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Breast cancer is generated through a multistep genetic and epigenetic process including activations of oncogenes and inactivations of tumor suppressor genes. Here, we report a critical role of ubiquitin-conjugating enzyme E2T (UBE2T), an E2 ubiquitin-conjugating enzyme, in mammary carcinogenesis. Immunocytochemical staining and in vitro binding assay revealed that UBE2T interacted and colocalized with the BRCA1/BRCA1-associated RING domain protein (BARD1) complex. Knocking down of UBE2T expression with small interfering RNA drastically suppressed the growth of breast cancer cells. Interestingly, in vivo ubiquitination assay indicated BRCA1 to be polyubiquitinated by incubation with wild-type UBE2T protein, but not with C86A-UBE2T protein, an E2 activity–dead mutant, in which the 86th residue of cysteine was replaced with alanine. Furthermore, knocking down of UBE2T protein induced upregulation of BRCA1 protein in breast cancer cells, whereas its overexpression caused the decrease of the BRCA1 protein. Our data imply a critical role of UBE2T in development and/or progression of breast cancer through the interaction with and the regulation of the BRCA1/BARD1 complex. [Cancer Res 2009;69(22):8752–60]

Supplementary Figure Legends 1-8 from Critical Roles of Mucin 1 Glycosylation by Transactivated Polypeptide N-Acetylgalactosaminyltransferase 6 in Mammary Carcinogenesis

Supplementary Figures 1-3 from Critical Roles of Mucin 1 Glycosylation by Transactivated Polypeptide N-Acetylgalactosaminyltransferase 6 in Mammary Carcinogenesis

Supplementary Figures 1-3 from Gene Amplification and Overexpression of PRDM14 in Breast Cancers

Supplementary Figure 1 from Ubiquitination and Downregulation of BRCA1 by Ubiquitin-Conjugating Enzyme E2T Overexpression in Human Breast Cancer Cells

Supplementary Figure 4 from Critical Roles of Mucin 1 Glycosylation by Transactivated Polypeptide N-Acetylgalactosaminyltransferase 6 in Mammary Carcinogenesis

Supplementary Table 1 from Gene Amplification and Overexpression of PRDM14 in Breast Cancers

Supplementary Figure 5 from Critical Roles of Mucin 1 Glycosylation by Transactivated Polypeptide N-Acetylgalactosaminyltransferase 6 in Mammary Carcinogenesis

Supplementary Figure 3 from Ubiquitination and Downregulation of BRCA1 by Ubiquitin-Conjugating Enzyme E2T Overexpression in Human Breast Cancer Cells

Supplementary Table 1 from Critical Roles of Mucin 1 Glycosylation by Transactivated Polypeptide N-Acetylgalactosaminyltransferase 6 in Mammary Carcinogenesis

Several genes that encode PR (PRDI-BF1 and RIZ) domain proteins (PRDM) have been linked to human cancers. To explore the role of the PR domain family genes in breast carcinogenesis, we examined the expression profiles of 16 members of the PRDM gene family in a panel of breast cancer cell lines and primary breast cancer specimens using semiquantitative real-time PCR. We found that PRDM14 mRNA is overexpressed in about two thirds of breast cancers; moreover, immunohistochemical analysis showed that expression of PRDM14 protein is also up-regulated. Analysis of the gene copy number revealed that PRDM14 is a target of gene amplification on chromosome 8q13, which is a region where gene amplification has frequently been detected in various human tumors. Introduction of PRDM14 into cancer cells enhanced cell growth and reduced their sensitivity to chemotherapeutic drugs. Conversely, knockdown of PRDM14 by siRNA induced apoptosis in breast cancer cells and increased their sensitivity to chemotherapeutic drugs, suggesting that up-regulated expression of PRDM14 may play an important role in the proliferation of breast cancer cells. That little or no expression of PRDM14 is seen in noncancerous tissues suggests that PRDM14 could be an ideal therapeutic target for the treatment of breast cancer. [Cancer Res 2007;67(20):9649–57]

Supplementary Figure 8 from Critical Roles of Mucin 1 Glycosylation by Transactivated Polypeptide N-Acetylgalactosaminyltransferase 6 in Mammary Carcinogenesis

Supplementary Table 2 from Gene Amplification and Overexpression of PRDM14 in Breast Cancers

Supplementary Figure 6 from Critical Roles of Mucin 1 Glycosylation by Transactivated Polypeptide N-Acetylgalactosaminyltransferase 6 in Mammary Carcinogenesis

Supplementary Figure 2 from Ubiquitination and Downregulation of BRCA1 by Ubiquitin-Conjugating Enzyme E2T Overexpression in Human Breast Cancer Cells

Aim This study aims to investigate the association of patient age with defecation disorders and anal function after lower rectal cancer surgery. Methods We retrospectively reviewed the data of 141 consecutive patients with lower rectal cancer who underwent sphincter‐preserving operation. The patients were classified into five categories by age thresholds at 65, 70, 75, 80, and 85 years, for disaggregate analysis. Anal manometry was used for measuring the maximum resting pressure, high‐pressure zone, and maximum squeeze pressure. Anal manometry was performed preoperatively and at 3, 6, 9, and 12 months postoperatively. The Wexner and low anterior resection syndrome scores were assessed at 1, 3, 6, 9, and 12 months after rectal surgery or stoma closure for patients with ileostomy. Results The data of 117 patients were reviewed. No significant differences were found between the younger and elderly groups in any characteristics across the six age groups. The preoperative intra‐anal pressures of the elderly patients were slightly lower than those of the younger patients; however, there was no significant difference in the course of postoperative intra‐anal pressures. Defecation disorder, as measured by the Wexner and low anterior resection syndrome scores, improved significantly in elderly patients compared to younger patients. Conclusion There was no significant difference in the course of postoperative intra‐anal pressures between the elderly and younger patients. However, defecation disorders in elderly patients significantly improved compared with younger patients. Sphincter‐preserving operation can be a viable treatment option for active elderly patients., The intra‐anal pressures were the same between the younger and the elderly after rectal surgery; however, defecation disorders in elderly patients significantly improved compared with those in younger patients. These new findings may help determine the optimal surgical procedure for lower rectal cancer in elderly patients. Sphincter‐preserving operation can be a good treatment option for active elderly patients.

Background Few cases have been reported of colorectal cancer with inferior mesenteric artery (IMA) branching abnormalities; therefore, the lymphatic flow in such cases remains unknown. We report the first case of locally advanced rectal cancer in which the IMA arose from the superior mesenteric artery (SMA) in which we achieved to visualize the lymphatic flow. Case presentation A 65-year-old woman complaining of bloody stools was investigated in our hospital and suspected with rectal cancer. Colonoscopy and abdominal enhanced computed tomography (CT) revealed a circumscribed, localized ulcerative tumor in the rectum. 3-Dimensional contrast-enhanced computed tomography (3D-CT) showed that the IMA arose from the SMA. The patient was diagnosed with rectal cancer (cT3N0M0, cStage IIa) and laparoscopic low anterior resection was performed. The sigmoid colon was resected using the medial approach. Only the plexus of the colic branch of the lumbar splanchnic nerve was observed at the site where the root of the IMA usually exists and showed interruption of the indocyanine green (ICG) fluorescence-illuminated lymphatics. The root of the IMA was ligated, and Japanese D3 lymphadenectomy was performed, preserving the accessory middle colic artery. All fluorescent lymph nodes were resected. The pathological diagnosis was pT4aN1aM0 stage IIIb. The patient’s postoperative course was uneventful. Adjuvant chemotherapy was administered, and the patient was recurrence-free at 1.5 years after surgery. Conclusions We were able to perform safe and appropriate surgery oncologically, despite abnormal vascular anatomy, due to preoperative identification using 3D-CT and intraoperative navigation using ICG administration.

Multidisciplinary treatment for locally advanced rectal cancer requires an accurate assessment of the risk of metastasis to the lateral lymph nodes (LNs). We herein aimed to stratify the risk of pathological metastasis to lateral LNs based on the preoperatively detected malignant features. All patients with rectal cancer who underwent surgery from January 2016 to July 2020 were identified. We recorded the TNM factors; perirectal and lateral LN sizes; and MRI findings, including mesorectal fascia involvement, extramural vascular invasion (EMVI), tumor site, and tumor distance from the anal verge. 101 patients underwent rectal resection with lateral lymph node dissection, of whom 16 (15.8%) exhibited pathological metastases to the lateral LNs. Univariate analyses demonstrated that lateral LN metastasis was significantly correlated with mrEMVI positivity (p = 0.0023) and a baseline lateral LN short-axis length of ≥ 5 mm (p

Hiroshi Yamaguchi,1 Yasutoshi Kimura,1 Masafumi Imamura,1 Minoru Nagayama,1 Tatsuya Ito,1 Daisuke Kyuno,1 Tsuyoshi Kono,1 Akina Kimura,1 Emi Akizuki,1 Toshihiko Nishidate,1 Kenji Okita,1 Takayuki Nobuoka,1 Toru Mizuguchi,1,2 Koichi Hirata,3 Ichiro Takemasa1 1Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, School of Medicine, Sapporo, Japan; 2Department of Nursing and Surgical Science, Sapporo Medical University School of Health Science, Sapporo, Japan; 3Department of Surgery, JR Sapporo Hospital, Sapporo, JapanCorrespondence: Hiroshi YamaguchiDepartment of Surgery, Surgical Oncology and Science, Sapporo Medical University, South 1, West 16, Sapporo 060-8543, JapanTel +81 11-611-2111 Ext 32810Fax +81 11-613-1678Email hyama@sapmed.ac.jpIntroduction: Delayed gastric emptying (DGE) remains an important problem after pancreaticoduodenectomy (PD). There is a lack of effective treatments for early recovery of oral dietary intake. Rikkunshito (RKT), a Japanese herbal medicine, has been gaining attention as a facilitator of gastric emptying. We evaluated the effects of RKT on DGE after PD.Methods: In this prospective, randomized, open-labeled study, patients were randomly allocated before PD in a 1:1 ratio to the RKT group or the control group that received no additional treatment. The RKT group received 2.5 g of RKT three times daily (7.5 g/day) from postoperative day (POD) 1 to POD 21. The primary endpoint was the incidence of DGE. Secondary endpoints were short-term postoperative outcomes including oral dietary intake volume and perioperative changes in levels of the hormones ghrelin and leptin. Patients were observed until hospital discharge.Results: Twenty-six patients in each group (n = 52) completed the protocol treatment and were included in the analysis set. There were no statistically significant differences in basic characteristics and operative factors. The overall incidence of DGE was not statistically different between the RKT and control groups (30.8% vs 30.8%, p> 0.9999). There were no statistically significant differences in the amount of postoperative oral dietary intake represented by total dietary intake (TDI) up to POD 14 and POD 21, complications, and length of hospital stay. No adverse events related to this study were observed. In the RKT group, total ghrelin and acyl-ghrelin were significantly upregulated and leptin was significantly downregulated earlier than in the control group.Conclusion: RKT treatment from POD 1 to 21 did not reduce the incidence of DGE and had no clinically beneficial effect on short-term postoperative outcomes irrespective of changes in hormone levels.Keywords: delayed gastric emptying, pancreaticoduodenectomy, Rikkunshito, ghrelin, leptin

Background Accurate identification of tumor sites during laparoscopic colorectal surgery helps to optimize oncological clearance. We aimed to assess the timing of the local injection preoperatively and clarify the usefulness and limitation of tumor site marking using indocyanine green (ICG) fluorescence imaging. Methods Consecutive patients who underwent primary colorectal cancer surgery from September 2017 to January 2019 were included. Preoperatively, lower endoscopy was used to inject the ICG solution into the submucosal layer near the tumor. During laparoscopic surgery, ICG fluorescence marking as the tumor site marking was detected using a laparoscopic near-infrared camera system. The detection rate and factors associated with successful intraoperative ICG fluorescence visualization including the interval between local injection and surgery were evaluated. Results One hundred sixty-five patients were enrolled. Using the laparoscopic near-infrared system, the intraoperative detection rates of ICG marking were 100% for ICG injection within 6 days preoperatively, 60% for injection between 7 and 9 days preoperatively, and 0% for injection earlier than 10 days preoperatively. There were no complications associated with ICG marking. Additionally, this method did not disturb the progress of the surgical procedure because injected ICG in the submucosal layer did not cause any tissue inflammation, and if ICG spilled into the serosa, it was invisible by white light. Conclusion Advantages of ICG fluorescence tumor site marking were high visibility of infrared imaging during laparoscopic colorectal surgery and minimal adverse events of surgery. One of the most important findings regarding practical use was a rapid decrease in fluorescence marking visibility if one week passed from the time of ICG local injection.

This report describes the combination of a transanal total mesorectal excision (TaTME) and neoadjuvant therapy with Imatinib mesylate (IM) for a gastrointestinal stromal tumor (GIST) of the lower rectum. A 49-year-old man presented with a submucosal tumor with ulcer located 3 cm above the anal verge. Histopathologically, a biopsy showed spindle-shape cells, positive for C-kit and CD34, negative for smooth muscle actin, desmin and S-100 protein. Genetically, this GIST had the mutation in KIT exon 11. IM (400 mg/d) was administered as neoadjuvant therapy for 80 days. The GIST shrank from 4.7 to 3.3 cm in diameter. Abdominal and transanal approach were started at the same time. The tumor was resected by TaTME successfully. The manometric pressure data and anal function were preserved before and after surgery. TaTME and neoadjuvant therapy with IM provide a treatment option which can preserve anal function for the lower rectal GIST.

The low anterior resection syndrome (LARS) score (LS) has been widely validated and has become an international tool for evaluating postoperative bowel dysfunction. However, many physicians still use the conventional incontinence scores in LARS treatment. Moreover, interpretation of LS and its relationship with conventional incontinence scores are not yet well understood. Here we compared the LS with the Cleveland Clinic Incontinence Score (CCIS) to clarify the clinical utility and characteristics of the LARS score.We performed a multicentre observational study, recruiting 246 rectal cancer patients following sphincter-preserving surgery. Patients completed the LS, CCIS, and SF36 questionnaires.The response rate was 76.4%, and a total of 180 patients were analysed. The LS was strongly correlated with the CCIS (P 0.001, rs = 0.727). However, among 116 patients determined to not have incontinence (CCIS 0-5), 51 (44%) were diagnosed with LARS (29 with minor LARS and 22 with major LARS). Among 68 patients without LARS, only 3 were diagnosed as having incontinence (CCIS 6). In comparison with background factors, aging and elapsed time were associated with only LS. High LS and CCIS both showed significant quality-of-life impairment as assessed by the SF-36.This is the first study to determine the difference in the numeric values between the CCIS and LS. The LS can be a convenient tool for LARS screening, identifying a wide range of patients with LARS, including those with incontinence evaluated by CCIS. Assessment using the CCIS may often underestimate LARS.

Circumferential resection margin (CRM) is essential for oncological quality assessment in rectal cancer surgery. CRM represents a surrogate parameter for oncological outcomes and is important for stratifying treatment strategies in Western nations. In Japan, the mesentery is removed for specimen processing in order to extract as many lymph nodes (LNs) as possible; consequently, CRM cannot be measured. Given the diversification of treatment strategies for rectal cancer, the lack of measurement of CRM to assess surgical outcomes is a crucial issue that must be resolved. Therefore, it is necessary to establish a method enabling measurement of CRM while enjoying the advantages of the Japanese method. In the method we developed, the mesentery is removed from the rectum more than 2 cm away from the tumor, and the vicinity of the tumor is circularized. It is necessary to investigate the usefulness of this method prospectively in a multi-center study.

BACKGROUND Transperineal abdominoperineal excision (TpAPE) is an emerging approach for low rectal cancers but is technically challenging. Based on an anatomical study we conducted previously, we have standardized the TpAPE procedure. Here, we aimed to validate the feasibility of the standardized TpAPE by investigating the short-term outcomes. METHODS From January 2018 to November 2020, a total of 405 patients underwent laparoscopic or robotic rectal resection for rectal cancer in our institution. For the current study, we analyzed data for the 31 patients who underwent TpAPE. The abdominal phase was performed synchronously with the perineal phase using either a laparoscopic or robotic approach. Short-term outcomes included operative and pathological results. RESULTS Of the 31 cases, we identified anterior quadrant tumor invasion in 21. Most of the cases were advanced, with 6 staged as cT3 and 20 as T4. Of the 27 cases not involving distant metastasis, neoadjuvant therapy was performed in 19. No inadvertent rectal perforation or urethral injury was found intraoperatively. The median procedural duration to specimen removal was 250 min (interquartile range, 204-287), and the median intraoperative blood loss was 10 ml (interquartile range, 5-40). Regarding postoperative complications, perineal wound infection developed in 11 cases. A positive circumferential resection margin was found in 3, corresponding to the positive rate of 9.7%. These three cases were among the first 12 cases involving standardized TpAPE. CONCLUSIONS The current results indicate that TpAPE can be performed safely and might represent a useful option for low rectal cancer resection.

Introduction Transperineal minimally invasive abdominoperineal excision (TpAPE) may help minimize surgical invasiveness and make it possible to perform two-team surgery, although this procedure is regarded as difficult. The anatomical structures are complicated and have not been clearly defined, particularly on the anterior side of the anorectal junction in men. We investigated the anatomical configuration around the anterior wall of the anorectal junction, focusing on the structure of the striated muscles, to establish a standard procedure for TpAPE. Methods We scrutinized the T2 -weighted MRI scans of 106 men, and two male cadavers were used to examine the muscular structure surrounding the anorectal junction. We established our standardized procedure for TpAPE based on these anatomical studies. We also analyzed the clinicopathological findings from five men who had undergone TpAPE at our institution. Results Using MRI, we detected band-like muscles bilaterally, just medial to the puborectal muscle in all analyzed patients, which we termed the rectal anterolateral muscle. We also detected the muscles that may correspond to the rectal anterolateral muscle when inspecting the cadavers. The standardized TpAPE procedures were carried out uneventfully for the five cases, and intraoperative complications such as urethral injury and inadvertent rectal perforation did not occur. Conclusion We standardized the TpAPE procedure based on anatomical examination of the muscular structure around the anal canal. The findings can contribute to safe implementation of TpAPE.

Patients with cancer should appropriately receive antiemetic therapies against chemotherapy-induced nausea and vomiting (CINV). Antiemetic guidelines play an important role in managing CINV. Accordingly, the first Japanese antiemetic guideline published in 2010 by the Japan Society of Clinical Oncology (JSCO) has considerably aided Japanese medical staff in providing antiemetic therapies across chemotherapy clinics. With the yearly advancements in antiemetic therapies, the Japanese antiemetic guidelines require revisions according to published evidence regarding antiemetic management worldwide. A revised version of the first antiemetic guideline that considered several upcoming evidences had been published online in 2014 (version 1.2), in which several updated descriptions were included. The 2015 JSCO clinical practice guideline for antiemesis (version 2.0) (in Japanese) has addressed clinical antiemetic concerns and includes four major revisions regarding (1) changes in emetogenic risk categorization for anti-cancer agents, (2) olanzapine usage as an antiemetic drug, (3) the steroid-sparing method, and (4) adverse drug reactions of antiemetic agents. We herein present an English update summary for the 2015 JSCO clinical practice guideline for antiemesis (version 2.0).

Surgical site infection (SSI) occurs at a high rate after ileostomy closure. The effect of preventive negative-pressure wound therapy (NPWT) on SSI development in closed wounds remains controversial. We conducted a prospective multicenter study to evaluate the usefulness of preventive NPWT for SSI after ileostomy closure. From January 2018 to November 2018, 50 patients who underwent closure of ileostomy created after surgery for colorectal cancer participated in this study. An NPWT device was applied to each wound immediately after surgery and then treatment was continued for 3 days. The primary endpoint was 30-day SSI, and the secondary endpoints were the incidence of seroma, hematoma, and adverse events related to NPWT. No patients developed SSI, seroma, or hematoma. Adverse events that may have been causally linked with NPWT were contact dermatitis in two patients and wound pain in one patient, and there were no cases of discontinuation or decompression of NPWT. The use of NPWT following ileostomy closure may be useful for reducing the development of SSI in colorectal cancer patients. This is a prospective multicenter pilot study and we are planning a comparative study based on these successful results. Registration number: UMIN000032053 ( https://www.umin.ac.jp/ ).

Background The low anterior resection syndrome (LARS) score is a patient-reported outcome measure to evaluate the severity of bowel dysfunction after rectal cancer surgery by scoring the major symptoms of LARS. The aim of this study was to translate the English version of the LARS score into Japanese and to investigate the validity and reliability of the LARS score. Methods The LARS score was translated in Japanese following current international recommendations. A total of 149 rectal cancer patients completed the LARS score questionnaire and were also asked a single question assessing the impact of bowel function on quality of life (QoL). A total of 136 patients answered the LARS score questionnaire twice. Results The Japanese LARS score showed high convergent validity, based on its good correlation between the LARS score and QoL (p

Tumor angiogenesis is an important therapeutic target in colorectal cancer (CRC). We aimed to identify novel genes associated with angiogenesis in CRC. Using RNA sequencing analysis in normal and tumor endothelial cells (TECs) isolated from primary CRC tissues, we detected frequent upregulation of adipocyte enhancer‐binding protein 1 (AEBP1) in TECs. Immunohistochemical analysis revealed that AEBP1 is upregulated in TECs and stromal cells in CRC tissues. Quantitative RT‐PCR analysis showed that there is little or no AEBP1 expression in CRC cell lines, but that AEBP1 is well expressed in vascular endothelial cells. Levels of AEBP1 expression in Human umbilical vein endothelial cells (HUVECs) were upregulated by tumor conditioned medium derived from CRC cells or by direct coculture with CRC cells. Knockdown of AEBP1 suppressed proliferation, migration, and in vitro tube formation by HUVECs. In xenograft experiments, AEBP1 knockdown suppressed tumorigenesis and microvessel formation. Depletion of AEBP1 in HUVECs downregulated a series of genes associated with angiogenesis or endothelial function, including aquaporin 1 (AQP1) and periostin (POSTN), suggesting that AEBP1 might promote angiogenesis through regulation of those genes. These results suggest that upregulation of AEBP1 contributes to tumor angiogenesis in CRC, which makes AEBP1 a potentially useful therapeutic target., We identified that adipocyte enhancer‐binding protein 1 (AEBP1) is upregulated in tumor endothelial cells in primary colorectal cancers. Upregulation of AEBP1 in vascular endothelial cells promotes cell proliferation, migration, and angiogenesis. We also found that AEBP1 might mediate tumor angiogenesis through regulating expression of angiogenesis‐related genes, including aquaporin 1 (AQP1) and periostin (POSTN).

The current status of site-specific cancer registry has not been elucidated, but sufficient system is found in some societies. The purpose of this study was to clear the present condition of site-specific cancer registries in Japan and to suggest for the improvement. The questionnaire was conducted by the study group of the Ministry of Health, Labor, and Welfare. It consisted of 38 questions, conflicts of interest, clinical research method, informed consent and funding for registry. We distributed this questionnaire to 28 academic societies, which had published the clinical practice guideline(s) assessed under Medical Information Network Distribution Service (MINDS). The concept of the importance in assessment for medical quality by the data of the site-specific cancer registry was in good consensus. But the number of the society with the mature registry was limited. The whole-year registry with the scientific researches in the National Clinical Database (NCD) and in the Translational Research Informatics Center (TRI) might seem to be in success, because assured enhancement may be estimated. Now, academic societies have the structural factors, i.e., the financial limitation in the registry maintenance and the data analysis, and in the difficulty of employment of the researchers with skill and talent. To manage the site-specific cancer registry effectively, the scientific registry system will be essentially important. Each academic society had much experienced highly qualified clinical researches in past. Accordingly, the scientific suggestion and co-operation should be of great importance for the improvement.

Since acute abdomen requires accurate diagnosis and treatment within a particular time limit to prevent mortality, the Japanese Society for Abdominal Emergency Medicine, in collaboration with four other medical societies, launched the Practice Guidelines for Primary Care of Acute Abdomen that were the first English guidelines in the world for the management of acute abdomen. Here we provide the highlights of these guidelines (all clinical questions and recommendations were shown in supplementary information). A systematic and comprehensive evaluation of the evidence for epidemiology, diagnosis, differential diagnosis, and primary treatment for acute abdomen was performed to develop the Practice Guidelines for Primary Care of Acute Abdomen 2015. Because many types of pathophysiological events underlie acute abdomen, these guidelines cover the primary care of adult patients with nontraumatic acute abdomen. A total of 108 questions based on nine subject areas were used to compile 113 recommendations. The subject areas included definition, epidemiology, history taking, physical examination, laboratory test, imaging studies, differential diagnosis, initial treatment, and education. Japanese medical circumstances were considered for grading the recommendations to assure useful information. The two-step methods for the initial management of acute abdomen were proposed. Early use of transfusion and analgesia, particularly intravenous acetaminophen, were recommended. The Practice Guidelines for Primary Care of Acute Abdomen 2015 have been prepared as the first evidence-based guidelines for the management of acute abdomen. We hope that these guidelines contribute to clinical practice and improve the primary care and prognosis of patients with acute abdomen.

Background: Since acute abdomen requires accurate diagnosis and treatment within a particular time limit to prevent mortality, the Japanese Society for Abdominal Emergency Medicine in collaboration with four other medical societies launched the Practice Guidelines for Primary Care of Acute Abdomen that were the first English guidelines in the world for the management of acute abdomen. Here we provide the highlights of these guidelines (all CQ and recommendations were shown in supplementary information). Methods: A systematic and comprehensive evaluation of the evidence for epidemiology, diagnosis, differential diagnosis, and primary treatment for acute abdomen was performed to develop the Practice Guidelines for Primary Care of Acute Abdomen 2015. Because many types of pathophysiological events underlie acute abdomen, these guidelines cover the primary care of adult patients with nontraumatic acute abdomen. Results: A total of 108 questions based on 9 subject areas were used to compile 113 recommendations. The subject areas included definition, epidemiology, history taking, physical examination, laboratory test, imaging studies, differential diagnosis, initial treatment, and education. Japanese medical circumstances were considered for grading the recommendations to assure useful information. The two-step methods for the initial management of acute abdomen were proposed. Early use of transfusion and analgesia, particularly intravenous acetaminophen, were recommended. Conclusions: The Practice Guidelines for Primary Care of Acute Abdomen 2015 have been prepared as the first evidence-based guidelines for the management of acute abdomen. We hope that these guidelines contribute to clinical practice and improve the primary care and prognosis of patients with acute abdomen.

Pancreatic regeneration (PR) is an interesting phenomenon that could provide clues as to how the control of diabetes mellitus might be achieved. Due to the different regenerative abilities of the pancreas and liver, the molecular mechanism responsible for PR is largely unknown. In this review, we describe five representative murine models of PR and thirteen humoral mitogens that stimulate β-cell proliferation. We also describe pancreatic ontogenesis, including the molecular transcriptional differences between α-cells and β-cells. Furthermore, we review 14 murine models which carry defects in genes related to key transcription factors for pancreatic ontogenesis to gain further insight into pancreatic development.

The purpose of this article is to disseminate the standard of antiemetic therapy for Japanese clinical oncologists. On the basis of the Appraisal of Guidelines for Research and Evaluation II instrument, which reflects evidence-based clinical practice guidelines, a working group of the Japanese Society of Clinical Oncology (JSCO) reviewed clinical practice guidelines for antiemesis and performed a systematic review of evidence-based domestic practice guidelines for antiemetic therapy in Japan. In addition, because health-insurance systems in Japan are different from those in other countries, a consensus was reached regarding standard treatments for chemotherapy that induce nausea and vomiting. Current evidence was collected by use of MEDLINE, from materials from meetings of the American Society of Clinical Oncology National Comprehensive Cancer Network, and from European Society of Medical Oncology/Multinational Association of Supportive Care in Cancer guidelines for antiemesis. Initially, 21 clinical questions (CQ) were selected on the basis of CQs from other guidelines. Patients treated with highly emetic agents should receive a serotonin (5-hydroxytryptamine; 5HT3) receptor antagonist, dexamethasone, and a neurokinin 1 receptor antagonist. For patients with moderate emetic risk, 5HT3 receptor antagonists and dexamethasone were recommended, whereas for those receiving chemotherapy with low emetic risk dexamethasone only is recommended. Patients receiving high-emetic-risk radiation therapy should also receive a 5HT3 receptor antagonist. In this paper the 2010 JSCO clinical practice guidelines for antiemesis are presented in English; they reveal high concordance of Japanese medical circumstances with other antiemetic guidelines that are similarly based on evidence.

Peritoneal metastasis is recognized as a predictor of poor prognosis in patients with colorectal cancer, and whether surgical intervention for peritoneal metastasis has any clinical benefit has remained controversial. The purposes of this study were to identify prognostic factors in cases of unresectable colorectal cancer with synchronous peritoneal metastasis and to clarify the impacts of primary tumor resection with high tie lymph node dissection. A multi-institutional retrospective analysis was conducted of 579 patients who underwent resection of the primary tumor for unresectable colorectal cancer with peritoneal metastasis between 1991 and 2007. For these 579 patients, clinicopathological variables were analyzed for prognostic significance using Cox proportional hazards model and propensity score analysis to mitigate the selection bias. Multivariate analysis revealed hematogenous metastasis (p

Pancreatic tumors are chemoresistant and malignant, and there are very few therapeutic options for pancreatic cancer, as the disease is normally diagnosed at an advanced stage. Although attempts have been made to develop vaccine therapies for pancreatic cancer for a couple of decades, none of the resultant protocols or regimens have succeeded in improving the clinical outcomes of patients. We herein review vaccines tested within the past few years, including peptide, biological and multiple vaccines, and describe the three sets of criteria used to evaluate the therapeutic activity of vaccines in solid tumors.

Advances in minimally invasive laparoscopic surgery have grown to reduced-port surgery (RPS). Single-incision laparoscopic surgery (SILS) is considered the ultimate RPS for improving cosmesis and reducing postoperative pain and the risk of abdominal wall morbidities. Several reports have described both superior short-term and similar long-term results of SILS for colorectal malignancies when compared with standard laparoscopic surgery. However, there are some limitations such as instrument collision and insufficient countertraction. In a recent attempt to overcome the technical issues in SILS, by combining the use of the da Vinci robotic surgical system with the single-incision platform, the recognized challenges are somewhat simplified. Only a few reports of single-port robotic surgery for rectal disease have been conducted; however, the current robotic arm and equipment are still rather bulky and have a limited intrapelvic range of motion. Pure single approach may be not suited for sufficient oncological clearance.

Colorectal cancer (CRC) is a mortal disease due to treatment resistance, recurrence and distant metastasis. Emerging evidence has revealed that a small sub-population of cancer cells termed cancer stem cells (CSCs)/ cancer-initiating cells (CICs) is endowed with high levels of tumor-initiating ability, self-renewal ability and differentiation ability and is responsible for treatment resistance, recurrence and distant metastasis. Eradication of CSCs/CICs is essential to improve current treatments. However, the molecular mechanisms by which CSCs/CICs are maintained are still elusive. In this study, we aimed to determine the molecular mechanisms by which colorectal (CR)-CSCs/CICs in are maintained human primary CRC cells. CR-CSCs/CICs were isolated by sphere-culture and the ALDEFLUOR assay, and transcriptome analysis revealed that the gene ST6 N-Acetylgalactosaminide Alpha-2,6-Sialyltransferase 1 (ST6GALNAC1) was expressed at high levels in CR-CSCs/CICs. Overexpression of ST6GALNAC1 enhanced the expression of sialyl-Tn (STn) antigen, which is carried by the CSC marker CD44, and increased the sphere-forming ability and resistance to a chemotherapeutic reagent. The opposite phenomena were observed by gene knockdown using siRNA. Furthermore, the Akt pathway was activated in ST6GANAC1-overexpressed cells, and activation of the pathway was cancelled by gene knockdown of galectin-3. The results indicate that ST6GALNAC1 has a role in the maintenance of CR-CSCs/CICs by activating the Akt pathway in cooperation with galectin-3 and that ST6GalNAC1 (or STn antigen) might be a reasonable molecule for CSC/CIC-targeting therapy.

Colorectal carcinoma (CRC) is one of the most frequently diagnosed cancers and the leading cause of cancer-related death for both men and women. Recent studies have revealed that a small sub-population of cancer cells, termed cancer stem-like cells (CSCs)/cancer-initiating cells (CICs), are endowed with tumor-initiating ability, self-renewal ability and differentiation ability. CSCs/CICs are resistant to current therapies including chemotherapy and radiotherapy. Thus, CSCs/CICs are responsible for recurrence and metastasis, and eradication of CSCs/CICs is essential to cure cancer. In this study, we isolated CR-CSCs/CICs as sphere-cultured cells and found that a product derived from LY6/PLAUR domain containing 3 (LYPD3) is preferentially expressed in CSCs/CICs. Gene overexpression and gene knockdown experiments revealed that LYPD3 has a role in the maintenance of CR-CSCs/CICs. The findings provide a novel molecular insight into CR-CSCs/CICs.

Colorectal cancer (CRC) is one of the most common malignancy, and the prognosis is not still satisfactory due to treatment resistance, recurrence and distant metastasis. Cancer stem cells (CSCs)/cancer-initiating cells (CICs) is endowed with higher tumor-initiating ability, self-renewal ability and differentiation ability, and CSCs/CICs are resistant to treatments. Thus, CSCs/CICs are thought to be responsible for recurrence and distant metastasis, and eradication of CSCs/CICs is essential to cure CRCs. However, the molecular mechanisms of CSCs/CICs are remain unknown, and we aimed to elucidate molecular aspects of CR-CSCs/CICs in this study. We screened the transcriptome data of primary human CR-CSCs/CICs that we previously established, and found that LEM domain containing 1 (LEMD1) is preferentially expressed in CR-CSCs/CICs. LEMD1 belongs to cancer-testis (CT) antigen, and has five transcript variants (variant 1 [V1] - variant 5 [V5]). We found that LEMD1 V1, V2 and V3 is expressed in testis and CR-CSCs/CICs, whereas LEMD1 V4 and V5 is ubiquitously expressed. LEMD1 gene knockdown experiments using siRNAs and gene overexpression experiments revealed that LEMD1 has a role in the maintenance of CR-CSCs/CICs. These observations indicate that CR-CSC/CIC-specific LEMD1 variants are reasonable target of CR-CSC/CIC-targeted therapy.

Surgery involving elderly patients is becoming increasingly common due to the rapid aging of societies all over the world. The objective of this study was to elucidate the prognostic differences between elderly and young patients who undergo liver resection. A systematic review based on the PRISMA flow diagram was conducted. Ovid Medline and PubMed were used to search for relevant literature published between January 2000 and March 2013, and the modified MINORS score was used to assess the methodological quality. In cases of hepatocellular carcinoma and miscellaneous liver tumors, the morbidity and mortality rate did not differ significantly between the elderly and young patients. For patients with colorectal metastatic liver cancer, the mortality of the young patients was 2.7 times lower than that of elderly patients. Our review of high-quality retrospective studies was able to elucidate the clinical risks of age on the outcomes after liver surgery in specific patient populations.

Background The Pringle maneuver is used to minimize blood loss during liver transection; however, it may cause reperfusion injury, which can cause increased intraoperative lactate levels and an immune compromised state. This may further lead to infectious complications. Methods Here, we divided 77 patients who underwent hepatectomy between December 2007 and August 2010 into two groups: the chronic hepatitis and liver cirrhosis (CH + LC) group and normal liver (NL) group. We investigated the effect of the highest intraoperative lactate level on occurrence of infectious complications after hepatectomy by assessing the correlations of the highest intraoperative lactate level with total Pringle time, operative factors, and various parameters in serum after surgery. Parameters showing significant correlations with postoperative complications of Clavien-Dindo grade III or higher, with a wound or intra-abdominal infection, were analyzed by using interactive dot diagrams to determine cut-off values with the highest sensitivity and specificity. Results We noted that, to prevent postoperative infectious complications, the highest lactate level during liver resection should be maintained at

症例は66歳，男性．主訴は腹部膨満感および下痢．近医にてS状結腸狭窄を指摘され，手術目的に当科紹介となる．大腸内視鏡検査では，S状結腸に多発する憩室を認め，同部位は約15cmにわたり著明に狭窄していた．入院時の血液検査では，血清carbohydrate antigen（CA）19-9値（基準値37U/ml）が1894.0U/mlと異常高値を示した．消化管，膵胆道系の悪性腫瘍の合併を疑い，精査を施行するもS状結腸憩室症による腸管狭窄以外に異常所見を認めなかった．S状結腸憩室症による腸管狭窄および同部位に潜在する結腸癌の可能性から手術適応と判断し，腹腔鏡補助下S状結腸切除術を施行した．摘出標本の病理組織学的所見は，粘膜下層の線維化，固有筋層の肥厚を認めたが，腫瘍性病変は存在しなかった．CA19-9免疫染色では，陰窩上皮に陽性細胞を認めた．術後血清CA19-9値は経時的に低下し，術後約4カ月後には29.7U/mlまで減少したことから術前の異常高値は，S状結腸憩室部からのCA19-9産生によるものと考えられた．

UFT is composed of tegafur, a prodrug of 5-fluorouracil, and uracil, at a fixed ratio of 1: 4. UFT is widely used with leucovorin as adjuvant chemotherapy in patients with colon cancer. As reported, UFT/leucovorin should not be taken simultaneously with food because a high fat content will reduce the systemic exposure to the active cytotoxic moiety of UFT. In this single-dose, randomized, two-way crossover study, we investigated the effects of a low-fat Japanese meal on the pharmacokinetics and oral bioavailability of UFT (2 × 100-mg capsules; dose in terms of tegafur) and leucovorin (1 × 25-mg tablet). Patients (n = 12) were randomly assigned to receive both drugs after an overnight fast or 5 min after eating a standard Japanese breakfast (641 kcal), with a 3-day washout period between treatments. Pharmacokinetics (n = 12) were determined for tegafur, 5-fluorouracil, uracil, leucovorin, and 5-methyltetrahydrofolate (an active metabolite of leucovorin). For 5-fluorouracil pharmacokinetics, the maximum plasma concentration and the area under the curve were reduced by 73.7% and 47.4%, respectively, when UFT was taken postprandially, and the maximum plasma concentration and the area under the curve for uracil were reduced by 84.1% and 68.9%, respectively, compared with dosing on an empty stomach. These decreases in the systemic exposure to 5-fluorouracil were quite marked and may have an impact on its antitumor effect. A low-fat meal affects the pharmacokinetics of UFT similarly to a high-fat meal.

Breast cancer is generated through a multistep genetic and epigenetic process including activations of oncogenes and inactivations of tumor suppressor genes. Here, we report a critical role of ubiquitin-conjugating enzyme E2T (UBE2T), an E2 ubiquitin-conjugating enzyme, in mammary carcinogenesis. Immunocytochemical staining and in vitro binding assay revealed that UBE2T interacted and colocalized with the BRCA1/BRCA1-associated RING domain protein (BARD1) complex. Knocking down of UBE2T expression with small interfering RNA drastically suppressed the growth of breast cancer cells. Interestingly, in vivo ubiquitination assay indicated BRCA1 to be polyubiquitinated by incubation with wild-type UBE2T protein, but not with C86A-UBE2T protein, an E2 activity–dead mutant, in which the 86th residue of cysteine was replaced with alanine. Furthermore, knocking down of UBE2T protein induced upregulation of BRCA1 protein in breast cancer cells, whereas its overexpression caused the decrease of the BRCA1 protein. Our data imply a critical role of UBE2T in development and/or progression of breast cancer through the interaction with and the regulation of the BRCA1/BARD1 complex. [Cancer Res 2009;69(22):8752–60]