Enhanced recovery pathways in colorectal surgery: a consensus paper by the Associazione Chirurghi Ospedalieri Italiani (ACOI) and the PeriOperative Italian Society (POIS).

Enhanced Recovery After Surgery (ERAS) pathway is a multi-disciplinary, patient-centered protocol relying on the implementation of the best evidence-based perioperative practice. In the field of colorectal surgery, the application of ERAS programs is associated with up to 50% reduction of morbidity rates and up to 2.5 days reduction of postoperative hospital stay. However, widespread adoption of ERAS pathways is still yet to come, mainly because of the lack of proper information and communication. Purpose of this paper is to support the diffusion of ERAS pathways through a critical review of the existing evidence by members of the two national societies dealing with ERAS pathways in Italy, the PeriOperative Italian Society (POIS) and the Associazione Italiana Chirurghi Ospedalieri (ACOI), showing the results of a consensus development conference held at Matera, Italy, during the national ACOI Congress on June 10, 2019.

Regional heterogeneity and complementation in the expression of the tumor-associated glycoprotein 72 epitopes in colorectal cancer.

We analyzed the immunohistochemical expression of three epitopes of the tumor-associated glycoprotein 72 (TAG-72) in whole cross-sections of primary colorectal carcinomas and in regional lymph node metastases using monoclonal antibodies (MAbs) B72.3, CC-49, and CC-83, which recognize distinct carbohydrate antigenic determinants. B72.3, CC-49, and CC-83 reacted with 13 of 27 (48%), 25 of 27 (92%), and 21 of 27 (77%) carcinomas, respectively. The immunoreactivity with lymph node metastases followed a similar pattern; MAb CC-49 was again the most reactive of the three antibodies, since it labeled 13 of 15 metastatic lesions. Positive reactions of the MAbs with the primary tumors were not always predictive of the immunorecognition of their metastases. Distinct areas within whole cross-sections of TAG-72-positive primary carcinomas demonstrated marked differences in the expression of the three epitopes. CC-49 tended to react with the highest number of areas and with the highest percentages of carcinoma cells within each area. In no instances did B72.3 demonstrate reactivity superior to that of either CC-49 or CC-83. Tumors negative for the CC-49 epitope in any area also did not express the other two TAG-72 epitopes. However, the comparison of the immunostaining obtained with each MAb in TAG-72-positive primary lesions revealed areas where CC-83 was clearly more reactive than CC-49. Moreover, one lymph node metastasis, negative for CC-49, was recognized by CC-83. Thus, the combined use of MAbs CC-49 and CC-83 resulted in additive immunostaining of primary and metastatic colorectal carcinoma cells. The study provides evidence of intratumoral heterogeneity in the glycosylation pattern of the TAG-72 antigen in colorectal cancer and emphasizes the advantages of cocktails of anti-tumor-associated antigen MAbs in the immunodetection of colorectal tumor cells.

Unbalanced germ-line expression of hMLH1 and hMSH2 alleles in hereditary nonpolyposis colorectal cancer.

We analyzed the hMLH1 and hMSH2 genes in 30 unrelated hereditary nonpolyposis colorectal cancer (HNPCC) patients using mutational and immunohistochemical analyses combined whenever possible with primer extension assays, designed to estimate hMLH1 and hMSH2 transcript expression in peripheral blood lymphocytes. Single-strand conformational polymorphism screening and PCR-direct sequencing revealed seven hMLH1 and five hMSH2 sequence variants in 14 unrelated HNPCC patients, including three definite pathogenic mutations, four amino acid substitutions of uncertain pathogenic significance, and five polymorphisms. Immunohistochemistry indicated the lack of either hMLH1 or hMSH2 protein expression in tumors from 13 patients, and the absence of both hMLH1 and hMSH2 immunostaining was observed in the tumor from one additional case. The lack of hMLH1 or hMSH2 immunostaining was associated with the presence of microsatellite instability in the corresponding tumor and was also observed in tumors from patients negative for pathogenic mutations by mutational screening. There was a marked unbalance in the allelic expression of either hMLH1 or hMSH2 transcripts in three of eight unrelated HNPCC patients that could be analyzed, although a less marked unbalance was detected in two additional patients. Tumors from patients with germ-line unbalance in hMLH1 or hMSH2 transcript expression did not express the corresponding mismatch repair protein and displayed microsatellite instability. Our results indicate that constitutional alterations in hMLH1 and hMSH2 transcript expression may represent genetic markers for HNPCC carrier status also in cases in which mutational analysis did not detect a definite pathogenic variant. This suggests that transcript deregulation may represent a relevant mode of germ-line inactivation for mismatch repair genes.

Adjuvant postoperative radiotherapy in rectal cancer: 148 cases treated at Florence University with 8 years median follow-up.

BACKGROUND AND PURPOSE: To analyse the outcome, the treatment related side effects, the prognostic significance of clinical parameters in a group of patients with rectal cancer receiving postoperative radiotherapy after radical resection. MATERIALS AND METHODS: From 1980 to 1990 148 consecutive patients with rectal carcinoma stage B2-B3 or C1-C2-C3 were treated with postoperative radiotherapy after radical surgery. All patients received 50 Gy in 25 sessions in 5 weeks. In 42 a "flash' dose of 5 Gy was also given within 24 h before surgery. Median follow up was 8.1 years. RESULTS: At 5 years the overall survival was 54%, the determined (cancer specific) survival 61%, the local recurrence-free survival 88%. The influence of stage, histotype, distance from anal margin, type of surgery, number of involved nodes and flash dose were analysed. Overall and determined survival and distant metastasis rate were significantly influenced (P < 0.005) by the pathological stage. Patients with more than 3 involved nodes presented a significantly lower determined survival (P < 0.001) and a higher distant relapse rate (P < 0.005) than those with 3 or less involved nodes. A higher determined survival (P < 0.01) was also found in patients receiving the preoperative "flash'; this group was however unbalanced in respect to the relative number of cases with 3 or less involved nodes. The incidence of major side effects requiring surgery or hospitalization for medical treatment was 35% before 1985 and 12% thereafter. The systematic use of small bowel visualization during simulation and the discontinuation of the flash dose were the main modifications introduced in the second period. As a consequence of the small bowel visualization the size of lateral fields was slightly reduced and some patients were excluded from the treatment. CONCLUSIONS: Value of postoperative radiotherapy to decrease the incidence of local recurrence was confirmed in this retrospective study; the incidence of side effects was however considerable and did not support the addition of chemotherapy as advised by the NIH consensus meeting. Our policy was therefore moved to preoperative irradiation whose combination with chemotherapy was recently reported to be better tolerated and highly effective.

Integrin Beta-4 expression in colorectal-cancer.

Integrin alpha 6 beta 4 plays an important role in the interaction of epithelia with basement membranes, and its expression appears to be profoundly altered during tumor progression. Using a quantitative immunochemical assay, we investigated the expression of the beta 4 subunit associated with alpha 6 in 25 primary carcinomas, and in matching normal mucosae. alpha 6 beta 4 was expressed in all the carcinoma and mucosa samples. The highest beta 4 levels were detected in tumors at high clinical stage (Dukes' stage C). Furthermore, beta 4 reactivity inversely correlated with the degree of differentiation. By immunohistochemistry,beta 4 expression was particularly strong in the epithelium lining the upper third of the crypts and the absorbing surface of normal mucosa. In villous adenomas, beta 4 immunostaining tended to be enhanced in the epithelium lining the outer surfaces of neoplastic villi, but only 5 of 8 samples tested scored positive. In carcinomas, beta 4 expression was detected in 18 of 21 samples tested, and was strongly influenced by the pattern of tumor growth and by the type and level of differentiation. Carcinomas, or areas of carcinomas, with cohesive and differentiated growth pattern demonstrated weak beta 4 expression at the tumor-stroma interface. Carcinoma cells at the lumenal surface of the intestine, and carcinomas, or areas of carcinomas, composed of small clusters of cells surrounded by stroma, demonstrated strong beta 4 expression. Altogether, our observations indicate that in colorectal tumors the expression of the beta 4 subunit is strongly influenced by microenvironmental factors and tends to increase in high stage, poorly differentiated lesions.

Marked variation of thymidylate synthase and folylpolyglutamate synthetase gene expression in human colorectal tumors.

Patients with advanced colorectal cancer are currently being treated with 5-fluorouracil (5-FU)-based chemotherapy. A growing number of patients with resectable disease receive adjuvant therapy with 5-FU/levamisole (LEV) or 5-FU/folinic acid (LV). However, many patients still fail on these treatments, due to occurrence of natural or acquired tumor resistance. Among clinically relevant mechanisms of resistance to fluoropyrimidines, increased expression of thymidylate synthase (TS) has been emphasized. Another potentially relevant mechanism involves a decrease in folylpolyglutamate synthetase (FPGS) expression. To establish the value of these genes as prognostic factors and predictors of the outcome of 5-FU-based chemotherapy in colorectal cancer, we measured their expression in colorectal tumors from patients undergoing surgery and postoperative chemotherapy and compared it with that in normal colonic mucosa. This was done by a semi quantitative, nonradioisotopic polymerase chain reaction (PCR) method using beta-actin as an internal standard and expressed as a TS/beta-actin or a FPGS/beta-actin mRNA ratio. In tumor samples from 21 colorectal cancer patients, TS gene expression varied 118-fold. The median TS/beta-actin ratio was, in fact, 41.36 x 10(-3) (range 2.49 x 10(-3) to 294.54 x 10(-3)). Little variation in TS gene expression was observed in corresponding normal colic mucosa; the TS/beta-actin gene ratio was lower (median 26.16 x 10(-3); range 8.49 x 10(-3) to 69.49 x 10(-3)). Among tumor explants from 20 patients, FPGS expression varied over 161-fold. A similar marked variation was also observed in normal colonic mucosal samples (over 185-fold). Overall and disease-free survival data suggest an inverse association between the level of tumor TS and FPGS expression and clinical prognosis. The availability of this sensitive and accurate assay for gene expression should now make it possible to extend these laboratory/clinical correlations to larger populations.

In vitro bioeffects of the antiestrogen LY117018 on desmoid tumor and colon cancer cells.

BACKGROUND: Clinical and experimental evidence suggest that estrogen has a role in the natural history of desmoid tumor (DT) and colorectal carcinoma. METHODS: The biological effects of LY117018, a nonsteroidal antiestrogen benzothiophene derivative, were assessed on a human adenocarcinoma cell line (HCT8 cells), and on DT cells and colorectal cancer derived fibroblasts in primary culture. RESULTS: LY117018 inhibited cell proliferation and collagen type I synthesis in DT cells. The compound also reduced cell growth in HCT8 cells and colorectal cancer fibroblasts. Binding experiments revealed the presence of estrogen binding sites in DT cells and frozen tissues but LY117018 did not displace [3H]17 beta E2 binding to DT cells. CONCLUSIONS: Present results demonstrate that LY117018 inhibits epithelial and fibroblastic colon cancer cells proliferation and proliferation and differentiation of desmoid cells in vitro. The lack of displacement of [3H]17 beta E2 binding to desmoid cells by LY117018 suggests the existence of distinct LY117018 binding sites.

Flow cytometric analysis of DNA ploidy and cell proliferation activity in colorectal carcinoma.

The aim of this study was to evaluate the relationship between DNA ploidy, proliferative activity and other prognostic factors and the survival of patients with colorectal cancer. 45 patients were prospectively investigated for 6 years. Fresh multiple samples for flow cytometric analysis of DNA content were collected during surgical resection of primary tumor. A 42% frequency of aneuploidy was observed with a median DNA index value of 1.54. The proliferative activity (%S+G2M cells) was higher in the aneuploid cell sub-population (28.6%) compared to the diploid counterpart (22.7%)(p = 0.05). No significant relationship between DNA ploidy and tumor site, Dukes' stage, histological type, grading age or sex was observed. No correlation between DNA ploidy and survival was demonstrated, including in the analysis of patient subsets according to stage. No additive prognostic information was obtained from a breakdown analysis as a function of DI values, percentages of aneuploid cells and proliferative activity. This study suggests that flow cytometric content analysis lacks prognostic value in colorectal carcinoma.

Antimicrobial chemoimmunoprophylaxis in colorectal surgery with cefotetan and thymostimulin: prospective, controlled multicenter study. Italian Study Group on Antimicrobial Prophylaxis in Abdominal Surgery.

Surgical antimicrobial prophylaxis was performed with a controlled study on 859 evaluable patients randomized into two groups treated with chemoprophylaxis only or chemo- and immunoprophylaxis in colorectal surgery. Immuno and chemoprophylactic treatment (425 patients) consisted of 70 mg i.m. thymostimulin per day for 7 days beginning 48 h before surgery plus 2 g cefotetan at the moment of induction of anesthesia; the other group (434 patients) received only the single dose of antibiotic. Results in the two different groups were significantly different regarding abdominal abscess and the total infectious episodes in the surgical site with lower frequency in patients receiving both thymostimulin and the antibiotic (cefotetan). Moreover the respiratory tract infections were more than double in those patients not treated with perioperative immunotherapy. Stratifying patients on the basis of grade of skin test reaction, we observed a significantly lower percentage of surgical site infection in hypoergic patients receiving chemo- and immunoprophylaxis.

Amoxicillin/clavulanic acid versus cefotaxime for antimicrobial prophylaxis in abdominal surgery: a randomized trial.

Amoxicillin/clavulanic acid (amoxicillin 2 g/clavulanic acid 200 mg) has been administered in comparison to cefotaxime (2 g) for antimicrobial prophylaxis in 476 evaluable patients undergoing abdominal surgery at high risk of septic complications. Both antibiotics were administered as a single infusion. 205 evaluable patients (110 in amoxicillin/clavulanic acid group and 95 in cefotaxime group) underwent upper gastrointestinal surgery (including gastroduodenal and biliary surgery). The wound infection rate was 4.5% for amoxicillin/clavulanic acid and 7.4% for cefotaxime, with no significant differences. Intra-abdominal abscesses were observed in 3 patients in the amoxicillin/clavulanic acid group and in 1 patient in the cefotaxime group. 271 evaluable patients (135 in amoxicillin/clavulanic acid group and 136 in cefotaxime group) underwent lower gastrointestinal surgery (including colorectal surgery). The wound infection rate was 11% for amoxicillin/clavulanic acid and 13% for cefotaxime, with no significant differences. A purulent discharge was present in 3 patients in both groups. Intra-abdominal abscesses were observed in 3 patients in the amoxicillin/clavulanic acid group and in 4 patients in the cefotaxime group. No serious adverse events and no cases of diarrhea were observed. In conclusion, in our experience amoxicillin/clavulanic acid proved to be as effective as cefotaxime in protecting patients from surgical infections in abdominal surgery. Its use in surgical prophylaxis may help decrease the cost of treatment and reduce the risk of resistance to antibiotics and superinfections.

Telethermography and axillary node status as predictors of early relapse in breast cancer: preliminary report.

The authors report on 141 primary, non-metastatic, breast cancer patients with a minimum follow-up of 12 months after surgery to a maximum of 5 years. All cases were studied according to the patterns of the preoperative telethermography (TH) and nodal status (N). Prognosis was evaluated in terms of incidence of relapse. A statistically significant correlation was found between TH+ and early relapse, and for N+, but there was no correlation between TH and N, both for negative and positive values. The results suggest a complementary prognostic value of the two parameters.

[Intramuscular hemangioma: problems of differential diagnosis from angiosarcoma]. / L'emangioma intramuscolare: problemi di diagnosi differenziale con l'angiosarcoma.

Despite recent technical advances in diagnostic imaging (computerised tomography, magnetic resonance), intramuscular haemangiomas are relatively uncommon and often difficult to diagnose. Angiosarcomas are probably the most important tumour to be differentiated from hemangiomas, in order to define the optimal therapeutic approach. Only biopsy allows a proper preoperative diagnosis, although this diagnostic technique involves some risks. Total excision is the treatment of choice. Radiotherapy has been employed without substantial results. A review of the literature and a case report are presented here.

[Repair of stricture in Crohn's disease: treatment of choice?]. / La stricturoplastica nella malattia di Crohn: intervento di scelta?

Strictureplasty has become one of the surgical options available for skip-lesions and for duodenal, multiple small bowel or anastomotic strictures caused by Crohn's disease. Over a sixteen-year period, 44 patients underwent strictureplasty for 269 symptomatic strictures associated with Crohn's disease. After a median follow-up of 50 months (range 18-89) a second additional operation for symptomatic recurrence was performed in 10 patients, two of whom developed new symptomatic strictures after 3 and 36 months, requiring a third operation. Of all the strictures present at surgery, 174 were treated performing strictureplasties (156 were closed transversely using Heineke-Mickulicz, 16 in a side-to-side Finney fashion and 2 in the manner of Jabolay) and 88 with synchronous resection. Furthermore, 7 other strictures were treated with a side-to-side ileocolic (5 strictures in 3 patients) or ileoileal (2 strictures in one patient) anastomosis. No operative mortality was recorded and there were no septic complications due to anastomotic leak. The mean follow-up period was 47.8 +/- 42.4 months (range 3-132). Symptomatic restrictures of previous strictureplasty sites requiring surgery occurred in 8.8% of cases. Furthermore, no statistically significant difference (Kaplan-Meier) was observed in the reoperation rate among patients affected respectively by skip lesions or multiple strictures or among patients treated only by strictureplasty or with an associated resection. We concluded that strictureplasty is a valuable adjunct to resection in the treatment of Crohn's strictures.

[Prevention of infectious postoperative complications in Crohn's disease]. / La prevenzione delle complicanze settiche post-operatorie nella malattia di Crohn.

Mortality and post-operative complications are elevated in Crohn's disease, for many reasons: pre-existing septic complications, malnutrition, impaired cell-mediated immunity, failure to identify enteric fistulas and/or abdominal abscess during surgical operation. From 1984 to 1996 in 383 patients with Crohn's disease we performed 426 surgical procedures, observing post-operative complications in 28 of these (6.5%). However, septic complications in the surgical field were only 7 (1.6%). A 83-year-old patient died after surgery because of heart failure. The risk of post-operative complications was significantly higher in patients with elevate Prognostic Nutritional Index (PNI). We treated patients with malnutrition pre-operatively using parenteral nutrition (TPN). In 100 patients undergoing TPN we observed a significant PNI reduction (from 53.3 +/- 13 to 42.1 +/- 6.9) and a significative improvement of transport proteins correlated with nutritional status, such as pre-albumin (from 21.2 mg/dl +/- 9.8 to 26.5 mg/dl +/- 7.8) and retinol binding protein (from 3.8 mg/dl +/- 1.6 to 4.6 mg/dl +/- 1.7). During surgical operations we recorded fistulas caused by disease, observing 336 fistulas in 258 patients. The treatment of fistulas (by suture or less frequently by resection of the intestinal tract involved in the inflammatory process) prevented septic post-operative complications: indeed we did not observe enteric fistulas in any patient post-operatively. We conclude that the improvement of nutritional status and the adequate treatment of enteric fistulas prevents septic complications in nearly all patients.

[The prevention of the aorto-mesenteric compression syndrome in interventions for ileoanal anastomoses]. / Prevenzione della sindrome del compasso aorto-mesenterico negli interventi di ileo-ano-anastomosi.

Restorative proctocolectomy with ileal-anal anastomosis can induce a duodenal stenosis due to the compression between superior mesenteric artery (SMA) and aorta when the ileum is pulled-down to the anus stretching the SMA. This situation may require prolonged nasogastric intubation or even surgery. In our experience this occurred in 10% of pts. Aiming to avoid this complication we have performed an intestinal derotation just before ileal-anal anastomosis abolishing any possibility of duodenal compression. Comparing this latter group of patients to those who didn't receive intestinal derotation, we observed a significant reduction of nasogastric tube drainage and of the nasogastric intubation time. We think that intestinal derotation could be effective in preventing SMA syndrome after restorative proctocolectomy and ileal-anal anastomosis.

Anal carcinoma occurring in Crohn's disease patients with chronic anal fistula.

This paper reports six patients with perianal Crohn's disease (CD), who developed anal cancer in chronic anal fistulas. Tumors have been often diagnosed at an advanced stage and had a worse prognosis than cancers arising in the general population as tumor symptoms may mimic symptoms of CD, resulting in delay in diagnosis. Patients with perianal CD should undergo a careful surveillance program for ano-rectal carcinoma, including routine biopsy of any suspected lesion. When malignancy is found, an aggressive surgical approach and complementary therapy are mandatory.

Strictureplasty in Crohn's disease: surgical option.

PURPOSE: The objective of this study was to review early and late results of our personal experience with strictureplasty for patients affected by Crohn's disease. METHOD: During a 16-year period, 44 of 383 patients underwent strictureplasty. Of the 269 strictures present at surgery, 174 were treated by performing strictureplasties (156 were closed transversely according to the Heineke-Mikulicz technique, 16 were done side-to-side in the Finney manner, and 2 were done according to Jaboulay technique), and 88 were treated with a synchronous resection. An individualized technique was used for seven other strictures, with side-to-side ileocolic (5 strictures in 3 patients) or ileoileal anastomosis (2 strictures in one patient). RESULTS: No operative mortality was recorded, nor were septic complications caused by anastomotic leakage observed. The mean follow-up period was 47.8 +/- 42.4 (range, 3-132) months. After a median follow-up period of 50 (range, 18-89) months, a second operation for symptomatic recurrence was performed on ten patients, and two of them developed new symptomatic strictures after 3 and 36 months, requiring a third operation. Symptomatic restrictures of previous strictureplasty sites requiring surgery occurred in 8.8 percent of cases. Furthermore, no statistically significant difference (Kaplan-Meier) was observed in the reoperation rate among the patients with skip lesions or closed strictures or among patients treated by strictureplasty alone or with associated resection. CONCLUSION: We conclude that strictureplasty is a valuable adjunct or alternative to resection in the treatment of Crohn's strictures.