Prognostic relevance of methylation markers in patients with non-muscle invasive bladder carcinoma

There is increasing evidence for the role of epigenetic gene silencing in superficial bladder cancer. The aim of the current study was to investigate the prognostic value of epigenetic alterations in patients with non-muscle invasive bladder carcinoma. We checked the methylation status of 20 cancer associated genes (p14ARF, p16 CDKN2A, STAT-1, SOCS-1, DR-3, DR-6, PIG-7, BCL-2, H-TERT, BAX, EDNRB, DAPK, RASSF-1A, FADD, TMS-1, E-Cadherin, ICAM-1, TIMP-3, MLH-1, COX-2) for DNA methylation. We analysed microdissected tumour samples from 105 consecutive patients with primary non-muscle invasive bladder carcinoma. Quantitative methylation analysis of CpG sites in the promoter region of the genes was performed with methylation sensitive quantitative real time PCR ('Methylight'). Univariate analysis for association with tumour recurrence was carried out with the Kaplan-Meier analysis and the log-rank test. Follow-up data were available in 95/105 patients (91.4%). A tumour recurrence was observed in 26 patients (27.3%). We could identify six genes (SOCS-1, STAT-1, BCL-2, DAPK, TIMP-3, E-Cadherin), where methylation was associated with tumour recurrence. In Kaplan-Meier analysis, TIMP-3 showed a significant association with recurrence free survival. Methylation of TIMP-3 predicted prolonged disease free interval. In this study, we report a comprehensive analysis on prognostic relevance of gene methylation in non-muscle invasive bladder cancer. We identified one gene (TIMP-3) where methylation was associated with a more favourable outcome. Our data strongly support the usefulness of gene methylation as a prognostic marker in patients with non-muscle invasive bladder cancer.     

Carditis: a manifestation of gastroesophageal reflux disease

This series consists of 141 patients in whom cardiac mucosa (CM) was present in biopsy samples from the gastroesophageal junctional region. Inflammation of CM, irrespective of its exact anatomic location, was defined as carditis and classified as acute or chronic based on the number of inflammatory cells present. In all cases, CM showed significant chronic inflammation. One hundred and eleven (79%) of the 141 patients with carditis showed no evidence of gastritis in biopsy samples from the gastric antrum and body. Helicobacter pylori was present in 20 of 141 (14%) patients; of these, 17 had evidence of a pangastritis, with 15 of these patients also showing H. pylori in CM. Patients with severe chronic inflammation in CM had a significantly higher acid exposure of the lower esophagus as quantitated by a 24-hour pH test than those with mild chronic inflammation in CM. Acute inflammation was uncommon in CM; it was present in only 26 of 141 (18.4%) patients. There was no significant difference in acid exposure of the lower esophagus between patients with and without acute inflammation in CM. The presence of acute inflammation in CM was significantly associated with distal gastritis and H. pylori infection. Men with carditis had quantitatively higher acid exposure of the lower esophagus than did women with this disorder. This difference was greatest in men with severe inflammation in CM who had no evidence of distal gastritis. These findings provide evidence that chronic inflammation in CM is strongly associated with acid reflux and that H. pylori is not a significant etiologic factor in carditis. They also show that in patients with CM in whom H. pylori gastritis develops, the infection frequently spreads to involve CM, resulting in acute inflammation with neutrophils that is superimposed on the chronic inflammation already present.     

Laparoscopic ultrasonic epithelial ablation of the lower esophagus after nissen fundoplication in a porcine model: assessment of tissue damage and healing process.

A substantial population of patients with Barrett's esophagus has undergone antireflux surgery but still requires annual surveillance endoscopy. These patients would benefit from a definitive ablation of the Barrett's mucosa, which would remove the malignant potential of this disease. This study evaluates the efficacy of applying ultrasonic energy to remove the epithelium of the lower esophagus in a porcine model with prior Nissen fundoplication. Four Yakutan minipigs underwent laparoscopic Nissen fundoplication. After 2 weeks they underwent transgastric Cavitron ultrasonic surgical aspirator (CUSA; Valleylab, Boulder, CO) ablation of the lower esophageal epithelium. Healing of the mucosa was assessed by endoscopy at 2 weeks and pathological examination at 4 weeks after ablation. All pigs underwent successful laparoscopic Nissen fundoplication. Complete lower esophageal epithelial ablation was accomplished through the fundoplication in three animals. One pig developed a bezoar that prohibited ablation. At 2 weeks endoscopy showed patchy squamous epithelial regeneration, which was confirmed histologically. Esophageal specimens at 4 weeks showed complete regeneration of squamous epithelium with a partially healed small ulcer in one animal. No stricture formation was seen. We conclude that the CUSA technique can completely ablate Barrett's mucosa in the setting of a prior antireflux procedure. Healing with squamous mucosal regeneration is rapid and complete.     

Fulminant amebic colitis

PURPOSE: The morphologic features of fulminant amebic colitis are poorly documented. In this report, we describe the clinical and pathologic findings in four of these cases. METHODS: The surgical pathology reports and accompanying histologic slides were examined from four patients who underwent surgical resections for fulminant amebic colitis. Clinical information was obtained from the patients' medical records. RESULTS: Large, geographic mucosal ulcers were typically present and were accompanied by yellow-green pseudomembranes. The muscularis externa was usually attenuated and necrotic, imparting a wet blotting paper consistency. Large numbers of amebic trophozoites were present within the inflammatory exudates. The mucosa adjacent to and undermined by the ulcers was often hemorrhagic or inflamed, resembling ischemic colitis or idiopathic inflammatory bowel disease, respectively. Two patients died within four weeks of their surgery. A third patient died one year later as a result of AIDS-related complications. The remaining patient has been lost to follow-up. CONCLUSION: An uncommon but life-threatening manifestation of intestinal amebiasis is a fulminant colitis. Early surgical intervention and intensive antiamebic chemotherapy are essential for efficacious managment.     

Chronic alcohol consumption intensifies caerulein-induced acute pancreatitis in the rat

Rats were chronically fed either an ethanol-containing diet (36% of total calories derived from alcohol) or a pair-fed, control diet (no alcohol) for 8 wk, and acute pancreatitis (AP) was subsequently induced by a 3-h iv infusion of caerulein (CR) at a dose of 5 μg/kg/hr. CR-induced AP in control rats (no alcohol) was characterized by a significant elevation in serum lipase content, pancreatic interstitial edema, infrequent occurrences of karyorrhexis, and the appearance of vacuoles in acinar cells. Chronic feeding of the ethanol diet followed by treatment with CR resulted in increases in serum lipase content, interstitial edema, karyorrhexis, and acinar vacuolization that were significantly greater than that seen in rats fed the control diet and treated with CR. It is concluded that chronic ethanol intake in the rat intensifies AP that is subsequently induced by CR.     

Effects of preoperative chemotherapy on gastric adenocarcinomas. A morphologic study of 25 cases.

BACKGROUND. Surgical neoadjuvant therapy for gastric adenocarcinoma affords the opportunity to evaluate critically the histologic effects of preoperative chemotherapy. METHODS. Morphologic alterations in gastric adenocarcinomas were examined in the surgical-resection specimens from 25 patients after 6 weeks of preoperative chemotherapy. The group included 1 patient with a complete response; 4, with subtotal responses; 4, with partial responses; and 16, with no response to preoperative chemotherapy. RESULTS. Histologic manifestations of preoperative chemotherapy included mucosal edema, aggregates of histiocytes in the submucosa and muscularis externa, and stromal fibrosis of the submucosa and muscularis externa. Cytologic manifestations were uncommon and included a single case of signet ring cell carcinoma with diminution of the cytoplasmic vacuoles after preoperative chemotherapy. Clinical follow-up was limited, but 3 of the 25 patients died within 5-8 months after the diagnosis of gastric adenocarcinoma. The gastric-resection specimens from these three patients did not show any histologic manifestations of preoperative chemotherapy. CONCLUSION. As in tumors at other sites, the efficacy of surgical neoadjuvant therapy for gastric adenocarcinoma can be assessed, based on the histologic response of the resected tumor to preoperative chemotherapy.     

Carcinoma of the cystic duct

Two patients with carcinoma of the cystic duct presented with obstructive jaundice due to extrinsic compression of the common hepatic duct by the tumor. Sonography and computed tomography showed dilatation of the intrahepatic bile ducts and gallbladder. In one patient, a calculus seen in the gallbladder neck suggested Mirizzi syndrome. In the other, a small soft tissue mass was indistinguishable from a common duct tumor or an enlarged lymph node. In both cases, direct cholangiography demonstrated extrinsic compression and displacement of the common duct with proximal biliary dilatation and nonvisualization of the gallbladder. Carcinoma of the cystic duct should be considered whenever there is evidence of cystic duct obstruction and/or when cholangiography shows extrinsic mass effect on the common duct.     

Prevalence ofCampylobacter pylori and association with antral mucosal histology in subjects with and without upper gastrointestinal symptoms

To determine the incidence and significance of Campylobacter pylori in patients undergoing routine endoscopic evaluation at this hospital, biopsies of the antrum were obtained from 132 patients and from 15 asymptomatic volunteers. Specimens were cultured and silver stained for the presence of C. pylori and were examined histologically. C. pylori was detected in 67 (51%) patients and two (13%) volunteers (P = 0.006). In patients, C. pylori was found significantly more often when the mucosa was inflamed (67%) than when the mucosa was normal (13%), and both volunteers with C. pylori had chronic gastritis on histological examination. When compared to the volunteers, patients with upper gastrointestinal symptoms had a significantly increased prevalence of antral inflammation, even if the endoscopic examination was normal. C. pylori is infrequently found in young asymptomatic adults but is found in both asymptomatic volunteers and patients in association with all forms of histological antral gastritis which is prevalent in patients with both normal endoscopic findings and peptic ulcer disease.     

Limb salvage surgery for bone and soft tissue sarcoma. A phase II pathologic study of preoperative intraarterial cisplatin.

Preoperative therapy has been tested as part of limb salvage therapy for localized bone and soft tissue sarcoma of the extremities. The activity of cisplatin (CDDP) by intraarterial (IA) infusion was evaluated in 40 cases of which 36 were evaluable for response. All patients had high-grade sarcomas. All but 3 patients received 3 or 4 courses (24 patients received 4 courses) of CDDP at a dosage of 120 to 150 mg/m2 given over 6 hours every 2 weeks by IA infusion. Patients younger than 18 years of age received the higher dose of CDDP. Treatment was well tolerated with combination antiemetics. One patient experienced severe hearing loss with the first cycle of the higher CDDP dose. Pathologic evaluation of resected osteosarcoma showed a favorable response (90% or greater necrosis) in 8 of 20 evaluable cases and in 3 of 4 patients with malignant fibrous histiocytoma (MFH) of bone (without osteoid). In soft tissue sarcomas, minimal (50% to 89%) necrosis was seen in two of nine cases and none had 90% or greater necrosis. Patients received postoperative chemotherapy based on pathologic response, but the value of this postoperative adjuvant therapy requires further follow-up and is uncertain in this small study. IA CDDP can often cause significant tumor necrosis in patients with bone sarcomas, whereas soft tissue sarcomas are less sensitive to this therapy.