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症例は57歳の女性で，約3年前より脾嚢胞性病変を指摘されていた．2度の上腹部疝痛発作を主訴に来院した．発作時腹膜刺激症状および血清CA19-9の異常高値，CTでは脾嚢胞を認めたが嚢胞壁の形態変化なく腹水はなかった．保存的加療にて一時軽快したが，症状が再燃したため腹腔鏡下脾臓摘出術を行った．組織学的には脾類上皮嚢胞と診断され，嚢胞壁の一部に出血，壊死巣を認めた．嚢胞内のCA19-9は高値で，免疫組織学的には類上皮に一致してCA19-9がびまん性に陽性であった．術後経過は良好で，術後1か月で血清CA19-9値は正常化した．嚢胞壁一部の出血，壊死により腹部疝痛発作，血清CA19-9値の上昇を来したと考えられた．血清CA19-9が高値を示した脾嚢胞の本邦報告例は28例で，これらに自験例を加えて検討した．

近年，肝細胞癌症例の高齢化に伴い，高齢者手術症例は増加傾向にある．それに伴い，術前から様々な併存症を有する症例も増加傾向にある．これら併存症を有する症例をより安全に手術することを目的に当科での肝細胞癌初回手術症例を対象に全身状態，肝局所因子の両面から術後合併症発生の予測を行った． 2002年7月から2008年12月に当科にて経験した肝細胞癌初回手術例131例のうち，何らかの処置を必要とする術後合併症を認めた51例を合併症群，合併症の無い80例を非合併症群として検討を行った． 背景肝機能の単変量解析では合併症群でコリンエステラーゼ，アルブミン，ヘパプラスチンが有意に低く，総ビリルビン，AST，ZTT，ICG-R15値が有意に高かった．多変量解析ではアルブミンが有意な因子であった．腫瘍因子では両群間に差を認めなかった．治療因子では術中出血量に有意差を認め500 g以上が合併症発生の危険因子であった．幕内基準を基に手術適応を決定していること，アルブミンが有意な因子であったことからこれらを含む肝障害度を背景肝機能因子とし，出血量を含むH-POSSUMを全身状態評価・手術因子評価とし多変量解析した結果，肝障害度BまたはC，H-POSSUM合併症発生予測50%以上はともに合併症発生の危険因子であった． これらを用い症例を4群に分類すると，予測術後合併症発生率50%未満かつ肝障害度BまたはCの症例での合併症発生率は60.0%，予測術後合併症発生率50%以上かつ肝障害度Aの症例での合併症発生率は50.0%，予測術後合併症発生率50%以上かつ肝障害度BまたはCの症例での合併症発生率は80.0%であり，予測術後合併症発生率50%未満かつ肝障害度Aの症例での合併症発生率21.6%と比較して有意に合併症発生は高率であった． 標準的な検査で算定できる肝障害度とH-POSSUMの組み合わせにより，肝切除の術前状態を正確に把握し，術後合併症を予測することが可能で，肝疾患以外の合併症を有する症例でも，術前肝障害度AでH-POSSUM 50%未満の症例では安全に肝切除手術を施行することが可能である．

今回われわれは梅の種子が原因でイレウスをきたした1例を経験したので報告する．症例は82歳，女性．8年前に子宮癌で放射線療法施行歴があった．嘔吐，腹痛を主訴に当院を受診した．イレウスと診断しイレウス管減圧による保存的加療を2週間施行したが，軽快しなかったため手術を施行した．回腸全体に放射性腸炎を認め，回腸末端の狭窄部位に梅の種子が嵌頓し穿孔しており同部位を切除した．植物種子によるイレウスの本邦報告例は自験例を含めて15例のみで非常に稀である．原因となった異物としては梅の種子が11例と圧倒的に多かった．また，13例は原因となる器質的疾患が存在していた．大腸の場合は大腸癌，小腸の場合は放射性腸炎が多かった．何らかの腸管狭窄を伴う場合は，異物が梅の種のように比較的小さくてもイレウスの原因となりうることを十分考慮する必要がある．また全例術前に異物誤嚥を確認できておらず繰り返しの問診が重要であると考えられた．

74歳，女性．当院整形外科入院中に粘血便を主訴に当科紹介受診となった．直腸診にて肛門縁より約6cmの部位に弾性硬の腫瘤を触知した．腹部CTで直腸にmulti concentric ring signを呈する腫瘤を指摘され，直腸腫瘍による腸重積が疑われた．注腸造影では腫瘍は蟹の爪様の陰影欠損として描出され，先進部はRa，Rbの境界部にありRsより重積している直腸粘膜が描出された．整復を試みたが不可能であった．以上より，腸重積症を合併した直腸癌と診断し手術を施行した．術中所見ではRsからRbにかけて腸重積が確認された．用手的整復を試みたが，重積腸管が損傷する危険性があったため整復を断念しハルトマン手術を行った．組織学的診断は高分化腺癌，SE，N1 StageIIIaであった．成人の直腸S状部癌を先進部とする成人腸重積症は非常に稀である．成人の腸重積症例は，症状・所見に乏しい慢性の経過を取ることが多く，診断時には整復困難な状態に陥っておることが予想される．そのため，無理な保存的整復には固執せずに手術を施行するべきであると考えられた．

Chemotherapy for advanced colorectal cancer has developed remarkably in recent years. However, medical practitioners are occasionally unwilling to initiate a standard multi-agent chemotherapy regimen for patients whose general condition is poor. We report the case of a patient with aggressively growing liver metastases and impending organ failure and symptoms who was successfully treated with the induction of anti-epidermal growth factor receptor( EGFR) antibody single- agent therapy. With the selection of some biomarkers, induction with anti-EGFR antibody single-agent therapy might be a beneficial therapeutic option for the treatment of colorectal cancer in patients with imminent organ failure and severe symptoms caused by local tumor progression.

KRAS mutations occur in 30–40% of all cases of human colorectal cancer (CRC). However, to date, specific therapeutic agents against KRAS-mutated CRC have not been developed. We previously described the generation of mouse models of colon cancer with and without Kras mutations (CDX2P-G22Cre;Apcflox/flox; LSL-KrasG12D and CDX2P-G22Cre;Apcflox/flox mice, respectively). Here, the two mouse models were compared to identify candidate genes, which may represent novel therapeutic targets or predictive biomarkers. Differentially expressed genes in tumors from the two mouse models were identified using microarray analysis, and their expression was compared by quantitative reverse transcription–PCR (qRT–PCR) and immunohistochemical analyses in mouse tumors and surgical specimens of human CRC, with or without KRAS mutations, respectively. Furthermore, the functions of candidate genes were studied using human CRC cell lines. Microarray analysis of 34 000 transcripts resulted in the identification of 19 candidate genes. qRT–PCR analysis data showed that four of these candidate genes (Clps, Irx5, Bex1 and Rcan2) exhibited decreased expression in the Kras-mutated mouse model. The expression of the regulator of calcineurin 2 (RCAN2) was also observed to be lower in KRAS-mutated human CRC. Moreover, inhibitory function for cancer cell proliferation dependent on calcineurin was indicated with overexpression and short hairpin RNA knockdown of RCAN2 in human CRC cell lines. KRAS mutations in CRC lead to a decrease in RCAN2 expression, resulting in tumor proliferation due to derepression of calcineurin–nuclear factor of activated T cells (NFAT) signaling. Our findings suggest that calcineurin–NFAT signal may represent a novel molecular target for the treatment of KRAS-mutated CRC.

Purpose: Oncogenic KRAS mutations are found in 40-50% of human colorectal cancers. However, specific therapeutics has not been yet available. We aimed to search new therapeutic molecular targets or biomarkers in KRAS mutated colorectal cancers. Experimental design: We generated Apcflox/flox; CDX2P9.5-G22Cre and LSL-KrasG12D; Apcflox/flox; CDX2P9.5-G22Cre mice, that had been considered as sporadic colon cancer mouse model with Kras wild and mutant, respectively. We observed the carcinogenesis at the age of 3-4 weeks by necropsy, and harvested the tumors for gene expression profiling. We compared the gene expression by Microarray (GeneChip, Affymetrix) between each 3 tumors from these mice strains. Genes with >5 fold changes between the two groups were selected as candidate genes, and subsequently narrow these down by bibliographic search for further analyses in human colorectal cancers. Result: In macroscopic findings, extensive polyps were generated in cecum and proximal colon, but not in other site of gastrointestinal tract. Tumors occurred in the both strains were considered as well differentiated adenocarcinomas in hematoxylin-eosin staining. It was confirmed that tumors generated in Apcflox/flox; CDX2P9.5-G22Cre mice had Cre-targeted Apc 580D alleles and wild-type Kras, and that tumors generated in LSL-KrasG12D; Apcflox/flox; CDX2P9.5-G22Cre mice had both Cre-targeted Apc 580D alleles and activated oncogenic KrasG12D. In the subsequent gene expression profiling, we identified 31 genes with >5 fold change in Microarray analyses. Of these, we focused on some genes that showed lower expression in Kras mutant tumor than in Kras wild type tumor. We confirmed the lower expressions of these genes in murine tumors by quantitative RT-PCR, and the lower expression in early-staged human colorectal cancers with oncogenic KRAS mutant by immunohistochemistry staining. To analyze the functions, the retroviral vectors that lead overexpression of these genes were constructed and infected to SW480 and RKO CRC cell lines. Proliferation and migration is being analyzed using these cell lines. Conclusion: We identified novel genes associated with oncogenic KRAS mutation, using the analyses of gene expression in colon cancer mouse model. Citation Format: Hiroaki Niitsu, Takao Hinoi, Yasuo Kawaguchi, Kazuhiro Sentani, Naohide Oue, Yusuke Sotomaru, Tomohiro Adachi, Yasufumi Saito, Masashi Miguchi, Masatoshi Kochi, Manabu Shimomura, Wataru Yasui, Hideki Ohdan. Gene expression profiling for oncogenic Kras mutation in mice and human colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 823. doi:10.1158/1538-7445.AM2015-823

Background & Aims: The transforming growth factor-beta (TGF-beta) signal is a tumor-suppressor pathway that is commonly inactivated in about 90% of microsatellite instability (MSI) colorectal cancer (CRC). However, there was little evidence what gene is regulated by TGF-beta signal in the multistep progression sequence of CRC. The first aim of the present study was to generate a mouse model that is null for Tgfbr2 and Apc in the colon epithelium and forms tumors in the colon. The second aim was to analyze the tumors that arose in the mice model for the purpose to identify the gene regulated by TGF-beta signal. Method & Result: Previously we have described the generation of the ‘CDX2P-G19Cre;Apcflox/flox mice’ (called Apc KO mice) which is randomly null for Apc in the colonic epithelium. By mating Tgfbr2flox/flox mice with Apcflox/flox and CDX2P9.5-G19Cre mice, we have finally generated a mouse model ‘CDX2P-G19Cre;Apcflox/flox;Tgfbr2flox/flox mice’ (called Apc+Tgfbr2 KO mice) which is null for Apc and Tgfbr2. In these model, the tumors with well differentiated adenocarcinoma arose mainly in proximal colon and most of mice died at 4 weeks age due to tumor bleeding. Therefore the mice were harvested at 3 weeks age to evaluate the development of colon tumors. Total RNAs of only cancerous tissue areas were extracted from frozen samples by the laser capture microdissection method. We compared gene expression profiles of these mice's tumors (n = 3, respectively) with Mouse Exon 1.0 ST Array (Affymetrix). Gene X expression of Apc+Tgfbr2 KO mice tumors was most highly upregurated by 9.25-fold compared with Apc KO mice (p = 0.045). The array data was validated by quantitative PCR. For human CRC samples, mutations of repetitive mononucleotide tracts in the coding regions of TGFBR2 were identified by direct sequencing. By immunohistochemical analysis, the expression of X was classified according to the percentage of stained cancer cells. The expression was considered to be ‘positive’ if ≥30% of cancer cells were stained. An analysis demonstrated that 11 (100%) of 11 mutated TGFBR2 cases were positive for X, whereas 10 (66.7%) of 15 wild type TGFBR2 cases were positive (P = 0.033), indicating that high expression of X was correlated with TGFBR2 mutation in human CRCs samples. Additionally, the cell proliferation assay revealed that silencing of X led to a significant reduction in CRC cell proliferation. Conversely, forced expression of X enhanced CRC cell proliferation in vitro. Conclusion: We have generated an in vivo model system that Apc and Tgfbr2 were inactivated only in the colonic epithelium and tumors with well differentiated adenocarcinoma arose mainly in proximal colon. The analysis of this model revealed that Gene X is regulated by a TGF-beta signal and likely promotes cell proliferation in CRC. Citation Format: Masashi Miguchi, Takao Hinoi, Manabu Shimomura, Tomohiro Adachi, Yasufumi Saito, Hiroaki Niitsu, Masatoshi Kochi, Yusuke Sotomaru, Hideaki Ijichi, Tsuneo Ikenoue, Kunitoshi Shigeyasu, Kohji Tanakaya, Kazuhiro Sentani, Naohide Oue, Wataru Yasui, Hideki Ohdan. The generation of colorectal cancer mouse model based on microsatellite instability and the identification of transforming growth factor-beta signal target. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2301. doi:10.1158/1538-7445.AM2015-2301

Introduction: Previous study showed that Synbiotics might have beneficial effect in human and animal colitis like ulcerative colitis. However, it is not well known that the influence of Synbiotics for tumorigenesis in colon cancer. The aim of present study was to investigate the influence of Synbiotics in colon cancer mouse model and colitis associated cancer mouse model. Methods: Mouse stains carrying colon epithelium-preferential Apc mutation (CPC;Apc mice), that show sporadic colorectal adenomas and carcinomas are used in this study. We also used CPC;Apc mice consumed 1%Dextran Sulfate Sodium (DSS) as colitis associated colon cancer model, developing apploximately fourfold more adenomas and adenocarcinomas than CPC;Apc not consumed. At first, 9 of CPC;Apc mice were administerated symbiotics (Probiotics (Lactobacillus) 0.1g + Prebiotics (Oligosaccharide) 10mg/0.3ml/body) between 7 and 20 age in weeks and 10 was not administerated. Secondaly, using 9 of CPC;Apc consumed 1%DSS was administrated Symbiotics, 8 of not administrated, 7 of only Probiotics, and 7 of only Prebiotics. Body weight was measured weekly. Fecal microbial analysis was performed. At sacrifice in 21 age in weeks, the small and large bowel were histologically assessed. Results: Synbiotics administration group has no differences of tumorigenesis comparing to control group (tumor incidence rate(88.9%(8/9) vs. 62.5% (5 / 8); control vs. Synbiotics; p = 0.21)average tumor number(3.2 vs. 2.1; p = 0.38), average tumor greatest diameter 5.8 vs. 5.1 mm; p = 0.51). Using CPC;Apc consumed 1%DSS, Symbiotics administration group showed inhibiting morbidity (50% (8 / 16) vs. 80% (8 / 10); control vs. Synbiotics; p = 0.04) and weight loss, and less tumor incidence than control (18.8 vs. 9.6; control vs. Synbiotics; p = 0.01). On the other hands, administration of probiotics or prebiotics alone had no significant differences of tumorigeneis. Conclusion: This data suggest that Synbiotics administration may have influence of inhibiting tumorigenesis in the colitis associated colon cancer. Citation Format: Yasufumi Saito, Takao Hinoi, Tomohiro Adachi, Manabu Shimomura, Masashi Miguchi, Hiroaki Niitsu, Masatoshi Kochi, Hideki Ohdan, Kazuhiro Sentani, Naohide Oue, Wataru Yasui. Impact of synbiotics administration on tumorigenesis of colon cancer mouse model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2303. doi:10.1158/1538-7445.AM2015-2303

Purpose Non-steroidal anti-inflammatory drugs (NSAIDs) have shown potential as chemopreventive agents against cancer formation, especially colorectal cancers. However, the mechanisms by which these drugs act are not fully understood. In this study, CPC;Apc mice, a human colorectal cancer mouse model treated with sulindac, were evaluated according to tumor initiation and prognosis and gene expression profile of the tumors were analyzed. Methods CPC;Apc mice, originating from ApcFlox/wt mice harbor a Cdx2-Cre transgene in which colorectal tumorigenesis was driven by Apc allelic loss and represent a genetic model of human colorectal cancer (CRC) were treated with control (n=20) or sulindac (160ppm, n=22) for 12 weeks and their colorectal tumors were evaluated. Gene expression analysis was performed to identify genes differentially expressed in tumor cells from sulindac-treated mice. The gene expression was validated through quantitative real-time polymerase chain reaction in vivo. Results Body weight of mice with control or sulindac was no significantly difference ( P = 0.801). However, we observed that sulindac significantly suppressed the tumor progression relative to untreated controls (the colon tumors size per mouse: median of 4.2mm, range 2.3-5.9 versus 5.0mm, range 3.1-8.7, respectively ; P = 0.007 ), but not the initiation (the colon tumor numbers per mouse: median of 1.5, range 0-5 versus 1.0 tumors, range 0-8 respectively ; P = 0.979) in CPC;Apc mice. We identified some upregulated (n = 6, >1.4 fold ) and downregulated (n = 5, >1.4 fold) target genes by microarray assay. We validated expression of these candidate genes in human colorectal cancer. Conclusion We have identified for the first time that sulindac affected tumor progression by delayed and suppressing it, but had no effect on the initiation of tumor in CRC mice model. Citation Format: Tomohiro Adachi, Takao Hinoi, Yuu Sasaki, Manabu Shimomura, Yasufumi Saito, Masashi Miguchi, Hiroaki Niitsu, Yuusuke Sotomaru, Naohide Oue, Wataru Yasui, Hideki Ohdan. Sulindac delayed and suppressed the tumor progression, was not effective on inhibition of tumor initiation in a human colorectal cancer mouse model (CPC;Apc mouse). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 250. doi:10.1158/1538-7445.AM2014-250

Malignant peripheral nerve sheath tumors (MPNSTs) are rare soft tissue tumors that arise from a peripheral nerve or exhibit nerve sheath differentiation. Most of these tumors arise on the trunk, extremities, or head and neck regions; they are very rarely located in the abdominal cavity. The patient was a 71-year-old man who was referred to our hospital for a mass and pain in the right lower abdomen. Abdominal computed tomography revealed a large (9 × 9 cm), well-circumscribed, lobulated, heterogeneously enhanced mass in the pelvis. Exploratory laparotomy revealed a large mass in the greater omentum, and the tumor was completely excised. Histopathological analysis revealed that the tumor was composed of spindle cells with high mitotic activity. On staining the tumor, positive results were obtained for S-100 but negative results were obtained for c-kit, cluster of differentiation (CD)34, α-smooth muscle actin, and desmin. These findings strongly supported a diagnosis of MPNST primarily arising from the greater omentum. To the best of our knowledge, this is the first reported case of an MPNST arising from the greater omentum. In this report, we have described the case of a patient with an MPNST arising from the greater omentum and have discussed the clinical characteristics and management of MPNSTs.

The standard operation for colitic cancer in ulcerative colitis (UC) is restorative proctocolectomy; however, sporadic colorectal cancer (CRC) can coincidentally arise in patients with UC and the optimal procedure remains controversial. Therefore, it is crucial to preoperatively determine whether the CRC in UC is a sporadic or colitic cancer. We report a case of avoiding proctocolectomy for sporadic CRC in a patient with UC based on preoperative diagnosis involving p53 immunostaining. A 73-year-old man with CRC in UC had undergone sigmoid colectomy with lymphadenectomy because of the submucosal deep invasion pathologically after endoscopic mucosal resection. The cancer was diagnosed sporadic cancer preoperatively not only based on the endoscopic, clinical, and histological patterns but also that the colon epithelium was unlikely to develop dysplasia as the circumference and unaffected UC mucosa did not detect p53 protein overexpression. Recent reports have shown that the immunohistochemical detection of p53 protein overexpression can be useful for a differential diagnosis and as a predictor of dysplasia and colitic cancer. The analysis of p53 mutation status based on immunostaining of p53 protein expression in the unaffected UC mucosa can be useful for the decision regarding a surgical procedure for CRC in patients with UC.

Lynch syndrome (LS) is a disorder caused by mismatch repair gene mutations, which have been recognized to be associated with an increased frequency of colorectal and extracolorectal tumors. However, it remains controversial as to whether total or segmental colectomy should be performed to treat colorectal cancer in patients with LS. A 58-year-old male underwent total colectomy with ileostomy for advanced transverse colon cancer. He was also found to have LS based on his characteristic family history and the findings of a preoperative examination, including a microsatellite instability analysis of past multiple metachronous cancers. The postoperative histological findings showed mucinous adenocarcinoma without lymph node metastasis, and the loss of the MSH2 protein expression was confirmed on an immunohistochemical examination. The present case provided important information on the clinical management of multiple developing metachronous colorectal cancers in patients with LS.

Background In stage IV colorectal cancer (CRC) with unresectable metastases, whether or not resection of the primary tumor should be indicated remains controversial. We aim to determine the impact of primary tumor resection on the survival of stage IV CRC patients with unresectable metastases. Methods We retrospectively investigated 103 CRC patients with stage IV colorectal cancer with metastases, treated at Hiroshima University Hospital between 2007 and 2013. Of these, those who had resectable primary tumor but unresectable metastases and received any chemotherapy were included in the study. We analyzed the overall survival (OS) and short-term outcomes between the patients who received up-front systemic chemotherapy (USC group) and those who received primary tumor resection followed by chemotherapy (PTR group). Results Of the 57 included patients, 15 underwent USC and 42 PTR. The median survival times were 13.4 and 23.9 months in the USC and PTR groups, respectively (P = 0.093), but multivariate analysis for the overall survival showed no significant difference between the two groups (hazard ratio, 1.30; 95% confidence interval (CI), 0.60 to 2.73, P = 0.495). In the USC group, the disease control rate of primary tumor was observed in 12 patients (80.0%), but emergency laparotomy was required for 1 patient. Morbidity in the PTR group was observed in 18 cases (42.9%). Conclusions The overall survival did not differ significantly between the USC and PTR groups. USC may help avoid unnecessary resection and consequently the high morbidity rate associated with primary tumor resection for stage IV CRC with unresectable metastases.