Bevacizumab as adjuvant treatment of colon cancer: updated results from the S-AVANT phase III study by the GERCOR Group.

BACKGROUND: The bevacizumab-Avastin® adjuVANT (AVANT) study did not meet its primary end point of improving disease-free survival (DFS) with the addition of bevacizumab to oxaliplatin-based chemotherapy in stage III colon cancer (CC). We report here the long-term survival results (S-AVANT). PATIENTS AND METHODS: Patients with curatively resected stage III CC were randomly assigned to FOLFOX4, FOLFOX4-bevacizumab, or XELOX-bevacizumab. RESULTS: A total of 2867 patients were randomized: FOLFOX4: n = 955, FOLFOX4-bevacizumab: n = 960, XELOX-bevacizumab: n = 952. With a median of 6.73 years follow-up (interquartile range 5.51-10.54), 672 patients died, of whom 198 (20.7%), 250 (26.0%), and 224 (23.5%) were in the FOLFOX4, FOLFOX4-bevacizumab, and XELOX-bevacizumab arms, respectively. The 10-year overall survival (OS) rates were 74.6%, 67.2%, and 69.9%, (P = 0.003) and 5-year disease-free survival (DFS) rates were 73.2%, 68.5%, and 71.0% (P = 0.174), respectively. OS and DFS hazard ratios were 1.29 [95% confidence interval (CI) 1.07-1.55; P = 0.008] and 1.16 (95% CI 0.99-1.37; P = 0.063) for FOLFOX4-bevacizumab versus FOLFOX4 and 1.15 (95% CI 0.95-1.39; P = 0.147) and 1.1 (95% CI 0.93-1.29; P = 0.269) for XELOX-bevacizumab versus FOLFOX4, respectively. CC-related deaths (n = 542) occurred in 157 (79.3%) patients receiving FOLFOX4, 205 (82.0%) receiving FOLFOX4-bevacizumab, and 180 (80.4%) receiving XELOX-bevacizumab (P = 0.764), while non-CC-related deaths occurred in 41 (20.7%), 45 (18.0%), and 44 (19.6%) patients, respectively. Cardiovascular-related and sudden deaths during treatment or follow-up were reported in 13 (6.6%), 17 (6.8%), and 14 (6.3%) patients, in the FOLFOX4, FOLFOX4-bevacizuamb, and XELOX-bevacizumab arms, respectively (P = 0.789). Treatment arm, sex, age, histological differentiation, performance status, T/ N stages, and localization of primary tumor were independent prognostic factors of OS in stage III. CONCLUSIONS: S-AVANT confirms the initial AVANT report. No benefit of the bevacizumab addition to FOLFOX4 adjuvant therapy in patients with stage III CC was observed in terms of DFS with a negative effect in OS, without increase in non-CC related deaths. CLINICAL TRIAL IDENTIFICATION: NCT00112918.

Aminoguanidine prevents the impairment of cardiac pumping mechanics in rats with streptozotocin and nicotinamide-induced type 2 diabetes.

BACKGROUND AND PURPOSE: Aminoguanidine (AG), an inhibitor of advanced glycation endproducts, has been shown to prevent arterial stiffening and cardiac hypertrophy in streptozotocin (STZ) and nicotinamide (NA)-induced type 2 diabetes in rats. Our aims were to examine whether AG produced benefits on cardiac pumping mechanics in the STZ and NA-treated animals in terms of maximal systolic elastance (E(max)) and theoretical maximum flow (Q(max)). EXPERIMENTAL APPROACH: After induction of type 2 diabetes, rats received daily injections of AG (50 mg kg(-1), i.p.) for 8 weeks and were compared with age-matched, untreated, diabetic controls. Left ventricular (LV) pressure and ascending aortic flow signals were recorded to calculate E(max) and Q(max), using the elastance-resistance model. Physically, E(max) reflects the contractility of the myocardium as an intact heart, whereas Q(max) has an inverse relationship with the LV internal resistance. KEY RESULTS: Both type 2 diabetes and AG affected E(max) and Q(max), and there was an interaction between diabetes and AG for these two variables. The E(max) and Q(max) were reduced in rats with type 2 diabetes, but showed a significant rise after administration of AG to these diabetic rats. Moreover, the increase in Q(max) corresponded to a decrease in total peripheral resistance of the systemic circulation when the STZ and NA-induced diabetic rats were treated with AG. CONCLUSIONS AND IMPLICATIONS: AG therapy prevented not only the contractile dysfunction of the heart, but also the augmentation in LV internal resistance in rats with STZ and NA-induced type 2 diabetes.

Aminoguanidine prevents fructose-induced deterioration in left ventricular-arterial coupling in Wistar rats.

BACKGROUND AND PURPOSE: Aminoguanidine (AG), an inhibitor of advanced glycation endproducts, has been identified as a prominent agent that prevents the fructose-induced arterial stiffening in male Wistar rats. Our aims were to examine whether AG produced benefits on the left ventricular (LV)-arterial coupling in fructose-fed (FF) animals in terms of the ventricular and arterial chamber properties. EXPERIMENTAL APPROACH: Rats given 10% fructose in drinking water (FF) were daily treated with AG (50 mg x kg(-1), i.p.) for 2 weeks and compared with the untreated FF group. In anaesthetised rats, LV pressure and ascending aortic flow signals were recorded to calculate LV end-systolic elastance (E(es), an indicator of myocardial contractility) and effective arterial volume elastance (E(a)). The optimal afterload (Q(load)) determined by the ratio of E(a) to E(es) was used to measure the coupling efficiency between the left ventricle and its vasculature. KEY RESULTS: There was a significant interaction between fructose and AG in their effects on E(a). Fructose loading significantly elevated E(a) and AG prevented the fructose-derived deterioration in arterial chamber elastance. Both fructose and AG affected E(es) and Q(load), and there was an interaction between fructose and AG for these two variables. Both E(es) and Q(load) exhibited a decline with fructose feeding but showed a significant rise after AG treatment in the FF rats. CONCLUSIONS AND IMPLICATIONS: AG prevented not only the contractile dysfunction of the heart caused by fructose loading, but also the fructose-induced deterioration in matching left ventricular function to the arterial system.

Elective laparoscopically assisted sigmoidectomy for the sigmoid volvulus.

BACKGROUND: The laparoscopic approach for the treatment of sigmoid volvulus has been a rare surgical indication. This phase 2 study investigated the feasibility and surgical outcomes of elective laparoscopic surgery for sigmoid volvulus. METHODS: Patients with sigmoid volvulus were first offered colonoscopic decompression for their acute colonic obstruction. If the colonic decompression was successful, complete bowel preparation was performed, followed by elective laparoscopically assisted sigmoidectomy. The details of the laparoscopic procedures are shown in the video. Briefly, the redundant sigmoid colon is totally mobilized by a laparoscopic medial-to-lateral dissection sequence, after which it is exteriorized, transected, and reconstructed by end-to-end anastomosis. In the authors' experience, the medial-to-lateral approach is highly efficient for the laparoscopic mobilization of the redundant sigmoid colon. We believe that the longer the lateral abdominal wall attachment of the sigmoid colon is preserved, the better the exposure and the easier the dissection. If the risk of anastomotic leakage is considered high in a specific case, protective ileostomy is selectively preformed. Before entering the current study, the patients were well informed about the advantages and disadvantages of laparoscopic surgery. The enrollment of patients was selective according to the appropriate eligibility criteria. This study was approved by the Institutional Review Board of the National Taiwan University Hospital. The patients' clinicopathologic data and surgical outcomes were prospectively evaluated. RESULTS: Between August 2001 and April, 2005, a total of 14 patients (10 men and 4 women) with sigmoid volvulus were treated with the described procedure. The age distribution of the patients was 68.4 +/- 12.2 years. The attack of sigmoid volvulus was the first episode for eight patients, the second episode for 4 patients, and the third episode (or more) for two patients. The body mass index (BMI) of the patients was 26.8 +/- 4.4 kg/m(2). The physical status (classification of American Society of Anesthesiology [ASA]) was 1 for five patients, 2 for eight patients, and 3 for 1 patient. During the laparoscopy, all the patients presented with the pathognomonic findings of sigmoid volvulus including redundant sigmoid colon, narrow sigmoid mesenteric pedicle, and mesosigmoiditis with mesenteric fibrosis and scarring, as shown in the video. The length of the resected colon was 32 +/- 6 cm. The operation time was 194.6 +/- 32.4 min, and the blood loss was 44.0 +/- 12.4 ml. The abdominal wound consisted of four 5 to 12 mm working ports and a 5 cm major wound for exteriorization of the sigmoid colon. Some surgeons have shown that a sigmoid volvulus can be resected through a 5-cm left lower quadrant incision with very little mobilization of the colon because of its redundancy. In this context, the laparoscopic approach competed with the minilaparotomy method in terms of adequate sigmoid resection, lysis of mesosigmoid adhesion, and tension-free colorectal anastomosis. Protective ileostomy was performed for the only patient with a physical status of ASA 3. There was no mortality in this case series. However, pneumonia developed postoperatively in one patient, acute myocardial infarction in one patient, and wound infection in two patients. Excluding the two patients who experienced postoperative pneumonia and acute myocardial infarction, the duration of the postoperative ileus was 48 +/- 12 h, the postoperative hospitalization was 7 +/- 1 days, and the degree of postoperative pain was 3.5 +/- 0.5 according to the visual analog scale. The return to partial activity required 18 +/- 2.5 days, and the return to full activity required 28.4 +/- 5.6 days. As compared with the overall costs for a conventional sigmoid colectomy, which are completely covered by the National Bureau of Health Insurance of Taiwan, the expenses for the patients undergoing laparoscopic procedures were significantly higher by approximately 24,000.0 NT dollars +/- 2,635.0 (1 U.S. dollar = 32 NT dollars). These higher expenses must be borne by the patients themselves. CONCLUSION: Considering that patients with sigmoid volvulus often are elderly and chronically ill, laparoscopic elective surgery after a successful colonoscopic decompression may be a good choice for a selected group of patients in terms of minimized surgical complications and quick convalescence.

Aminoguanidine prevents arterial stiffening in a new rat model of type 2 diabetes.

BACKGROUND: Formation of advanced glycation end-products (AGEs) on collagen within the arterial wall may be responsible for the development of diabetic vascular injury. This study focused on investigating the role of aminoguanidine (AG), an inhibitor of AGE formation, in the prevention of noninsulin-dependent diabetes mellitus (NIDDM)-derived arterial stiffening and cardiac hypertrophy in rats. MATERIALS AND METHODS: The NIDDM was induced in male Wistar rats, which were administered intraperitoneally with 180 mg kg(-1) nicotinamide (NA) 30 min before an intravenous injection of 50 mg kg(-1) streptozotocin (STZ). After induction of diabetes mellitus type 2, animals receiving daily peritoneal injections with 50 mg kg(-1) AG for 8 weeks were compared with the age-matched, untreated, diabetic controls. RESULTS: After exposure to AG, the STZ-NA diabetic rats had improved aortic distensibility, as evidenced by 18.8% reduction of aortic characteristic impedance (P < 0.05). Treatment of the experimental syndrome with AG also resulted in a significant increase in wave transit time (+23.7%, P < 0.05) and a decrease in wave reflection factor (-26.6%, P < 0.05), suggesting that AG may prevent the NIDDM-induced augmentation in systolic load of the left ventricle. Also, the glycation-derived modification on aortic collagen was found to be retarded by AG. The diminished ratio of left ventricular weight to body weight suggested that prevention of the diabetes-related cardiac hypertrophy by AG may correspond to the drug-induced decline in aortic stiffening. CONCLUSIONS: Long-term administration of AG to the STZ-NA diabetic rats imparts significant protection against the NIDDM-derived impairment in vascular dynamics, at least partly through inhibition of the AGE accumulation on collagen in the arterial wall.

Multimedia article. Laparoscopic abdominoperineal resection for lower rectal cancers: how do we do it?

BACKGROUND: The appropriateness of the laparoscopic approach for the resection of rectal cancer has been controversial, although it is well established in colon cancer. This is a phase II study of laparoscopic abdominoperineal resection (APR) in the treatment of lower rectal cancers. METHODS: Patients with lower rectal adenocarcinoma located within 6 cm above the anal verge were recruited and subjected to laparoscopic APR. The surgical principle included en bloc resection with high ligation of inferior mesenteric vessels by no-touch isolation and total mesorectal excision. Details of the surgical procedures are presented in the video. The technical efficiency and outcome of this surgical approach were evaluated prospectively. This study was approved by the institutional review board of National Taiwan University Hospital (NTUH). RESULTS: A total of 22 patients were enrolled in the study from January 2003 to December 2004 under the ethical guidelines of clinical trials in NTUH. There were 12 females and 10 males, with an age distribution of 62.5 +/- 10.4 years. The body mass index was 24.8 +/- 4.0 kg/m2. Physical status (American Society of Anesthesiology classification) was class I in 12, class II in eight, and class III in two patients. Tumor size was 44.0 +/- 12.0 mm in diameter. Two patients were in pathologic TNM stage I, 14 in stage II, and six in stage III. The operation time was 214.0 +/- 28.4 min. Blood loss was 54.0 +/- 14.0 ml. Because the tumor specimen was retrieved from a perineal wound, the five 5 to 12 mm working ports constituted the abdominal wound. There were no major complications. However, wound infection of port sites was detected in one patient. The patients had a quick convalescence, as evaluated by the length of postoperative ileus (48.0 +/- 12.0 h), length of hospitalization (8.0 +/- 2.0 days), and degree of postoperative pain (3.5 +/- 0.5 visual analogue scale). Return to partial activity, full activity, and work was 2.0 +/- 0.5, 4.0 +/- 0.8, and 6.0 +/- 0.5 weeks, respectively. The number of cleared lymph nodes was 14.0 +/- 2.0. During follow-up (median, 18 months; range, 6-30), lung metastasis and local pelvic recurrence developed in one and two patients, respectively. Besides the expenses covered by the National Bureau of Health Insurance of Taiwan, the additional payment by patients undergoing laparoscopic procedures was NTD 24,000 +/- 3000 (1 U.S. dollar = 32 NTD). CONCLUSIONS: In our clinical setting, laparoscopic APR can be performed with good technical efficiency, quick functional recovery, and mild disability. The short-term oncologic results of laparoscopic APR seem to be acceptable, but further long-term follow-up for these patients is mandatory to define the oncologic outcomes of this approach.

C2GnT-M is downregulated in colorectal cancer and its re-expression causes growth inhibition of colon cancer cells.

Changes in carbohydrates on the cell surface are associated with tumor malignancy. The mucin-type core 2 beta-1,6-N-acetylglucosaminyltransferase (C2GnT-M) is highly expressed in the gastrointestinal tract and catalyses the formation of core 2, core 4, and blood group I branches on O-glycans. In the present study, we evaluated the role of C2GnT-M in colorectal cancer. C2GnT-M downexpression was observed in 73.6% of the primary tumors from colorectal cancer patients (39 of 53) analysed by cancer profiling array. Consistently, the majority of colon cancer cell lines and primary colon tumors expressed lower levels of C2GnT-M than did normal colon tissues by RT-PCR. HCT116 cells stably transfected with C2GnT-M inhibited expression of the core 1 structure, Galbeta1,3GalNAcalpha1-Ser/Thr, on the cell surface. Moreover, C2GnT-M expression suppressed cell adhesion, motility, and invasion as well as colony formation ability. The growth of C2GnT-M-transfected HCT116 and SW480 cells was dramatically suppressed, and the cell death induced by C2GnT-M was demonstrated by an increase in the annexin V-positive cells. Interestingly, C2GnT-M inhibited cell adhesion to collagen IV and fibronectin, and decreased tyrosine phosphorylation of paxillin, indicating that the changes in cancer behavior may be partly mediated by integrin-signaling pathways. Tumor growth in vivo was also significantly suppressed by C2GnT-M in the xenografts of nude mice. These results demonstrate that C2GnT-M is frequently downregulated in colorectal cancer and suppresses colon cancer cell growth.

Thermal and photochemistry of a pyrene dihydrodioxin (PDHD) and its radical cation: a photoactivated masking group for ortho-quinones.

Pyrene dihydrodioxins (1 and 2) have been synthesized and shown to be effective photochemical blocking groups for pyrene-4,5-dione (3). The mechanism of quinone release proceeds through the formation of a remarkably stable radical cation. Direct evidence is provided that this radical cation is not only thermally labile but also photochemically labile, and that both pathways lead to quinone extrusion. Once initiated with UV light, the pyrene quinone product serves as an electron-transfer photosensitizer for the further release of quinone with visible light.

Microvessel density, cyclo-oxygenase 2 expression, K-ras mutation and p53 overexpression in colonic cancer.

BACKGROUND: Tumour angiogenesis, cyclo-oxygenase (COX) 2 expression, K-ras mutation and p53 overexpression are commonly involved in colorectal tumorigenesis, but their interrelationship and clinicopathological effects remain inconclusive. METHODS: Clinicopathological data from 114 consecutive patients with primary stage III colorectal cancer were evaluated prospectively. Microvessel density (MVD) of the tumour was defined by counting the number of microvessels in hotspots, visualized by immunocytochemical staining of endothelial CD34. K-ras mutation was analysed by the restriction enzyme cleavage method. COX-2 expression and p53 overexpression were determined by immunocytochemistry. RESULTS: Increased MVD in hotspots was significantly associated with COX-2 expression (P < 0.001), K-ras mutation (P = 0.007) and p53 overexpression (P = 0.006). COX-2 expression was not associated with either K-ras mutation or p53 overexpression. Clinicopathologically, greater MVD and COX-2 expression were significantly associated with vascular invasion of cancer cells (MVD, P = 0.027 and COX-2 expression, P = 0.006), but p53 overexpression and K-ras mutation were not. Multivariate analysis indicated that greater MVD (P = 0.002) and p53 overexpression (P = 0.016) were significant independent predictors of tumour recurrence, whereas COX-2 expression (P = 0.634) and K-ras mutation (P = 0.356) were not. CONCLUSION: Tumour angiogenesis may be associated with tumour metastasis and is significantly influenced by K-ras mutation, p53 overexpression and COX-2 expression in patients with colonic cancer.

Clinicopathological and molecular biological features of colorectal cancer in patients less than 40 years of age.

BACKGROUND: The aim of the present study was to identify the clinicopathological and molecular biological characteristics of early-onset colorectal cancers. METHODS: The clinicopathological and molecular biological parameters of 138 consecutive patients with colorectal cancer aged less than 40 years were compared with those of 339 patients aged 60 years or more. RESULTS: The younger patients with colorectal cancer had more mucin-producing (14.5 versus 4.7 per cent; P < 0.001) and poorly differentiated (7.2 versus 3.3 per cent; P = 0.015) tumours, a higher incidence of synchronous (5.8 versus 1.2 per cent; P = 0.007) and metachronous (4.0 versus 0.6 per cent; P = 0.023) colorectal cancers, and more advanced tumour stage (P < 0.001) than older patients. The operative mortality rate was lower (0.7 versus 5.0 per cent; P = 0.026), and cancer-specific survival was similar (in stage I, II and III disease; P > 0.05) or better (in stage IV disease; 95 per cent confidence interval 22.50 to 28.41 versus 12.61 to 17.05 months; P < 0.001). There was a higher percentage of normal p53 expression (61.1 versus 46.8 per cent; P = 0.023) and high-frequency microsatellite instability (MSI-H) (29.4 versus 6.3 per cent; P < 0.001), and a similar family history of cancer (17.5 versus 14.2 per cent; P > 0.05), compared with older patients. CONCLUSION: Young patients with colorectal cancer have several distinct clinicopathological and molecular biological features. The mechanisms underlying the inconsistency between the presence of MSI-H and a family history of cancer in these early-onset colorectal cancers deserve further investigation.

Neurophysiological effects of recurrent laryngeal and thoracic vagus nerves on mediating the neurogenic inflammation of the trachea, bronchi, and esophagus of rats.

The present study aims to investigate the neurophysiological effects of recurrent laryngeal nerve and thoracic vagus nerve on the non-cholinergic regulation of neurogenic plasma extravasation of the rat trachea, bronchi, and esophagus. Through thoracotomy, three nerve components, the right thoracic vagal trunk, thoracic vagus nerve, and recurrent laryngeal nerve, were identified. The experiment was sequentially conducted in four steps. First, the individual nerve component was electrically stimulated and the induced inflammatory responses, as quantified by the area density of India ink-labelled blood vessels in the trachea, bronchial trees and esophagus, were compared. Second, we assessed the relative importance of medial and lateral side of the right thoracic vagus nerve in inducing the inflammatory responses by alternative stimulation of one side with simultaneous severance of the other side of this nerve. Third, we examined the effects of transection of the lateral half of the right thoracic vagus nerve on the degeneration of axon fibers located at the following three sites: the nerve segment proximal to cutting site, bronchial and esophageal nerve branches. Finally, we directly observed the inflammatory histopathology of the right lower trachea after stimulation of the medial half of the right thoracic vagus nerve with transection of its lateral half. In this study, we found that the right recurrent laryngeal nerve was predominant in mediating the neurogenic inflammatory responses of upper and dorsal portions of trachea, whereas the right thoracic vagus nerve was predominant in mediating those of the right lower ventral wall of trachea, right main bronchus, and right lobar bronchial trees. The axon fibers of the right thoracic vagus nerve responsible for mediating the neurogenic inflammatory responses of the right lower ventral trachea were mainly accumulated in the medial half, whereas those innervating the right main bronchus, right lobar bronchial trees, and lower esophagus were largely in the lateral half of this nerve. Transection of the lateral half of the right thoracic vagus nerve resulted in significant degeneration of myelinated fibers in its bronchial and esophageal nerve branches. Histopathological examination of the right lower trachea after electrical stimulation of the medial half of thoracic vagus nerve demonstrated the silver-stained leaky venules with accumulations of inflammatory cells. We thus concluded that afferent C-fibers to upper and dorsal portions of trachea were mainly from recurrent laryngeal nerve. In contrast, the neurogenic inflammatory responses of the right lower trachea were predominantly mediated by the medial half of the right thoracic vagus nerve, and those of the right main bronchus, bronchial trees and lower esophagus were largely by the lateral half of this nerve.

Color Doppler vascularity index can predict distant metastasis and survival in colon cancer patients.

The purpose of this study was to investigate the clinical usefulness of the color Doppler vascularity index (CDVI) in patients with colon cancer before surgery. Forty-four patients with sonographically visible tumor mass of colon cancer were investigated. The CDVI of each tumor was determined using transabdominal color Doppler ultrasound. The CDVI was defined as the ratio of the number of the colored pixels within a tumor section to the number of total pixels in that specific tumor section and was calculated by using Encomate software (Electronic Business Machine Co. Ltd., Taipei, Taiwan). The correlation between the CDVI and clinicopathological factors, mode of recurrence, and patient survival was studied. For comparison, microvessel density (the mean number of microvessels in three areas of highest vascular density at x200 magnification) of the tumors of these 44 patients was also evaluated by using immunohistochemical staining of surgical specimens with anti-CD34. The microvessel density was not correlated with Dukes' classification, clinicopathological factors, and survival. The CDVI was significantly higher in the patients with lymph node metastases and vascular invasion than in those without such metastases and invasion (P = 0.006 and P = 0.0098, respectively). Moreover, in patients with a high CDVI (> 15%) and positive vascular invasion, survival was significantly poorer than in those with low CDVI (< or = 15%) and negative invasion (P = 0.0037 and 0.0039, respectively). Multivariate analysis indicated that liver metastasis, vascular invasion, and CDVI are independent prognostic factors in the patients with colon cancer. According to the mode of recurrence in 36 patients who underwent curative resection, the frequency of the distant organ recurrence was significantly higher in the high CDVI group (40%) than in the low CDVI group (0%). The CDVI is a good preoperative indicator of recurrence and patient survival in colon cancer. Thus, the CDVI may be helpful in stratifying patients for adjuvant therapy.

Spontaneous bowel perforation in infants and young children: a clinicopathologic analysis of pathogenesis.

BACKGROUND: In children beyond the neonatal stage, spontaneous bowel perforation with no specific cause is rare. It has attracted little notice and does not fit into any established clinical category. This often results in treatment delays. To determine the underlying pathogenesis, a clinicopathologic analysis of this group of patients was performed. METHODS: From 1984 through 1997, 15 previously healthy children (10 boys and 5 girls) with bowel perforations were enrolled in this study. Children in whom the specific cause was established were excluded. The ages of the patients ranged from 3 months to 5 years, 5 months (average age: 2 years, 4 months). Data on clinical course, surgical and pathologic findings, and outcomes were analyzed. RESULTS: All the patients had high fever and acute, watery diarrhea with clinical dehydration. Abdominal distension developed and bowel perforation ensued 5 to 30 days after the onset of diarrhea. In all cases, the perforation consisted of either an isolated patch of bowel (n = 8) or patchy lesions in a segment (n = 7), which was confined to one of the following three anatomic watershed areas: the splenic flexure (n = 7); the lower sigmoid (n = 3); and the ileocecal region (n = 5). One patient died, and three had major sequelae including intra-abdominal abscess, adhesion ileus, and peristomal fistula. Specimens from 13 patients were submitted for histopathologic evaluation. All specimens had acute suppurative inflammation diffusely around the perforation site. Seven had areas of coagulation necrosis of the muscularis propria, especially in the inner circular muscle layer. CONCLUSION: In acute diarrheal diseases, dehydration may cause bowel ischemia and lead to perforation. Physicians should be alert to the possibility of this abdominal catastrophe when progressive abdominal distension followed by acute diarrheal episodes occurs in children.

Hypermethylation of the p16 gene in sporadic T3N0M0 stage colorectal cancers: association with DNA replication error and shorter survival.

Hypermethylation in the promoter region of the p16 gene was suspected to be involved in the tumorigenesis of colorectal cancers, although its clinical and biological significance remains obscure. In this study, we collected 84 T3N0M0 stage primary colorectal cancers that were curatively resected. The clinicopathologic data were reviewed. p16 hypermethylation was determined by a methylation-specific polymerase chain reaction (PCR). p53 overexpression was detected by immunocytochemistry (ICC). The point mutations in the 12 and 13 codons of the K-ras gene were screened by restriction enzyme analysis. Loss of heterozygosity (LOH) of the DCC (Deleted in Colorectal cancer) gene was examined by PCR using primers of the DCC (18q21) microsatellite marker. The DNA replication error (RER) was examined using 7 microsatellite markers at distinct chromosomal loci. p16 hypermethylation, regarded as an indication of p16 inactivation, was evident in 24 (28.6%) of the tumors. No correlation was found between p16 hypermethylation and various clinicopathologic factors, includinig age, sex, tumor location, tumor size, growth pattern, tumor differentiation, mucin production, vascular and/or lymphatic invasion, lymphocyte infiltration of the tumor, and serum level of carcinoembryonic antigen. There was no association between p16 hypermethylation of K-ras gene mutation, p53 overexpression and LOH of the DCC gene. However, p16 hypermethylation was significantly associated with DNA RER (p = 0.01). Survival analysis revealed a significant survival disadvantage of p16-hypermethylated versus non-p16-hypermethylated tumors (p = 0.0001). These findings indicate that p16 hypermethylation plays a role in the carcinogenesis of a subset of colorectal cancers; and the presence of p16 hypermethylation predicts shorter survival in T3N0M0 stage colorectal cancers.