John W. Cromwell

Prolongation of cardiac xenograft survival by depletion of complement

Complement (C) activation is thought to be critical for the hyperacute rejection of xenografts. We investigated the role of C in the rejection of discordant cardiac xenografts by studying outcome in recipients depleted of C, using a highly purified form of cobra venom factor (CVF) in both a small (guinea pig [GP]-to-rat) and large (pig-to-baboon) animal model. A single dose of 30 or 60 units CVF given i.v. to rats completely abrogated hemolytic C activity for up to 72 hr. The lack of hemolytic C activity correlated with nearly undetectable serum levels of C3. Doses of 30 U/kg daily or 60 U/kg every other day over a 7-day period sustained C depletion without morbidity or mortality. Rats receiving GP cardiac xenografts during CVF therapy had significantly prolonged xenograft survival (88 +/- 10 hr in CVF-treated rats vs. 18.6 +/- 7.2 min in control rats, P < 0.001). Rats that rejected GP xenografts at 4 days posttransplant had higher levels of anti-GP antibodies than control rats, without hemolytic C activity at rejection. This rise in xenoreactive Ig reflected an increase in circulating IgG and IgM against GP antigens recognized before transplantation. Histologic analysis of GP cardiac xenografts taken from CVF-treated rats revealed leukocyte and monocyte margination along blood vessels, beginning at 12 hr posttransplant. Progressive cell infiltration, interstitial hemorrhage, and necrosis were observed over the next 72 hr. Rejected GP xenografts showed diffuse deposition of IgM and fibrin within blood vessels but no evidence of C3 deposition. A nonspecific pattern of IgG deposition was noted. CVF was tested in baboons. Complete C depletion was achieved with a dose of 60 U/kg, and was not associated with any morbidity or mortality. Xenotransplantation of a pig heart was performed in one baboon receiving CVF, 60 U/kg/day, for 2 consecutive days. Xenograft survival was prolonged to 68 hr, compared with 90 +/- 30 min in control baboons. Lack of hemolytic activity was noted during engraftment and at rejection. Histology showed evidence of vascular rejection. Immunopathology showed diffuse deposition of IgM, fibrin, and C4, and absence of C3 or membrane attack complex. We conclude that highly purified CVF can achieve marked C depletion with minimal morbidity and no associated fatalities. CVF alone can significantly prolong discordant cardiac xenograft survival. In the GP-to-rat model, the improvement in graft survival achieved with CVF was better than with conventional immunosuppression or isolated acute antibody depletion.(ABSTRACT TRUNCATED AT 400 WORDS)

Salvage Radical Surgery After Failed Local Excision for Early Rectal Cancer

AbstractOBJECTIVES: Local recurrence after transanal excision of rectal cancer is often amenable to salvage radical proctectomy, but the long-term results remain unknown. This study was designed to determine the outcome of salvage radical surgery after failed local excision in patients with early rectal cancer. METHODS: We retrospectively reviewed the charts of 29 patients who underwent salvage radical surgery for local recurrence after a full-thickness transanal excision for Stage I rectal cancer. End points included local and distant recurrences and disease-free survival after salvage radical surgery. Comparisons between groups were performed by chi-squared test. RESULTS: Recurrence involved the rectal wall in 26 patients (90 percent) and was purely extrarectal in only 3 (10 percent). Mean time between local excision and radical operation was 26 months. The resection was considered curative in 23 patients (79 percent). The stage of the recurrent tumor was more advanced than the primary tumor in 27 patients (93 percent). At a mean follow-up of 39 (range, 2–147) months after radical surgery, 17 patients (59 percent) remained free of disease. The disease-free survival rate was 68 percent for patients with tumors with favorable histology vs. 29 percent for patients with tumors with unfavorable histology. CONCLUSION: Salvage surgery for recurrence after local excision of rectal cancers may not provide results equivalent to those of initial radical treatment. In the present study the poor results of salvage surgery emphasize the importance of appropriate selection of the initial treatment of Stage I rectal cancer.

Treatment of locally recurrent rectal cancer.

PURPOSE: This study was designed to analyze the outcome for patients with isolated local recurrence after radical treatment of rectal cancer and to identify predictors of curative resection. METHODS: The medical records of 87 patients who developed isolated local recurrence after curative radical surgery for primary rectal cancer were retrospectively reviewed. Survival rates from the time of recurrence were calculated using the Kaplan-Meier method. Tumor stage and histology, patient characteristics, and treatment variables were analyzed using logistic regression to identify predictors of curative surgery. RESULTS: Symptomatic treatment alone or chemotherapy and/or radiation therapy was provided to 23 patients (26 percent), and surgical exploration was performed in 64 patients. In 22 patients (25 percent), the tumor was considered unresectable at surgery (n=13) or was resected for palliation with gross or microscopic positive margins (n=9). In 42 patients (48 percent), curative-intent resection was performed. The only independent predictors of resectability were younger age at diagnosis, earlier stage of the primary tumor, and initial treatment by sphincter-saving procedure. There was no difference in survival between patients who had no surgery and those who had palliative surgery. The estimated five-year survival rate for patients who had curative-intent resection was better than for those who had no surgery or palliative surgery (35vs. 7 percent;P=0.01). Of the 42 patients who underwent curative-intent resection, 14 (33 percent) developed a second recurrence at a mean of 15±11 months after reoperation. Twenty-five percent of patients developed major complications. CONCLUSIONS: Salvage surgery for locally recurrent rectal cancer may be helpful in a selected group of patients. The stage and treatment of the primary tumor may help to identify patients with the best chance for curative-intent resection.

Prolongation Of Renal Allograft Survival In A Large Animal Model By Oral Rapamycin Monotherapy

We assessed the efficacy of 5 dose levels of oral rapamycin for prolonging renal allograft survival in pigs. Untreated and triple therapy groups (cyclosporine, azathioprine, and prednisone) served as controls. Immunosuppression was administered for 28 days posttransplant and then stopped. Rapamycin whole-blood concentrations were followed weekly. Chemistry, hematology, and lipid values were monitored post-transplant. For rapamycin-treated pigs, median survival time (MST) correlated with both dose and trough levels (ng/ml). All kidneys had some degree of rejection seen on necropsy. After rejection, pneumonia was the most common cause of death. No specific end-organ toxicity was noted on histopathologic examination. Triglyceride and cholesterol levels increased in all treated pigs (both rapamycin and triple therapy) vs. untreated controls--however, all values were within normal limits. Mean ALT levels increased in weeks 2 to 4 in the higher-dose rapamycin groups but returned to baseline in pigs surviving after the drug was stopped. ALT levels did not increase above twice normal in any group. Creatinine levels correlated with the degree of rejection seen on biopsy. We noted no other toxicities. We conclude that rapamycin, given as oral monotherapy, is an effective and safe immunosuppressant in our large animal renal allograft model. Outcome correlated with dose and whole-blood levels.

Medical and Surgical Management of Pelvic Floor Disorders Affecting Defecation

Pelvic floor disorders that affect stool evacuation include structural (for example, rectocele) and functional disorders (for example, dyssynergic defecation (DD)). Meticulous history, digital rectal examination (DRE), and physiological tests such as anorectal manometry, colonic transit study, balloon expulsion, and imaging studies such as anal ultrasound, defecography, and static and dynamic magnetic resonance imaging (MRI) can facilitate an objective diagnosis and optimal treatment. Management consists of education and counseling regarding bowel function, diet, laxatives, most importantly behavioral and biofeedback therapies, and finally surgery. Randomized clinical trials have established that biofeedback therapy is effective in treating DD. Because DD may coexist with conditions such as solitary rectal ulcer syndrome (SRUS) and rectocele, before considering surgery, biofeedback therapy should be tried and an accurate assessment of the entire pelvis and its function should be performed. Several surgical approaches have been advocated for the treatment of pelvic floor disorders including open, laparoscopic, and transabdominal approach, stapled transanal rectal resection, and robotic colon and rectal resections. However, there is lack of well-controlled randomized studies and the efficacy of these surgical procedures remains to be established.

Pelvic wall involvement denotes a poor prognosis in T4 rectal cancer

PURPOSE: An aggressive surgical approach with en bloc resection of involved structures is often possible with anterior rectal cancers that invade adjacent visceral organs, but is rarely possible in tumors that invade the pelvic wall. However, most staging systems include both situations in the same group of T4 rectal cancers. We performed a retrospective study of patients with stage T4 rectal cancer undergoing surgery to assess the influence of different organ involvement on resectability and survival. METHODS: A retrospective review was conducted of 84 patients with T4 rectal cancer treated at the University of Minnesota and affiliated hospitals over a ten-year period. Forty-seven patients (56 percent) were staged for local invasion on the basis of final pathology, 19 (23 percent) on the basis of operative findings, and 18 (21 percent) on the basis of ultrasound images. Patients were divided into two groups, those with or without pelvic wall involvement. Resectability, local control, and overall survival were compared between groups. Survival curves were estimated by the Kaplan-Meier method and compared by log-rank test. Multivariate analysis was performed with Cox proportional and logistic regression. RESULTS: Thirty-one patients (37 percent) had involvement of the pelvic wall, whereas 53 patients (63 percent) had visceral involvement only. All 29 patients with distant metastasis died of their disease. Forty-seven of the 55 patients without distant metastasis underwent tumor resection. Age and pelvic wall involvement were the only two factors independently associated with the probability of resection in logistic regression analysis (P=0.0067 andP=0.037, respectively). The only factor that affected median survival in patients without distant metastasis was tumor resection (49.1 months for resectionvs. 6.1 months for no resection,P=0.017). Patients with visceral involvement had a longer median survival (49.2 months) than those with pelvic wall involvement (13.2 months), but the difference did not reach statistical significance (P=0.058). CONCLUSION: Rectal cancers with pelvic and visceral involvement have different rates of resectability and median survival. These differences should be reflected in the TNM classification system.

Factors associated with conversion from laparoscopic to open colectomy using the National Surgical Quality Improvement Program (NSQIP) database.

Conversion rates from laparoscopic to open colectomy and associated factors are traditionally reported in clinical trials or reviews of outcomes from experienced institutions. Indications and selection criteria for laparoscopic colectomy may be more narrowly defined in these circumstances. With the increased adoption of laparoscopy, conversion rates using national data need to be closely examined. The purpose of this study was to use data from the American College of Surgeons National Surgical Quality Improvement Program (ACS‐NSQIP) to identify factors associated with conversion of laparoscopic to open colectomy at a national scale in the United States.

Is the abdominal repair of rectal prolapse safer than perineal repair in the highest risk patients? An NSQIP analysis.

BACKGROUND: Although the perineal approach in the surgical management of rectal prolapse has a higher recurrence, it is the accepted approach for higher-risk patients because of its lower morbidity. OBJECTIVE: The aim of this study was to determine outcomes of abdominal versus perineal approaches to rectal prolapse repair. DESIGN SETTINGS: A retrospective study was performed comparing outcomes of patients undergoing different types of surgical approaches (open abdominal, laparoscopic, perineal) for rectal prolapse. PATIENTS: The American College of Surgeons National Surgical Quality Improvement Participant User Data Files (2008–2009) were queried for patients undergoing adult, elective procedures for rectal prolapse. MAIN OUTCOME MEASURES: Univariate analysis and multivariate logistic regression were performed to look at age, ASA classification, procedure type, and resultant mortality rate. RESULTS: One thousand four hundred sixty-nine patients meeting our criteria were identified. Older patients (age>80) and higher-risk patients (ASA classifications 3and 4) were significantly associated with the selection of the perineal approach. The overall mortality rate was 0.5%. The mortality rate for all perineal procedures was 0.9% in comparison with 0.13% for all abdominal operations (p = 0.033). The mortality rate for the highest-risk groups (ASA 3 and 4) for perineal procedures was 1.3% in comparison with 0.35% in the abdominal procedure group; the relative risk for mortality was 4 times greater in the perineal procedure group than in the abdominal procedure group. LIMITATIONS: The retrospective design and standardized outcomes measured use administrative-level data and prevent the assessment of procedure-specific outcomes. CONCLUSIONS: Hospital mortality for the surgical repair of rectal prolapse is uncommon. The decision to choose the abdominal approach for the repair of rectal prolapse may not be as prohibitive as previously thought for higher-risk patients. Because of the broad range of functionality within each ASA classification, the operation offered should always be individualized, and patient selection is the most important factor.

Effect of BMI on outcomes in proctectomy.

BACKGROUND: The unique surgical challenges of proctectomy may be amplified in obese patients. We examined surgical outcomes of a large, diverse sample of obese patients undergoing proctectomy. OBJECTIVE: The purpose of this work was to determine whether increased BMI is associated with increased complications in proctectomy. DESIGN: This was a retrospective review. SETTINGS: The study uses the American College of Surgeons National Surgical Quality Improvement Program database (2010 and 2011). PATIENTS: Patients included were those undergoing nonemergent proctectomy, excluding rectal prolapse cases. Patients were grouped by BMI using the World Health Organization classifications of underweight (BMI <18.5); normal (18.5-24.9); overweight (25.0-29.9); and class I (30.0-34.9), class II (35.0-39.9), and class III (≥40.0) obesity. MAIN OUTCOME MEASURES: We analyzed the effect of preoperative and intraoperative factors on 30-day outcomes. Continuous variables were compared with Wilcoxon rank-sum tests and proportions with the Fisher exact or &khgr;2 tests. Logistic regression controlled for the effects of multiple risk factors. RESULTS: Among 5570 patients, class I, II, and III obesity were significantly associated with higher rates of overall complications (44.0%, 50.8%, and 46.6% vs 38.1% for normal-weight patients; p < 0.05). Superficial wound infection was significantly higher in classes I, II, and III (11.6%, 17.8%, and 13.0% vs 8.0% for normal-weight patients; p < 0.05). Operative times for patients in all obesity classes were significantly longer than for normal-weight patients. On multivariate analysis, an obese BMI independently predicted complications; ORs (95% CIs) were 1.36 (1.14-1.62) for class I obesity, 1.99 (1.54-2.54) for class II, and 1.42 (1.02-1.96) for class III. LIMITATIONS: This study was a retrospective design with limited follow-up. CONCLUSIONS: Class I, II, and III obese patients were at significantly increased risk for morbidity compared with normal BMI patients. Class II obese patients had the highest rate of complications, a finding that deserves further investigation.

Sarcopenia is a Predictor of Surgical Morbidity in Inflammatory Bowel Disease

Background: Sarcopenia is associated with an increased risk of operative morbidity and mortality. The impact of sarcopenia in inflammatory bowel disease (IBD) has not been evaluated. This study assessed the role of sarcopenia on operative outcomes in IBD. Methods: A retrospective review of American College of Surgeons National Surgical Quality Improvement Program data of patients with IBD was completed. Records were abstracted for comorbidities and perioperative complications. The Hounsfield unit average calculation was used from preoperative computed tomography (CT). Criteria for sarcopenia were based on the lowest 25th percentile. Complications were graded using the Clavien–Dindo classification system. Statistical analysis was completed using SAS. Results: There were 178 patients included. Sarcopenic patients were more likely to be older (P = 0.001), have hypertension (odds ratio = 2.23), and be diabetic (5.27). In those patients younger than 40 years, sarcopenia was an independent predictor of complications. This subset was significantly more likely to have a normal or elevated body mass index. Conclusions: In this population, the average age of sarcopenic patients is increased from those who do not meet criteria. Among patients younger than 40 years, sarcopenia affects surgical outcomes. Assessment of sarcopenia can be used to improve preoperative management and describe risks before surgery in patients with IBD.