Feasibility of umbilical loop ileostomy in overweight and obese patients with rectal cancer during laparoscopic surgery: Preliminary results.

We examined the feasibility of umbilical diverting ileostomy for overweight and obese patients with rectal cancer undergoing laparoscopic surgery. Four patients who were overweight or obese (BMI > 27 kg/m2 ) were initially scheduled for the creation of a conventional loop ileostomy. Intraoperatively, however, this was considered too complicated because of thick subcutaneous fat, bulky mesentery, or both. Instead, patients received a diverting ileostomy with the placement of an umbilical stoma. All patients had protruding umbilical ileostomies. No severe stoma-related complications were encountered. One patient had minor skin dehiscence, and another had paralytic ileus but resumed oral intake after a short time. Performing a temporary loop ileostomy at the umbilicus was safe and feasible in this small group of overweight and obese patients. This stoma placement may avoid the problems inherent to conventional loop ileostomy in obese subjects.

[A Case of Gastric Cancer Associated with Sjögren's Syndrome and Interstitial Pneumonia].

A 77-year-old man presented with poor appetite and dyspnea. A gastroendoscopy showed an advanced gastric cancer and a CT scan demonstrated diffuse interstitial infiltrative shadows in both lungs. Laboratory data showed high level of anti-SSA and anti-SSB antibodies, suggestive of interstitial pneumonia associated with Sjögren's syndrome. Although the levels of KL-6 and SP-D, markers of interstitial pneumonia, decreased after steroid and immunosuppressive therapy, the CT findings of interstitial pneumonia showed no remarkable change. Surgery was performed 2 months after the administration of prednisolone since the respiratory function had improved, allowing the administration of general anesthesia. A CT scan revealed remarkable improvement of the lung lesions after the surgery. Therefore, it is likely that Sjögren's syndrome and interstitial pneumonia manifested as paraneoplastic syndromes in the presented case.

[A Case of Bullous Pemphigoid Relieved after Sigmoid Colon Cancer Resection].

A 76-year-old man presented with many bullous lesions and erythema over his whole body in August 2014. Blood examination showed an elevation of the anti-BP180 antibody (658 U/mL) and a biopsied specimen of the skin lesions showed subepidermal bulla. A diagnosis of bullous pemphigoid was made based on the clinical and histological findings. Although 20 mg/day of prednisolone was administered, there was a poor response and consequently the dose of steroid was increased to 70 mg/day after 2 weeks. Bullous pemphigoid related to a malignant tumor was suspected. Colonic endoscopic examination revealed a sigmoid colon cancer and he underwent a sigmoidectomy with lymphodenectomy. The histopathological findings revealed a moderately-differentiated adenocarcinoma, pT1b, pN1, pStage Ⅲa, and he received adjuvant chemotherapy(UFT/ LV). The dermatological findings were rapidly relieved after tumor resection and anti-BP180 antibody was normalized. He has had no signs or symptoms of recurrence, both of the cancer and the bullous pemphigoid, for 9 months after the operation.

[A Case of Local Recurrence and Lung Metastasis from a Rectal Cancer Treated with Systemic Chemotherapy and Cyberknife].

A 73-year-old man underwent abdominoperineal resection for a rectal cancer. He developed a hip pain 3 years and 6 months after the surgery. A CT scan revealed a local recurrence in the perineum and multiple lung metastases in the bilateral lung. He received systemic chemotherapy consisting of XELOX with bevacizumab. Thereafter, the hip pain was slightly relieved. The hip pain worsened 1 year and 6 months after the recurrence. The border between the perineal tumor and skin was very narrow, and conventional radiation therapy could cause a perineal skin necrosis and subsequent poor wound healing. Therefore, we selected a Cyberknife treatment. The hip pain was relieved and a CT scan showed a reduction of the perineal tumor's size after the Cyberknife treatment. A Cyberknife treatment may be effective and promising as palliation for patients with local recurrence of rectal cancer.

A randomized phase III trial exploring the prognostic value of extensive intraoperative peritoneal lavage in addition to standard treatment for resectable advanced gastric cancer: CCOG 1102 study.

A randomized controlled trial has started in Japan to evaluate the efficacy of extensive intraoperative peritoneal lavage in the treatment of resectable advanced gastric cancer. Patients with T3 or deeper carcinoma of the stomach are intraoperatively randomized to either extensive intraoperative peritoneal lavage + arm or extensive intraoperative peritoneal lavage- arm. A total of 300 patients will be accrued from 20 institutions. The primary endpoint is disease-free survival, and secondary end-points are overall survival, peritoneal recurrence-free survival and incidence of adverse events.

Surgical resection of hepatic metastasis from gastric cancer: a review and new recommendation in the Japanese gastric cancer treatment guidelines.

Liver metastases from gastric cancer are rarely indicated for surgery because they are often diagnosed as multiple nodules occupying both lobes and coexist with extra hepatic disease. A literature search identified no clinical trials on hepatectomy for this disease; only retrospective studies of a relatively small number of cases collected over more than a decade, mostly from a single institution, were found. Five-year survival rates from these reports ranged from 0 % to 37 %, and long-term survivors were observed among carefully selected case series. The most commonly reported prognostic factor was the number of metastatic nodules, and patients with a solitary metastasis tended to have superior outcome. Patients diagnosed to have a small number of metastatic nodules by modern imaging tools could be indicated for surgery. Because both intrahepatic and extrahepatic recurrences are common,patients are likely to benefit from perioperative adjuvant chemotherapy, although it is not possible at this time to specify which regimen is the most appropriate

[A case of colorectal cancer with pelvic recurrence treated by systemic chemotherapy and radiotherapy].

A 63-year-old man who had a history of rectal cancer and was treated with low anterior resection in February 2006, presented with liver metastases in September 2007 and underwent right anterior sectionectomy of the liver. He developed a pelvic wall recurrence with buttock pain in September 2009. This was treated with conventional radiation therapy and Cyber- Knife. The buttock pain was relieved after CyberKnife treatment and the patient received systemic chemotherapy in the outpatient clinic. Subsequently, he developed a left sacral recurrence with buttock pain and gait disturbance in August 2013. Since the tumor was located close to the field previously subjected to radiotherapy, we opted for CyberKnife treatment again. Although the pain subsided, our patient died of lymphangitic carcinomatosis in April 2014, 7 years and 2 months after the surgery. In this case, CyberKnife was effective in treating pelvic recurrence with pain, and thus, may have a significant role to play in the multidisciplinary treatment of metastatic colorectal cancer.

[Four cases of bevacizumab-related gastrointestinal perforation].

We report 4 cases of gastrointestinal perforation associated with systemic administration of bevacizumab. Case 1: A 51- year-old man with colorectal cancer (CRC) received mFOLFOX+bevacizumab (Bev). A small intestinal perforation occurred 7 days after Bev administration (Bev-a) and was successfully treated with omental packing. Case 2: A 50-year-old woman with CRC received capecitabine+Bev. A small intestinal perforation was detected 5 days after Bev-a, and was successfully treated with primary suture and an omental flap. Case 3: A 74-year-old man with CRC received CapeOX+Bev. A duodenal perforation occurred on the same day as Bev-a, but could be treated conservatively. Case 4: A 57-year-old man with lung cancer received DTX+Bev. A small intestinal perforation occurred 13 days after Bev-a, but this could be managed with primary suture and an omental flap. The gastrointestinal perforation presented with mild abdominal pain and was detected within 14 days after Bev-a in each of these 4 cases. Three patients were successfully treated with only minimal surgical procedures and 1 patient could be managed with conservative treatment for a perforated duodenal ulcer.

CPT-11 as a second-line treatment for patients with advanced/metastatic gastric cancer who failed S-1 (CCOG0702).

BACKGROUND: In Japan, CPT-11 is often used to treat unresectable gastric cancer in the second-line setting. However, evidence regarding benefit of second-line chemotherapy remains sparse, especially after failing S-1. METHODS: A phase II study to evaluate the efficacy and safety of weekly administration of CPT-11 at a dose of 100 mg/m(2) after failing a S-1-containing first-line treatment was planned with response rate as a primary end point. UGT1A1*6, *27, and *28 genotyping were performed in all cases, and those found to have either homozygous for *28, homozygous for *6, heterozygous for both *6 and *28, and heterozygous for *27 were rendered ineligible for the phase II trial. RESULTS: Two patients of homozygous for *28, two patients of homozygous for *6, and one patient of heterozygous for *27 were found among 39 recruited patients. The median number of courses delivered was 3 courses. The overall response rate was 15.4 % and disease control rate was 65.4 %. The median time to treatment failure was 87.5 days and median overall survival was 268 days. Twenty-two (73 %) of 30 valuable patients experienced protocol-specified skip of treatment and 8 (30 %) of patients could continue treatment with dose reduction. ≥G3 neutropenia was found in 30 % and ≥G3 anorexia and diarrhea were found in 23 and 17 %, respectively. CONCLUSION: Weekly CPT-11 at 100 mg/m(2) showed moderate response among gastric cancer patients who were refractory to S-1, but the disease control rate seemed meaningful. Even after selection of patients by UGT1A1 polymorphism of *6, *27, and *28, severe toxic events could not be prevented completely.

Hypothermia predicts hepatic failure after extensive hepatectomy in mice.

AIM: To investigate the effect of hypothermia on the function of the liver remnant (LR) after extended hepatectomy. METHODS: We performed a 75% partial hepatectomy (PH) in male C57BL/6J mice. Body temperature was measured with a rectal probe. The study mice were prospectively grouped as hypothermic (HT) or normothermic (NT) if their body temperature was < 34 °C vs ≥ 34 °C, respectively. Blood and liver samples were obtained at 24 and 48 h after 75% PH. Various factors during and after 75% PH were compared at each time point and the most important factor for a good outcome after 75% PH was determined. RESULTS: At 24 and 48 h after 75% PH, LR weight was decreased in HT mice compared with that in NT mice and the assay results in the HT mice were consistent with liver failure. NT mice had normal liver regeneration. Each intra- and post-operative factor which showed statistical significance in univariate analysis was evaluated by multivariate analysis. The most important factor for a good outcome after 75% PH was body temperature at both 24 and 48 h after surgery. CONCLUSION: Hypothermia after an extensive hepatectomy predicts impending liver failure and may be a useful clinical marker for early detection of liver failure after extended hepatectomy.

Matrix metalloproteinase-9 in the initial injury after hepatectomy in mice.

AIM: To investigate the role of matrix metalloproteinase (MMP)-9 in the pathogenesis of postoperative liver failure (PLF) after extended hepatectomy (EH). METHODS: An insufficient volume of the remnant liver (RL) results in higher morbidity and mortality, and a murine model with 80%-hepatectomy was used. All investigations were performed 6 h after EH. Mice were first divided into two groups based on the postoperative course (i.e., the PLF caused or did not), and MMP-9 expression was measured by Western blotting. The source of MMP-9 was then determined by immunohistological stainings. Tissue inhibitor of metalloproteinase (TIMP)-1 is the endogenous inhibitor of MMP-9, and MMP-9 behavior was assessed by the experiments in wild-type, MMP-9(-/-) and TIMP-1(-/-) mice by Western blotting and gelatin zymography. The behavior of neutrophils was also assessed by immunohistological stainings. An anti-MMP-9 monoclonal antibody and a broad-spectrum MMP inhibitor were used to examine the role of MMP-9. RESULTS: Symptomatic mice showed more severe PLF (histopathological assessments: 2.97 ± 0.92 vs 0.11 ± 0.08, P < 0.05) and a higher expression of MMP-9 (71085 ± 18274 vs 192856 ± 22263, P < 0.01). Nonnative leukocytes appeared to be the main source of MMP-9, because MMP-9 expression corresponding with CD11b positive-cell was observed in the findings of immunohistological stainings. In the histopathological findings, the PLF was improved in MMP-9(-/-) mice (1.65% ± 0.23% vs 0.65% ± 0.19%, P < 0.01) and it was worse in TIMP-1(-/-) mice (1.65% ± 0.23% vs 1.78% ± 0.31%, P < 0.01). Moreover, neutrophil migration was disturbed in MMP-9(-/-) mice in the immunohistological stainings. Two methods of MMP-9 inhibition revealed reduced PLF, and neutrophil migration was strongly disturbed in MMP-9-blocked mice in the histopathological assessments (9.6 ± 1.9 vs 4.2 ± 1.2, P < 0.05, and 9.9 ± 1.5 vs 5.7 ± 1.1, P < 0.05). CONCLUSION: MMP-9 is important for the process of PLF. The initial injury is associated with MMP-9 derived from neutrophils, and MMP-9 blockade reduces PLF. MMP-9 may be a potential target to prevent PLF after EH and to overcome an insufficient RL.

Phosphorylation of 4E-BP1 predicts sensitivity to everolimus in gastric cancer cells.

We studied the effect of everolimus, an inhibitor of the mammalian target of rapamycin (mTOR) on human gastric cancer cell lines. Cell proliferation in 3 of 8 cell lines was effectively inhibited by everolimus. Basal phosphorylation level of 4E-BP1 (T37/46, T70) was significantly higher in everolimus-sensitive cells than in everolimus-resistant cells. In subcutaneous xenograft model, immunohistochemistry analysis revealed that everolimus-sensitive cells expressed high levels of phospho-4E-BP1 (T37/46). In conclusion, phosphorylation of 4E-BP1 may be a predictive biomarker of everolimus sensitivity in gastric cancer.

[A case of lymph node recurrence of endocrine cell carcinoma of stomach effectively treated with carboplatin and etoposide].

We report a patient with lymph node recurrent endocrine cell carcinoma of the stomach who responded remarkably to carboplatin and etoposide chemotherapy. A 67-year-old woman underwent total gastrectomy under the diagnosis of poorly differentiated gastric carcinoma with esophagus and lymph node invasion. Adjuvant chemotherapy was not conducted because of the delay of postoperative recovery despite III b staging. Recurrence in thoracic paratracheal lymph node was diagnosed 6 months after surgery by follow-up CT scan. Carboplatin and etoposide were administrated for 4 months(6 courses of treatment), and complete response was obtained after 3 courses of treatment. The absence of recurrence was confirmed for 6 months after treatment. Although grade 4 neutropenia, grade 3 nausea and grade 2 vomiting were observed in first course of treatment, supportive therapy with G-CSF and aprepitant were useful for the continuity of treatment. Carboplatin and etoposide therapy may be one of the better candidates for stomach endocrine cell carcinoma in terms of its effects and tolerability, compared with a chemotherapy regimen combined with cisplatin.

Antethoracic pedicled jejunum reconstruction with the supercharge technique for esophageal cancer.

BACKGROUND: Gastric tube is the first choice as an esophageal substitute for reconstruction after esophagectomy. Colon or jejunum is selected for patients in whom stomach cannot be used. Colon interposition is reported to have a high incidence of anastomotic leakage and mortality. For safer surgical treatment, the authors adopted supercharged pedicle jejunum reconstruction as the operation of choice in patients with esophageal cancer who had no stomach to use as an esophageal substitute. The aim of this study was to review our experience with this technique. METHODS: From 2003 to 2009, esophagectomy and antethoracic pedicled jejunum reconstruction with the supercharge technique was performed in 27 patients with esophageal cancer at the Department of Gastroenterological Surgery (Surgery II), Nagoya University Hospital. Medical records of these 27 patients were retrospectively reviewed to determine demographic data, diagnosis, functional results, and perioperative course. RESULTS: Median operating time, blood loss, hospital stay, and duration of enteral feeding were 636 min (range 454-856 min), 580 ml (range 208-1959 ml), 27 days (range 16-72 days), and 80 days (range 26-1740 days), respectively. There were no in-hospital deaths. Anastomotic leakage occurred in two patients and was successfully managed conservatively. In 2 of 27 patients, the pedicled jejunum was of insufficient length, and additional procedures were needed to complete the anastomosis. CONCLUSIONS: Although antethoracic pedicled jejunum reconstruction with the supercharge technique is technically demanding, it is a reliable technique and contributes to successful reconstruction after esophagectomy for patients in whom stomach is not available for reconstruction.

The efficacy and safety of bevacizumab beyond first progression in patients treated with first-line mFOLFOX6 followed by second-line FOLFIRI in advanced colorectal cancer: a multicenter, single-arm, phase II trial (CCOG-0801).

PURPOSE: The aim of this study was to evaluate the efficacy and safety of the planned continuation of bevacizumab beyond first progression (BBP) in Japanese patients with metastatic colorectal cancer (mCRC). METHODS: Previously untreated patients with assessable disease were treated with mFOLFOX6 plus bevacizumab until tumor progression, followed by FOLFIRI plus bevacizumab. The primary endpoint of the study was the second progression-free survival (2nd PFS), defined as duration from enrollment until progression after the second-line therapy. Secondary endpoints of the study were overall survival (OS), survival beyond first progression (SBP), progression-free survival (PFS), response rate (RR), disease control rate (DCR), and safety. RESULTS: In the first-line setting, 47 patients treated with mFOLFOX6 plus bevacizumab achieved RR of 61.7 %, DCR of 89.4 %, and median PFS of 13.1 months (95 % CI, 8.7-17.5 months). Thirty-one patients went on to receive a second-line therapy with FOLFIRI plus bevacizumab and achieved RR of 27.6 %, DCR of 62.1 %, and median PFS of 7.3 months (95 % CI, 5.0-9.6 months). Median 2nd PFS was 18.0 months (95 % CI, 13.7-22.3 months). The median OS and SBP were 30.8 months (95 % CI, 27.6-34.0 months) and 19.6 months (95 % CI, 13.5-25.7 months), respectively. No critical events associated with bevacizumab were observed during the second-line therapy. CONCLUSION: The planned continuation of bevacizumab during a second-line treatment, BBP strategy, is feasible for the Japanese mCRC patients.

Simple and reproducible hepatectomy in the mouse using the clip technique.

AIM: To investigate the reliability of massive hepatectomy models by using clip techniques. METHODS: We analyzed anatomical findings in 100 mice following massive hepatectomy induced by liver reduction > 70%. The impact of various factors in the different models was also analyzed, including learning curves, operative time, survival curves, and histopathological findings. RESULTS: According to anatomical results, models with 75%, 80%, and 90% hepatectomy produced massive hepatectomy. Learning curves and operative times were most optimal with the clip technique. Each hepatectomy performed using the clip technique produced a reasonable survival curve, and there were no differences in histopathological findings between the suture and clip techniques. CONCLUSION: Massive hepatectomy by the clip technique is simple and can provide reliable and relevant data.

Matrix metalloproteinase-9 contributes to parenchymal hemorrhage and necrosis in the remnant liver after extended hepatectomy in mice.

AIM: To investigate the effect of matrix metalloproteinase-9 (MMP-9) on the remnant liver after massive hepatectomy in the mouse. METHODS: Age-matched, C57BL/6 wild-type (WT), MMP-9(-/-), and tissue inhibitors of metalloproteinases (TIMP)-1(-/-) mice were used. The mice received 80%-partial hepatectomy (PH). Samples were obtained at 6 h after 80%-PH, and we used histology, immunohistochemical staining, western blotting analysis and zymography to investigate the effect of PH on MMP-9. The role of MMP-9 after PH was investigated using a monoclonal antibody and MMP inhibitor. RESULTS: We examined the remnant liver 6 h after 80%-PH and found that MMP-9 deficiency attenuated the formation of hemorrhage and necrosis. There were significantly fewer and smaller hemorrhagic and necrotic lesions in MMP-9(-/-) remnant livers compared with WT and TIMP-1(-/-) livers (P < 0.01), with no difference between WT and TIMP-1(-/-) mice. Serum alanine aminotransaminase levels were significantly lower in MMP-9(-/-) mice compared with those in TIMP-1(-/-) mice (WT: 476 ± 83 IU/L, MMP-9(-/-): 392 ± 30 IU/L, TIMP-1(-/-): 673 ± 73 IU/L, P < 0.01). Western blotting and gelatin zymography demonstrated a lack of MMP-9 expression and activity in MMP-9(-/-) mice, which was in contrast to WT and TIMP-1(-/-) mice. No change in MMP-2 expression was observed in any of the study groups. Similar to MMP-9(-/-) mice, when WT mice were treated with MMP-9 monoclonal antibody or the synthetic inhibitor GM6001, hemorrhagic and necrotic lesions were significantly smaller and fewer than in control mice (P < 0.05). These results suggest that MMP-9 plays an important role in the development of parenchymal hemorrhage and necrosis in the small remnant liver. CONCLUSION: Successful MMP-9 inhibition attenuates the formation of hemorrhage and necrosis and might be a potential therapy to ameliorate liver injury after massive hepatectomy.

Long-term follow up of patients who were positive for peritoneal lavage cytology: final report from the CCOG0301 study.

BACKGROUND: In gastric cancer patients who have positive results for peritoneal lavage cytology the disease is defined as CY1, and classified as stage IV, and this population has generally suffered a dismal outcome. For this population, we had conducted a phase II trial, with the 2-year survival rate as the primary endpoint, to test the strategy of D2 dissection followed by chemotherapy with single-agent S-1 (1 M tegafur-0.4 M gimestat-1 M otastat potassium). Forty-eight patients were enrolled, of whom 47 were found to have been eligible for analysis. The 2-year survival rate of 46 % exceeded our expectations. METHODS: Further follow up was conducted to confirm whether radical surgery could be recommended for the CY1 population. RESULTS: The 5-year overall and relapse-free survival rates were 26 and 21 %, respectively. CONCLUSIONS: Gastrectomy with curative intent could be considered for patients with CY1 disease provided they are scheduled to receive effective postoperative chemotherapy.

Suppressor of cytokine signaling 4 detected as a novel gastric cancer suppressor gene using double combination array analysis.

BACKGROUND: Molecular mechanisms behind the oncogenesis of gastric cancer (GC) have yet to be identified. METHODS: A novel candidate tumor-suppressor gene, which is also associated with inhibition of epidermal growth factor (EGF), was sought by means of double combination array analysis for use as a prognostic marker of GC. This consisted of expression array and single nucleotide polymorphism array analysis, along with a literature search. Cancerous and noncancerous tissues from an 82-year-old man with GC were analyzed simultaneously. RESULTS: The expression array and literature search identified that the suppressor of cytokine signaling 4 (SOCS4), a negative feedback regulator of EGF signaling, had significantly attenuated expression in tumor tissue. Although chromosomal deletion was not found at 14q22 where SOCS4 is located, numerous CpG sites were observed in the promoter region of the SOCS4 gene. Several GC cell lines showed reactivation of SOCS4 mRNA expression after treatment with 5-aza-2'-deoxycytidine. Using surgically resected specimens, we found that 40 of 50 (80%) tumor tissues exhibited promoter hypermethylation of the SOCS4 gene. Consequently, SOCS4 expression in tumor tissues was significantly weaker than in noncancerous counterparts (P < 0.0001). In the survival analysis, SOCS4 hypermethylation was associated with a poor prognosis of GC patients (P = 0.0320). CONCLUSIONS: Double combination array analysis suggested that SOCS4 could be a novel candidate for further exploration as a tumor-suppressor gene in GC. Hypermethylation was the mechanism by which SOCS4 was silenced and was implicated in the development of GC. SOCS4 methylation might be an informative marker in predicting the prognosis.