Epidemiology of Follicular Lymphoma.

Follicular lymphoma (FL) is a common indolent lymphoma subtype in Western countries. FL incidence increases with age, and shows considerable variation by race/ethnicity and geography. In the United States and France, FL incidence has been stable since 2000, whereas in other Western and Asian countries it has been increasing. Five-year relative survival rates have been increasing in Western and Asian countries. Progress on identifying FL-specific risk factors has accelerated with the implementation of the InterLymph nested classification and the availability of larger epidemiologic studies and pooled analyses. Identification of risk factors for FL requires further research.

An analysis of the effect of statins on the risk of Non-Hodgkin's Lymphoma in the Women's Health Initiative cohort.

Statins have been shown to induce a phosphoprotein signature that modifies MYC (myelocytomatosis viral oncogene) activation and to have anti-inflammatory activity that may impact the risk of Non-Hodgkin's lymphoma (NHL). We analyzed the relationship between statins and risk of NHL using data from the Women's Health Initiative (WHI). The study population included 161,563 postmenopausal women ages 50-79 years from which 712 cases of NHL were diagnosed after 10.8 years of follow-up. Information on statin use and other risk factors was collected by self- and interviewer-administered questionnaires. Multivariable-adjusted HR and 95% CI evaluating the relationship between statin use at baseline, as well as in a time-dependent manner and risk of NHL, were computed from Cox proportional hazards analyses. A separate analysis was performed for individual NHL subtypes: diffuse large B-Cell lymphoma (DLBCL) (n = 228), follicular lymphoma (n = 169), and small lymphocytic lymphoma (n = 74). All statistical tests were two-sided. There was no significant association between use of statins at baseline and risk of NHL (HR 0.85, 95% C.I. 0.67-1.08). However, in the multivariable-adjusted time-dependent models, statin use was associated with a borderline lower risk of NHL (HR 0.81, 95% C.I. 0.66-1.00). Considering subtypes of NHL, statin use was associated with a lower risk of DLBCL (HR 0.62, 95% C.I. 0.42-0.91). This effect was driven by lipophilic statins (HR 0.62, 95% C.I. 0.40-0.96). In the WHI, statins were associated with a lower overall risk of DLBCL, particularly attributable to lipophilic statins. These results may have impact on primary or secondary prevention of NHL, particularly DLBCL.

Transformation of follicular lymphoma - Why does it happen and can it be prevented?

Follicular lymphoma is a clinical disease with a multitude of presentations and behaviors. Although infrequent, transformation of follicular lymphoma to a more aggressive behaving subtype - prototypically diffuse large B-cell lymphoma - confers a substantially adverse prognosis. There is no consensus for optimal management after transformation is recognized. Historically considered a distinct clinical event, this review highlights the multiple subclinical transformational events that either variably or cumulatively result in clinical recognition of transformed follicular lymphoma. Known and suspected events include genetic and epigenetic perturbations, metabolomic changes, and alterations in the microenvironment. This diverse spectrum of pathways leads to heterogeneous clinical presentations and outcomes of transformed follicular lymphoma. Current options for prevention of transformation are limited to known strategies of managing follicular lymphoma before the transformation is recognized. Although most retrospectively analyzed studies suggest an association of lower transformation rates with early systemic therapy, specific components of therapy such as anti-CD20 antibodies, anthracyclines, or purine analogues are less strongly associated with "preventative' value. Thus, the goal of preventing transformation is of limited value among all factors that go into decisions on early management of follicular lymphoma. Future opportunities to prevent clinical evidence of transformation will benefit from early detection of markers of subclinical transformation and development of therapies to specifically target the biology implied by those markers.

The incidence of biopsy-proven transformation in follicular lymphoma in the rituximab era. A retrospective analysis from the Czech Lymphoma Study Group (CLSG) database.

The aim of this study is to assess the incidence, risk factors, and outcome of biopsy-proven transformation in follicular lymphoma (FL) patients in the rituximab era. Transformation was analyzed in 1233 patients with initially diagnosed FL grades 1-3A, identified between 2002 and 2012 in the prospectively maintained Czech Lymphoma Study Group database. Only patients with histologically proven transformation (HT) were included. HT occurred in 58 cases at a median of 3.0 years from the initial FL diagnosis; the HT rate was 4% at 5 years. Transformation occurred most frequently at the first relapse (84% patients). Median OS from the HT was 2.5 years (95% CI 0.4-4.6) and 6-year OS with HT was shorter compared to all FLs (60 vs. 83.9%; 95% CI). A bulky tumor (≥ 10 cm), increased lactate dehydrogenase, age ≥ 60 years, and International Prognostic Index (intermediate/high risk), but not Follicular Lymphoma International Prognostic Index, were associated with transformation (p < 0.05). In the first line, 70% of patients received rituximab (including 36% rituximab maintenance), 57% CHOP-like regimens, and 2.6% of patients were treated with fludarabine-based therapy, whereas 11% of patients were watched only. The patients treated with R-CHOP in the first line (n = 591) showed the transformation rate at 5 years of 4.23% (95% CI 2.52-5.93); subsequent rituximab maintenance (n = 276) vs. observation (n = 153) was associated with a lower transformation rate (p.033; HR 3.29; CI 1.10-9.82). The transformation rate seems to be lower than in previous series, which may be influenced by broad use of rituximab, but prognosis of HT developed during therapy continues to be poor.

Linfoma cutáneo primario de células T pleomórficas de pequeño y mediano tamaño CD4+ con expresión de marcadores de linfocito T helper folicular y resolución espontánea / Primary Cutaneous CD4+ Small/Medium-Sized Pleomorphic T-Cell Lymphoma With Expression of Follicular T-Helper Cell Markers and Spontaneous Remission

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The optimal management of follicular lymphoma: an evolving field.

Follicular lymphoma consists of a heterogeneous group of diseases that can vary dramatically in clinical course. As with other indolent lymphomas, follicular lymphoma is felt to be highly treatable, but ultimately incurable. The appropriate management of this disease ranges from close observation to chemoimmunotherapy based on presenting symptoms and comorbidities. In this article, we focus on the optimal management of follicular lymphoma, including prognostication, indications for treatment, and current treatment options. While a number of front-line chemoimmunotherapy options exist, R-CHOP (rituximab, cyclophosphamide, vincristine, prednisone) and BR (bendamustine, rituximab) tend to be favored due to efficacy and tolerability. Post-induction options include maintenance rituximab and radioimmunotherapy, but neither has demonstrated an overall survival benefit. In relapsed disease, patients can receive an alternative chemoimmunotherapy regimen or radioimmunotherapy, or participate in a clinical trial. There are a number of new biologic targeted therapies with promising activity in follicular lymphoma that have the potential to change our approach to this disease.

Trans fatty acid intake is associated with increased risk and n3 fatty acid intake with reduced risk of non-hodgkin lymphoma.

We evaluated the association of dietary fat and protein intake with risk of non-Hodgkin lymphoma (NHL) in a clinic-based study in 603 cases (including 218 chronic lymphocytic leukemia/small lymphocytic lymphoma, 146 follicular lymphoma, and 105 diffuse large B-cell lymphoma) and 1007 frequency-matched controls. Usual diet was assessed with a 128-item food-frequency questionnaire. Unconditional logistic regression was used to estimate ORs and 95% CIs, and polytomous logistic regression was used to assess subtype-specific risks. trans Fatty acid (TFA) intake was positively associated with NHL risk [OR = 1.60 for highest vs. lowest quartile (95% CI = 1.18, 2.15); P-trend = 0.0014], n3 (ω3) fatty acid intake was inversely associated with risk [OR = 0.48 (95% CI = 0.35, 0.65); P-trend < 0.0001], and there was no association with total, animal, plant-based, or saturated fat intake. When examining intake of specific foods, processed meat [OR = 1.37 (95% CI = 1.02, 1.83); P-trend = 0.03], milk containing any fat [OR = 1.47 (95% CI = 1.16, 1.88); P-trend = 0.0025], and high-fat ice cream [OR = 4.03 (95% CI = 2.80, 5.80); P-trend < 0.0001], intakes were positively associated with risk, whereas intakes of fresh fish and total seafood [OR = 0.61 (95% CI = 0.46, 0.80); P-trend = 0.0025] were inversely associated with risk. Overall, there was little evidence for NHL subtype-specific heterogeneity. In conclusion, diets high in TFAs, processed meats, and higher fat dairy products were positively associated with NHL risk, whereas diets high in n3 fatty acids and total seafood were inversely associated with risk.

Fruits and vegetables consumption and risk of non-Hodgkin's lymphoma: a meta-analysis of observational studies.

Epidemiologic evidence suggests that intakes of fruits and/or vegetables may play a role in the etiology of non-Hodgkin's lymphoma (NHL), but the findings are inconsistent. We aimed to assess fruits and/or vegetables intakes in relation to risk of NHL by a meta-analytic approach. We searched on PubMed database from January 1966 to September 2012 to indentify case-control and cohort studies. We used a random-effects model to compute summary risk estimates. For vegetables, the summary relative risks (RRs) of NHL for high versus low intake for case-control, cohort and all studies were 0.75 (95% CI, 0.60-0.94; N = 8), 0.90 (95% CI, 0.81-1.00; N = 5) and 0.81 (95%CI, 0.71-0.92; N = 13) ; and the corresponding RRs for intake of 1 serving per day were 0.88 (95% CI, 0.80-0.96; N = 8), 0.96 (95% CI, 0.92-1.00; N = 5) and 0.92 (95%CI, 0.87-0.96; N = 13). For fruits and vegetables combined, the summary RR for high versus low intake was 0.78 (95%CI, 0.66-0.92; N = 4), and for intake of 1 serving per day was 0.95 (95%CI, 0.91-1.00; N = 4). Regarding histological subtypes, vegetables intake was significantly inversely associated with diffuse large B-cell lymphoma and follicular lymphoma, but not small lymphocytic lymphoma/chronic lymphocytic leukemia (high vs. low intake, RR = 0.70, 0.70 and 1.01, respectively; N = 7, 7 and 10, respectively). Fruits intake was generally not associated with total NHL, or any histological subtypes. Our findings suggest that intakes of vegetables, and fruits and vegetables combined, but not fruits alone, significantly reduce risk of NHL.

Complementary IL-23 and IL-27 anti-tumor activities cause strong inhibition of human follicular and diffuse large B-cell lymphoma growth in vivo.

Interleukin (IL)-23 and IL-27 are pro-inflammatory cytokines that share functional and structural similarities and may exert anti-tumor activities against solid and hematological malignancies. Here, we asked whether IL-23 and IL-27, alone or in combination, may act directly against human follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) cells. In this study, we demonstrated for the first time that human primary FL and DLBCL cells expressed complete and functional IL-23 and IL-27 receptors (R) and that IL-23 and IL-27 exerted anti-tumor activities in vitro and in vivo through different and complementary mechanisms. In vivo studies using severe combined immunodeficiency /non-obese diabetic mice-injected subcutaneously with human SU-DHL-4 cell line revealed that IL-23 inhibited directly tumor-cell proliferation, whereas IL-27 impaired the angiogenic program of lymphoma cells resulting in strong reduction of cell growth. In addition, combined treatment of IL-23 and IL-27 amplified the anti-tumor effects in vivo as compared with administration of each cytokine alone. These anti-tumor mechanisms were confirmed by in vitro experiments performed with primary lymphoma cells and cell lines. Our results strongly encourage the development of future clinical trials to evaluate the toxicity and efficacy of the IL-23 and IL-27 in lymphoma patients.

Follicular lymphoma: 2011 update on diagnosis and management.

DISEASE OVERVIEW: Follicular lymphoma (FL) is generally an indolent B-cell lymphoproliferative disorder of transformed follicular center B cells. FL is characterized by diffuse lymphoadenopathy, bone marrow involvement, splenomegaly, and less commonly other extranodal sites of involvement. In general, cytopenias can occur but constitutional symptoms of fever, nightsweats, and weight loss are uncommon. DIAGNOSIS: Diagnosis is based on histology of preferably biopsy of a lymph node. Immunohistochemical staining is positive in virtually all cases for cell surface CD19, CD20, CD10 and monoclonal immunoglobulin, as well as cytoplasmic expression of bcl-2 protein. The overwhelming majority of cases have the characteristic t(14;18) translocation involving the IgH/bcl-2 genes. RISK STRATIFICATION: The Follicular Lymphoma International Prognostic Index prognostic model for FL uses five independent predictors of inferior survival: age > 60 years, hemoglobin <12 g/dL, serum LDH > normal, Ann Arbor stage III/IV, number of involved nodal areas > 4. The presence of 0-1, 2, and ≥3 adverse factors defines low, intermediate, and high-risk disease with median 10 year survivals in the pre-rituximab era of approximately 71, 51, and 36 months, respectively. With the use of more modern therapies, specifically anti-CD20 monoclonal antibody, the outcome has improved. RISK-ADAPTED THERAPY: Observation continues to be adequate for asymptomatic patients with low bulk disease and no cytopenias. For patients needing therapy, most patients are treated with chemotherapy plus rituximab, which has improved response rates, duration of response, and overall survival. Randomized studies have shown additional benefit for maintenance rituximab both following chemotherapy-rituximab and single agent rituximab. Autologous stem cell transplantation has not shown a survival benefit in first remission patients. Stem cell transplantation (SCT) including both autologous and allogeneic SCT or experimental agent therapy is considered for recurrent disease.

Relapse of leprosy presenting as nodular lymph node swelling.

Lymphadenopathy is known to be associated with lepromatous leprosy and has also been observed as a feature of type-2 lepra reaction. However, nodular lymph node enlargement is not commonly reported in leprosy patients or as a feature of relapse. We herewith are presenting a case of bacteriological relapse in a patient of lepromatous leprosy treated 22 years before till smear negativity with WHO multidrug therapy (MDT) multibacillary type (MB). She presented with prominent nodular swelling of the cervical group of lymph nodes along with generalized lymphadenopathy, which was mistakenly treated as tubercular lymphadenopathy. A diagnosis of late bacteriological relapse of lepromatous leprosy presenting with prominent lymphadenopathy and ENL was made after relevant investigations. The patient was started on treatment with WHO MDT MB (daily dapsone and clofazimine and monthly rifampicin) and thalidomide (200 mg/day). Nerve pain regressed within 2 weeks of therapy. The lymph nodal swelling regressed within 3 months of starting treatment.

Vaccination strategies in follicular lymphoma.

Follicular lymphoma is one of the most immune-responsive cancers. The clonal tumor immunoglobulin expressed on the surface of malignant B cells, termed idiotype, has been used as a tumor-specific antigen in therapeutic vaccination strategies for follicular lymphoma and other B-cell malignancies. A number of phase 1 and phase 2 clinical trials have established the safety and immunogenicity of idiotype vaccine in follicular lymphoma. Three randomized, double-blind, controlled phase 3 clinical trials have recently been completed to definitively evaluate the clinical benefit of idiotype vaccine in follicular lymphoma. This review focuses on the results of these idiotype vaccine trials and discusses potential strategies to enhance the efficacy of vaccines in the future.

Non-Hodgkin lymphoma in women: reproductive factors and exogenous hormone use.

Few studies of reproductive hormone exposures and non-Hodgkin lymphoma (NHL) have examined NHL subtypes. Associations between reproductive hormonal factors and risk of all NHL and of two predominant subtypes, diffuse large-cell lymphoma (DLCL) (n = 233) and follicular lymphoma (n = 173), were investigated among women (n = 581) in a large, population-based, case-control study (1,591 cases, 2,515 controls). Controls (n = 836) identified by random digit dialing were frequency matched by age and county to incident NHL cases ascertained in the San Francisco Bay Area of California in 1988-1993. Adjusted unconditional logistic regression was used to obtain odds ratios. More than four pregnancies indicated a possible lower risk of all NHL (odds ratio (OR) = 0.81, 95% confidence interval (CI): 0.55, 1.2; p-trend = 0.06) and of DLCL (OR = 0.53, 95% CI: 0.31, 0.90; p-trend = 0.01). Exclusive use of menopausal hormone therapy for > or =5 years was associated with a reduced risk of all NHL (OR = 0.68, 95% CI: 0.48, 0.98) and of DLCL (OR = 0.50, 95% CI: 0.30, 0.85). Oral contraceptive use indicated a lower risk of all NHL (OR = 0.68, 95% CI: 0.49, 0.94), and perhaps DLCL (OR = 0.79, 95% CI: 0.51, 1.2), and of follicular lymphoma (OR = 0.75, 95% CI: 0.46, 1.2). Results suggest that endogenous and exogenous reproductive hormones confer different risks by NHL subtype and are associated with a reduced risk of DLCL in women.

The role of idiotype vaccines in the treatment of human B-cell malignancies.

Twelve years after the first formal demonstration that it is possible to vaccinate a cancer patient against an antigen derived from his/her own tumor, idiotype vaccines are now well into Phase III clinical trials for the treatment of follicular lymphoma. Meanwhile, their potential has also begun to be explored in other non-Hodgkin's lymphoma settings, such as that of mantle cell lymphoma. Another well known field of potential application for idiotype vaccines is that of multiple myeloma. However, the currently available results, even with the advent of dendritic cells, seem to be less promising than those obtained in lymphoma, to such an extent that idiotype vaccines are currently tested in multiple myeloma patients in the context of more aggressive therapeutic strategies.