Neoadjuvant chemoradiotherapy followed by esophagectomy vs. surgery alone in the treatment of resectable esophageal squamous cell carcinoma.

In order to improve the survival of esophageal cancer patients, a trimodality therapy consisting of esophagectomy in combination with neoadjuvant chemoradiotherapy (CRT) has been developed. In this study, we evaluated whether neoadjuvant CRT improved the outcomes of patients with resectable esophageal squamous cell carcinoma (ESCC) compared to surgery alone. Eighty-eight patients with resectable ESCC were treated with either neoadjuvant CRT followed by surgical resection (Group A, n=52), or surgery alone (Group B, n=36). CRT consisted of 5-fluorouracil (5-FU, 500 mg/m2 on days 1-5) and cisplatin (CDDP, 10-20 mg/kg body weight on days 1-5), repeated after 3 weeks. Survival analysis was performed using the log-rank test with the Kaplan-Meier method. The clinical response of the primary tumor and metastatic nodes was 80.8%. The postoperative complications profile was similar between the two groups, except for anastomotic leakage. The median survival time (MST) was not reached in Group A and was 27.4 months in Group B. The estimated 5-year overall survival (OS) rate was 50.3% in Group A and 39.9% in Group B (P=0.134). As regards stage II/III disease, Group A exhibited a better disease-free survival (DFS) compared to Group B (5-year DFS: 57.2% in Group A vs. 31.4% in Group B; P=0.025). Simultaneous locoregional and distant recurrences were more common in the surgery alone group (Group B, P=0.047). Neoadjuvant CRT with 5-FU and CDDP did not contribute to a better prognosis in patients with resectable ESCC. However, it may be beneficial for patients with stage II/III disease.

Trimodality therapy of esophagectomy plus neoadjuvant chemoradiotherapy improves the survival of clinical stage II/III esophageal squamous cell carcinoma patients.

The prognosis of advanced esophageal cancer patients is poor. Trimodality therapy of surgical resection plus neoadjuvant chemoradiotherapy (CRT) has been developed to improve survival through locoregional control, leading to prevention of micrometastasis. We investigated whether or not neoadjuvant CRT led to survival benefits in TNM stage II/III esophageal cancer patients. We retrospectively reviewed 62 patients with stage II or III esophageal squamous cell carcinoma (ESCC) treated with neoadjuvant CRT. All patients received esophagectomy 4-7 weeks after CRT consisting of 40 Gy irradiation and chemotherapy (5-FU, 500 mg/m2/day, days 1-5 and cisplatin, 10-20 mg/body, days 1-5). Clinical response and survival rates were analyzed using Kaplan-Meier methods, with p<0.05 considered as significant. The clinical effect rate of CRT for both primary tumors and metastatic nodes was 82.3%. Operative and hospital mortality rates were 1.65 and 6.5%, respectively. The 3-year overall survival (OS) and disease-free survival (DFS) rates were 52.6 and 49.2%, respectively. A significant difference was noted between stages II and III for both OS and DFS. The 5-year OS rates were 64.2% for stage II, 33.1% for stage III (T4 and non-T4) and 46.9% for stage III (non-T4 only) patients. The depth of tumor invasion (T3 vs. T4), resectability (R0 vs. R1, R2), lymph node metastasis (positive vs. negative), and the effect of CRT were proven to be independent prognostic factors for univariate analysis, with resectability and the effect of CRT for multivariate analysis. These data suggest that CRT in stage II/III (non-T4) ESCC patient contributed to tumor shrinkage, leading to higher resectability and longer survival. Neoadjuvant CRT appears to be a promising option for these patients.

Surgery for ulcerative colitis in 1,000 patients.

BACKGROUND AND AIMS: Ileal pouch-anal anastomosis (IPAA) has become the standard treatment for patients with ulcerative colitis (UC) who ultimately require a colectomy. Herein, we report results of our 24-year experience with that surgical method at our hospital. PATIENTS AND METHODS: Data were collected regarding surgical procedures and postoperative pathologic diagnoses for 1,000 UC patients, with early and late complications also noted. The pouch functioning rate was calculated using the Kaplan-Meier method. RESULTS: We performed 1,000 operations for UC over a 24-year period. The mean patient age at the time of operation was 35 years, and the most frequent indication for a colectomy was intractable disease. The overall rates of pouch success after 10 and 20 years were 97% and 89%, respectively. During the study period, 944 patients underwent IPAA at our hospital, of whom 12 (1.3%) were eventually diagnosed with Crohn's disease (CD). Pouch success was higher in patients with UC, with a functioning ileal pouch after 10 and 20 years found in 97% and 92%, respectfully, whereas the proportions of patients with CD and a functioning ileal pouch were lower at 82% and 20%, respectively (p < 0.01). CONCLUSION: A restorative proctocolectomy with an IPAA is a safe procedure, with low rates of mortality and major morbidity. We do not recommend routine application of IPAA in any subset of patients with known CD.

[Gastrojejunostomy for irresectable gastric cancer with pyloric stenosis-new role of surgery in the era of S-1].

We report a patient with an advanced gastric cancer complicated by pyloric stenosis who was effectively treated by S-1 mono-therapy after gastrojejunostomy. A 62-year-old man consulted a general practitioner for abdominal pain and anorexia. Gastric roentgenography and upper gastrointestinal endoscopy showed gastric cancer(Borrmann Type 3) with pyloric stenosis. He was referred to our department. He underwent laparotomy, which revealed a T4 tumor invading the pancreas head, but neither liver nor peritoneal metastasis. A gastrojejunostomy was made. After the operation, chemotherapy of S-1(120 mg/day, day 1-21)+cisplatin(100 mg/day, day 8)was administered. After 2 courses, level of tumor marker decreased remarkably and abdominal enhanced computed tomography showed a significant size reduction of lymph nodes and that direct invasion to the pancreas was not clear any more. Second laparotomy was carried out and curative surgery was performed. After 4 courses of S-1(120 mg/day, day 1 approximately 28)mono-therapy as adjuvant chemotherapy, bone metastasis was confirmed by scintigram. Then methotrexate+5-FU, irinotecan+cisplatin and cisplatin+paclitaxel were chosen as second-, third-and fourth-line chemotherapy, which were not effective for long. He died 572 a days after the initial surgery. In the past, gastrojejunostomy was regarded as useful palliative treatment for those with gastric outlet stenosis to ameliorate the QOL. As S-1 is taking major role in the chemotherapy for advanced gastric cancer recently, usefulness of bypass surgery for such patients is highlighted even for longer survival time.

Extracellular adenosine induces apoptosis in Caco-2 human colonic cancer cells by activating caspase-9/-3 via A(2a) adenosine receptors.

BACKGROUND: Extracellular adenosine has been shown to induce apoptosis in a variety of cells via an intrinsic pathway linked to adenosine uptake into cells and the ensuing signaling cascades and an extrinsic pathway linked to adenosine receptors. The present study was designed to understand the mechanism underlying adenosine-induced apoptosis of Caco-2 human colonic cancer cells. METHODS: To observe cell viability, an MTT assay was carried out in Caco-2 cells untransfected or transfected with the A(2a) adenosine receptor pcDNA3.1. Apoptotic cell death was assessed with flow cytometry using propidium iodide and annexin V and internucleosomal DNA fragmentation analysis. Activities of caspase-3, -8, and -9 were measured using a caspase fluorometric assay kit. Mitochondrial membrane potentials were monitored using a DePsipher kit. Expression of adenosine receptors was examined with the reverse transcription-polymerase chain reaction (RT-PCR) method. RESULTS: Extracellular adenosine induced Caco-2 cell apoptosis in a concentration-dependent (1-20 mM) and treatment time-dependent (24-72 h) manner. The adenosine effect was inhibited by DMPX, an inhibitor of A(2a) adenosine receptors and SQ22536, an inhibitor of adenylate cyclase. CGS21680, an agonist of A(2a) adenosine receptors, and forskolin, an adenylate cyclase activator, mimicked the adenosine action. Caco-2 cell death was still induced by overexpressing A(2a) adenosine receptors, and adenosine further promoted the cell death. Adenosine disrupted mitochondrial membrane potentials and activated caspase-9 and -3, but not caspase-8. CONCLUSIONS: Extracellular adenosine induces apoptosis in Caco-2 cells by activating caspase-9 and the downstream effector caspase caspase-3 in association with mitochondrial damage via A(2a) adenosine receptors.

Pouchitis atlas for objective endoscopic diagnosis.

"Pouchitis" is a term for nonspecific mucosal inflammation of the pouch after total proctocolectomy and ileal pouch-anal anastomosis for ulcerative colitis. Pouchitis is the most frequent complication of the pelvic pouch at the late stage. To improve the accuracy of the pouchitis diagnosis, sets of clinical symptoms and endoscopic findings (with or without histology of biopsy samples) have previously been evaluated. Endoscopic findings are central to the diagnosis, and a universal consensus of various endoscopic findings must be the initial step toward an objective diagnosis of pouchitis. Since a proper signpost for the endoscopic evaluation of pouchitis has been absent, we developed this pouchitis atlas to minimize the diagnostic variation inherent among individual endoscopists. We also propose new criteria for the diagnosis of pouchitis: the Japanese criteria for diagnosis of pouchitis. These criteria are based on clinical symptoms and endoscopic findings that are clearly categorized in the atlas, and exclude infectious enteritis, anastomotic insufficiency, pelvic infection, anal dysfunction, and Crohn's disease. Advantages of the new criteria include ease of bedside diagnosis, without the calculation of points required by the other criteria for pouchitis. This pouchitis atlas, together with our new criteria, should contribute to the establishment of a clear-cut diagnosis for pouchitis and promote better evaluation and treatment of this novel intestinal inflammation.

Cyclooxygenase-2 expression after preoperative chemoradiotherapy correlates with more frequent esophageal cancer recurrence.

AIM: To investigate the relationship between cycloo-xygenase-2 (COX-2), and vascular endothelial growth factor (VEGF), and to determine the clinical significance of this relationship in esophageal cancer patients undergoing chemoradiotherapy (CRT). METHODS: Immunohistochemical staining was used to evaluate COX-2 and VEGF expression in 40 patients with histologically-confirmed esophageal squamous carcinoma (ESCC) who were undergoing preoperative CRT. RESULTS: Fourteen out of 40 ESCC patients showed a pathological complete response (CR) after CRT. COX-2 and VEGF protein expressions were observed in the cytoplasm of 17 and 13 tumors, respectively, with null expression in 9 and 13 tumors, respectively. COX-2 expression was strongly correlated with VEGF expression (P<0.05). There were also significant associations between COX-2 expression, tumor recurrence, and lymph-node involvement (P=0.0277 and P=0.0095, respectively). COX-2 expression and VEGF expression had significant prognostic value for disease-free survival (log-rank test; P=0.0073 and P=0.0341, respectively), but not for overall survival, as assessed by univariate analysis. CONCLUSION: Our results suggest that COX-2 expression correlates with VEGF expression and might be a useful prognostic factor for more frequent tumor recurrence in ESCC patients undergoing neoadjuvant CRT. These findings support the use of anti-angiogenic COX-2 inhibitors in the treatment of ESCC.

A case of solid neuroendocrine carcinoma of the breast in a 40-year-old woman.

We report a case of neuroendocrine carcinoma in a 40-year-old woman who presented with two lumps in her left breast. Mammography failed to reveal any lesions because she had so-called dense breasts, but ultrasonography showed 4 irregular hypoechoic masses. Magnetic resonance imaging also showed 4 homogeneous lobulated tumors with early contrast enhancement, suggesting malignancy. Core needle biopsy and subsequent immunohistochemical examination of the specimens was performed. Neuroendocrine carcinoma was diagnosed. The tumor cells were diffusely positive for chromogranin A and synaptophysin, and some were positive for CD56. We performed total mastectomy with sentinel lymph node biopsy, which showed no metastasis. Recurrence has not been detected at 36 months after surgery.

[A long survival case of sigmoid colon cancer patient with initially unresectable hepatic metastases].

The prognosis of a colorectal cancer patient with unresectable hepatic metastases is extremely poor. To improve the prognosis, when the hepatic metastases were initially unresectable, we performed second-look hepatectomy (s-l hepatectomy) after neoadjuvant hepatic arterial 5-FU infusion plus UFT (HAI-PMC). Here, we report the case of a sigmoid colon cancer patient with initially unresectable hepatic metastases showing a prolonged survival (6.5 years) by second-look operation after HAI-PMC. A 57-year-old woman was diagnosed with sigmoid colon cancer with unresectable liver metastases. Sigmoidectomy and hepatic arterial catheterization were performed in the initial operation, and HAI-PMC was performed 6 months after. Metastatic foci of the liver had shrunk (90.9%), but solitary metastatic lung cancer was detected during HAI. As no other metastatic lesion was observed, partial resection of the liver and lung was performed as a second-look operation, 6 months after the initial operation. The woman continued venous infusion chemotherapy as an outpatient, and she survived for 6.5 years after the initial operation. This result suggests that strategic multidisciplinary treatment utilizing s-l hepatectomy after neoadjuvant chemotherapy can lead to better prognosis for colorectal cancer patients with hepatic metastases.

Luminally released serotonin stimulates colonic motility and accelerates colonic transit in rats.

Enterochromaffin (EC) cells of the epithelial cells release 5-HT into the lumen, as well as basolateral border. However, the physiological role of released 5-HT into the lumen is poorly understood. Concentrations of 5-HT in the colonic mucosa, colonic lumen, and feces were measured by HPLC in rats. To investigate whether intraluminal 5-HT accelerates colonic transit, 5-HT and (51)Cr were administered into the lumen of the proximal colon, and colonic transit was measured. To investigate whether 5-HT is released into the lumen, we used an ex vivo model of isolated vascularly and luminally perfused rat proximal colon. To investigate whether luminal 5-HT is involved in regulating stress-induced colonic motility, the distal colonic motility was recorded under the stress loading, and a 5-HT(3) receptor antagonist (ondansetron, 10(-6) M, 0.5 ml) was administered intraluminally of the distal colon. Tissue content of 5-HT in the proximal colon (15.2 +/- 4.3 ng/mg wet tissue) was significantly higher than that in the distal colon (3.3 +/- 0.7 ng/mg wet tissue), while fecal content and luminal concentration of 5-HT was almost the same between the proximal and distal colon. Luminal administration of 5-HT (10(-6)-10(-5) M) significantly accelerated colonic transit. Elevation of intraluminal pressure by 10 cmH(2)O significantly increased the luminal concentration of 5-HT but not the vascular concentration of 5-HT. Stress-induced stimulation of the distal colonic motility was significantly attenuated by the luminal administration of ondansetron. These results suggest that luminally released 5-HT from EC cells plays an important role in regulating colonic motility in rats.

Restraint stress stimulates colonic motility via central corticotropin-releasing factor and peripheral 5-HT3 receptors in conscious rats.

Although restraint stress accelerates colonic transit via a central corticotropin-releasing factor (CRF), the precise mechanism still remains unclear. We tested the hypothesis that restraint stress and central CRF stimulate colonic motility and transit via a vagal pathway and 5-HT(3) receptors of the proximal colon in rats. (51)Cr was injected via the catheter positioned in the proximal colon to measure colonic transit. The rats were subjected to a restraint stress for 90 min or received intracisternal injection of CRF. Ninety minutes after the administration of (51)Cr, the entire colon was removed, and the geometric center (GC) was calculated. Four force transducers were sutured on the proximal, mid, and distal colon to record colonic motility. Restraint stress accelerated colonic transit (GC of 6.7 +/- 0.4, n=6) compared with nonrestraint controls (GC of 5.1 +/- 0.2, n=6). Intracisternal injection of CRF (1.0 microg) also accelerated colonic transit (GC of 7.0 +/- 0.2, n=6) compared with saline-injected group (GC of 4.6 +/- 0.5, n=6). Restraint stress-induced acceleration of colonic transit was reduced by perivagal capsaicin treatment. Intracisternal injection of CRF antagonists (10 microg astressin) abolished restraint stress-induced acceleration of colonic transit. Stimulated colonic transit and motility induced by restraint stress and CRF were significantly reduced by the intraluminal administration of 5-HT(3) antagonist ondansetron (5 x 10(-6) M; 1 ml) into the proximal colon. Restraint stress and intracisternal injection of CRF significantly increased the luminal content of 5-HT of the proximal colon. It is suggested that restraint stress stimulates colonic motility via central CRF and peripheral 5-HT(3) receptors in conscious rats.

Incidence of and risk factors for dysplasia in mucosectomy area in ulcerative colitis patients undergoing restorative proctocolectomy.

BACKGROUND AND AIMS: We evaluated the incidence of dysplasia in the mucosectomy area using resected specimens to determine preoperative risk factors for the occurrence of dysplasia in this area. PATIENTS AND METHODS: We prospectively studied a consecutive series of 137 patients, each of whom underwent a restorative proctocolectomy with a mucosectomy and hand-sewn ileal J-pouch anal anastomosis between January 2003 and December 2004. Sections from the anal transitional zone mucosa were taken from the dentate line to 2.5 cm above the resected line and stained with hematoxylin and eosin then characterized as indefinite for dysplasia, low-grade dysplasia, and high-grade dysplasia based on the criteria of an international working group for rectal mucosal atypia. RESULTS: Dysplasia of the mucosectomy area was present in six (4.4%) of the patients, including one with low-grade and five with high-grade dysplasia. A multivariate analysis showed relations between age at time of surgery (>or=40 years) and duration of disease (>or=10 years) with a risk for development of mucosectomy area dysplasia. CONCLUSION: The incidence of dysplasia of the mucosectomy area was 4.4%, and preoperative risk factors were shown to be duration of disease and age at time of surgery.

Persistent CXCR4 expression after preoperative chemoradiotherapy predicts early recurrence and poor prognosis in esophageal cancer.

AIM: To study the effect of CXC chemokine receptor-4 (CXCR4) expression on disease progression and prognosis in esophageal cancer. METHODS: CXCR4 expression was evaluated in 37 patients with histologically confirmed esophageal squamous carcinomas (ESCC) undergoing preoperative chemoradiotherapy (CRT) by immunohistochemical staining. RESULTS: Eleven out of 37 ESCC patients showed a pathological complete response (CR) after CRT. CXCR4 protein expression was observed in cell cytoplasms of 13 tumors, and null expression was seen in 13 tumors. Distant recurrence was significantly more common in patients with positive CXCR4 expression (P = 0.0318). After a median follow-up time of 31.6 mo, 19 patients progressed (12 of 19 expressed positive CXCR4) and 11 died (10 of 11 expressed positive CXCR4). Overall survival was significantly correlated with lymph node metastasis (952.1 +/- 53.8 d in negative group vs 475.1 +/- 56.2 d in positive group, P = 0.023), distant metastasis (874.0 +/- 60.4 d in negative group vs 434.9 +/- 75.2 d in positive group, P = 0.014) and CRT (811.5 +/- 51.2 d in responder group vs 459.6 +/- 94.0 d in non-responder group, P = 0.00038) and further with an absence of CXCR4 expression or no residual tumor (959.8 +/- 51.0 d in null expression or no tumor group vs 412.0 +/- 57.1 d in positive expression group, P = 0.0001). CONCLUSION: Persistent positive CXCR4 expression is implicated in tumor aggressiveness and poor prognosis in ESCC after CRT, and preoperative CRT may improve the prognosis of ESCC via CXCL12-CXCR4 signaling pathway.

Leukocyte removal therapy for ulcerative colitis does not affect postoperative complications.

BACKGROUND: We investigated the incidence of postoperative complications in patients treated with or without preoperative leukocyte removal therapy (LRT). METHODS: The case notes of 387 patients with ulcerative colitis (UC) who underwent surgical intervention were retrospectively reviewed. One hundred nine patients were treated with LRT within 8 weeks before surgery (LRT group), and 278 had not received LRT since at least 8 weeks before surgery (without LRT group). We reviewed the postoperative complications according to type of initial operation. RESULTS: Of the patients who underwent an ileal J-pouch anal anastomosis (IPAA) without an ileostomy, 3 (6.5%) in the LRT group developed pouch-related complications (PRC), while 11 (7.5%) in the without LRT group developed PRC. The overall postoperative complication rates were 28.3% in the LRT group and 21.8% in the without LRT group. For patients who underwent an IPAA with an ileostomy, the overall rates of postoperative complications were 39.1% in the LRT group and 31.8% in the without LRT group. Among those undergoing a total colectomy, 33.3% in the LRT group and 18.2% in the without LRT group had postoperative complications. No statistically significant differences were demonstrated between the two groups with respect to postoperative complications. CONCLUSIONS: Our results suggest that preoperative LRT does not influence the rate of postoperative complications in UC patients.

ECA39 is a novel distant metastasis-related biomarker in colorectal cancer.

AIM: To investigate the possible role of polysaccharide-K (PSK) -related markers in predicting distant metastasis and in the clinical outcome of colorectal cancer (CRC). METHODS: Firstly, we used protein microarrays to analyze the in vitro expression profiles of potential PSK-related markers in the human colorectal adenocarcinoma cell line SW480, which carries a mutant p53 gene. Then, we investigated the clinical implications of these markers in the prognosis of CRC patients. RESULTS: ECA39, a direct target of c-Myc, was identified as a candidate protein affected by the anti-metastatic effects of PSK. Immunohistochemistry revealed that ECA39 was expressed at significantly higher levels in tumor tissues with distant metastases compared to those without (P<0.00001). Positive ECA39 expression was shown to be highly reliable for the prediction of distant metastases (sensitivity: 86.7%, specificity: 90%, positive predictive value: 86.7%, negative predictive value: 90%). A significantly higher cumulative 5-yr disease free survival rate was observed in the ECA39-negative patient group (77.3%) compared with the ECA39-positive patient group (25.8%) (P<0.05). CONCLUSION: Our results suggest that ECA39 is a dominant predictive factor for distant metastasis in patients with advanced CRC and that its suppression by PSK might represent a useful application of immunotherapy as part of a program of integrated medicine.

Diffuse gastroduodenitis and pouchitis associated with ulcerative colitis.

We experienced a very rare case of ulcerative colitis (UC) accompanied with analogous lesions in the stomach, duodenum, and ileal J-pouch. Ileal J-pouch anal anastomosis was performed on a 29-year old woman in 1996. Six years later, she was admitted again to our hospital because of epigastralgia, nausea, watery diarrhea and low fever. Based on the results of endoscopic examination, we diagnosed it as pouchitis. Moreover, on hypotonic duodenography, expansion of the duodenal bulb and the descending portion were poor. Kerckring folds disappeared with typical lead-pipe appearance. The pathogenesis of the gastric and duodenal lesion in this patient was similar to that of the colonic lesions of UC. For the gastroduodenal lesions in this patient, symptomatic remission was obtained following administration of crushed mesalazine tablets (1500 mg/d) for 14 d with continuous administration of omeprazole. Firstly we used ciprofloxacin to treat pouchitis. On the fifth day, she got a fever because of catheter infection. In the catheter culture, methicillin-resistant Staphylococcus aureus (MRSA) was detected. Therefore we changed ciprofloxacin to vancomycin hydrochloride (Vancomycin). Vancomycin was very effective, and the stool frequency dramatically improved in three days. Now she continues to take mesalazine, but her condition is stable and there has been no recurrence of pouchitis.

Clinical significance of hiatal hernia in the development of gastroesophageal reflux after distal gastrectomy for cancer of the stomach.

BACKGROUND AND AIMS: The relationship between gastroesophageal reflux disease and sliding hernia is controversial, especially following distal partial gastrectomy in patients with gastric cancer. The aim of this study was to examine the relationship between gastroesophageal reflux disease and sliding hernia of the esophagus after distal gastrectomy using the gastroesophageal scintigraphy and endoscopy. METHODS: Forty-five distal gastrectomy patients diagnosed with cancer of the stomach were studied. Twenty-five patients presented with reflux symptoms, such as heartburn and/or regurgitation and 20 patients exhibited no reflux symptoms. All of the patients were examined by gastroesophageal scintigraphy and their reflux indices were determined. Thirty-eight of the patients underwent upper endoscopy and both sliding hernias and reflux symptoms were classified as mild or severe. RESULTS: Sliding hernias were diagnosed in all of the subjects and 65.8% of the patients exhibited reflux symptoms. Evidence of endoscopic esophagitis was noted in only 39.5% of the patients. The reflux indices for the mild and severe hernia groups were 5.03 +/- 2.2 and 10.3 +/- 6.4, respectively (P < 0.05). More severely symptomatic esophagitis was prevalent in the severe hernia group in comparison to the mild group (P < 0.05). CONCLUSION: The results suggest that the onset of gastroesophageal reflux after distal gastrectomy is induced by the surgical procedures and that hiatal hernia may be an important factor in the etiology of reflux esophagitis.

Postoperative joint symptoms: a risk factor for pouchitis in ulcerative colitis patients.

BACKGROUND: The prevalence and significance of joint symptoms appearing in patients with ulcerative colitis (UC) following a colectomy are unclear. AIM: We investigated the relationship between joint symptoms during steroid tapering following an ileal pouch-anal anastomosis (IPAA) and the cumulative risk for developing pouchitis. PATIENTS AND METHODS: The medical records of 571 patients who underwent an IPAA with a mucosectomy were retrospectively reviewed to evaluate their joint symptoms. A diagnosis of pouchitis was obtained using the Pouchitis Disease Activity Index (PDAI) and the cumulative risk of pouchitis was estimated using a Kaplan-Meier life table analysis. RESULTS: Joint symptoms during steroid tapering were reported by 126 (22.0%) of the UC patients and each of those had involvement of the small joints of the hand. The main symptoms were pain and stiffness, especially in the morning. The cumulative risk for developing pouchitis after 10 years was found to be 20% in patients who experienced joint symptoms during steroid tapering and 10% in those without those symptoms (p = 0.001). CONCLUSION: The presence of joint symptoms during steroid tapering is a significant risk factor for the development of pouchitis in patients who have undergone an IPAA for UC.

A(1) adenosine receptor signal and AMPK involving caspase-9/-3 activation are responsible for adenosine-induced RCR-1 astrocytoma cell death.

Extracellular adenosine reduced viability of RCR-1 rat astrocytoma cells in a dose (0.3-10mM)- and treatment time (24-72h)-dependent manner. In the apoptosis assay using propidium iodide (PI) and annexin V, treatment with adenosine (1mM) for 72h increased the population of PI-negative/annexin V-positive cells, that is related to early apoptosis, and that of PI-positive/annexin V-positive cells, that is related to late apoptosis/secondary necrosis. In addition, nuclei of cells treated with adenosine (1mM) for 72h were reactive to an antibody against single-stranded DNA. Adenosine activated caspase-3, -8 and -9, but mitochondrial membrane potentials were not affected. Adenosine-induced RCR-1 cell death was significantly inhibited by 8-CPT, an antagonist of A(1) adenosine receptors, and forskolin, an adenylate cyclase activator. SQ22536, an adenylate cyclase inhibitor, alternatively, exhibited an effect similar to adenosine. CHA, an agonist of A(1) adenosine receptors, activated caspase-3 and -9, but not caspase-8. Adenosine-induced cytotoxicity of RCR-1 cells was also significantly inhibited by dipyridamole, an inhibitor of adenosine transporter, and AMDA, an inhibitor of adenosine kinase. AICAR, an activator of AMP-activated protein kinase (AMPK), reduced RCR-1 cell viability, but synergistic effect was not obtained with co-treatment with adenosine and AICAR. AICAR activated caspase-3 and -9, but not caspase-8. An additive inhibition was found in the co-presence of 8-CPT and dipyridamole. Extracellular adenosine, thus, appears to activate caspase-9 followed by the effector caspase, caspase-3, at least via two independent pathways linked to A(1) adenosine receptor-mediated adenylate cyclase inhibition and adenosine uptake into cells/conversion to AMP/activation of AMPK, possibly regardless of mitochondrial damage, thereby leading to RCR-1 cell death, dominantly by apoptosis. Moreover, caspase-8 activation could again contribute to adenosine-induced cytotoxicity, although the underlying mechanism is currently unknown. Collectively, the results of the present study may represent a new pathway for caspase activation relevant to diverse adenosine signals in cell death.

Successful chemotherapeutic modality of doxorubicin plus dacarbazine for the treatment of desmoid tumors in association with familial adenomatous polyposis.

PURPOSE: Desmoid tumors are locally aggressive and can be fatal in familial adenomatous polyposis (FAP) patients if they are not suitable for surgery or radiation therapy. Here, we prospectively investigated the efficacy of a chemotherapeutic regimen involving doxorubicin (DOX) and dacarbazine (DTIC) for inoperable FAP-associated desmoid tumors. PATIENTS AND METHODS: From an initial group of 120 FAP patients, seven of the 11 individuals with symptomatic unresectable desmoid tumors that were unresponsive to conventional hormone therapy were enrolled onto this study. The general chemotherapy regimen comprised four or five cycles of DOX (20 mg/m2 daily) plus DTIC (150 mg/m2 daily) throughout 4 days of drip intravenous infusion (day 1 through 4) every 28 days, followed by the cyclooxygenase-2 inhibitor meloxicam (10 mg/m2). The primary end point was relapse-free survival. The secondary end points included toxicity, clinical improvement, and tumor regression according to computed tomography. RESULTS: Significant tumor regression was observed clinically and radiologically in all seven patients. Three patients showed a complete response. The average progression-free survival period was 74.0 months (range, 32.5 to 107.5 months). Three patients showed grade 3 adverse events with no treatment-related mortality. All seven patients survived and remained without tumor progression. An adenomatous polyposis coli germline-mutation analysis revealed no mutations in the specified regions. CONCLUSION: A chemotherapeutic regimen of DOX plus DTIC followed by meloxicam is an effective and safe treatment for FAP-associated desmoid tumors. This modality should be considered for use as first-line chemotherapy in symptomatic desmoid tumors that are unresponsive to conventional medical therapy, due to the absence of useful presymptomatic markers.