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Background Cigarette smoking, alcohol drinking and obesity are known to be risk factors for colorectal cancer. These factors may affect survival after diagnosis, but evidence has been inconsistent. We investigated subsite-specific associations between prediagnosis smoking, alcohol drinking and body mass index and survival in colorectal cancer. Methods Subjects were 1300 patients (colon 778; rectum 502; concurrent 20) with histologically confirmed colorectal cancer diagnosed during 1997–2013 at a single institution in Japan. Histories of smoking and alcohol drinking, height and prediagnosis weight were assessed using a self-administered questionnaire. Using Cox proportional hazards model, hazard ratios and 95% confidence intervals of mortality were estimated. Results During a median follow-up period of 6.7 years, 479 deaths were documented. Ever-smoking was associated with an increased risk of all-cause death among patients with colon cancer (hazard ratio: 1.47; 95% confidence interval: 1.07–2.02 compared with never-smoking). According to colon subsite, this increased risk was clear in patients with proximal colon cancer (hazard ratio: 2.09; 95% confidence interval: 1.28–3.40). There was no association between smoking and rectal cancer survival. Alcohol drinking was not associated with survival for either colon or rectal cancer. Among patients with rectal cancer, higher body mass index was associated with a lower risk of all-cause (Ptrend = 0.0006) and disease-specific death (Ptrend = 0.02). For colon cancer, lower body mass index tended to be associated with a higher risk of all-cause death (Ptrend = 0.05). Conclusions The results indicate that lifestyles identified as risk factors for colorectal cancer may impact differently on patient survival according to anatomic subsite.

More than 90% of oral cancers are histopathologically squamous cell carcinomas (SCCs). According to clinical behavior and histopathological features, we hypothesize that oral SCC can originate from either oral squamous epithelium or minor salivary glands. Here, we examined whether some oral SCCs originate from minor salivary glands, and investigated whether these tumors show particularly aggressive biological behavior. The mRNA expression profiles of samples obtained from six patients with oral floor SCC (five men, one woman; mean age, 62.7 years) were analyzed using a microarray containing 32,878 probes. The six samples were divided into two groups by clustering of expression levels of 845 probes differentially expressed in normal oral squamous epithelium and normal salivary glands. The expression profile in four cases was similar to that of normal oral squamous epithelium, and in two cases was similar to that of normal salivary glands. Furthermore, we identified nine genes that reveal the origin of the oral SCC. Subsequently, we examined the expression levels of these nine marker genes by reverse transcriptase‐polymerase chain reaction to determine the origin of 66 oral SCCs. Twelve of the 66 oral SCCs were considered to originate from minor salivary glands, and these tumors showed high metastatic potential (p = 0.044, Chi‐square test). Furthermore, SCC derived from minor salivary glands showed a poor event‐free survival rate (p = 0.017, Kaplan–Meier analysis). In conclusion, determination of the origin of oral SCC is helpful in planning treatment for patients with oral SCC., What's new? In spite of several past attempts, no distinct factors controlling the biological aggressiveness of oral squamous cell carcinoma (SCC) have been identified. Determining the origin of the cancer cells could help predict biological aggressiveness, however. Here, the authors provide evidence that oral SCC has two different origins, as mucosal or salivary SCC. Furthermore, they identify nine genes able to reveal the origin of oral SCC. Based on their expression levels, the authors determined that twelve of the 66 oral SCCs in their sample originated from minor salivary glands. Salivary SCC tumors showed high metastatic potential and poor event‐free survival rate.

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.

3521 Background: dCRT with 5-FU/MMC is a standard treatment for cStage II/III SCCA. S-1 is an oral fluoropyrimidine and has a greater effect on radiosensitivity. We conducted this trial of dCRT with S-1/MMC to determine the recommended dose (RD) of S-1 in dose-finding (phase I) part and to evaluate the efficacy and safety in confirmatory (phase II) part for cStage II/III SCCA. We reported the RD of S-1 and the 3-year survival at 2019 Gastrointestinal Cancers Symposium. We report the final data after 5-year follow-up. Methods: Eligibility criteria included histologically proven SCCA, cStage II/III (UICC 6th), PS 0-1, and age 20-80 years. dCRT consisted of MMC (10 mg/m2 on days 1, 29) and S-1 (60 mg/m2/d in level 0 and 80 mg/m2/d in level 1 on days 1-14, 29-42) with concurrent radiotherapy of 59.4 Gy/33fr. The dose-finding part adopted the 3+3 cohort design. The primary endpoint of confirmatory part was 3-year event-free survival (EFS). The sample size was 65 in the confirmatory part, with one-sided alpha of 5% and power of 80%, threshold and expected 3-year EFS as 60% and 75%. Key secondary endpoints were overall survival (OS) and progression-free survival (PFS) and colostomy-free survival (CFS), and adverse events. Final analysis was planned after 5-year follow-up for all pts. Results: From Feb/2010 to Mar/2015, 69 pts (3 in level 0 and 66 [7 in phase I and 59 in phase II] in level 1) were enrolled. Pts characteristics for level 1 were as follows: M/F, 12/54; Age, median 64 (range 33-80); cStage II/IIIA/IIIB, 29/9/28. Three in level 1 were ineligible and 63 eligible assigned to level 1 were included in efficacy analysis. In the dose-finding part, RD of S-1 was determined as 80 mg/m2/d. The complete response rate was 81% (95% CI, 69.1-90.0%) on central review. With a median follow-up of 5.4 years, 3- and 5-year EFS was 65.0% (90% CI 54.1-73.9%) and 63.4% (95% CI 50.2-73.9%). 5-year OS, PFS, and CFS were 84.1% (95% CI 72.5-91.1%), 84.1% (95% CI 72.4-91.1%), and 73.0% (95% CI 60.2-82.3%), respectively. In a univariable analysis, male sex (p = 0.045) prognosticated for poor OS and cT3 or T4 (p = 0.001), male sex (p = 0.019) and, PS 1 (p = 0.048) prognosticated for poor CFS. Nine (14.3%) of 63 pts at a dose level 1 developed recurrence or disease progression. Locoregional recurrence only and distant metastasis were observed in 1 pts (1.6%) and 8 pts (12.7%) respectively. Among all treated 65 pts, only 5 pts (7.7%) showed grade 3 late toxicities including jejunum obstruction, jejunum ulcer, proctitis, lower gastrointestinal hemorrhage, anal pain, radiation dermatitis, and ureteral stenosis. No Grade 4 or 5 late toxicities were observed. Conclusions: dCRT with S-1/MMC showed acceptable toxicities and favorable 5-year survival and could be a possible treatment option for pts with locally advanced SCCA. Clinical trial information: jRCTs031180002.

We have previously demonstrated that the stromal cell‑derived factor (SDF‑1)/CXCR4 system is involved in the metastasis of head and neck cancer. Additionally, it has been revealed that the blockade of CXCR4 by subcutaneous daily injection with AMD3100, a CXCR4 antagonist, may be effective in preventing metastasis in CXCR4‑related head and neck cancer. Recent investigations have suggested that AMD070, a novel orally bioavailable inhibitor of CXCR4, may be minimally invasive compared with AMD3100. In the present study, we examined the effect of AMD070 on metastasis induced by the SDF‑1/CXCR4 axis in B88‑SDF‑1 oral cancer cells, which express high levels of SDF‑1 and CXCR4. Although treatment with AMD070 did not affect the anchorage‑dependent growth of B88‑SDF‑1 cells, it significantly suppressed the anchorage‑independent growth. Moreover, the SDF‑1/CXCR4‑dependent migration and invasion of B88‑SDF‑1 cells was significantly inhibited following treatment with AMD070. Subsequently, we performed an experimental therapy using AMD070 to prevent the distant metastasis of B88‑SDF‑1 cells in vivo. Daily oral administration of AMD070 significantly inhibited the lung metastasis of B88‑SDF‑1 cells in nude mice. These results indicated that AMD070 could be useful as a novel orally bioavailable inhibitor of oral cancer metastasis.

686 Background: dCRT with 5-FU/MMC is a standard treatment for cStage II/III SCCA. S-1 is an oral fluoropyrimidine and has a greater effect on radiosensitivity. We conducted this trial of dCRT with S-1/MMC to determine the recommended dose (RD) of S-1 in phase I part (P I) and to evaluate the efficacy and safety in phase II part (P II) for cStage II/III SCCA. When the primary endpoint in P II part is proven to be satisfactory, we can regard this combined treatment as the new standard treatment. Methods: Eligibility criteria included histologically proven SCCA, cStage II/III (UICC 6th), PS 0-1, and age 20-80 years. dCRT consisted of MMC (10 mg/m2 on days 1, 29) and S-1 (60 mg/m2/d in level 0 and 80 mg/m2/d in level 1 on days 1-14, 29-42) with concurrent 3-dimensional RT of 59.4 Gy/33fr. The P I adopted the 3+3 cohort design. The primary endpoint of P II was proportion of 3-year event-free survival (% 3-year-EFS). The sample size was 65 in the P II, with one-sided alpha of 5% and power of 80%, threshold and expected % 3-year EFS as 60% and 75%. Results: From Feb/2010 to Mar/2015, 69 pts (3 in level 0 and 66 [7 in P I and 59 in P II] in level 1) were enrolled. Pts’s backgrounds for level 1 were as follows: M/F, 12/54; Age, median 64 (range 33-80); cStage II/IIIA/IIIB, 29/9/28. Three in level 1 were ineligible and 63 eligible assigned to level 1 were included in efficacy analysis. In the P I, considering the details of DLTs, RD of S-1 was determined as 80 mg/m2/d. In the 63 eligible of level 1, %3-year EFS was 65.0% (90% CI 54.1-73.9%). % 3-year OS, PFS, and colostomy-free survival were 87.3% (95% CI 76.2-93.4%), 85.7% (74.3-92.3%), and 76.2% (63.7-84.9%), respectively. The complete response rate was 81% on central review. Among 65 pts receiving level 1 dCRT, common grade 3 or 4 acute toxicities were leukopenia (63.1%), neutropenia (40%), diarrhea (20%), radiation dermatitis (15.4%), and febrile neutropenia (3.1%). Only 6 (9.2%) showed grade 3 late toxicities. No treatment-related deaths were observed. Conclusions: Although dCRT with S-1/MMC showed acceptable toxicities and favorable 3-year survival, this study did not meet its primary endpoint. Clinical trial information: UMIN000003237.

Oral cancer cells have a significantly augmented nuclear factor-κB (NF-κB) activity and the inhibition of this activity suppresses tumor growth. Bortezomib is a proteasome inhibitor and a drug used for molecular-targeted therapy (targets NF-κB). In this study, we investigated whether bortezomib would be effective as an inhibitor of proliferation and a radiosensitizer for the treatment of oral cancer. We demonstrate that bortezomib inhibits NF-κB activity and cell proliferation. The combined treatment with bortezomib and radiation (RT) suppressed NF-κB activity and cell growth in vitro and in vivo compared with RT treatment alone. To investigate the mechanisms by which bortezomib suppresses tumor growth, the expression of signaling molecules downstream of NF-κB were examined by ELISA. The combined treatment significantly inhibited the radiation-induced production of angiogenic factors and decreased the number of blood vessels in the tumor tissues. Although the expression of anti-apoptotic proteins was upregulated by RT, bortezomib downregulated the RT-induced expression of these proteins. Moreover, the expression of cleaved poly(ADP-ribose) polymerase in vitro and in vivo was enhanced by bortezomib, indicating that bortezomib inhibits tumor growth by inducing apoptosis. This study clearly demonstrates that bortezomib significantly inhibits tumor growth and that the combined treatment with bortezomib and RT results in a significant inhibition of tumor growth. The mechanisms underlying the inhibition of tumor growth by bortezomib include the suppression of angiogenesis and the induction of apoptosis. A novel molecular targeting therapy including bortezomib may be effective in the treatment of oral cancer by suppressing NF-κB activity.

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.

Salivary gland cancers (SGCs) frequently metastasize to cervical lymph nodes and distant organs. Currently, the mechanisms responsible for the metastatic behavior of SGC cells are not fully understood. We previously demonstrated that the stromal cell-derived factor-1 (SDF-1; also known as CXCL12)/CXCR4 system is involved in the establishment of metastasis in oral squamous cell carcinoma. In the present study, we investigated the role of CXCR4 in the metastatic behavior of SGCs. We examined the expression of CXCR4 mRNA and protein in human SGC cell lines by quantitative RT-PCR and western blotting, respectively. The expression of CXCR4 mRNA and protein were frequently upregulated in 5 out of 6 SGC cell lines. Functional CXCR4 expression was demonstrated by the ability of these SGC cell lines to migrate toward an SDF-1 gradient. SDF-1 rapidly activated extracellular signal-regulated kinase (ERK)1/2 in SGC cell lines. Immunohistochemical analysis revealed that CXCR4 protein expression was detected in either the nucleus or cytoplasm of cancer cells in 16 out of 20 tissues of adenoid cystic carcinoma (ACC) and in 4 out of 6 tissues of mucoepidermoid carcinoma, which are representative of SGC. Furthermore, ACC cell lines exhibited dramatic metastasis to the lung following intravenous inoculation, whereas AMD3100, a CXCR4 antagonist, significantly inhibited lung metastasis of the cells, ameliorated body weight loss and improved the survival rate of tumor-bearing nude mice. These results indicate that CXCR4 expression contributes to the metastatic potential of SGCs.

Docetaxel (DOC) and 5-fluorouracil (5-FU) are important anticancer agents widely used in the treatment of a variety of cancers including oral squamous cell carcinoma (OSCC). The purpose of this study was to determine the antitumor efficacy of the sequential administration of DOC and 5-FU against OSCC cells (B88 and CAL27 cells) in vitro and in vivo. In in vitro growth inhibition assays, sequential treatment with DOC followed by 5-FU was more effective in inhibiting cancer cell growth than 5-FU followed by DOC, single treatment with DOC or 5-FU, or combined treatment with DOC and 5-FU. Furthermore, DOC followed by 5-FU significantly inhibited tumor growth in vivo compared to 5-FU followed by DOC. To understand the mechanisms underlying the enhanced growth inhibitory effect of the administration sequence, DOC followed by 5-FU, we examined the expression of 5-FU metabolic enzymes such as thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and orotate phosphoribosyl transferase (OPRT), which were known to regulate the antitumor effect of 5-FU, by real-time RT-PCR and western blot analysis. Downregulation of TS and DPD expression and upregulation of OPRT expression were induced by DOC treatment, suggesting that DOC enhanced the efficacy of 5-FU by altering the expression of its metabolic enzymes. These results indicate that sequential treatment with DOC followed by 5-FU could be a promising therapeutic strategy for oral cancer.

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．

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.

We updated the tRNADB-CE by analyzing 939 complete and 1301 draft genomes of prokaryotes and eukaryotes, 171 complete virus genomes, 121 complete chloroplast genomes and approximately 230 million sequences obtained by metagenome analyses of 210 environmental samples. The 287 102 tRNA genes in total, and thus two times of the tRNA genes compiled previously, are compiled, in which sequence information, clover-leaf structure and results of sequence similarity and oligonucleotide-pattern search can be browsed. In order to pool collective knowledge with help from any experts in the tRNA research field, we included a column to which comments can be added on each tRNA gene. By compiling tRNAs of known prokaryotes with identical sequences, we found high phylogenetic preservation of tRNA sequences, especially at a phylum level. Furthermore, a large number of tRNAs obtained by metagenome analyses of environmental samples had sequences identical to those found in known prokaryotes. The identical sequence group, therefore, can be used as phylogenetic markers to clarify the microbial community structure of an ecosystem. The updated tRNADB-CE provided functions, with which users can obtain the phylotype-specific markers (e.g. genus-specific markers) by themselves and clarify microbial community structures of ecosystems in detail. tRNADB-CE can be accessed freely at http://trna.nagahama-i-bio.ac.jp.

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.

We have previously demonstrated that the stromal cell-derived factor (SDF)-1/CXCR4 system is involved in the metastasis of head and neck cancer. Additionally, it has been shown that the blockade of CXCR4 by subcutaneous daily injection with AMD3100, a CXCR4 antagonist, may be effective in preventing metastasis in CXCR4-related head and neck cancer. Recent investigations have suggested that AMD070, a novel orally bioavailable inhibitor of CXCR4, may be minimally invasive compared with AMD3100. In the present study, we examined the effect of AMD070 on metastasis induced by the SDF-1/CXCR4 axis in B88-SDF-1 oral cancer cells, which express high levels of SDF-1 and CXCR4. Although treatment with AMD070 did not affect the anchorage-dependent growth of B88-SDF-1 cells, it significantly suppressed the anchorage-independent growth. Moreover, the SDF-1/CXCR4-dependent migration and invasion of B88-SDF-1 cells was significantly inhibited following treatment with AMD070. Subsequently, we performed an experimental therapy using AMD070 to prevent the distant metastasis of B88-SDF-1 cells in vivo. Daily oral administration of AMD070 significantly inhibited the lung metastasis of B88-SDF-1 cells in nude mice. Furthermore, AMD070 treatment did not induce body weight loss despite the tumor bearing-condition of the mice. In addition, we could not detect the apparent macroscopic organ abnormalities associated with the daily oral administration of AMD070. These results indicated that AMD070 could be useful as a novel orally bioavailable inhibitor of oral cancer metastasis. Citation Format: Nobuyuki Kuribayashi, Daisuke Uchida, Makoto Kinouchi, Kyoko Kuribayashi, Tomonori Hasegawa, Shuma Yagisawa, Hitoshi Kawamata. Effect of a novel orally bioavailable CXCR4 inhibitor, AMD070, on the metastasis of oral cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4191.

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.

Currently 5-fluorouracil (5-FU) plays a central role in the chemotherapeutic regimens for colorectal cancers and thus it is important to understand the mechanisms that determine 5-FU sensitivity. The expression profiles of human colon cancer cell line DLD-1, its 5-FU-resistant subclone DLD-1/FU and a further 21 types of colon cancer cell lines were compared to identify the novel genes defining the sensitivity to 5-FU and to estimate which population of genes is responsible for 5-FU sensitivity. In the hierarchical clustering, DLD-1 and DLD-1/FU were most closely clustered despite over 100 times difference in their 50% inhibitory concentration of 5-FU. In DLD-1/FU, the population of genes differentially expressed compared to DLD-1 was limited to 3.3%, although it ranged from 4.8% to 24.0% in the other 21 cell lines, thus indicating that the difference of 5-FU sensitivity was defined by a limited number of genes. Next, the role of the cellular inhibitor of apoptosis 2 (cIAP2) gene, which was up-regulated in DLD-1/FU, was investigated for 5-FU resistance using RNA interference. The down-regulation of cIAP2 efficiently enhanced 5-FU sensitivity, the activation of caspase 3/7 and apoptosis under exposure to 5-FU. The immunohistochemistry of cIAP2 in cancer and corresponding normal tissues from colorectal cancer patients in stage III revealed that cIAP2 was more frequently expressed in cancer tissues than in normal tissues, and cIAP2-positive patients had a trend toward early recurrence after fluorouracil-based chemotherapy. Although the association between drug sensitivity and the IAP family in colorectal cancer has not yet been discussed, cIAP2 may therefore play an important role as a target therapy in colorectal cancer.

Background Alternative splicing is a molecular mechanism by which different combinations of exons can be alternatively spliced to produce different mRNA isoforms. Recently, several databases have been published to predict the alternative splicing of mRNA; cancer-specific alternative splicing has also been predicted with these databases. Those variants may be potentially useful targets for cancer therapy, however, the accuracy and veracity of these databases have yet to be confirmed. Methods In this study, we analyzed 17 genes by reverse transcriptase-polymerase chain reaction (RT-PCR) that were predicted to have cancer-specific alternative splicing by using the splicing database, the Alternative Splicing Annotation Project (ASAP) by Lee et al, between 38 cancer cell lines from various organs and 9 corresponding normal tissues. By designing 2 types of primer sets for RT-PCR including (1) primers flanking the alternatively spliced exons and (2) primers spanning the exon/exon junctions, cancer-associated splicing variants were investigated. Results The alternatively splicing events were detected in 15 of 17 genes (88%); 35 of 43 variants (81%) were detected successfully with RT-PCR. Among these variants, M-RIP, HYAL2, CDCA1, and MSMB genes showed differential expressions between cancer cell lines and corresponding normal tissues. Furthermore, RT-PCR with surgically resected gastric cancer tissues (diffuse type, 6; intestinal type, 4) confirmed that 2 variants of CDCA1 were upregulated in cancer tissues, whereas both variants of MSMB were expressed predominantly in normal tissues. Conclusion Alternative splicing variants, especially in CDCA1, were detected in this study and may be potentially useful as diagnostic markers and/or novel targets for anticancer therapy.

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．

短期間で増悪した原発性アミロイドーシスに伴う続発性慢性偽性腸閉塞症（secondary chronic intestinal pseudo-obstruction；以下，Secondary CIP）を経験した．症例は56歳の男性で，2004年より腹部膨満感が出現し近医で特発性CIPと診断された．2005年初めより症状が増悪したため，イレウスチューブを5か月間以上留置するも改善せず，2006年に当科紹介・入院となった．イレウスチューブから連日2,000 ml以上の排液を認め，イレウスチューブの再挿入時に十二指腸穿孔が疑われ緊急手術となった．術中所見では十二指腸損傷は同定できなかったが，Treitz靭帯から回盲弁の口側100 cmまでの小腸の著明な拡張，腸管壁の脆弱化が認められたため，小腸を約300 cm切除し，空腸瘻を作成した．病理組織学的検査所見で原発性アミロイドーシスに続発するCIPの診断となったが，術後半年で原病死した．原発性アミロイドーシスに伴うCIPは予後不良であり，対処療法しかないのが現状である．

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.

The goal of this study was to clarify the dynamics of oxygenation (partial pressure of oxygen, pO(2)) in SCC VII murine tumors in mice after X-ray irradiation.Changes in pO(2) in tumors were measured by 1.2-GHz electron paramagnetic resonance (EPR) spectroscopy after they were exposed to various doses of irradiation. The pO(2) in tumors was followed for up to six days after irradiation at doses of 0, 5, 10, 15, and 20 Gy. Paramagnetic crystals were used as an oximetry probe and implanted into normal or tumor tissues in mice for prolonged periods.The pattern of tumor oxygen after a single dose of radiation with the 5-Gy dose was different from those with other doses (10, 15, and 20 Gy). After 5 Gy, pO(2) increased rapidly (P0.01, Student's t test) and then returned to the level observed before irradiation by 12h (P0.01). In contrast, after 10, 15, or 20 Gy, pO(2) increased rapidly by 6h after irradiation, continued to increase until at least 24h (P0.01), and then gradually decreased.In tumors that received 5 Gy, post-irradiation increases in pO(2) at 4h after irradiation were detected by EPR oximetry (P0.01) noninvasively.

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.

Novel tools are needed for comprehensive comparisons of interspecies characteristics of massive amounts of genomic sequences currently available. An unsupervised neural network algorithm, Self-Organizing Map (SOM), is an effective tool for clustering and visualizing high-dimensional complex data on a single map. We modified the conventional SOM, on the basis of batch-learning SOM, for genome informatics making the learning process and resulting map independent of the order of data input. We generated the SOMs for tri- and tetranucleotide frequencies in 10- and 100-kb sequence fragments from 38 eukaryotes for which almost complete genome sequences are available. SOM recognized species-specific characteristics (key combinations of oligonucleotide frequencies) in the genomic sequences, permitting species-specific classification of the sequences without any information regarding the species. We also generated the SOM for tetranucleotide frequencies in 1-kb sequence fragments from the human genome and found sequences for four functional categories (5' and 3' UTRs, CDSs and introns) were classified primarily according to the categories. Because the classification and visualization power is very high, SOM is an efficient and powerful tool for extracting a wide range of genome information.

症例は48歳の女性. 2002年11月に右乳癌に対して右胸筋温存乳房切除術(Bt+Ax)を施行された.組織学的所見はpapillo-tubular carcinoma, T2, N0, M0, Stage IIA, ER(-), PgR(-), Hercep Test 3(+)であった.経過中他の腫瘍マーカーは正常であったが2004年4月に血清HER-2/neu蛋白値の上昇を認め腹部CTにて肝外側区域に腫瘍性病変を指摘された.乳癌肝転移の診断で2004年6月肝外側区域切除術を施行,術後補助療法としてTrastuzumabおよびDocetaxel併用療法を施行した.術後1年を経ても再発の所見を認めていない. 血清HER-2/neu蛋白値はHER-2陽性乳癌に対しては既存の腫瘍マーカーより特異度や感度が高く,術後局所再発などの検出や, Trastuzumabに対する治療効果も予測できる可能性がある.また,乳癌肝転移は肝切除のみでの転移巣制御は困難で,血清HER-2/neu蛋白高値の場合にはTrastuzumabを中心とした術後補助療法が適応になるものと思われた.

症例は60歳の男性.排尿時重苦感を主訴に当院受診,腹部超音波検査および腹部CT検査で右水腎症および回盲部腫瘤を指摘され精査加療目的で当科入院となった.入院時には腹部に圧痛を認めず,血液検査所見でも異常所見を認めなかった.大腸内視鏡検査では盲腸に表面平滑で粘膜下腫瘍様の隆起性病変を,腹部CT検査では回盲部に辺縁不明瞭な腫瘤を認めこの部位で右尿管を圧迫しており右水腎症の状態であった.以上の所見より虫垂原発の悪性腫瘍と診断し結腸右半切除術およびS状結腸部分切除術を施行した.病理組織検査では腫瘍と思われた部分は線維性肉芽組織で,虫垂開口部の隆起性病変は間質の線維化による非腫瘍性病変と診断された.回盲部腫瘤性病変の良悪性の鑑別に際しては虫垂入口部の隆起性病変や水腎症は虫垂炎の一つの所見であることを念頭に置き,術中迅速組織診を積極的に施行して術式を決定する必要があると思われた.

昭和53年 (1978年) 1月から, 平成14年 (2002年) 12月までの25年間に白河厚生総合病院において808例の大腸癌の手術を施行した。切除数は, 713例 (切除率88.25%), 治癒切除数593例 (治癒切除率73.4%) であった。内訳は結腸癌446例, 直腸癌369例 (7例は多発癌) で, 男女別では, 男性429例, 女性379例であった。臨床的病期および組織学的病期による進行程度はそれぞれ, stage IIIa, stage IIが多かった。切除例の5年生存率は67.2%, 治癒切除例は79.5%であった。

With the increasing amount of available genome sequences, novel tools are needed for comprehensive analysis of species-specific sequence characteristics for a wide variety of genomes. We used an unsupervised neural network algorithm, a self-organizing map (SOM), to analyze di-, tri-, and tetranucleotide frequencies in a wide variety of prokaryotic and eukaryotic genomes. The SOM, which can cluster complex data efficiently, was shown to be an excellent tool for analyzing global characteristics of genome sequences and for revealing key combinations of oligonucleotides representing individual genomes. From analysis of 1- and 10-kb genomic sequences derived from 65 bacteria (a total of 170 Mb) and from 6 eukaryotes (460 Mb), clear species-specific separations of major portions of the sequences were obtained with the di-, tri-, and tetranucleotide SOMs. The unsupervised algorithm could recognize, in most 10-kb sequences, the species-specific characteristics (key combinations of oligonucleotide frequencies) that are signature features of each genome. We were able to classify DNA sequences within one and between many species into subgroups that corresponded generally to biological categories. Because the classification power is very high, the SOM is an efficient and fundamental bioinformatic strategy for extracting a wide range of genomic information from a vast amount of sequences.[Supplemental material is available online atwww.genome.org.]

福島県県南地域を診療圏とする白河厚生総合病院外科における胃癌手術例の臨床的検討を行った。昭和56年 (1981年) 1月から, 平成12年 (2000年) 12月までの20年間に1,132例の胃癌の手術を施行した。切除数は1,023例 (切除率90.4%), 治癒切除数894例 (治癒切除率79.0%) であり, 切除例の5年生存率は68.3%, 治癒切除例は75.6%であった。20年間の症例の前期10年間と, 最近の10年間での比較では, 切除数は減少しているが, 切除率は上昇した。進行程度, 組織分類, 深達度, リンパ節転移などで早期のものが増え, 5年生存率も次第に向上してきた。

We have previously demonstrated that stromal cell-derived factor (SDF)-1/CXCR4 system enhances the metastases of oral cancer cells via induction of mGluR5. In this study, we examined the transcriptional regulation of mGluR5 induced by the SDF-1/CXCR4 system, using oral cancer cells, B88, which express functional CXCR4 and have highly metastatic potentials. mGluR5 was markedly induced both by the exogenous SDF-1 addition and overexpression of SDF-1 in B88 cells. These induction was completely inhibited by a MEK inhibitor, U0126, and partially inhibited by a PI3K inhibitor, wortmannin. Furthermore, these inhibitors significantly inhibited the SDF-1/CXCR4 dependent cell-migration in the presence or absence of mGluR5 agonist, DHPG. Recently, several investigators demonstrated that activation of the ERK1/2 pathway is responsible for the transcription of several cancer-associated microRNAs (miRNAs). Thus, we performed miRNA microarray in SDF-1 stimulated B88 cells. we isolated miR-30 family which has predictive binding sites in 3'-UTR of mGluR5 mRNA in silico analysis. We now analyze the regulation of these miRNA by MEK/ERK1/2 and PI3K/Akt pathway. Citation Format: Nobuyuki Kuribayashi, Daisuke Uchida, Makoto Kinouchi, Sayaka Izumi, Kyoko Kuribayashi, Hitoshi Kawamata. Mechanism of transcriptional regulation of metabotropic glutamate recepter-5 induced by the CXCR4 signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1328. doi:10.1158/1538-7445.AM2017-1328

We have demonstrated that CXCR4 system is involved in the metastatic process of oral cancer. Recently, we identified the miR-518c-5p as a downstream target of the CXCR4 system. In this study, we examined the function of miR-518c-5p on the metastasis of oral cancer. We transfected miR-518c expression vector into oral cancer cells, B88 and CAL27, and isolated stable transfectants, B88-518c and CAL27-518c, respectively. The growth and migration of both cells were significantly enhanced in compared with those of mock cells. LNA-based miR-518c-5p inhibitor significantly impaired the enhanced cell growth and migration of these cells, indicating that these phenomena were dependent on the expression of miR-518c-5p, not on that of miR-518c-3p. Next, we examined the function of miR-518c-5p in vivo. miR-518c or mock transfectants were inoculated into the masseter muscle or the blood vessels of nude mice. Tumor volume, lymph nodes metastasis, and lung metastasis were significantly increased in the mice inoculated with miR-518c transfectants. Furthermore, we examined the mRNA expression induced by miR-518c-5p using B88 cells and B88-518c cells by cDNA microarray analysis. Consequently, some of the genes involved in the cell growth and metastasis were upregulated in the B88-518c cells. These results indicate that CXCR4 system regulates the metastases of oral cancer via induction of miR-518c-5p. Citation Format: Makoto Kinouchi, Daisuke Uchida, Nobuyuki Kuribayashi, Yuske Komiyama, Shuji Tsuchida, Hitoshi Kawamata. MicroRNA-518c-5p promotes the metastasis of oral cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2535. doi:10.1158/1538-7445.AM2017-2535

We have previously demonstrated that a stromal cell-derived factor-1 (SDF-1; CXCL12)/CXCR4 system is involved in the establishment of metastasis in oral cancer. Recently, small non coding RNAs, microRNAs (miRNAs) have been shown to be involved in the metastatic process of several types of cancers. However, the miRNAs that contribute to metastases induced by the SDF-1/CXCR4 system in oral cancer are largely unknown. In this study, we examined the metastasis-related miRNAs induced by the SDF-1/CXCR4 system using B88-SDF-1 oral cancer cells, which exhibit functional CXCR4 and distant metastatic potential in vivo. Through miRNA microarray analysis, we identified the upregulation of miR-518c-5p in B88-SDF-1 cells, and confirmed the induction by real-time PCR analysis. Although an LNA-based miR-518c-5p inhibitor did not affect cell growth of B88-SDF-1 cells, it did significantly inhibit the migration of the cells. Next, we transfected a miR-518c expression vector into parental B88 cells and CAL27 oral cancer cells and isolated stable transfectants, B88-518c and CAL27-518c cells, respectively. The anchorage-dependent and -independent growth of miR-518c transfectants was significantly enhanced compared with the growth of mock cells. Moreover, we detected the enhanced migration of these cells. The LNA-based miR-518c-5p inhibitor significantly impaired the enhanced cell growth and migration of miR-518c transfectants, indicating that these phenomena were mainly dependent on the expression of miR-518c-5p. Next, we examined the function of miR-518c-5p in vivo. miR-518c transfectants or mock transfectants were inoculated into the masseter muscle or the blood vessels of nude mice. Tumor volume, lymph nodes metastasis, and lung metastasis were significantly increased in the mice inoculated with the miR-518c transfectants. These results indicated that miR-518c-5p regulates the growth and metastasis of oral cancer as a downstream target of the SDF-1/CXCR4 system.