Role of redox-activated DNA damage response in the regulation of drug-induced NKG2D and DNAM-1 ligand expression on human senescent multiple myeloma cells

Increasing evidence indicate that stimulation of the host immune response represents a promising therapeutic approach against cancer. Multiple Myeloma (MM) is a debilitating malignancy in which abnormal plasma cells (PCs) accumulate in the bone marrow, and a number of evidence showed that MM cells are potential targets of Natural Killer (NK) cell killing. The expression of NK cell activating DNAM-1 and NKG2D ligands on multiple myeloma cells has been described, and although the regulation of NKG2D ligands is not completely understood, increasing evidence demonstrate that cellular stress and induction of DNA damage response can up-regulate their expression. Little information is available about the mechanisms controlling DNAM-1 ligand regulation. In this study, we show that myeloma cells treated with low doses of therapeutic agents commonly used in the management of patients with MM, such as doxorubicin, melphalan, and bortezomib, up-regulate DNAM-1 and NKG2D ligands. Accordingly, therapeutic drug treatment of MM cells increases NK-cell degranulation, being the NKG2D and DNAM-1 receptors the major triggering molecules. Similar data were also obtained using ex vivo primary PCs derived from MM patients. We demonstrated that drug-induced NKG2D and DNAM-1 ligand up-regulation was triggered by the DNA damage response pathway and, in particular, ATM/ATR and Chk1/2 have a key role. By contrast, p53 phosphorylation is induced by chemotherapeutic treatments but is not involved in ligand up-regulation. We showed that low doses of genotoxic agents lead MM cells to enter in a premature senescence, characterized by a G2M phase-arrested cell cycle, and that NKG2D and DNAM-1 ligand up-regulation occurs preferentially on senescent cells. Moreover, our experiments demonstrated a role for the Reactive Oxygen Species (ROS) in drug-induced DNA damage response activation and subsequent ligand up-regulation and senescent phenotype. Altogether, our findings have identified a common pathway that can trigger the up-regulation of different NK cell-activating ligands and suggest that NK cells represent an immunosurveillance mechanism toward cells undergoing stress-induced senescent programs

How I diagnose and treat splenic lymphomas.

The incidental finding of an isolated splenomegaly during clinical assessment of patients evaluated for unrelated causes has become increasingly frequent because of the widespread use of imaging. Therefore, the challenging approach to the differential diagnosis of spleen disorders has emerged as a rather common issue of clinical practice. A true diagnostic dilemma hides in distinguishing pathologic conditions primarily involving the spleen from those in which splenomegaly presents as an epiphenomenon of hepatic or systemic diseases. Among the causes of isolated splenomegaly, lymphoid malignancies account for a relevant, yet probably underestimated, number of cases. Splenic lymphomas constitute a wide and heterogeneous array of diseases, whose clinical behavior spans from indolent to highly aggressive. Such a clinical heterogeneity is paralleled by the high degree of biologic variation in the lymphoid populations from which they originate. Nevertheless, the presenting clinical, laboratory, and pathologic features of these diseases often display significant overlaps. In this manuscript, we present our approach to the diagnosis and treatment of these rare lymphomas, whose complexity has been so far determined by the lack of prospectively validated prognostic systems, treatment strategies, and response criteria

Pseudotemporal ordering of spatial lymphoid tissue microenvironment profiles trails Unclassified DLBCL at the periphery of the follicle

: We have established a pseudotemporal ordering for the transcriptional signatures of distinct microregions within reactive lymphoid tissues, namely germinal center dark zones (DZ), germinal center light zones (LZ), and peri-follicular areas (Peri). By utilizing this pseudotime trajectory derived from the functional microenvironments of DZ, LZ, and Peri, we have ordered the transcriptomes of Diffuse Large B-cell Lymphoma cases. The apex of the resulting pseudotemporal trajectory, which is characterized by enrichment of molecular programs fronted by TNFR signaling and inhibitory immune checkpoint overexpression, intercepts a discrete peri-follicular biology. This observation is associated with DLBCL cases that are enriched in the Unclassified/type-3 COO category, raising questions about the potential extra-GC microenvironment imprint of this peculiar group of cases. This report offers a thought-provoking perspective on the relationship between transcriptional profiling of functional lymphoid tissue microenvironments and the evolving concept of the cell of origin in Diffuse Large B-cell Lymphomas

Prevalence of Salmonellae, Listeriae, and Yersiniae in the Slaughterhouse Environment and on Work Surfaces, Equipment, and Workers

In 1995 and 1996 a nine-month study was carried out in 11 pig abattoirs located in the Molise region (Italy) to evaluate the degree of contamination of- the slaughterhouse environment, work surfaces, equipment, and personnel by Salmonella spp., Listeria spp., and Yersinia spp. A total of 219 samples were taken over three replications including slaughtering floor and wall, hooks, work-tables, chopping blocks, knives, cleavers, dehairing devices, hands of personnel, clothing, hand-wash basins, and cold room handles, floor, wall, and hooks. Overall, six abattoirs (54.5%) had one or more positive sites, while only 14 of the 219 sites (6.4%) tested were positive for any of considered microorganisms. Salmonella spp. were isolated from 1 of 9 cleavers (11.1 %), 1 of 16 worktables (6.25%), and 1 of 18 slaughtering floors (5.6%). Yersinia enterocolitica was found on 3 slaughtering floors (16.7%) and on 2 worktables (12.5%). Yersinia kristensenii was detected on 2 slaughtering floor swabs (11.1 %). Listeria monocytogenes was isolated from 2 of 20 cold room floor swabs (13.3%) and from 1 of 14 hand-wash basins (7.1%). Other species of Listeria were detected on slaughtering wall and floor swabs and on chopping blocks. Our study indicates that slaughtering floors, cold room floors, and worktables are important sites in abattoirs that may possibly harbor pathogens like Salmonella spp., Yersinia enterocolitica , and Listeria monocytogenes , and that cleaning and sanitizing of the slaughterhouse environment and equipment need a greater emphasis

Pseudotemporal ordering of spatial lymphoid tissue microenvironment profiles trails Unclassified DLBCL at the periphery of the follicle

We have established a pseudotemporal ordering for the transcriptional signatures of distinct microregions within reactive lymphoid tissues, namely germinal center dark zones (DZ), germinal center light zones (LZ), and peri-follicular areas (Peri). By utilizing this pseudotime trajectory derived from the functional microenvironments of DZ, LZ, and Peri, we have ordered the transcriptomes of Diffuse Large B-cell Lymphoma cases. The apex of the resulting pseudotemporal trajectory, which is characterized by enrichment of molecular programs fronted by TNFR signaling and inhibitory immune checkpoint overexpression, intercepts a discrete peri-follicular biology. This observation is associated with DLBCL cases that are enriched in the Unclassified/type-3 COO category, raising questions about the potential extra-GC microenvironment imprint of this peculiar group of cases. This report offers a thought-provoking perspective on the relationship between transcriptional profiling of functional lymphoid tissue microenvironments and the evolving concept of the cell of origin in Diffuse Large B-cell Lymphomas

Weekly administration of vincristine, cyclophosphamide, mitoxantrone and bleomycin (VEMB) in the treatment of elderly aggressive non Hodgkin's lymphoma

Background and Objective. Aim of the study was to assess the efficacy of VEMB, a short-lasting therapeutic regimen (50 days) which alternates two myelotoxic drugs (cyclophosphamide and mitoxantrone) every week with two less hematologically toxic drugs (vincristine and bleomycin) in the treatment of aggressive NHL in the elderly (over 70). Design and Methods. Between November 1994 and March 1996, 37 patients aged more than 70 years, with highly or moderately malignant NHL (according to the Working Formulation) have been enrolled into the study. The stage of the disease ranged between II and IV according to Ann Arbor. Mean age was 77 years; 14 patients (38%) had stage IV; 19 patients (51%) had LDH higher than normal; 26 patients (70%) had extranodal and 9 patients (24%) had bulky disease at time of diagnosis. Results. Sixty-two percent of patients achieved a complete and 22% a partial remission. Non-responders amounted to 5%. Four patients (11%) died during the therapy; Nine patients (24%) experienced grade III-IV neutropenia. The most frequently observed event was mild neurotoxicity (43% of cases). The overall survival rate at 30 months was 55%. DFS at 24 months was 66%. Interpretation and Conclusions. VEMB is a therapeutic regimen whose efficacy is comparable to that of the other derived MACOP-B therapeutic regimens used in the elderly NHL. It has proved to have a good feasibility, though the number of toxic deaths should not be neglected

Hodgkin's disease presenting below the diaphragm. The experience of the Gruppo Italiano Studio Linfomi (GISL)

Background and Objective. Infradiaphragmatic Hodgkin\ub4s disease is rare, making up 5-12% of cases in clinical stages I and II; consequently, several questions concerning prognosis and treatment strategy remain to be answered. The aim of this study was to analyze the clinical and prognostic characteristics and outcome of his condition. Methods. A series of 282 patients with CS I-II Hodgkin\ub4s disease (HD) was investigated. In 31 patients the disease was confined below the diaphragm (BDHD), and in the remaining above the diaphragm (ADHD). The presenting features and outcomes were compared in the two groups. Results. The BDHD group was older (p < 0.0002), had a higher frequency of males (p < 0.08) and a different histological subtype group distribution (p < 0.0001). Stage II BDHD patients had a worse overall survival rate (OS) than stage II ADHD patients (68.8% vs 86.6% at 8 years, p < 0.01) if age is not considered; patients with more than 40 years of age, in fact, had the same survival rates as those with ADHD. BDHD patients with intra-abdominal disease alone had worse prognostic factors and OS (p = 0.12) than patients with inguinal-femoral nodes. Interpretation and Conclusions. Although BDHD patients present distinct features, they have the same OS and relapse-free survival rate as age-adjusted ADHD patients. According to our experience patients with stage I peripheral BDHD respond well to radiotherapy-based regimens. Those with stage II and or intra-abdominal disease are more challenging; chemotherapy or a combined therapy seem to be more suitable approaches for these patients

Long-term results from MOPPEBVCAD chemotherapy with optional limited radiotherapy in advanced Hodgkin's disease

The purpose was to verify the 5-year results of the MOPPEBVCAD chemotherapy regimen with limited radiotherapy in relation to the promising preliminary data. Mechlorethamine, vincristine, procarbazine, prednisone, epidoxorubicin, bleomycin, vinblastine, lomustine, melphalan, and vindesine were delivered according to a schedule derived through hybridization, intensification, and shortening of the corresponding alternating CAD/MOPP/ABV regimen. Radiotherapy was restricted to sites of bulky involvement or to areas that responded incompletely to chemotherapy. This multicenter, controlled, nonrandomized trial involved 145 eligible patients. Radiotherapy was administered to 47 patients, 46 of whom were in complete remission after chemotherapy. Remissions were complete in 137 patients (94%), partial in 4 (3%), and null in the remaining 4. Tumor-specific, overall, relapse-free, and failure-free survival at 5 years were 0.89, 0.86, 0.82, and 0.78, respectively. Hematologic toxicity was considerable, whereas nonhematologic side effects were fully acceptable. Most of the unfavorable prognostic factors lost their clinical weight. Only age and lymphocyte depletion histologic type were statistically correlated with major follow up endpoints; performance status and bone marrow involvement were subordinate to age. Seven patients developed a second cancer (including 3 myelodysplasias). MOPPEBVCAD with selected radiotherapy is a highly effective regimen in advanced Hodgkin\ub4s disease. Early and late toxicity are no more severe than what would be expected with other alternating or hybrid regimens. A comparison with ABVD, which is currently considered the standard regimen for advanced Hodgkin\ub4s disease, is needed