Restorative proctocolectomy: an example of how surgery evolves in response to paradigm shifts in care.

AIM: Surgical technique constantly evolves in response to the pressure of progress. Ileal pouch anal anastomosis (IPAA) is a good example. We analysed the effect of changes in practice on the technique of IPAA and its outcomes. METHOD: Patients undergoing primary IPAA at this institution were divided into three groups by date of the IPAA: those operated from 1983 to 1993, from 1994 to 2004 and from 2005 to 2015. Demographics, patient comorbidity, surgical techniques, postoperative outcomes, pouch function and quality of life were analysed. RESULTS: In all, 4525 patients had a primary IPAA. With each decade, increasing numbers of surgeons were involved (decade I, 8; II, 16; III, 31), patients tended to be sicker (higher American Society of Anesthesiologists score) and three-staged pouches became more common. After an initial popularity of the S pouch, J pouches became dominant and a mucosectomy rate of 12% was standard. The laparoscopic technique blossomed in the last decade. 90-day postoperative morbidity by decade was 38.3% vs 50% vs 48% (P < 0.0001), but late morbidity decreased from 74.2% through 67.1% to 30% (P < 0.0001). Functional results improved, but quality of life scores did not. Pouch survival rate at 10 years was maintained (94% vs 95.2% vs 95.2%; P = 0.06). CONCLUSION: IPAA is still evolving. Despite new generations of surgeons, a more accurate diagnosis, appropriate staging and the laparoscopic technique have made IPAA a safer, more effective and enduring operation.

Clinical implications of acellular mucin pools in resected rectal cancer with pathological complete response to neoadjuvant chemoradiation.

AIM: Approximately 20% of rectal cancers treated with neoadjuvant chemoradiation achieve a pathological complete response (pCR), which is associated with an improved oncological outcome. However, in a proportion of patients with a pCR, acellular pools of mucin are present in the surgical specimen. The aim of this study was to evaluate the clinical implications of acellular mucin pools in patients with rectal adenocarcinoma achieving a pCR after neoadjuvant chemoradiation followed by proctectomy. METHOD: A single-centre colorectal cancer database was searched for patients with clinical Stage II and Stage III rectal adenocarcinoma who achieved a pCR (i.e. ypT0N0M0) after neoadjuvant chemoradiation followed by proctectomy between 1997 and 2007. Patients were categorized according to the presence or absence of acellular mucin pools in the resected specimen, and groups were compared. Patient demographics, tumour and treatment characteristics, and oncological outcomes were recorded. Primary outcomes were 3-year local and distant recurrences, and disease-free and overall survivals. RESULTS: Two hundred and fifty-eight patients with clinical Stage II or Stage III rectal adenocarcinoma were treated by neoadjuvant chemoradiation. Fifty-eight of these patients had a 58 pCR. Eleven of the 58 patients with a pCR had acellular mucin pools in the surgical specimen. The median follow up was 40 months. The groups were statistically similar with respect to demographics, chemoradiation regimens, distance of tumour from the anal verge, clinical stage and surgical procedure. No patient had local recurrence. Patients with acellular mucin pools had increased distant recurrence (21%vs 5%), decreased disease-free survival (79%vs 95%) and decreased overall survival (83%vs 95%) rates, although none of these differences was statistically significant. CONCLUSION: The presence of acellular mucin pools in a proctectomy specimen with a pCR does not affect local recurrence, but may suggest a more aggressive tumour biology.

Strictureplasty for obstructing small-bowel lesions in diffuse radiation enteritis--successful outcome in five patients.

INTRODUCTION: Complications from chronic radiation enteritis can lead to resection or bypass of large segments of intestine, placing the patient at risk for short-bowel syndrome. We have operated on five patients with complications of chronic radiation enteritis in the setting of limited intestinal reserve. In each case, strictureplasty was used as an adjunct to resection or bypass to treat short, relatively isolated radiation strictures with the goal of preserving intestinal length and avoiding dependence on parenteral nutrition. METHODS: There were four females and 1 male, mean age 57 (range, 45-71) years. Complications developed from 1 to 30 years after radiation therapy and all patients had undergone at least one prior laparotomy for complications of radiation enteritis. Four patients had resultant short bowel syndrome and were dependent on parenteral nutrition preoperatively. Indications for the present operations were chronic small-bowel obstruction (3 patients), enterocutaneous fistula and bowel obstruction (1 patient), and chronic small-bowel obstruction along with a rectovaginal fistula (1 patient). Details of the operative procedure, postoperative complications, and eventual weaning from parenteral nutrition were determined by review of the medical records. RESULTS: Strictureplasty was performed either alone (1 patient) or was accompanied by resection or bypass (4 patients). Postoperative complications developed in 3 patients and were comprised of pancreatitis (1), acute renal failure (1), and wound infection (1). There were no anastomotic leaks, reoperations, or deaths. All four patients on preoperative parenteral nutrition were successfully weaned postoperatively and were maintained on enteral nutrition at last follow-up (mean 42, range, 18-120 months). One patient developed recurrent small-bowel obstruction requiring reoperation ten years after the strictureplasty surgery. CONCLUSIONS: Strictureplasty may be an effective and safe tool to conserve intestinal length in certain highly selected patients with chronic radiation enteritis and small-bowel strictures, namely those with limited intestinal reserve where strictures are located within long segments of diseased bowel which, if resected or bypassed, would have significant nutritional or metabolic consequences. Strictureplasty is not indicated for the treatment of perforation, hemorrhage, fistula, or short segments of disease in patients with adequate intestinal reserve.

Safety and longterm efficacy of strictureplasty in 314 patients with obstructing small bowel Crohn's disease.

BACKGROUND: Since its introduction in the early 1980s, strictureplasty (SXP) has become a viable option in the surgical management of obstructing small bowel Crohn's disease. Questions still remain regarding its safety and longterm durability in comparison to resection. Precise indications and contraindications to the procedure are also not well defined. STUDY DESIGN: A retrospective review of all patients undergoing SXP for obstructing small bowel Crohn's disease at the Cleveland Clinic between 1984 and 1999 was conducted. A total of 314 patients underwent a laparotomy that included the index SXP The total number of SXPs performed was 1,124, with a median of two (range 1 to 19) per patient. Sixty-six percent of patients underwent a synchronous bowel resection. Recurrence was defined as the need for reoperation. Followup information was determined by personal interviews, phone interviews, or both. RESULTS: The overall morbidity rate was 18%, with septic complications occurring in 5% of patients. Preoperative weight loss (p = 0.004) and older age (p = 0.008) were found to be significant predictors of morbidity. The surgical recurrence rate was 34%, with a median followup period of 7.5 years (range 1 to 16 years). Age was found to be a significant predictor of recurrence (p = 0.02), with younger patients having a shorter time to reoperation. CONCLUSIONS: This large series of patients with longterm followup confirms the safety and efficacy of strictureplasty in patients with obstructing small bowel Crohn's disease. The 18% morbidity and 34% operative recurrence rates compare favorably with reported results of resective surgery. Caution should be used in patients with preoperative weight loss, because they experienced higher complication rates. Although young patients seem to follow an accelerated course, SXP remains indicated as part of an overall strategy to conserve intestinal length.

Hepatic tumor radioembolization in a rat model using radioactive rhenium (186Re/188Re) glass microspheres.

PURPOSE: The aim of this study was to fully characterize newly developed radioactive rhenium glass microspheres in vivo by determining their biodistribution, stability, antitumor effect, and toxicity after hepatic arterial injection in a syngeneic rat hepatoma model. The dose response of the tumors to increasing amounts of radioactive 186Re and 188Re microspheres was also determined. METHODS AND MATERIALS: Rhenium glass microspheres were made radioactive by neutron activation and then injected into the hepatic artery of Sprague-Dawley rats containing 1-week-old Novikoff hepatomas. The biodistribution of the radioactivity and tumor growth were determined 1 h and 14 days after injection. RESULTS: Examination of the biodistribution indicated a time-dependent, up to 7-fold increase in Novikoff hepatoma uptake as compared to healthy liver tissue uptake. After 14 days, the average T:L ratio was 1.97. Tumor growth in the rats receiving radioactive microspheres was significantly lower than in the group receiving nonradioactive microspheres (142% vs. 4824%, p = 0.048). Immediately after injection, 0.065% of the injected radioactivity was measured in the thyroid; it decreased to background levels within 24 h. CONCLUSION: Radioactive rhenium microspheres are effective in diminishing tumor growth without altering hepatic enzyme levels. The microspheres are safe with respect to their radiation dose to healthy tissue and radiation release in vivo and can be directly imaged in the body with a gamma camera. Furthermore, rhenium microspheres have an advantage over pure beta-emitting microspheres in terms of preparation and neutron-activation time. In sum, this novel radiopharmaceutical may provide an innovative and cost-effective approach for the treatment of nonresectable liver cancer.

Vasopressin selectively increases 5-fluorouracil uptake by colorectal liver metastases following hepatic artery bolus infusion.

BACKGROUND: Poor drug uptake secondary to the hypovascularity of colorectal liver metastases may partially explain their limited response to hepatic artery chemotherapy. Vasoconstrictors can increase tumor perfusion but their effect on drug uptake has not been well-characterized. The aim of this study was to determine whether vasopressin could selectively increase tumor uptake of 5-FU. MATERIALS AND METHODS: A syngeneic rat model of colorectal liver metastases was used. Control group rats underwent a 60-s hepatic artery infusion of 14C-5-FU (30 mCi/150 microL). Treatment group rats had vasopressin (60 mIU/kg, dose determined in pilot study) added to the 14C-5-FU infusion. Mean systemic arterial pressure was minimally affected. Tumor:liver (T/L UR) and tumor center:periphery (C/P UR) 5-FU uptake ratios were determined using quantitative autoradiography techniques. Differences in tumor size (< or > 4 mm) and location (superficial vs deep) were accounted for. Statistical analysis was by repeated measures ANOVA (P = 0.01 significant). RESULTS: A total of 161 tumors in 18 rats was analyzed. T/L URs were significantly higher in the treatment group compared to controls for tumors <4 mm (1.72 +/- 0.14 vs 0.70 +/- 0.16, P <0.001), tumors >4 mm (0.99 +/- 0.15 vs 0.45 +/- 0.16, P = 0.01), deep tumors (1.17 +/- 0.13 vs 0.68 +/- 0.15, P = 0.01), and superficial tumors (1.54 +/- 0. 15 vs 0.47 +/- 0.17, P <0.001). C/P URs did not differ significantly between the groups. CONCLUSIONS: The results of this study show that vasopressin selectively enhances the uptake of 5-FU by colorectal liver metastases in a rat model of hepatic artery infusion. This may represent a promising strategy for improving tumor response rates and patient survival.

Perfusion to colorectal cancer liver metastases is not uniform and depends on tumor location and feeding vessel.

Future effective therapies for hepatic metastases may depend on a better understanding of perfusion to these tumors. The purpose of this project was to define blood flow to colorectal cancer liver metastases using quantitative autoradiography (QAR). Liver tumors were established in F1 hybrids of WF x BN rats by intrasplenic injection of a DMH-induced rat colon adenocarcinoma. Rats underwent laparotomy 4-5 weeks later and [14C]iodoantipyrine (a radiotracer) was infused via the hepatic artery (HA) or portal vein (PV). Livers were harvested, frozen in liquid nitrogen, and sectioned at 20 microns through all tumors. QAR compared optical density of cross sections of tumors to surrounding normal liver tissue. Tumor:liver perfusion ratios (T/L PR) and tumor center:tumor periphery perfusion ratios (C/P PR) were calculated. All groups were analyzed with regard to tumor location and size. Seventy-seven tumors in 6 rats in the HA infusion group were analyzed; 74 tumors in 8 rats in the PV group were analyzed. Statistical analysis was by repeated measures analysis of variance. Mean HA T/L PR = 0.97 +/- 0.13, mean PV T/L PR = 0.25 +/- 0.11. Mean HA T/L PR for deep tumors was 1.38 +/- 0.17 and for superficial tumors was 0.57 +/- 0.15 (P < 0.01). Mean HA T/L PR for small tumors was 1.09 +/- 0.12 and for large tumors was 0.86 +/- 0.21 (P = 0.27). Mean PV T/L PR for deep tumors was 0.27 +/- 0.14 and for superficial tumors was 0.24 +/- 0.15 (P = 0.71). Mean PV T/L PR for small tumors was 0.31 +/- 0.15 and for large tumors was 0.20 +/- 0.14 (P = 0.54). Mean HA C/P PR = 1.15 +/- 0.15, mean PV C/P PR = 0.81 +/- 0.14 (P = 0.06). Mean HA C/P PR for small tumors was 1.37 +/- 0.16 and for large tumors was 0.92 +/- 0.17 (P = 0.01). Mean PV C/P PR for small tumors was 0.78 +/- 0.18 and for large tumors was 0.72 +/- 0.13 (P = 0.71). HA perfusion of tumors is significantly higher than PV perfusion compared to surrounding normal liver tissue. HA perfusion varies significantly depending on tumor location. There was a trend toward HA perfusion to the tumor center being slightly greater than to the periphery whereas the reverse was seen for PV perfusion. Tumor size did not affect overall perfusion but it did affect regional HA tumor perfusion.

Development of a reliable colorectal cancer liver metastasis model.

UNLABELLED: The liver is the most frequent and most fatal site of distant spread of colorectal cancer. Most current animal models of liver metastases utilize direct liver or intravascular injection (dissimilar to mechanisms of metastasis) or immunosuppression to establish metastases. AIM: The aim of this study was to develop a reliable rat model of liver metastases in immunocompetent hosts, whereby metastases spread hematogenously as in colorectal cancer. METHODS: WB-2054 is a poorly differentiated colon adenocarcinoma induced by 1,2 DMH in a WF x BN F1 hybrid rat. WB-2054-M0, Ml, M2, M3, and M4 are successive metastatic variant cell lines obtained through serial application of the Fidler hypothesis. WF x BN F1 rats were inoculated intrasplenically with 1 x 10(6)(M0) or 5 x 10(6)(M0-M4) cells; the spleen was left intact. Animals were evaluated 4 to 12 weeks postinjection and, if no metastases were found, reexplored 1-2 weeks later. Animals with liver metastases were sacrificed, and full abdominal and thoracic zoopsy was performed. Livers were excised and serially sectioned, to determine size, number, and location of liver metastases, and studied histologically to confirm the nature of the metastases. RESULTS: 44% (4/9), 80% (8/10), 86% (65/76), 94% (34/36), and 100% (65/65) of animals inoculated with the M0, M1, M2, M3, and M4 cell lines, respectively, developed liver metastases. Metastases were uniformly spread throughout all lobes of the livers. CONCLUSION: We have developed an extremely hepatotrophic metastatic colorectal cancer cell line. Intrasplenic injection of WB-2054-M4 cells is a reliable model for producing colorectal cancer liver metastases without the need for immunosuppression and should prove valuable in colorectal liver metastasis experiments.