John L. Reagan

Mature Human Langerhans Cells Derived from CD34+ Hematopoietic Progenitors Stimulate Greater Cytolytic T Lymphocyte Activity in the Absence of Bioactive IL-12p70, by Either Single Peptide Presentation or Cross-Priming, Than Do Dermal-Interstitial or Monocyte-Derived Dendritic Cells

The emerging heterogeneity of dendritic cells (DCs) mirrors their increasingly recognized division of labor at myriad control points in innate and acquired cellular immunity. We separately generated blood monocyte-derived DCs (moDCs), as well as Langerhans cells (LCs) and dermal-interstitial DCs (DDC-IDCs) from CD34+ hematopoietic progenitor cells. Differential expression of CD11b, CD52, CD91, and the CD1 isoforms proved useful in distinguishing these three DC types. All mature DCs uniformly expressed comparable levels of HLA-DR, CD83, CD80, and CD86, and were potent stimulators of allogeneic T cells after exposure either to recombinant human CD40L trimer or a combination of inflammatory cytokines with PGE2. moDCs, however, required 0.5–1 log greater numbers than LCs or DDC-IDCs to stimulate comparable T cell proliferation. Only moDCs secreted the bioactive heterodimer IL-12p70, and moDCs phagocytosed significantly more dying tumor cells than did either LCs or DDC-IDCs. LCs nevertheless proved superior to moDCs and DDC-IDCs in stimulating CTL against a recall viral Ag by presenting passively loaded peptide or against tumor Ag by cross-priming autologous CD8+ T cells. LCs also secreted significantly more IL-15 than did either moDCs or DDC-IDCs, which is especially important to the generation of CTL. These findings merit further comparisons in clinical trials designed to determine the physiologic relevance of these distinctions in activity between LCs and other DCs.

Increased incidence of non-Hodgkin lymphoma, leukemia, and myeloma in patients with diabetes mellitus type 2: a meta-analysis of observational studies

Hematologic malignancies are a heterogeneous group of conditions with an unclear etiology. We hypothesized that diabetes mellitus type 2 is associated with increased risk of developing lymphoma, leukemia, and myeloma. A literature search identified 26 studies (13 case-control and 13 cohort studies) evaluating such an association. Outcome was calculated as the odds ratio (OR) using a random effects model. Heterogeneity and publication bias were evaluated using the I(2) index and the trim-and-fill analysis, respectively. Quality was assessed using the Newcastle-Ottawa scale. The OR for non-Hodgkin lymphoma was increased at 1.22 (95% confidence interval [CI], 1.07-1.39; P < .01) but the OR for Hodgkin lymphoma was not. There was an increased OR for peripheral T-cell lymphoma (OR = 2.42, 95% CI, 1.24-4.72; P = .009) but not for other non-Hodgkin lymphoma subtypes. The OR for leukemia was 1.22 (95% CI, 1.03-1.44; P = .02) and the OR for myeloma was 1.22 (95% CI, 0.98-1.53; P = .08). Although diabetes mellitus type 2 seems to increase the risk of developing lymphoma, leukemia, and myeloma, future studies should focus on evaluating other potential confounders such as obesity, dietary habits, physical activity, and/or antidiabetic therapy.

Plasmablastic Lymphoma: A Systematic Review

Plasmablastic lymphoma (PBL) is a very aggressive variant of diffuse large B-cell lymphoma initially described in the oral cavity of HIV-infected individuals. PBL represents a diagnostic challenge given its characteristic morphology and lack of CD20 expression, and also a therapeutic challenge, with early responses to therapy, but with high relapse rates and poor prognosis. In recent years, our understanding and clinical experience with PBL has increased in both HIV-positive and -negative settings. However, given its rarity, most of the data available rely on case reports and case series. The main goal of this article is to systematically review the most recent advances in epidemiology; pathophysiology; clinical, pathologic, and molecular characteristics; therapy; and prognosis in patients with PBL. Specific covered topics include new pathological markers for diagnosis, its association with Epstein-Barr virus, and the need of more intensive therapies.

Obesity but not overweight increases the incidence and mortality of leukemia in adults: A meta-analysis of prospective cohort studies

The main objectives of the present meta-analysis of prospective cohort studies were to evaluate the role of obesity on the incidence and mortality of leukemia in adults. Obesity was associated with a relative risk (RR) of 1.26 (95% CI 1.17-1.37; p < 0.001) for leukemia incidence and 1.29 (95% CI 1.11-1.49; p = 0.001) for mortality. Obesity was also associated with an increased incidence of acute myeloid leukemia (RR 1.53, 95% CI 1.26-1.85; p<0.001), chronic lymphocytic leukemia (RR 1.17, 95% CI 1.08-1.27; p < 0.001), chronic myeloid leukemia (RR 1.16, 95% CI 1.04-1.30; p = 0.007) and acute lymphoblastic leukemia (RR 1.62, 95% CI 1.12-2.32; p = 0.009). The risk of incidence and mortality of leukemia in adults was consistently higher in obese men.

Bortezomib in combination with infusional dose-adjusted EPOCH for the treatment of plasmablastic lymphoma

Plasmablastic lymphoma (PBL) is a rare and aggressive CD20‐negative lymphoma. Despite improvements of the biology behind PBL, it still represents a challenge from the diagnostic and therapeutic perspectives for pathologists and clinicians. PBL is characterized by high rates of relapse and short median survival with standard approaches. Here, we report the use of the combination of bortezomib and infusional etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (V‐EPOCH) in three patients with PBL; two were HIV‐positive and one was HIV‐negative. All three patients obtained a durable complete response to V‐EPOCH with survival times of 24, 18 and 12 months respectively.

Marrow cell genetic phenotype change induced by human lung cancer cells.

Microvesicles have been shown to mediate varieties of intercellular communication. Work in murine species has shown that lung-derived microvesicles can deliver mRNA, transcription factors, and microRNA to marrow cells and alter their phenotype. The present studies evaluated the capacity of excised human lung cancer cells to change the genetic phenotype of human marrow cells. We present the first studies on microvesicle production by excised cancers from human lung and the capacity of these microvesicles to alter the genetic phenotype of normal human marrow cells. We studied 12 cancers involving the lung and assessed nine lung-specific mRNA species (aquaporin, surfactant families, and clara cell-specific protein) in marrow cells exposed to tissue in co-culture, cultured in conditioned media, or exposed to isolated lung cancer-derived microvesicles. We assessed two or seven days of co-culture and marrow which was unseparated, separated by ficoll density gradient centrifugation or ammonium chloride lysis. Under these varying conditions, each cancer derived from lung mediated marrow expression of between one and seven lung-specific genes. Microvesicles were identified in the pellet of ultracentrifuged conditioned media and shown to enter marrow cells and induce lung-specific mRNA expression in marrow. A lung melanoma and a sarcoma also induced lung-specific mRNA in marrow cells. These data indicate that lung cancer cells may alter the genetic phenotype of normal cells and suggest that such perturbations might play a role in tumor progression, tumor recurrence, or metastases. They also suggest that the tissue environment may alter cancer cell gene expression.

Multiple myeloma-induced hyperammonemic encephalopathy: an entity associated with high in-patient mortality.

Hyperammonemia attributed to multiple myeloma (MM) has been rarely reported. We present 6 patients from our institution and 34 from the literature with MM-induced hyperammonemic encephalopathy. The median age was 67 years with male:female ratio of 1.8:1. The median ammonia level was 114 umol/L. IgG and IgA MM was seen in 40% and 35% of cases, respectively. The in-patient mortality was 48%. The in-patient mortality was 31% in patients who received MM-directed therapy and 100% in those who did not received MM-directed therapy. Hyperammonemic encephalopathy is a rare complication in MM and is associated with high in-patient mortality.

Cellular immunotherapy for refractory hematological malignancies

BackgroundAcute myeloid leukemia (AML) and other aggressive refractory hematological malignancies unresponsive to upfront therapy remain difficult conditions to treat. Often, the focus of therapy is centered on achieving complete remission of disease in order to proceed with a consolidative stem cell transplant. At issue with this paradigm is the multitude of patients who are unable to achieve complete remission with standard chemotherapeutic options. A major benefit of transplantation is the graft versus tumor effect that follows successful engraftment. However, with this graft versus tumor effect comes the risk of graft versus host disease. Therefore, alternative treatment options that utilize immunotherapy while minimizing toxicity are warranted. Herein, we propose a novel treatment protocol in which haploidentical peripheral blood stem cells are infused into patients with refractory hematological malignancies. The end goal of cellular therapy is not engraftment but instead is the purposeful rejection of donor cells so as to elicit a potent immune reaction that appears to break host tumor tolerance.Methods/designThe trial is a FDA and institutional Rhode Island Hospital/The Miriam Hospital IRB approved Phase I/II study to determine the efficacy and safety of haploidentical peripheral blood cell infusions into patients with refractory hematological malignancies. The primary objective is the overall response rate while secondary objectives will assess the degree and duration of response as well as safety considerations. Patients with refractory acute leukemias and aggressive lymphomas over the age of 18 are eligible. Donors will be selected amongst family members. Full HLA typing of patients and donors will occur as will chimerism assessments. 1-2x108 CD3+ cells/kilogram will be infused on Day 0 without preconditioning. Patients will be monitored for their response to therapy, in particular for the development of a cytokine release syndrome (CRS) that has been previously described. Blood samples will be taken at the onset, during, and following the cessation of CRS so as to study effector cells, cytokine/chemokine release patterns, and extracellular vesicle populations. Initially, six patients will be enrolled on study to determine safety. Provided the treatment is deemed safe, a total of 25 patients will be enrolled to determine efficacy.DiscussionCellular Immunotherapy for Refractory Hematological Malignancies provides a novel treatment for patients with relapsed/refractory acute leukemia or aggressive lymphoma. We believe this therapy offers the immunological benefit of bone marrow transplantation without the deleterious effects of myeloablative conditioning regimens and minus the risk of GVHD. Laboratory correlative studies will be performed in conjunction with the clinical trial to determine the underlying mechanism of action. This provides a true bench to bedside approach that should serve to further enrich knowledge of host tumor tolerance and mechanisms by which this may be overcome.Trial registrationNCT01685606.

Obesity Is Associated With Increased Relative Risk of Diffuse Large B-Cell Lymphoma: A Meta-Analysis of Observational Studies

BACKGROUND The relation between body mass index (BMI) and incidence of diffuse large B-cell lymphoma (DLBCL) has been suggested, but no systematic review has been undertaken. MATERIAL AND METHODS We performed a literature search through December 2012. Meta-analyses were performed to quantify the relative risk (RR) of DLBCL incidence in overweight and obese persons compared with normal weight individuals using the random-effects model. Subset analyses were performed according to study design, sex, and geographic region. Overweight was defined as a BMI 25 to 29.9 kg/m(2), and obesity was defined as a BMI of 30 kg/m(2). Meta-regression, using an unrestricted maximum likelihood model, was performed to evaluate the linear association between BMI and odds of DLBCL. RESULTS Our study included 6 case-control and 10 cohort studies. The RR of DLBCL in overweight individuals was 1.14 (95% confidence interval [CI], 1.04-1.24; P = .004), and in obese individuals, RR was 1.29 (95% CI, 1.16-1.43; P < .001). The RR of DLBCL in overweight men and women was 1.22 and 1.27, respectively. In overweight individuals, both prospective and case-control studies showed an RR of 1.13. The RR of DLBCL in obese men and women was 1.40 and 1.34, respectively. In obese individuals, the RR in prospective studies was 1.25 and in case-control studies it was 1.33. Meta-regression analysis showed a 14% increase in DLBCL incidence for each 10 kg/m(2) increase in BMI. CONCLUSION An increased BMI is associated with higher RR of DLBCL regardless of sex. Also, there seems to be a linear association between BMI and DLBCL incidence.

Viral lymphomagenesis: from pathophysiology to the rationale for novel therapies

The association between viruses and lymphomas has long been recognized; however, the pathophysiological phenomena behind this relationship are unclear, and have been the object of intense research. Although our understanding of such mechanisms is slowly improving, much is still left to learn. With the recent advances in cancer biology, a diversity of biological pathways and novel targets and agents have been described in patients with haematological malignancies and successfully put into clinical practice. Clear examples are rituximab and brentuximab vedotin in patients with B cell lymphomas and Hodgkin lymphoma respectively. The main purpose of this review is not only to succinctly summarize what we know regarding the pathogenesis and pathophysiology of virally induced lymphomas and to describe the current practices in terms of diagnosis of treatment of such lymphomas, but also to provide a scientific rationale for the use of novel therapies that are likely to improve the outcomes of patients with these conditions.