Sekhar Dharmarajan

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 patients physiologic state and associated comorbidities.

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.

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.

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.

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.

Clinically Enlarged Lateral Pelvic Lymph Nodes Do Not Influence Prognosis after Neoadjuvant Therapy and TME in Stage III Rectal Cancer

PurposeThe 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.MethodsPretherapy 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−).ResultsOf 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.ConclusionsThe 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.

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.

In vivo molecular imaging characterizes pulmonary gene expression during experimental lung transplantation.

Experimental gene therapy is a promising strategy to prevent ischemia‐reperfusion (I/R) injury and allograft rejection after lung transplantation, and methods will eventually be needed to characterize pulmonary transgene expression in vivo in humans. Therefore, we studied positron emission tomography (PET) as a means of performing in vivo molecular imaging in rodent models of lung transplantation. Rats were transfected endotracheally with adenovirus encoding a fusion gene of a mutant Herpes simplex virus‐1 thymidine kinase and the green fluorescent protein gene (the former serving as an imaging reporter gene). Twenty‐four hours after transfection, lungs were transplanted in groups representing normal transplantation, I/R injury and acute allograft rejection. Imaging was obtained either 24 h after transplantation to study reperfusion injury or 4 days after transplantation to study graft rejection. After imaging, lungs were excised and analyzed for thymidine kinase activity. Imaging detected transgene expression in transplanted lungs even in the presence of acute rejection or I/R injury. The PET imaging signal correlated with in vitro lung tissue assays of thymidine kinase activity (r2= 0.534). Thus, noninvasive molecular imaging with PET is a feasible, sensitive and quantitative method for characterizing pulmonary transgene expression in experimental lung transplantation.

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

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.

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.