肛門から出血する病気を集める事を目的として開設された肛門病センターが大腸疾患の増加に伴い大腸肛門病センターとなり,現在では年間の新患外来患者数は6000名を超え,手術例も肛門疾患2200例の他に直腸癌100例,結腸癌73例,肛門管癌14例,UC19例,crohn215例,機能性疾患である直腸脱70例,直腸瘤7例を数える.
このようなセンターとのかかわりを通して私自身が経験した肛門病診療の流れを振り返る.

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During the last decade several advances have been achieved regarding the etiology, diagnosis and treatment of anal disorders. Laser Doppler flowmetry, for example, has revealed that increased tone of the internal anal sphincter is associated with a decrease in anodermal bloodflow, especially at the posterior midline. Treatment of chronic anal fissure by lateral internal sphincterotomy results in a significant pressure drop with a concomitant increase of anodermal bloodflow at the fissure site. Based on these and other findings chronic anal fissures are considered at present as ischemic ulcers. It has been shown that nitric oxide mediates the relaxation of the internal anal sphincter. The activity of this sphincter can be influenced by local application of exogenous NO-donors such as GTN and ISDN. The potential role of these drugs in the treatment of anal fissure will be discussed. Headache is the most important drawback of these NO-donors. Therefore attention is focused on other agents such as Botox, Indoramin, Calcium channel blockers and L-Arginine.
Other advances have been achieved in the diagnosis and treatment of perianal fistulas. Preoperative assessment of fistulas has been improved significantly since the introduction of hydrogen peroxide enhanced endoanal ultrasound and endoanal MRI. For the treatment of high transsphincteric fistulas new techniques have been developed in order to minimize sphincter damage and to prevent continence disturbances. The transanal advancement flap repair, the muscle filling procedure according to Iwadare and the use of fibrin glue represent these new techniques. For patients with fecal incontinence several new treatment modalities are now available such as dynamic graciloplasty, sacral neuro-modulation, implantation of silicone biomaterial and the Secca procedure. All these new techniques illustrate that many advances in anal disorders have been achieved in recent years.

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Numerous approaches have been focused on developing new tools for the detection of colorectal cancer at an earlier stage, or extending a further insight of raidio-, and chemo-sensitivity, which gives a clue to increase therapeutic efficacy and/or predict response. We herein introduce our approaches and achieves so far.
Early Detection of Colorectal Cancers
Microarray technologies can be used for mutation detection in DNAs from cancer tissues, stools, and cancer cell lines. For early detection of colorectal cancers by mutational analysis, we have developed β3-catenin, x-ras, and BRAF oligonucleotide microarrays, and several microarrays to detect mutations in stool DNA are under developing. We also developed a new approach for a robust microsatellite instability (MSI) analysis. Five Bethesda microsatellite markers (BAT-25, BAT-26, D5S346, D2S123, and D17S250) for MSI have been tested by denaturing high-performance liquid chromatography (DHPLC) analysis. It took just 9 min per PCR product to determine MSI using this new protocol. Our microarrays and new MSI analysis mighty be useful for colorectal cancer diagnosis at an earlier stage.
Chemoradiotherapy of Rectal Cancer
It was recently reported that microarray gene expression profiling was capable of response prediction of rectal adenocarcinomas to preoperative chemoradiotherapy. It will be very helpful to predict the responsiveness of chemoradiotherapy by using microarray expression profiling. High sensitivity and specificity of response prediction was obtained in microarray analysis. We are also performing microarray analysis to predict responsiveness of rectal cancers in preoperative chemoradiotherapy.
Chemotherapy of Advanced Colorectal Cancer
5-Fluorouracil (5-FU) has been mainstay of chemotherapeutic option for patients with advanced colorectal cancer. However, 5-FU resistance becomes a problem for chemotherapy. Thymidylate synthase (TS) has been focused as an important molecule leading to 5-FU resistance. High TS protein or mRNA levels in tumors have tended to be associated with a worse response to 5-FU. Nevertheless, recent reports have shown the opposite i. e., level of TS protein in primary tumors does not aid in predicting outcome or response to 5-FU. Thus, it is now generally accepted that other, yet unknown mechanisms have to be involved in resistance to 5-FU-based chemotherapy. Because understanding of these unknown mechanisms by which tumors become resistant to 5-FU is an essential step towards predicting or overcoming that resistance, we have been screening new targets linked to 5-FU resistance by means of 2-DE-based proteomics. From this assessment, we were able to confirm not only that 5-FU resistance can be mediated by abnormal regulation of single protein such as mitochondrial F1F0-ATP synthase, metabotropic glutamate receptor 4, but also that various mechanisms are existed depending on type of colorectal cancer cell. Now our approaches are therefore, focusing on finding of the 'common' (or 'crossed') 5-FU resistance mechanism (s) applying for all types of colorectal cancer cells and it might be a basis to increase an efficacy of 5-FU-based chemotherapy.

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