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Dietary factors may affect the prognosis of digestive tract cancer, but evidence has been sparse. We investigated the association between pretreatment intake of 6 Japanese foods (including soy food, miso [soybean paste] soup and seaweed) and the risk of death among patients with histologically confirmed major digestive tract cancers (stomach, 1931; colon, 793; rectum, 510) diagnosed during 1997‐2013 at a single institution in Japan. Pretreatment dietary intake was assessed using a food frequency questionnaire, and the patients were followed until December 2016. The Cox proportional hazards model was used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Among the patients with stomach cancer, frequent intake of soy food was inversely associated with the risk of all‐cause (P trend for four frequency groups = 0.01; HR = 0.72, 95% CI: 0.50‐1.04 for highest vs lowest group) and stomach cancer (P trend = 0.03; HR = 0.63, 95% CI: 0.40‐0.99) death. A similar inverse association was also found for intake of miso soup. In contrast, frequent seaweed intake was inversely associated with the risk of all‐cause death among the patients with colon cancer (P trend = 0.03). Rectal cancer patients who had frequently consumed seaweed tended to have a lower risk of rectal cancer death (P trend = 0.02). These findings indicate that pretreatment intake of Japanese foods such as soybean products and seaweed may have favorable effects on patient survival of stomach and colorectal cancer, although this needs to be confirmed by further research., The aim of this patient cohort study is to clarify the relationship between intake of selected traditional Japanese foods and survival after diagnosis of stomach and colorectal cancer. The results indicate that intake of Japanese foods such as soybean products and seaweed may have a favorable effect on patient survival of stomach and colorectal cancer.

Purpose Capecitabine-based adjuvant chemotherapy for colorectal cancer patients often causes adverse events (AEs), such as diarrhea, stomatitis, anorexia, and hand-foot syndrome (HFS). Cystine and theanine were reported to attenuate some chemotherapy-associated AEs, and hence are also expected to attenuate capecitabine-induced AEs. Therefore, we aimed to investigate the safety and efficacy of cystine/theanine treatment in colorectal cancer patients undergoing capecitabine-based adjuvant chemotherapy after surgery. Methods A total of 100 colorectal cancer patients treated with capecitabine as an adjuvant chemotherapy after surgery were randomly allocated into the cystine/theanine group (n = 52) or the placebo group (n = 48). The primary endpoint was incidence rate of diarrhea of grade 1 or higher in accordance with the Common Terminology Criteria for AEs (CTCAE) v.4.0, Japanese Clinical Oncology Group (JCOG) version. The secondary endpoints included incidence rates of other AEs (CTCAE v.4.0-JCOG), as well as the incidence rate of HFS according to the HFS grading scale. Results There were no significant differences in capecitabine-induced AEs between the two groups. However, the incidence rate of diarrhea of grade 1 or higher tended to be lower in the cystine/theanine group than the placebo group (18.4% vs. 28.9%, p = 0.169) as well as the incidence rate of HFS of grade 1 or higher (CTCAE v.4.0-JCOG or HFS grading scale) (67.4% vs. 77.8%, p = 0.185, 67.3% vs. 80.0%, p = 0.124, respectively). Conclusion This trial demonstrated that cystine/theanine treatment of colorectal cancer patients undergoing capecitabine-based adjuvant chemotherapy after surgery is safe and has the tendency to reduce the incidence rate of diarrhea or HFS. Trial registration UMIN000024784

Background The risk of venous thromboembolism (VTE) after surgery for malignancy in Japanese patients is unclear; hence, standard prevention protocols have not been established, especially for minimally invasive surgeries. We aimed to investigate the additional effect of low-molecular-weight heparin (LMWH) on the prevention of VTE after laparoscopic surgery for gastrointestinal malignancy. Study Design From February 2013 to January 2017, Four hundred patients scheduled for laparoscopic surgery were included. Cases were randomly allocated to the physical therapy group (Control group; 201 patients) or to the combination-therapy group (LMWH group; 199 patients) in which enoxaparin sodium (20 mg twice a day) was administered for 1 week postoperatively in addition to the physical therapy. A diagnosis of VTE was made by contrast-enhanced computed tomography or ultrasonography when symptomatic or D-dimer was ≥10 μg/ml. Results VTE was observed in 1.2% and 4.0% patients of the LMWH and Control groups, respectively (odds ratio [OR]=0.3, 95% confidence interval [CI]: 0.03–1.53). Pulmonary embolism was confirmed only in the Control group (1.7%). No major bleeding occurred in either group. Logistic multiple regression analysis revealed that surgical time extension (OR=1.02, 95%CI: 1.00–1.04) was a risk factor of VTE, while administration of LMWH (OR=0.21, 95%CI: 0.03–0.99), male sex (OR=0.12, 95%CI: 0.01–0.60), and early cancer (OR=0.17, 95%CI: 0.02–0.82) reduced the risk of VTE. Conclusions Postoperative LMWH administration is safe. The additional effect of the LMWH administration to the physical therapy was not statistically proved in this study. However, it could be useful for the patients with risk factors such as female, long operation time, and higher cancer stage.

Cancer stem cells (CSCs) define a subpopulation of cancer cells that are resistant to therapy. However, little is known of how CSC characteristics are regulated. We previously showed that dormant cancer stem cells are enriched with a CD274low fraction of cholangiocarcinoma cells. Here we found that BEX2 was highly expressed in CD274low cells, and that BEX2 knockdown decreased the tumorigenicity and G0 phase of cholangiocarcinoma cells. BEX2 was found to be expressed predominantly in G0 phase and starvation induced the USF2 transcriptional factor, which induced BEX2 transcription. Comprehensive screening of BEX2 binding proteins identified E3 ubiquitin ligase complex proteins, FEM1B and CUL2, and a mitochondrial protein TUFM, and further demonstrated that knockdown of BEX2 or TUFM increased mitochondria-related oxygen consumption and decreased tumorigenicity in cholangiocarcinoma cells. These results suggest that BEX2 is essential for maintaining dormant cancer stem cells through the suppression of mitochondrial activity in cholangiocarcinoma. Funding Statement: This research was supported in part by the Biomedical Research Core of Tohoku University Graduate School of Medicine. This research was supported in part by JSPS KAKENHI grant numbers JP: 19K08430, 17K10716, and 16K07132, and Practical Research for Innovative Cancer Control from AMED by grant number JP17ck0106197, The Cooperative Research Project Program of Joint Usage/Research Center at The Institute of Development, Aging and Cancer, Tohoku University, and Takeda Medical Foundation. Declaration of Interests: There are no financial conflicts of interest. Ethics Approval Statement: This study was conducted according to the principles expressed in the Declaration of Helsinki and was approved by the Ethics Committees at Miyagi Cancer Center (Natori, Japan) and Tohoku University Graduate School of Medicine (Sendai, Japan). The protocol of animal experiments was approved by the Miyagi Cancer Center Animal Care and Use Committee (permit number: MCC-AE-2019-8).

Cigarette smoking and alcohol drinking may affect the prognosis of stomach cancer, but evidence has been inconsistent. We investigated the associations between pretreatment smoking and alcohol drinking and the risk of all-cause and stomach cancer death among 1,576 patients with histologically confirmed stomach cancer diagnosed during 1997-2010 at a single hospital in Japan. Histories of smoking and alcohol drinking were assessed using a self-administered questionnaire. The patients were followed until December 31, 2013. The Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). During 9,625.1 person-years, 670 all-cause and 419 stomach cancer deaths were documented. Among the patients overall, ever-drinking was significantly associated with an increased risk of all-cause death (HR: 1.25; 95% CI: 1.03-1.51), but not stomach cancer death. Positive linear associations with the frequency of drinking (ptrend = 0.02) and the amount of alcohol consumed per day (ptrend = 0.03) were observed for the risk of all-cause death. Ever-smoking was not related to either the risk of all-cause or stomach cancer death. Conversely, among the patients who underwent curative resection, a significant positive association was found between ever-smoking and the risk of stomach cancer death (HR: 2.44; 95% CI: 1.17-5.08). A positive association was also found for earlier age at start of smoking (ptrend = 0.0046). Pretreatment smoking and alcohol drinking have significant effects on stomach cancer survival. Lifestyle adjustments throughout life may improve survival.

Sixty years since its introduction, 5-FU still forms the core of chemotherapy regimens for many types of malignancies. 5-FU is a time-dependent drug but is rapidly degraded in plasma by dihydropyrimidine dehydrogenase (DPD). Although originally developed in an intravenous form, 5-FU oral prodrugs were developed with the goal of improving efficacy and minimizing toxicity as well as to capitalize on the advantages of oral drug administration. The inactive 5-FU prodrug is gradually converted into the active form in the systemic circulation. UFT, S-1, and capecitabine are oral 5-FU prodrugs currently in clinical use. However, the efficacy of 5-FU can be further improved by its combination with DPD inhibitors and biochemical modulators, such as uracil and leucovorin, in addition to modifying administration schedules. Areas covered: We focused on the drug delivery of oral 5-FU prodrugs, their pharmacokinetics, and the development of DPD inhibitors. Since oral 5-FU prodrugs have been formulated into combination drugs, we also discussed the regulatory approval of combination drugs. Expert opinion: Many regimens that include intravenously administered 5-FU can be replaced by oral 5-FU prodrugs. Patients would benefit from development of combination 5-FU oral prodrug formulations and its associated path through the combination drug regulatory approval process.

The information presented herein extends our recent study of TTT (Trial for Triplet Antiemetic Therapy). One of our main clinical questions has been whether a 2nd generation serotonin receptor antagonist (5-HT3ra) would be superior to 1st generation 5-HT3ra when administering triplet antiemetic therapy for the prevention of chemotherapy induced nausea & vomiting (CINV), since a prior Japanese trial demonstrated palonosetron to be superior to granisetron for controlling the delayed phase of CINV induced by highly emetogenic chemotherapy (HEC) and to doublet antiemetic therapy including dexamethasone for anthracycline and cyclophosphamide containing regimens (AC). In this study, we assessed the efficacies of 1st and 2nd generation 5-HT3ra agents for use as triplet antiemetic therapy for AC, by monitoring CINV, focusing especially daily CR in the delayed phase. Between 2012 and 2015, 491 women with breast cancer receiving AC were recruited from 11 institutions in Japan, and randomly assigned to either single-dose palonosetron (0.75mg) or granisetron (40μg/kg) prior to chemotherapy on day 1, both with dexamethasone (9.9 mg intravenously) and aprepitant (125mg orally) on day 1 followed by additional doses (80mg orally) on days 2 and 3. Age, institution and habitual alcohol intake were used as stratification factors. The primary endpoint was a complete response (CR). Statistical analysis was done by Mantel-Haenszel Method. This trial was registered with UMIN000007882. All 491 patients were included in efficacy analyses (ITT): 246 patients in the palonosetron group and 245 in the granisetron group. We previously reported that the difference in CR during the delayed phase, i.e. 24 hours after the administration of AC, did not reach statistical significance (53.8% vs 58.5%) in MASCC 2016. However, daily CR in the palonosetron group was much higher than that in the granisetron group after 48 hours. Palonosetron showed better efficacy in controlling CINV during the late period of the delayed phase, i.e. 48 hours after AC administration, than granisetron as triplet antiemetic therapy for AC. The pattern of CINV reportedly shows two peaks including an acute phase caused by serotonin and a delayed phase caused by substance P, though the pattern of CINV with triplet antiemetic therapy administration might be different if the suppression of each of these peaks were to be achieved more efficiently. CINV may not be divided into two phases in the future, or the borderline area between the acute and delayed phases may require revision. The analysis of the late period of the delayed phase was ad hoc in this trial. However, when conducting studies related to CINV, it might be worthwhile to revise the borderline area between the two phases of CINV to facilitate elucidating the mechanisms underlying this potentially debilitating side effect of chemotherapy. Citation Format: Ogata H, Saito M, Tsuneizumi M, Kutomi G, Hosoya K, Kawai Y, Sugizaki K, Katsumata N, Senuma K, Kitabatake T, Suda M, Uomori T, Miura K, Kurata M, Nitta Y, Yonemoto N, Matsuoka J. Difference between 1st and 2nd generation serotonin receptor antagonists in triplet antiemetic therapy for highly emetogenic chemotherapy in breast cancer patients – according to recent multi-institutional double-blind randomized clinical research on the AC regimen [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-11-03.

Recently, a series of novel arylthioindole compounds, potent inhibitors of tubulin polymerization and cancer cell growth, were synthesized. In the present study the effects of 2-(1H-pyrrol-3-yl)-3-((3,4,5-trimethoxyphenyl)thio)-1H-indole (ATI5 compound) on cell proliferation, cell cycle progression, and induction of apoptosis in human T-cell acute leukemia Jurkat cells and their multidrug resistant Jurkat/A4 subline were investigated. Treatment of the Jurkat cells with the ATI5 compound for 48 hrs resulted in a strong G2/M cell cycle arrest and p53-independent apoptotic cell death accompanied by the induction of the active form of caspase-3 and poly(ADP-ribose) polymerase-1 (PARP-1) cleavage. ATI5 treatment also caused non-cell death related mitotic arrest in multidrug resistant Jurkat/A4 cells after 48 hrs of treatment suggesting promising opportunities for the further design of pyrrole-containing ATI compounds as anticancer agents. Cell death resistance of Jurkat/A4 cells to ATI5 compound was associated with alterations in the expression of pro-survival and anti-apoptotic protein-coding and microRNA genes. More importantly, findings showing that ATI5 treatment induced p53-independent apoptosis are of great importance from a therapeutic point of view since p53 mutations are common genetic alterations in human neoplasms.

5-Fluorouracil (5-FU), a core anticancer agent for malignancies, induces gastrointestinal (GI) toxicities. Despite recent advances in tumor immunology, it still remains unknown how GI toxicities affect antitumor immunity. S-1 is a tegafur-based oral 5-FU prodrug which has been widely introduced in Japan and other countries. The alternate-day S-1 administration has been proposed to minimize its GI and other toxicities without reducing its anticancer efficacy. In this study, two S-1 administration regimens were compared in mice to evaluate their impact of GI toxicities on immunity. In the daily group as a standard administration model, S-1 was administered for 14 days on and 14 days off, and in the alternate-day group as a non-GI toxicity model, S-1 was administered every other day for 28 days. As well as physical findings, regulatory T cells, Th1 cells and other cells in murine lymphoid tissues were analyzed with flow cytometry. Only the daily group exhibited body weight loss and GI toxicities. In the daily group, a proportion of regulatory T cells in the intestinal lymphoid tissue were demonstrated to be six-fold higher than in the control without S-1, and the proportion of Th1 cells showed a decreasing trend. However, the alternate-day group exhibited almost no change in T-cell subsets. GI toxicities of 5-FU may have a negative influence on antitumor immunity due to increased proportions of regulatory T cells and decreased proportions of Th1 cells. The alternate-day S-1 administration may be a useful regimen with its minimal influence on T-cell subsets.

We, herein, examined the role of the intraluminal contents and continuity of colonic intrinsic neurons in intracolonic capsaicin-induced enhancement of colonic motility and defecation. Five beagle dogs were equipped with three strain gauge force transducers throughout the colon. The colonic contractile activity in response to intracolonic capsaicin was studied in intact dogs, dogs after colonic cleansing and dogs with transection/re-anastomosis (T/R) between the proximal and middle colon. The effects of intravenous yohimbine, a α2 adrenergic antagonist, on the colonic motility and defecation were also studied in the same models. In intact dogs, capsaicin (10 mg) and yohimbine (2 mg/kg) immediately induced contractions throughout the colon, with defecation occurring in all experiments. In dogs after colonic cleansing and T/R, the capsaicin (10 mg)-induced enhancement of colonic motility was decreased in the middle and distal colon, and capsaicin-induced defecation was observed in 0–20 % of experiments (p

The glucagon provocative test is useful for the diagnosis of gastrinoma. The aim of this study was to determine the criteria for the glucagon provocative test.This study reviewed 8 patients that underwent the glucagon provocative test preoperatively and in whom the diagnosis was confirmed as gastrinoma histologically. The glucagon provocative test was performed by administering glucagon (20 μg/kg) intravenously, followed by 20 μg/kg h for the next 30 min, and plasma gastrin levels were measured 3 and 1 min before and 3, 5, 7, 10, 15, 20, and 30 min after the administration of glucagon. This study evaluated the peak value of plasma gastrin and the time required to reach the peak.Two of the 8 patients had multiple endocrine neoplasm type 1. The basal plasma gastrin levels ranged from 524 to 10,300 pg/ml. The time required to reach the peak was 3-10 min for all patients. The increase in the peak from the basal value was 235-8,920 pg/ml, and the percentage of increase was 38-337 %.These results suggest that a diagnosis of gastrinoma should thus be made when plasma gastrin levels peak within 10 min after glucagon administration, with an increase of greater than 200 pg/ml and greater than 35 % of the basal value.

Lynch syndrome is an autosomal dominant disorder with an estimated prevalence of 3 % of all colorectal cancers. It is attributed to germline mutations in DNA mismatch repair (MMR) genes, which confer increased susceptibility to cancers of the colorectum, endometrium, stomach, small intestine, hepatobiliary system, kidney, urinary bladder, brain, and ovary. We report a thought-provoking Lynch syndrome case with a family history and simultaneous tumors in the colon, pelvis, and liver. These findings made diagnosis and treatment complicated. However, the multidisciplinary approaches followed by a medical oncologist, gynecologist, surgeon, radiologist, and pathologist led to a favorable outcome. This patient had two primary cancers of the colon and ovary, and systemic metastases of colon cancer. The loss of MSH6 protein expression was proven by immunohistochemical examination, but the germline MSH6 mutation was not detected by DNA sequence analysis. Regarding this discrepancy, some possibilities, e.g., genomic rearrangements and epigenetic modifications, which can be missed by conventional sequence analysis, were considered. Theoretically, Lynch syndrome cases with MSH6 impairment exhibit late onset and low penetrance compared to other major cases with MLH1 or MSH6 mutations. Irinotecan hydrochloride (CPT-11) has favorable effects on MMR-deficient tumor cells with high microsatellite instability, although its clinical benefit remains controversial. In this case, the first-line chemotherapy bevacizumab + FOLFIRI regimen has been effective for over a year in the partial response state. We discuss the diagnostic, therapeutic, pathological, and molecular biological characteristics of this intriguing case, indicating the importance of family history, histological assessment, and molecular biological etiology in Lynch syndrome cases presenting a complicated phenotype.

Ileal interposition (IT), in which the distal ileum is transposed isoperistaltically into the proximal jejunum, is considered as a procedure for metabolic or antidiabetes surgery. Our aim was to study the effects of IT on glycemic control, fat metabolism, and hormonal changes in obese rats with spontaneous diabetes.Animals were divided into either an IT or a sham (SH) group. They underwent an oral glucose tolerance test (OGTT) before and 4 and 8 weeks after the operation. All animals were killed 10 weeks after operation for analyses of tissue weight (liver, pancreas, epididymal fat, brown fat), immunoblotting of uncoupling protein-1 (UCP1) protein in brown adipose tissue (BAT), and fasting plasma levels of glucose, insulin, glucagon-like peptide (GLP)-1, peptide YY (PYY), glucose-dependent insulinotropic polypeptide (GIP), and leptin.Body weight increased postoperatively in both groups compared with preoperative weight, but it did not differ between the 2 groups. Eight weeks postoperatively, integrated blood glucose levels during the OGTT were decreased in IT compared with SH (P.05). Fasting plasma levels of insulin, GLP-1, and GIP did not differ between the 2 groups, but PYY levels were higher in the IT animals (P.01). The weight of epididymal and BATs, homeostasis model assessment insulin resistance, and fasting plasma leptin levels were decreased in the IT group (P.05). Expression of UCP1 was higher in IT than SH animals (P.05).These results suggest that IT improves glucose and lipid metabolism by decreasing insulin resistance and epididymal fat, and increased expression of UCP1 in BAT might be among the mechanisms responsible.

Interleukin-23 (IL-23) plays an essential role in the mucosal immune system. It has been suggested that IL-23 is able to induce carcinogenesis as well as inflammation and a recent study revealed that IL-23R is expressed in colorectal carcinoma cells. However, neither the differences in the IL-23R expression among the patients nor the concrete functions of IL-23 in colorectal carcinoma cells have been revealed. The aim of the present study was to examine the characteristics of IL-23R expression in colorectal carcinoma and the direct effects of IL-23 on colorectal cancer cells. We examined the IL-23R expression in human colorectal cancer tissue samples by immunohistochemistry. Cell proliferation and invasion assays under IL-23 stimulation were performed using cultured cells derived from colorectal cancer. ELISA and real-time PCR were used to evaluate the transforming growth factor (TGF)-β production due to IL-23 stimulation. All of the TNM stage IV patients were positive for IL-23R. IL-23R expression in the carcinoma tissue was also relatively high at the deepest point of invasion in certain cases. The proliferative and invasive activities and/or TGF-β production of DLD-1 cells increased by IL-23 stimulation, whereas no change was observed in the activities of MIP101 and KM12c cells. IL-23 directly enhanced the malignancy of the colon carcinoma cells. An autocrine mechanism via TGF-β production may underlie these effects. IL-23 is therefore a potential target for cancer immunotherapy. However, the homogeneity in IL-23R expression and the effects of IL-23 on colorectal carcinoma cells should be considered.

A 23-year-old female was referred with constipation that lasted for 2 years. Preoperative examinations revealed multiple submucosal tumors beside the anorectum, along with subcutaneous tumors in the left buttock. The pathological diagnosis was leiomyoma. Low anterior resection of the rectum with regional lymph node dissection, along with the resection of the subcutaneous tumors in the left buttock through the transdermal approach, was performed, since multiple tumor formation indicated a high malignant potential. The tumors were diagnosed as multiple leiomyomas with no malignancy. Disease categories such as intravenous leiomyomatosis, leiomyomatosis peritonealis disseminata, Alport syndrome, and Currarino syndrome have been reported to be associated with leiomyomatosis; however, the current case of "peri-anorectal leiomyomatosis" was not classified into any of these. The patient was monitored with careful checkups, and the postoperative course was satisfactory for over 5 years without any sign of recurrence or metastasis. Although the clinicopathological features of this case are quite rare and no therapeutic guidelines for such a disease have yet been established, radical resection should be considered, and the elucidation of the histogenesis of this disease will help establish future therapeutic guidelines.

The treatments and prognoses of pelvic organ carcinomas differ, depending on whether the primary tumor originated in the rectum, urinary bladder, prostate, ovary, or uterus; therefore, it is essential to diagnose pathologically the primary origin and stages of these tumors. To establish the panels of immunohistochemical markers for differential diagnosis, we reviewed 91 of the NCBI articles on these topics and found that the results correlated closely with those of the public protein database, the Human Protein Atlas. The results revealed the panels of immunohistochemical markers for the differential diagnosis of rectal adenocarcinoma, in which [+] designates positivity in rectal adenocarcinoma and [-] designates negativity in rectal adenocarcinoma: from bladder adenocarcinoma, CDX2[+], VIL1[+], KRT7[-], THBD[-] and UPK3A[-]; from prostate adenocarcinoma, CDX2[+], VIL1[+], CEACAM5[+], KLK3(PSA)[-], ACPP(PAP)[-] and SLC45A3(prostein)[-]; and from ovarian mucinous adenocarcinoma, CEACAM5[+], VIL1[+], CDX2[+], KRT7[-] and MUC5AC[-]. The panels of markers distinguishing ovarian serous adenocarcinoma, cervical carcinoma, and endometrial adenocarcinoma were also represented. Such a comprehensive review on the differential diagnosis of carcinomas of pelvic organs has not been reported before. Thus, much information has been accumulated in public databases to provide an invaluable resource for clinicians and researchers.

今回，我々は家族性大腸腺腫症（familial adenomatous polyposis；以下，FAPと略記）術後に発生したストーマ部の回腸癌を2例経験した．1例目は58歳の男性で，FAPのため31歳時に大腸全摘術，永久回腸ストーマ造設術を施行した．50歳頃からのストーマ部のポリープが直径約5cm大にまで増大した．2例目は65歳の女性で，FAPのため41歳で大腸全摘術，永久回腸ストーマ造設術を施行した．63歳頃からのストーマ部のポリープが直径3～4cm大にまで増大した．いずれの症例に対しても，腫瘤を含む回腸部分切除，回腸ストーマ再造設を行った．病理組織学上はいずれも腺癌であった．癌発生の原因は不明であるが，FAPという遺伝要因に，ストーマ部における物理的・化学的刺激などの環境要因が加わって起こる可能性が推測され，ストーマ造設・ケアにおける注意と定期的なフォローが重要と考えられた．

症例は39歳の女性で，内科的治療に抵抗性の全大腸炎型潰瘍性大腸炎に対し大腸全摘・回腸嚢肛門吻合・回腸瘻造設術を施行した．術後経過は良好で，約4か月後，回腸瘻閉鎖術を行ったが，術後腸閉塞を発症し，術後第10病日よりイレウスチューブ挿入するも改善は乏しかった．第39病日多量の下血が出現，プレショック状態となり，第41病日緊急手術を施行した．術中内視鏡検査にて小腸粘膜に多発するびらんと血液の滲出を認めたが，活動性出血は認めず，びらん部からの生検を行い，手術を終了した．病理組織学的検査所見上，潰瘍性大腸炎類似の小腸病変が示唆され，プレドニゾロンの静注を開始した．また，血管造影検査にて血管外漏出を認めた第2空腸動脈領域に塞栓術を施行した．その後下血は治まり，再手術後第27病日に退院した．これまでの文献を踏まえ，本症例の病態に対する考察を加えて報告する．

症例は69歳の女性で，強皮症の治療中に腹部膨満が出現し，二次性慢性偽性腸閉塞症（chronic intestinal pseudo-obstruction；以下，CIPと略記）および腸管嚢腫様気腫症（pneumatosis cystoides intestinalis；以下，PCIと略記）と診断された．保存的治療により一度は改善したが，その後再増悪した．食事再開とともに発熱などの症状の増悪を繰り返す状態となったため，PCI部の空腸の切除術を施行した．術後経過は良好で，食事量は増加し栄養状態の改善も図れた．CIPに対する外科的治療には議論がある．CIPにPCIを伴い経口摂取が困難な場合，PCI部の切除を考慮する必要があるが，病変が限局的であれば，強皮症のような全身病に合併した場合であっても切除の有効性は高いと思われた．

The apoptosis and antiapoptotic signaling pathways are important for regulating carcinogenesis and cancer progression, and for determining prognosis. Molecules involved in apoptosis represent potential cancer diagnostic markers and therapeutic targets. The inhibitor of apoptosis protein (IAP) family includes several important molecules involved in apoptosis that might represent such targets. Increasing evidence has demonstrated that the IAP family of proteins is integral for antiapoptotic and nuclear factor-κB signal transduction, and enhanced expression of IAPs contributes to colon carcinogenesis and its poor prognosis, as well as to drug resistance of tumors. X-linked IAP, cIAP1, cIAP2, and survivin are prognostic markers of colorectal cancer, and survivin and cIAP2 are also utilized to predict the effect of anticancer treatment in colorectal cancer patients. Novel therapies such as YM155 and LY2181308 targeting survivin, AEG35156 and phenoxodiol targeting X-linked IAP, AT-406 as a Smac mimetic, and survivin peptides are currently being evaluated in clinical trials. This report reviews the involvement of the IAP family in colorectal adenocarcinoma in order to summarize the role of the IAP family members as diagnostic and therapeutic targets, and to provide an overview of the future course of research in this area.

症例は41歳の男性で，前医にて甲状腺癌，多発肺転移の診断で手術を行い，最終診断は濾胞癌の未分化転化であった．当院で頸部への放射線治療を行っていた．腹痛，全身倦怠感を主訴に来院した．左上腹部と臍右に鶏卵大の圧痛を伴う腫瘤を触知し，血液生化学検査では炎症反応の上昇，高度の貧血，凝固線溶系の亢進を認め精査加療目的で入院となった．腹部US，CTで小腸腫瘍による腸重積症の診断となり，腹腔鏡補助下で緊急手術を施行した．術後，経口摂取が一時期可能にはなったが，徐々に全身状態が悪化し，術後第20病日に永眠された．病理組織学的診断は甲状腺未分化癌による小腸転移であった．甲状腺未分化癌が小腸に転移することはまれで，国内外での報告は，自験例を含め5例である．若干の文献的考察を加え報告する．

症例は64歳の男性で，約2年前より肛門部の腫瘍，肛門周囲からの排膿を自覚するも放置．腫瘍の増大，臀部痛のため，座位不能となり受診．精査にて，広範な臀部膿瘍をともなった肛門管癌の診断で，有茎腹直筋皮弁，植皮を付加した腹会陰式直腸切断術を施行した．病理組織学的には中分化型腺癌でAI，N1，H0，P0，Stage IIIaで根治度Aの手術であった．今回，広範な臀部膿瘍をともなった肛門管癌症例を経験したので，文献的考察を加え報告する.

症例は60歳の女性で，腹部膨満を主訴に近医を受診後，胸腹水を伴う卵巣癌の疑いで当院婦人科紹介となった．血液検査にてCA125の異常高値を認め，腹部超音波，腹部造影CT・MRIにて，子宮と接する巨大な多房性嚢胞性腫瘤で，嚢胞内に乳頭状に増殖する充実性部分を認め，卵巣癌（漿液性嚢胞腺癌）が疑われた．開腹所見は両側付属器に異常はなく，空腸から管外に発育する約20cm大の腫瘤を認め，一部は膀胱へ浸潤していたため，合併切除を行った．術後胸腹水の再出現は認めず，第15病日に退院となった．病理組織学的にはc-kit陽性で小腸gastrointestinal stromal tumor（GIST）と診断された．嚢胞性GISTは比較的まれで，CA125の上昇とPseudo-Meigs症候群と同様の機序を呈したきわめて特異な病態であったため術前診断が困難であった．Pseudo-Meigs症候群を来した小腸GISTは本邦では初めての症例である．

5-Fluorouracil (5-FU) is a key anticancer drug that for its broad antitumor activity, as well as for its synergism with other anticancer drugs, has been used to treat various types of malignancies. In chemotherapeutic regimens, 5-FU has been combined with oxaliplatin, irinotecan and other drugs as a continuous intravenous infusion. Recent clinical chemotherapy studies have shown that several of the regimens with oral 5-FU drugs are not inferior compared to those involving continuous 5-FU infusion chemotherapy, and it is probable that in some regimens continuous 5-FU infusion can be replaced by oral 5-FU drugs. Historically, both the pharmaceutical industry and academia in Japan have been involved in the development of oral 5-FU drugs, and this review will focus on the current knowledge of 5-FU anabolism and catabolism, and the available information about the various orally-administrable 5-FU drugs, including UFT, S-1 and capecitabine. Clinical studies comparing the efficacy and adverse events of S-1 and capecitabine have been reported, and the accumulated results should be utilized to optimize the treatment of cancer patients. On the other hand, it is essential to elucidate the pharmacokinetic mechanism of each of the newly-developed drugs, to correctly select the drugs for each patient in the clinical setting, and to further develop optimized drug derivatives.

Tacrolimus, a 23-member macrolide lactone discovered in 1984 from the actinomycete Streptomyces tsukubaensis, was the first macrolide immunosuppressant agent. Tacrolimus was first used for patients after liver transplantation to reduce the activity of the patient's immune system and the risk of organ rejection. Oral tacrolimus was recently approved for use in steroid-refractory moderate-to-severe ulcerative colitis in Japan. This review focuses on the clinical efficacy and safety data of tacrolimus in moderate-to-severe refractory ulcerative colitis.

腹腔内デスモイド腫瘍に対して薬物療法で良好な経過をたどった1例を経験したので報告する．症例は72歳の男性で，直腸癌術後，異時性肺転移術後の経過観察中に腹腔内腫瘍が出現，直腸癌腹腔内再発と診断し開腹術を施行した．腫瘍は小腸間膜内にあり切除可能であったが，広範な小腸合併切除を要するため切除しなかった．病理組織学的検査でgastrointestinal stromal tumorと診断されメシル酸イマチニブを投与したが，治療抵抗性で有害事象も強かった．永久標本を再検討したところβ-カテニンの核内発現が認められデスモイド腫瘍と診断された．メシル酸イマチニブを中止し高用量タモキシフェン/スリンダク併用療法を開始したところ，2か月後のCTで腫瘍の縮小が認められたが，5か月後には腫瘍径に変化は見られなくなった．手術を勧めたが患者が拒否したため，開始後2年経過した現在も継続中であり，これまでのところデスモイド腫瘍の再増大を認めていない．

A 74-year-old man was hospitalized for the investigation of fever and severe general fatigue. Laboratory examinations revealed severe leukocytosis, with a leukocyte count of 29 500/mm(3). Computed tomography, ultrasonography, and endoscopic retrograde cholangiopancreatography showed a pancreatic tumor with a diameter of 70 mm. We performed distal pancreatectomy with splenectomy and gastrectomy because there was invasion of the posterior wall of the stomach. The leukocyte count decreased to 16 900/mm(3) immediately following the operation, but it began to increase again a week later, ultimately reaching 213 000/mm(3). We measured the serum granulocyte-colony stimulating factor (G-CSF) concentration and the G-CSF expressions in the resected specimens with immunohistochemistry, the findings of which confirmed the diagnosis of G-CSF-producing pancreatic cancer. G-CSF-producing tumors are considered to be in a category of rare malignant diseases originating in various organs, which carry a poor prognosis. However, G-CSF-producing pancreatic cancer is extremely rare. On postoperative day (POD) 35, an intraabdominal recurrence was detected with marked leukocytosis, and on POD 42 the patient died without receiving postoperative cancer therapy.

In colorectal cancer (CRC) patients, metastasis to the regional lymph node (LN) is an important first step in the dissemination of cancers. To identify the genes possibly involved in LN metastasis of CRC, we analyzed LN metastases in an orthotopic implantation mouse model with 22 CRC cell lines using Matrigel, an extracellular matrix protein derived from mice sarcoma, and combined the data with gene expression profiles of cDNA microarray of those cell lines. With this implantation analysis, the incidence of LN metastasis was 60% in 228 orthotopically implanted mice and varied from 100% to 0% among the cell lines. KM12c and Clone A showed LN metastasis in all orthotopically implanted mice, but DLD-1, HCT-8, and SW948 did not show LN metastases at all. In contrast, the incidence of liver and lung metastasis in 22 CRC cell lines was 13% and 1%, respectively. Combining those data with cDNA microarray in vitro, we isolated 636 genes that were differentially expressed depending on the incidence of LN metastasis. Among those genes, the expression level of ring finger protein 125 (RNF125), previously known as an E3 ubiquitin ligase in T cell activation, was significantly different between primary tumors in Stage III CRC patients with LN metastasis and Stage II patients without LN metastasis. In conclusion, the orthotopic implantation mice model with Matrigel was useful, and we isolated candidate genes such as RNF125 that possibly play an important role in LN metastasis of CRC cells.

A 54-year-old man, with the chief complaints of hematuria, pollakisuria, and pneumaturia, was referred to our hospital, with a diagnosis of giant urinary bladder adenocarcinoma with massive invasion to the rectum. On the basis of the radiological diagnosis and findings of hematoxylin and eosin (H&E) of biopsy specimens, it was difficult to conclude whether the adenocarcinoma originated in the bladder or in the rectum. The immunohistochemical staining of the biopsy specimens showed cytokeratin 7 (CK7)(-) and CK20(+), which supported the notion that the adenocarcinoma possibly originated from the rectum. Although the prognosis of T4 bladder adenocarcinomas has been reported to be quite poor in comparison with that of transitional cell carcinomas, the postoperative prognosis of T4 rectal adenocarcinomas has been reported to be more favorable and such tumors are recommended to be surgically resected. Because no distant metastasis was detected, the patient underwent total pelvic exenteration with a reconstruction of the ileal conduit. Although the resected tumor measured 12 cm in diameter with n1 metastasis, the radial margin was cancer-negative, and the tumor was curatively resected. The immunohistochemical diagnosis of the resected tumor showed carcinoembryonic antigen(+), CK7(-), CK20(+), thrombomodulin(-), and uroplakin(-), which supported the rectal origin. At present the patient is undergoing postoperative adjuvant chemotherapy for rectal cancer.

症例は58歳, 男性. 4カ月間にわたり増悪と軽快を繰り返す右下腹部の腫瘤を主訴に近医を受診し, desmoidが疑われ当科紹介となった. 生検標本について免疫組織化学検査を追加したところ, 炎症性筋線維芽細胞性腫瘍 (inflammatory myofibroblastic tumor : 以下IMTと略記) が疑われ, 腫瘤摘出術を行った. 腫瘤は下腹部正中やや右寄りの皮下に認め, 腹直筋にも浸潤していたため, 周囲脂肪組織, 腹直筋と共に腫瘍を切除した. 腫瘍の大きさは50×55×30mmで, 切除標本では, 境界不明瞭で黄色調と白色調の部分が混在していた. 病理組織診断では, 紡錘形細胞の束状配列, 形質細胞やリンパ球などの炎症細胞や組織球が混在し, 免疫染色でHHF-35陽性, α-SMA陽性, β-catenin核染色性陰性であり, IMTと診断した. IMTは束状に増生する筋線維芽細胞にリンパ球, 形質細胞, 好酸球など種々の炎症細胞浸潤を伴い, 近年その発症機序が注目されている炎症性かつ腫瘍性の病変である.

Natural products (NPs) are evolutionarily designed and contain more complex and challenging structures than synthetic compounds. Since the 1980s, the pharmaceutical industry has gradually shifted to a strategy of developing targeted agents by screening libraries of synthetic compounds. However, NPs have recently received renewed focus as a rich repository for drug discovery. Irinotecan was developed as a derivative of camptothecin and was applied in standard regimens for metastatic colorectal cancer (CRC) worldwide. Additionally, polysaccharide K is approved for CRC in Japan and Taiwan in combination with cytotoxic agents. However, after the approval of irinotecan in 1996, no anti-cancer agents derived from NPs have been approved for CRC.This review discusses NPs that are currently under investigation for the treatment of CRC. In addition, other NPs derived as purified ingredients and crude extracts are listed and also discussed.The use of NPs for the discovery of anti-cancer agents has not been fully investigated. New technologies that are currently applied for synthetic compounds may be utilized for anti-cancer drug discovery including NPs for CRC.

Comprehensive gene-expression analysis is very useful for classifying specific cancers into subgroups on the basis of their biological characteristics; it is used both prognostically and predictively. The purpose of this study was to classify unresectable advanced or recurrent colorectal cancer (CRC) by gene-expression profiling of formalin-fixed paraffin-embedded tissues and to correlate CRC subgroups with clinicopathological and molecular features and clinical outcomes. One hundred patients with advanced or recurrent CRC were enrolled. RNA extracted from FFPE tissues was subjected to gene-expression microarray analysis. The patients were stratified into four subgroups (subtypes A1, A2, B1, and B2) by unsupervised hierarchical clustering. By use of principle-components analysis (PCA), the patients were divided into subtypes A and B on the basis of component 1 and into subtypes 1 and 2 on the basis of component 2. Subtype A was significantly enriched among patients without the KRAS mutation and with an earlier clinical stage at diagnosis. With regard to anti-EGFR therapy, progression-free survival (PFS) was better for patients in subtype A without the KRAS mutation than for those with the KRAS mutation (P = 0.047). PFS for patients without the KRAS mutation in subtype B was comparable with that for patients with the KRAS mutation (P = 0.55). Similar results were observed in a validation set. We found that gene-expression profiles enabled stratification of CRC patients into four subgroups. The efficacy of anti-EGFR therapy was correlated with component 1 from PCA. This comprehensive study may explain the heterogeneity of unresectable advanced or recurrent CRC and could be useful for identifying novel biomarkers for CRC treatment.

The aim of the present study was to compare in a prospective, multicenter trial the results early and late after pylorus-preserving gastrectomy (PPG) versus conventional distal gastrectomy (CDG) with Billroth I anastomosis for early gastric cancer. Eighty-one patients with early gastric cancer were randomized and then underwent either PPG or CDG. Duration of operation, intraoperative blood loss, days until removal of the nasogastric tube, days until start of oral intake, and decrease in body weight were studied as parameters for outcomes early after the surgery. Late results were studied in patients followed for longer than 3 years. Change in body weight, status of oral intake, symptoms suggesting early dumping syndrome, and overall satisfaction were addressed in the questionnaire. The presence of gallstones was examined with ultrasonography. There were no differences in early results between PPG and CDG. The incidence of early dumping syndrome was lower in PPG (8%) than in CDG (33%). Other late results including the incidence of gallstones were not different between the 2 groups. These results indicate that PPG is as safe as CDG and has an advantage in terms of early dumping syndrome.

下部直腸の全周性結節集簇様病変の1例について手術治療に関しての文献的考察を加え報告する.症例は60歳,女性.2001年9月の職:場検診にて直腸病変を指摘された.11月20日,手術目的で当科入院.精査の結果,下部直腸全体を占拠する結節集簇様腺管絨毛腺腫と診断した.2001年11月28日,直腸部分切除をともなう下部直腸粘膜筒状切除術を施行し,transverse coloplasty pouchを作製して直腸肛門吻合を行った.回腸瘻も造設したが6カ月後に閉鎖し,その後の経過は良好である.大きな結節集簇様病変では,内視鏡的切除が困難で,悪性成分の混在もあり得るため外科的切除の適応になる.下部直腸の全周性病変に対しては括約筋機能を温存するため粘膜筒状切除術の適応があるが,腫瘍の遺残や術後便失禁等の機能障害も報告されている.自験例では腫瘍の完全切除に加えて,良好な排便機能を保つことができた.

The RAS-RAF-MEK-ERK pathway is one of the best characterized kinase cascades. During the exploration of small molecules that inhibit RAF1 kinase, regorafenib (BAY 73-4506) was discovered as a multikinase inhibitor which demonstrated anti-cancer, anti-angiogenic, and apoptotic activities in metastatic colorectal cancer. This was not the first multikinase inhibitor discovered for the disease; indeed, before regorafenib was approved by FDA as a multikinase inhibitor for metastatic colorectal cancer in 2012, sorafenib (BAY 43-9006) had already been developed to be the first in the world as a multikinase inhibitor for malignancy. Indeed, the only difference between the two compounds is fluorine bound to its proximal phenyl ring although the end result is a considerably different profile, both as a kinase inhibitor as well as in its clinical application.In this drug discovery case history, the authors review the design, discovery, and development of both regorafenib and sorafenib from back in the 1990s. Furthermore, the authors highlight the drug's anti-cancer and anti-angiogenic properties as well as its efficacy, safety pharmacology and toxicology based on FDA documents.In order to better predict the efficacy of kinase inhibitors and to utilize them more efficiently, our understanding of drug discovery, the approaches for kinase profiling, and technologies needed for their development are paramount. Indeed, the authors believe that the field should better explore the use of predictive biomarkers that might be able to better assess these therapeutics. Pharmaceutical scientists must also consider the cost effectiveness of the targeted agents developed as a number of the drugs developed are very expensive.

A clinical trial of S-1 with leucovorin (S-1/LV) in metastatic colorectal cancer (CRC) patients demonstrated promising efficacy; however, the gastrointestinal toxicities were so severe that it has not been applied in the clinical setting. On the other hand, alternate-day administration of S-1 has been proposed to attenuate the adverse events without reducing its anticancer activity. Our present study was conducted to confirm the feasibility of alternate-day administration of S-1/LV in in vivo xenograft tumor models.Mice were treated with S-1/LV in a daily group (2 weeks of administration followed by 2 weeks of withdrawal) or an alternate-day group (administration on alternate days for 4 weeks), then the mice were killed and the xenograft tumors were resected. We compared body weight changes, condition of feces, mucosal injury and myelosuppression and assessed adverse reactions, tumor volume, tumor growth inhibition (TGI) and expression of Ki67, TUNEL, cIAP2 and XIAP to evaluate the antitumor activity and tumor apoptosis.Severe weight loss, diarrhea, mucosal injury and myelosuppression were observed only in the daily group; however, some myelosuppression was also observed in the alternate-day group. The TGI in the alternate-day group was better than in the daily group, possibly resulting from apoptosis due to the suppression of cIAP2 but not XIAP.Our findings suggest that alternate-day administration of S-1/LV for CRC treatment can achieve high antitumor activity without severe adverse reactions, and we propose that clinical trials with this regimen should be conducted in CRC patients.

Reflux gastroesophagitis is a common postgastrectomy complication after proximal gastrectomy, and conservative treatments including protease inhibitors and proton pump inhibitors are effective in most patients. Here we report a patient with severe reflux gastroesophagitis after proximal gastrectomy, in whom surgical treatment of duodenal switch was effective. An 80-year-old man complained of intractable heartburn, anorexia, and body weight loss after having undergone proximal gastrectomy, with reconstruction by esophagogastrostomy with valvuloplasty and pyloroplasty, for early gastric cancer 14 months before referral to our department. Oral administration of protease inhibitors and proton pump inhibitors was ineffective. Laboratory evaluation showed poor nutritional status. On endoscopic examination, we noted the redness, bleeding, and multiple erosions in the esophagus and the gastric remnant. He was diagnosed to have severe gastroesophagitis due to reflux of duodenal juice into the gastric remnant and esophagus. We performed duodenal switch to divert duodenal juice from the gastric remnant and esophagus; the duodenum was transected 2 cm distal to the pylorus, the duodenal distal end was closed, and a 50-cm Roux limb from the proximal jejunum was anastomosed to the proximal end of the duodenum. The heartburn disappeared postoperatively, and endoscopic examination revealed marked improvement of the reflux gastroesophagitis. One year postoperatively, the patient is free from symptoms including heartburn. His body weight increased, and laboratory data showed improvement in nutritional status. In conclusion, the duodenal switch may be surgical treatment of choice for intractable reflux gastroesophagitis after proximal gastrectomy.

Familial adenomatous polyposis is an autosomal dominant hereditary disease leading to the development of numerous colorectal polyps with malignant potential. Extra-colonic neoplasms are observed often in patients with familial adenomatous polyposis, but clinical characteristics of gastric cancer associated with familial adenomatous polyposis are not well understood. We studied the clinical characteristics of five Japanese patients who developed gastric cancer after undergoing colectomy for familial adenomatous polyposis. Gastric cancer was found on gastroduodenal endoscopy performed during postoperative follow-up in all five patients. Mean ages at the time of colectomy and at the time of diagnosis of gastric cancer were 39.2 and 58 years, respectively. Importantly, gastric fundic gland polyps were undetectable in these five patients. The mean duration between colectomy and diagnosis of gastric cancer was more than 20 years in three of five patients (mean: 19 years and 1 month). Cancers were multiple in three of five patients. Two patients developed metachronous gastric cancer in the gastric remnant. All five patients presented with well to moderately differentiated adenocarcinoma; four of the five patients were stage IA. Characteristics of the gastric cancer with familial adenomatous polyposis include a long duration between occurrence of gastric cancer and colectomy, metachronous cancers, multicentric lesions, and a high rate of well to moderately differentiated adenocarcinoma. Long-term and periodic gastroduodenal surveillance endoscopy is recommended for patients with FAP who underwent colectomy.

To evaluate the foregut and hindgut hypotheses for metabolic surgery in obese rats with diabetes. Otsuka Long-Evans Tokushima fatty rats were divided into a sham operation group, a partial duodeno-jejunal bypass (P-DJB) group, and a complete DJB (C-DJB) group. P-DJB is a model to test foregut hypothesis, whereas C-DJB is a model to test both hypotheses. We performed oral glucose tolerance tests (OGTT) on all groups at baseline, and then 4 and 8 weeks postoperatively. The rats were killed thereafter and the plasma levels of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) were measured. A separate sub-group of C-DJB rats underwent OGTT after treatment with the GLP-1 antagonist, the PYY antagonist, or saline. Marked improvement of the blood glucose control during the OGTT was noted 8 weeks after C-DJB, but not 8 weeks after P-DJB or the sham operation. The serum GLP-1 and PYY levels were higher in the C-DJB group than in the other two groups. Pretreatment with the GLP-1 antagonist increased the blood glucose levels 30 min after the OGTT in the C-DJB rats. Improvement in glucose metabolism after DJB was associated with the inflow of bile and pancreatic juice into the ileum, supporting validity of the hindgut hypothesis. GLP-1 appears to play a role in this improvement.

Background/aims Recently the role of tumor-associated macrophages (TAMs) on immunity has been variously discussed. We studied a series of cell surface antigens in TAMs in colorectal cancer tissues and their corresponding normal tissues using flow cytometry to find out prognostic indicators of these patients. Methodology We assessed the numbers of CD14+ macrophages positive for each of the cell surface antigens (CD80, CD86, HLA-DR, CD1a, CD40 and CD83) in cancer tissues and corresponding normal tissues among 31 patients with colorectal cancer, and performed the univariate and multivariate analysis to find out prognostic indicators for overall survival among the patients. Results The numbers of CD80+, CD86+ and HLA-DR+ TAMs in the cancer tissues were higher than those in corresponding normal tissues. Inversely CD40+ and CD83+ macrophages in cancer tissues were less than those in normal tissues. With the multivariate analysis, the number of CD40+ TAMs, as well as lymph node metastasis and distant metastasis, was shown to be an independent prognostic factor of colorectal cancer patients. Conclusions The dense infiltration of CD40+ TAM in colorectal cancer tissues indicates a favorable prognosis, which suggests that CD40 plays an important role in the tumor immunity of colorectal cancer.

5-FU is a core anticancer agent for GI and other malignancies, and infusional 5-FU regimens have been widely utilized. Orally administrable fluoropyrimidine prodrugs have been developed to enhance the anticancer efficacy of 5-FU and to reduce its adverse reactions.S-1 is an FT-based oral 5-FU prodrug in combination with a DPD inhibitor (CDHP) and an OPRT inhibitor (Oxo), which exerts the following effects: i) maintaining normal gut immunity, Oxo can decrease GI toxicities of 5-FU; ii) sustaining high plasma 5-FU concentrations, Cmax of FBAL after S-1 administration is extremely low, which dramatically decreases adverse reactions such as HFS, neurotoxicities and cardiotoxicities; iii) plasma 5-FU concentrations vary less extensively after S-1 administration and iv) S-1 can be safely administered to patients with DPD deficiency. Furthermore, the alternate-day S-1 administration can reduce the GI toxicities and myelotoxicities of 5-FU without reducing its anticancer efficacy, enabling patients to continue the oral administration for 6 - 12 months.Replacement of regimens with infusional 5-FU and other fluoropyrimidines by the alternate-day S-1 administration may be recommended because the latter procedure is efficient for patients while sustaining the enhanced anticancer efficacy of 5-FU and without reducing its dose intensity.

Afferent limb syndrome is a relatively rare cause of small bowel obstruction after restorative total proctocolectomy with ileal pouch-anal anastomosis for patients with ulcerative colitis or familial adenomatous polyposis.This report describes three patients who developed recurrent small bowel obstruction after ileal pouch-anal anastomosis. The bowel obstruction was caused by torsion of the ileum at the inlet of the ileal J-pouch, which was thought to be a variant of afferent limb syndrome. This variant of afferent limb syndrome is characterized by a flexible afferent limb of the pelvic pouch due to the lack adhesion of the ileum in the abdominal cavity. Preoperative diagnosis required multiple series of contrast small bowel enemas. Strictureplasty and ileopexy effectively resolved the recurrent bowel obstruction caused by this variant of afferent limb syndrome.

Ulcerative colitis is occasionally exacerbated by fulminant manifestation of colitis. Severe ulcerative colitis is usually defined based on Trulove and Witts’ criteria (Table 1) (Truelove & Witts, 1955). The incidence of severe colitis in ulcerative colitis is 5 to 15 percent (Chen et al., 1998). If the patient is not improving despite intensive medical therapy, emergency colectomy is mandatory. In such a case, the patient is often malnourished and anemic, and has received high dose of steroids; therefore, the usual option in patients with severe ulcerative colitis is subtotal colectomy and ileostomy with preservation of the rectum (Gurland & Wexner, 2002). Restorative proctectomy can be done at a later time after the patient has recovered fully and steroids have been withdrawn (Fig. 1).

症例は62歳の女性.脳動脈瘤の破裂によるクモ膜下出血と診断され,動脈瘤クリッピング術後第5病日に突然に下血が出現し,さらに4日後に大量下血がみられた.内視鏡にて下部直腸の後壁側,歯状線より3cm口側に,湧出性の出血を伴う血管の露出を認め,地図状の浅い潰瘍性病変を認めた.エタノールの局注にて止血しえたが,再出血をきたした.ショック状態となったため,緊急直腸切断術を行い救命しえた.病理組織学的には急性潰瘍の像を呈し,上皮細胞が完全に脱落し,筋層を越える組織欠損を伴い,リンパ球,好中球,形質細胞などの炎症性細胞の浸潤を認めた.また潰瘍近傍の小動脈には血栓形成や血管壊死性の変化を認めた.本症例は脳障害による中枢性のストレスが主な発生原因と考えられた.

Colorectal cancer is one of the most common malignancies worldwide and 70% of tumors are resectable, but patients with metastatic diseases cannot be cured with current treatment modalities. Inhibition of the apoptotic pathway is one of the factors that may be responsible for carcinogenesis and drug resistance, and the inhibitor of apoptosis protein (IAP) family is thought to prevent apoptosis through inhibition of direct caspases and pro-caspases. Recently an increasing amount of evidence has been accumulated regarding cIAP2 and other IAP proteins of the antiapoptotic pathway and NF-kappaB signal transduction. IAPs are abnormally regulated and expressed in the majority of human malignancies at elevated levels. As a result, they have recently been reported to be therapeutic targets. The downregulation of cIAP2 efficiently enhances apoptosis through the activation of caspase 3/7 and 5-fluorouracil (5-FU) sensitivity in colorectal cancer cells exposed to 5-FU. This report reviews the evidence for cIAP2 and other IAP molecules as a therapeutic target for malignancies including colorectal cancer. So far, the information on colorectal cancer is limited; so this study includes other malignancies as well, in order to summarize the current knowledge of drug development targeting IAP molecules and provide an overview of the future course.