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Aim Sarcopenia has been reported as a prognostic predictor in various conditions; however, it has not been examined in patients with perforation panperitonitis. Methods A total of 103 consecutive patients with perforation panperitonitis who underwent emergency surgery from 2008 to 2016 were retrospectively evaluated. Skeletal muscle index (SMI) was measured as the cross‐sectional area (cm2) of skeletal muscle in the L3 region on computed tomography images normalized for height (cm2/m2). Sarcopenia was defined as an SMI of ≤43.75 and ≤41.10 cm2/m2 in men and women, respectively. The impact of sarcopenia on postoperative outcomes was investigated. Results Sarcopenia was present in 50 (48.5%) patients. Severe complications (Clavien‐Dindo grade ≥IIIb) and in‐hospital mortality were more frequently observed in patients with than without sarcopenia (28.0% vs 9.4%, P = .015) (20.0% vs 5.7%, P = .029) respectively. Multivariate analysis showed that age, sarcopenia, and renal dysfunction were independent risk factors for severe complications and in‐hospital mortality. The optimal cut‐off levels of age and SMI for predicting these were ≥79 years and SMI, Sarcopenia is a predictive factor of severe complications and in‐hospital mortality following emergency surgery for perforation panperitonitis, especially in elderly patients. Estimation of sarcopenia may discriminate patients eligible or not eligible for emergency surgery among elderly patients.

OBJECTIVE The aim of this study is to identify biomarkers that predict efficacy of preoperative therapy and survival for esophageal squamous cell carcinoma (ESCC). BACKGROUND It is essential to improve the accuracy of preoperative molecular diagnostics to identify specific patients who will benefit from the treatment; thus, this issue should be resolved with a large-cohort, retrospective observational study. METHODS A total of 656 patients with ESCC who received surgery after preoperative CDDP + 5-FU therapy, docetaxel + CDDP + 5-FU therapy or chemoradiotherapy (CRT) were enrolled. Immunohistochemical analysis of TP53, CDKN1A, RAD51, MutT-homolog 1, and programmed death-ligand 1 was performed with biopsy samples obtained before preoperative therapy, and expression was measured by immunohistochemistry. RESULTS In all therapy groups, overall survival was statistically separated by pathological effect (grade 3 > grade 2 > grade 0, 1, P < 0.0001). There was no correlation between TP53, CDKN1A, MutT-homolog 1, programmed death-ligand 1 expression, and pathological effect, whereas the proportion of positive RAD51 expression (≥50%) in cases with grade 3 was lower than that with grade 0, 1, and 2 (P = 0.022). In the CRT group, the survival of patients with RAD51-positive tumor was significantly worse than RAD51-negative expressors (P = 0.0119). Subgroup analysis of overall survival with respect to positive RAD51 expression indicated preoperative chemotherapy (CDDP + 5-FU or docetaxel + CDDP + 5-FU) was superior to CRT. CONCLUSIONS In ESCC, positive RAD51 expression was identified as a useful biomarker to predict resistance to preoperative therapy and poor prognosis in patients who received preoperative CRT. Administration of preoperative chemotherapy may be warranted for patients with positive RAD51 expression.

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.

Key Clinical Message We encountered a patient with a large retroperitoneal solitary fibrous tumor, in whom we could preserve approximately 150 cm of the ileum even after pancreaticoduodenectomy combined with resection of the superior mesenteric artery, thus preventing short bowel syndrome.

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.

Patients with advanced esophageal cancer frequently experience dysphagia and dyspnea, and relief of such symptoms is important. We wished to clarify the efficacy of endoscopic stent placement in patients with dysphagia or dyspnea caused by advanced esophageal cancer. A database of patients with esophageal cancer who underwent esophageal and airway stent insertion between 2005 and 2012 was analyzed retrospectively. Effects and complications of stent insertion, and survival after stent insertion, were investigated. Eighteen patients were treated by esophageal (n = 10) and/or airway (n = 9) stent placement. Marked improvements in food intake were recognized in eight patients after esophageal stenting. Marked improvements in breathing were observed in all patients after airway stenting. Dysphagia scores in the esophageal stent group as well as dyspnea grades in Common Terminology Criteria for Adverse Events v4.0 (CTCAE 4.0) in the airway stent group were significantly improved (p = 0.0078). In the esophageal stent group, major complications (CTCAE grade ≥3) occurred in seven of ten patients (70 %). In the airway stent group, major complications occurred in three of nine patients (33 %). Median survival of all 18 patients was 87.5 (range 13–1952) days after esophageal and/or airway stent placement. Stent placement is effective for the improvement of malignant dysphasia and dyspnea caused by advanced esophageal cancer.

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.

Despite the widespread use of proton beam therapy (PBT) as locoregional therapy, there is currently a lack of histological evidence about the therapeutic effect of PBT for hepatocellular carcinoma (HCC). We present a case of hepatectomy and histological examination of HCC initially treated by PBT. A 76-year-old man with chronic hepatitis C underwent routine ultrasound surveillance, which revealed a 22-mm HCC in segment 4 of the liver. His hepatic reserve was adequate for surgical resection of the tumor; however, he chose to undergo PBT because of his cardiac disease. The patient received 66 Gy in 10 fractions with no toxicity exceeding grade 1. Six months after completion of PBT, contrast computed tomography showed that the tumor had increased in size to 27 mm, and the marginal part of the tumor, but not the central region, was enhanced. Additionally, two new hypervascular nodules were present in segments 5 and 6. The patient underwent surgical treatment 7 months after PBT. The operation and postoperative clinical course were uneventful. Nine months later, however, computed tomography demonstrated new, small, enhanced nodules in the remnant liver (segments 3, 5 and 6) and sacrum. In conclusion, PBT is a valuable treatment for HCC; however, it is difficult to evaluate therapeutic effect of HCC during the early post-irradiation period and provide an alternative treatment if PBT is not effective, especially in HCC cases with good liver function.

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．

The significance of neoadjuvant chemoradiotherapy (NACRT) for esophageal squamous cell carcinoma (ESCC) remains controversial with regard to the pathological response and long-term survival. We herein review the current status of and future perspectives regarding NACRT followed by esophagectomy for locally advanced ESCC. Some studies have suggested that a pathological complete response with NACRT is more common in patients with ESCC than in those with adenocarcinoma and that NACRT provided a survival benefit limited to patients with ESCC. However, NACRT may increase the risk of postoperative complications after esophagectomy. It is obvious that a favorable pathological response is the most important factor for obtaining a survival benefit, although no established parameters have been implemented clinically to predict the response to NACRT. Prospective clinical studies and basic research studies to identify predictive biomarkers for the response to NACRT are needed to aid in the development of NACRT treatment strategies for patients with ESCC.

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.

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.

Epigenetic alterations that do not involve a change in the DNA sequence have been increasingly recognized to be important key events in the regulation of the gene expression and carcinogenesis. Major epigenetic mechanisms include the methylation of cytosine in DNA, changes in the histone and chromatin structure due to covalent posttranslational modification of histone proteins and the RNA-mediated regulation of the gene expression. Esophageal squamous cell carcinoma (ESCC) continues to be associated with a very poor prognosis, indicating that obtaining a clear understanding of the pathogenesis of ESCC is desired for improving clinical outcomes. In this review, we discuss the recent progress in research on epigenetic alterations in ESCC, with respect to the following points: (1) DNA methylation, including global hypomethylation and DNA hypermethylation at CpG islands in the promoters of tumor suppressor genes, (2) histone acetylation/deacetylation and histone methylation with the alteration of histone-modifying enzymes and (3) alterations in the expression of microRNA and the recently emerging long non-coding RNA. We then discuss the interplay among these epigenetic events and the crosstalk between epigenetic and genetic changes in ESCC. It is therefore important to understand the molecular mechanisms underlying the development and progression of ESCC to improve the treatment outcome of this devastating disease, although this information is quite complicated and confusing.

Summary Both internal and external oxidative stresses act on DNA and can induce carcinogenesis. 8-hydroxydeoxyguanosine (8-OHdG) is an indicator of oxidative stress and it leads to transversion mutations and carcinogenesis. 8-OHdG is excision-repaired by 8-OHdG DNA glycosylase (OGG1). The purpose of this study is to clarify the effect of oxidative DNA damage and repair enzymes on esophageal carcinogenesis. The levels of 8-OHdG and OGG1 were immunohistochemically evaluated in resected specimens, including squamous cell carcinoma (SCC) in 97 patients with esophageal cancer. Higher levels of 8-OHdG in normal esophageal epithelium were associated with a higher smoking index (P = 0.0464). The 8-OHdG level was higher in cancerous areas than in normal epithelia (P = 0.0061), whereas OGG1 expression was weaker in cancerous areas than in normal epithelia (P < 0.0001). An increase of OGG1 expression in normal epithelium was observed as 8-OHdG levels increased (P = 0.0011). However, this correlation was not observed in cancerous areas. High OGG1 expression in the cytoplasm was related to deeper tumors (P = 0.0023), node metastasis (P = 0.0065) and stage (P = 0.0019). Oxidative DNA damage, which is attributable to smoking as well as disturbances in DNA repair systems, appears to be closely related to esophageal carcinogenesis and its progression.

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.

Alterations in the regulation of gene expression that do not involve a change in the DNA sequence have been increasingly recognized as an important key event of carcinogenesis, referred to as "epigenetic" changes. Major epigenetic mechanisms include the methylation of cytosines in DNA, changes of histone and chromatin structure by covalent posttranslational modifications of histone proteins and alterations in the expression of microRNAs. These epigenetic alterations have also been identified in esophageal squamous cell carcinoma (ESCC). In this brief review, we will discuss DNA hypermethylation of the tumor suppressor gene promoters, histone modifications including histone acetylation/deacetylation and histone methylation and microRNAs in ESCC. Clinical implications of these epigenetic alterations in ESCC will be also discussed.

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 report an unusual case of gastric carcinosarcoma with rhabdomyosarcomatous and neudoendocrinal differentiation in a 71-year-old Japanese female. Gastric carcinosarcoma with rhabdomyosarcomatous and neuroendocrinal differentiation is a rare tumor. The tumor developed in the body of the stomach and was exophytic in appearance. By histochemical analysis, the tumor was shown a part of positive for desmin and myoglobin and a part of positive for synaphtophysin and vimentin. We conclude that, though rare, gastric carcinosarcoma with rhabdomyosarcomatous and neuroendocrinal differentiation thus is reviewed in the English literatures.

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.

Esophageal cancer is frequently associated with head-and-neck cancer. It is difficult to select treatment modalities for synchronous multiple cancers in the upper aerodigestive tract. A 58-year-old woman had synchronous quintuple cancer of the upper aerodigestive tract and was in a poor nutritional state due to oral pain and dysphagia. Clinical stages of cancer in the oral cavity, hypopharynx, cervical esophagus, middle thoracic esophagus, and lower thoracic esophagus were IVA (cT4a N2b M0), I (cT1 N0 M0), IA (cT1 N0 M0), IA (cT1 N0 M0), and IIA (cT3 N0 M0), respectively. After preoperative chemoradiotherapy, curative resection of oral cavity cancer and a tube jejunostomy were performed. Then, pharyngolaryngectomy, total esophagectomy, and pharyngostomy were performed. Finally, after additional radiotherapy to the oral cavity, pharyngogastrostomy with gastric tube and microvascular anastomosis were performed. The patient achieved oral intake and is in good condition and has at this writing remained recurrence free for 26 months. This report suggests that even if there are multiple cancers, adopting multimodal treatment strategies for controlling each cancer may lead to a chance to obtain a complete cure.

Replacing the thoracic esophagus with the colon is one mode of reconstruction after esophagectomy for esophageal cancer. There is, however, a high incidence of postoperative necrosis of the transposed colon. This study evaluated the outcomes of colon interposition with the routine use of superdrainage by microvascular surgery. Twenty-one patients underwent colon interposition from 2004 to 2009. The strategy for colon interposition was to: (i) use the right hemicolon; (ii) reconstruct via the subcutaneous route; (iii) perform a microvascular venous anastomosis for all patients; and (iv) perform a microvascular arterial anastomosis when the arterial blood flow was insufficient. The clinicopathologic features, surgical findings, and outcomes were investigated. The colon was used because of a previous gastrectomy in 18 patients (85.7%) and synchronous gastric cancer in three patients (14.3%). Eight patients (38.1%) underwent preoperative chemoradiotherapy including three (14.3%) treated with definitive chemoradiotherapy. Seven patients (33.3%) underwent microvascular arterial anastomosis to supplement the right colon blood supply. Pneumonia occurred in four patients (19.0%). Anastomotic leakage was observed in five patients (23.8%); however, no colon necrosis was observed. The 3-year and 5-year overall survival rates were both 50.6%. Colon interposition with superdrainage results in successful treatment outcomes. This technique is one option for colon interposition employing the right hemicolon.

Both squamous cell carcinomas and adenocarcinomas can develop in the esophagogastric junction. To clarify the appropriate lymph node dissection range, lymph node metastases from cancers in the esophagogastric junction were investigated.The nodal metastases were analyzed in 64 patients with squamous cell carcinoma and 129 with adenocarcinoma according to Siewert's classification, which is based on topographic anatomical criteria for adenocarcinoma.The squamous cell carcinomas located above the esophagocardial junction had more frequent metastasis to the lower and middle mediastinal lymph nodes in proportion to the depth of the tumor. Nodal metastasis was also often detected in the abdominal lymph nodes. In contrast, adenocarcinomas metastasized less frequently to the mediastinal lymph nodes, and the metastatic rates in the abdominal nodes were higher than those from squamous cell carcinoma.Esophagectomy with mediastinal and abdominal lymph node dissection is considered to be an appropriate approach for surgical resection of squamous cell carcinomas, whereas transhiatally extended gastrectomy with lower mediastinal and abdominal lymph node dissection is recommended for the treatment of adenocarcinomas.

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.

Background & aims: 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. Methods: 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). Results: AFB1-DNA adducts were detected in hepatocyte nuclei in 18/279 patients (6%), including13/83 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. Conclusion: 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.

Esophageal perforation with mediastinal abscess formation is a potentially life-threatening complication after chemoradiotherapy (CRT) in patients with esophageal cancer. We present the case of a 64-year-old woman with cervico-thoracic esophageal cancer who had previously undergone distal gastrectomy. Definitive CRT was initially performed since the patient refused laryngectomy. However, she developed an esophageal fistula and a subsequent cervico-mediastinal abscess, which made oral intake impossible. In order to address the fistula, abscess, and cancer, we decided to perform a staged operation. The patient first underwent total pharyngo-laryngo-esophagectomy and abscess drainage. She next underwent esophageal reconstruction with an ileocolonic conduit through a subcutaneous route. The patient is currently alive and well after surgery. This case suggests that surgical resection may be performed in high-risk patients with cervico-thoracic esophageal cancer via a two-stage operation.

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.

The DNA repair system surveys the genome, which is always suffering from exposure to both exogenous as well as endogenous mutagens, to maintain the genetic information. The fact that the basis of this DNA repair system is highly conserved, from prokaryote to mammalian cells, suggests the importance of precise genome maintenance mechanisms for organisms. In the past 15 years, considerable progress has been made in understanding how repair processes interact and how disruptions of these mechanisms lead to the accumulation of mutations and carcinogenesis. In 1993, two groups reported that DNA mismatch repair could be associated with hereditary non-polyposis colorectal cancer, indicating a connection between faulty DNA repair function and cancer. More recently, an inherited disorder of DNA glycosylase, which removes mutagenic oxidized base from DNA, has been reported in individuals with a predisposition to multiple colorectal adenomas and carcinomas. This is the first report that directly indicates the role of the repair of oxidative DNA in human inherited cancer. Studies from gene knockout mice have elucidated the principal role of these repair systems in the process of carcinogenesis. Moreover, clinical samples derived from cancer patients have shown the direct involvement. This review focuses on the function of DNA mismatch repair and oxidative DNA/nucleotide repair among various DNA repair systems in cells, both of which are essentially involved in the carcinogenesis of gastrointestinal tract cancer.

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.

Esophageal squamous cell carcinoma is a form of cancer that has varying incidence rates among different countries, distinct geographic areas and different ethnic groups. According to previous reports, p53 gene mutations have been identified in 20-80% of these tumors, and these mutations have occurred at an early stage. These findings suggest that such mutations play an important role in esophageal carcinogenesis, and highlight the importance of mutagens, which cause sequence alterations in the p53 gene. In order to clarify the environmental factors and the molecular mechanisms that may be responsible for the occurrence and prevention of a specific mutation in the process of esophageal carcinogenesis, we analyzed p53 gene mutations in 95 samples of esophageal squamous cell carcinoma. We further reviewed published reports investigating the frequency of p53 gene mutations in esophageal cancer from high-risk areas to normal-risk areas and compared these findings to our results in Japan. The frequency of p53 gene mutations in Japanese esophageal cancer is 47.4% and there are three prominent features: (1) a predominance of transversions, in particular the G:C to T:A transversion; (2) a relatively low frequency of transitions; and (3) a relatively high percentage of frameshift mutations. These results indicate the possible importance of the benzo[a]pyrene metabolite and oxidative DNA damage in esophageal carcinogenesis and scarcely correlate with DNA replication errors or alkylation in comparison to other gastrointestinal cancers. In addition, we observed a peculiar sequence of frameshift mutations. Taken together, these data suggest that this tumor suppressor gene plays a critical role in the multistep carcinogenesis process for esophageal squamous cell cancer.

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.

Despite the widespread use of proton beam therapy (PBT) as locoregional therapy, there is currently a lack of histological evidence about the therapeutic effect of PBT for hepatocellular carcinoma (HCC). We present a case of hepatectomy and histological examination of HCC initially treated by PBT. A 76-year-old man with chronic hepatitis C underwent routine ultrasound surveillance, which revealed a 22-mm HCC in segment 4 of the liver. His hepatic reserve was adequate for surgical resection of the tumor; however, he chose to undergo PBT because of his cardiac disease. The patient received 66 Gy in 10 fractions with no toxicity exceeding grade 1. Six months after completion of PBT, contrast computed tomography showed that the tumor had increased in size to 27 mm, and the marginal part of the tumor, but not the central region, was enhanced. Additionally, two new hypervascular nodules were present in segments 5 and 6. The patient underwent surgical treatment 7 months after PBT. The operation and postoperative clinical course were uneventful. Nine months later, however, computed tomography demonstrated new, small, enhanced nodules in the remnant liver (segments 3, 5 and 6) and sacrum. In conclusion, PBT is a valuable treatment for HCC; however, it is difficult to evaluate therapeutic effect of HCC during the early post-irradiation period and provide an alternative treatment if PBT is not effective, especially in HCC cases with good liver function.

Taxanes are among the most active agents and they are now known to be an indispensable component in chemotherapy for breast cancer. However, some patients are resistant to taxanes and the identification of the molecular characteristics that can predict the sensitivity to taxanes would be useful in selecting the most appropriate patients to receive taxane therapy. Taxanes are antimicrotubular agents that promote microtubular assembly and stabilize microtubules by preventing depolymerization. They interfere with normal mitotic transition and causes cell cycle arrest in the G2-M metaphase. CHFR (checkpoint with forkhead-associated and ring finger) is a recently identified gene, which functions as an important checkpoint protein early in G2-M transition. Its activation delays the cell cycle in prophase and promotes cell survival in response to the mitotic stress induced by either nocodazole or taxane. CHFR is frequently downregulated in human cancers, mostly owing to the hypermethylation of its promoter region. CHFR downregulation has been found in primary cancers or in the established tumor cells of various origins, such as the lung, colon, esophagus, and stomach. The aberrant hypermethylation of CHFR promoter appears to be a good molecular marker to predict sensitivity to taxanes in gastric, lung, and colon cancer. A downregulation of CHFR was observed in breast cancer cells, however, no apparent promoter hypermethylation has yet been reported. In addition, an alteration of the CHFR expression or aberrant promoter hypermethylation in primary breast cancer has not been fully investigated. In this study, we examined the methylation status of the promoter region of CHFR gene in 110 primary breast cancers. We observed the hypermethylation of the CHFR promoter region in only one case (0.9%). We herein show that the aberrant hypermethylation of this region is quite a rare event in primary breast carcinoma.

Microsatellite instability (MSI) is associated with defective DNA mismatch repair in various human malignancies. Using a unique fluorescent technique, we have observed two distinct modes of dinucleotide microsatellite alterations in human colorectal cancer. Type A alterations are defined as length changes ofor =6 bp. Type B changes are more drastic and involve modifications ofor =8 bp. We show here that defective mismatch repair is necessary and sufficient for Type A changes. These changes were observed in cell lines and in tumours from mismatch repair gene-knockout mice. No Type B instability was seen in these cells or tumours. In a panel of human colorectal tumours, both Type A MSI and Type B instability were observed. Both types of MSI were associated with hMSH2 or hMLH1 mismatch repair gene alterations. Intriguingly, p53 mutations, which are generally regarded as uncommon in human tumours of the MSI+ phenotype, were frequently associated with Type A instability, whereas none was found in tumours with Type B instability, reflecting the prevailing viewpoint. Inspection of published data reveals that the microsatellite instability that has been observed in various malignancies, including those associated with Hereditary Non-Polyposis Colorectal Cancer (HNPCC), is predominantly Type B. Our findings indicate that Type B instability is not a simple reflection of a repair defect. We suggest that there are at least two qualitatively distinct modes of dinucleotide MSI in human colorectal cancer, and that different molecular mechanisms may underlie these modes of MSI. The relationship between MSI and defective mismatch repair may be more complex than hitherto suspected.

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.