Rapid stimulation of human renal ENaC by cAMP in Xenopus laevis oocytes

Among the compensatory mechanisms restoring circulating blood volume after severe haemorrhage, increased vasopressin secretion enhances water permeability of distal nephron segments and stimulates Na+ reabsorption in cortical collecting tubules via epithelial sodium channels (ENaC). The ability of vasopressin to upregulate ENaC via a cAMP-dependent mechanism in the medium to long term is well established. This study addressed the acute regulatory effect of cAMP on human ENaC (hENaC) and thus the potential role of vasopressin in the initial compensatory responses to haemorrhagic shock. The effects of raising intracellular cAMP (using 5 mmol/L isobutylmethylxanthine (IBMX) and 50 ìmol/L forskolin) on wild-type and Liddle-mutated hENaC activity expressed in Xenopus oocytes and hENaC localisation in oocyte membranes were evaluated by dual-electrode voltage clamping and immunohistochemistry, respectively. After 30 min, IBMX + forskolin had stimulated amiloride-sensitive Na+ current by 52 % and increased the membrane density of Na+ channels in oocytes expressing wild-type hENaC. These responses were prevented by 5 ìmol/L brefeldin A, which blocks antegrade vesicular transport. By contrast, IBMX + forskolin had no effects in oocytes expressing Liddle-mutated hENaC. cAMP stimulated rapid, exocytotic recruitment of wild-type hENaC into Xenopus oocyte membranes, but had no effect on constitutively over-expressed Liddle-mutated hENaC. Extrapolating these findings to the early cAMP-mediated effect of vasopressin on cortical collecting tubule cells, they suggest that vasopressin rapidly mobilises ENaC to the apical membrane of cortical collecting tubule cells, but does not enhance ENaC activity once inserted into the membrane. We speculate that this stimulatory effect on Na+ reabsorption (and hence water absorption) may contribute to the early restoration of extracellular fluid volume following severe haemorrhage (AU)

Rapid stimulation of human renal ENaC by cAMP in Xenopus laevis oocytes.

Among the compensatory mechanisms restoring circulating blood volume after severe haemorrhage, increased vasopressin secretion enhances water permeability of distal nephron segments and stimulates Na(+) reabsorption in cortical collecting tubules via epithelial sodium channels (ENaC). The ability of vasopressin to upregulate ENaC via a cAMP-dependent mechanism in the medium to long term is well established. This study addressed the acute regulatory effect of cAMP on human ENaC (hENaC) and thus the potential role of vasopressin in the initial compensatory responses to haemorrhagic shock. The effects of raising intracellular cAMP (using 5 mmol/L isobutylmethylxanthine (IBMX) and 50 µmol/L forskolin) on wild-type and Liddle-mutated hENaC activity expressed in Xenopus oocytes and hENaC localisation in oocyte membranes were evaluated by dual-electrode voltage clamping and immunohistochemistry, respectively. After 30 min, IBMX + forskolin had stimulated amiloride-sensitive Na(+) current by 52% and increased the membrane density of Na(+) channels in oocytes expressing wild-type hENaC. These responses were prevented by 5 µmol/L brefeldin A, which blocks antegrade vesicular transport. By contrast, IBMX + forskolin had no effects in oocytes expressing Liddle-mutated hENaC. cAMP stimulated rapid, exocytotic recruitment of wild-type hENaC into Xenopus oocyte membranes, but had no effect on constitutively over-expressed Liddle-mutated hENaC. Extrapolating these findings to the early cAMP-mediated effect of vasopressin on cortical collecting tubule cells, they suggest that vasopressin rapidly mobilises ENaC to the apical membrane of cortical collecting tubule cells, but does not enhance ENaC activity once inserted into the membrane. We speculate that this stimulatory effect on Na(+) reabsorption (and hence water absorption) may contribute to the early restoration of extracellular fluid volume following severe haemorrhage.

Differential expression of NF-kappaB target genes in MALT lymphoma with and without chromosome translocation: insights into molecular mechanism.

Mucosa-associated lymphoid tissue (MALT) lymphoma is characterized by t(11;18)(q21;q21)/API2-MALT1, t(1;14)(p22;q32)/BCL10-IGH and t(14;18)(q32;q21)/IGH-MALT1, which commonly activate the nuclear factor (NF)-kappaB pathway. Gastric MALT lymphomas harboring such translocations usually do not respond to Helicobacter pylori eradication, while most of those without translocation can be cured by antibiotics. To understand the molecular mechanism of these different MALT lymphoma subgroups, we performed gene expression profiling analysis of 21 MALT lymphomas (13 translocation-positive, 8 translocation-negative). Gene set enrichment analysis (GSEA) of the NF-kappaB target genes and 4394 additional gene sets covering various cellular pathways, biological processes and molecular functions have shown that translocation-positive MALT lymphomas are characterized by an enhanced expression of NF-kappaB target genes, particularly toll like receptor (TLR)6, chemokine, CC motif, receptor (CCR)2, cluster of differentiation (CD)69 and B-cell CLL/lymphoma (BCL)2, while translocation-negative cases were featured by active inflammatory and immune responses, such as interleukin-8, CD86, CD28 and inducible T-cell costimulator (ICOS). Separate analyses of the genes differentially expressed between translocation-positive and -negative cases and measurement of gene ontology term in these differentially expressed genes by hypergeometric test reinforced the above findings by GSEA. Finally, expression of TLR6, in the presence of TLR2, enhanced both API2-MALT1 and BCL10-mediated NF-kappaB activation in vitro. Our findings provide novel insights into the molecular mechanism of MALT lymphomas with and without translocation, potentially explaining their different clinical behaviors.

Biopsy examination of squamous cell carcinoma of the tongue: source of significant prognostic information?

Histological analysis of tumour resection for squamous cell carcinoma (SCC) of the tongue yields prognostic information. We analysed histological slides of biopsy and tumour resection specimens using an adapted malignancy grading score and analysed variables of neck dissections. There was moderate correlation between biopsy and tumour resection using malignancy grading scores (correlation coefficient 0.45); good agreement of tumour grade (79%), tumour depth (76%), and type of invasive front (80%), but correlation was only fair to moderate (κ=0.38, κ=0.51, and κ=0.41, respectively). Correlation of the biopsy grading score and invaded nodes in the neck, extra capsular spread, and soft tissue disease was not significant.

Aggressive angiomyxoma of larynx: case report and literature review.

OBJECTIVE: We report the second known case of aggressive angiomyxoma of the larynx. METHOD: Case report and a review of the world literature concerning angiomyxoma of the larynx and recent advances in the immunohistochemical, cytogenic and clinical study of its female pelvic counterpart. RESULTS: Aggressive angiomyxoma is a rare mesenchymal tumour originally thought only to occur in the female pelvis and peritoneum, or rarely in the male genital tract. A 47-year-old man presented with a one-month history of dysphonia. He was found to have a supraglottic mass on endoscopic examination, and underwent a laryngofissure approach excision biopsy and covering tracheostomy. Histological analysis showed a characteristic proliferation of spindle cells widely separated by loose, myxoid stroma with a prominent vascular component. Aggressive angiomyxoma was diagnosed. CONCLUSION: To our knowledge, this is the second report in the world literature of aggressive angiomyxoma of the larynx. Comparison with the female pelvic counterpart facilitates diagnosis, aided by recent advances, and suggests that complete surgical excision with a wide margin is the treatment of choice.

Altered cryptal expression of luminal potassium (BK) channels in ulcerative colitis.

Decreased sodium (Na(+)), chloride (Cl(-)), and water absorption, and increased potassium (K(+)) secretion, contribute to the pathogenesis of diarrhoea in ulcerative colitis. The cellular abnormalities underlying decreased Na(+) and Cl(-) absorption are becoming clearer, but the mechanism of increased K(+) secretion is unknown. Human colon is normally a K(+) secretory epithelium, making it likely that K(+) channels are expressed in the luminal (apical) membrane. Based on the assumption that these K(+) channels resembled the high conductance luminal K(+) (BK) channels previously identified in rat colon, we used molecular and patch clamp recording techniques to evaluate BK channel expression in normal and inflamed human colon, and the distribution and characteristics of these channels in normal colon. In normal colon, BK channel alpha-subunit protein was immunolocalized to surface cells and upper crypt cells. By contrast, in ulcerative colitis, although BK channel alpha-subunit protein expression was unchanged in surface cells, it extended along the entire crypt irrespective of whether the disease was active or quiescent. BK channel alpha-subunit protein and mRNA expression (evaluated by western blotting and real-time PCR, respectively) were similar in the normal ascending and sigmoid colon. Of the four possible beta-subunits (beta(1-4)), the beta(1)- and beta(3)-subunits were dominant. Voltage-dependent, barium-inhibitable, luminal K(+) channels with a unitary conductance of 214 pS were identified at low abundance in the luminal membrane of surface cells around the openings of sigmoid colonic crypts. We conclude that increased faecal K(+) losses in ulcerative colitis, and possibly other diseases associated with altered colonic K(+) transport, may reflect wider expression of luminal BK channels along the crypt axis.

Cyclooxygenase-2 expression and its association with increased angiogenesis in human abdominal aortic aneurysms.

Although the mechanism whereby non-steroidal anti-inflammatory drugs may reduce abdominal aortic aneurysm (AAA) development is unknown, one potential route is via inhibition of the cyclooxygenase (COX) enzyme. Despite the fact that evidence from animal models suggests a role for the COX-2 isoform in promotion of AAA development, only very limited data exist on COX-2 expression in human AAAs. Semiquantitative immunohistochemistry for COX-2 was performed on a series of formalin-fixed, paraffin-embedded human AAAs (n = 49). Associated clinicopathological data, including the degree of inflammatory cell infiltration and neorevascularization, were obtained. COX-2 protein was detected in 46 of 49 (94%) human AAAs. Expression of COX-2 protein varied widely between AAAs. COX-2 protein localized to cells in the inflammatory infiltrate with a morphology characteristic of macrophages. COX-2 expression increased with the extent of inflammatory cell infiltration (P < 0.001) and with the degree of AAA neorevascularization (P < 0.001). Logistic regression analysis identified neorevascularization (P < 0.001) as the only significant independent predictor of COX-2 positivity in human AAAs. COX-2 protein is present at increased levels in the majority of human AAAs and is expressed by mononuclear cells in the inflammatory cell infiltrate. Promotion of angiogenesis by COX-2 may play a role in AAA development.

Lymphocyte-rich classical Hodgkin lymphoma (LRCHL): clinico-pathological characteristics and outcome of a rare entity.

BACKGROUND: To investigate the proportion, clinical characteristics and outcome of lymphocyte-rich classical Hodgkin lymphoma (LRCHL) in relation to nodular lymphocyte predominant HL (NLPHL) and classical HL (cHL). PATIENTS AND METHODS: A series of 2743 HL patients of all stages enrolled into three EORTC trials (H7, H8, H34) conducted between 1988 and 2000 and forming an unbiased series of HL patients was studied. RESULTS: Detailed histological classification after panel review was available in 96% of the cases to allow selection of all cases with features potentially compatible with the WHO-definition of LRCHL for this study. Cases with dominance of lymphocytic infiltrate and relative paucity of eosinophils and fibrosis could be selected for re-classification. Twenty-one (0.8%) LRCHL cases were identified of which three were originally classified as NLPHL, seven as nodular sclerosis HL (NSHL) and 11 as mixed cellularity (MCHL), indicating that LRCHL is a rare disease. CONCLUSIONS: Clinical evaluation of the unselected series of patients (n = 2743) showed that LRCHL and NLPHL cases more often presented with favorable features. Clinical outcome adjusted on ab initio patient prognosis did not differ between the three histological entities. These results strongly suggest that LRCHL corresponds to an early stage in the spectrum of cHL rather than a biologically different disease entity.

Enhanced large intestinal potassium permeability in end-stage renal disease.

The capacity of the colon for potassium (K+) secretion increases in end-stage renal disease (ESRD), to the extent that it makes a substantial contribution to K+ homeostasis. This colonic K+ adaptive response may reflect enhanced active K+ secretion, and be associated with an increase in apical membrane K+ permeability. In this study, this hypothesis was tested in patients with normal renal function or ESRD, by evaluating the effect of barium ions (a K+ channel inhibitor) on rectal K+ secretion using a rectal dialysis technique, and the expression of high conductance (BK) K+ channel protein in colonic mucosa by immunohistochemistry. Under basal conditions, rectal K+ secretion was almost threefold greater (p < 0.02) in ESRD patients (n = 8) than in patients with normal renal function (n = 10). Intraluminal barium (5 mmol/l) decreased K+ secretion in the ESRD patients by 45% (p < 0.05), but had no effect on K+ transport in patients with normal renal function. Immunostaining using a specific antibody to the BK channel alpha-subunit revealed greater (p < 0.001) levels of BK channel protein expression in surface colonocytes and crypt cells in ESRD patients (n = 9) than in patients with normal renal function (n = 9), in whom low levels of expression were mainly restricted to surface colonocytes. In conclusion, these results suggest that enhanced colonic K+ secretion in ESRD involves an increase in the apical K+ permeability of the large intestinal epithelium, which most likely reflects increased expression of apical BK channels.

Surgical pathological second opinion in thyroid malignancy: impact on patients' management and prognosis.

OBJECTIVES: To evaluate the effect of inter-institutional surgical pathology review of thyroid cancer on patients' treatment and prognosis. METHODS: All cases referred to the Institute of Pathology at Leeds for thyroid pathology review between January 2001 and March 2003 were included. The referring pathologists reports were compared to those produced in the MDT meeting by the expert pathologist. Whenever there was disagreement a third expert opinion was sought who was blinded for both diagnoses. Effects on management and prognosis were evaluated if there was disagreement. RESULTS: Of the 66 patients reviewed, 12 (18%) had a different pathological diagnosis (kappa=0.33). Two had their diagnosis changed from malignant to benign and a further two from benign to malignant. Eight patients had their prognosis downgraded and four upgraded after histopathological review. Five patients had their management affected by the new pathological diagnosis. CONCLUSION: A second opinion of surgical pathology for thyroid tumours can result in major therapeutic and prognostic modifications. All cases of suspected thyroid cancers should be reviewed in a multidisciplinary meeting supported by pathologist with experience in thyroid pathology.

Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial.

BACKGROUND: Neither chemotherapy with a single-alkylating agent nor aggressive combination chemotherapy cures advanced stage low-grade non-Hodgkin lymphomas, even when combined with radiotherapy. Our aim was to compare administration of immediate chlorambucil treatment with a policy of delaying chlorambucil until clinical progression necessitated its use, in asymptomatic patients with advanced-stage, low-grade non-Hodgkin lymphoma. METHODS: 309 patients with asymptomatic, advanced-stage, low-grade non-Hodgkin lymphomas were recruited from 44 UK centres between Feb 1, 1981, and July 31, 1990. 158 patients were randomised to receive immediate systemic therapy with oral chlorambucil 10 mg per day continuously. The remaining 151 were randomised to an initial policy of observation, with systemic therapy delayed until disease progression. In both groups, local radiotherapy to symptomatic nodes was allowed. FINDINGS: Median length of follow-up was 16 years. Overall survival or cause-specific survival did not differ between the two groups (median overall survival for oral chlorambucil 5.9 [range 0-17.8] years and for observation 6.7 [0.5-18.9] years, p=0.84; median cause-specific survival 9 [0-17.8] years and 9.1 [0.67-18.9] years, respectively p=0.44). In a multivariate analysis, age younger than 60 years, erythrocyte sedimentation rate (ESR) 20 mm/h or less, and stage III disease, conferred significant advantages in both overall survival (p<0.0001, 0.03, and 0.03, respectively) and cause-specific survival (p=0.002, 0.008, and 0.001, respectively). In the observation group, at 10 years' follow-up, 19 patients were alive and had not received chemotherapy. The actuarial chance of not needing chemotherapy (non-lymphoma deaths censored) at 10 years was 19% (40% if older than 70 years). INTERPRETATION: An initial policy of watchful waiting in patients with asymptomatic, advanced stage low-grade non-Hodgkin lymphoma is appropriate, especially in patients older than age 70 years.

Diffuse large B-cell lymphoma: a clinicopathologic analysis of 444 cases classified according to the updated Kiel classification.

The purpose of this study was: to compare the survival of diffuse large B-cell lymphomas (DLBCL) stratified according to the up-dated Kiel classification. A retrospective study of a cohort of 1378 cases was organized in 1996 by the Non-Hodgkin's Lymphoma Classification Project, and the DLBCL were classified according to the updated Kiel classification. The distribution of the different types and subtypes was as follows: centroblastic (CB, 85.4%), composed of the polymorphic (CB-PM, 58.6%), monomorphic (CB-MM, 17.1%) and multilobated (CB-ML, 9.7%) subtypes; immunoblastic (IB, 11.2%), with (8.3%) or without (2.9%) plasmacytoid differentiation; and anaplastic large cell lymphoma (ALCL) of B-cell type (3.4%). The rate of diagnostic agreement between pathologists was 78% for CB and 65% for IB lymphoma. The 5-year overall survival (OAS) for the entire group was 47% and the 5-year failure-free survival (FFS) was 42%. No significant differences in survival were found between the three major groups (CB, IB, ALCL). However, the 5-year OAS and FFS of patients with DLBCL not containing immunoblasts (CB-MM+CB-ML) was 51 and 52%, respectively, and was significantly better than the survival of those containing immunoblasts (CB-PM+IB+ALCL), which was 44 and 38% (p = 0.06 and p = 0.037), respectively. These results did not appear to be due to differences in the clinical features of the two groups, and was most significant for patients with low stage or low risk disease. However, histologic subtyping was not an independent risk factor for the entire group by multivariate analysis. In conclusion, patients with CB-MM and CB-ML (without immunoblasts) had a significantly better OAS and FFS than those with CB-PM, IB and ALCL (with immunoblasts). Therefore, we conclude that additional studies are still needed to further evaluate the importance of immunoblastic differentiation in DLBCL.

Peripheral T-cell lymphoma (excluding anaplastic large-cell lymphoma): results from the Non-Hodgkin's Lymphoma Classification Project.

BACKGROUND: Peripheral T-cell lymphoma (PTCL) is rare in most parts of the world. Therefore, we have evaluated the 96 cases of PTCL diagnosed within the Non-Hodgkin's Lymphoma Classification Project (NHLCP) (1378 cases) for their geographical distribution, pathologic features and diagnostic reliability, as well as clinical presentation and outcome. MATERIALS AND METHODS: Diagnoses of all cases were rendered independently by five experienced hematopathologists based on morphology only, and after introduction of the immunophenotype and clinical data. Divergent diagnoses were jointly discussed and a final consensus diagnosis was established in each case. Reliability of the diagnoses was evaluated statistically, and the clinical features and outcome were analyzed according to the consensus diagnoses. RESULTS: Seven per cent of all non-Hodgkin's lymphoma (NHL) cases reviewed were classified as PTCL and the frequency varied from 1.5% to 18.3% in different countries. The interobserver agreement with the consensus diagnosis of PTCL was 86% in the Revised European-American Lymphoma (REAL) classification, but the designation of subtypes was less reliable. Diagnostic reliability improved from 41% to 86% after immunophenotyping, but did not improve further with the addition of detailed clinical data. Clinically, angiocentric nasal lymphoma presented in young females (median age 49 years) at extranodal sites, but with few adverse risk factors, whereas angioimmunoblastic lymphoma presented most often in older males (median age 65 years) at nodal and extranodal sites with numerous risk factors. The 5-year overall and failure-free survivals for patients with PTCL treated with doxorubicin (Adriamycin)-containing regimens were only 26% and 20%, respectively. Both failure-free and overall survival were strongly correlated with the performance status and International Prognostic Index scores at presentation, but differences in survival were not observed between the major histological types. However, within the PTCL 'not otherwise specified' category, but not angioimmunoblastic lymphoma, the number of transformed blasts was prognostically relevant. CONCLUSIONS: PTCLs can be diagnosed reliably by experienced hematopathologists, but immunophenotyping is absolutely necessary. Currently, all types of PTCL should be considered high-grade lymphomas. An increased ability to distinguish T-lymphocyte subsets is needed in order to better subclassify the PTCLs for therapeutic and prognostic purposes.

BCL10 in malignant lymphomas--an evaluation using fluorescence in situ hybridization.

BCL10 is a tumour suppressor gene originally cloned from a t(1;14)(p22;q32) breakpoint in a case of mucosa-associated lymphoid tissue (MALT) lymphoma. Translocations involving this gene, though uncommon, are sometimes encountered in MALT lymphomas. This gene is thought to play an important role in the development of malignant lymphomas. Fluorescence in situ hybridization (FISH) was therefore undertaken on 22 cases of malignant lymphoma of varying histology to establish the incidence of rearrangements involving the BCL10 gene. Initially, one case with a novel t(1;2)(p22;p12) translocation involving the BCL10 gene was identified, in a marginal zone lymphoma of the MALT type, and was reported elsewhere. Seven other cases were subsequently identified with abnormalities in the 1p region, including a translocation with a breakpoint in the 1p22 region in a case of lymphoblastic lymphoma. However, none of these involved the BCL10 gene. Mutation analysis of BCL10 was then performed on 57 cases of malignant lymphoma, including 17 MALT lymphomas, by single-strand conformational polymorphism (SSCP) analysis of tumour DNA. Tissue was obtained for mutation analysis for 12 of the 22 cases analysed by FISH. Selected cases with SSCP band shifts were further studied by direct sequencing. Polymorphisms were identified in eight cases, but no mutations of pathogenic significance were identified. Further RT-PCR and mutation analysis was performed on cDNAs from 12 cases (four MALT, seven diffuse large B-cell lymphoma, one Hodgkin's disease) in which DNA analysis had already been completed. This included the MALT lymphoma with the t(1;2)(p22;p12) rearrangement. Again, no mutations were identified in the coding sequence. This study confirms that rearrangements of the BCL10 gene are uncommon in lymphoma (1/22) and may be limited tothe MALT subtype of non-Hodgkin's lymphomas. It was also found that breakpoints or rearrangements in the 1p22 region do not necessarily involve the BCL10 gene. Moreover, the absence of mutations at both the DNA (0/60) and the mRNA (0/12) level indicates that this gene is not frequently inactivated by mutation, in those tumours in which it is not involved in translocations. Our findings suggest that the BCL10 gene is unlikely to have a frequent or key role in general lymphomagenesis.

Genetic events during the transformation of a tamoxifen-sensitive human breast cancer cell line into a drug-resistant clone.

Tamoxifen resistance is a serious clinical problem commonly encountered in the management of patients with breast cancer. The mechanisms leading to its development are unclear. Tamoxifen acts via multiple pathways and has diverse effects. Hence transformation from a tamoxifen-sensitive to a resistant phenotype could involve multiple genetic events. Knowledge of the genetic pathways leading to resistance may facilitate the development of novel therapeutic strategies. In this study, a variation of conventional comparative genomic hybridization (CGH) has been employed to detect genetic alterations associated with tamoxifen resistance. MCF-7, a tamoxifen-sensitive human breast cancer cells line, and its tamoxifen-resistant clone, CL-9 were used. Both cell lines showed extensive areas of concordance but consistent differences were seen with the acquisition of tamoxifen resistance. These differences included the amplification of 2p16.3 approximately p23.2, 2q21 approximately q34, 3p12.3 approximately p14.1, 3p22 approximately p26, 3q, 12q13.2 approximately q22, 13q12 approximately q14, 17q21.3 approximately q23, 20q11.2 approximately q13.1 and 21q11.2 approximately q21 as well as the deletion of 6p21.1, 6p23 approximately p25, 7q11.1 approximately q31, 7q35 approximately q36, 11p15, 11q24, 13q33, 17p, 18q12 approximately q21.1, 19p, 19q13.3, 22q13.1 approximately q13.2. These findings were supported by conventional cytogenetics and chromosome painting. The regions identified by CGH potentially harbor genes that could be important in the development of tamoxifen resistance.

Systemic anaplastic large-cell lymphoma: results from the non-Hodgkin's lymphoma classification project.

Anaplastic large-cell lymphoma (ALCL) is a heterogeneous process that may have a T-cell, B-cell, or indeterminant (null) phenotype and which may or may not express the anaplastic lymphoma kinase (ALK) oncoprotein. Because the clinical significance of these variants of ALCL is unclear, we evaluated the cases of ALCL-T/null and ALCL-B identified in the Non-Hodgkin's Lymphoma Classification Project. We evaluated 1,378 cases of non-Hodgkin's lymphoma (NHL), and a consensus diagnosis of ALCL-T/null was made in 33 patients (2.4%) with a diagnostic accuracy of 85%. Compared to 96 patients with other forms of peripheral T-cell lymphoma (PTCL), those with ALCL-T/null were significantly younger, less likely to have advanced-stage disease or bone marrow involvement, more likely to have a low International Prognostic Index score, and had a significantly better survival. Among those with ALCL-T/null, there were no significant differences in the clinical features or survival on the basis of ALK expression. A consensus diagnosis of ALCL-B was made in 15 patients (1.1%), and the diagnostic accuracy was 67%. However, compared to 366 patients with other forms of diffuse large B-cell lymphoma (DLBCL), those with ALCL-B were no different with regard to clinical features or survival. We conclude that patients with ALCL-T/null have favorable prognostic features and excellent survival and should be separated from those with other forms of PTCL for prognostic and therapeutic purposes. In contrast, patients with ALCL-B appear to be similar to those with other forms of DLBCL.

ChlVPP alternating with PABlOE is superior to PABlOE alone in the initial treatment of advanced Hodgkin's disease: results of a British National Lymphoma Investigation/Central Lymphoma Group randomized controlled trial.

The purpose of this randomized trial was to compare the efficacy of 6 cycles of prednisolone, Adriamycin (doxorubicin), bleomycin, vincristine (Oncovin) and etoposide (PABlOE) with 3 cycles of PABIOE that alternate with 3 cycles of chlorambucil, vinblastine, procarbazine and prednisone (ChlVPP) in patients with advanced Hodgkin's disease. Between October 1992 and April 1996, 679 patients were entered onto the study. 41 of these did not match the protocol requirements on review and were excluded from further analysis, most of these being reclassified as NHL on histological review. Of the remaining 638 patients, 319 were allocated to receive PABIOE and 319 were allocated to receive ChlVPP/PABlOE. The complete remission (CR) rates were 78% and 64%, for ChlVPP/PABlOE and PABIOE respectively after initial chemotherapy (P< 0.0001). 124 patients were re-evaluated subsequently following radiotherapy to residual masses. The CR rates changed from 78% to 88% for ChlVPP/PABlOE and from 64% to 77% for PABlOE when re-evaluated in this manner (treatment difference still significant, P = 0.0002). The treatment associated mortality in the PABlOE arm was 2.2% (7 deaths), while there were no such deaths in the ChlVPP/PABlOE arm (P = 0.015). The failure-free survival was significantly greater in the ChlVPP/PABlOE arm (P< 0.0001) as was the overall survival (P = 0.01). The failure-free and overall survival rates at 3 years were 77% and 91% in the ChlVPP/PABlOE arm, compared with 58% and 85% in the PABIOE arm, respectively. These results indicate that ChlVPP alternating with PABIOE is superior to PABIOE alone as initial treatment for advanced Hodgkin's disease.

Novel translocation of the BCL10 gene in a case of mucosa associated lymphoid tissue lymphoma.

Interest has focused on a recently identified gene, BCL10, thought to play an important role in the genesis of extranodal, marginal zone (MALT) lymphomas. This gene belongs to a family containing caspase recruitment domains (CARD), that are involved in the apoptotic pathway. Translocations of the BCL10 gene to the immunoglobulin heavy chain locus at 14q32 have been described. We report herein a case of MALT lymphoma showing t(1; 2)(p22; p12). The translocation was shown to involve the BCL10 gene and the immunoglobulin kappa light chain locus by fluorescence in situ hybridization.