Flavio G. Rocha

The effect of sustained delivery of vascular endothelial growth factor on angiogenesis in tissue-engineered intestine.

Our group has previously created a functional neointestine that is capable of restoring absorptive function. However, the endogenous level of vascular endothelial growth factor (VEGF) is markedly reduced in the construct compared to native bowel. Therefore, we wanted to locally deliver VEGF in a sustained fashion to upregulate angiogenesis in the neointestine. Rat recombinant VEGF was encapsulated in poly(lactide-co-glycolide) microspheres by a double emulsion method. Release kinetics and bioactivity were determined in vitro. Tissue-engineered intestine was generated by seeding donor neonatal rat intestinal organoid units onto a biodegradable polyglycolic acid scaffold along with VEGF-containing or empty microspheres, and wrapped in the omentum of recipient rats. After 4 weeks, the neointestinal cysts were analyzed for morphometry, VEGF levels, epithelial proliferation, and capillary density. Sustained release of biologically active VEGF was confirmed by in vitro studies. Intestinal constructs with VEGF microspheres were significantly larger than those containing empty microspheres. Tissue VEGF levels were significantly higher in neointestine loaded with encapsulated VEGF compared to those without growth factor. Epithelial cellular proliferation and capillary density were significantly increased in the VEGF-containing neointestinal constructs compared to empty constructs. Tissue-engineered intestine responds to sustained delivery of VEGF by upregulating microvasculature and epithelial proliferation.

High mobility group AT-hook 1 (HMGA1) is an independent prognostic factor and novel therapeutic target in pancreatic adenocarcinoma

High mobility group AT‐hook 1 (HMGA1) proteins are architectural transcription factors that are overexpressed by pancreatic adenocarcinomas. The authors hypothesized that tumor HMGA1 status represents a novel prognostic marker in pancreatic adenocarcinoma. They also tested the hypothesis that HMGA1 promotes anchorage‐independent cellular proliferation and in vivo tumorigenicity.

Impact of Radiologic Intervention on Mortality in Necrotizing Pancreatitis : The Role of Organ Failure

BACKGROUND Our group previously reported that organ failure and mortality in necrotizing pancreatitis (NP) are not different between patients with infected and sterile necrosis. Since that report, management of this disease has evolved to include image-guided percutaneous catheter drainage (PCD) to improve morbidity and mortality. We evaluated the effect of PCD on mortality in NP. DESIGN Retrospective analysis. SETTING Tertiary care referral center. PATIENTS A total of 689 consecutive patients treated for acute pancreatitis between 2001 and 2005, of whom 64 (9.3%) had pancreatic necrosis documented on contrast-enhanced computed tomography. MAIN OUTCOME MEASURES Mortality and organ failure. RESULTS In the 64 patients with documented NP, overall mortality was 16%. Thirty-six patients (56%) had organ failure according to the Atlanta classification. Compared with patients with sterile necrosis, those with infected necrosis did not have an increased prevalence of organ failure or increased need for intubation, pressors, or dialysis but had an increased mortality. Mortality in patients treated conservatively was 1 of 29 (3%); in those with PCD alone, 6 of 11 (55%); in those with PCD and surgery, 2 of 17 (12%); and in those with surgery alone, 1 of 7 (14%). All patients treated with PCD alone had organ failure, whereas 10 (59%) of those with PCD and surgery had organ failure. CONCLUSION The use of PCD did not improve the mortality of NP among patients with organ failure.

Prevalence of Primary Fungal Infections in Necrotizing Pancreatitis

Background/Aims: Prophylactic use of carbapenems (meropenem and imipenem) and other broad-spectrum antibiotics in necrotizing pancreatitis has been suggested as a risk factor for pancreatic fungal infections. The aim of our study was to determine the prevalence of primary fungal infections and the pattern of antibiotic use in necrotizing pancreatitis at our institution. Methods: Records on 689 consecutive patients with acute pancreatitis between 2000 and 2004 were reviewed. Necrotizing pancreatitis was identified by contrast-enhanced computed tomography (CT) scan. Data on antibiotic usage were collected and microbiologic data obtained from radiologic, endoscopic, and surgical interventions (pancreatic aspiration, drain placement or debridement) were reviewed for evidence of fungal infection. Pancreatic fungal infections were classified as primary if the positive culture was obtained at the time of initial intervention. Results: Among 64 patients with necrotizing pancreatitis, there were no cases of primary pancreatic fungal infections and 7 cases (11%) of secondary pancreatic fungal infections. Fifteen patients (23%) developed pancreatic bacterial infections. Among 62 patients with necrotizing pancreatitis in whom antibiotic exposure was known, 45% received carbapenems for a median duration of only 6 days, and 84% received non-carbapenem antibiotics for a median duration of 14 days. Conclusion: Limited use and short duration of carbapenem therapy may be factors contributing to the absence of primary fungal infections in our study.

Nonoperative management of patients with a diagnosis of high-grade small bowel obstruction by computed tomography.

OBJECTIVE To determine the natural history and treatment of high-grade small bowel obstruction (HGSBO). Small bowel obstruction is a frequent complication of abdominal surgery. Complete and strangulating obstructions are managed operatively while partial obstructions receive a trial of nonoperative therapy. The management and outcome of patients with HGSBO diagnosed by computed tomography (CT) has not been examined. DESIGN Retrospective medical record review. Outcomes for nonoperative vs operative management were analyzed using Fisher exact and log-rank tests. SETTING Tertiary care referral center. PATIENTS One thousand five hundred sixty-eight consecutive patients admitted from the emergency department with a diagnosis of small bowel obstruction between 2000 and 2005 by CT criteria. MAIN OUTCOME MEASURES Recurrence of symptoms and complications. RESULTS One hundred forty-five patients (9%) with HGSBO were identified, with 88% follow-up (median, 332 days; range, 4-2067 days). Sixty-six (46%) were successfully managed nonoperatively while 79 (54%) required an operation. Length of stay and complications were significantly increased in the operative group (4.7 days vs 10.8 days and 3% vs 23%; P < .001). Nonoperative management was associated with a higher recurrence rate (24% vs 9%; P < .005) and shorter time to recurrence (39 days vs 105 days; P < .005) compared with operative intervention. Computed tomography signs of ischemia, admission laboratory results, and presence of cancer or inflammatory bowel disease were not predictive of an operation. CONCLUSIONS Patients with HGSBO by CT can be managed safely with nonoperative therapy; however, they have a significantly higher rate of recurrence requiring readmission or operation within 5 years.

Glucagon-like peptide 2 is an endogenous mediator of postresection intestinal adaptation.

BACKGROUND After massive small bowel resection, the remnant intestine undergoes compensatory adaptation. We tested the hypothesis that glucagon-like peptide-2 (GLP-2) is an endogenous mediator of postresection intestinal adaptation. METHODS Rats were allocated to 1 of 4 groups: groups 1 and 2 rats underwent mid-small bowel transection and reanastomosis; groups 3 and 4 rats underwent 75% mid-small bowel resection and reanastomosis. Groups 2 and 4 rats were administered 1.8 mg of antirat GLP-2 antibody twice daily beginning immediately after the surgical procedure; groups 1 and 3 rats were administered rabbit serum (control). Ileal specimens were harvested on postoperative day 7. RESULTS Ileal mucosa from group 3 animals displayed morphologic and proliferative indices of adaptation. Each of these indices of adaptation was inhibited by GLP-2 immunoneutralization (group 4). Morphologic and proliferative parameters in the ileum from animals that had undergone transection with reanastomosis were unaffected by GLP-2 immunoneutralization. CONCLUSIONS These results suggest that GLP-2 is an endogenous mediator of postresection intestinal adaptation.

A historic perspective on the contributions of surgeons to the understanding of acute pancreatitis

BACKGROUND Acute pancreatitis is a disease with a broad spectrum of presentation, severity, and treatment. Current management involves a multidisplinary team of surgeons, gastroenterologists, and interventional radiologists whose varied clinical skills contribute to the evolving diagnostic and therapeutic strategies for this disease. However, critical aspects of therapy have remained the responsibility of the general surgeon. The purpose of this review is to examine the many contributions of surgeons in acute pancreatitis. DATA SOURCES A review of the literature taken from PubMed on seminal articles published by surgeons on the subject of acute pancreatitis. CONCLUSIONS Surgeons have made significant contributions to the understanding of the pathophysiology and evolution of therapy of acute pancreatitis. The specialty should continue to take a leadership role to improve outcomes.

Nanoparticle-aptamer bioconjugates for targeted antineoplastic drug delivery

Targeted drug delivery technologies can provide physicians with new approaches to treat and manage patients with cancer. Nucleic acid ligands (aptamers) are a novel class of targeting molecules that can be used in a similar manner to antibodies. Beyond use as drugs themselves, aptamers have the potential to serve as targeting ligands to deliver drugs, imaging agents, or other bioactive agents to the intended site of action. Bioconjugates of nanoparticles and aptamers can selectively bind and be taken up by cancer cells. In this article we review progress to date for antineoplastic drug delivery using nanoparticle-aptamer bioconjugates.Aptamers are isolated through a process of in vitro selection, also referred to as systematic evolution of ligands by exponential enrichment (SELEX). There is an increasing numbers of aptamers for cancer targeting being reported in the literature. These aptamers often interact with antigens that are overexpressed exclusively, or preferentially, on cancer cells or in the cancer microenvironment. As novel drug delivery vehicles, nanoparticle-aptamer bioconjugates may be developed to target a myriad of diseases including many cancers by delivering a variety of therapeutic agents specifically to the site of interest.The first in vivo study of antineoplastic drug delivery by a bioconjugate employed nanoparticle encapsulating docetaxel and aptamers that bind certain prostate cancer cells. In this study using a xenograft murine model of prostate cancer, these bioconjugates were shown to significantly improve tumor reduction after intratumoral injection compared with all controls. Furthermore, the docetaxel-loaded nanoparticle-aptamer bioconjugates demonstrated reduced toxicity in terms of acute bodyweight loss compared with the controls. In vitro, the efficacy of the docetaxel-loaded nanoparticle-aptamer bioconjugate was shown to be due to intracellular delivery of the drug to the cancer cells, and the bioconjugate without the drug had no cytotoxicity.Nanoparticle-aptamer bioconjugates may prove to be useful not only for management of cancer but also various other indications. New aptamers, multivalent targeting strategies, and multimodal treatments such as simultaneous radio- and chemotherapy may further increase the efficacy of these bioconjugates and facilitate their clinical translation for therapeutic and diagnostic applications.

Influence of carcinoid syndrome on the clinical characteristics and outcomes of patients with gastroenteropancreatic neuroendocrine tumors undergoing operative resection

Background: The incidence, clinical characteristics, and long‐term outcomes of patients with gastroenteropancreatic neuroendrocrine tumors and carcinoid syndrome undergoing operative resection have not been well characterized. Methods: Patients undergoing resection of primary or metastatic gastroenteropancreatic neuroendrocrine tumors between 2000 and 2016 were identified from an 8‐institution collaborative database. Clinicopathologic and postoperative characteristics as well as overall survival and disease‐free survival were compared among patients with and without carcinoid syndrome. Results: Among 2,182 patients who underwent resection, 139 (6.4%) had preoperative carcinoid syndrome. Patients with carcinoid syndrome were more likely to have midgut primary tumors (44.6% vs 21.4%, P < .001), lymph node metastasis (63.4% vs 44.3%, P < .001), and metastatic disease (62.8% vs 26.7%, P < .001). There was no difference in tumor differentiation, grade, or Ki67 status. Perioperative carcinoid crisis was rare (1.6% vs 0%, P < .01), and the presence of preoperative carcinoid syndrome was not associated with postoperative morbidity (38.8% vs 45.5%, P = .129). Substantial symptom improvement was reported in 59.5% of patients who underwent curative‐intent resection, but occurred in only 22.7% who underwent debulking. Despite an association on univariate analysis (P = .04), carcinoid syndrome was not independently associated with disease‐free survival after controlling for confounding factors (hazard ratio 0.97, 95% confidence interval 0.64–1.45). Preoperative carcinoid syndrome was not associated with overall survival on univariate or multivariate analysis. Conclusion: Among patients undergoing operative resection of gastroenteropancreatic neuroendrocrine tumors, the prevalence of preoperative carcinoid syndrome was low. Although operative intervention with resection or especially debulking in patients with carcinoid syndrome was disappointing and often failed to improve symptoms, after controlling for markers of tumor burden, carcinoid syndrome was not independently associated with worse disease‐free survival or overall survival.

Comparative analysis of resected duodenal and ampullary adenocarcinoma.

362 Background: Duodenal and ampullary adenocarcinomas are rare gastrointestinal cancers that share similar anatomic location and treatment strategy. We report a single-institution experience regarding the association between clinicopathologic features, treatment, and survival outcomes. Methods: A retrospective review of all patients resected with curative intent for duodenal adenocarcinoma (DUO) between 2005-2015 and ampullary adenocarcinoma (AMP) between 2011-2015 at VMMC was performed. For AMP, histologic subtyping into intestinal (IT) and pancreatobiliary (PB) phenotypes was determined. Demographic and clinicopathologic parameters were compared between DUO and AMP patients using Chi-square test. Overall survival was calculated using Kaplan-Meier analysis and prognostic factors were identified by univariate Cox regression. Results: Patients with DUO (n = 44) presented at higher T-stage (p = 0.002) and with larger tumors (4.35cm vs 2.33cm, p < 0.001) than AMP patients (n = 46). DUO patients had a higher...