F. Erroi

Experience with 647 consecutive tumors of the duodenum, ampulla, head of the pancreas, and distal common bile duct.

Between 1946 and 1987, 647 patients with periampullary tumors were diagnosed at the University of Chicago Medical Center. These included 549 tumors located in the head of the pancreas, 40 in the distal common bile duct, 29 in the duodenum, and 29 at the ampulla of Vater. Ninety-eight per cent of all tumors were adenocarcinoma, with 93% of the remaining being duodenal carcinoid or sarcoma. Operability rate ranged from 81% to 97%, according to the tumor location and histologic type. A combination of laparotomy, biopsy, and bypass was performed in 433 patients and only one survived 5 years (0.2%). Resectability rate ranged from 16.5% for pancreatic adenocarcinoma to 89.3% for ampullary tumors. Of the 133 resections, 80 were pancreatoduodenectomies, 29 total pancreatectomies, 7 duodenectomies, 2 gastrectomies, 8 common bile duct resections, and 7 local excisions. Overall 19% of patients who underwent radical resection died in the immediate postoperative period, although mortality has decreased to 5% since 1981. Mortality was 20% after a standard pancreatoduodenectomy and 24.1% after a total pancreatectomy. Five-year actuarial survival rates, including perioperative deaths, were 8.8%, 20%, and 32% for pancreatic, duodenal, and ampullary adenocarcinoma, respectively. One half of patients with sarcoma and two-thirds with carcinoid of the duodenum survived 5 years. No patient with distal common bile duct adenocarcinoma achieved a 5-year survival rate. Multivariate analysis on all patients operated on (n = 566) revealed that the 5-year survival rate was significantly related to intent of operation (palliative 0.2%, curative 12%; p less than 0.001), histologic type (adenocarcinoma 2%, carcinoid and sarcoma 31%; p less than 0.0001), and site (ampullary and duodenal 21%, biliary and pancreatic 0.9%; p less than 0.001). A second multivariate analysis, evaluating only those patients with adenocarcinoma who survived the perioperative period of the radical resection (n = 97) analyzed the influence of tumor size and differentiation, lymphatic, capillary, and perineural microinvasion, lymph node status, and type of procedure (pancreatoduodenectomy vs. total pancreatectomy) on 5-year survival. None of these additional variables was significantly associated with long-term survival rates. In addition we evaluated the presence of local or distant recurrence after resection by analyzing the findings from all autopsies performed on these patients (n = 49): 29.4% of patients died with local recurrence alone, 23.5% with distant recurrence alone, and 47.1% had both local and distant recurrences.(ABSTRACT TRUNCATED AT 400 WORDS)

Endoscopic dilation of benign esophageal strictures in a surgical unit: a report on 95 cases.

Ninety-five patients were treated by endoscopic dilation without fluoroscopic guidance between 1997 and 2005 for benign esophageal strictures. The etiologies were: anastomotic (38), postfundoplication (13), caustic (14), peptic (11), radiation-induced (10) and others (9). The strictures were classified at every session on a 0 to 4 scale on the basis of the diet and the luminal diameter. Savary-Gillard or Through-the Scope balloon dilators were used depending on the type and the location of the stenosis. A total of 472 dilation sessions were carried out without serious complications. A normal and a semisolid diet were respectively achieved in 75% and 91%. Recurrence of dysphagia was found in 33% and 51% of the patients respectively after 2 months and 1 year. Improvement of dysphagia, the number of sessions, and recurrence were significantly better in the patients with postsurgical stenosis as compared with those affected by caustic, peptic, and radiation-induced strictures.

Aberrant gene methylation in non-neoplastic mucosa as a predictive marker of ulcerative colitis-associated CRC.

Background Promoter hypermethylation plays a major role in cancer through transcriptional silencing of critical genes. The aim of our study is to evaluate the methylation status of these genes in the colonic mucosa without dysplasia or adenocarcinoma at the different steps of sporadic and UC-related carcinogenesis and to investigate the possible role of genomic methylation as a marker of CRC. Results The expression of Dnmts 1 and 3A was significantly increased in UC-related carcinogenesis compared to non inflammatory colorectal carcinogenesis. In non-neoplastic colonic mucosa, the number of methylated genes resulted significantly higher in patients with CRC and in those with UC-related CRC compared to the HC and UC patients and patients with dysplastic lesion of the colon. The number of methylated genes in non-neoplastic colonic mucosa predicted the presence of CRC with good accuracy either in non inflammatory and inflammatory related CRC. Methods Colonic mucosal samples were collected from healthy subjects (HC) (n = 30) and from patients with ulcerative colitis (UC) (n = 29), UC and dysplasia (n = 14), UC and cancer (n = 10), dysplastic adenoma (n = 14), and colon adenocarcinoma (n = 10). DNA methyltransferases-1, -3a, -3b, mRNA expression were quantified by real time qRT-PCR. The methylation status of CDH13, APC, MLH1, MGMT1 and RUNX3 gene promoters was assessed by methylation-specific PCR. Conclusions Methylation status of APC, CDH13, MGMT, MLH1 and RUNX3 in the non-neoplastic mucosa may be used as a marker of CRC: these preliminary results could allow for the adjustment of a patients surveillance interval and to select UC patients who should undergo intensive surveillance.

High-Energy Laser Therapy of Barrett's Esophagus: Preliminary Results

Abstract.We present the preliminary results obtained by our research group utilizing Nd:YAG and diode lasers to treat Barrett’s esophagus (BE). A total of 15 patients with BE (mean age 58 years) underwent endoscopic laser therapy: 11 with intestinal metaplasia, 2 with low-grade dysplasia, and 2 with high-grade dysplasia. The mean length of BE was 4 cm (range 1–12 cm). Six of these patients also underwent antireflux surgery, and nine were prescribed acid-suppressive medication. Endoscopic Nd:YAG laser treatment was carried out from 1997 to 1999; thereafter, diode laser was employed. The mean follow-up of these patients after the first laser session was 28 months. Patients underwent a mean of 6.5 laser sessions (range 3–17 sessions), with no apparent complications. The mean energy per session was 1705 JJ. Only six of these patients (40%) showed complete endoscopic and histologic remission, but a mean of 77% (SD 23.8%) of the total metaplastic tissue in all these patients was ablated. The percentage of healed mucosa was higher in patients with short-segment BE (92%) (p < 0.05) and in subjects treated by two or more laser sessions per centimeter of BE length (89%) (p < 0.05). All four patients with dysplasia showed histologic regression to nondysplastic BE or to squamous epithelium, without recurrence during a mean follow-up of 30 months. The patients who underwent antireflux surgery and those prescribed pharmacologic treatment had similar results. Nd:YAG and diode laser treatment of BE is a safe, effective procedure; it required two sessions per centimeter of metaplasia; and it achieved complete regression of the dysplasia. Further studies are necessary to quantify its effect on cancer incidence.

Mismatch repair gene defects in sporadic colorectal cancer enhance immune surveillance

Background There is evidence that colorectal cancers (CRC) with DNA mismatch repair deficiency (MMR-D) are associated with a better prognosis than the generality of large bowel malignancies. Since an active immune surveillance process has been demonstrated to influence CRC outcome, we investigated whether MMR-D can enhance the immune response in CRC. Patients and Methods A group of 113 consecutive patients operated for CRC (42 stage I or II and 71 with stage III or IV) was retrospectively analyzed. The expression of MMR genes (MSH2, MLH1, MSH6 and PSM2) and co-stimulatory molecule CD80 was assessed by tissue microarray immunohistochemistry. In addition, tumor infiltrating mononuclear cells (TIMC) and T cell subpopulations (CD4, CD8, T-bet and FoxP-3) were quantified. The effect of specific siRNA (siMSH2, siMLH1, siMSH6 and siPSM2) transfection in HT29 on CD80 expression was quantified by flow cytometry. Non parametric statistics and survival analysis were used. Results Patients with MMR-D showed a higher T-bet/CD4 ratio (p = 0.02), a higher rate of CD80 expression and CD8 lymphocyte infiltration compared to those with no MMR-D. Moreover, in the MMR-D group, the Treg marker FoxP-3 was not expressed (p = 0.05). MMR-D patients with stage I or II and T-bet expression had a significant better survival (p = 0.009). Silencing of MSH2, MLH1 and MSH6, but not PSM2, significantly increased the rate of CD80+ HT29 cells (p = 0.007, p = 0.023 and p = 0.015, respectively). Conclusions CRC with MMR-D showed a higher CD80 expression, and CD8+ and Th1 T-cell infiltration. In vitro silencing of MSH2, MLH1 and MSH6 significantly increased CD80+ cell rate. These results suggest an enhanced immune surveillance mechanism in presence of MMR-D.

CD80 down-regulation is associated to aberrant DNA methylation in non-inflammatory colon carcinogenesis

BackgroundThe lack of positive costimulatory molecules represents one of the mechanisms by which tumor cells evade immune surveillance. Promoter hypermethylation plays a major role in cancer development through transcriptional silencing of critical genes. The aim of this study was to examine the expression of the costimulatory molecule CD80 in relationship with genomic methylation in non-inflammatory colon carcinogenesis.MethodsColonic mucosal samples were collected from healthy subjects (n = 30) and from dysplastic adenoma (n = 14), and colon adenocarcinoma (n = 10). DNA methyltransferases-1, −3a, −3b and CD80 mRNA expression were quantified by real time qRT-PCR. The methylation status of CDH13, APC, MLH1, MGMT1 and RUNX3 gene promoters was assessed by methylation-specific PCR. CD80 expression was assessed in HT29, HCT-15 and LoVo cell lines after treatment with the DNA-methyltransferase inhibitor 5-Aza-2′-deoxycytidine.ResultsCD80 mRNA levels were significantly lower in the non-inflammatory dysplastic colonic mucosa of patients with one or more methylated genes and inversely correlated with patients’ methylation scores (τ = −0.41, p = 0.05 and τ = −0.37, p = 0.05, respectively). Treatment with 5-Aza-2′-deoxycytidine significantly increased CD80 expression both in terms of the level of CD80 mRNA (p = 0.007) and of CD80+ cells (p = 0.003).ConclusionsThese results indicate that the failure of immune surveillance mechanisms in non-inflammatory colon carcinogenesis may be linked to genomic methylation directly or indirectly affecting CD80 expression.

Cost-Effectiveness analysis of postoperative surveillance protocols following radical surgery for colorectal cancer

Abstract Introduction : Up to 30–50% of patients who undergo radical surgery for colorectal cancer (CRC) develop tumor relapse. The aim of this study was to assess various surveillance protocols utilized in a tertiary referral hospital in Northern italy. Methods : Data concerning 373 consecutive patients who underwent radical surgery for CRC between 1990 and 2006 and whose data had been entered into a prospective database were considered eligible for this study. the overall costs and the percentages of recurrence following the various surveillance protocols were calculated. Results : one hundred two (27.35%) of the patients suffered a recurrence after a mean of 17.6 (95% Ci 13.9–21.1) months. the combination of physical examination, colonoscopy, thorax-abdominal computed tomography (CT) scan, and serum carcinoembryonic antigen (CEA) dosage was found to be the most cost/effective one to monitor stages i and ii colon cancer; while physical examination, rigid sigmoidoscopy, thorax-abdominal CT scan, and serum Cea dosage were found to be the most cost/effective surveillance to monitor stages iii and iV of colon cancer and rectal cancer. Conclusions : Adherence to follow-up guidelines and early detection are vital factors affecting the curability of relapsed cancer in CRC patients who undergo surgery. the first five years after surgery was found to be the most risky period for recurrence. Cost/effectiveness analysis indicate that follow-up protocols should be tailored to the risk of recurrence with the aim of identifying relapse when the disease is at an asymptomatic, presumably more curable stage.

Laser photoablation of colorectal adenomas: A 12-year experience

Background:We analyze laser photoablation as an alternative treatment of large sessile polyps in inoperable patients.Methods:Ninety-four colorectal polyps (mean diameter 3.09 ± 2.7 cm, range 1–15 cm) were treated using high-energy lasers (Nd:YAG and diode). Grade of dysplasia was low in 51, high in 35, with focally invasive cancer in eight.Results:After 405 laser sessions (4.3 per polyp) five procedure-related complications were observed: two strictures, two bleedings, and one perforation. The last needed a surgical resection; the others were successfully treated by endoscopic therapy. Fifty-seven polyps (61%) were completely eradicated and the growth was controlled in all but two (98%). No degeneration was found after 28-month follow-up of treated adenomas with low- or high-grade dysplasia. Outcome of treatment was dependent on the dimension and grade of the dysplasia (p < 0.05), but not on the polyps’ position (rectum or colon). Relief of rectal bleeding was obtained in 90%, of mucus discharge in 77%, and of tenesmus in 100% of cases.Conclusions:Laser photoablation of colonic adenomas can be considered a valid procedure not only to relieve symptoms, but also to control the risk of degeneration in patients unfit for surgery or when surgical treatment is considered excessively invalidating.

Synchronous polyps predict metachronous colorectal lesions after curative resection of colorectal cancer.

Abstract Background: The principal aim of endoscopic follow-up programs after curative resection of colorectal cancer (CRC) is to improve survival and identify local recurrence and metachronous CRC. The aim of our study was to identify the possible predictors of metachronous colorectal lesions. Methods: The records of 348 consecutive patients with CRC and who completed at least 1 year of endoscopic follow-up after surgery were analyzed. In this group, 336 patients underwent surgery for primitive CRC and 12 for metachronous cancer. Patients’ characteristics, operative details, and endoscopical follow-up findings were retrieved. Multivariate survival analyses were used to identify patient categories at risk of metachronous colonic lesions. Results: 128 patients presented a metachronous lesion: 118 adenomas and 10 adenocarcinomas. At multivariate analysis, active smoke (HR = 1.84, p = 0.03), neoadjuvant therapy (HR = 0.24, p = 0.01), and presence of synchronous polyps (HR = 1.55, p = 0.04) resulted independent predictors of metachronous adenoma after CRC removal while neoadjuvant therapy (HR = 0.25, p = 0.02), active smoke (HR = 1.54, p = 0.04), and presence of synchronous polyps (HR = 1.86, p = 0.02) resulted independent predictors of metachronous lesions after CRC removal. Conclusions: This study demonstrated a high rate of metachronous lesions in the early follow-up after curative CRC resection. The negative effects of synchronous polyps should be carefully evaluated when planning patients’ follow-up.

Su1923 Immune Microenvironment in Colonic Carciongenesis: Sporadic Mismatch Repair Genes Defects Are Associated to Hicd80+ Lamina Propria Monuclear Cells Infiltration

BACKGROUND Genomic defects in DNA mismatch repair (MMR) genes (MSH2, MLH1, PSM2 or MSH6) characterize the hereditary non polyposis colon cancer (HNPCC). However most colorectal cancers (CRC) with high-frequency microsatellite instability are sporadic, wherein the MMR defect develops because of inactivation of the MLH1 gene by DNA methylation. Multiple retrospective studies, including a population-based study and a metaanalysis, have demonstrated that patients with MMR-deficient colon cancers have a more favourable stage-adjusted prognosis compared with patients whose tumors have intact MMR. Since the immune environment of CRC has been demonstrated to influence its prognosis, we aimed to investigate the interplay between MMR genes and the immune environment in CRC PATIENTS AND METHODS A group of 98 consecutive patients operated on for colorectal cancer was retrospectively analysed. Familial and medical history were retrieved to assess the presence of Bethesda criteria for HNPCC diagnosis. Immunohistochemistry for CD80, TLR4, MyD88, MSH2, MLH1, MSH6 and PSM2 was performed on tissue sections. Moreover, lamina propria mononuclear cells (LPMC), polymorphonuclear cells and eosoinophil tumour infiltration was quantified. Patients were stratified in three groups: no MMR genes defect, MMR gene defects alone and MMR genes defects and at least one positive Bethesda criteria. Non parametric statistics was used. RESULTS In the three groups no difference was observed in term of polymorphonuclear cells and eosinophil infiltration and in term of TLR4 and MyD88 expression. On the contrary, LPMC infiltration was significantly higher in patients who had a MMR gene defect alone compared to patients who had no MMR genes defect and to those with MMR gene defect and positive Bethesda criteria (p= 0.014). Similarly, a significantly higher frequency of patients with high CD80 expression was observed in patients who had a MMR genes defect alone compared to patients who had no MMR gene defect and to those with MMR genes defect and positive Bethesda criteria (p=0.048). CONCLUSION In patients with MMR defects and no Bethesda criteria for HNPCC antigen presenting cells function seems enhanced as shown by higher frequency of hiCD80+ patients and higher LPMC infiltration. This immune activation may play a role in the prognosis of these patients.