BCL10 mutation does not represent an important pathogenic mechanism in gastric MALT-type lymphoma, and the presence of the API2-MLT fusion is associated with aberrant nuclear BCL10 expression

Two recurrent translocations have been associated with mucosa-associated lymphoid tissue (MALT)-type lymphoma, t(11;18)(q21;q21) and t(1;14)(p22;q32). The first, t(11;18)(q21;q21), results in the fusion protein API2-MLT (API2-MALT1). Through t(1;14)(p22;q32), the BCL10 gene is entirely transferred to the IgH gene, resulting in its overexpression. Wild-type BCL10 is implicated in apoptosis, and it has been suggested that mutated forms gain oncogenic activity. The occurrence of genomic BCL10 mutations in 35 gastric MALT-type lymphomas with or without t(11;18)(q21;q21) (10 and 25 cases, respectively) was investigated. DNA extracted from either whole tissue sections or microdissected clusters of tumor cells was used. Five polymerase chain reactions amplifying the coding exons were performed and were followed by direct sequencing of the products. Twenty differences with the published BCL10 sequence, all single nucleotide substitutions, were detected in 16 cases. Of these, 12 represented known polymorphisms, either at codon 8, 213, or 5. Of the remaining 8 substitutions, 2 were silent and 6 resulted in amino acid substitutions. Mutation analysis results were correlated with the BCL10 expression pattern. Aberrant nuclear BCL10 expression was detected in 14 cases. No association could be demonstrated between the latter and the presence of BCL10 mutations. In contrast, all 10 cases carrying t(11;18)(q21;q21) showed nuclear expression, whereas this staining pattern was absent in 21 of 25 cases without t(11;18)(q21;q21). These results demonstrate that BCL10 mutations are rare in gastric MALT-type lymphoma and are not related to the aberrant nuclear expression of BCL10. In contrast, they indicate that the presence of the API2-MLT fusion protein is associated with aberrant nuclear BCL10 expression.     

Evaluation of in vivo endoscopic autofluorescence spectroscopy in gastric cancer

BACKGROUND: The aim of this study was to evaluate light-induced autofluorescence spectroscopy for the in vivo diagnosis of gastric cancer. METHODS: A total of 344 endogenous fluorescence spectra were obtained from normal (164) and cancerous gastric mucosa (180) in 15 patients with pure adenocarcinoma and in 16 patients with gastric cancer containing signet-ring cells. A special light source capable of delivering either white or violet-blue light for the excitation of tissue autofluorescence via the endoscope was used. Endogenous fluorescence spectra emitted by the tissue were collected with a fiberoptic probe and analyzed with a spectrograph. RESULTS: Gastric adenocarcinoma exhibits specific changes in the emitted fluorescence spectra as compared with normal gastric mucosa. By algorithmic classification of the spectra, a sensitivity of 84%, specificity of 87%, a likelihood ratio for a positive test of 6.5 and for a negative test of 0.18 were obtained for the diagnosis of pure adenocarcinoma of the stomach. However, gastric cancer with signet-ring cells exhibits great variation in emitted autofluorescence spectra as compared with normal mucosa. The sensitivity for the diagnosis of all carcinomas containing signet-ring cells was 55%, specificity 85%, the likelihood ratio for a positive test was 3.7 and for a negative test, 0.53. The diagnostic value decreases with increasing numbers of signet-ring cells and tumor grade. CONCLUSIONS: Light-induced autofluorescence spectroscopy is a new and promising bio-optical technique for the endoscopic in vivo diagnosis of gastric adenocarcinoma. The poor diagnostic accuracy for signet-ring cell carcinoma may be explained by the diffuse and frequent submucosal growth of this tumor and the presence of collagen fibers.     

Determinants and consequences of atrial fibrosis in patients undergoing open heart surgery

OBJECTIVE: Atrial fibrillation (AF) is a frequent complication following open-heart surgery (OHS). Increased atrial fibrosis may indicate the presence of an intrinsic arrhythmogenic substrate. The aim of this prospective study was to determine whether atrial fibrosis is associated with increased prevalence of AF after OHS. METHODS: Right atrial appendages were obtained from 259 patients undergoing OHS; none of the patients had a history of AF. Atrial fibrosis was quantitatively analyzed with point counting. All patients were followed prospectively until hospital discharge. None of the patients received anti-arrhythmic prophylaxis. Post-operative AF was defined as an episode of AF lasting > or = 5 min. RESULTS: Quantitation of atrial fibrosis yielded a mean volume percentage of 15.8 +/- 4.3% (V%; range 4.6-32.4%). Patient age was found to correlate with the amount of atrial fibrosis (r = 0.165; P < 0.01) and surface P-wave duration (r = 0.249; P < 0.01). The degree of fibrosis combined with P-wave duration predicted post-operative AF (P < 0.01). Age (> 60 years) and P-wave duration (> or = 100 ms) were independent predictors of post-operative AF (age: relative risk 2.20; P-wave: relative risk 2.69; P < 0.05). The patients were divided into three groups: group 1, V% = 4.6-13.8%; group 2, V% = 13.9-23.1%; group 3, V% = 23.2-32.4%. A total of 52 patients (20.1%) developed AF, which occurred least commonly in group 1 (16.3%) and group 2 (21.2%) as compared with group 3 (33.3%). CONCLUSIONS: Atrial fibrosis provides a pathophysiological substrate for post-operative AF. The results support the importance of P-wave duration as a predictor of post-operative AF, and explain the increased prevalence of AF in elderly patients after OHS.     

Induction of aneuploidy by increasing chromosomal instability during dedifferentiation of hepatocellular carcinoma

To gain more insight into the role of chromosomal instability (CIN), the cytogenetic hallmark of most solid tumors, we performed fluorescence in situ hybridization (FISH) on interphase nuclei of cytological specimens enabling the correct detection of chromosome copies in intact tumor cells of 18 well (G1), moderately (G2), or poorly (G3) differentiated hepatocellular carcinomas (HCCs). A close correlation between the morphological dedifferentiation and increasing copy numbers and variation of FISH signals was seen for chromosomes 1 and 8, respectively (P < or = 0.0002). Four HCC G1 had constant chromosome patterns for chromosomes 1 and/or 8 with a mean of signals per nucleus < or =5.08 and < or =3 different signal combinations, indicating a low level of CIN, as confirmed by FISH using probes for centromeres of chromosomes 3, 7, and 17. In contrast to this, five HCC G2-3 revealed > or =8.46 signals per nucleus and 23-41 different signal combinations, indicating high levels of CIN. In the remaining cases, signal counts from 5.96-8.46 and 7-15 combinations were seen. Here, nuclei with constant aberration patterns and low copy numbers occurred alongside nuclei with inconstant patterns and high copy numbers. It is evident that in these cases a transition from well to moderately differentiated HCC developed in parallel to an increase in CIN, possibly induced by a major dysregulation of mitotic control mechanisms. In conclusion, CIN may induce a stepwise increase of aneuploidy in HCC that is mirrored by the morphological dedifferentiation of tumor cells.     

Evidence for naive T-cell repopulation despite thymus irradiation after autologous transplantation in adults with multiple myeloma: role of ex vivo CD34+ selection and age

Immunodeficiency following autologous CD34+-purified peripheral blood stem cell (PBSC) transplantation could be related to T-cell depletion of the graft or impaired T-cell reconstitution due to thymus irradiation. Aiming to assess the role of irradiated thymus in T-cell repopulation, we studied 32 adults with multiple myeloma, randomly assigned to receive high-dose therapy including total body irradiation (TBI) followed by autologous transplantation with either unselected or CD34+-selected PBSCs. The median number of reinfused CD3+ cells was lower in the selected group (0.03 versus 14 x 10(6)/kg; P =.002). Lymphocyte subset counts were evaluated from month 3 to 24 after grafting. Naive CD4+ T cells were characterized both by phenotype and by quantification of T-cell receptor rearrangement excision circles (TRECs). The reconstitution of CD3+ and CD4+ T cells was significantly delayed in the CD34+-selected group, but eventually led to counts similar to those found in the unselected group after month 12. Mechanism of reconstitution differed, however, between both groups. Indeed, a marked increase in the naive CD62L+CD45RA+CD4+ subset was observed in the selected group, but not in the unselected group in which half of the CD45RA+CD4+ T cells appear to be CD62L-. Age was identified as an independent adverse factor for CD4+ and CD62L+CD45RA+CD4+ T-cell reconstitution. Our results provide evidence that infusing PBSCs depleted of T cells after TBI in adults delays T-cell reconstitution but accelerates thymic regeneration.     

Daily life,needs and expectations of patients with acromegaly in France: An on-line survey

Acromegaly can impair quality of life, but impact on patients’ daily life, needs and expectations have been poorly explored.

Long-term (> 8 weeks) home inotropic therapy as destination therapy in patients with advanced heart failure or as bridge to heart transplantation

Congenital heart disease (CHD) affects approximately 250,000 adults in the UK. Most of these patients would benefit from specialized follow-up. However, there is at present a significant shortfall of specialized tertiary care expertise and facilities for this growing cardiovascular field in the UK and around the world. We aimed to report our experience with a joint adult CHD clinic run in a district general hospital with regular input from the local cardiology team and a visiting adult CHD specialist. In total, 148 patients aged 33.6+/-14.1 years were seen once or more in 12 clinics over the study period (September 1999 to January 2003). Diagnostic case mix consisted of 2.9% complex, 67.9% moderate and 29.2% minor cases of CHD. Twenty percent of patients visited the counterpart tertiary center for additional investigations (mostly MRI) and 8% for intervention (with no operative mortality). There was one death during the study period giving an overall mortality of 0.2%/year. Patients were referred to the clinic from tertiary centres, the local cardiology and paediatric clinics and with time from obstetric and community sources. Nonattendance rates were relatively low, comparing favourably with tertiary care. This model of joint care for the adult CHD patient at a general district hospital with regular onsite specialized input appears to be effective and highlights the need for additional resource allocation to provide optimal care for these patients. Our data may be useful in future planning for CHD services.     

Decreasing sensitivity to RANTES (regulated on activation,normally T cell-expressed and -secreted) neutralization of CC chemokine receptor 5-using,non-syncytium-inducing virus variants in the course of human immunodeficiency virus type 1 infection

In approximately half of human immunodeficiency virus (HIV) type 1-infected individuals, the development of CXC chemokine receptor 4-using, syncytium-inducing (SI) virus variants precedes a rapid progression to acquired immunodeficiency syndrome (AIDS). In other individuals, only CC chemokine receptor 5-using (R5), non-SI (NSI) virus variants are present throughout infection. These individuals may be either long-term survivors (LTSs) or rapid progressors. The basis for this variable disease progression in individuals with only R5 virus variants is not yet fully understood. In this study, the beta-chemokine sensitivity of biological HIV-1 clones isolated from 13 individuals who harbored only R5, NSI virus variants (7 LTSs and 6 progressors) was investigated. We found a statistically significant decrease in sensitivity of virus variants to RANTES (regulated on activation, normally T cell-expressed and -secreted) neutralization during the course of progressive infection, but not during follow-up of LTSs. Our data suggest that a role exists for RANTES neutralization sensitivity of HIV-1 in AIDS pathogenesis.