Analysis of the potential risk factors for defecation problems and their bowel management based on the long-term bowel function in patients with persistent cloaca: results of a nationwide survey in Japan.

AIM OF THE STUDY: We conducted a nationwide survey of persistent cloaca (PC) to determine its current status in Japan. This study clarifies the potential risk factors for defecation problems in patients with PC. METHODS: Patient information was obtained via questionnaire, and a total of 213 PC patients who responded to a questionnaire on defecation problems and their bowel functions were enrolled in this study. We evaluated the constipation, incontinence, and soiling as bowel functions. Univariate and multivariate analyses were performed using a logistic regression analysis to clarify the risk factors for defecation problems. RESULTS: Of 213 patients with PC, 55 (25.8%) had defecation problems. A multivariate logistic regression analysis showed that sacral agenesis, as an associated anomaly, was significantly associated with defecation problems (odds ratio [OR] 3.19, 95% confidence interval [CI] 1.11-9.16, p = 0.03). The other multivariate logistic regression analysis showed that the PC patients who underwent antegrade continence enema and regularly took laxatives after anorectoplasty had defecation problems (OR 12.4, 95% CI 2.35-65.6, p = 0.003, OR 2.84, 95% CI 1.24-6.55, p = 0.01). CONCLUSION: Sacral agenesis is the potential risk factor of defecation problems in the patients with PC who underwent anorectoplasty. Those patients require vigorous defecation management.

Valproic acid overcomes transforming growth factor-ß-mediated sorafenib resistance in hepatocellular carcinoma.

Sorafenib is a multi-kinase inhibitor approved for hepatocellular carcinoma, but rarely causes tumor regression in patients with chronic liver diseases. To investigate whether growth factor-mediated signaling is involved in sorafenib resistance, HepG2 and PLC/PRF/5 hepatoma cells were exposed to epidermal growth factor (EGF), hepatocyte growth factor (HGF) or transforming growth factor-ß (TGF-ß) prior to treatment with sorafenib. Furthermore, to identify an effective combination treatment with sorafenib, growth factor-sensitized cells were treated with sorafenib alone or in combination with celecoxib, lovastatin or valproic acid (VPA). Trypan blue staining and Annexin V assays showed that the cytotoxic effect of sorafenib was inhibited by 15-54% in cells sensitized to TGF-ß (P<0.05). Western blotting analysis showed that TGF-ß significantly activated extracellular signal-regulated kinase (ERK)-mediated AKT signaling, and sorafenib failed to suppress both ERK and AKT in TGF-ß-sensitized cells. The decreased anti-tumor effect of sorafenib was rescued by chemical inhibition of ERK and AKT. When TGF-ß-sensitized cells were treated with sorafenib plus VPA, the levels of phosphorylated ERK and AKT were considerably suppressed and the numbers of dead cells were increased by 3.7-5.7-fold compared with those exposed to sorafenib alone (P<0.05). Moreover, low dose sorafenib-induced cell migration was effectively suppressed by combination treatment with sorafenib and VPA. Collectively, TGF-ß/ERK/AKT signaling might play a critical role in sorafenib resistance in hepatoma cells, and combination treatment with VPA may be effective against this drug resistance.

Blockade of ataxia telangiectasia mutated sensitizes hepatoma cell lines to sorafenib by interfering with Akt signaling.

Sorafenib is a multi-kinase inhibitor applicable to hepatocellular carcinoma (HCC), but its limited therapeutic effects are a major problem to be solved. Here, we show that blockade of ataxia telangiectasia mutated (ATM) improves the antitumor effects of sorafenib. When hepatoma cell lines HepG2 and PLC/PRF/5 were treated with sorafenib plus ATM small inhibitory RNAs, ATM inhibitor KU55933 or caffeine, Akt signaling was suppressed and the cytotoxic effects were significantly potentiated. Moreover, ATM inhibition effectively suppressed the sorafenib-induced cell migration. Taken together, manipulation of ATM activity might be a useful strategy for improving sorafenib treatment of HCC.

Effects of neuromodulation with sacral magnetic stimulation for intractable bowel or bladder dysfunction in postoperative patients with anorectal malformation: a preliminary report.

BACKGROUND AND PURPOSE: The effects of neuromodulation with sacral magnetic stimulation (SMS) were examined in postoperative patients with bowel or bladder dysfunction. PATIENTS AND METHODS: SMS was performed at the S3 level using a MagPro® instrument (Medtronic Inc., USA) while the patients were under light sedation. One treatment course consisted of stimulation delivered at 15 Hz for 5 s, 10 times over an interval of 1 min. Three patients with bladder or bowel dysfunction refractory to conservative treatment were examined. RESULTS: Case 1 is a 7-year-old male with a rectourethral fistula. This patient developed a hyperdynamic bladder after a laparoscopic pull-through operation at the age of 7 months. The administration of an anticholinergic agent slightly improved the condition. SMS was started at the age of 4 years with one trial each year. A marked expansion of bladder volume from 20 ml before trial to 120 ml after the third trial was obtained. Case 2 (a 4-year old female with a recto-vaginal fistula) and Case 3 (a 8-year-old female with an ano-vestibular fistula) showed severe constipation after radical surgery during infancy. Case 2 needed appendicostomy. After SMS, bowel movements could become controllable with enemas. No adverse effects were observed for any of the three cases. CONCLUSIONS: These results suggest that SMS might be a useful modality to improve postoperative bowel or bladder dysfunction.

Effect of sacral magnetic stimulation on the anorectal manometric activity: a new modality for examining sacro-rectoanal interaction.

We examined the interaction between the sacral neural system and the anorectal activity using a technique comprising repetitive magnetic stimulation. Thirteen control children without any bowel dysmotility (age range; 3 month old to 15 year old), 20 patients with chronic constipation (1 month old to 14 year old), and nine pre-operative patients with Hirschsprung's disease (1 month old to 6 year old) were examined. Magnetic stimulation was applied at the S3 level using the MagPro (Medtronic) device while simultaneously performing manometric recordings of the anorectal activity. In the 13 controls and the 20 patients with chronic constipation, the rectoanal reflex was demonstrated by balloon rectal dilatation. The sphincter response to magnetic stimulation was biphasic in the controls, consisting of an initial rise followed by a decrease in the sphincter pressure, while it varied among the patients with chronic constipation including a biphasic response in 16 patients, no response in three patients, and only a transient rise in pressure in one patient. In nine pre-operative patients with Hirschsprung's disease, no rectoanal reflex was observed, however, the sphincter pressure increased due to magnetic stimulation in six patients, while three patients exhibited no recordable responses. These results suggest that the repetitive magnetic stimulation technique is a valuable modality for investigating the neural interaction between the sacral nervous system and the anorectum.

Fecoflowmetric profiles in postoperative patients with Hirschsprung's disease.

PURPOSE: The objective of this study is to evaluate the anorectal function from the viewpoint of fecoflowmetry in postoperative patients with Hirschsprung's disease (HD). METHODS: This study evaluated 23 long-term follow-up patients who had undergone a radical operation for HD. Their mean age was 11 years. The types of HD included rectosigmoid colon type, 18 cases, and entire colon type, 5 cases. An anorectal manometric study was performed before fecoflowmetry. After normal saline solution was administrated as an imitation stool into the rectal cavity under pressure monitoring, the patients defecated on a fecoflowmeter. After discussing the maximum defecation flow (Flow-max), fecoflow pattern (FFP), tolerance rate (TR), anal canal pressure (AP), and Kelly's clinical scores (Kelly-Scores), the significant parameters were identified to elucidate the anorectal activity. RESULTS: (1) A close relationship was observed between the FFP and Kelly-Scores (P = .0027). (2) Flow-max, TR, and AP in patients with good Kelly-Scores were significantly higher than those in patients with fair Kelly-Scores (P < .05). (3) The Flow-max accurately reflected the TR, Kelly-Scores, and AP. Flow-max >45 mL per second, TR >70%, or AP >30 mm Hg was statistically regarded as a borderline level of fecal continence (P < .002). CONCLUSIONS: The Flow-max and FFP are considered to be useful parameters for postoperative patients with HD.

Effects of the herbal medicine Inchinko-to on liver function in postoperative patients with biliary atresia--a pilot study.

BACKGROUND/PURPOSE: A continuation of liver fibrosis after undergoing successful Kasai operation has become the important clinical issue in the long-term follow-up of patients with biliary atresia (BA). The aim of this study is to evaluate the efficacy of the herbal medicine Inchinko-to (TJ-135) on the treatment of liver fibrosis in patients with BA without jaundice, especially from the viewpoint of the long-term effects of TJ-135. METHODS: Six postoperative patients with BA ranging between 3 and 13 years of age with normal serum total bilirubin levels (total bilirubin < 1.0 mg/dL [17 micromol/L]) received TJ-135 from 2 to 4 years. The liver enzyme (glutamic oxaloacetic transaminase [GOT], glutamic pyruvic transaminase [GPT], gamma glutamyl transpeptidase[gamma-GTP]transpeptidase[gamma-GTP] levels and hyaluronic acid (HA) levels were compared before and after the administration of TJ-135. The monthly collected data were averaged on a 1-year basis. The record of one postoperative patient with BA and a normal serum total bilirubin level was incorporated as a control. This patient showed portal hypertension and did not receive TJ-135. RESULTS: Five of the six patients who showed abnormal values for liver enzymes, exhibited a significant decrease in serum GOT, gamma-GTP, or GPT levels after a 1 to 3-year administration of TJ-135, and the improvement in these parameters persisted thereafter. Furthermore, one patient who had an abnormally high value of HA also showed a significant decrease in the serum level of HA. In the remaining patient with normal liver enzyme values, no significant change was observed during the administration of TJ-135. The control patient exhibited a chronological decrease in the serum GOT and GPT levels by 5 years of age, but the serum gamma-GTP and HA levels remained stable throughout the postoperative period. CONCLUSIONS: The long-term effectiveness of TJ-135 was only found in those patients with abnormal liver enzyme levels and HA, thereby suggesting that TJ-135 has a protective and antifibrotic effect on the liver.