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We performed esophagojejunostomy after totally laparoscopic total gastrectomy (TLTG) using functional end-to-end anastomosis (FEEA) as the first choice and laparoscopic-assisted total gastrectomy (LATG) using a circular stapler with a transorally inserted anvil as the second choice.We examined 109 patients with gastric cancer who underwent TLTG and LATG. Among these, 100 patients underwent TLTG and the rest underwent LATG.The length of resected esophageal segment in LATG patients was significantly longer than that in TLTG patients (P0.001). The length of the resected esophagus segment was inversely correlated with body mass index in cases of esophagojejunostomy by FEEA (P0.05). Multivariate analysis revealed that T factor, N factor, and severe complications were the independent factors for survival.Esophagojejunostomy using FEEA or a circular stapler with a transorally inserted anvil should be selected according to the length of the resected esophageal segment and/or body mass index.

The relationship between postoperative complications and long-term survival after surgery for esophageal squamous cell carcinoma (ESCC) is controversial. A total of 210 patients with ESCC who underwent subtotal esophagectomy with a reconstructed gastric tube were investigated according to the development of postoperative complications. The associations of age, gender, T and N factors, and pStage with grade 0–2 complications (NSC) and grade 3 and higher complications (SC) were compared by propensity score-matching analysis. Fifty-one pairs of NSC and SC groups were selected for the final analysis. We divided 102 patients between the NSC and SC groups or between the no pulmonary complication (NPC) and the pulmonary complication (PC) groups. The overall survival (OS) and disease-free survival (DFS) were determined by the Kaplan–Meier method and were compared by log-rank tests. Possible predictors of OS and DFS were subjected to univariate analysis and multivariate Cox proportional hazard regression analysis. The propensity score matching revealed that the 5-year OS and DFS of the NSC group were not different from those of the SC group. However, the 5-year OS of the PC group was significantly worse than that of the NPC group, while no significant differences were observed in the DFS between the PC and NPC groups. In the multivariate analysis, UICC pStage, pulmonary complication, and American Heart Association (AHA) classification for OS and UICC pStage for DFS were significant prognostic factors. The OS and DFS did not differ in patients with or without severe postoperative complications. However, postoperative pulmonary complications were independent predictors of poorer OS, but not DFS, in patients who underwent R0 resection for ESCC.

Background/aim The aim of this study was to clarify the treatment strategy for synchronous squamous cell carcinoma of the esophagus (ESCC) and head and neck cancer (HNC). Patients and methods Treatment outcomes of 91 patients with synchronous ESCC and HNC were evaluated. Thirty-eight patients received simultaneous definitive chemoradiotherapy (CRT) and 15 patients underwent simultaneous resection. Results Among the patients who received simultaneous CRT, adverse events (grade 3-5) were recognized in 14 patients (40%), including one case of death due to aspiration pneumonia. Complete response was observed in 22 patients with ESCC (58%) and 19 patients with HNC (50%). The five-year survival rate was 44%. There were no in-hospital deaths after simultaneous resection; however, postoperative complications were recognized in 4 patients. The five-year OS was 70%. Conclusion The treatment of synchronous ESCC and HNC must be decided by adopting a strategy that is appropriate for each case. Both simultaneous CRT and simultaneous resection are feasible and effective treatment options.

We report a case of a 43-year-old man who presented with gradually intensifying abdomenal pain of acute onset and was shown by contrast-enhanced computed tomography (CT) examination to have acute aortic dissection (Stanford type B). A diagnosis of gastrointestinal necrosis was made and he underwent emergency surgery. At laparoscopy, he was found to have no superior mesenteric arterial pulse and intestinal necrosis from the upper jejunum to the right transverse colon. Resection of the superior mesenteric artery (SMA) perfusion area was performed. Postoperatively, ischemia in the perfusion area of the celiac artery was also diagnosed, manifesting as gallbladder necrosis, portal vein gas accompanying gastric wall necrosis, perforation of the remaining upper jejunum, and hepatic and splenic infarction. However, development of a collateral circulation originating in the left colic branch of the inferior mesenteric artery (IMA) enabled retrograde provision of blood to the celiac artery through the SMA pancreaticoduodenal arcade. Thus, in this case, spontaneous development of a natural bypass created a new route for arterial perfusion, contributing to the patient’s survival. When ischemia of the celiac artery and SMA perfusion areas occur, collateral circulation can develop from the IMA., 症例は43 歳男性．急性大動脈解離（Stanford type B）の診断で厳重な血圧管理を行われていたが，増強する腹痛出現し消化管壊死と診断され当科加療要請された．緊急手術の所見で上腸間膜動脈の拍動なく，上位空腸から横行結腸右側にかけて腸管が壊死していたため，上腸間膜動脈潅流域の大量腸切除を行った．術後に胆嚢壊死，門脈内ガスを伴う胃壁壊死，残存した上位空腸の穿孔，肝梗塞，脾梗塞など腹腔動脈の潅流域にも虚血所見を認めた．しかし下腸間膜動脈の分枝である左結腸動脈の側副血行路が発達することで，逆行性に上腸間膜動脈の膵十二指腸アーケードを介し腹腔動脈に供血され，上記虚血症状は軽快し救命し得た．腹腔動脈や上腸間膜動脈の虚血がある場合，下腸間膜動脈の側副血行路が発達しやすいことが示唆された．

Background Obturator hernia (OH) is a rare but serious disease associated with high morbidity and mortality due to advanced patient age and comorbidities. This study evaluated the feasibility of a laparoscopic approach to OH. Study Design We retrospectively reviewed the records of 32 patients (median age 84 years; 31 women) with OH treated between 2003 and 2016. Results Five patients with incidental OH underwent total extraperitoneal (TEP) repair. Of 27 patients with incarcerated OH, 18 patients underwent laparotomy, 13 of which required bowel resection, and the remaining 9 patients underwent preoperative ultrasound-guided manual OH reduction. Of 6 patients with successful OH release, 3 and 2 patients underwent TEP and transabdominal preperitoneal repair, respectively, and 1 patient declined the operation. Three patients with failure underwent laparoscopic exploration and conversion to open operation for bowel resection. Comparing the open and laparoscopic groups, the median operation times were 67.5 minutes vs 124 minutes, respectively (p = 0.004); median postoperative stay was 19 vs 11 days, respectively (p = 0.028); and Clavien-Dindo grade II or higher complications tended to be lower (28% vs 8%, respectively; p = 0.359). Even in patients without bowel resection, the median postoperative stay was significantly shorter in the laparoscopic group compared with the open group (7.5 vs 15 days, respectively; p = 0.032). During a mean follow-up of 24.5 months, the 3-year recurrence rate for OH was 25% for non-mesh repair and 0% for mesh repair (p = 0.335). Three- and 5-year cumulative survival rates were 83% and 71%, respectively. Conclusions Laparoscopic operations after ultrasound-guided manual reduction can be an alternative to emergent laparotomy in select OH patients.

T4 esophageal cancer (EC) that invades the trachea or bronchus often has poorer prognosis than other T4 ECs. We investigated the long-term results of definitive chemoradiotherapy (dCRT) or induction chemoradiotherapy followed by surgery (iCRT-S) in patients with T4 EC with tracheobronchial invasion (TBI). From 2003 to 2013, 71 patients with T4 EC with TBI were treated in our institution; 58 underwent dCRT, and 13 underwent iCRT-S. The long-term results associated with survival were retrospectively analyzed, and prognostic factors were examined by univariable and multivariable analysis. The 1-, 2-, and 5-year overall survival for all patients with T4 EC with TBI treated by dCRT or iCRT-S was 57, 29, and 19%, respectively. Multivariable analysis revealed that clinical lymph node (LN) metastasis and the treatment period were significant prognostic factors. Clinical LN positivity had significantly poorer prognosis than LN negativity. The treatment outcome in the later period was significantly better than that in the earlier period. In particular, the outcome after dCRT revealed significantly better prognosis in the later compared with the earlier period, whereas the outcome after iCRT-S did not show such a difference. With respect to treatment modality, no significant difference in survival was observed between dCRT and iCRT-S. Clinical LN negativity and later treatment period were significantly good prognostic factors for T4 EC with TBI. The recent improvements in dCRT outcomes may help to achieve survival comparable to that of iCRT-S.

Long-term dialysis often causes physiological and metabolic problems that may affect the outcomes of surgery. The aim of this study was to elucidate whether emergency surgery for acute abdomen yields similar outcomes in dialysis patients versus non-dialysis patients. The subjects were 126 patients who underwent emergency surgery for acute abdomen between January, 2007 and November, 2011 in our hospital. They were divided into a dialysis group (HD group; n = 9) and a non-dialysis group (non-HD group; n = 117) and their postoperative morbidity and mortality were compared. Postoperative morbidity and mortality were significantly worse in the HD group. All 9 of these patients succumbed to postoperative complications versus only 5 of the 117 patients in the non-HD group. The outcomes of emergency surgery for acute abdomen were significantly worse for dialysis patients than for non-dialysis patients. Prompt diagnosis, initiation of the most suitable surgical procedure, and meticulous postoperative cares are imperative to improving the surgical outcomes of dialysis patients.

Background Neuroendocrine carcinoma (NEC) of the esophagus is a rare and highly aggressive disease but the biological features are poorly understood. The objective of this study was to analyze the clinicopathological and immunohistochemical features of NEC of the esophagus. Methods Fourteen patients diagnosed with NEC of the esophagus from 1998 to 2013 were included in this study. Clinicopathologic features, therapeutic outcomes and immunohistochemical results were analyzed. Results Eleven out of 14 cases showed protruding or localized type with or without ulceration. Only three patients were negative for both lymph node and organ metastasis and seven cases were positive for metastases to distant organs and/or distant lymph nodes. Of the six patients with limited disease (LD), three patients were treated by surgery. Three patients with LD and seven patients with extensive disease (ED) were initially treated with chemotherapy, except for one who underwent concurrent chemo-radiotherapy due to passage disturbance. The median survival of patients with LD was 8.5 months, whereas that of patients with LD was 17 months. Among the 14 cases, 12 cases (83.3%), 13 cases (91.7%) and 12 cases (83.3%) showed positive immunostaining for choromogranin A, synaptophysin and CD56, respectively. Nine of 14 cases (64.2%) presented positive staining for c-kit and most (8/9, 88%) simultaneously showed p53 protein abnormality. Two cases were negative for c-kit and p53, and positive for CK20. Conclusion Consistent with previous reports, the prognosis of NEC of esophagus is dismal. From the results of immunohistochemical study, NEC of esophagus might be divided into two categories due to the staining positivity of c-kit and p53. This study provides new insight into the biology of NEC of the esophagus.

We herein report a case involving a 70-year-old man who was diagnosed with early gastric cancer that occurred after coronary artery bypass grafting (CABG) using the right gastroepiploic artery (RGEA) for effort-induced angina. He was successfully treated by laparoscopic surgery. Preoperative cardiac three-dimensional computed tomography and coronary angiography showed an occlusion of the RGEA graft, which could lead to ligation of the RGEA to dissect the lymph nodes along the RGEA. The laparoscopic approach helps to identify and avoid injury to the RGEA graft because of its enlarged and precise viewing field compared with laparotomy followed by retractor placement. Laparoscopic surgery is a useful method in such cases to reduce perioperative complications risk.

Laparoscopic-assisted percutaneous endoscopic gastrostomy (LAPEG) was performed in consecutive three patients for whom it was unable to place a percutaneous endoscopic gastrostomy (PEG). The mean operation time was 40.3 min, and mean blood loss was 1.3 g. Three trocars were placed, two for working and another for endoscopy, and a PEG was established by an usual Introducer method. There were no complications both intra- and post-operatively. LAPEG might be a safe alternative when the application of PEG is difficult.

This multicenter phase II study was designed to determine the efficacy and tolerability of oxaliplatin, levoforinate, and infusional 5-fluorouracil (FOLFOX4) as a second-line therapy for Japanese patients with unresectable advanced or metastatic colorectal cancer. A total of 53 patients with progressive disease after first-line chemotherapy were enrolled in the study. The treatment was repeated every 2 weeks until disease progression or unacceptable toxicity occurred, or the patient chose to discontinue the treatment. Four patients were ineligible and one did not receive the protocol therapy. Therefore, the response rate, overall survival (OS), and progression-free survival (PFS) were evaluated in 48 patients; toxicity was evaluated in 52 patients, excluding the patient who had not received the protocol therapy. A partial response was observed in 10 patients. The overall response rate was 20.8% (95% confidence interval [CI], 10.5%–35.0%). The median PFS was 5.6 months (95% CI, 4.1–7.0 months) and the median OS was 19.6 months (95% CI, 11.4–24.3 months). The most frequently encountered grade 3/4 hematological symptom was neutropenia (43.1%). The toxicity profile was generally predictable and manageable. The results showed good tolerability and efficacy for second-line FOLFOX4 in patients with advanced colorectal cancer, thus indicating the promise of this regimen as an effective second-line therapy for advanced colorectal cancer in the Japanese population.

The purpose of this study was to clarify the effect of preoperative chemoradiotherapy (CRT) for esophageal cancer on the postoperative course, and to determine the clinical significance of salvage esophagectomy after definitive CRT. Based on their preoperative treatment, 477 patients with esophageal cancer were classified into three groups: 253 patients who received surgery alone (Group I), 197 who received planned CRT (30–45 Gy, Group II), and 27 who received a salvage esophagectomy (radiation ≥60 Gy, Group III). Postoperative complications developed in 25, 40, and 59% of the patients in Groups I, II, and III, respectively, with pulmonary complications developing in 10, 15, and 30%, and anastomotic leakage developing in 13, 23, and 37%, respectively. Mortality rates were 2.4, 2.0, and 7.4%, respectively. Multivariate analysis revealed preoperative therapy to be an independent factor associated with postoperative risks: the odds ratios (ORs) of Groups II and III compared to Group I were 1.8 and 4.0 for pulmonary complications, while they were 1.9 and 2.8, respectively, for anastomotic leakage. No critical complications developed in the 14 patients who received salvage surgery performed with strict surgical indications after 2005. The survival of Group III was not significantly different from that of Groups I and II. Most patients who received an R1/R2 resection after definitive CRT died within 2 years after salvage surgery. Preoperative CRT is associated with postoperative complications especially in patients with R2 resection, while long-term survival can be achieved after R0 resections. Salvage surgery should be considered for carefully selected patients in whom R0 resection can be achieved.

An esophagectomy followed by reconstruction for esophageal cancer is a highly aggressive operation. The purpose of this study was to justify a two-stage operation for high-risk patients with esophageal cancer. The clinical results of 27 patients who underwent two-stage operation were compared with 118 patients who underwent a simultaneous resection and reconstruction (control subjects). The reasons for the selection of the two-stage operation were underlying general disease in 13 patients (liver dysfunction, n = 6; pulmonary disease, n = 3; poor performance status, n = 2; diabetes and renal failure, n = 1 each) and high-risk operation in 14 other patients (colon interposition, n = 7; salvage operation after definitive chemoradiotherapy, n = 4; and intraoperative events, n = 3). The patients initially underwent an esophagectomy and a cervical esophagostomy. Reconstruction was usually performed 2–3 weeks later. The patients in the two-stage group were older than the control patients (mean 67.8 vs. 61.6 years old). The morbidity rate of the two-stage operation was 29.6%, which was not statistically different than control patients (32.2%). Postoperative complications in the two-stage operation were anastomotic leakage in 5 patients, and pneumonia and wound infection in 1 patient each. No patient experienced in-hospital death. The survival rates were not statistically different between the two groups. A two-stage operation is a safe operation that prevents the occurrence of critical postoperative complications, and it thus may be considered an important treatment strategy for high-risk patients with esophageal cancer.

Background Anastomotic leakage with an intractable cutaneous fistula frequently develops after an esophagectomy and reconstruction via the subcutaneous route. Methods A pectoralis major muscle (PMM) flap was used for the treatment of 6 patients with esophageal cancer who developed anastomotic leakage with fistula after reconstruction via the subcutaneous route. A gastric tube and colon had been used for reconstruction in 2 and 4 patients, respectively. A trimming and repair of the leakage site was initially performed and the anastomotic site was then covered with a muscle flap. Results Recurrent anastomotic leakage did not develop in 5 patients. Among these patients, oral intake was initiated from 11–15 days after the repair operation in 4 patients. A patient having recurrent anastomotic leakage after a repair operation recovered well with conservative therapy. Conclusion The coverage with a PMM flap over the repair site is a simple method for preventing the development of recurrent leakage after a repair operation. Even when recurrent anastomotic leakage has occurred after this operation, healing is normally expected by means of conservative treatment. We, therefore, recommend this method for the repair of intractable anastomotic leakage after reconstruction via the subcutaneous route for esophageal cancer.

Objective: This phase II study evaluated the toxicity and efficacy of a novel dosing schedule of docetaxel and S-1 as treatment for advanced gastric cancer. Methods: Patients with measurable advanced or recurrent gastric cancer and no prior exposure to the investigational drugs were treated with intravenous docetaxel 35 mg/m2 on days 1 and 15, and oral S-1 80 mg/m2/day on days 1–14 every 4 weeks. The primary endpoint was objective response. Results: Thirty-five eligible patients were enrolled and received a total of 151 cycles of treatment (median 3, range 1–19). One complete response and 13 partial responses were observed, with an overall response rate of 40% (95% CI: 24–56%). Median progression-free survival and median overall survival times were 4.5 and 14.2 months, respectively. The most common grade 3–4 toxicities were neutropenia (23%) and leukocytopenia (15%). Conclusion: Biweekly docetaxel combined with S-1 is active in advanced or recurrent gastric cancer, and can be administered with proper management of adverse events in an outpatient clinic.

Background:p53 gene mutations have been reported in over half of all human cancers and they appear to occur in the early stage of cancer, thus indicating the important role that such mutations may play in the carcinogenesis of the digestive tract. This study investigated the differences in p53 abnormalities between cancers of the upper and lower gastrointestinal tract. Materials and Methods: The DNA of 354 specimens of gastrointestinal cancer (esophagus 85, stomach 112, colon 157) was extracted and then p53 gene mutations were investigated by direct sequencing; the loss of heterozygosity was also synchronously analyzed in all cases. Results: (1) p53 gene mutation: p53 gene mutations were found in 41 samples (48.2%) in the esophagus, 18 samples (16.0%) in the stomach and 36 samples (22.9%) in the colon. p53 mutations were more frequently identified in well-differentiated cancers and a close correlation was recognized between p53 mutations and loss of heterozygosity. (2) Mutation spectrum: the ratio of transversion was 43.9% in esophagus, 33.3% in stomach and 25.0% in the colon tumors. Reciprocally, the ratio of transition was 31.7, 66.7, and 72.2%, respectively. Discussion: The frequency of p53 transversion mutations was extremely high in the upper digestive tract, whereas transition mutations were more frequently observed in the lower digestive tract. The investigation of the spectrum of mutations in p53 is therefore expected to lead to a better understanding of the agents responsible for inducing cancer.

In Japan, most esophageal cancers are squamous cell carcinomas, and the results of esophagectomy have improved remarkably in recent years. The object of this study was to evaluate advances in operative therapy for esophageal cancer in Japan.We evaluated mortality, morbidity, and prognosis in 1000 consecutive patients who underwent esophagectomy for esophageal cancer at a single institution in Japan. The patients were divided into 3 groups according to the period when esophagectomy was performed: Group I (n = 197), 1964-1980; group II (n = 432), 1981-1993; and group III (n = 371), 1993-2006.The incidence of squamous cell carcinoma was 94%. The morbidity rates were 62%, 38%, and 33 %, in groups I, II, and III, respectively (P0.01, groups I vs II and III), and the in-hospital mortality rates were 14.2%, 5.1%, and 2.4%, respectively (P0.01, between each group). The 5-year overall survival rate was 30% (14%, 27%, and 46% in groups I, II, and III, respectively; P0.0001). Multivariate analysis revealed age, gender, depth of invasion, node metastasis, distant metastasis, curability, extent of lymphadenectomy, resectability, and the period when the operation was performed as independent prognostic factors.Generally, esophagectomy has been performed safely without critical complications; however, the prognosis has improved remarkably with advances in surgical techniques and treatment modalities.

Acute lung injury (ALI) is one of most serious complications to occur after an esophagectomy for esophageal cancer. However, the pathogenesis of ALI is still unclear. The cytokine levels of pleural drainage fluid as well as peripheral blood were measured in 27 patients who had undergone an extended radical esophagectomy. Both the clinical factors and cytokine levels were compared between 11 patients with (group I) and 16 without ALI (group II). ALI occurred more frequently in patients who underwent colon interposition than in those who received a gastric tube reconstruction (86%vs 25%, P = 0.009). The operation time of group I was significantly longer than that of group II. A logistic regression analysis revealed colon interposition to be an independent factor associated with the ALI (P < 0.05). Postoperative anastomotic leakage and systemic inflammatory response syndrome (SIRS) occurred more frequently in group I than in group II (P < 0.01). Both the serum interleukin-6 (IL-6) and IL-8 levels of group I were significantly higher than those of group II. IL-1beta and tumor necrosis factor-alpha were undetectable in the peripheral blood, whereas they were detectable in the pleural effusion. The IL-1beta of pleural effusion was higher in group I than group II. In conclusion, greater surgical stress, such as a longer operative time, is thus considered to be associated with the first attack of ALI. The adverse events developing in the extra-thoracic site, such as necrosis and local infection around anastomosis may therefore be the second attack. Furthermore, ALI may cause not only SIRS but also other complications such as anastomotic leakage.

MUTYH is a mammalian DNA glycosylase that initiates base excision repair by excising adenine opposite 8-oxoguanine and 2-hydroxyadenine opposite guanine, thereby preventing G:C to T:A transversion caused by oxidative stress. Recently, biallelic germ-line mutations of MUTYH have been found in patients predisposed to a recessive form of hereditary multiple colorectal adenoma and carcinoma with an increased incidence of G:C to T:A somatic mutations in the APC gene. In the present study, a systematic histologic examination revealed that more spontaneous tumors had developed in MUTYH-null mice (72 of 121; 59.5%) than in the wild type (38 of 109; 34.9%). The increased incidence of intestinal tumors in MUTYH-null mice (11 tumors in 10 of 121 mice) was statistically significant compared with the wild type (no intestinal tumors in 109 mice). Two adenomas and seven adenocarcinomas were observed in the small intestines, and two adenomas but no carcinomas were found in the colons. In MUTYH-null mice treated with KBrO3, the occurrence of small intestinal tumors dramatically increased. The mean number of polyps induced in the small intestines of these mice was 61.88 (males, 72.75; females, 51.00), whereas it was 0.85 (males, 0.50; females, 1.00) in wild-type mice. The tumors developed predominantly in the duodenum and in the upper region of the (jejunum) small intestines. We conclude that MUTYH suppresses spontaneous tumorigenesis in mammals, thus providing experimental evidence for the association between biallelic germ-line MUTYH mutations and a recessive form of human hereditary colorectal adenoma and carcinoma. [Cancer Res 2007;67(14):6599–604]

Therapeutic strategies for positive peritoneal lavage cytology [CY(+)] findings have not yet been established. The aim of the present study was to compare the effects of neoadjuvant systemic chemotherapy and surgery followed by S-1 adjuvant chemotherapy for treating gastric carcinoma in patients with CY(+) status without peritoneal metastasis.Twenty-three patients with CY(+) status without peritoneal metastasis who underwent curative surgery for gastric carcinoma between October 1999 and December 2014 were included in the study. Ten patients received neoadjuvant systemic chemotherapy followed by surgery, whereas 13 patients underwent surgery, in nine cases followed by S-1 adjuvant chemotherapy.The 5-year survival in both groups was 15%, and no significant difference was observed. However, the prognosis for patients with CY(-) status after neoadjuvant systemic chemotherapy was significantly better than that of patients who were still CY(+) after neoadjuvant systemic chemotherapy (p0.01). Among all patients, the prognosis of those with less than clinical N2 disease was significantly better than that of patients with clinical N3 (p0.01). In multivariate analysis, clinical lymph node metastasis was the only independent prognostic factor for CY(+) patients without peritoneal metastasis (p0.05).The prognosis of gastric carcinoma with CY(+) without peritoneal metastasis is still stage IV disease and is dependent on the degree of clinical lymph node metastasis, in spite of therapeutic treatment.

Oxidative damage of nucleotides within DNA or precursor pools caused by oxygen radicals is thought to play an important role in spontaneous mutagenesis, as well as carcinogenesis and aging. In particular, 8-oxodGTP and 2-OHdATP are potent mutagenic substrate for DNA synthesis. Mammalian MTH1 catalyzes hydrolysis of these mutagenic substrates, suggesting that it functions to prevent mutagenesis caused by these oxidized nucleotides. We have established MTH1(-/-) mice lacking the 8-oxodGTPase activity, which were shown to be susceptible to lung, liver and stomach cancers. To examine in vivo mutation events due to the MTH1-deficiency, a reporter gene, rpsL of Escherichia coli, was introduced into MTH1(-/-) mice. Interestingly, the net frequency of rpsL(-) forward mutants showed no apparent increase in MTH1(-/-) mice as compared to MTH1(+/+) mice. However, we found differences between these two genotypes in the class- and site-distributions of the rpsL(-) mutations recovered from the mice. Unlike MutT-deficient E. coli showing 1000-fold higher frequency of A:T--C:G transversion than the wild type cells, an increase in frequency of A:T--C:G transversion was not evident in MTH1 nullizygous mice. Nevertheless, the frequency of single-base frameshifts at mononucleotide runs was 5.7-fold higher in spleens of MTH1(-/-) mice than in those of wild type mice. Since the elevated incidence of single-base frameshifts at mononucleotide runs is a hallmark of the defect in MSH2-dependent mismatch repair system, this weak site-specific mutator effect of MTH1(-/-) mice could be attributed to a partial sequestration of the mismatch repair function that may act to correct mispairs with the oxidized nucleotides. Consistent with this hypothesis, a significant increase in the frequency of G:C--T:A transversions was observed with MTH1(-/-) MSH2(-/-) mice over MSH2(-/-) mice alone. These results suggest a possible involvement of multiple anti-mutagenic pathways, including the MTH1 protein and other repair system(s), in mutagenesis caused by the oxidized nucleotides.

BACKGROUND Endoscopic mucosal resection (EMR) is a less invasive localized treatment for patients with esophageal carcinoma. However, indications for EMR use in cases of superficial esophageal carcinoma are controversial. The authors evaluated histopathologic risk factors for lymph node metastasis and recurrence. METHODS In the specimens resected, the authors examined depth, the superficial area and the area attached to or infiltrating the lamina muscularis mucosa. RESULTS The authors found that the superficial area and the attached or infiltrated area reflected the depth of the tumor. However, there was a recurrence of esophageal carcinoma even in m3 cases attached only to the lamina muscularis mucosa. CONCLUSIONS The authors concluded that m1 and m2 esophageal carcinoma had almost no risk of lymph node metastasis and recurrence no matter how extensive the superficial area. In addition, sm2 and sm3 carcinoma have a high frequency of lymph node metastasis and recurrence. M3 and sm1 carcinoma run the risk of lymph node metastasis and recurrence however small the superficial area and the area attached to or infiltrating the lamina muscularis mucosa. Treatment strategies for patients with superficial esophageal carcinoma, including EMR, should take the above findings into account. Cancer 2002;94:570–5. © 2002 American Cancer Society.

To clarify mechanisms involved in the carcinogenesis of multiple oesophageal squamous cell carcinoma, the expression of p53 protein in 46 lesions surgically excised from 13 Japanese patients was investigated immunohistochemically and the relation of p53 protein accumulation to the patient’s history of alcohol consumption and cigarette smoking was analyzed. p53 protein accumulation was observed in 13 main lesions, that is in 6 (85.7%) of 7 subjects with a history of heavy drinking and smoking, but only in 1 (16.7%) of 6 with no such history (Fisher’s exact test, p = 0.025). As regards the 46 lesions, p53 protein accumulation was evident in 22 (88.0%) of 25 lesions of the high-risk patients, but in 7 (33.3%) of 21 lesions of the other subjects (Fisher’s exact test, p < 0.001). p53 protein accumulation was similarly recognized in all oesophageal lesions in 5 of 7 high-risk patients. Thus, use of both alcohol and cigarettes is clearly associated with a high frequency of p53 protein accumulation in multiple oesophageal squamous cell carcinoma present at the same time. These findings are considered to support the concept of field carcinogenesis of the oesophagus.

S-1 adjuvant chemotherapy is commonly administered postoperatively for stage II and III advanced gastric cancer.This study included 113 patients treated with S-1 adjuvant chemotherapy after surgery for stage II and III advanced gastric cancer. These patients were divided into 4 groups: group A (n = 63), who had a longer duration (≥6 months) and earlier S-1 administration (≤6 weeks) after surgery; group B (n = 16), who had a longer and later S-1 administration (6 weeks) after surgery; group C (n = 27), who had a shorter duration (6 months) and earlier S-1 administration after surgery; and group D (n = 7), who had a shorter and later S-1 administration after surgery.The recurrence rates in groups A, B, C, and D were 15.7, 43.8, 44.4, and 57.1 %, respectively (A vs. B, p0.05, A vs. C and D, p0.01). The survival time of group A was significantly longer than that of other groups (p0.005). In addition, the survival time of patients with severe complications was significantly shorter than that of patients with non-severe complications (p0.05). An earlier S-1 administration after surgery was the only independent prognostic factor in the multivariate analysis.The prognosis of advanced gastric cancer was significantly related to the start of S-1 adjuvant treatment within 6 weeks after surgery.

A 55-year-old man had laparoscopic cholecystectomy for acute cholecystitis and unexpected gallbladder cancer, followed by a liver bed resection and lymph node dissection. Eleven years later, he had a port-site recurrence of gallbladder cancer requiring resection; at that time, no other site of recurrence was observed. The patient has survived for 20 months without another recurrence. Although a rare finding, clinicians should be alert to the possibility of such a recurrence even 11 years after complete cure of the primary tumor, particularly in patients who have undergone laparoscopic cholecystectomy for unexpected gallbladder cancer.

Global DNA hypomethylation is associated with increased chromosomal instability and plays an important role in tumorigenesis. The methylation status of the long interspersed nuclear element-1 (LINE-1) element is a useful surrogate marker for global DNA methylation. Although LINE-1 hypomethylation is recognized as a poor prognostic marker, the correlation of LINE-1 methylation level with tumor suppressor gene mutation, chromosomal instability, and clinical significance in esophageal squamous cell carcinoma (ESCC) remains unclear. Using resected tumor tissues and the corresponding normal esophageal mucosa from 105 patients with ESCC, bisulfite pyrosequencing analysis was performed to quantify the LINE-1 methylation levels. p53 mutations in exons two to ten were detected by polymerase chain reaction direct sequencing. Chromosomal instability was assessed by single nucleotide polymorphism array comparative genomic hybridization analysis. The LINE-1 methylation level of ESCC was significantly lower than matched normal mucosa. LINE-1 methylation levels of normal mucosa from the esophagus had a significant inverse correlation with both cigarette smoking and alcohol consumption of the study subjects. LINE-1 hypomethylation of ESCC was significantly associated with lymph node metastasis, lymphovascular invasion, the frequency of p53 mutation and poor survivability. The LINE-1 methylation levels in ESCC had a significant inverse association with the percentage of copy number alterations in the whole genome, mirroring chromosomal instability. Our results suggested that whole genome hypomethylation caused by chronic inflammation could initiate carcinogenesis of esophageal squamous cells through chromosomal instability. In addition, chromosomal instability associated with the global hypomethylation might correlate highly with the progression of ESCC.

There seemed to be characteristic risk factors in cirrhotic patients for posthepatectomy complications because these patients have less hepatic reserve as compared with noncirrhotic patients. The aim of the current study was to identify these characteristic risk factors in cirrhotic patients. We performed 419 primary hepatectomies for hepatocellular carcinoma. The patients were divided into the cirrhotic group (n = 198) and the noncirrhotic group (n = 221), and the risk factors for posthepatectomy complications were compared between the groups. Thirty-six cirrhotic patients (18.2%) experienced Clavien's Grade III or more complications. Tumor size, intraoperative blood loss, duration of operation, major hepatectomy (two or more segments), and necessity of blood transfusion were found to be significant risk factors in univariate analyses. Multivariate analysis revealed that major hepatectomy and intraoperative blood loss were independent risk factors for posthepatectomy complications in patients with cirrhosis. On the other hand, the duration of operation was only an independent risk factor for posthepatectomy complication in noncirrhotic patients. Cirrhotic patients should avoid a major hepatectomy and undergo a limited resection preserving as much liver tissue as possible and meticulous surgical procedures to lessen intraoperative blood loss are mandatory to prevent major posthepatectomy complications.

Some esophageal diseases such as carcinoma, esophagitis, and collagen diseases have often been reported to show a diffusely thickened esophageal wall in the roentogenogram findings. In the current report, a preoperative upper gastrointestinal series and an endoscopic examination showed a diffusely infiltrative type carcinoma, but other examinations did not suggest any diseases such as esophagitis or collagen diseases which might cause a thickening of the esophageal wall or a constriction, of the esophagus. A postoperative histological examination revealed the primary carcinoma to remain only within the mucosal layer, while a large degree of lymphatic vessel permeation reached the adventitia over a wide area. An extraordinary degree of lymphatic permeation spread through the esophageal wall, and stromal fibrosis developed as a result of such lymphatic permeation. These histological phenomena might thus have led to the macroscopic appearance of infiltrative type esophageal carcinoma.

The role of family history in the multiple occurrence of cancer in the upper aerodigestive tract (UADT) remains unclear. The family histories of close relatives were examined in 167 patients with either hypopharyngeal or cervical esophageal cancer (PhCe cancer) and in 167 control subjects with benign diseases. The odds ratio for PhCe cancer was 2.6 in relation to family history of UADT cancers. Based on the family histories of close relatives, 167 cases with PhCe cancer were divided into 3 groups (Group I, 18 cases with a family history of UADT cancer; Group II, 37 cases with a family history of other cancers; Group III, 112 cases with no family history of any cancers). The mean age of the cases in group I was 59.4, which was younger than in group III (64.2). Second primary squamous-cell carcinomas in the UADT were more frequently recognized in group I (39%) than in group III (11%). However, no differences were observed in the smoking and drinking habits of male patients between each group. These results thus suggest that a family history of UADT cancers appears to be associated with the multiple occurrence of UADT cancers as well as the development of PhCe cancer.

Although the surgical technique and perioperative management have been improving, the mortality and morbidity rates for transthoracic esophagectomy followed by reconstruction are still comparatively high among the surgery for gastrointestinal cancers. Necrosis of reconstructed organ is a rare but fatal complication associated with high mortality rate. It is quite important to promptly and accurately diagnose the disturbance of blood circulation of reconstructed organs and appropriately treat those diseases. Otherwise, the patients could easily fall into endotoxic shock, disseminated intravascular coagulation(DIC) and multiple organ failure( MOF). Here, we will summarize the way of diagnosis and treatment for the necrosis of reconstructed organs and present 2 cases of reconstruction organ necrosis (gastric tube and ascending colon) after esophagectomy in our institute.

Surgical risk of laparoscopic gastrectomy for gastric cancer in high risk patients was evaluated with E-PASS scoring system.This study was based on 63 patients with gastric cancer who underwent laparoscopic gastrectomy; 14 patients belonging to high risk group (ASA≥3) and 49 classified as low risk group (ASA≤2). Fifty six patients who underwent conventional gastrectomy were used for comparison.Intra- and postoperative complications were found in 4 and 3 of 14 high risk patients, respectively. We found a significant correlation between E-PASS score and complications. E-PASS score in high risk group was significantly higher than the value in low risk group. The estimated in-hospital mortality rate was significantly different between the two groups. When conventional gastrectomy group for high risk patients was compared, postoperative morbidity and mortality rates were similar in two surgical procedures; however E-PASS score and the estimated in-hospital mortality rate with conventional gastrectomy were significantly higher than the value with laparoscopic gastrectomy.There were no fatal complications in high risk patients with laparoscopic gastrectomy and E-PASS score was within safety margin. Extension of laparoscopic surgery in high risk patients was feasible when careful procedure was performed by a surgical team.

The clinical significance of neoadjuvant chemoradiotherapy (NACRT) for potentially resectable esophageal squamous cell carcinoma (ESCC) is unclear.Patients with clinical stage II-III ESCC were classified into an NACRT group (n=76) and surgery alone group (n=92). The prognosis and the incidence of postoperative complications were retrospectively investigated. The pathological response to NACRT and patient prognosis were also analyzed.The 5-year survival rate was 47.7% in the surgery alone group and 56.5% in the NACRT group (p=0.4831). The 5-year survival rates of patients in whom NACRT was markedly effective was clearly better than that of the other patients (ineffective/slightly effective: 36.9%, moderately effective: 53.8%, markedly effective: 100%). The incidence of postoperative complications was 31.5% in the surgery alone group and 40.8% in the NACRT group (p=0.2121).A pathological complete response to NACRT is critical for improving the survival of patients with clinical stageII-III ESCC.

Hepatitis B or C virus infection is considered to be the main cause of hepatocellular carcinoma (HCC) in Japan. Aflatoxin B1 (AFB1) is a carcinogen associated with HCC in regions with high exposure. Mutations in codon 249, exon 7 are a hallmark of AFB1 exposure. Therefore, to clarify the role of AFB1 in hepatocarcinogenesis, we examined AFB1-DNA in liver tissue and sequenced TP53 in Japanese patients with HCC.Hepatocyte AFB1-DNA adducts were determined immunohistochemically and direct sequencing of TP53 was done to determine mutations in 188 of 279 patients who underwent hepatic resection for HCC. We assessed hepatitis C virus antibodies (HCV Ab) and HBSAg expression; patients without either were defined as having non-B non-C hepatocellular carcinoma (NBNC HCC).AFB1-DNA adducts were detected in hepatocyte nuclei in 18/279 patients (6%), including 13/83 patients (16%) with NBNC HCC and 5/51 patients (10%) expressing hepatitis B surface antigen. None of the patients with HCV Ab (n=136) were positive for AFB1-DNA. The incidence of the G-T transversion and mutations in exon 7 of TP53 in patients with AFB1-DNA adducts were significantly higher in patients with than in patients without AFB1-DNA adducts. All three patients with the codon 249 AGG-AGT mutation had AFB1-DNA adducts.Although exposure to AFB1 is thought to be low in Japan, it is still associated with hepatocarcinogenesis, particularly in NBNC HCC and hepatitis B individuals.

Colorectal perforation is a life-threatening disease with high mortality and morbidity. The correct and prompt diagnosis and accurate judgment of severity are necessary. We retrospectively investigated 30 patients with colorectal perforation to assess predictors of mortality and severity, and evaluated the usefulness of computed tomography (CT) for the initial diagnosis. The severity of peritonitis was assessed using clinical factors and Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (POSSUM) scores. Abdominal free air was detected by CT in 92% of patients with colorectal perforation, whereas only 36.6% showed evidence of abdominal free air by conventional radiography. The perforation site was correctly diagnosed in 14 of 25 cases (56%). Overall mortality was 16.7%. Survivors were younger than nonsurvivors, and POSSUM physiological and mortality scores were significantly lower for survivors compared with nonsurvivors. The amount of intraperitoneal soiling by large bowel content determined disease severity in terms of the need for postoperative respiratory management. In conclusion, CT is necessary for precise diagnosis, and the POSSUM score is helpful for the evaluation of disease mortality and severity.

Genomic sequences encoding the 3′ exonuclease (proofreading) domains of both replicative DNA polymerases, pol delta and pol epsilon, were explored simultaneously in human colorectal carcinomas including six established cell lines. Three unequivocal sequence alterations, including one previously reported, were found, and all these were considered as dysfunctional mutations in light of the local amino-acid sequences. In particular, the F367S mutation found in the POLE gene encoding the pol epsilon catalytic subunit, which includes the proofreading domain, is the first found in human diseases. Surprisingly, the tumours carrying these proofreading domain mutations were all defective in DNA mismatch repair (MMR). In addition to the two cell lines with acknowledged MMR gene mutations, the third tumour was also demonstrated to harbour a distinct mutation in MLH1, and indeed exhibited a microsatellite-unstable phenotype. These findings suggest that, in concert with MMR deficiency, defective polymerase proofreading may also contribute to the mutator phenotype observed in human colorectal cancer. Our observations may suggest previously unrecognised complexities in the molecular abnormalities underlying the mutator phenotype in human neoplasms.

Background A high frequency of p53 protein expression or gene mutation has been reported in the early stages of esophageal squamous cell carcinoma (ESCC), and thus loss of p53 function is thought to be very important in esophageal carcinogenesis. However, there is controversy surrounding the correlation between p53 dysfunction and ESCC tumor progression. The complexity arises from the different modalities, such as mutation analysis, immunohistochemistry, and the detection of loss of heterozygosity (LOH) at the p53 genomic locus. Methods In this study, we comprehensively analyzed p53 gene mutation, p53 protein expression, and LOH at 17p13 in 94 surgically resected Japanese cases of ESCC. Results The frequency of p53 gene mutation was 60.6%. The rate of positive p53 protein expression was 56.4%. The frequency of LOH at 17p13 was 67.5%. There was a statistically significant correlation between the presence of a gene mutation and LOH, whereas, there was no significant correlation between gene mutation and protein expression. Conclusions Despite the importance of loss of p53 function in esophageal carcinogenesis, none of the examined parameters, either singly or combined, correlated with overall survival. Taken together, p53 function is a primary target for esophageal carcinogenesis but there is no apparent correlation with the malignant phenotype in ESCC. J. Surg. Oncol. 2011;104:169–175. © 2011 Wiley-Liss, Inc.

Purpose The aim of this study was to establish a simple criterion to predict prognosis of patients with gastric carcinoma. Methods Two hundred four patients with gastric carcinoma, who had been treated with curative resection, were enrolled. One point was added for each category among four pathological factors of depth of tumor, lymph node metastasis, venous invasion, and lymphatic invasion. Pathological Prognostic Score (PPS) was determined by an aggregate of these points for each category. Results There existed a significant difference between survivals of patients with PPS 0 or 1 and 2 or 3 (P = 0.0002). Similarly, there also existed a significant difference between survivals of patients with PPS 2 or 3 and 4 (P = 0.010). Conclusions PPS can be quite simple criteria to predict prognosis of gastric carcinoma with a strict stratification. J. Surg. Oncol. 2010;102:11–17. J. Surg. Oncol. 2010;102:73–76. © 2010 Wiley-Liss, Inc.

Metachronous gastric carcinoma arising in a gastric tube used for esophageal reconstruction has been occasionally encountered in long-term survivors of esophageal cancer. This study investigated 10 cases of gastric tube cancer in order to clarify the characteristics and the outcome of these patients.Four hundred and seventy-one patients underwent a radical esophagectomy at Kyushu University Hospital between 1989 and 2003. There were 10 cases of gastric tube cancer after an esophagectomy.The interval between the esophagectomy and the development of the gastric tube cancer ranged from 1.1 to 7 years. There was no peak for the incidence of gastric tube cancer. In 6 of 10 cases of gastric tube cancer, endoscopic or surgical resection were performed for the treatment; however, chemotherapy was administered to the other 4 cases for several reasons. The prognosis of patients who underwent resection was better than that of the other patients.Frequent endoscopic examinations are therefore important even several years after performing an esophagectomy, since the risk of gastric tube cancer is higher than the risk of a recurrence of esophageal cancer several years after an esophagectomy. Only an early diagnosis permits a less invasive and appropriate approach for the treatment of gastric tube cancer.

The significance of the Glasgow prognostic score (GPS), an inflammation-based prognostic score, as an indicator of aggressiveness in gastric carcinoma has not been investigated fully.Two hundred thirty-two patients with gastric carcinoma were enrolled. Patients who had both an elevated C-reactive protein (1.0 mg/dL) and hypoalbuminemia (3.5 g/dL) were allocated a traditional GPS (TGPS) of 2. Patients who had one of these abnormal values were allocated a TGPS of 1, and patients who had neither were allocated a TGPS of 0.There existed a significant difference between the survival of adjacent groups of patients when examined using the TGPS (P = .05 for TGPS 0 vs 1 and P = .006 for TGPS 1 vs 2). Multivariate analysis based on TGPS demonstrated that TGPS (P = .020) and tumor stage (P = .0007) proved to be independent prognostic indicators for worse prognosis.The preoperative measurement of an inflammation-based prognostic score can demonstrate a strict stratification for the prognosis of patients with gastric carcinoma.

The prognosis of adenocarcinoma of the esophagogastric junction is worse than that in adenocarcinoma of other parts of the stomach. In particular, the clinical features and prognosis of adenocarcinoma of the esophagogastric junction and the differences between Siewert's type II and III tumors in Japan were evaluated.We analyzed one hundred and forty patients with adenocarcinoma of the esophagogastric junction including one patient with a type I tumor, sixty-seven patients with type II tumors, and seventy-two patients with type III tumors.The prognosis of patients with type III tumors was poorer in comparison to that of type II tumors in adenocarcinoma of the esophagogastric junction (p0.05). A significant difference was observed in the survival of patients with type III tumors between those with positive and negative lymph nodes (p0.001). However, there was no such difference in patients with type II tumors. In a multivariate analysis, lymph node metastasis, age and the depth of tumor invasion were all found to be independent prognostic factors.The prognosis of patients with lymph node metastasis of type III adenocarcinoma of the esophagogastric junction was found to be extremely poor. An aggressive treatment after surgery may therefore be necessary to improve the survival of this population.

The purpose of this study was to clarify the indications for an esophagectomy in elderly patients (especially patients over 80 years of age) with esophageal cancer.A total of 668 patients with thoracic esophageal cancer who underwent an esophagectomy by the transthoracic approach were divided into three groups according to age, namely, groups I (80 years, n=16), II (70-79 years, n=158), and III (or=69 years, n=494). In group I, surgery was only done in patients with PS 0 or 1, as well as normal cardiac and pulmonary functions.The incidence of preoperative pulmonary risk was 16% and 7% in groups II and III, respectively (P0.01). The morbidity rates of group II and III were 42% and 32%, respectively (P0.05). Pulmonary complications occurred in 18% and 10%, respectively, and cardiovascular complications occurred in 11% and 4%, respectively (P0.01). In group I, the morbidity and 30-day mortality rates were 25% and 0%, respectively, and pulmonary and cardiovascular complications occurred only in one patient each (6%). No significant differences were observed in cause-specific survival.In the elderly, preoperative pulmonary risk is frequently present, and careful perioperative management is needed while paying special attention to pulmonary and cardiovascular complications. However, when the indications for surgery can be strictly determined, an esophagectomy is considered a viable treatment alternative with satisfactory prognosis even in patients 80 years of age and older without any increased morbidity or mortality.

Bone marrow (BM) is a prognostically relevant indicator organ of micrometastasis; however, the clinical importance of BM micrometastasis in gastric cancer patients is not yet known. In the present study, the BM of 267 consecutive patients with primary gastric cancer was examined for tumor cells using immunocytochemical techniques. Real-time quantitative RT-PCR was used to ensure that the tumor cells were detected properly. Among the 267 cases analyzed, 30 cases (11.2%) had cytokeratine-positive cells in the bone marrow. Positive findings were related to the tumor stage (P

Purpose: To investigate the effects of the expression of hypoxia-inducible factor 1α (HIF-1α) and p53 on the prognosis of human gastric cancer, the clinicopathologic characteristics of the tumors and the clinical outcome were analyzed. Experimental Design: The expressions of HIF-1α and p53 proteins were studied by immunohistochemistry in 216 specimens of primary gastric cancer. Results: HIF-1α(+)/p53(+) tumors more frequently showed an undifferentiated type, an infiltrative growth appearance, and an invasive lymphatic involvement compared with HIF-1α(−)/p53(−) tumors. HIF-1α(+)/p53(+) tumors also had more lymph node metastasis compared with HIF-1α(−)/p53(−) tumors. When stratified for HIF-1α and p53 positivity, the patients who were p53-negative and HIF-1α-negative had the most favorable prognosis, whereas patients who were p53-positive and HIF-1α-positive had the worst prognosis (P = 0.0018). Using a multivariate Cox regression analysis, the depth of invasion, lymph node metastasis, and HIF-1α positivity were all found to be independent prognostic factors in patients with gastric cancer. Conclusion: Thus, HIF-1α is considered to be a useful independent prognostic factor in gastric cancer, and the combination of a HIF-1α protein overexpression with nonfunctional p53 tends to indicate a dismal prognosis.

We are conducting a prospective randomized trial to evaluate the survival benefit of adjuvant chemotherapy with S-1 (tegafur, gimeracil, oteracil potassium) and UFT (uracil-tegafur) after curative surgery for patients with Stage II and III rectal cancer. Patients are randomized to either administration of UFT (control) or S-1. UFT was orally administered for 5 days (400 mg/m2/day) followed by two days rest for a year. S-1 was orally administered for 4 weeks (80 mg/m2/day) followed by two weeks rest for a year. The primary endpoint is relapse-free survival (RFS) rate, and the secondary endpoints are overall survival time (OS) and frequency or level of adverse events. We aim to include 400 patients in each of the treatment groups and assume that the registration period will last until 2009.

The multiple occurrence of primary squamous cell carcinoma of the esophagus is often observed, and most such occurrences are double cancers. There have also been some cases with three or more intra-esophageal cancers, however, no detailed clinicopathologic study has yet been performed in the literature.Two hundred and fifty patients of primary esophageal squamous cell carcinoma without preoperative treatment that underwent esophageal resection were re-evaluated by serial histopathologic investigations and we analyzed the data of ten patients with three or more intraesophageal cancers.The clinical and histopathologic characteristics were as follows; 1) all but one of the cases were male, 2) all patients had a history of both heavy smoking and drinking but only one case had a family history of esophageal cancers among their siblings, 3) the depth of invasion in the carcinomas was restricted to within the submucosal layer of the esophageal wall, which was defined as superficial esophageal carcinoma, almost all (90%) of the cases accompanied esophageal squamous epithelial dysplasia.Based on these prominent characteristics of considerable multiple intra-esophageal cancers, a new clinical entity of "esophageal field cancers" could thus be suggested.

Oxidative damage to diverse physiological molecules, including proteins, lipids, and nucleic acids, is an inevitable outcome of various cellular activities in living organisms. In particular, some oxidised forms of nucleotides cause miscoding of genetic information, and have therefore been present as a major threat for cells. Multigene systems to counteract such oxidative damage have evolved in diverse organisms. In E coli , several mutants designated ‘mutator’ have been isolated, and in these cells the mutation rate is significantly elevated, due to disruption of genes regulating the spontaneous mutation rate on the genome. Previous studies using these mutators have identified three genes that function in the system to counteract mutagenic oxidative damage. The mutT− strain is one of the mutators that exhibit the highest spontaneous mutation rate. Maki H et al have shown that the product of the mutT gene hydrolyses an oxidised form of guanine nucleotides, 8-oxo-2′-deoxyguanosine 5′-triphosphate (8-oxo-dGTP).1 8-oxo-dGTP incorporated into the genome stably pairs with adenine as well as cytosine in the template strand, accumulation of this oxidised form of guanine nucleotides leads to an increase in base substitution mutations—that is, A:T to G:C and G:C to T:A transversions. In the mutT− strain, the rate for A:T to C:G transversion is indeed elevated 1000 fold over the wild type level.2 The other two genes that function in cooperation with mutT are mutM (fpg) and mutY , both of which encode a DNA glycosylase to excise deleterious bases on the genome.3 The former excises 8-oxo-guanine in the opposite site of cytosine on the genome, the latter removing adenine that pairs with 8-oxo-guanine. Thus, even in cells lacking MUT , G:C to T:A transversions are suppressed low.4 Multiplicity of cellular anti-mutagenic systems guarantees the spontaneous mutation rate on the genome at an extremely low …

Oxygen radicals, which can be produced through normal cellular metabolism, are thought to play an important role in mutagenesis and tumorigenesis. Among various classes of oxidative DNA damage, 8-oxo-7,8-dihydroguanine (8-oxoG) is most important because of its abundance and mutagenicity. The MTH1 gene encodes an enzyme that hydrolyzes 8-oxo-dGTP to monophosphate in the nucleotide pool, thereby preventing occurrence of transversion mutations. By means of gene targeting, we have established MTH1 gene-knockout cell lines and mice. When examined 18 months after birth, a greater number of tumors were formed in the lungs, livers, and stomachs of MTH1 -deficient mice, as compared with wild-type mice. The MTH1 -deficient mouse will provide a useful model for investigating the role of the MTH1 protein in normal conditions and under oxidative stress.

Lymphocyte infiltration (LI) around cancerous lesions is an important immune response. The purpose of this study is to evaluate the prognostic significance of LI after preoperative treatment for esophageal cancer.Preoperative chemoradiotherapy (CR therapy), either bleomycin 30 mg or cisplatin 120 mg/m(2) plus radiation 30 Gy, was performed on 51 cases with esophageal cancer, while hyperthermo-chemoradiotherapy (HCR therapy) was also indicated in 71 cases. Using resected specimens, both the histopathologic effectiveness and degree of LI to cancerous lesions were evaluated.The incidences of the cases in which preoperative treatment was effective were 56% and 92.3% in LI (-) and LI (++) group (p0.05). The presence of LI resulted in favorable prognosis; the 5-year survival rates of LI (++) and LI (+) patients were 75.5% and 46.1%, both of which were significantly better than LI (-) (27.8%, p0.05 and p0.01, respectively). Especially among cases whose preoperative treatment was moderately effective, a multivariate analysis revealed LI to be a favorable prognostic factor independent of other clinicopathologic factors (p = 0.0171). Regarding the preoperative treatment, the incidence of LI (++) was higher in the HCR group (16.9%) than in the CR group (2.0%, p0.01).LI appears to be a prognostic predictor after preoperative CR therapy while, in addition, simultaneous hyperthermia may stimulate LI in cases with esophageal cancer.