EBNA)-positive cell line, FL-18-EB, was established from the EBV-infected culture of the same pleural effusion cells. Both cell lines had the same monoclonal surface immunoglobulin (IgG kappa), and they had the same karyotype as that of the fresh pleural effusion cells in which a reciprocal translocation between the long arm of chromosomes 14 and 18 [t(14;18)(q32;q21)] was detected. Gene rearrangement analysis of immunoglobulin heavy-chain gene (JH) and kappa light-chain gene (J kappa) showed the same rearranged configuration in the two cell lines; however, some morphological and phenotypic differences were found. The FL-18-EB cells, which were morphologically similar to common EBNA-positive lymphoblastoid cell lines of normal B cell origin at the initial phase of culture, were larger than the FL-18 cells and contained multinucleated giant cells. The FL-18 cells lacked cytoplasmic immunoglobulin and were positive for common acute lymphoblastic leukemia antigen (CALLA), whereas the FL-18-EB cells had cytoplasmic immunoglobulin and were negative for CALLA. Thus, the phenotype of FL-18-EB seems to be a result of a shift by EBV infection to a more mature stage in the B cell differentiation pathway than that of FL-18. The paired availability of EBV-free and EBV-infected cell lines of a neoplastic clone is unique and valuable in considering EBV infectibility of neoplastic B cells and resultant phenotypic changes.