Long-Term Outcomes of Bariatric and Metabolic Surgery in Japan: Results of a Multi-Institutional Survey.

BACKGROUND: The number of bariatric procedures performed in Japan is increasing. There are isolated reports of bariatric surgery, but there have been no nationwide surveys including long-term data. METHODS: We retrospectively reviewed data for patients who underwent bariatric and metabolic surgery throughout Japan and reviewed outcomes. Surveys were sent to ten institutions for number of procedures, preoperative patient weight and preoperative obesity-related comorbidities, and data at 1, 3, and 5 years postoperatively. Improvement of type 2 diabetes mellitus at 3 years after surgery was stratified by baseline ABCD score, based on age, body mass index, C-peptide level, and duration of diabetes. RESULTS: Replies were received from nine of the ten institutions. From August 2005 to June 2015, 831 patients, including 366 males and 465 females, underwent bariatric procedures. The mean age was 41 years, and mean BMI was 42 kg/m2. The most common procedure was laparoscopic sleeve gastrectomy (n = 501, 60 %) followed by laparoscopic sleeve gastrectomy with duodenojejunal bypass (n = 149, 18 %). Laparoscopic Roux-en-Y gastric bypass was performed in 100 patients (12 %), and laparoscopic adjustable gastric banding was performed in 81 (10 %). At 3 years postoperatively, the remission rate of obesity-related comorbidities was 78 % for diabetes, 60 % for hypertension, and 65 % for dyslipidemia. Patients with complete remission of diabetes at 3 years postoperatively had a higher ABCD score than those without (6.4 ± 1.6 vs 4.2 ± 2.0, P < 0.05). CONCLUSIONS: Bariatric and metabolic surgery for Japanese morbidly obese patients is safe and effective. These results are comparable with the results of previous studies.

Cell division cycle-associated protein 1 overexpression is essential for the malignant potential of colorectal cancers.

To identify new cancer biomarkers and therapeutic targets for colorectal cancers (CRCs), we performed immunohistochemical analysis using tissue microarrays covering archival tumor tissue samples from 434 CRC patients and antibodies to cell division cycle-associated protein 1 (CDCA1) that was originally identified as an oncoantigen by our gene expression profile database, and compared its expression with several clinicopathological factors. Strong CDCA1 positivity was associated with poorer prognosis for patients with CRC (P=0.019) and multivariate analysis confirmed its independent prognostic value. In addition, transfection of siRNAs against CDCA1 suppressed its expression and induced apoptosis of CRC cells. These results suggest that CDCA1 could be a prognostic biomarker and a potential therapeutic target for CRCs.

CCDC3 is specifically upregulated in omental adipose tissue in subjects with abdominal obesity.

OBJECTIVE: The aim of this study was to search for novel markers of visceral adiposity. METHODS: Visceral (omental) and subcutaneous adipose tissues were obtained from 43 Japanese men. Microarray analysis using total RNA from visceral and subcutaneous adipose tissues obtained from five men with abdominal obesity and five nonobese men was first conducted. Then the expression pattern of candidate genes identified in the human study in mouse models of adiposity was examined. RESULTS: Among 30,500 genes evaluated, the mRNA expression of CCDC3 (encoding coiled-coil domain-containing protein 3) was upregulated in omental adipose tissues from abdominally obese subjects (3.07-fold) but not in subcutaneous adipose tissues (0.89-fold). Similar expression patterns were found in two distinct mouse models of obesity. In the analysis of all 43 men, CCDC3 mRNA levels in omental, but not in subcutaneous adipose tissue, were positively correlated with waist circumference and body mass index. CCDC3 was predicted to be a secretory protein, which was confirmed by western blotting, as overexpressed CCDC3 was secreted into the culture media. CONCLUSIONS: The expression of CCDC3 is specifically increased in visceral adipose tissues in abdominally obese subjects. These results suggest that CCDC3 is a potential biomarker for estimating visceral adiposity.

[A case of advanced rectal cancer with bladder carcinoma salvaged from myocardial infarction during operation, showing tumor regression by XELOX treatment, good quality of life].

We report a case of advanced rectal cancer with bladder carcinoma. The patient was a 81-year-old man who complained of abdominal bloating. A colonoscopy showed that he had advanced lower rectal cancer. CT scan revealed many lymph node metastases around the tumor, and also a bladder tumor. He experienced myocardial infarction during the operation but was relieved by PCI. During the operation, sigmoid colostomy was performed. The curative operation was declined and chemotherapy was selected. Capecitabine(2, 000mg/m / 2, biweekly)plus oxaliplatin(130mg/m2, day 1)was selected. At first, he complained of peripheral vein pain. The speed of oxaliplatin infusion was slowed and the pain was relieved. He had Grade 3 platelet decrease, but the number improved after 3 weeks. The tumor marker decreased after 3 courses, 6 courses after CT scan revealed that the tumor and lymph node metastases had evidently decreased. Capecitabine plus oxaliplatin(XELOX)was considered to be a useful chemotherapy against advanced rectal cancer, even for older patients or high risk groups.

[Current situation and issues regarding preoperative chemotherapy for HER2-positive breast cancer].

OBJECTIVE: The clinical significance of preoperative chemotherapy, including trastuzumab for HER2-positive breast cancer, was examined based on hormone receptors(HR)to clarify future issues. SUBJECTS: 104 HER2-positive breast cancer patients who completed preoperative chemotherapy and underwent surgery from May 2005 to August 2010. All patients received sequential treatment with taxane±trastuzumab for FEC(5-FU+epirubicin+cyclophosphamide)therapy, and from 2008 they received trastuzumab postoperatively for one year. RESULTS: Concerning the histological effects, the rate of comprehensive pCR(CpCR)in the 104 patients(31 HR-negative administered trastuzumab, 15 HR-negative not administered trastuzumab, 28 HR-positive administered trastuzumab, 30 HR-positive not administered trastuzumab)was 65%, 47%, 21% and 23% for each group, respectively CpCR was a significant factor(p<0. 05)in prolonged distant disease-free survival(DDFS)in the HR-negative group. Distant metastasis occurred in 14 patients, namely, brain metastasis in 7 patients(4 HR-negative administered trastuzumab, 1 HR-negative not administered trastuzumab, 2 HR-positive administered trastuzumab). The therapeutic efficacy was pINV in 5 of these 7 patients(3HR-negative administered trastuzumab, 1 HR-negative not administered trastuzumab, 1 HR-positive administered trastuzumab), and 4 of those 5 patients received trastuzumab postoperatively. DISCUSSION: The responsiveness to preoperative chemotherapy including trastuzumab for HER2-positive breast cancer differs between HR-positive and HR-negative. pINV patients seem to be at a high risk for brain metastasis regardless of HR, and it may be difficult to suppress its occurrence only with trastuzumab adjuvant therapy.

Beta-catenin-activated hepatocellular adenoma showing hyperintensity on hepatobiliary-phase gadoxetic-enhanced magnetic resonance imaging and overexpression of OATP8.

We report a male case of beta-catenin-activated hepatocellular adenoma (HCA) focusing on findings of gadoxetic-acid-enhanced magnetic resonance imaging (EOB-MRI) and discussing the molecular background and possible clinical significance. The patient was a 31-year-old man in whom computed tomography (CT) showed a large nodule of 14 cm in diameter in the right liver lobe. On dynamic contrast-enhanced CT, heterogeneous and slight to moderate enhancement was observed during the early phase, with washout in the late phase. Focal fat deposits and a scar-like portion in the lesion were also seen. Most of the lesion was slightly hyperintense compared with the background liver on the hepatobiliary phase of EOB-MRI. After operation, this patient was confirmed pathologically as having beta-catenin-activated HCA with a portion suggestive of malignant transformation. In addition, intense organic anion transporter polypeptide 8 expression was observed throughout the tumor by immunohistochemical staining.

[Alternate-day oral therapy with S-1 for adjuvant chemotherapy of gastric cancer].

Postoperative adjuvant chemotherapy with S-1 is a standard treatment for several digestive cancers. We conducted alter- nate-day oral therapy as postoperative adjuvant chemotherapy with S-1, for 31 patients with pathological stage II / IIIgastric cancer for whom radical resection had been performed. We examined the effects, the rate of compliance with all of the dosing instructions, cancer recurrence, and the survival rate with S-1 by the administration method for 31 cases. Twenty-eight patients(90. 3%)could be administered S-1 for one year. Those with side effects were admitted in 4 cases(13%). Those with side effects of grade 3 or more were not admitted. The 3-year survival rate was obtained; stage II 91%, and stage III 67% in gastric cancer. Four patients had recurrences at; the rate of 13%. In conclusion, the number of side effects was decreased, and a high rate of compliance with all dosing instructions was achieved in alternate-day oral therapy with S-1, compared with the daily oral method. This method can be a safe and useful way to administer S-1 oral therapy.

Abnormal development of intrinsic innervation in murine embryos with anorectal malformations.

INTRODUCTION: Constipation, soiling, and incontinence are common problems after definitive repair of anorectal malformations (ARMs) in children. We studied the expression of substance P (SP), vasoactive intestinal peptide (VIP), and c-kit in the rectum of murine embryos with or without ARMs at later developmental stages. METHODS: On the 9th embryonic day (E9), pregnant Institute of Cancer Research mice were fed etretinate, a synthetic vitamin A analogue (60 mg/kg), whereas controls were fed only with sesame oil. Embryos were excised between E14 and E18, and prepared for histological examination. The SP, VIP, and c-kit expressions were examined by immunohistochemical staining for the SP, VIP, and c-kit antigens, respectively. RESULTS: On E14 and E15, the expression levels of the anti-SP and anti-VIP antibodies in the rectum did not differ between the control and etretinate-treated group. However, as compared to the controls, a decreased SP and VIP immunoreactivity was observed in the circular muscle layer of the rectum between E16 and E18. On the other hand, on E14 and E15, the expression of anti-c-kit antibody in the rectum did not differ between the etretinate-treated and control group. However, c-kit immunoreactivity was slightly higher in the circular muscle layer of the rectum in the controls on E16 and E17, and considerably higher on E18 than that of the muscle layer in the etretinate-treated group. CONCLUSION: At later developmental stages, the expression levels of SP, VIP, and c-kit reduced in the circular muscle layer of the rectum in mice with etretinate-induced ARMs. This result indicates that reduced SP, VIP, and c-kit expression levels in the circular muscle layer may cause severe constipation in children who develop severe ARMs after definitive surgery.

[A case of advanced small intestinal cancer treated with S-1 plus cisplatin].

A66 -year-old woman was referred to our hospital because of abdominal pain in 2005. Computed tomography(CT) showed severe wall thickening of the proximal part of the jejunum and extensive intraperitoneal lymph node swelling. Therefore she was diagnosed with primary advanced small intestinal cancer. Surgery was performed to prevent the gastrointestinal obstruction and bleeding. Extensive lymph node metastases, including those in the paraaortic area, were observed. Because a curative resection seemed impossible, only a partial resection of jejunum was performed. After the operation, a regimen of chemotherapy with S-1(80mg/body, alternate-day dosage)and CDDP(100mg/body), was administered once every 5 weeks. At the end of the 4th course, the tumor marker was normalized and CT showed a marked decrease in the size lymph nodes; a complete response(CR)was achieved. But when a total 9 courses of chemotherapy was completed during the 17- month follow-up period after the operation, the tumor marker re-rose, and CT showed extensive intraperitoneal lymph node swelling again, so it was diagnosed the recurrence of as a disease. Chemotherapy was administered again, but was not effective. The patient died 29 months after the operation.

Visible drug delivery by supramolecular nanocarriers directing to single-platformed diagnosis and therapy of pancreatic tumor model.

Nanoparticle therapeutics are promising platforms for cancer therapy. However, it remains a formidable challenge to assess their distribution and clinical efficacy for therapeutic applications. Here, by using multifunctional polymeric micellar nanocarriers incorporating clinically approved gadolinium (Gd)-based magnetic resonance imaging contrast agents and platinum (Pt) anticancer drugs through reversible metal chelation of Pt, simultaneous imaging and therapy of an orthotopic animal model of intractable human pancreatic tumor was successfully performed without any serious toxicity. The strong tumor contrast enhancement achieved by the micelles correlated with the 24 times increase of r(1) of the Gd chelates, the highest for the formulations using clinically approved Gd chelates reported to date. From the micro-synchrotron radiation X-ray fluorescence spectrometry scanning of the lesions, we confirmed that both the Gd chelates and Pt drugs delivered by the micelles selectively colocalized in the tumor interior. Our study provides new insights for the design of theranostic micelles with high contrast enhancement and site-specific clinical potential.

Relation of the expression of transcriptional factor TFAP2B to that of adipokines in subcutaneous and omental adipose tissues.

To determine the potential role of the transcriptional factor-activating enhancer-binding protein-2beta (TFAP2B) in the regulation of expression of adipokines, adiponectin, leptin, and interleukin-6 (IL-6) in vivo, we quantified the mRNA expression levels of these adipokines and TFAP2B in visceral (omental) and abdominal subcutaneous adipose tissues of 66 individuals with variable degree of adiposity and studied their correlations with BMI and their plasma concentrations. We found that BMI correlated negatively with plasma adiponectin levels and positively with those of leptin. Adiponection mRNA expression in subcutaneous fat correlated negatively with BMI, whereas leptin mRNA levels in the omentum correlated with plasma leptin levels and BMI. In contrast, IL-6 mRNA levels in subcutaneous and omental fat did not correlate with BMI. IL-6 mRNA levels in the omental fat correlated with plasma IL-6 levels. Whereas TFAP2B mRNA expression did not correlate with BMI, it correlated negatively with adiponectin expression in the subcutaneous adipose tissue. Furthermore, TFAP2B mRNA expression correlated negatively with leptin and positively with IL-6 expression in both subcutaneous and omental adipose tissues. These relationships are consistent with our in vitro observations and indicate that TFAP2B seems to regulate the expression of various adipokines in vivo.

Investigation using an HER-2/neu transgenic mouse model of a newly developed MR contrast agent with the effect of an antitumor drug.

PURPOSE: To assess whether Gd-DTPA-Gel-Cis, a conjugate of gadolinium (Gd), cis diamminedichloroplatinum (Cis), diethylenetriaminepentaacetic acid (DTPA)-dianhydride, and bovine gelatin (Gel) can be used as an intravascular contrast agent at MRI and as an antitumor cell proliferation agent in vitro. MATERIALS AND METHODS: We injected Gd-DTPA-Gel-Cis (200 mg/mL) into the caudal vein of female HER-2/neu transgenic mice with spontaneous mammary tumors. The tumor signal intensity was measured with a 0.3 Tesla MRI scanner. HER-2/neu-expressing NT cells were treated with Gd-DTPA-Gel-Cis (5 microM cisplatin, 200 mg/mL Gel), Cis alone (5 microM cisplatin), or Gel alone (200 mg/mL gelatin). Differences of P < 0.05 were considered to be statistically significant. RESULTS: On T1-weighted MRI scans of mice injected with Gd-DTPA-Gel-Cis we observed a 23% increase in signal intensity. The survival rates of cells exposed to Gd-DTPA-Gel-Cis or Cis were 70.9% and 58.3%, respectively, of the survival rates observed after treatment with Gel alone. Gd-DTPA-Gel-Cis showed significant toxicity (P < 0.05). CONCLUSION: Gd-DTPA-Gel-Cis shows promise for use as an MRI contrast medium and as an antitumor agent.

An initial clinical study on the efficacy of cisplatin-releasing gelatin microspheres for metastatic liver tumors.

PURPOSE: To evaluate the antitumor effect and side effects of cisplatin-releasing gelatin microspheres (Cis-GMSs) for metastatic liver tumors. METHODS: Cis-GMSs that degraded over 14 days were employed. The subjects comprised a total of nine cases. Transcatheter hepatic artery embolization (TAE) using Cis-GMSs (Cis-GMSs-TAE) was performed 13 times in total. Six cases, each containing one to five tumors in a single segment to an entire lobe were treated by Cis-GMSs-TAE. In the remaining three cases with six or more metastatic liver tumors, the right and left lobes were treated by Cis-GMSs-TAE at a 2-week interval. RESULTS: There were two complete response (CR), one partial response (PR) and six stable disease (SD) cases. The response rate was 33.3%. The average rate of reduction in tumor diameter was 32%. Disappearance of metastatic liver tumors was observed in only two of the nine cases. As for side effects and complications, post-embolization syndrome was observed in eight cases, but no severe complications such as cholangitis or liver abscess were observed. CONCLUSION: Considering the mild side effects by Cis-GMSs-TAE, it is suggested that Cis-GMSs-TAE should be tried at least once as topical therapy for metastatic liver tumors when the response to systemic chemotherapy and other treatments is not satisfactory.

A case report of pulmonary-renal syndrome treated with continuous hemodiafiltration and hemodialysis.

This case describes a 40-year-old man complaining of general malaise, dyspnea with hemoptysis and anuria. Laboratory data indicated renal failure and the presence of systemic inflammation. His chest radiograph and computed tomography showed bilateral diffuse interstitial alveolar infiltration. These findings indicated acute deterioration of chronic renal dysfunction complicated by interstitial pneumonitis. He initially received daily conventional hemodialysis (HD), an antibiotic and oxygen therapy. However, his renal and pulmonary function continued to deteriorate. Antineutrophil cytoplasm antibodies against myeloperoxidase (MPO-ANCA) and antibodies against proteinase 3 (PR3-ANCA) were negative. We suspected that his pulmonary-renal syndrome was caused by ANCA-negative vasculitis. We applied mechanical ventilation, pulsed methylprednisolone therapy and continuous hemodiafiltration (CHDF) combined with HD. PaO(2)/FiO(2) ratio and mean pulmonary arterial pressure gradually improved after initiation of CHDF. He was finally separated from mechanical ventilation after 44 days in the hospital. He is currently alive with the support of conventional HD.

A case of Crohn's disease involving the gallbladder.

Crohn's disease is well known to affect any part of the gastrointestinal tract including the oral cavity and anus. Various extraintestinal complications have been reported in Crohn's disease, but extraintestinal involvement characterized by granulomatous lesions is uncommon. Here, we have reported a case about the involvement of the gallbladder in Crohn's disease. A 33-year-old woman was diagnosed having panperitonitis due to intestinal perforation and cholecystitis. The patient was moved to the surgical service for an emergency operation. On the resected specimen, there was a broad longitudinal ulcer at the mesenteric side. The mucosa of the gallbladder was nodular and granular, and the wall was thickened. The surface epithelium of the gallbladder was partially eroded and pyloric gland metaplasia was observed focally. Rokitansky-Aschoff sinuses were also present. From the lamina propria to the subserosal layer, there were several well-formed epithelioid cell granulomas, which were the non-caseating sarcoidal type different from the foreign-body and xanthomatous granulomas. Periodic-acid Schiff and acid fast stains revealed no organism within the granulomas. Lymphoid aggregates were present throughout the gallbladder wall. Sections from the resected ileum showed typical features of the Crohn's disease. When cholecystectomy is performed in a patient with Crohn's disease, the possibility of gallbladder involvement should be carefully examined by histopathological tests.

The relation between negative emotional suppression and emotional distress in breast cancer diagnosis and treatment.

Our objective was to investigate differences in emotional distress between negative emotional suppression and expression patients in the progress of medical treatment, including the operation. We studied the differences in affective response between patients who suppress negative emotion and those who express negative emotion by using Profile of Mood States (McNair, Lorr, & Droppleman, 1971) at four sessions: (a) at the first visit to the clinic, (b) immediately after being told the diagnosis of breast cancer, (c) after the operation, and (d) at 3 months after discharge. Our results showed that emotional suppression patients tended to report more emotional distress (in particular, anxiety, depression, and anger) than did emotional expression patients on 3 sessions, the exception being after the operation. Also, patients who suppress anger and anxiety felt strong psychological distress. We suggest that it is essential to encourage suppressive patients to express both negative and positive emotion clearly and appropriately.

Prevention of hemorrhagic shock-induced lung injury by heme arginate treatment in rats.

Hemorrhagic shock followed by resuscitation (HSR) induces oxidative stress, which leads to acute lung injury. Heme oxygenase (HO)-1 (EC 1.14.99.3), the rate-limiting enzyme in heme catabolism, is inducible by oxidative stress and is thought to play an important role in the protection from oxidative tissue injuries. In this study, we examined expression of HO-1 as well as tissue injuries in the lung, liver, and kidney after HSR in rats. We also pretreated animals with heme arginate (HA), a strong inducer of HO-1, and examined its effect on the HSR-induced lung injury. HO-1 expression significantly increased in the liver and kidney following HSR, while its expression in the lung was very low and unchanged after HSR. In contrast to HO-1 expression, tissue injury and tumor necrosis factor-alpha (TNF-alpha) gene expression was more prominent in the lung compared with those in the liver and kidney. HA pretreatment markedly induced HO-1 in pulmonary epithelial cells, and ameliorated the lung injury induced by HSR as judged by the improvement of histological changes, while it decreased TNF-alpha and inducible nitric oxide synthase gene expression, lung wet weight to dry weight ratio, and myeloperoxidase activity. In contrast, inhibition of HO-1 by tin-mesoporphyrin administration abolished the beneficial effect of HA pretreatment. These findings suggest that tissues with higher HO-1 may be better protected than those with lower HO-1 from oxidative tissue injury induced by HSR. Our findings also indicate that HA pretreatment can significantly suppress the HSR-induced lung injury by virtue of its ability to induce HO-1.

Late resistance to adenoviral p53-mediated apoptosis caused by decreased expression of Coxsackie-adenovirus receptors in human lung cancer cells.

Adenovirus-mediated wild-type p53 gene transfer induces apoptosis in a variety of human cancer cells. Although clinical trials have demonstrated that a replication-deficient recombinant adenovirus expressing the wild-type p53 gene (Ad-p53) is effective in suppressing growth of non-small cell lung cancer (NSCLC), we often experienced late resistance to this treatment. To elucidate the mechanism of late resistance to Ad-p53 in human lung cancer cells, we generated 5 different resistant variants from p53-susceptible H1299 NSCLC cells by repeated infections with Ad-p53. We first examined the transduction efficiency of adenoviral vector by Ad-LacZ transduction followed by X-gal staining in parental and 5 resistant H1299 cell lines. Their sensitivity to viral infection decreased in correlation with the magnitude of resistance, and Ad-p53-mediated tumor suppression could be restored by dose escalation of Ad-p53 in the resistant variants. The expression of Coxsackie and adenovirus receptor (CAR) and alphaV integrins, which are cellular receptors for attachment and internalization of the virus, respectively, was next investigated in these cell lines. Flow cytometry revealed that alphaVbeta3 and alphaVbeta5 integrin expression was consistent, while p53-resistant cell lines showed that diminished CAR expression correlated with the magnitude of the resistance. Our results demonstrated that decreased CAR expression could be one of the mechanisms of late resistance to Ad-p53, which may have a significant impact on the outcome of adenovirus-based cancer gene therapy.

Differences in emotional distress between breast tumor patients with emotional inhibition and those with emotional expression.

The differences in affective status between patients who restrain their negative emotion and those who express negative emotion after being given their breast cancer diagnosis were studied using the Profile of Mood States (POMS) at two sessions: (i) at the first visit to the outpatient surgery clinic, and (ii) immediately after being given the diagnosis of breast cancer. Eighty-seven patients completed the POMS and the Courtauld Emotional Control Scale (CECS) at the first visit to the outpatient surgery clinic at Shiga University of Medical Science Hospital. They also completed the POMS immediately after being given the diagnosis of breast cancer. Breast cancer patients who restrain their negative emotion (n = 8) were highly anxious, depressed and confused after being given the diagnosis compared to breast cancer patients who express negative emotion (n = 8). Emotional distress in benign breast tumor patients was reduced after being given the diagnosis regardless of the trend of emotional inhibition. That is, emotional distress in patients who restrain their emotions was considerably increased compared with that of patients who expressed their emotions when they were faced with a life-threatening disease. These results suggest that it may be therapeutic to advise breast cancer patients to express their negative emotion.