Bcl-6 p53 mutations in lymphomas carrying the bcl-2/Jh rearrangement

BACKGROUND AND OBJECTIVES: The t(14;18)(q32;q21) chromosomal translocation is the hallmark of follicular lymphomas (FL). The translocation induces the overexpression of the Bcl-2 protein and prolongs the survival of clonogenic cells. Tumor cells may acquire additional molecular alterations that may be associated with histologic progression or with chemo-resistance. DESIGN AND METHODS: We analyzed the distribution and association of bcl-6 and p53 mutations in 55 consecutive bcl-2/Jh+ lymphoma samples derived from 43 patients obtained at the time of diagnosis and, in 5 of these patients, during follow-up. A total of 29 bcl-6 point mutations were detected in seventeen patients (40%) associated with major or minor breakpoints of the bcl-2/Jh fusion gene. In seven cases a p53 mutation was detected. Three cases corresponded to FL with the minor breakpoint in the bcl-2 gene and these patients had a favorable clinical evolution, whereas the 4 patients with p53 mutations and the major breakpoint had a bad clinical outcome with morphologic transformation to high-grade lymphoma in three cases. The sequential analysis of 5 patients showed a different timing in the acquisition of mutations: one patient showed bcl-6 and p53 mutations at diagnosis, another patient showed bcl-6 mutations at diagnosis and acquired a p53 mutation later whereas the third patient had a p53 mutation before the appearance of the bcl-6 mutation. RESULTS: We did not find significant differences in survival between patients with FL who showed exclusively bcl-6 mutations and those without bcl-6 mutations, but those patients with a high International Progostic Index score and p53 mutations showed the lowest overall survival (p = 0.002). INTERPRETATION AND CONCLUSIONS: These findings suggest that bcl-2/Jh lymphomas show molecular heterogeneity and that bcl-6 and p53 mutations may be acquired during the evolution of such lymphomas. Bcl-6 mutations, by themselves, do not seem to be associated with a bad prognosis. Rearrangements at the minor bcl-2 locus may have a different molecular evolution.     

Early and late results of the acid suppression and duodenal diversion operation in patients with barrett's esophagus: analysis of 210 cases

The usual surgical treatment for patients with Barrett's esophagus (BE) is a classic Nissen fundoplication or posterior gastropexy with cardial calibration. However, some surgical reports as well as our experience suggest that the rate of failure of the Nissen fundoplication or Hill's posterior gastropexy in patients with BE is significantly higher than in those with reflux esophagitis without BE, probably due in part to the persistence of duodenal reflux into the esophagus. Our aim was to determine the late subjective and objective results of an operation consisting in "acid suppression" (vagotomy-partial gastrectomy) and "duodenal diversion" (Roux-en-Y anastomosis) as a primary surgical procedure for patients with BE. Altogether, 210 patients were subjected to this technique. It consisted in a primary operation in 142 patients and revision surgery in 68. They underwent complete clinical, radiologic, endoscopic, histologic, and manometric studies. In some cases 24-hour pH studies, Bilitec studies, gastric emptying, and gastric acid secretion evaluations were performed. There were two deaths (0.95%), and postoperative morbidity was low (5.3%). The late mean follow-up (58 months) for 146 patients who completed a follow-up longer than 24 months showed Visick I and II grades in 91.1% of the cases. In 14.9% of the cases 24-hour pH monitoring showed excessive acid reflux 1 year after surgery. No dysplasia or adenocarcinoma has appeared up to now. Functional studies showed significant alleviation of lower esophageal sphincter (LES) incompetence, with abolition of duodenal reflux into the esophagus. Gastric emptying of solids was normal, and basal and peak gastric acid output remained at a low level 8 to 10 years after surgery. In patients with BE, with severe damage of the LES and esophageal peristalsis, the "suppression diversion" operation completely abolishes the reflux of injurious components of the refluxate and improves sphincter competence. This effect is permanent and avoids the appearance of dysplasia or adenocarcinoma.     

Nonanatomic Thoracoscopic Wedge Resection for Diffuse Lung Disease and Indeterminate Pulmonary Nodule

Video technology has revolutionized thoracoscopy dramatically, considerably increasing its indications. The clinical charts of patients who underwent a video-thoracoscopic procedure during a 6-year period were reviewed. Any patient in whom lung wedge resection for diffuse disease or an indeterminate nodule was performed met the inclusion criteria. Early and long-term outcomes were analyzed. A total of 310 thoracoscopic procedures were performed in the 250 patients reviewed. Of these patients, 60 presented with diffuse lung disease and 71 with an indeterminate pulmonary nodule. The total morbidity among diffuse disease patients was 5% (one intercostal vessel hemorrhage and two air leaks). Overall mortality for this group was 11% and was related to previous respiratory status and underlying disease. Patients not requiring preoperative mechanical ventilation ended up requiring it postoperatively, for a crossover rate of 23%. There was no morbidity or mortality in patients who did not require mechanical ventilation. The therapeutic impact index (defined as the total number of patients divided by the patients in whom initiation or withdrawal of specific treatment was due to the biopsy result) for diffuse lung disease was 0.9. Regarding lung nodule resection, early morbidity was present in one patient, who developed a persistent air leak. Late morbidity was present in three patients, who developed persistent intercostal pain. Total morbidity was 5.6%. No mortality was observed for this group. Nonanatomic wedge resection via video-thoracoscopy for diffuse pulmonary disease and indeterminate lung nodule is feasible using minimally invasive methods. Morbidity and mortality are related to the underlying disease and the respiratory status; they are not necessarily due to the procedure.     

Dehydroepiandrosterone sulfate and growth axis hormones in patients after surgery

We selected 38 patients scheduled for cholecystectomy and studied their serum concentrations of dehydroepiandrosterone (DHEA) and growth axis hormones [growth hormone/insulin-like growth factor-1 (GH/IGF-1)]. We aimed to determine whether alterations in these concentrations resulted from surgical stress or, on the contrary, preceded surgery and were themselves a cause of chronic diseases that reduce life expectancy. We measured the serum concentrations of DHEA sulfate (DHEA-S), ACTH, cortisol, human GH (hGH), IGF-1, and IGF-1 binding protein-3 (IGFBP-3) preoperatively and then 2 and 7 days after surgery; we also compared the preoperative findings with those of a healthy control group. The results were analyzed by gender because DHEA and GH/IGF-1 are known to present sexual dimorphism. There were no significant differences between the preoperative and control results for any of the parameters studied. We found a significant reduction in the concentrations of DHEA-S and IGF-1 on days 2 and 7 after surgery versus the preoperative values. We conclude that the decrease in DHEA-S in patients after surgery is a result of surgical trauma and does not precede surgical stress. The decrease in hormone levels observed in patients with chronic disease may therefore be a result, not a cause, of disease, as some have claimed. Further studies with a later endpoint would be of interest to assess any subsequent return of DHEA-S levels to baseline measurements.     

Polymerase chain reaction diagnosis in fungal keratitis caused by Alternaria alternata

PURPOSE: To contribute toward assessing the effectiveness of polymerase chain reaction as a rapid method in diagnosis of torpid keratitis caused by opportunistic fungi. METHODS: Interventional case report. A 50-year-old man with a corneal abscess in the right eye treated for a period of 6 months with different combinations of broad-spectrum antibiotics and steroids was referred to our center. Corneal scraping was taken for microbiological study, including classic cultures and polymerase chain reaction. Amplified DNA was sequenced to identify the pathogen. RESULTS: Polymerase chain reaction amplification was negative for Acanthamoeba species and positive for fungi. The sequence analysis showed Alternaria alternata as the causal agent in 24 hours. Cultures confirmed the identification in 10 days. CONCLUSION: Polymerase chain reaction amplification with subsequent DNA-typing was revealed to be a useful method for detection of ocular pathogens such as A. alternata involved in cases of torpid keratitis, even in the presence of broad-spectrum antimicrobial therapy.     

Hemiretinal vein occlusion associated with membranous glomerulonephritis

PURPOSE: To report a patient in whom the finding of hemiretinal vein occlusion led to the diagnosis of membranous glomerulonephritis. DESIGN: Interventional case report. METHODS: A 44-year-old tennis instructor presented with a 1-week history of blurred vision in the left eye. Examination of the left eye demonstrated a best-corrected visual acuity of 20/40 and an inferior hemiretinal vein occlusion. RESULTS: Blood pressure was normal, and the patient was referred for a medical examination, which revealed membranous glomerulonephritis. The patient was treated with oral prednisone and cyclosporine. Four months after presentation, the left eye demonstrated resolution of the vascular abnormalities and had a best-corrected visual acuity of 20/20. CONCLUSION: Retinal vein occlusion may be associated with membranous glomerulonephritis. Treatment of the systemic disease may be associated with regression of the retinal vascular abnormalities.     

Purification and characterization of a phospholipase A2 isoenzyme isolated from Lachesis muta snake venom

A new phospholipase A2 (PLA2) isoenzyme was isolated from Lachesis muta crude venom, and was named LM-PLA2-II. This enzyme was purified by gel filtration on a Sephacryl S-200 HR column followed by reverse-phase chromatography on a C2/C18 column. LM-PLA2-II consists of a single polypeptide chain with an apparent molecular mass of 18 kDa and an isoelectric point at pH 5.4. The amino terminal sequence of the enzyme revealed a high degree of homology with other PLA2s from several sources. LM-PLA2-II has a high indirect hemolytic activity and a potent inhibitory effect on platelet aggregation induced by ADP and collagen. It also produces a significant paw edema reaction in rats. The edematous response in rats was abolished by pretreatment with either indomethacin or dexamethasone, suggesting the involvement of cyclo-oxygenase. Pretreatment of LM-PLA2-II with p-bromophenacyl bromide abolished all of these actions, clearly indicating that the biological activities, including the edematogenic effect, are dependent entirely on its enzymatic activity.     

Modulation of dendritic release of dopamine by metabotropic glutamate receptors in rat substantia nigra

A superfusion system was used to study the effects of metabotropic glutamate receptor (mGluR) ligands upon the release of [(3)H]dopamine ([(3)H]DA) previously taken up by rat substantia nigra (SN) slices. trans-(+/-)-1-Amino-(1S,3R)-cyclopentane dicarboxylic acid (trans-ACPD; 100 and 600 microM), a group I and II mGluR agonist, evoked the release of [(3)H]DA from nigral slices. This last effect was reduced significantly by (2S,3S,4S)-2-methyl-2-(carboxycyclopropyl)-glycine (MCCG; 300 microM), an antagonist of group II mGluR, or by the addition of tetrodotoxin (D-APV; 1 microM) to the superfusion medium. D-(-)-2-Amino-5-phosphono-valeric acid (100 microM), an N-methyl-D-aspartate receptor antagonist, or the presence of Mg(2+) (1.2mM) in the superfusion medium did not modify trans-ACPD-induced [(3)H]DA release. In addition, a group II mGluR agonist such as (2S,1'R,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)-glycine (DCG-IV; 100 microM) significantly induced the release of [(3)H]DA from nigral slices, whereas a group I mGluR agonist such as (RS)-3,5-dihydroxyphenylglycine (DHPG; 50 and 100 microM) did not modify the release of the [(3)H]-amine. Further experiments showed that the NMDA (100 microM)-evoked release of [(3)H]DA was decreased significantly by prior exposure of SN slices to trans-ACPD. Finally, partial denervation of the DA nigro-striatal pathway with 6-hydroxydopamine (6-OH-DA) increased trans-ACPD-induced release of [(3)H]DA, whereas it decreased trans-ACPD inhibitory effects on NMDA-evoked release of [(3)H]DA from nigral slices. The present results suggest that the dendritic release of DA in the SN is regulated by mGluR activation. Such nigral mGluR activation may produce opposite effects upon basal and NMDA-evoked release of DA in the SN. In addition, such mGluR-induced effects in the SN are modified in response to partial denervation of the DA nigro-striatal pathway.