[A Case of UFT/LV-Induced Acute Liver Failure after Surgery for Sigmoid Colon Cancer].

Oral uracil and tegafur plus Leucovorin(UFT/LV)therapy is one of the standard adjuvant chemotherapies for colorectal cancer, and is widely used without any serious adverse events. Herein, we describe a case of UFT/LV-induced acute liver failure in a 75-year-old woman who underwent laparoscopic sigmoidectomy for sigmoid colon cancer. She was diagnosed with advanced colon cancer and lymph node metastasis by postoperative histopathological analysis, and adjuvant chemotherapy was initiated. After 30 days of commencing the therapy, the patient visited our hospital with complaints of severe diarrhea and difficulty in food intake. The apparent cause of these symptoms was unclear on computed tomography(CT), and mild liver damage was revealed in blood test results. The hepatic disorder gradually progressed after the hospitalization, and the condition was diagnosed as acute hepatic insufficiency. Additionally, obvious atrophy of the liver parenchyma and significant ascites were confirmed on CT. Two months later, the platelet count decreased markedly, but fortunately, no bleeding occurred. There has been no recurrence since 2 years after the surgery without any additional adjuvant therapy.

The possibility of a transanal tube as an alternative to diverting stoma in terms of preventing severe postoperative anastomotic leakage after laparoscopic low anterior resection.

PURPOSE: The purpose of this study was to reveal whether a transanal tube (TAT) could act as an alternative to a diverting stoma (DS) after laparoscopic low anterior resection. PATIENTS AND METHODS: A total of 89 consecutive rectal cancer patients whose tumors were located within 15 cm from the anal verge who underwent laparoscopic low anterior resection without a DS at our institution between May 12, 2015 and August 31, 2019 were included. All patients received a postoperative Gastrografin enema study (GES) through a TAT between the 3rd and 10th postoperative day. We planned two study protocols. From May 12, 2015 to March 31, 2017, we conducted a second operation including a DS construction immediately when radiological anastomotic leakage (rAL) was detected (Group A, n=46). From April 1, 2017 to August 31, 2019, we continued TAT drainage even if rAL was detected and repeated the GES weekly until the rAL was healed (Group B, n=43). RESULTS: In Group A (n=46), 14 cases of rAL were included, 11 of which underwent stoma construction. The remaining 3 patients who refused stoma construction were treated conservatively. In Group B (n=43) rAL was encountered in 10, and 7 of these patients were treated successfully by TAT continuous drainage. The rate of DS in Group B (7.0%) was significantly lower than that in Group A (23.9%) (p=0.028). CONCLUSIONS: A TAT could act as a DS to mitigate the symptoms of anastomotic leakage after laparoscopic low anterior resection.

[A Case of Gastric Small Cell Carcinoma with Rapid Regrowth after Surgery].

The patient was a 59-year-old man with type 2 advanced gastric cancer in the antrum. Abdominal computed tomography revealed the primary tumor with regional lymph node metastasis. Distal gastrectomy and D2 lymph node dissection were performed. Histopathological findings indicated gastric small cell carcinoma. Lymph node metastasis was observed microscopically in the #6 lymph nodes. Peritoneal lavage cytology was positive. The pathologic stage of the disease was pT2(MP), med, INF b, ly2, v2, pPM0, pDM0, pN2(6/33: #5, #6), M1, P0, CY1, H0, stage Ⅳ, R1(cy+). After surgery, he received chemotherapy with capecitabine plus oxaliplatin. However, after 1 course of therapy the disease had progressed, and the patient was diagnosed with peritoneal metastasis. Chemotherapy of CDDP plus CPT-11 was initiated, and after 5 courses the patient died.

[A Case of Inverted LECS for GIST in the Remnant Stomach after Distal Gastrectomy].

Laparoscopy and endoscopy cooperative surgery(LECS)is the surgical procedure used to avoid excessive resection of the gastrointestinal wall and preserve its function. We report the case of a patient who was successfully treated with inverted LECS for gastrointestinal stromal tumor(GIST)in the remnant stomach and underwent distal gastrectomy. The patient was a 75- year-old man who received distal gastrectomy for gastric ulcer 28 years before. Three years before he was diagnosed as having gastric submucosal tumor(SMT)as a gastrointestinal tumor(GIST)by using EUS. As the tumor increased, he was admitted to our hospital. Upper gastrointestinal endoscopy revealed a 30mm SMT just below the cardiac part of the remnant stomach. Biopsy by EUS-FNA revealed CD34(-), c-kit(+), S-100(-), and a-SMA(-), which indicated gastric GIST. Inverted LECS was performed. His postoperative course was good, and he was discharged from the hospital 9 days after the surgery.

[A Case of Long-Term Disease-Free Survival of a Gastric Cancer Patient with Peritoneal Dissemination and Transverse Colon Invasion].

A 71-year-old man visited our hospital because ofepigastralgia and anorexia. Upper gastrointestinal endoscopy revealed type 1 gastric cancer. Contrast-enhanced abdominal CT revealed gastric wall thickening in the midgastric region and direct invasion ofthe transverse colon. CT findings also revealed a suspicion ofdissemination on the omentum and para-aortic lymph node swelling. We diagnosed gastric cancer with transverse colon invasion. Therefore, we performed distal gastrectomy with transverse colectomy and D2+No.16b1 lymph node dissection after obtaining patient consent. We observed direct tumor invasion into the transverse colon and seeding nodules on the omentum. Liver metastasis was not seen, and ascitic cytology was negative. He was discharged 16 days postoperatively, without any complications. Histopathological analysis revealed poorly differentiated adenocarcinoma and gastrocolic fistula. Postoperatively, S-1 was administered for 4 years as adjuvant chemotherapy. There has been no recurrence for 9 years after surgery.

[A Case of Goblet Cell Carcinoid of the Appendix Treated by Laparoscopic Ileocecal Resection after Diagnosis by Colonoscopic Examination for Positive Occult Blood].

A79 -year-old woman underwent colonoscopic examination for positive occult blood. Aneoplastic lesion was seen in the orifice of the vermiform appendix. She was referred to our hospital and underwent colonoscopic examination again. The biopsy revealed poorly differentiated adenocarcinoma or mixed adenoneuroendocrine carcinoma(MANEC), and she was diagnosed with carcinoma of the appendix. She was treated by laparoscopic ileocecal resection with lymph node dissection (D3). Histopathological examination revealed goblet cell carcinoid(GCC)of the appendix with serosal invasion. No metastasis was detected in the dissected lymph nodes. This patient has been followed-up for 6 months after surgery and no recurrences have been detected.

[A Case of Intussusception Caused by Colon Cancer in A 25-Year-Old Woman].

A 25-year-old woman presented to our hospital with left flank pain and diarrhea. Contrast-enhanced abdominal computed tomography(CT)showed a target sign in the descending colon. She was diagnosed with intussusception of the colon. Colonoscopy revealed a tumor at the splenic flexure. We performed surgery and found an invaginated transverse colon at the splenic flexure. Reduction was unsuccessful with Hutchinson's maneuver, and we performed partial resection of the invaginated colon. Histopathological diagnosis was adenocarcinoma, tub1, SM2. Adult intussusception is uncommon, especially in young adults. It is usually caused by a polyp or tumor. We report a case of intussusception caused by colon cancer in a young female patient, and review the literature.

[A Case of Long-Term Survival with Multidisciplinary Therapy for a Patient with Multiple Metastases from Rectal Cancer].

Combined modality therapy is sufficient to treat advanced rectal cancer with multiple metastases. Her, we report a case of long-term survival in a patient with multiple metastases from rectal cancer. A5 8-year-old man had previously undergone low anterior resection for advanced rectal cancer. Multiple liver and lung metastases were identified prior to operation; therefore, we initiated chemotherapy(FOLFOX). Partial resection of metastatic lesions and radiofrequency ablation(RFA)were also administered, but newly developed liver, lung, and adrenal gland metastases were identified. We changed the chemotherapy regimen and administered topical therapies(partial resection, RFA, hepatic arterial infusion chemotherapy, radiotherapy)for each chemotherapy-refractory metastatic lesion. Although the patient is in a tumor-bearing state, he is still alive 10 years after his first operation. This combined modality therapy is an option for patients with chemotherapy-refractory metastases from rectal cancer.

False-Positive Cases of Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomographic Scans in Metastasis of Esophageal Cancer.

Of 129 esophagectomies at our institute from June 2010 to March 2015, we experienced three preoperative positron emission tomography-computed tomographic (PET/CT) false positives. Bone metastasis was originally suspected in 2 cases, but they were later found to be bone metastasis negative after a preoperative bone biopsy and clinical course observation. The other cases suspected of mediastinal lymph node metastasis were diagnosed as inflammatory lymphadenopathy by a pathological examination of the removed lymph nodes. Conducting a PET/CT is useful when diagnosing esophageal cancer metastasis, but we need to be aware of the possibility of false positives. Therapeutic decisions should be made based on appropriate and accurate diagnoses, with pathological diagnosis actively introduced if necessary.

Rational role of amino acids in intestinal epithelial cells (Review).

There is much interest in precise functions of amino acids on mammalian growth and development. Some of amino acids play important roles in the control of gene expression by controlling the initiation phase of mRNA translation. The signal induced by leucine or arginine may stimulate cell growth. On the other hand, the other signal induced by glutamine may stimulate cellular proliferation and increase cell number, but inhibit the growth of cell size. However, there was no clear evidence that an individual amino acid specifically works as a signaling molecule. In our recent study, not only leucine, but also arginine is shown to activate the mTOR signaling pathway in rat intestinal epithelial cells. Furthermore, regarding L-Glutamine, an important amino acid that is required for culturing of numerous cell types, including rat intestinal epithelial cells, we have shown that it had an inhibitory effect on leucine- or arginine-induced activation of the mTOR signaling pathway. We have demonstrated that L-Glutamine inhibited the activation of p70 S6 kinase and phosphorylation of 4E-BP1 induced by arginine or leucine in rat intestinal epithelial cells. Based on these results, we are planning to confirm the effect of each amino acid including glutamine in an in vivo model using new born mice.

Sudden death from metastatic esophageal cancer to the ventricular septum.

A 67-year-old man was admitted to our hospital due to esophageal cancer. Cancer existed at the lower esophagus and subtotal esophagectomy and lymphadenectomy was performed. The postoperative course was uneventful. Pathological findings revealed moderately differentiated squamous cell carcinoma that metastasized to the abdominal lymph nodes which include the paraaortic lymph nodes. He complained of anorexia three months after the operation and was found to have multiple liver and mediastinal lymph node metastases. He was admitted for chemotherapy. Before starting chemotherapy, he suddenly died without any sign of hemorrhage or respiratory disorder. Autopsy showed metastatic lesions to the heart and mediastinal lymph nodes, liver, thoracic vertebrae, kidney, adrenal gland and heart. Metastatic nodules in the heart were on the ventricular septum where the conducting system exists. No direct invasion from the pericardium was observed. Blockade of the conducting system of the heart was considered to have caused the severe arrhythmia and sudden cardiac arrest.

Feasibility of oral administration of S-1 as adjuvant chemotherapy in gastric cancer: 4-week S-1 administration followed by 2-week rest vs. 2-week administration followed by 1-week rest.

In 2006, the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer (ACTS-GC) demonstrated that S-1 is an effective adjuvant therapy for gastric cancer. Following that study, S-1 has been used as the standard adjuvant therapy for gastric cancer in Japan. However, the 1-year completion rate was only 65.8% in the ACTS-GC study and feasibility remains a critical issue. We conducted a study to evaluate the feasibility of 2 weekly administration regimens of S-1 as adjuvant chemotherapy in gastric cancer. The criteria for eligibility included histologically proven stage II (excluding T1), IIIA or IIIB gastric cancer with D2 lymph-node dissection. The patients were randomly assigned to either arm A (S-1 administration for 4 weeks followed by 2 weeks of rest) or arm B (S-1 administration for 2 weeks followed by 1 week of rest). In each arm, treatment was continued for 12 months unless recurrence or severe adverse events were observed. The primary endpoint was feasibility (protocol treatment completion rate). The secondary endpoints were safety, relapse-free survival and overall survival. A total of 47 patients were assigned to arms A or B between May, 2008 and February, 2010. During the first interim analysis, the protocol treatment completion rates in arms A and B were 83 and 100%, respectively at 6 months and 49 and 89%, respectively, at 12 months (P=0.0046). Therefore, S-1 administration for 2 weeks followed by 1 week rest was more feasible as adjuvant chemotherapy in gastric cancer. Grade 3 adverse events in arm A included fatigue (8.0%), anorexia (8.0%), nausea (4.0%), vomiting (4.0%) and hand-foot syndrome (4.0%), whereas none were observed in arm B. There were no reported grade 4 adverse events in either arm. In conclusion, the 2-week S-1 administration followed by 1-week rest regimen appears to be a more feasible oral administration regimen for S-1 as adjuvant chemotherapy in gastric cancer.

Arginine and Leucine regulate p70 S6 kinase and 4E-BP1 in intestinal epithelial cells.

Amino acids, especially branched-chain amino acids such as l-Leucine, have been revealed to regulate activation of p70 S6 kinase and phosphorylation of 4E-BP1 through mTOR signaling pathway. In this study, we showed that a cationic amino acid, l-Arginine, also activated this signaling pathway in a rapamycin-sensitive manner in rat intestinal epithelial cells, and this l-Arginine-induced amino acid signal transduction involved the cationic amino acid transport system. The manner of l-Arginine- and l-Leucine-induced activation of p70 S6 kinase depended on the stimulation time and the concentration of each amino acid, which suggested that the mechanism of this amino acid signal acceptance might be saturable. l-Arginine and l-Leucine induced activation of p70 S6 kinase and phosphorylation of 4E-BP1 in a rapamycin-sensitive manner, which suggested the involvement of mTOR signaling pathway in these effects. l-Arginine-induced activation of p70 S6 kinase was inhibited by NG-Methyl-L-Arginine (NMMA) and L-N5-(1-Iminoethyl) Ornithine (NIO), inhibitors of nitric oxide synthase (NOS) which also block cationic amino acid transporters, system y(+). However, l-Leucine-induced activation of p70 S6 kinase was not affected with treatment of NOS inhibitors. In conclusion, l-Arginine regulates p70 S6 kinase activity and phosphorylation of 4E-BP1 through mTOR signaling pathway, which involves system y(+), cationic amino acid transporters.

Effects of a novel palatinose based enteral formula (MHN-01) carbohydrate-adjusted fluid diet in improving the metabolism of carbohydrates and lipids in patients with esophageal cancer complicated by diabetes mellitus.

BACKGROUND: During perioperative management of patients with gastrointestinal cancer complicated by diabetes mellitus, adequate alimentation is required, but we often face difficulties associated with hyperglycemia and other accompanying complications. Recently, we investigated the effects of a novel palatinose based enteral formula (MHN-01) in suppressing post-prandial hyperglycemia and improving lipid metabolism in experimental animals and perioperative management of patients with esophageal cancer complicated by diabetes mellitus. MATERIALS AND METHODS: We gave normal rats and rats with type 2 diabetes mellitus a single oral dose of fluid diet, and analyzed comparatively the time course of blood glucose level in each group until 3 h after the dose. In both the normal rat group and the type 2 diabetes group, peak blood glucose level after the MHN-01 dose was significantly lower than after a dose of ordinary fluid diet and was comparable to the peak level after a dose of a fluid diet rich in MUFA (monounsaturated fatty acid). We allowed normal mice free access to fluid diet for 43 days, and measured their body fat levels. Fat accumulation was significantly lower in mice given MHN-01 than in mice given ordinary fluid diet. We also analyzed the respiratory quotient and resting energy expenditure of normal Sprague-Dawley rats fed by MHN-01 or an ordinary fluid diet. The respiratory quotient of the MHN-01 group was significantly lower than the ordinary fluid group, although the resting energy expenditure of both groups was almost the same level. The effect of MHN-01 was estimated to be based on improvement of lipid metabolism. RESULTS: Between 2003 and 2005, among 164 patients who underwent radical thoracic esophagectomy and/or reconstruction for esophageal carcinoma at Okayama University Hospital, nine patients (5.5%) were diagnosed with diabetes mellitus in pre-operative screening and were treated with MHN-01. Clinical courses of two cases with severe status of diabetes mellitus were presented as successful case reports of MHN-01. CONCLUSION: MHN-01 was very useful in perioperative management of patients complicated by diabetes mellitus, unable to ingest food p.o. such as esophageal cancer or other diseases.

Glutamine is a key regulator for amino acid-controlled cell growth through the mTOR signaling pathway in rat intestinal epithelial cells.

Amino acids, especially branched-chain amino acids such as l-leucine, have been shown to regulate activation of p70 S6 kinase and phosphorylation of 4E-BP1 through the mTOR signaling pathway. In our recent study, l-arginine was also shown to activate the mTOR signaling pathway in rat intestinal epithelial cells. l-Glutamine is an amino acid that is required for culturing of numerous cell types, including rat intestinal epithelial cells. In this study, we showed that l-glutamine inhibited the activation of p70 S6 kinase and phosphorylation of 4E-BP1 induced by arginine or leucine in rat intestinal epithelial cells. Although the molecular mechanism of l-glutamine-induced inhibition of the mTOR signaling pathway is still unknown, the presence of this novel signal pathway may indicate that individual amino acids play specific roles for cellular proliferation and growth.

Five cases of early gastric cancer in the reconstructed gastric tube after radical resection for esophageal cancer.

We report seven early gastric cancers in five patients, which arose in the reconstructed gastric tube after radical resection for esophageal cancer. Four of them occurred in the middle gastric tube and three in the distal gastric tube. Three of 5 cases were reconstructed via the retromediastinal route and two via the presternal route. They all were diagnosed by follow-up endoscopy from 8 months to 5 years after esophagectomy. All of them were treated surgically with partial resection of the gastric tube because they were suspected to have invaded the submucosal layer or large enough to be treated with endoscopic mucosal resection (EMR). Histologically, six of seven were diagnosed as well differentiated adenocarcinoma and one as signet ring cell carcinoma. Although one of them died for reasons other than cancer itself, the others are alive and well without any recurrence. Recently, gastric tube cancer after esophagectomy has been increasingly reported to be accompanied with prolongation of survival of esophageal cancer patients. Total or partial gastrectomy is proposed for surgical treatment of gastric tube cancer, but the operating procedure is complicated and invasive, especially in the case of gastric tube reconstructed via the retromediastinal route. Total gastrectomy is much more invasive because it needs re-reconstruction with other organs. Therefore, it is important to detect the lesion in early stages so as to treat it with minimally invasive surgery such as EMR or partial resection. Hence intensive follow up with endoscopy is necessary after resection of esophageal cancer.

A case of advanced esophageal cancer with extensive lymph node metastases successfully treated with multimodal therapy.

Advanced esophageal cancer patients with extensive lymph node metastases show extremely poor prognosis and the long-term outcome is poorer with the involvement of more lymph nodes. We report here a long-surviving case of advanced esophageal cancer with histologically 34 lymph node metastases, in which surgical resection with three-field lymphadenectomy followed by adjuvant chemotherapy and radiotherapy was performed. A 53-year-old male was diagnosed as advanced middle esophageal cancer with multiple regional lymph node metastases such as paraesophageal, pretracheal, tracheobronchial and bifurcational lymph nodes and three intramural metastatic lesions. Subtotal esophagectomy with three-field lymphadenectomy was performed for the tumor. Histopathologically, the tumor was poorly differentiated squamous cell carcinoma and 34 lymph nodes including ligamentum arteriosum lymph nodes and pretracheal lymph nodes were proved to be metastatic. Numerous tumor cells were found in the lymphatic vessels near the metastatic lymph nodes. Chemotherapy [3000 mg of 5-fluorouracil (5-FU), 50 mg of cisplatin (CDDP) and 30 mg of methotrexate (MTX)] was administered in two courses, followed by radiation therapy (field size 21 x 20 cm in mediastinum, 10 MV X-rays, 2 Gy/fr, 5 fr/week, total 46 Gy). Subsequently, 1000 mg of 5-FU and 200 mg of CDDP were administered every 3-4 months without any significant toxicities. The patient has been alive and well without recurrence for 5 years following operation. For treatment of advanced esophageal cancer with extensive lymph node metastases, a wide resection of the tumor and regional lymph nodes should be performed, followed by adjuvant chemotherapy and radiotherapy.