Incidence of novel N-glycosylation sites in the B-cell receptor of lymphomas associated with immunodeficiency

Novel N-glycosylation sites are introduced by somatic mutation into the V genes of the majority of follicular lymphomas. Sites are positively selected and rare in normal memory B cells, indicating a potential role in tumour survival in the germinal centre (GC). The incidence of c. 40% in diffuse large B-cell lymphomas (DLBCL) parallels the known heterogeneity of the disease. Immunodeficiency-related non-Hodgkin's lymphomas (NHL) include post-transplant lymphoproliferative disorders (PTLD) and acquired immunodeficiency syndrome-related NHL (AIDS-NHL). Most PTLD derive from B cells that carry mutated VH genes and that have completed the GC reaction. All AIDS-NHL carry mutated VH genes and variable features of GC or post-GC cells. To determine if N-glycosylation is a feature of immunodeficiency-related lymphomas, we analysed the VH genes of 19 PTLD and 36 AIDS-NHL. Novel sites were rare in PTLD (4/19), similar to memory B cells (P = 0.15). AIDS-NHL, including DLBCL and Burkitt's lymphomas (BL), showed heterogeneity with 16 of 36 (44%) having novel sites. The findings indicate no selection of N-glycosylation sites in PTLD, consistent with post-GC features. The variable incidence of N-glycosylation sites in AIDS-NHL mirrors that in DLBCL and sporadic BL of immunocompetent hosts, supporting the known heterogeneity of these disorders, and possibly pointing to distinct routes of tumour development.     

The use of molecular assays in the management of viral hepatitis

Molecular assays are instrumental in the clinical management of viral hepatitis. During the past years, a wide variety of molecular assays have been developed and implemented. This considerably improved the understanding of the natural history and pathogenesis of Hepatitis B virus (HBV), Hepatitis C virus (HCV) or Hepatitis delta virus (HDV) hepatitis, but also caused uncertainties in the selection of the most appropriate assays for clinical requirements. Indeed, a rational choice and application of these assays requires adequate knowledge of the performance of the single test. Moreover, the choice of the most accurate assay for patients’ needs and physicians’ objectives, needs to be oriented to specific contexts, such as diagnosis, management or treatment. In the past, a hurdle in the routine use of assays for hepatitis viruses nucleic acid quantification was represented by the availability of only “home brew” methods which lacked standardization. Major improvement in addressing the use of molecular assays for viral hepatitis has been derived from recent standardization procedures that allowed a comparison between different tests after results were given as International Units. In addition, it should be reminded that, before getting into the market, molecular assays should be approved by European regulation authorities and validated using internationally recognized standards. A subsequent clinical validation should address the diagnostic accuracy of the assay. These proceedings have the aim of identifying which molecular tests, among those currently available, meet clinical requirements for each specific application.     

Weekly administration of 2-chlorodeoxyadenosine in patients with hairy-cell leukemia is effective and reduces infectious complications

BACKGROUND AND OBJECTIVE: It has been widely demonstrated that one single 7-day course continuous infusion (c.i.) 2-chlorodeoxyadenosine (2-CdA) at a dose of 0.1 mg/kg daily is dramatically effective in inducing high and prolonged complete remission (CR) rates in patients with hairy-cell leukemia (HCL). However, 2-CdA administration often results in severe neutropenia and lymphocytopenia both responsible for the infectious complications observed in these patients. We previously reported preliminary data regarding the effectiveness and toxicity of a modified protocol of 2-CdA administration (0.15 mg/kg 2 hours infusion once a week for 6 courses) in 25 HCL patients. This treatment schedule produced a similar overall response rate compared to standard 2-CdA regimen and appeared to be followed by a lower incidence of infectious episodes. In the present study we report response rate and toxicity of weekly 2CdA administration in a larger cohort of patients and with a longer follow-up. DESIGN AND METHODS: In a group of HCL patients with a pronounced decrease in neutrophils count (< 1 x 10(9)/L), we modified the standard protocol (0.1 mg/kg daily x 7 days c.i.) by administering 2-CdA at a dose of 0.15 mg/kg 2 hours infusion once a week for 6 courses. Thirty HCL patients, 24 males and 6 females with a median age of 56 years (range 37-76), entered into this protocol. Seventeen out of 30 patients were at diagnosis while the remaining 13 had been previously treated with alpha-interferon (alpha-IFN) (7), or 2-CdA (4) or deoxycoformycin (DCF) (2). RESULTS: Overall, 22/30 (73%) patients achieved CR and 8 (27%) partial remission (PR) with a median duration of response at the time of writing of 35 months, ranging from 6 to 58 months. Five patients (1 CR and 4 PR) have so far progressed. The treatment was very well tolerated. Five out of 30 patients (16%) developed severe neutropenia (neutrophils < 0.5 x 10(9)/L) and only in two of them we did register an infectious complication which required treatment with systemic antibiotics and granulocyte colony-stimulating factor (G-CSF). INTERPRETATION AND CONCLUSIONS: In conclusion, we confirm that weekly administration of 2-CdA at a dose of 0.15 mg/kg for 6 courses appears to be very effective in HCL inducing a high CR rate, similar to that observed with daily c.i. administration. CR durability and relapse/progression rates are also comparable to standard 2-CdA schedule. Moreover this new regimen seems to be safer in pancytopenic patients, markedly reducing life-threatening infectious complications.     

Analysis of T-cell receptor beta chain (T beta) gene rearrangements demonstrates the monoclonal nature of T-cell chronic lymphoproliferative disorders

We investigated the rearrangement patterns of the gene coding for the beta chain of the T cell receptor (T beta) in 11 patients with T-cell derived chronic lymphoproliferative disorders, including T-cell prolymphocytic leukemia (T-PLL) and T-cell chronic lymphocytic leukemia (T-CLL). We found that all five cases of T-PLL, and five of six cases of T-CLL, displayed T beta-gene rearrangements, clearly establishing their monoclonal nature. Clonality could not be determined in one case of T-CLL where the T beta gene was found unrearranged. Our results demonstrate that the majority of cases of both clinically aggressive T- PLL and clinically indolent T-CLL are monoclonal. These results suggest that the analysis of T beta gene rearrangements represents a valid tool for the differential diagnosis and clinical monitoring of T-cell derived chronic lymphoproliferative diseases.     

A phase III comparative trial of m-BACOD vs m-BNCOD in the treatment of stage II-IV diffuse non-Hodgkin's lymphomas

From September, 1984 to July, 1986 seventy previously untreated adult patients with advanced non-Hodgkin's lymphoma of intermediate or high grade histology were enrolled in an open phase III multicenter, comparative chemotherapeutic trial. The objectives were to compare, by means of response rate, duration of response and survival time, the efficacy and safety of substituting mitoxantrone for doxorubicin in the combination chemotherapy regimen m-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine and dexamethasone). Thirty-five patients were randomly assigned to receive m-B-NOVANTRONE TM (mitoxantrone)-COD (m-BNCOD) and 35 m-B-ADRIAMYCIN TM (doxorubicin)-COD. The complete response rate was 57% for both treatment groups, and no significant disease-free survival and survival differences were found between the two groups of patients. Patients treated with m-BACOD experienced severe alopecia more frequently (p less than 0.001) and, after 10 cycles, six adverse cardiac event of WHO grade greater than 1, as opposed to none among those who received m-BNCOD. The mitoxantrone-containing regimen (m-BNCOD) has equivalent efficacy and reduced toxicity compared to the standard doxorubicin-containing regimen (m-BACOD) in patients with poor prognosis NHL.     

Helicobacter pylori infection in dyspeptic cirrhotic patients

BACKGROUND/AIMS: To date, few studies have focused on the role of Helicobacter pylori (H. pylori) in cirrhotic patients with gastroduodenal disease and reported results are conflicting. The aim of this study was to assess the H. pylori infection rate in dyspeptic cirrhotic patients with or without gastroduodenal lesions at endoscopy. METHODOLOGY: In a prospective study, 226 consecutive dyspeptic cirrhotic patients were enrolled in the study upon assessment of H. pylori infection. Two-hundred dyspeptic non-cirrhotic patients were also included as controls. The presence of H. pylori was detected by rapid urease test and histology (Giemsa staining) in 3 biopsy specimens from the antrum and 3 from the gastric body. RESULTS: H. pylori infection was found in 135 (59.7%) cirrhotics and in 121 (60.5%) controls (p = NS). The prevalence of gastric ulcer was higher in cirrhotics than in controls (16% vs. 2.5%, p = 0.0001), while the prevalence of duodenal ulcer was similar (11% vs. 12%, respectively). The H. pylori infection rate was similar between cirrhotics and controls, both with gastric (83% vs. 80%) and with duodenal (88% vs. 96%) ulcers. Moreover, in our study, a H. pylori-related peptic lesion was the cause of previous gastroduodenal bleeding in 6 of 50 (12%) cirrhotic patients. CONCLUSIONS: Our results indicated that H. pylori infection is implicated in the pathogenesis of peptic ulcer in cirrhotic patients, similar to findings in non-cirrhotic patients.     

Reduced natural killer T-cells in B-cell chronic lymphocytic leukaemia identified by three monoclonal antibodies: Leu-11, A10, AB8.28

The proportion of E-rosette positive T-lymphocytes capable of reacting with three monoclonal antibodies (MoAbs)--Leu-11, A10, AB8.28--which appear to recognize specifically natural killer (NK) cells, was assessed in a series of untreated patients with B-cell chronic lymphocytic leukaemia (B-CLL). Irrespective of the clinical stage of the disease, the capacity of B-CLL T-lymphocytes to react with all three MoAbs was significantly reduced compared with that of normal circulating T-cells (Leu-11: 2.5% +/- 1.9 SD; A10: 2.3% +/- 1.3; AB8.28: 7% +/- 6.6 v Leu-11: 13.5% +/- 4.5; A10: 8.5% +/- 4.6; AB8.28: 12% +/- 5.5). Furthermore, a marked difference was demonstrated between the reactivity with the Leu-11, A10, AB8.28 MoAbs and the proportion of Leu-7 positive T-cells, which in B-CLL is significantly higher than in normal blood (23% +/- 12.1 v 11.9% +/- 5.9). These findings are in agreement with previous evidence of a discrepancy in B-CLL between the phenotypic expression, assessed by Leu-7 positivity, and the true functional activity of NK T-cells, and suggest that the Leu-11, A10 and AB8.28 MoAbs correlate well with the depressed NK function found in this disease.     

Disaster triage after the Haitian earthquake

In the aftermath of the devastating Haitian earthquake, we became the primary relief service for a large group of severely injured earthquake victims. Finding ourselves virtually isolated with extremely limited facilities and a group of critically injured patients whose needs vastly outstripped the available resources we employed a disaster triage system to organize their clinical care. This report describes the specific injury profile of this group of patients, their clinical course, and the management philosophy that we employed. It provides useful lessons for similar situations in the future.