Local treatment for rectal cancer in high selective patients by transanal endoscopic microsurgery (TEM) and radiotherapy

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AGA ABSTRACTS

• EXPRESSION OF MATRIX METALLOPROTEINASES AND TISSUE INHIBITORS OF METALLOPROTEINASES IN PANCREATIC CARCINOMA AND CHRONIC PANCREATITIS T.M.Gress 1, F.MiillerPillesch1, M.M.Lerch I, H.Beger2, H.Friess3, M,Bfiehler 3, G.Adler 1. Depts. of Internal Medicine I (1) and Surgery (2) University of Ulm, Germany and Inselspital, University of Bern, Switzerland (3) Matrix Metalloproteinases (MMPs) are a family of proteases degrading components of the extracelinlar Matrix. This study was done to verify, if the marked desmoplastic reaction in pancreatic carcinoma and chronic pancreatitis is associated with changes in the expression of MMPs and their specific inhihitors (TIMPa). METHODS: Total RNA from pancreatic tissues (carcinoma n=7, chronic pancreatitis n=8, controls n = 7 ) was used for Northern blot analysis. Northern blots were hybridized with 332p labelled eDNA probes for MMP-1 (interstitial collagenase), MMP-2 (72 kDa collagenase type IV), MMP-3 (stromelysin), MMP-9 (92 kDa collagenase type IV), TIMP-1 and TIMP-2 (TIMP=Tissue Inhibitor of Metalloproteinase) and for a number of genes coding for extracellular matrix components (e.g. collagens). In-site hybridization with 35S labelled probes was done to identify the predominant localization of overexpressed sequences in pancreatic tissue. RESULTS: Transcripts for MMP1 and MMP-3 could not be detected in any of the pancreatic tissues. Elevated transcript levels were found for MMP-1, MMP-9, TIMP-1 and TIMP-2 in pancreatic carcinoma and chronic pancreatitis. In both tissues enhanced expression of MMPs and TIMPs correlated to the degree of the desmoplastie reaction and to the transcript levels of extraeellular matrix proteins. In pancreatic carcinoma there was no significant correlation to tumor stage and differentiation grade. Preliminary evaluation of in-situ hybridization results revealed that in both, cancer and pancreatitis, MMP-2 was predominantly expressed in stromal cells and to a lasser degree in aeinar cells and tumor cells. In contrast, equivalent amounts 'of TIMP-2 transcripts were found in tumor cells, stromal cells and acinar cells. DISCUSSION: Pancreatic Cancer and chronic panereatitis are associated with enhanced expression of MMPs and TIMPs, which correlates to the severeness of the desmoplastic reaction and to the expression of genes coding for extracellular matrix components. Further studies using a larger number of patients will have to show, if enhanced : expression of MMPs is associated with invesiveness in pancreatic carcinoma or with the activity of the disease in chronic pancreatitis. At present in-vitro studies are being done to verify, if a disruption of the balance between matrix metalloproteinases and their specific inhibitors is associated with a metastatic or invasive phenotype of pancreatic cancer cell lines.

LOCALTREATMENT FOR RECTALCANCER IN HIGH SELECTIVEPATIEN'P3BY TRANSANALENDOSCOPIC MICROSURGERY(I'EM)AND RADIOTHERAPY M. Guerfieri,F. Feliciotti, A. Paganini, C. Mariotti, E.Lezocho Istituto di Scienze Chirurgiche, Universita' di Ancona, Ancona, Italy We report our experience on 61 patients (35 males,26 females;mean age 64) operated by TEM.58 full thickness excisions and 3 mucosectomies were performed. Indications for TEM were as follows:A.Histologicany confirmed sessile adenomas in the sigma-rectum within 25 om from the anal verge B.Well, moderately well differentiated, pT1 carcinomas C.WelI, moderately well differentiated pT2 carcinomas over 75 years of age (preop radiotherapy) D.pT2,pT3,pT4 tumors in pts at high risk for major surgery (palliative treatment) (preop radiotherapy) E. Chronic rectat ulceration, endometfiosis,carcin0id. 37 villous adenomas, 21 carcinomas (4 pT1,12 pT2 and 5 pT3 in elderly or high risk pts), 1 anal cancer pT1N2:palliative resection, 1 endometriosis, 1 rectal ulcer. No operative complications and no mortality were observed. Postoperative pain was mild and oral int0ke began after 2-4 days.Mean hospital stay was 5 days (3-12).Minor complications were:one pulmonary microembolism and 5 leaking sutures healed by medical therapy.One suture line stenoses resolved by dilatations.Major complications were observed only in one patient previous undergone to anterior rectal resection and with recurrent cancer on suture line that refused Miles operation: a recto-vaglnal fistula c~ccurred and required reoperation. At follOW ~up (mean 18 months) recurrence was observed in 2 pts (pT2):one was treated preoperatively with radiotheraphy and Miles but no tumor was observed on the surgical specimen. The other ((3 high risk patients) was treated with radiotheraphy and TEM : she is recurrence free after 12 months, TEM allows sate, full thickness removal of rectal lesions with accurate suture of the defect.Low morbidity and mortality are observed together with short hospital stay and rapid return to normal activities.

GASTROENTEROLOGY, Vol. 108, No. 4

• QUALITY OF LIFE AFTER RADICAL RESECTION FOR GASTRIC CANCER. J GRIFFITH, J May, S Young, D Johnston, HM Sue-ling. Academic Unit of Surgery and The Centre for Digestive Diseases, The General Infirmary, Leeds. Radical surgical resection is the only form of treatment which offers a chance of cure to patients with gastric cancer. However, this involves major surgery in elderly patients, many of whom require total gastrectomy. It is therefore possible that their quality of life may be diminished by such radical surgery. We assessed the physical performance (WHO score 0-4), physical and social ability (Troidl index 0-14) and psychological state (HAD 0-421 in 36 patients who underwent radical, potentially curative resection for gastric cancer, before operation and serially for 6 months after operation, and 32 age and sex matched controls. 27 (75%) of the patients underwent total gastrectomy with Eoux-en-y reconstruction. The results were expressed as the proportion of patients who were deemed to have a satisfactory score (WHO 0-I; Troidl >7; HAD7) HAD (<16) p
100 % 97 % 94 %

Pre-op 92 % 83 % 89 %

PATIENTS I month 36 % ** 67 % * 100 %

3 months 94 % 83 % 100 %

:.

Both the physical and the social performance of patients were significantly impaired one month after operation, but recovered rapidly by 3 months. In contrast, there was little change in the psychological state of patients after operation. These findings suggest that the post-operative reduction in quality of life is transient and that most patients enjoy a good quality of life after surgery for gastric cancer.

IDENTIFICATION OF TWO SPECIFIC REGIONS OF THE HUMAN MUC2 MUCIN GENE PROMOTER NECESSARY FOR HIGH LEVEL TRANSCRIPTION. J.R. Gum. Jr., J.W. Hicks, & Y.S. Kim. Departments of Anatomy and Medicine, UCSF and Gastrointestinal Research Laboratory, VAMC San Francisco, CA. The human MUC2 gene encodes a major goblet cell-specific mucin expressed in colon and small intestine. As such, the study of MUC2 gene regulation affords an excellent window into the processes of gene regulation and cell differentiation in the gut, as well as into the alterations in these processes that accompany malignant transformation. We have isolated and sequenced a genomic DNA clone containing over 8000 bp of the 5'-flanking region of the M U C 2 gene. This has facilitated a detailed characterization of the MUC2 gene promoter. The initial 500 bases upstream of the MUC2 transcription start site (cap site) contains 63% G+C content; thus it is only moderately enriched in these nucleotides. The sequence contains a TATA box located 24 bases upstream of the cap site and lacks consensus Spl sites. These characteristics are typical of many tissue specific gene promoters. Transient transfections of colon cancer cell lines LS174T, HM3, and LiM6 were performed using various lengths of the MUC2 5'-flanking sequence cloned upstream of a luciferase reporter gene using the pGenelight vector. Luciferase assays were performed and normalized to internal standards obtained using a co-transfected chloramphenicol acyltransferase-producing positive control vector. These experiments indicate that the M U C 2 5'-flanking sequence possesses promoter activity. Moreover, two regions of the Y-flanking sequence contain elements that function to increase transcriptional activity in all three cell lines. One element is located between bases -1308 and -641 (relative to the cap site); its deletion results in a 34.2+11.9% diminution in promoter activity. The second element is located between bases -91 and -73; its deletion results in a 75.0_+9.3% drop in activity. This 18 bp stretch contains a recognition site for the CACCC-binding protein, a transcription factor necessary for the activity of several promoters including those found in immunoglohin and beta-globin genes and those of SV40. It is also present in the apolipoprotein A2 enhancer and is required for active transcription in liver and small intestine. Ongoing work is addressed at characterizing nuclear protein binding sites of the MUC2 promoter and in producing transgenic mice expressing a MUC2 promoter/human growth hormone reporter gene to enable examination of expression in various cell types in rive.