細谷 好則

We report a case of acquired hemophilia A (AHA) after esophageal resection. The patient was an 80-year-old woman whose preoperative activated partial-thromboplastin time (APTT) was well within the normal range, at 34.9 s. She underwent thoracic esophagectomy and gastric pull-up for superficial esophageal cancer (operative time, 315 min; intraoperative blood loss, 245 ml). Intrathoracic and subcutaneous bleeding occurred spontaneously on postoperative day (POD) 39. The APTT was prolonged, at 140 s, and factor VIII inhibitor was 36 Bethesda U/ml. Treatment with recombinant activated factor VII, prednisolone, and cyclophosphamide resulted in remission within 2 months. This case supports an association between surgery and the triggering of factor VIII inhibitors. The diagnosis of AHA requires clinical acumen and must be considered in any patient with bleeding and a prolonged APTT.

Esophageal carcinosarcoma (ECS) is a rare malignant neoplasm associated with a poor patient prognosis. It is characterized by the presence of both malignant epithelial and mesenchymal components. Molecular-targeted therapy of several receptor tyrosine kinases (RTKs) has been reported to be effective in the treatment of various malignant tumors, including carcinosarcoma of several organs. This study aimed to assess the therapeutic potential of targeting RTKs in ECS. Overexpression of RTKs was assessed in 21 ECS cases by immunohistochemistry (IHC). Positively stained cases were further examined for RTK gene mutations and amplifications by direct sequencing analysis and fluorescence in situ hybridization. In epithelial components, KIT, platelet-derived growth factor receptor (PDGFR)A, PDGFRB, MET, epidermal growth factor receptor (EGFR) and HER-2 were overexpressed in 1 (4.8%), 1 (4.8%), 0 (0%), 11 (52.4%), 13 (61.9%) and 2 (9.5%) cases, respectively. In the mesenchymal components the corresponding numbers of cases were 2 (9.5%), 2 (9.5%), 0 (0%), 12 (57.1%), 11 (52.4%) and 0 (0%). No mutations in the c-kit, PDGFRA and c-met genes were found. Among 19 EGFR-positive tumors, 2 had EGFR missense mutations (T790A, exon 20) only in the mesenchymal component. Gene amplification or high polysomy of c-kit, PDGFRA, c-met and EGFR was observed in 1 (33.3%), 0 (0%), 3 (18.8%) and 10 (52.6%) cases, respectively. In conclusion, various RTKs, particularly MET and EGFR were overexpressed in ECSs suggesting that molecular-targeted therapies directed to MET, EGFR or other RTKs may be effective in inhibiting the growth or progression of the epithelial and/or mesenchymal component of ECS.

We report on a 53-year-old male with esophageal cancer. He had no evidence of distant metastasis, and received a subtotal esophagectomy. Histopathologically, the tumors were contiguous with Barrett's epithelium. Undifferentiated carcinoma components existed independently of differentiated adenocarcinoma components. Undifferentiated carcinoma was present proximal to the esophagogastric junction. Both tumors had invaded the submucosa and were associated with a prominent lymphoid stroma. Metastasis from undifferentiated carcinoma was found in the paraesophageal lymph nodes. Immunohistochemically, both components were negative for 34bE12 and positive for CAM5.2 and showed nearly identical staining patterns for p53, indicating that the tumors were derived from Barrett's epithelium. Because the undifferentiated carcinoma did not express CK20 or carcinoembryonic antigen, the properties of adenocarcinoma had apparently been lost during the process of tumor cell progression. This is the first report of undifferentiated carcinoma associated with Barrett's esophagus with adenocarcinoma.

OBJECTIVE: Adenosquamous carcinoma originating in the stomach is an unusual neoplasm with few existing histological studies. This study was aimed to gain insight into the histogenetic and clinicopathological characteristics of gastric cancer with squamous cell carcinoma (SCC) components. METHODS: From January 2001 to June 2010 a total of 1735 patients underwent a resection of gastric cancer. Histopathologically, eight patients had adenocarcinoma containing SCC components, in which the proportion of SCC components was above 25% of the total tumor mass in four patients. The immunohistochemical and clinicopathological characteristics of these eight patients were analyzed. RESULTS: The median survival duration was 22 months. Adenocarcinoma was present at the superficial layer of all tumors and SCC was primarily present at sites with deep invasion. Immunohistochemically, adenocarcinoma components were positive for cytokeratin (CK) 8/18/19 and CK7 in all cases. SCC components were positive for carcinoembryonic antigen and CK7 in more than 60% of patients. Expression patterns of p53 product were identical in both components. SCC components were positive for 34βE12 and adenocarcinoma components were negative for 34βE12 in all patients. CONCLUSIONS: SCC components are derived from squamous metaplasia in a pre-existing adenocarcinoma. A gastric adenocarcinoma with SCC components is associated with various patterns of metastasis and both SCC and adenocarcinoma components have the potential for metastasis. Gastric cancer with SCC components is a clinically aggressive tumor.

OBJECTIVE: Although studies have been conducted to identify factors that attract students to a career in surgery, the relative importance of factors that attract students to a particular training program remains unknown. Comparative data between countries may provide insights and ultimately provide guidance to program directors as they seek to attract the best applicants to their program. DESIGN: Blinded written survey, scored 1-5 on a list of 26 factors divided into 3 categories, including educational factors, lifestyle factors, and other. SETTING: Jichi Medical University, Japan and the David Geffen School of Medicine at University of California Los Angeles. PARTICIPANTS: Japan residents (N = 125), Japan Medical Students (N = 68), United States Residents (N = 99), and United States Students (N = 55). RESULTS: All 4 groups surveyed judged faculty quality among the most important factors, with educational program quality, clinical experience and perceptions of resident happiness also rated among the most important. A comparison of factors consistent with lifestyle and factors consistent with the educational program found significantly (p < 0.05) higher scores for educational factors by 3 groups surveyed. CONCLUSIONS: Resident applicants are most interested in training program factors related to the quality of the educational program and the faculty. Issues such as salary, vacation, night call, location, or benefits are considered less important. The results in Japan and the United States were remarkably similar despite major differences in the educational system and debt load at the time of graduation. Program directors should communicate the value of those factors considered important by applicants as part of the recruitment process. (J Surg 69: 167-172. (C) 2012 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

BACKGROUND: To decrease the incidence of internal hernia after laparoscopic gastric bypass, current recommendations include closure of mesenteric defects. Laparoscopic gastric resection is used increasingly for the treatment of gastric cancer, but the incidence of internal hernia in the treated patients has not been studied. METHODS: This study retrospectively reviewed 173 patients who underwent laparoscopic resection for gastric cancer at one institution, including distal and total gastric resections with antecolic Roux-en-Y reconstruction. RESULTS: An internal hernia occurred in 4 (7%) of 58 patients whose jejunojejunal mesenteric defect was not closed a mean of 326 days after surgery. All the patients underwent reoperation with reduction and repair of the hernia. In 115 subsequent cases, with closure of the mesenteric defect, internal hernias did not occur (0/115 cases; p < 0.05). CONCLUSION: Based on the current recommendations for patients undergoing bariatric surgery, closure of this potential hernia defect is mandatory after laparoscopic gastrectomy with a Roux-en-Y reconstruction for gastric cancer.

BACKGROUND: Although postoperative quality of life is an important outcomes measure, few tools exist to evaluate patients specifically after upper gastrointestinal surgery. The previously developed Dysfunction After Upper Gastrointestinal Surgery (DAUGS)32 scoring system has been further refined to include just 20 items. This study was undertaken to validate the refined evaluation tool. STUDY DESIGN: The study was performed as a survey, administered to patients after upper gastrointestinal resection at 3 separate institutions. RESULTS: The DAUGS20 score after gastrectomy (n = 662) was 27.8 and that after esophagectomy (n = 221) was 36.1, showing a significant difference (p < 0.05). The score after distal gastrectomy (n = 282) was 25.4 and that after total gastrectomy (n = 149) was 32.0, showing a significant (p < 0.05) difference. The α coefficient of all items on the DAUGS20 system was 0.904 and Cronbach's α coefficients of the subscales were 0.612 to 0.856, demonstrating high reliability of this evaluation tool. In addition, 7 factors were extracted from the 20 items using definitive factor analysis, to verify validity. CONCLUSIONS: Patient quality of life should be evaluated as an outcomes measure after surgical resection for cancer, just as overall survival is analyzed. The DAUGS20 score is reliable, has validity in the evaluation of postoperative patients, and is a valuable tool to assess patient quality of life after upper gastrointestinal surgery for cancer.

The patient is a 61-year-old man who had previously undergone an extended thymectomy for myasthenia gravis. Endoscopic examination during a routine follow-up visit revealed early gastric cancer in the proximal portion of the stomach. To undergo resection the patient received general and epidural anesthesia. The conditions were unfavorable for laparoscopic-assisted surgery because he had a body mass index of 33 and muscle relaxants could not be used. Pneumoperitoneum was induced with carbon dioxide, and the abdominal wall was lifted. An adequate working space was secured in the upper abdomen and proximal gastrectomy was successfully performed.

BACKGROUND: Esophagectomy after gastric reconstruction leads to significant weight loss. Ghrelin is known to stimulate appetite and cause weight increase. The objective of this study is to examine the relationship of serum ghrelin levels and weight loss in patients after esophagectomy for cancer. METHODS: Twenty-two patients underwent esophagectomy including gastric reconstruction. Serum ghrelin levels and weight were measured preoperatively and then postoperatively for 12 months in all patients. A questionnaire assessed appetite, amount of food eaten, satisfaction, and frequency of eating. RESULTS: Preoperatively, the mean serum ghrelin level was 67.9 ± 42.6 (fmol/mL ± SD), and at 1, 3, 6, and 12 months after surgery were 43.4 ± 28.1, 51.5 ± 32.2, 67.1 ± 50.9, and 84.9 ± 43.1, respectively. Compared with preoperative values, the mean body mass index decreased by 1.9 ± 1.5, 2.3 ± 1.8, 2.1 ± 2.3, 2.4 ± 2.7 at 1, 3, 6, and 12 months after surgery. While appetite score showed a decrease at 1 month (1.6 ± 0.92), appetite increased by 12 months postoperatively (2.7 ± 1.0) and showed a strong positive correlation (r = 0.743) with serum ghrelin levels. There were no significant differences in ghrelin levels when patients were stratified by disease stage, recurrence, or administration of adjuvant chemotherapy. CONCLUSIONS: Esophagectomy resulted in temporary reduction of ghrelin levels, but while levels returned to normal 3 months later, weight loss persisted at 12 months. Further study is needed to elucidate the mechanisms of persistent weight loss and design therapeutic interventions to recover the weight lost.

We report a case of a 51-year-old man with esophageal cancer who had a complete pathological response to preoperative chemotherapy with a combination of docetaxel, cisplatin and 5-fluorouracil (DCF). Endoscopy and esophagography showed a type II tumor 8 cm in diameter, located in the upper thoracic esophagus. On computed tomography the diagnosis was T3N1M0, stage III disease according to TNM classification. Before surgery, the patient received DCF therapy, consisting of docetaxel (60 mg/m(2)) on day 1, cisplatin (60 mg/m(2)) on day 1, and 5-fluorouracil (800 mg/m(2)) on days 1-5. The patient had grade 3 hematological toxicity, but two courses were administered as scheduled. After chemotherapy, esophagography and computed tomography showed that the tumor had shrunk. Esophagectomy with three-field lymph node dissection was performed. Histopathologically, an ulcer scar was found, with no residual cancer cells. There were no metastases in dissected lymph nodes. This regimen is considered to have a high potential.

BACKGROUND: Quality of life is an important outcome measure in the care of patients with cancer. We developed a new scoring system specifically for the evaluation of patients with upper gastrointestinal cancer and postoperative gastrointestinal dysfunction. This study was undertaken to evaluate the scoring system's validity in comparing outcomes after gastric resection. MATERIALS AND METHODS: Patients with gastric cancer, 3 months to 3 years postoperatively, were surveyed using the survey instrument. Postoperative dysfunction scores and the status of resuming activities of daily living were compared with the surgical procedure performed by analysis of variance and multiple-comparison techniques. RESULTS: Of 211 patients surveyed, 165 (119 men, 46 women; mean age, 65.1 ± 10.5 years) responded. Procedures included distal gastrectomy in 100, total gastrectomy in 57, and pylorus-preserving gastrectomy in 8. The overall dysfunction score was 61.8 ± 15.5. The dysfunction score was 58.9 ± 15.0 after distal gastrectomy, 66.8 ± 14.1 after total gastrectomy, and 62.4 ± 21.6 after pylorus-preserving gastrectomy. These values differed significantly among the groups (P = .007). Dysfunction scores according to postoperative activity status were 49.1 ± 15.6 in 71 patients who resumed their activities, 56.9 ± 15.7 in 39 patients with reduced activities, 57.3 ± 8.8 in 15 patients with minimal activities, and 63.3 ± 11.8 (P < .05) in 16 patients who did not resume activities because of poor physical condition. CONCLUSIONS: This scoring system for postoperative gastrointestinal dysfunction provides an objective measure of dysfunction related to specific surgical procedures and correlates with activities of daily living in the postoperative period.

AIM: Adipocyte lipolysis is mediated by a family of triglyceride (TG) lipases consisting of hormone-sensitive lipase (LIPE), adipose triglyceride lipase (PNPLA2) and carboxylesterase 1 (CES1); however, little is known about the relationship between the expression of each gene in different depots and TG lipase activity or obesity. METHOD: We measured both mRNA expression levels of the lipolytic enzymes (LIPE, PNPLA2 and CES1) and TG lipase activities of biopsy samples obtained from subcutaneous, omental and mesenteric adipose tissues of 34 patients who underwent abdominal surgery. The results were correlated with clinical parameters: adiposity measures, parameters for insulin resistance and plasma lipid levels. RESULTS: PNPLA2 mRNA levels were slightly higher in omental fat than subcutaneous fat. Cytosolic TG lipase activities were positively correlated with the mRNA levels of CES1 in subcutaneous fat and mesenteric fat, while they were correlated with those of PNPLA2 in omental fat. The mRNA levels of LIPE were negatively correlated with various measures of adiposity in subcutaneous fat. The mRNA levels of CES1 were positively correlated with various measures of adiposity, particularly those estimated by CT in the three depots; they were also positively correlated with plasma LDL-cholesterol levels in omental fat. In contrast, the mRNA levels of PNPLA2 were not significantly associated with adiposity. CONCLUSIONS: The positive correlations of the expression of CES1 with cytosolic TG lipase activities as well as with adiposity suggest that CES1 is involved in lipolysis, thereby contributing to the development of obesity-associated phenotypes. On the other hand, the expression of LIPE is negatively correlated with adiposity. These distinct regulatory patterns of lipolytic genes may underlie the complex phenotypes associated with human obesity.

Retinol-binding protein 4 (RBP4) is a recently identified adipokine that was involved in insulin resistance. RBP4 is predominantly expressed from the liver in normal metabolic state to transport retinoids throughout the body, but the exact physiological function and the regulatory mechanisms of adipocyte-derived RBP4 have not been revealed. We conducted the genetic analysis about metabolic parameters in Japanese and Mongolian; the minor allele carriers of regulatory single-nucleotide polymorphism (SNP -803G>A) showed significantly higher BMI in Japanese men (P = 0.009) and women (P = 0.017), and in Mongolian women (P = 0.009). Relative quantification of RBP4 transcripts in -803GA heterozygotes showed that the minor allele-linked haplotype-derived mRNA was significantly more abundant than the transcript from major allele. RBP4 promoter assay in 3T3L1 adipocytes revealed that the minor allele increased the promoter activity double to triple and the administration of 9-cis-retinoic acid (RA) and 8-bromo-cyclic adenosine monophosphate (8-Br-cAMP) enhanced the activity. Multiple alignment analysis of human, mouse, rat, and cattle RBP4 promoter suggested conserved seven transcription factor binding motifs. Electrophoretic mobility shift assay showed the -803G>A SNP modulate the affinity against unidentified DNA-binding factor, which was assumed to be a suppressive factor. These results collectively suggested that the minor allele of RBP4 regulatory SNP enhanced the expression in adipocytes, which may be associated with the adipogenesis.

BACKGROUND: In patients with adverse events of S-1, the dose is generally reduced or the treatment cycle is shortened. Whether the therapeutic effectiveness of modified regimens is similar to that of the standard dosage remains unclear. METHODS: We retrospectively studied patients with gastric cancer who received S-1 on alternate days. RESULTS: A total of 266 patients received S-1 on alternate days. In 116 patients, S-1 was initially given at the standard dosage but was switched to alternate-day treatment because of toxicity within 28 days on average. The other 150 patients initially received alternate-day treatment because of poor general condition. In the adjuvant chemotherapy group (n = 96), the 3-year survival rate was 88% in patients with stage II, 73% in stage IIIA, and 67% in stage IIIB who underwent D2 lymph-node dissection. In the palliative surgery group (n = 96), the response rate was 13%, with a median survival time (MST) of 624 days. In patients with unresectable/recurrent disease (n = 74), the response rate was 25%, with an MST of 338 days. Among the 116 patients who initially received treatment on consecutive days, 100% had grade 1, 53% had grade 2, and 5.2% had grade 3 adverse events. When S-1 was switched to alternate-day treatment, toxicity decreased in all patients. In the 266 patients who received alternate-day treatment, 8% had grade 1, 6% had grade 2, and 0% had grade 3 adverse events. CONCLUSION: Alternate-day treatment with S-1 may have milder adverse events without compromising therapeutic effectiveness.

We report a case of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis in a 62-year-old patient with gastric cancer. The myeloperoxidase-anti-neutrophil cytoplasmic antibody (MPO-ANCA) level was threefold above normal preoperatively. Vasculitis was seen on renal biopsy. Gastric resection revealed well-differentiated adenocarcinoma and vasculitis. The MPO-ANCA level returned to normal post-operatively. Although ANCA-associated vasculitis occasionally accompanies malignant tumors, this is the first documented case of concurrent gastric cancer-associated and ANCA-associated vasculitis, with post-operative resolution of the vasculitis.

Gallbladder cancer (GBC) is a highly fatal malignancy in humans. Genetic alterations in KRAS or TP53 as well as overexpression of ERBB2 have been shown to contribute to the development of certain types of GBC. However, many cases of GBC do not harbor such genetic changes, with other transforming events awaiting discovery. We here tried to identify novel cancer-promoting genes in GBC, with the use of a retroviral cDNA expression library. A retroviral cDNA expression library was constructed from a surgically resected clinical specimen of GBC, and was used to infect 3T3 fibroblasts in a focus formation assay. cDNA incorporated into the transformed foci was rescued by PCR. One such cDNA was found to encode free fatty acid receptor 2 (FFAR2), a G protein-coupled receptor for short-chain fatty acids. The oncogenic potential of FFAR2 was confirmed both in vitro with the focus formation assay and by evaluation of cell growth in soft agar as well as in vivo with a tumorigenicity assay in nude mice. The isolated FFAR2 cDNA had no sequence alterations, suggesting that upregulation of FFAR2 expression may contribute to malignant transformation. Indeed, all of quantitative RT-PCR, in situ hybridization, and immunohistochemical analyses showed that the amount of FFAR2 mRNA and its protein product was increased in digestive tract cancer specimens. Furthermore, short-chain fatty acids potentiated the mitogenic action of FFAR2 in 3T3 cells. Our data thus, for the first time, implicate FFAR2 in carcinogenesis of the digestive tract.

To identify novel cancer-promoting genes in biliary tract cancer (BTC), we constructed a retroviral cDNA expression library from a clinical specimen of BTC with anomalous pancreaticobiliary duct junction (APBDJ), and used the library for a focus formation assay with 3T3 fibroblasts. One of the cDNAs rescued from transformed foci was found to encode Indian hedgehog homolog (IHH). The oncogenic potential of IHH was confirmed both in vitro with the focus formation assay and in vivo with a tumorigenicity assay in nude mice. The isolated IHH cDNA had no sequence alterations, suggesting that upregulation of IHH expression may contribute to malignant transformation. Quantitation of IHH mRNA among clinical specimens has revealed that the expression level of IHH in BTC with APBDJ is higher than that in BTC without APBDJ and than in non-cancerous biliary tissues. Our data thus implicate a direct role of IHH in the carcinogenesis of BTC with APBDJ.

Gastrectomy reduces food intake and body weight (BW) hampering recovery of physical conditions. It also reduces plasma levels of stomach-derived orexigenic ghrelin. This study explored changes in orexigenic ghrelin system in rats receiving total gastrectomy with Billroth II (B-II) or Roux-en-Y (R-Y) method. Feeding and BW were reduced by gastrectomy and subsequently recovered to a greater extent with R-Y than B-II while plasma ghrelin decreased similarly. At postoperative 12th week, ghrelin contents increased in the duodenum and pancreas, plasma ghrelin levels increased upon fasting, and ghrelin injection promoted feeding but not in earlier periods. In summary, gastrectomized rats partially recover feeding and BW, in a reconstruction-dependent manner. At 12th week, ghrelin is upregulated in extra-stomach tissues, plasma ghrelin levels are physiologically regulated, and orexigenic effect of exogenous ghrelin is restored. This time-related recovery of ghrelin system may provide a strategy for promoting feeding, BW, and thereby physical conditions in gastrectomized patients.

Esophageal carcinosarcoma is an extremely rare tumor, and surgery is the mainstay of treatment. We report two patients with carcinosarcoma of the esophagus who received neoadjuvant chemoradiotherapy and underwent curative resection. Patient 1 was a 50-year-old man with a type 2 lesion in the upper thoracic esophagus; clinical stage was T3 or partial T4N1M0. After chemoradiotherapy the tumor and the lymph nodes become smaller, and subtotal esophagectomy was performed. Patient 2 was a 66-year-old man with a protruding lesion in the lower thoracic esophagus. Preoperative chemoradiotherapy was administered, and he had a partial response. However, surgery was postponed because of pneumonia; 11 months later, tumor enlargement was confirmed and we then performed subtotal esophagectomy. The therapeutic role and effectiveness of both chemotherapy and radiotherapy remain unclear. We reviewed 26 previously reported cases of esophageal carcinosarcoma treated by chemotherapy, radiotherapy, or both. These findings suggest that preoperative chemoradiotherapy may be effective for downstaging the primary tumor in patients with advanced esophageal carcinosarcoma.

We reviewed the clinicopathological characteristics of 14 patients who underwent resection of basaloid squamous carcinoma (BSC) of the esophagus. The mean age was 65.3 years, and all patients were male. Seven patients had superficial BSCs and 7 had advanced BSCs. BSCs were associated with high rates of lymph node metastases and venous invasion. With regard to immunohistochemistry, the rate of cyclin D1 expression was higher (13/14), and the preservation rate of E-cadherin expression was lower (4/14), than that seen in ordinary esophageal squamous cell carcinoma. Squamous cell carcinoma components were most often found at sites of lymph node metastases, whereas basaloid components predominated at sites of hematogenous metastases in 4 patients, including lung, brain, and liver. Seven of the 9 patients with stage I or II disease are alive without recurrence. All patients with stage III or IV tumors developed recurrent disease. Primary tumors responded well in 3 patients who received preoperative chemotherapy (5-fluorouracil plus cisplatin) and/or radiotherapy, but further studies are needed to clarify the role of chemoradiotherapy. We believe that control of the hematogenous spread of basaloid components may lead to improved outcomes in patients with esophageal BSC.

Background/Aims: Laparoscopic-assisted distal gastrectomy (LADG) is a minimally invasive procedure for patients with gastric carcinoma. We have previously reported gasless LADG with a Billroth-I reconstruction using a 5-7cm mini-laparotomy. We modified the technique for gasless LADG to include a Roux-en Y reconstruction and to expand the indications for its use. Methodology: A total of 40 patients with early stage gastric tumors (T1 n=38, T2 n=2) underwent this procedure. Following gasless laparoscopic distal gastrectomy with lymph node dissection, a jejunum to greater curvature of the gastric remnant anastomosis was performed using an intracorporeal laparoscopic stapled method. The jejuno-jejunal anastomosis was performed using a hand-sewn technique under direct vision through a mini-laparotomy. Results: The mean surgical time (n=40) was 222min, estimated blood loss 101ml, and the mean number of lymph nodes harvested was 21. There were no postoperative complications such as bleeding, leak, or cardio-pulmonary dysfunction. Mean body weight loss was 3.9 kg, and there is no evidence of recurrence during a mean follow-up of 14 months. Conclusions: Gasless LADG with Roux-en-Y reconstruction is a feasible, novel procedure for a minimally invasive approach to gastric cancer.

BACKGROUND: Esophageal carcinosarcoma is a very rare neoplasm and its clinicopathological characteristics and the prognostic factors that influence the clinical outcome of the patient remain a matter of controversy. PATIENTS AND METHODS: Twenty patients with esophageal carcinosarcoma were referred to our institutions. Tissue blocks were reviewed and sections containing both carcinomatous and sarcomatous components were stained for epithelial and mesenchymal markers and a proliferating cell marker. The prognosis of the esophageal carcinosarcoma patients was compared with 142 cases of esophageal squamous cell carcinoma. RESULTS: In the carcinomatous component, the expression of cytokeratin, epithelial membrane antigen, vimentin, smooth muscle actin, and S100 were detected in 20, 20, 1, 1, and 1 case, respectively, whereas in the sarcomatous component, expression of these were detected in 4, 2, 18, 15, and 3 cases, respectively. The Ki-67 labeling index of carcinomatous and sarcomatous components was 35.5% and 41.8%, respectively. The 5-year survival rate was not statistically different between squamous cell carcinoma and carcinosarcoma (p=0.219). However, for T1 cases only, carcinosarcoma patients had statistically poorer prognosis than did squamous cell carcinoma patients (p=0.008). CONCLUSION: The sarcomatous component shows various histological and immunohistochemical forms. In comparison with squamous cell carcinoma patients, carcinosarcoma patients had poorer prognosis amongst the T1 cases. For the treatment of esophageal carcinosarcoma, it is important to monitor lymph nodes and be watchful for hematogenous metastasis, as in cases of esophageal squamous cell carcinoma.

A 67-year-old woman underwent resection of a gastric tumor and a synchronous metastatic lesion of the liver in 1991. Histopathologically, both the primary and metastatic tumors were diagnosed as leiomyosarcoma. Four years after the initial resection, another liver metastasis was detected in the caudate lobe, and a partial hepatectomy was performed. Multiple bilateral lung metastases were identified 7 years later and one was resected. Immunohistochemically, tissues from both the primary and metastatic sites were positive for KIT and CD34, and a c-kit gene mutation was found in the resected lung lesion. The remaining lung metastases responded to treatment with imatinib mesylate, but the treatment was discontinued because of toxicity. The patient remains under observation and the lung lesions have not progressed. At present she has no symptoms, and she has had no further recurrences in the past 3 years. This case is extremely unusual; a slowly progressing gastrointestinal stromal tumor over the course of 17 years from the initial diagnosis, with hematogenous metastases at multiple sites.

Several options exist for reconstruction after total esophagectomy in patients with esophageal carcinoma. However, the options for a major resection after previous head and neck surgery in these patients are extremely limited. The procedure performed in 2 patients requiring esophagectomy after resection for previous head and neck malignancies is described. Both patients underwent previous chemoradiation therapy and free jejunal transfer for hypopharyngeal squamous cell carcinoma. Esophagectomy and reconstruction with a cervical gastrojejunal anastomosis combined with deltopectoral flaps were performed after the diagnosis of esophageal disease. Soft tissue defects were closed with a modified deltopectoral flap using de-epithelization. The deltopectoral flap is effective not only for cutaneous resurfacing, but also to promote delayed wound healing after radiation therapy. This report demonstrates a useful multidisciplinary approach for resection and reconstruction in patients after a previous free jejunal transfer.

We report a patient with synchronous gastrointestinal stromal tumors (GISTs) of the stomach and esophagus. The gastric GIST was larger than that in the esophagus, and no direct connection between the two lesions was seen microscopically. Based on molecular analysis, both lesions had the same c-kit mutation on exon 11, with deletion of codon 557-558. Analysis of normal gastric tissue showed no mutations. The gastric GIST was the primary lesion, and the esophageal tumor was thought to suggest a hematogenous metastasis. A liver metastasis in S6 appeared 6 months after surgery. Imatinib mesylate has been an effective treatment for liver metastasis at follow-up of 2 years. © 2008 Japan Esophageal Soceity and Springer.

BACKGROUND: The toxic effects of S-1 can lead to discontinuation of treatment. Strategies for reducing toxicity without compromising therapeutic effectiveness are required. METHODS: We used the human gastric cancer cell lines MKN28 and MKN45 to examine such strategies in vitro. The cell lines were treated with three different regimens, given on alternate days (alternate-day) or on consecutive days (consecutive-day). On consecutive days, treatment A provided the same total dose as the alternate-day treatment, and treatment B was given for the same number of days as the alternate-day treatment. A fourth group served as control. In vitro, the relative inhibition (RI) of tumor growth by 5-fluorouracil was calculated using the 2-(2-methyl-4-nitrophenyl)-3-(4-nitrophyl)-5-2, 4-disulfophenyl)-2H-tetrazolium (WST-8) method. We also carried out an in vivo experiment in which tumor-bearing nude mice (BALBc/nu-nu) were used to examine the antitumor activity of S-1. Leukocyte counts and gastrointestinal mucosal injury were compared in mice that received alternate-day and consecutive-day treatments. RESULTS: In vitro, for MKN28, the RI was 22.9% for alternate-day, 34.1% for consecutive-day A, and 37.7% for consecutive-day B treatments. For MKN45, the RI was 51.1% for alternate-day, 52.2% for consecutive-day A, and 50.5% for consecutive-day B treatments. In vivo, for MKN28, the treated groups showed higher inhibition than the control, and inhibition of tumor growth was higher with alternate-day than with consecutive-day treatment. The RI was significantly higher with alternate-day (49.3%) than with consecutive-day treatment (16.2%; P < 0.05). For MKN45, the RI was greater than 50% in both treated groups. With consecutive-day treatment, 5 of the 14 mice used died during treatment. Leukocyte counts were lower in the mice with consecutive-day than with alternate-day treatment, or control. Atrophic changes and inflammatory cell infiltration of the small intestinal mucosa were severe after consecutive-day, but minimal after alternate-day treatment. CONCLUSION: Experimentally, alternate-day treatment with S-1 is equivalent to consecutive-day treatment in terms of RI of tumor growth, with lower toxicity.

BACKGROUND: The endoscopic resection of early gastric cancers (EGC) is a standard technique in Japan and is increasingly used throughout the world. Further experience in the treatment of EGC and a clearer delineation of the factors related to lymph-node metastasis would permit a more accurate assessment of endoscopic resection. METHODS: The study group comprised 1,389 patients with EGC who underwent gastrectomy with lymph-node dissection. We evaluated the relations of lymph-node metastasis to clinicopathological factors. RESULTS: Of the 718 patients with intramucosal carcinomas, 14 (1.9%) had lymph-node metastasis. All cases of lymph-node metastasis were associated with ulceration. No lymph-node metastasis was found in patients with intramucosal carcinomas without ulceration, irrespective of tumor size and histological type. Lymph-node metastasis was present in 14 (4.7%) of the 296 patients who had cancer with a submucosal invasion depth of less than 500 microm (sm1). Significantly increased rates of lymph-node metastasis were associated with undifferentiated types, ulcerated lesions and lymphatic invasion. No lymph-node metastasis was found in patients with differentiated sm1 carcinomas 30 mm or less in diameter without ulceration. Lymph-node metastasis occurred in 29% of the patients who had cancer with a submucosal invasion depth of 500 microm or more (sm2). CONCLUSION: This large series of patients with EGC provides further evidence supporting the expansion of indications for endoscopic treatment, as well as warns against potential risks.

A 74-year-old man with diabetic nephropathy developed epigastric pain and high fever after endoscopic submucosal dissection (ESD) for early gastric cancer. Gastroscopy, endoscopic ultrasonography and computed tomography showed ulceration with a purulent lake, thickened entire gastric mucosal layers suggesting focal abscess formation, leading to the diagnosis of phlegmonous gastritis. He underwent total gastrectomy as an emergency. Histological findings of the resected specimen showed severe inflammatory cell infiltration and multiple focal abscess formation spreading to the entire gastric wall. In patients with poorer general conditions, phlegmonous gastritis should be considered as a serious complication after ESD, indicating a requirement of antibiotic prophylaxis.

The prolonged survival of patients receiving surgery for esophageal cancer has led to an increased incidence of adenocarcinoma arising in the gastric tube used for reconstruction (gastric tube cancer). In patients with advanced gastric tube cancer, resection of the gastric tube should be considered, but currently available procedures are very invasive. In patients undergoing curative surgery for gastric tube cancer that has developed after reconstruction through the retrosternal route, the gastric tube is usually resected through a median sternotomy, followed by reconstruction with the colon. However, postoperative complications often occur and treatment outcomes remain poor. We developed a new surgical technique for gastric tube resection without performing a sternotomy in patients with gastric tube cancer who had previously undergone reconstruction through the retrosternal route. Our technique was used to treat two patients. Two Kirschner wires were passed subcutaneously through the anterior chest the chest was lifted to extend the retrosternal space and secure an adequate surgical field. The stomach was separated from the surrounding tissue under videoscopic guidance. Total resection of the gastric tube was done. The retrosternal space was used to lift the jejunum. Roux-en-Y reconstruction was performed. Neither patient had suture line failure or surgical site infection. Their recovery was uneventful. Our surgical technique has several potential advantages including (i) reduced surgical stress (ii) the ability to use the retrosternal space for reconstruction after gastric tube resection and (iii) a reduced risk of serious infections such as osteomyelitis in patients with suture line failure. Our findings require confirmation by additional studies. © 2007 The Authors Journal compilation © 2007 The International Society for Diseases of the Esophagus.

To identify additional alterations to c-kit or platelet-derived growth factor receptor alpha (PDGFRA) genes in gastrointestinal stromal tumors (GIST), we investigated the methylation status of nine known methylation-sensitive CpG islands (p15, p16, p73, 0-6-methylguanine-DNA methyltransferase, E-cadherin, mutL homolog 1, colon cancer nonpolyposis type 2 (escherichia), methylated in tumors [MINT]1, MINT2, and MINT31), and compared the results with the malignant potential and gain-of-function mutation types of GIST. Thirty-five GIST (c-kit mutations in 25 cases, PDGFRA mutations in seven cases, and lacking either mutation in three cases) were subjected to methylation-specific polymerase chain reaction to detect the methylation status of the nine methylation-sensitive CpG islands. Aberrant DNA methylation of these loci was found in 94% of all GIST. The rates of DNA methylation at each locus were as follows: hMLH1, 60%; MINT2, 51%; MGMT, 49%; p73, 49%; p16, 20%; E-cadherin, 14%; MINT1, 9%; p15, 6%; and MINT31, 0%. CpG islands methylator phenotype, which was defined as methylation involving more than three gene promoters, was found in 57% of GIST with c-kit or PDGFRA gene mutations. According to the risk categories, CpG islands methylator phenotype was present in 55% of low-risk GIST, and in 58% of high-risk GIST. Our results suggested that in addition to c-kit or PDGFRA mutations, the aberrant methylation of CpG islands, especially of mismatch-repair genes, may have a role in the tumorigenesis of GIST.

PURPOSE: Our purpose was to study the characteristics of colorectal neoplasms in patients with gastric cancer (GC). METHODS: The study group comprised GC patients who underwent colonoscopy before resection of their GC. We examined the prevalence, site, and histology of colorectal neoplasms, as well as the clinicopathological features and treatment of the patients who had synchronous colorectal cancers (CRC). The logistic regression model was applied to investigate the features of the GC patients with concurrent CRC. RESULTS: We studied 466 GC patients (mean age 64.5 years; 147 women, 319 men), 143 (31%) of whom had a family history of gastrointestinal cancer. Synchronous colorectal adenoma and cancer were detected in 182 (39%) and 18 (4%) patients, respectively. Among the 18 synchronous CRCs, 11 were in the early stages and 10 of these were resected endoscopically. The other eight required simultaneous open radical surgery. All the GC patients with synchronous CRC were older than 50 years. Statistical analysis did not show a significant difference between the features of the patients with and those without concurrent CRC. CONCLUSIONS: The possibility of synchronous colorectal neoplasms in GC patients cannot be disregarded in clinical practice; however, screening of the large bowel may not be necessary in GC patients younger than 50 years.

We describe a 30-year-old man in whom upper endoscopy revealed multiple gastric carcinoids. The peripheral blood gastrin level was 2400 ng/ml (normal range, <200 ng/ml). Mucosal biopsy of the gastric body and fundus showed no atrophy; typical type A chronic atrophic gastritis was thus unlikely. Neither abdominal computed tomography nor selective angiography showed any evidence of tumor in the pancreas or at its periphery. However, the possibility of microgastrinoma could not be ruled out. We performed radioguided surgery with a somatostatin analog, diethylenetriamine pentaacetic acid-D-Phe1-octreotide labeled with (111)In (Octreo Scan). The location of the carcinoids was confirmed. Gastrinoma was ruled out. Total gastrectomy was performed, and the gastrin level decreased to the normal range. Macroscopically, 20 carcinoid tumors, measuring 30 mm in maximum diameter, were confirmed. Microscopic examination showed large numbers of endocrine cell micronests. Hyperplasia of parietal cells was observed, suggesting early-stage type A chronic atrophic gastritis. The antrum contained increased numbers of gastrin-positive cells, which probably caused the preoperative hypergastrinemia.

BACKGROUND/AIMS: To evaluate the feasibility and usefulness of gasless laparoscopy-assisted distal gastrectomy except when treating obese patients compared with open distal gastrectomy for early cancer. METHODOLOGY: We treated 92 patients with distal gastrectomy for early gastric cancer consecutively. Patients with massive submucosal invasion and/or LN swelling were allocated for the open method, and patients with slightly invasive submucosal cancer were allocated for gasless laparoscopy-assisted surgery. As exceptions we employed open surgery for overweight patients and gasless laparoscopy for elderly and/or feeble patients. RESULTS: We attempted to perform open and laparoscopy-assisted surgery on 52 and 40 patients, respectively. Three cases in the laparoscopy-assisted group were converted to open surgery because of obesity. The age was older and BMI was lower in the laparoscopy-assisted group. In terms of operative time and blood loss as well as postoperative recovery, the results for the laparoscopy-assisted group were superior to those of the open surgery group. There were no cases of cardiopulmonary complications for the laparoscopy-assisted group. CONCLUSIONS: Gasless laparoscopy-assisted distal gastrectomy is feasible and useful for early gastric cancer except when treating obese patients.

BACKGROUND: Many patients with gastric cancer respond to TS-1, but some fail to respond or have recurrence. Second-line therapy is needed. METHODS: We performed a pilot study in patients with advanced gastric cancer who did not respond to TS-1 or who had disease recurrence. The patients received oral doxifluridine (600 mg/day) on days 1 to 21 and an intravenous infusion of paclitaxel (70 mg/m(2)) on days 7, 14, and 21 of a 28-day cycle. The treatment was repeated until disease progression or prohibitive toxicity. Response rate, duration of response, median survival time (MST), effects on pleural effusion, ascites, and other signs, and toxicity were evaluated. RESULTS: The study group comprised 52 patients. The response rate was 28%. The duration of response was 103 days. The MST after the start of second-line treatment was 175 days (95% confidence interval, 135 to 224 days). Pleural effusion or ascites resolved or decreased in 73% of the patients. Hair loss occurred in 32 patients (62%), and leukopenia developed in 28 (54%, grade 3 in 1 patient and grade 2 or lower in the others). The MST after the start of treatment with TS-1 was about 16 months. CONCLUSION: A combination of doxifluridine and weekly paclitaxel is expected to be an effective second-line treatment for gastric cancer not responding to TS-1, especially in patients with malignant ascites or pleural effusion. However, it remains unclear whether paclitaxel plus doxifluridine results in a better response and survival benefit than paclitaxel alone in this subgroup of patients. Further studies are therefore necessary.

Background: The development of new surgical instruments and devices has facilitated the performance of esophagojej-unostomy after total gastrectomy. However, total prevention of dehiscence of anastomoses remains difficult. We introduced a new procedure for esophagojejunostomy using a circular stapler, requiring sacrifice of only a small part of the jejunum. Methods: The study group comprised 390 consecutive patients who underwent reconstruction by Roux-en-Y esophagojejunostomy, performed with a circular stapler, sacrificing a small part of the jejunum after total gastrectomy. We assessed anastomotic leakage and anastomotic stenosis after surgery. Results: Only 2 patients (0.5%) had leakage and 4 (1.0%) had anastomotic stenosis after reconstruction. All the patients were cured by conservative therapy. Conclusions: Esophagojejunostomy performed with a circular stapler after total gastrectomy, with sacrifice of only a small part of the jejunum, is a useful and easy procedure, with a leakage rate of 0.5%. Copyright (c) 2007 S. Karger AG, Basel

PURPOSE: Using an instrument we developed to assess postoperative dysfunction objectively (Surg Today 2005;35:535-42), we compared postoperative dysfunction after 2 - field versus 3 - field lymph node dissection retrospectively, in patents undergoing esophageal cancer surgery. METHODS: Subjects were selected randomly from among patients who had undergone radical surgery for squamous cell carcinoma of the thoracic esophagus followed by reconstruction with a gastric tube and a cervical anastomosis. Patients rated 32 items related to postoperative dysfunction according to a 5-grade scale. Postoperative gastrointestinal dysfunction was evaluated on the basis of the total score and the scores for seven symptom categories: decreased physical activity, symptoms of reflux, dumping-like syndrome, nausea and vomiting, passage dysfunction, pain, and diarrhea or soft feces. RESULTS: We studied 42 patients, 22 of whom underwent 2-field lymph node dissection and 20 of whom underwent 3-field dissection. The total gastrointestinal dysfunction score was significantly higher in the 3-field group than in the 2-field group (78.4 +/- 14.1 points vs 67.9 +/- 16.9 points, P = 0.038). When we analyzed the data according to the symptom categories, the 3-field group had higher scores for decreased physical activity, symptoms of reflux, dumping-like syndrome, nausea and vomiting, and passage dysfunction. CONCLUSION: Three-field lymph node dissection was associated with greater postoperative gastrointestinal dysfunction than 2-field lymph node dissection. Thus, the preoperative identification of those patients with esophageal cancer who are most likely to benefit from concurrent cervical lymph node dissection is essential.

Gastrointestinal stromal tumors (GISTs) are rare mesenchymal neoplasms with an annual incidence of approximately 10 to 20 per 1 million cases. Although pathologists have often observed incidental small GISTs in the stomach resected from patients with gastric cancer, no report on the real incidence of gastric GISTs is available. In this study, 100 whole stomachs resected from patients with gastric cancer were sectioned at 5-mm intervals and hematoxylin and eosin-stained slides (a mean of 130 slides for each case) were examined for microscopic GISTs. KIT (CD117), CD34, and desmin expression of the incidental tumors was evaluated by immunohistochemistry, and genomic DNA extracted from formalin-fixed and paraffin-embedded tumor tissues was analyzed for c-kit gene mutations in exon 11. In 35 of the 100 whole stomachs, we found 50 microscopic GISTs, all of which were positive for KIT and/or CD34 and negative for desmin. Most microscopic GISTs (45/50, 90%) were located in the upper stomach. Two of the 25 (8%) microscopic GISTs had c-kit gene mutations. Fifty-one leiomyomas with positive expression for desmin were observed in 28 of the 100 stomachs. Both leiomyomas and GISTs were found in 12 stomachs. These results indicate that microscopic GISTs are common in the upper portion of the stomach. Considering the annual incidence of clinical GISTs, only few microscopic GISTs may grow into a clinical size with malignant potential. Further studies are required to clarify the genetic events responsible for the transformation of microscopic GISTs to clinical GISTs.

The patient was a 75-year-old man. Under a diagnosis of angina pectoris, he was being treated with aspirin and ticlopidine hydrochloride at a local clinic. Severe postprandial pharyngeal/thoracic pain and hematemesis occurred. Upper digestive tract endoscopy revealed an extensive submucosal hematoma involving the esophageal orifice and cardia. Computed tomography (CT) scan did not show aortic dissociation or mediastinal emphysema. Antiplatelet therapy was discontinued, and follow-up was continued by fasting and conservative treatment with an H2-blocker. Ten days after onset, endoscopy showed the disappearance of the hematoma, and ingestion was started. Twenty-two days after onset, endoscopy revealed regeneration and cicatrization of the esophageal mucosa. In a detailed examination of heart diseases, angina pectoris was ruled out therefore, antiplatelet therapy was discontinued. There has been no recurrent esophageal submucosal hematoma for 4 years of follow-up. © Japan Esophageal Society and Springer-Verlag 2005.

A 58-year-old Japanese man complained of dysphagia, and esophagography and endoscopy showed a 7.5-cm-long protruding tumor in his middle esophagus. Biopsy diagnosed the lesion as basaloid squamous carcinoma. We assessed the tumor as T3N0M0 stage II. Preoperative chemoradiotherapy was started, consisting of 3 weeks of intravenous chemotherapy with 10mg/day cisplatin and 750 mg/day 5-fluorouracil and concurrent total 45-Gy external irradiation applied to the tumor. We evaluated the effectiveness as a partial response and performed curative resection with radical esophagectomy 23 days after the completion of chemoradiotherapy. The pathological findings showed necrosis and degeneration over two-thirds of the tumor. Postoperatively, he returned to physical labor and has had no evidence of recurrence for 5 years. Although basaloid squamous carcinoma of the esophagus is associated with poor prognosis because of its highly malignant potential, preoperative chemoradiotherapy followed by radical esophagectomy may allow for the possibility of improving the prognosis of a fatal process. © Japan Esophageal Society and Springer-Verlag 2005.

PURPOSE: To evaluate the efficacy of a streptococcal preparation, OK432, on malignant ascites in mice. METHODS: PC-C203U (PC203) is a preparation of another strain of the streptococcal family, with the lowest antineoplastic action. To examine the survival curves of mice after the inoculation of BAMC-1 tumor cells, we gave intraperitoneal OK432, PC203, or saline as a control. Intraperitonal neutrophils were counted by cytospin, and interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and macrophage inflammatory protein (MIP)-1alpha were measured by enzyme-linked immunosorbent assay, and 8 h after the administration of OK432, PC203, and saline. Using electron microscopy, we examined the greater omental milky spots, where the in situ proliferation of neutrophils or macrophages takes place. RESULTS: The OK432 group had the best survival and the control group the worst. The ratio of intraperitoneal neutrophils to BAMC-1 was highest in the OK432 group and lowest in the control group. Quantitative IL-1beta, IL-6 and MIP-1alpha levels were correlated closely with survival. Electron microscopic examination of the milky spots revealed massive proliferation of neutrophils in the OK432 group, but not in the PC203 or control groups. CONCLUSION: OK432 effectively activated intraperitoneal neutrophils and a series of immunological chain reactions through an increase in IL-1beta, IL-6, and MIP-1alpha levels. Milky spots could have important antitumor effects in terms of the spread of neutrophils.

PURPOSE: We evaluated the purpose reliability and validity of a preliminary scale, which we developed to assess postoperative dysfunction after surgery for gastric and esophageal carcinoma. METHODS: After interviews with 12 patients, reviews of previous studies, and discussions with experts, we identified the physical symptoms that develop after resection of upper gastrointestinal (GIT) carcinoma, and devised a preliminary scale comprised of 34 items. A questionnaire survey based on this scale was then sent to 283 patients. RESULTS: The questionnaire was returned by 223 patients (78.8%), and 219 responses (98.2%) were valid. Among the 219 respondents, 168 had gastric carcinoma and 51 had esophageal carcinoma. After the elimination of scale items regarded as irrelevant based on statistical considerations and the judgment of experts, factor analysis was done. Seven factors were valid, namely, limited activity due to decreased food consumption, reflux, gastric dumping, nausea and vomiting, deglutition difficulty, pain, and difficulty with passing stools, which were often poorly formed. Scale reliability was confirmed by a Cronbach alpha-coefficient of 0.924. The validity of the construction of this scale was confirmed using the known-group technique based on the operative procedures performed, and the results of factorial validity. CONCLUSION: Our preliminary scale is sufficiently reliable and valid, and will prove to be clinically useful.