Neoadjuvant Radiation Therapy in Locally Advanced Colon Cancer: a Cohort Analysis.

BACKGROUND: A paucity of data exists in the use of neoadjuvant chemoradiation therapy (NRT) for T4, non-metastatic colon cancer. This study was conducted to determine the effect of NRT on outcomes after resection for T4 colon cancer. METHODS: All patients with non-metastatic resected clinical T4 colon cancer from 2000 to 2012 at a tertiary care center were included. The cohort was divided into two groups-those that received NRT and those that did not (non-NRT). The primary outcomes were margin-negative resection and overall survival (OS). RESULTS: One hundred and thirty-one consecutive patients with non-metastatic clinical T4 colon cancer with a mean age of 65 years were included. NRT was used in 23 patients (17.4%). NRT group was noted to have non-statistically significant improvement in R0 resection rate (NRT 95.7% vs non-NRT 88.0%; p = 0.27) and local recurrence (NRT 4.3% vs non-NRT 15.7%; p = 0.15). There was a significant difference in T-stage downstaging between the two groups (NRT 30.4% vs non-NRT 6.5%; p = 0.007). In a bivariate analysis, NRT was associated with improved 5-year OS (NRT 76.4% vs non-NRT 51.5%; p = 0.03). This relationship did not persist in a Cox proportional hazard analysis that included age and comorbidity (HR 2.19; 95% CI 0.87-5.52; p = 0.09). CONCLUSIONS: The use of NRT in locally advanced T4 colon cancer is safe and associated with increased downstaging. While there was a trend toward improvement in local recurrence and the ability to obtain margin-negative resections in the NRT group, this was not significant. Significantly improved overall survival was not observed in a multivariable analysis.

Omission of Adjuvant Chemotherapy Is Associated With Increased Mortality in Patients With T3N0 Colon Cancer With Inadequate Lymph Node Harvest.

BACKGROUND: Adjuvant chemotherapy for T3N0 colon cancer is controversial. National guidelines recommend its use in patients with stage II with high-risk features, including lymph node harvest of less than 12, yet this treatment is underused. OBJECTIVE: The purpose of this study was to demonstrate that the use of adjuvant chemotherapy in patients with T3N0 adenocarcinoma with inadequate lymph node harvest is beneficial. DESIGN: This was a retrospective population-based study of patients with resected T3N0 adenocarcinoma of the colon. SETTINGS: The National Cancer Database was queried from 2003 to 2012. PATIENTS: A total of 134,567 patients with T3N0 colon cancer were included in this analysis. MAIN OUTCOME MEASURES: The use of chemotherapy, short-term outcomes, and overall survival was evaluated. Clinicopathologic factors associated with omission of chemotherapy were also analyzed. RESULTS: Inadequate lymph node harvest was observed in 23.3% of patients, and this rate decreased over the study period from 46.8% in 2003 to 12.5% in 2012 (p < 0.0001). Overall 5-year survival for patients with T3N0 cancer was 66.8%. Inadequate lymph node harvest among these patients was associated with lower overall 5-year survival (58.7% vs 69.8%; p < 0.001). The use of adjuvant chemotherapy among patients with T3N0 cancer after inadequate lymph node harvest was only 16.7%. In a multivariable analysis, factors associated with failure to receive chemotherapy included advanced age (OR = 0.44 (95% CI, 0.43-0.45)), increased comorbidities (OR = 0.7 (95% CI, 0.66-0.76)), and postoperative readmission (OR = 0.78 (95% CI, 0.67-0.91)). Patients with inadequate lymph node harvest who received adjuvant chemotherapy had improved 5-year survival (chemotherapy, 78.4% vs no chemotherapy, 54.7%; p < 0.001). Even when controlling for all of the significant variables, the administration of chemotherapy remained a predictor of decreased mortality (HR = 0.57 (95% CI, 0.54-0.60); p < 0.001). LIMITATIONS: This study was limited by its retrospective, population-based design. CONCLUSIONS: Patients with T3N0 colon cancer with inadequate lymph node harvest who receive adjuvant chemotherapy have increased overall survival. Despite this survival benefit, a fraction of these patients receive adjuvant chemotherapy. Barriers to chemotherapy are multifactorial.

Parastomal Hernia: Avoidance and Treatment in the 21st Century.

Despite medical and surgical advances leading to increased ability to restore or preserve gastrointestinal continuity, creation of stomas remains a common surgical procedure. Every ostomy results in a risk for subsequent parastomal herniation, which in turn may reduce quality of life and increase health care expenditures. Recent evidence-supported practices such as utilization of prophylactic reinforcement, attention to stoma placement, and laparoscopic-based stoma repairs with mesh provide opportunities to both prevent and successfully treat parastomal hernias.

Does Diverting Loop Ileostomy Improve Outcomes Following Open Ileo-Colic Anastomoses? A Nationwide Analysis.

BACKGROUND: Anastomotic leak is one of the most feared complications of gastrointestinal surgery. Surgeons routinely perform a diverting loop ileostomy (DLI) to protect high-risk colo-rectal anastomoses. STUDY DESIGN: The NSQIP database was queried from 2012 to 2013 for patients undergoing open ileo-colic resection with and without a DLI. The primary outcome was the development of any anastomotic leak-including those managed operatively and non-operatively. Secondary outcomes included overall complication rate, return to the OR, readmission, and 30-day mortality. RESULTS: Four thousand one hundred fifty-nine patients underwent open ileo-colic resection during the study period. One hundred eighty-six (4.5 %) underwent a DLI. Factors associated with the addition of a DLI included emergency surgery, pre-operative sepsis, and IBD. There were 197 anastomotic leaks (4.7 %) with 100 patients requiring reoperation (2.4 %). DLI was associated with a decrease in anastomotic leaks requiring reoperation (DLI vs no DLI: 0 (0 %) vs 100 (2.5 %); p = 0.02) and with increased readmission (OR 1.93; 95 % CI 1.30-2.85; p = 0.001). CONCLUSION: DLI is rarely used for open ileo-colic resection. There were no serious leaks requiring reoperation in the DLI group. A DLI was associated with an almost two-fold increase in the odds of readmission. Surgeons must weigh the reduction in serious leak rate with postoperative morbidity when considering a DLI for open ileo-colic resection.

Impaired outcome colitis-associated rectal cancer versus sporadic cancer.

BACKGROUND: The surgical management of colitis-associated rectal cancer (CARC) is not well defined. This study determines outcomes after surgery for CARC compared with sporadic rectal cancer. MATERIALS AND METHODS: This is a retrospective cohort study comparing 27 patients with CARC with 54 matched patients with sporadic cancer. Matching criteria included age, gender, neoadjuvant chemoradiation, and American Joint Committee on Cancer stage. Outcome measures were disease-free and overall survival, tumor characteristics, and postoperative morbidity. RESULTS: Compared to those with sporadic rectal cancer, patients with CARC underwent proctocolectomy more frequently (21 [78%] versus 6 [22%] P < 0.001) and were more likely to have mucinous tumors (11 [40.7%] versus 12 [22.3%] P = 0.03). Overall 3-y survival was significantly reduced in CARC patients compared with patients with sporadic rectal cancer. Those with CARC undergoing segmental proctectomy only demonstrated reduced overall and disease-free survival compared to patients with sporadic rectal cancer and to colitis patients undergoing proctocolectomy (P = 0.002). CONCLUSIONS: Patients with CARC undergoing proctectomy demonstrate reduced disease-free survival versus those undergoing proctocolectomy, and versus patients with sporadic rectal cancer undergoing proctectomy. These findings warrant further study and suggest that proctocolectomy should be considered the preferred surgical approach for CARC.

Optimal Colostomy Placement in Spinal Cord Injury Patients.

Barring unusual circumstances, sigmoid colostomy is the optimal technique for management of defecation in spinal cord injury (SCI) patients. We sought to provide evidence that a sigmoid colostomy is not difficult to perform in SCI patients and has better long-term results. The St. Louis Department of Veterans Affairs has a Commission on Accreditation of Rehabilitation Facilities (CARF)-approved SCI Unit. We reviewed the operative notes on all SCI patients who received a colostomy for fecal management by three ASCRS-certified colorectal surgeons at the St. Louis Department of Veterans Affairs from January 1, 2007 to November 26, 2012. There were 27 operations for which the recorded indication for surgery suggested that the primary disorder was SCI. Fourteen had traumatic SCI of the thoracic and/or lumbar spine and were evaluable. Of these 14 patients, 12 had laparoscopic sigmoid colostomy and two had open sigmoid colostomy. We encountered one evaluable patient with a remarkably large amount of retroperitoneal bony debris who successfully underwent laparoscopic sigmoid colostomy. In conclusion, sigmoid colostomy is the consensus optimal procedure for fecal management in SCI patients. Laparoscopic procedures are preferred. Care providers should specify sigmoid colostomy when contacting a surgeon.

Polyp Genetics.

The genetic events involved in the transformation of normal colonic epithelium to neoplastic polyps to invasive carcinoma, as initially proposed by Fearon and Vogelstein, form the foundation of our understanding of colorectal cancer. The identification of the polyp as the precursor lesion to colorectal cancer is the basis of many of our current practices for screening, surveillance, and prevention. The last three decades have seen a veritable explosion in our understanding of the molecular events involved in the pathogenesis of colorectal cancer. It is now clear that there are multiple genetic pathways in the polyp to carcinoma sequence. Some polyps previously thought to be nonneoplastic have now been shown to have malignant potential. Finally, increased understanding of the sequence of genetic events has led to the development of targeted therapeutics. The clinical translation of these scientific advances has made a significant impact on the management of patients with colorectal cancer. Accordingly, it is imperative that all clinicians caring for these patients have an understanding of the genetics of colorectal polyps and cancer. In this article, we review the etiology and genetic pathways to carcinoma associated with a range of polyps of the colon and rectum.

Acute health care resource utilization for ileostomy patients is higher than expected.

BACKGROUND: Patients requiring an ileostomy following colorectal surgery are at risk for increased health-care utilization after discharge. Prior studies evaluating postoperative ileostomy care may underestimate health-care utilization by reporting only "same-institution" readmission rates. OBJECTIVE: The aim of this study was to determine the rates of health-care utilization of new ostomates within 30 days of discharge in a multicenter environment. DESIGN: This is a retrospective cohort study. SETTINGS: This study was conducted at acute-care, community hospitals in California, Florida, Nebraska, and New York. PATIENTS: Adult patients who underwent colorectal surgery with primary anastomosis, colostomy, or ileostomy between July 2009 and September 2010 were identified. MAIN OUTCOME MEASURES: The primary outcome measured was hospital-based acute care, defined as hospital readmission or emergency department visit, at any hospital within 30 days of surgery. Multivariate regression models were used to compare the outcomes across groups. RESULTS: Overall, 75,136 patients underwent colectomy with most receiving a primary anastomosis (79.3%), whereas colostomies were created in 12.8% and ileostomies were created in 8.0%. Diagnoses of colorectal cancer (36.1%) or diverticular disease (22.0%) were most common. Patients with a colostomy (18.8%; adjusted odds ratio [AOR], 1.23 [95% CI, 1.17-1.30]) or ileostomy (36.1%; AOR, 2.28 [95% CI 2.15-2.42]) were significantly more likely than patients with a primary anastomosis (16.2%) to have a hospital-based acute-care encounter within 30 days of discharge. Among patients undergoing ileostomy, postoperative infection, renal failure, and dehydration were the most common diagnoses for hospital-based acute-care events. Overall, 20% of these encounters occurred at hospitals other than where the index surgery occurred. LIMITATIONS: Coding accuracy, the inability to capture events occurring in physician offices, and the retrospective study design were limitations of the study. CONCLUSIONS: Patients undergoing colorectal surgery with an ileostomy return to the hospital after discharge twice as frequently as those with a primary anastomosis or colostomy, often to hospitals other than the primary institution. As postdischarge health-care utilization becomes a measured quality metric, it is increasingly important to help these patients to safely transition to home.

Intestinal epithelial HuR modulates distinct pathways of proliferation and apoptosis and attenuates small intestinal and colonic tumor development.

HuR is a ubiquitous nucleocytoplasmic RNA-binding protein that exerts pleiotropic effects on cell growth and tumorigenesis. In this study, we explored the impact of conditional, tissue-specific genetic deletion of HuR on intestinal growth and tumorigenesis in mice. Mice lacking intestinal expression of HuR (Hur (IKO) mice) displayed reduced levels of cell proliferation in the small intestine and increased sensitivity to doxorubicin-induced acute intestinal injury, as evidenced by decreased villus height and a compensatory shift in proliferating cells. In the context of Apc(min/+) mice, a transgenic model of intestinal tumorigenesis, intestinal deletion of the HuR gene caused a three-fold decrease in tumor burden characterized by reduced proliferation, increased apoptosis, and decreased expression of transcripts encoding antiapoptotic HuR target RNAs. Similarly, Hur(IKO) mice subjected to an inflammatory colon carcinogenesis protocol [azoxymethane and dextran sodium sulfate (AOM-DSS) administration] exhibited a two-fold decrease in tumor burden. Hur(IKO) mice showed no change in ileal Asbt expression, fecal bile acid excretion, or enterohepatic pool size that might explain the phenotype. Moreover, none of the HuR targets identified in Apc(min/+)Hur(IKO) were altered in AOM-DSS-treated Hur(IKO) mice, the latter of which exhibited increased apoptosis of colonic epithelial cells, where elevation of a unique set of HuR-targeted proapoptotic factors was documented. Taken together, our results promote the concept of epithelial HuR as a contextual modifier of proapoptotic gene expression in intestinal cancers, acting independently of bile acid metabolism to promote cancer. In the small intestine, epithelial HuR promotes expression of prosurvival transcripts that support Wnt-dependent tumorigenesis, whereas in the large intestine epithelial HuR indirectly downregulates certain proapoptotic RNAs to attenuate colitis-associated cancer. Cancer Res; 74(18); 5322-35. ©2014 AACR.

Segmental versus extended resection for sporadic colorectal cancer in young patients.

BACKGROUND AND OBJECTIVES: Guidelines on the management of colon cancer state that extensive colectomy should be "considered" for patients of young age (<50). This study aimed to compare the risk of metachronous cancer, overall recurrence and mortality between segmental and extended colon resections in patients under the age of 50 with sporadic CRC. METHODS: We performed a retrospective review of patients age <50 undergoing surgery for CRC from 1991 to 2009. Patients were divided into two groups based on extent of resection: segmental versus extended. The primary outcomes analyzed were metachronous tumors, disease recurrence, and overall survival. RESULTS: Two hundred seventy one patients underwent segmental resection and 30 underwent extended resection. 3.3% in the segmental resection group developed metachronous CRC versus 0% in the extended resection group (P = 0.61). There was no significant difference in the risk of recurrence or mortality for those who underwent a segmental resection compared to those with an extended resection. In a regression model, type of surgery was not an independent risk factor for recurrence or mortality. CONCLUSIONS: Extended colectomy for sporadic CRC in patients younger than 50 does not improve disease-free or overall survival. Further study to determine if segmental resection is appropriate oncologic treatment is warranted.

Accordion complication grading predicts short-term outcome after right colectomy.

BACKGROUND: The Accordion severity grading system is a novel system to score the severity of postoperative complications in a standardized fashion. This study aims to demonstrate the validity of the Accordion system in colorectal surgery by correlating severity grades with short-term outcomes after right colectomy for colon cancer. METHODS: This is a retrospective cohort review of patients who underwent right colectomy for cancer between January 1, 2002, and January 31, 2007, at a single tertiary care referral center. Complications were categorized according to the Accordion severity grading system: grades 1 (mild), 2 (moderate), 3-5 (severe), and 6 (death). Outcome measures were hospital stay, 30-d readmission rate and 1-y survival. Correlation between Accordion grades and outcome measures is reflected by Spearman rho (ρ). One-year survival was obtained per Kaplan-Meier method and compared by logrank test for trend. Significance was set at P ≤ 0.05. RESULTS: Overall, 235 patients underwent right colectomy for cancer of which 122 (51.9%) had complications. In total, 52 (43%) had an Accordion grade 1 complication; 44 (36%) grade 2; four (3%) grade 3; 11 (9%) grade 4; seven (6%) grade 5; and four (3%) grade 6. There was significant correlation between Accordion grades and hospital stay (ρ = 0.495, P < 0.001) and 30-d readmission rate (ρ = 0.335, P < 0.001). There was a significant downward trend in 1-y survival as complication severity by Accordion grade increased (P = 0.02). CONCLUSIONS: The Accordion grading system is a useful tool to estimate short-term outcomes after right colectomy for cancer. High-grade Accordion complications are associated with longer hospital stay and increased risk of readmission and mortality.

Obesity increases risk for pouch-related complications following restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA).

PURPOSE: Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the preferred surgical treatment for patients with ulcerative colitis and familial adenomatous polyposis. As obesity is becoming more epidemic in surgical patients, the aim of this study was to investigate if obesity increases complication rates following IPAA. METHODS: This study was conducted as a retrospective review of patients undergoing IPAA between January 1990 and April 2011. Patients were categorized by body mass index (BMI): BMI < 30 (non-obese) and BMI ≥ 30 (obese). Preoperative patient demographics, operative variables, and postoperative complications were recorded through chart review. The primary outcome studied was cumulative complication rate. RESULTS: A total of 103 non-obese and 75 obese patients were identified who underwent IPAA. Obese patients had an increased rate of overall complications (80 % vs. 64%, p = 0.03), primarily accounted for by increased pouch-related complications (61% vs. 26%, p < 0.01). In particular, obese patients had more anastomotic/pouch strictures (27% vs. 6%, p < 0.01), inflammatory pouch complications (17 % vs. 4%, p < 0.01) and pouch fistulas (12% vs. 3%, p = 0.03). In a regression model, obesity remained a significant risk factor (odds ratio [OR] = 2.86, p = 0.01) for pouch-related complications. CONCLUSIONS: Obesity is associated with an increased risk of overall and pouch-related complications following IPAA. Obese patients should be counseled preoperatively about these risks accordingly.

Liver fatty acid-binding protein (L-Fabp) modifies intestinal fatty acid composition and adenoma formation in ApcMin/+ mice.

Evidence suggests a relationship between dietary fat intake, obesity, and colorectal cancer, implying a role for fatty acid metabolism in intestinal tumorigenesis that is incompletely understood. Liver fatty acid-binding protein (L-Fabp), a dominant intestinal fatty acid-binding protein, regulates intestinal fatty acid trafficking and metabolism, and L-Fabp deletion attenuates diet-induced obesity. Here, we examined whether changes in intestinal fatty acid metabolism following L-Fabp deletion modify adenoma development in Apc(Min)(/+) mice. Compound L-Fabp(-/-)Apc(Min)(/+) mice were generated and fed a 10% fat diet balanced equally between saturated, monounsaturated, and polyunsaturated fat. L-Fabp(-/-)Apc(Min)(/+) mice displayed significant reductions in adenoma number and total polyp area compared with Apc(Min)(/+)controls, reflecting a significant shift in distribution toward smaller polyps. Adenomas from L-Fabp(-/-)Apc(Min)(/+) mice exhibited reductions in cellular proliferation, high-grade dysplasia, and nuclear ß-catenin translocation. Intestinal fatty acid content was increased in L-Fabp(-/-)Apc(Min)(/+) mice, and lipidomic profiling of intestinal mucosa revealed significant shifts to polyunsaturated fatty acid species with reduced saturated fatty acid species. L-Fabp(-/-)Apc(Min)(/+) mice also showed corresponding changes in mRNA expression of enzymes involved in fatty acid elongation and desaturation. Furthermore, adenomas from L-Fabp(-/-)Apc(Min)(/+) mice displayed significant reductions in mRNA abundance of nuclear hormone receptors involved in cellular proliferation and in enzymes involved in lipogenesis. These findings collectively implicate L-Fabp as an important genetic modifier of intestinal tumorigenesis, and identify fatty acid trafficking and metabolic compartmentalization as an important pathway linking dietary fat intake, obesity, and intestinal tumor formation.

The efficacy of nonoperative management of acute complicated diverticulitis.

BACKGROUND: The surgical management of acute complicated diverticulitis has evolved to avoid emergency surgery in favor of elective resection. The optimal manner to accomplish this goal remains debatable. OBJECTIVE: The purpose of this study was to examine the efficacy of nonoperative management of acute diverticulitis with abscess or perforation. DESIGN: A retrospective review was performed of an institutional review board-approved database of patients admitted with a diagnosis of acute complicated diverticulitis from 1995 to 2008. Patient demographics, disease manifestation, management, and outcomes were collected. SETTINGS: This study was conducted at a tertiary care hospital/referral center. PATIENTS: Patients were included who presented with complicated diverticulitis defined as having an associated abscess or free air diagnosed by CT scan. MAIN OUTCOME MEASURES: Primary end points were the success of nonoperative management and need for surgery during the initial admission. RESULTS: One hundred thirty-six patients were identified with perforated diverticulitis: 19 had localized free air, 45 had abscess <4 cm or distant free air measuring <2 cm, 66 had abscess >4 cm or distant free air >2 cm, and 6 had distant free air with free fluid. Thirty-eight patients (28%) required percutaneous abscess drains and 37 (27%) required parenteral nutrition. Only 5 patients (3.7%) required urgent surgery at the time of admission, and 7 (5%) required urgent surgery for failed nonoperative management. Thus, the overall success rate of nonoperative management was 91%. One hundred twenty-four of 131 (95%) patients were treated with nonoperative management successfully. Twenty-five of 27 (92.5%) patients with free air remote from the perforation site were successfully treated nonoperatively. CONCLUSIONS: Nonoperative management of acute complicated diverticulitis is highly effective. For patients with free air remote from the site of perforation, nonoperative management is able to convert an emergent situation into an elective one in 93% of cases. The decision to attempt nonoperative therapy must be made based on the patient's physiologic state and associated comorbidities.

Clinically enlarged lateral pelvic lymph nodes do not influence prognosis after neoadjuvant therapy and TME in stage III rectal cancer.

PURPOSE: The significance of lateral pelvic lymph nodes (LPLN) in rectal cancer remains unclear. The purpose of this study was to determine the outcome of patients with LPLNs identified on pretherapy imaging who were treated with neoadjuvant therapy followed by proctectomy without LPLN dissection. METHODS: Pretherapy imaging of patients with stage III rectal cancer was reviewed to determine perirectal and LPLN enlargement. Data were collected on preoperative therapy, operative resection, adjuvant therapy, and patient outcomes and were correlated to the presence or absence of preoperatively identified LPLNs (LPLN+ and LPLN-). RESULTS: Of the 53 patients identified who were treated between 2000 and 2005, 30 (57%) were LPLN+ on preoperative imaging. All patients received preoperative radiation therapy and total mesorectal excision. The local recurrence was 13%, and there was no difference related to LPLN status. A comparison of the overall and disease-free survival in patients with and without enlarged LPLNs revealed no difference. CONCLUSIONS: The LPLNs that were identified on pretherapy imaging do not affect the overall or disease-free survival after the neoadjuvant therapy and proctectomy in stage III rectal cancer. A lateral pelvic lymph node dissection does not appear to be justified in stage III patients with LPLNs on pretherapy imaging who receive neoadjuvant therapy.

Laparoscopic versus open 2-stage ileal pouch: laparoscopic approach allows for faster restoration of intestinal continuity.

BACKGROUND: Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the treatment of choice for patients with ulcerative colitis and familial adenomatous. This study examined the impact of the surgical approach (laparoscopic versus open) to IPAA on short-term outcomes and time to ileostomy closure in 2-stage restorative proctocolectomies. STUDY DESIGN: A retrospective review was performed on a prospectively maintained database at Washington University School of Medicine for patients undergoing elective 2-stage restorative proctocolectomy and IPAA from April of 1999 through July of 2008. Outcomes for patients were analyzed according to laparoscopic versus open technique. RESULTS: A total of 124 patients (55 laparoscopy, 69 open) were included in this study. Laparoscopic IPAA took, on average, 79.2 minutes longer to complete than open IPAA (p < 0.0001) and required significantly more intravenous fluid administration (p = 0.0004). There was no significant difference between laparoscopic and open IPAA with respect to estimated blood loss, blood transfusions, postoperative narcotic usage, return of bowel function, length of stay, and hospital readmission rates. Total complications were not statistically significant between the 2 groups. Patients in the laparoscopic IPAA group underwent ileostomy closure an average of 24.1 days sooner than patients in the open group (p = 0.045). Multivariate analysis revealed that surgical approach (p = 0.018) and length of stay (p = 0.004) were associated with faster time to closure of loop ileostomy. CONCLUSIONS: Laparoscopic IPAA is safe, with postoperative morbidity comparable with open IPAA. Laparoscopic IPAA can lead to faster recovery and result in faster progression to restoration of intestinal continuity in patients undergoing 2-stage restorative proctocolectomy.

Molecular imaging of pulmonary gene expression with positron emission tomography.

Gene expression imaging is one form of molecular imaging used to visualize, characterize, and quantify, spatially and temporally, normal as well as pathologic processes at cellular and subcellular levels within intact living organisms. Most studies to date have employed positron emission tomography as the imaging platform to detect, monitor, and quantify gene expression in the lungs. These studies have shown that imaging can be used to determine the onset and duration of transgene expression, the effectiveness of different gene delivery systems, and the linearity of vector dose-response relationships. This rapidly developing field can be expected to provide useful new tools with which to study gene expression in transgenic animals and in humans during gene therapy.

Molecular imaging of the lungs.

An emerging suite of new imaging techniques offer the ability to monitor and quantify molecular and cellular processes in the lungs noninvasively. These techniques take advantage of dramatic advances in both imaging technology as well as molecular and cell biology. Molecular imaging is being used with increasing regularity in research protocols, and forms of molecular imaging have found their way into the patient care setting (eg, positron emission tomography imaging in cancer). Such techniques will afford the basic scientist as well as the clinician an unprecedented opportunity for in vivo study of the lung biology that drives normal pulmonary physiology as well as pathophysiology.

Animal models for bronchiolitis obliterans syndrome following human lung transplantation.

Lung transplantation is the only viable treatment option that can improve survival and enhance the quality of life of patients with end-stage lung diseases such as emphysema, cystic fibrosis, idiopathic pulmonary fibrosis, and primary pulmonary hypertension. However, the long-term survival of lung allografts is still limited by the development of bronchiolitis obliterans syndrome (BOS), an irreversible condition unresponsive to therapy. BOS is the most significant cause of long-term morbidity and mortality after lung transplantation. Over the past decade, several animal models have been developed to investigate BOS. These are valuable to elucidate the immunologic and pathologic mechanisms that lead to BOS and to test treatment options for BOS. In this review, we discuss the advantages and disadvantages of different animal models and highlight work that has been done with each model.

Inhibition of nuclear factor kappaB by IkappaB superrepressor gene transfer ameliorates ischemia-reperfusion injury after experimental lung transplantation.

OBJECTIVES: Ischemia-reperfusion injury after lung transplantation is associated with significant morbidity and mortality. The activation of the transcription factor nuclear factor kappaB is central to the 2 important pathways that characterize ischemia-reperfusion injury, namely the inflammatory response and apoptosis. The purpose of this study was to determine the effects of nuclear factor kappaB inhibition on experimental lung transplant ischemia-reperfusion injury with gene transfer of the nuclear factor kappaB inhibitor IkappaB in a superrepressor form (IkappaBSR). METHODS: An orthotopic left lung transplant model in isogeneic rats was used, with 18 hours of prolonged cold storage of donor lung grafts used to create severe ischemia-reperfusion injury. Donor rats underwent endobronchial gene transfection with saline alone or adenovirus encoding either beta-galactosidase control or IkappaBSR 48 hours before harvest. The function of transplanted lung grafts was assessed on the basis of isolated graft oxygenation, wet/dry lung weight ratio, and myeloperoxidase activity. Nuclear factor kappaB activation was assessed by means of enzyme-linked immunosorbent assay. Apoptotic cell death was assessed by evaluating the levels of histone-associated DNA fragments and caspase-3 activity. RESULTS: Treatment of donor lung grafts with IkappaBSR resulted in significantly improved oxygenation compared with that seen in control tissue 24 hours after transplantation. IkappaBSR-treated lungs also demonstrated less pulmonary edema and reduced neutrophil infiltration 24 hours after reperfusion. Nuclear factor kappaB activation and apoptotic cell death induction 2 hours after transplantation was significantly reduced in IkappaBSR-treated lungs compared with in control lungs. CONCLUSIONS: Inhibition of nuclear factor kappaB activation by IkappaBSR gene transfer improves transplanted lung graft oxygenation, decreases pulmonary edema and neutrophil sequestration, and reduces apoptotic cell death after experimental lung transplantation.