ABSTRACT:The Swiss Group for Clinical Cancer Research (SAKK) and the Nordic Lymphoma Group conducted the SAKK 35/10 randomized phase 2 trial to compare rituximab (R) alone vs R plus lenalidomide (L) as initial treatment for follicular lymphoma (FL). Patients with grade 1 to 3A FL, requiring systemic therapy, were randomized to either R (n = 77; 375 mg/m2 IV × 1, weeks 1-4) or rituximab-lenalidomide (RL) (n = 77; R on the same schedule and L at 15 mg daily continuously). Responders (evaluated at 10 weeks) repeated R during weeks 12 to 15 with or without L (for a total of 18 weeks). Both arms had 47% of patients with a poor risk score on the FL International Prognostic Index. The primary end point, complete response (CR)/CR unconfirmed rates at 6 months, was superior with the combination, and after a median follow-up of 9.5 years, this has translated into a longer duration of response (median, not reached vs 3.2 years; hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.21-0.86; P = .014), progression-free survival (9.3 vs 2.3 years; HR, 0.57; 95% CI: 0.37-0.89; P = .0128), and time to next treatment (median, not reached vs 2.1 years; HR, 0.43; 95% CI, 0.27-0.67; P < .001). Over 60% of RL responders remained in first CR at 10 years. Overall survival was similar in both arms (77% vs 78% at 10 years; P = .881). Toxicity was more common with RL but manageable. The SAKK 35/10 trial's long-term results confirmed a durable benefit of a short-term chemotherapy-free first-line RL regimen in symptomatic FL. This trial was registered at www.clinicaltrials.gov as #NCT0137605.

The treatment of splenic marginal zone lymphoma is debated: splenectomy (the old standard-of-care) is better than chemotherapy but maybe not better than rituximab-containing treatment. We examined all 358 patients diagnosed with splenic marginal zone lymphoma in Sweden 2000-2020. The median overall survival was 11.0 years. The median age was 73 years; 61% were women. Age was the only independently prognostic clinical characteristic. Eighty-six patients were started on wait-and-watch, 90 rituximab monotherapy, 47 rituximab-chemotherapy, 88 splenectomy, 37 chemotherapy, and 10 both systemic therapy and splenectomy. Overall survival was inferior in patients treated with chemotherapy, but equal in patients treated with rituximab, rituximab-chemotherapy and splenectomy. Patients treated with both systemic therapy and splenectomy showed good outcome, suggesting that surgery can be safely reserved for nonresponders. After adjustment for age, survival did not differ between patients started on wait-and-watch and those treated with splenectomy or rituximab-containing therapy. Over time, rituximab use and survival increased in patients ≥73 years. This is, to our knowledge, the largest population-based study of splenic marginal zone lymphoma patients treated with upfront rituximab. We conclude that wait-and-watch remains the most reasonable option in asymptomatic splenic marginal zone lymphoma patients. Symptomatic patients should be offered single-agent rituximab in first line.

Background:The Swiss Group for Clinical Cancer Research (SAKK) and the Nordic Lymphoma Group (NLG) conducted the SAKK 35/10 randomized phase-2 trial (NCT0137605) to compare the effectiveness of rituximab (R) alone versus R combined with lenalidomide (L) as the initial treatment for symptomatic follicular lymphoma (FL). The primary endpoint analysis, which demonstrated higher complete remission (CR) rates with the combination therapy, was previously reported (Zucca et al. Blood 2019). This report provides a long-term analysis of time-to-event endpoints with a median follow-up of approximately 10 years. Methods:A total of 154 eligible patients with untreated grade 1 to 3a FL requiring systemic therapy were centrally randomized to receive either R monotherapy (375 mg/m2 IV on day 1 of weeks 1-4 and repeated during weeks 12-15 for responding patients) or R+L. In the combination arm, R was administered at the same schedule as the monotherapy, while L was taken orally at a daily dose of 15 mg, starting 14 days before the first R administration, and continued until 14 days after the last R administration, for a total of 18 weeks. Random assignment to treatment arms was stratified based on histological grade (1-2 vs 3a), bulky disease (<6 vs ≥6 cm), Follicular Lymphoma International Prognostic Index (FLIPI) score (1-2 vs ≥3), and centre, using the minimization method. The sample size was determined to detect a 20% increase in the CR/CRu rate with 90% power, using a one-sided Z-test with a false positive rate of 10% to compare the two treatment arms. The assessed endpoints, including progression-free survival (PFS), time to next anti-lymphoma treatment (TTNT), duration of CR/CRu (DoR), and overall survival (OS), were defined according to NCI international standardized criteria (Cheson et al. J Clin Oncol 1999). Results:Seventy-seven patients (median age 63 years, 52% with stage IV and 47% with poor-risk FLIPI score) were assigned to the single-agent rituximab arm, and 77 patients (median age 61 years, 48% with stage IV and 47% with poor-risk FLIPI score) were assigned to the combination arm. The results for the primary endpoint were consistent with the positive initial analysis. At a median follow-up of 9.5 years, the overall survival was similar in both arms (77% vs. 78% at 10 years, p=0.881). However, significant, and sustained improvements were seen in all other time-to-event endpoints. Patients in the R+L arm had a longer PFS (median, 9.3 vs. 2.3 years; HR=0.58, 95% CI: 0.37-0.89; p=0.013) and TTNT (median, not reached vs. 2.1 years; HR=0.43, 95% CI: 0.27-0.67; p<0.001). DoR with R+L was also longer (median not reached vs 3.2 years with R only; HR=0.42, 95% CI: 0.21-0.86; p=0.014) and with over 60% of responders still in first remission at 10 years. The improved outcomes with R+L were not associated with unexpected toxicity. Grade ≥3 adverse events were more common with the combination regimen (56% vs. 22% of patients), with grade 3-4 neutropenia in 23% of patients receiving R+L and in 7% of those receiving R alone. Fatigue, diarrhea, and skin rash were more frequent with R+L, but mostly of grade 1-2 (grade 3 occurred in ≤ 5% in both arms, and no grade 4 was reported). The side effects were manageable, and there were no treatment-related deaths in either arm. Two cases of biopsy-proven into diffuse large B-cell lymphoma were reported in the R+L arm, and two cases of Hodgkin lymphoma were described in the R arm. Although their causal relationship with treatment is not completely clear, the number of second solid cancers was significantly higher in the R+L arm. Two cases of prostate cancer, two lung adenocarcinomas (one in situ), one small cell lung carcinoma, one rectal cancer, and four skin cancers (three squamous cell and one basal cell), were observed in the R+L arm, while only one solid tumor (prostate cancer) occurred in the R arm (p=0.09). Only one patient died of a second solid cancer (small cell lung carcinoma in the R+L arm). The rate of POD24 was 29% in the R+L arm vs. 34% in the R-arm (p=0.483). Conclusions:The long-term results of the SAKK 35/10 trial demonstrated a durable benefit for the R+L combination compared to R alone. Notably, the adopted R+L schedule is considerably shorter than the standard R2 regimen (18 vs. 120 weeks). This provides a promising alternative when treatment is required but durable immunosuppression is undesirable.

BACKGROUND:Hodgkin lymphoma (HL) patients have a good prognosis after adequate treatment. Previous treatment with mantle field irradiation has been accompanied by an increased long-term risk of cardiovascular disease (CVD). This study identified co-morbidity factors for the development of cardiovascular side effects and initiated an intervention study aimed to decrease morbidity and mortality of CVD in HL survivors.DESIGN:Hodgkin lymphoma patients aged ≤45 years diagnosed between 1965 and 1995 were invited to participate. In total, 453 patients completed a questionnaire that addressed co-morbidity factors and clinical symptoms. Of these, 319 accepted to participate in a structured clinical visit. The statistical analyses compared individuals with CVD with those with no CVD.RESULTS:Cardiovascular disease was reported by 27.9%. Radiotherapy (odds ratio [OR]: 3.27), hypertension and hypercholesterolemia were shown to be independent risk factors for the development of CVD. The OR for CVD and valve disease in patients who received radiotherapy towards mediastinum was 4.48 and 6.07, respectively. At clinical visits, 42% of the patients were referred for further investigation and 24% of these had a cardiac ultrasound performed due to previously unknown heart murmurs.CONCLUSION:Radiotherapy towards mediastinum was an independent risk factor for CVD as well as hypercholesterolemia and hypertension. A reasonable approach as intervention for this cohort of patients is regular monitoring of hypertension and hypercholesterolemia and referral to adequate investigation when cardiac symptoms appear. Broad knowledge about the side effects from radiotherapy in the medical community and well-structured information regarding late side effects to the patients are all reasonable approaches as late effects can occur even 40 years after cancer treatment.

When treating limited stage classical Hodgkin lymphoma (cHL), balancing treatment efficacy and toxicity is important. Toxicities after extended-field radiotherapy are well documented. Investigators have aimed at reducing toxicity without compromising efficacy, mainly by using combined modality treatment (CMT), i.e. chemotherapy and limited-field radiotherapy. In some clinical trials, radiotherapy has been omitted. We evaluated 364 patients with stage I-IIA cHL treated between 1999 and 2005. Patients were treated with two or four cycles of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) according to presence of risk factors, followed by 30 Gy limited-field (reduced compared to involved-field) radiotherapy. After a median follow-up of 16 years for survival, freedom from progression at five and ten years was 93% and overall survival at 5 and 10 years was 98% and 96%, respectively. Only two relapses, out of 27, occurred after more than 5 years. There was no excess mortality compared to the general population. Of the analysed subgroups, only patients with progression within five years showed significant excess mortality. The absence of excess mortality questions the concept of omitting radiotherapy after short-term chemotherapy, a strategy that has been associated with an elevated risk of relapse but not yet with a proven reduced long-term excess mortality.

The SAKK 35/10 phase 2 trial, developed by the Swiss Group for Clinical Cancer Research and the Nordic Lymphoma Group, compared the activity of rituximab vs rituximab plus lenalidomide in untreated follicular lymphoma patients in need of systemic therapy. Patients were randomized to rituximab (375 mg/m2 IV on day 1 of weeks 1-4 and repeated during weeks 12-15 in responding patients) or rituximab (same schedule) in combination with lenalidomide (15 mg orally daily for 18 weeks). Primary end point was complete response (CR)/unconfirmed CR (CRu) rate at 6 months. In total, 77 patients were allocated to rituximab monotherapy and 77 to the combination (47% poor-risk Follicular Lymphoma International Prognostic Index score in each arm). A significantly higher CR/CRu rate at 6 months was documented in the combination arm by the investigators (36%; 95% confidence interval [CI], 26%-48% vs 25%; 95% CI, 16%-36%) and confirmed by an independent response review of computed tomography scans only (61%; 95% CI, 49%-72% vs 36%; 95% CI, 26%-48%). After a median follow-up of 4 years, significantly higher 30-month CR/CRu rates and longer progression-free survival (PFS) and time to next treatment (TTNT) were observed for the combination. Overall survival (OS) rates were similar in both arms (≥90%). Toxicity grade ≥3 was more common in the combination arm (56% vs 22% of patients), mainly represented by neutropenia (23% vs 7%). Addition of lenalidomide to rituximab significantly improved CR/CRu rates, PFS, and TTNT, with expected higher, but manageable toxicity. The excellent OS in both arms suggests that chemotherapy-free strategies should be further explored. This trial was registered at www.clinicaltrials.gov as #NCT01307605.

Recent prospective studies have shown that dysregulation of the immune system may precede the development of B‐cell lymphomas (BCL) in immunocompetent individuals. However, to date, the studies were restricted to a few immune markers, which were considered separately. Using a nested case–control study within two European prospective cohorts, we measured plasma levels of 28 immune markers in samples collected a median of 6 years before diagnosis (range 2.01–15.97) in 268 incident cases of BCL (including multiple myeloma [MM]) and matched controls. Linear mixed models and partial least square analyses were used to analyze the association between levels of immune marker and the incidence of BCL and its main histological subtypes and to investigate potential biomarkers predictive of the time to diagnosis. Linear mixed model analyses identified associations linking lower levels of fibroblast growth factor‐2 (FGF‐2 p = 7.2 × 10 −4 ) and transforming growth factor alpha (TGF‐α, p = 6.5 × 10 −5 ) and BCL incidence. Analyses stratified by histological subtypes identified inverse associations for MM subtype including FGF‐2 ( p = 7.8 × 10 −7 ), TGF‐α ( p = 4.08 × 10 −5 ), fractalkine ( p = 1.12 × 10 −3 ), monocyte chemotactic protein‐3 ( p = 1.36 × 10 −4 ), macrophage inflammatory protein 1‐alpha ( p = 4.6 × 10 −4 ) and vascular endothelial growth factor ( p = 4.23 × 10 −5 ). Our results also provided marginal support for already reported associations between chemokines and diffuse large BCL (DLBCL) and cytokines and chronic lymphocytic leukemia (CLL). Case‐only analyses showed that Granulocyte‐macrophage colony stimulating factor levels were consistently higher closer to diagnosis, which provides further evidence of its role in tumor progression. In conclusion, our study suggests a role of growth‐factors in the incidence of MM and of chemokine and cytokine regulation in DLBCL and CLL.

Purpose For indolent lymphoma, the optimal timing, sequence, and choice of therapeutic regimens remain a matter of debate. In two Nordic Lymphoma Group randomized trials, symptomatic or clearly progressing patients were treated first line with a rituximab-containing regimen without chemotherapy. The purpose of this study was to assess long-term survival, risk of transformation, and need of new therapies. Methods Data were collected at cross-sectional follow-up for 321 patients with indolent lymphoma (84% with follicular lymphomas [FL]) included in one of two Nordic Lymphoma Group trials (accrual 1998 to 1999 and 2002 to 2008). All patients received first-line therapy with one or two cycles of four weekly infusions of rituximab 375 mg/m2, and 148 were randomly allocated to the addition of interferon alfa-2a. Follow-up data were retrieved from initial trial databases and medical records on repeated clinical evaluations. Results At the end of follow-up, 73% of patients were alive, with a median follow-up after random assignment of 10.6 years. Among all, 36% (38% with FL) had never needed chemotherapy. For patients with FL who required new therapy within 24 months because of early disease progression, the 10-year survival rate was 59% versus 81% for those with longer remission. Interferon was not shown to improve long-term outcome. Transformation was diagnosed in 20% of all patients (2.4% per person-year) and in 18% with FL. An additional malignancy was found in 12%. Conclusion Approximately one third of patients with symptomatic indolent lymphoma (30% with FL, 23% without FL) did not need new therapy in the long term after first-line rituximab without chemotherapy. In the entire cohort, 10-year survival was excellent with no major safety issues, which suggests that chemotherapy can be delayed safely in the majority of patients.

Chronic inflammation may be involved in cancer development and progression. Using 28 inflammatory-related proteins collected from prospective blood samples from two case-control studies nested in the Italian component of the European Prospective Investigation into Cancer and nutrition (n = 261) and in the Northern Sweden Health and Disease Study (n = 402), we tested the hypothesis that an inflammatory score is associated with breast cancer (BC) and Β-cell Non-Hodgkin Lymphoma (B-cell NHL, including 68 multiple myeloma cases) onset. We modelled the relationship between this inflammatory score and the two cancers studied: (BC and B-cell NHL) using generalised linear models, and assessed, through adjustments the role of behaviours and lifestyle factors. Analyses were performed by cancer types pooling both populations, and stratified by cohorts, and time to diagnosis. Our results suggested a lower inflammatory score in B-cell NHL cases (β = −1.28, p = 0.012), and, to lesser, extent with BC (β = −0.96, p = 0.33) compared to controls, mainly driven by cancer cases diagnosed less than 6 years after enrolment. These associations were not affected by subsequent adjustments for potential intermediate confounders, notably behaviours. Sensitivity analyses indicated that our findings were not affected by the way the inflammatory score was calculated. These observations call for further studies involving larger populations, larger variety of cancer types and repeated measures of larger panel of inflammatory markers.

AbstractThe B-cell activation markers CXCL13, sCD23, sCD27, and sCD30 are associated with future lymphoma risk. However, a lack of information about the individual dynamics of marker–disease association hampers interpretation. In this study, we identified 170 individuals who had donated two prediagnostic blood samples before B-cell lymphoma diagnosis, along with 170 matched cancer-free controls from the Northern Sweden Health and Disease Study. Lymphoma risk associations were investigated by subtype and marker levels measured at baseline, at the time of the repeated sample, and with the rate of change in the marker level. Notably, we observed strong associations between CXCL13, sCD23, sCD27, and sCD30 and lymphoma risk in blood samples collected 15 to 25 years before diagnosis. B-cell activation marker levels increased among future lymphoma cases over time, while remaining stable among controls. Associations between slope and risk were strongest for indolent lymphoma subtypes. We noted a marked association of sCD23 with chronic lymphocytic leukemia (ORSlope = 28, Ptrend = 7.279 × 10−10). Among aggressive lymphomas, the association between diffuse large B-cell lymphoma risk and slope was restricted to CXCL13. B-cell activation seemed to play a role in B-cell lymphoma development at early stages across different subtypes. Furthermore, B-cell activation presented differential trajectories in future lymphoma patients, mainly driven by indolent subtypes. Our results suggest a utility of these markers in predicting the presence of early occult disease and/or the screening and monitoring of indolent lymphoma in individual patients. Cancer Res; 77(6); 1408–15. ©2017 AACR.

Background: We studied immune marker trajectories (i.e. intra-individual changes in immune marker concentrations over time) of ten immune markers in relation to multiple myeloma (MM) risk. Low blood concentrations of MCP-3, MIP-1α, VEGF, FGF-2, Fractalkine, and TGF-α have been associated with myeloma risk in a previous study of single blood samples per participant collected around six years before diagnosis (Vermeulen et al., submitted). Longitudinal studies regarding these immune markers may provide substantial input to understanding their natural history in myeloma development and how these markers could be used in clinical routine.

Patients with advanced CD20 + indolent lymphoma, requiring therapy, were randomized to rituximab (four weekly infusions of 375 mg/m(2)) or to rituximab combined with 5 weeks of interferon-α2a (IFN-α2a) (3-4.5 MIU daily) as priming. Responding patients were eligible for a second cycle with the same allocated treatment. In total, 156 patients were randomized to rituximab and 157 to rituximab + IFN-α2a. In the intention-to treat (ITT) population, 244 patients (78%) responded to cycle 1. After a second cycle the complete remission/complete remission unconfirmed (CR/CRu) rate was 41% with the combination versus 24% with monotherapy (p = 0.005). The median time to treatment failure (primary endpoint) in ITT patients was 28 vs. 21.5 months, respectively (p = 0.302). After a long median follow-up (61 months), 33% (42% of patients responding to cycle 1) were still failure-free with an overall survival rate of 88% and with no difference between the treatment groups. The trial was registered at ClinicalTrials.gov Identifier: NCT01609010.

Background: Previous trials from the Swiss Group for Clinical Cancer Research (SAKK) and the Nordic Lymphoma Group (NLG) showed that therapy with single-agent rituximab can produce long-term remissions in a sizeable subset of follicular lymphoma (FL) patients, with overall survival not inferior to chemo-immunotherapy, providing the rationale for the development of chemotherapy-free treatment strategies. Promising results have also been reported with the combination of rituximab and lenalidomide. The SAKK 35/10 phase-2 study was developed and conducted by the SAKK in cooperation with the NLG to compare the activity of rituximab plus lenalidomide versus single-agent rituximab in the first-line FL therapy.

Recent epidemiological investigations have reported on the association between telomere length (TL) and a number of malignancies, including B-cell lymphoma (BCL). The reported results for BCLs are however inconsistent. We carried out a nested case-control study to determine whether TL is associated with future risk of BCL. Using quantitative polymerase chain reaction, the relative TL (i.e. the ratio of telomere repeat copy number to single gene copy number) was measured in mononuclear cell DNA of prediagnostic peripheral blood samples of 464 lymphoma cases and 464 matched controls (median time between blood collection and diagnosis, 4.6 years). Conditional logistic regression was used to analyze the association between TL and the risk of developing lymphoma and histologic subtypes. TL was significantly longer in cases compared to controls (p = 0.01). Multivariable models showed a significantly increased risk of BCL [odds ratio (OR) = 1.66, 1.80 and 3.20 for quartiles 2-4, respectively, p-trend = 0.001], diffuse large B-cell lymphoma (DLBCL) (OR = 1.20, 2.48 and 2.36 for quartiles 2-4, respectively, p-trend = 0.03) and follicular lymphoma (FL) (OR = 1.39, 1.90 and 2.69 for quartiles 2-4, respectively, p-trend = 0.02) with increasing TL. This study suggests an association between longer leucocyte TL and increased risk of BCL which was most pronounced for DLBCL and FL.

It has been suggested that mitochondrial dysfunction and DNA damage are involved in lymphomagenesis. Increased copy number of mitochondrial DNA (mtDNA) as a compensatory mechanism of mitochondrial dysfunction previously has been associated with B-cell lymphomas, in particular chronic lymphocytic leukemia (CLL). However, current evidence is limited and based on a relatively small number of cases. Using a nested case-control study, we extended these findings with a focus on subtype-specific analyses. Relative mtDNA copy number was measured in the buffy coat of prospectively collected blood of 469 lymphoma cases and 469 matched controls. The association between mtDNA copy number and the risk of developing lymphoma and histologic subtypes was examined using logistic regression models. We found no overall association between mtDNA and risk of lymphoma. Subtype analyses revealed significant increased risks of CLL (n = 102) with increasing mtDNA copy number (odds ratio = 1.34, 1.44, and 1.80 for quartiles 2-4, respectively; P trend = .001). mtDNA copy number was not associated with follow-up time, suggesting that this observation is not strongly influenced by indolent disease status. This study substantially strengthens the evidence that mtDNA copy number is related to risk of CLL and supports the importance of mitochondrial dysfunction as a possible mechanistic pathway in CLL ontogenesis.

BACKGROUND:Cadmium (Cd) and lead (Pb) are hypothesised to be risk factors for non-Hodgkin's lymphoma (NHL), a group of haematological malignancies with a suspected environmental aetiology. Within the EnviroGenoMarkers study we utilised pre-diagnostic erythrocyte concentrations of Cd and Pb to determine whether exposure was associated with risk of B-cell NHL and multiple myeloma.METHODS:194 incident cases of B-cell NHL and 76 cases of multiple myeloma diagnosed between 1990 and 2006 were identified from two existing cohorts; EPIC-Italy and the Northern Sweden Health and Disease Study. Cases were matched to healthy controls by centre, age, gender and date of blood collection. Cd and Pb were measured in blood samples provided at recruitment using inductively coupled plasma-mass spectrometry. Logistic regression was applied to assess the association with risk. Analyses were stratified by cohort and gender and by subtype where possible.RESULTS:There was little evidence of an increased risk of B-cell NHL or multiple myeloma with exposure to Cd (B-cell NHL: OR 1.09 95%CI 0.61, 1.93, MM: OR 1.16 95% CI: 0.40, 3.40 ) or Pb (B-cell NHL: 0.93 95% CI 0.43, 2.02, multiple myeloma: OR 1.63 95%CI 0.45, 5.94) in the total population when comparing the highest to the lowest quartile of exposure. However, gender and cohort specific differences in results were observed. In females the risk of B-cell NHL was more than doubled in those with a body burden of Cd >1 µg/L (OR 2.20 95%CI; 1.04, 4.65).CONCLUSIONS:This nested case-control study does not support a consistent positive association between Cd or Pb and NHL, but there is some indication of a gender specific effect suggesting further research is warranted.

BACKGROUND:The relation between vitamin D status and lymphoma risk is inconclusive. OBJECTIVE:We examined the association between prediagnostic plasma 25-hydroxyvitamin D [25(OH)D] and lymphoid cancer risk. DESIGN:We conducted a study nested within the European Prospective Investigation into Cancer and Nutrition cohort of 1127 lymphoma cases and 1127 matched controls with a mean follow-up time of 7.1 y. Conditional logistic regression was used to estimate multivariable-adjusted incidence rate ratios of lymphoma risk in relation to plasma 25(OH)D. Season-standardized and season-specific 25(OH)D quartiles were used. We also analyzed 25(OH)D as a continuous variable and used predefined cutoffs. RESULTS:No statistically significant association between plasma 25(OH)D and overall lymphoid cancer risk was observed. A positive association for B-cell non-Hodgkin lymphoma was noted only in those with a diagnosis made during the first 2 y of follow-up (P-heterogeneity = 0.03), which suggests the possibility of reverse causality. Further analysis restricted to participants with ≥2 y of follow-up time showed a significant association between 25(OH)D and chronic lymphocytic leukemia (CLL) (n = 161): adjusted incidence rate ratios were 0.40 (95% CI: 0.18, 0.90; P-trend = 0.05) and 0.31 (95% CI: 0.13, 0.76; P-trend = 0.03) for the top compared with the bottom season-standardized and season-specific quartiles, respectively. Data on dietary vitamin D intake provided further support for the observed association (incidence rate ratio: 0.33; 95% CI = 0.12, 0.89; P-trend = 0.006). CONCLUSIONS:Our findings do not support a protective role of high 25(OH)D concentration in lymphoid cancers overall. However, they suggest that higher concentrations of 25(OH)D are associated with a reduced risk of CLL.

The objective was to investigate the effects of omega-3 fatty acids, known for their anti-inflammatory effects, on time to lymphoma progression and survival in the TLL mouse, a strain genetically prone to developing aggressive T-cell lymphoma. Compared to mice fed a standard diet, TLL mice fed omega-3 (menhaden fish oil) experienced a significant delay in disease progression and were more likely to remain alive and symptom free during the first 8 months of the study. In contrast, omega-6 supplementation (corn oil) did not significantly affect lymphoma progression. Irrespective of diet, all mice eventually progressed, and 1-year survival was not different between the groups. Immunological analysis demonstrated a significantly altered B-cell compartment and fewer NK cells in healthy C57Black6 mice fed omega-3, compared to controls. In conclusion, a diet rich in omega-3 fatty acids delays lymphoma development in the TLL mouse possibly by mechanisms that include complex effects on immune function.

BACKGROUND:Moloney murine leukemia virus (Mo-MLV) has proven valuable for studies of the pathogenesis of malignant lymphoma. Inoculation of newborn mice induces T cell lymphoma with 100% incidence. The TLL (T cell lymphoma/leukemia)-strain was previously established and was shown to spontaneously develop T cell lymphoma at high frequency.MATERIALS AND METHODS:Differential screening of cDNA libraries was performed to discover an involvement of Mo-MLV and genomic sequencing was used to identify the chromosomal position of Mo-ML V proviral integration sites. Immunophenotypes of the tumors were established by flow cytometty. Disease frequency curves were created according to the Kaplan-Meier method.RESULTS:Two independent Mo-MLV germ line integrations were characterized on chromosomes 2 and 14, giving rise to two substrains of mice denoted TLL-2 and TLL-14. The chromosomal position of the integrated provirus affected the frequency of disease, as well as the immunophenotype of the tumors.CONCLUSION:The data suggest that factors influencing the transcriptional activity of the chromosomal regions, leading to differences in proviral expression, could underlie the observed difference in tumor frequency.