Faculty Bibliography

BACKGROUND AND AIMS/OBJECTIVE:NLRP3 inflammasome is known to be involved in inflammatory bowel diseases. However, it is controversial whether it is pathogenic or beneficial. This study evaluated the roles of NLRP3 inflammasome in the pathogenesis of inflammatory bowel disease in IL-10-/- mice and humans. METHODS:NLRP3 inflammasome in colonic mucosa, macrophages, and colonic epithelial cells were analysed by western blotting. The NLRP3 inflammasome components were studied by sucrose density gradient fractionation, chemical cross-linking, and co-immunoprecipitation. The role of NLPR3 inflammasome in the pathogenesis of colitis was extensively evaluated in IL-10-/- mice, using a specific NLPR3 inflammasome inhibitor glyburide. RESULTS:NLRP3 inflammasome was upregulated in colonic mucosa of both IL-10-/- mice and Crohn's patients. NLRP3 inflammasome activity in IL-10-/- mice was elevated prior to colitis onset; it progressively increased as disease worsened and peaked as macroscopic disease emerged. NLRP3 inflammasome was found in both intestinal epithelial cells and colonic macrophages, as a large complex with a molecular weight of ≥ 360 kDa in size. In the absence of IL-10, NLRP3 inflammasome was spontaneously active and more robustly responsive when activated by LPS and nigericin. Glyburide markedly suppressed NLRP3 inflammasome expression/activation in IL-10-/- mice, leading to not only alleviation of ongoing colitis but also prevention/delay of disease onset. Glyburide also effectively inhibited the release of proinflammatory cytokines/chemokines by mucosal explants from Crohn's patients. CONCLUSIONS:Abnormal activation of NLRP3 inflammasome plays a major pathogenic role in the development of chronic colitis in IL-10-/- mice and humans. Glyburide, an FDA-approved drug, may have great potential in the management of inflammatory bowel diseases.

BACKGROUND:Intraoperative radiotherapy (IORT) has advantages over external beam radiation therapy (EBRT). Few studies have described side effects associated with its addition. We evaluated our institution's experience with abdominopelvic IORT to assess safety by postoperative complication rates. METHODS:Prospectively collected IRB-approved database of all patients receiving abdominopelvic IORT (via high dose rate brachytherapy) at Johns Hopkins Hospital between November 2006 and May 2014 was reviewed. Patients were discussed in multidisciplinary conferences. Those selected for IORT were patients for whom curative intent resection was planned for which IORT could improve margin-negative resection and optimize locoregional control. Perioperative complications were classified via Clavien-Dindo scale for postoperative surgical complications. RESULTS:A total of 113 patients were evaluated. Most common diagnosis was sarcoma (50/113, 44%) followed by colorectal cancer (45/113, 40%), most of which were recurrent (84%). There were no perioperative deaths. A total of 57% of patients experienced a complication Grade II or higher: 24% (27/113) Grade II; 27% (30/113) Grade III; 7% (8/113) Grade IV. Wound complications were most common (38%), then gastrointestinal (25%). No radiotherapy variables were significantly associated with complications on uni/multi-variate analysis. CONCLUSIONS:Our institution's experience with IORT demonstrated historically expected postoperative complication rates. IORT is safe, with acceptable perioperative morbidity.

BACKGROUND:High dose-rate Intra-Operative Radiation Therapy (HD-IORT) is used to provide effective local control for patients with high-risk locally advanced or recurrent tumors. However, the utility of HD-IORT for patients with bladder cancer has not been studied. OBJECTIVE:To characterize our institutional experience with HD-IORT in patients with cancer requiring genitourinary surgery, in an effort to identify patients with bladder cancer that may benefit from HD-IORT. METHODS:We performed a retrospective review of all patients who have undergone HD-IORT during genitourinary surgery at our institution. Patients were stratified by surgical margin status, and primary outcomes assessed were overall survival, recurrence free survival and 90-day complications. Patients undergoing cystectomy and HD-IORT with sarcomatoid urothelial cancer were compared to a similar cohort undergoing cystectomy alone. A sample case of one such patient is discussed in detail. RESULTS:84 patients at our institution have undergone HD-IORT with genitourinary surgery. Positive surgical margin status was the greatest predictor of both OS (HR = 3.42) and RFS (HR = 2.61). The overall 90-day complication rate was 61%, with wound infections (43%) and GI complications (21%) being most common. 4 of these patients had sarcomatoid urothelial histology, and all are still alive with >2 yrs follow up. This compares to a 52% 1 yr survival in our sarcomatoid urothelial cohort (25 pts) that did not undergo HD-IORT. CONCLUSIONS:Our institutional experience with HD-IORT has been promising, particularly among patients with locally advanced disease and sarcomatoid histology. We are currently enrolling patients in a multi-institutional registry to assess the utility of HD-IORT in high risk bladder cancer.

BACKGROUND:Timing of surgical intervention for acute ulcerative colitis has not been fully examined during the modern immunotherapy era. Although early surgical intervention is recommended, historical consensus for "early" ranges widely. The purpose of this study was to evaluate outcomes according to timing of urgent surgery for acute ulcerative colitis. METHODS:All non-elective total colectomies in ulcerative colitis patients were identified in the National Inpatient Sample from 2002 to 2014. Procedures, comorbidities, diagnoses, and in-hospital outcomes were collected using International Classification of Disease, 9th Revision codes. An operation was defined as early if within 24 hours of admission. Results were compared between the early versus delayed surgery groups. RESULTS:We found 69,936 patients that were admitted with ulcerative colitis, and 2650 patients that underwent non-elective total colectomy (3.8%). Early intervention was performed in 20.4% of patients who went to surgery. More early operations were performed laparoscopically (28.1% versus 23.3%, p = 0.021) and on more comorbid patients (Charlson Index, p = 0.008). Median total hospitalization costs were $20,948 with an early operation versus $33,666 with a delayed operation (p < 0.001). Delayed operation was an independent risk for a complication (OR = 1.46, p = 0.001). Increased hospitalization costs in the delayed surgery group were statistically significantly higher with a reported complication (OR = 3.00, p < 0.001) and lengths of stay (OR = 1.26, p < 0.001). CONCLUSION/CONCLUSIONS:Delayed operations for acute ulcerative colitis are associated with increased postoperative complications, increased lengths of stay, and increased hospital costs. Further prospective studies could demonstrate that this association leads to improved outcomes with immediate surgical intervention for medically refractory ulcerative colitis.

AIM/OBJECTIVE:The perineal wound following abdominoperineal excision (APR) is associated with a high complication rate. We aimed to evaluate the risk factors for wound complications and examine the effect of flap reconstruction on wound healing. METHOD/METHODS:The American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database was searched for patients who underwent APR for rectal adenocarcinoma. They were divided into two groups: primary closure of the perineal wound and flap reconstruction. A logistic regression analysis was performed to identify the risk factors for deep surgical site infection (SSI) and wound dehiscence. RESULTS:A total of 8449 (94%) patients from the database underwent primary closure and 550 (6%) underwent flap reconstruction. Patients who underwent flap reconstruction had a longer operation time, a higher incidence of deep SSI, wound dehiscence, more blood transfusion requirement and a higher rate of return to the operating room (all P < 0.001). Risk factors for deep SSI were African American race (OR 1.5, P = 0.02), American Society of Anesthesiologists (ASA) classification ≥ 4 (OR 3.2, P < 0.001), body mass index (BMI) ≥ 35 kg/m(2) (OR 1.7, P = 0.006), weight loss (OR 2, P < 0.001) and closure with a flap (OR 1.9, P < 0.001). Risk factors for wound dehiscence included ASA classification ≥ 4 (OR 2.2, P = 0.003), history of smoking (OR 2.2, P < 0.001), history of chronic obstructive pulmonary disease (OR 1.7, P = 0.03), BMI ≥ 35 kg/m(2) (OR 1.9, P = 0.001) and closure with a flap (OR 2.9, P < 0.001). CONCLUSION/CONCLUSIONS:Perineal wound complications are related to a patient's race, ASA classification, smoking, obesity and weight loss. Compared with primary closure, closure with a flap was associated with higher odds of wound infection and dehiscence and was not protective of wound complications in the presence of other risk factors. Therefore optimizing the patient's medical condition will lead to a better outcome irrespective of the technique used for perineal wound closure.

High volume hospitals (HVHs) and high volume surgeons (HVSs) have better outcomes after complex procedures, but the association between surgeon and hospital volumes and patient outcomes is not completely understood. Our aim was to evaluate the impact of surgeon and hospital volumes, and their interaction, on postoperative outcomes and costs in patients undergoing pelvic exenteration (PE) in the state of Maryland. A review of the Maryland Health Services Cost Review Commission database between 2000 and 2011 was performed. Patients were compared for demographics and clinical variables. The differences in length of hospital stay , length of intensive care unit (ICU) stay, operating room (OR) cost, and total cost were compared for surgeon volume and hospital volume controlling for all other factors. Surgery performed by HVS at HVH had the shortest ICU stay and lowest OR cost. When PE was performed by a low volume surgeon at an HVH, the OR cost and total cost were the highest and increased by $2,683 (P < 0.0001) and $16,076 (P < 0.0001), respectively. OR costs reduced when surgery was performed by an HVS at an HVH ($-1632, P = 0.008). PE performed by HVS at HVH is significantly associated with lower OR costs and ICU stay. We feel this is indicative of lower complication rates and higher quality care.

BACKGROUND:Perineal wound following abdominoperineal resection (APR) is associated with high complication rate and delayed healing. We aim to evaluate the risk factors for delayed wound healing and wound complications following APR. METHODS:A retrospective review of patients who underwent APR was performed. Non-delayed wound healing occurred within 6 weeks. Major complications included infection, necrosis, and dehiscence that required surgical interventions. Minor complications included drainage and superficial dehiscence that were treated conservatively. Patients were compared for type of wound closure (primary vs. flap reconstruction). Effect of patients' demographic and clinical variables on time to healing, and on major and minor wound complications was examined. RESULTS:215 patients were identified, of which 175 (81 %) had primary closure and 40 (19 %) had flap reconstruction. Overall, major wound complications occurred in 14 (7 %) of patients and minor wound complications occurred in 48 (22 %). Mean time to wound healing was 6.3 weeks in the primary closure group and 9.3 weeks in the flap reconstruction group (p = 0.02). Delayed wound healing occurred in 44 (25 %) of the primary closure group and in 25 (62 %) of the flap reconstruction group (p < 0.001). Delayed wound healing was associated with smoking (p = 0.005), hypoalbuminemia (p = 0.05), neoadjuvant chemotherapy (p = 0.02), and flap reconstruction (p = 0.03). Hypoalbuminemia was associated with major wound complications (p = 0.002), while neoadjuvant chemotherapy was associated with minor wound complications (p = 0.01). CONCLUSIONS:Wound complications and delayed healing are related to patients' nutritional status, smoking, and neoadjuvant chemotherapy. Patients with these risk factors are at risk of delayed wound healing even if they underwent flap reconstruction.

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.