Vedolizumab as a rescue therapy for patients with medically refractory Crohn's disease.

AIM: Vedolizumab, a monoclonal antibody resulting in gut-selective anti-inflammatory activity, was approved by the US Food and Drug Administration in 2014 for use in patients with Crohn's disease (CD). The aim of this study was to investigate the efficacy of vedolizumab as a rescue therapy when other medical therapies have failed. METHOD: A retrospective review was performed on consecutive patients with CD receiving vedolizumab at the Penn State Hershey IBD Center between May 2014 and March 2016. These patients were unresponsive or intolerant to tumour necrosis factor (TNF) antagonist therapy, and previously would have been candidates for surgery. Outcomes included surgical intervention, clinical response and endoscopic improvement. RESULTS: A total of 48 patients with medically refractory CD receiving vedolizumab were included. The median length of follow-up was 69 weeks (range 15-113 weeks). A majority (81%) of patients previously failed at least two TNF antagonists, and 77% had prior surgery for CD. Surgical intervention was required in 21 (44%) patients and 13 (27%) patients required intra-abdominal operations. At the conclusion of the study, 23 (48%) patients reported continued improvement of symptoms, and 22 of 37 (59%) patients undergoing endoscopy showed improvement. Patients with the inflammatory CD phenotype were more likely to improve clinically and avoid surgery. CONCLUSION: Vedolizumab alone or in combination with immunomodulators or steroids may be used as a rescue therapy in patients with medically refractory CD and may decrease the rate of surgical intervention. Patients with the inflammatory CD phenotype had the best clinical response and decreased need for surgery, suggesting that vedolizumab is most effective in the inflammatory phenotype.

Compliance with Clostridium difficile treatment guidelines: effect on patient outcomes.

Guidelines for the severity classification and treatment of Clostridium difficile infection (CDI) were published by Infectious Diseases Society of America (IDSA)/Society for Healthcare Epidemiology of America (SHEA) in 2010; however, compliance and efficacy of these guidelines has not been widely investigated. This present study assessed compliance with guidelines and its effect on CDI patient outcomes as compared with before these recommendations. A retrospective study included all adult inpatients with an initial episode of CDI treated in a single academic center from January 2009 to August 2014. Patients after guideline publication were compared with patients treated in 2009-2010. Demographic, clinical, and laboratory data were collected to stratify for disease severity. Outcome measures included compliance with guidelines, mortality, length of stay (LOS), and surgical intervention for CDI. A total of 1021 patients with CDI were included. Based upon the 2010 guidelines, 42 (28·8%) of 146 patients treated in 2009 would have been considered undertreated, and treatment progressively improved over time, as inadequate treatment decreased to 10·0% (15/148 patients) in 2014 (P = 0·0005). Overall, patient outcomes with guideline-adherent treatment decreased CDI attributable mortality twofold (P = 0·006) and CDI-related LOS by 1·9 days (P = 0·0009) when compared with undertreated patients. Compliance with IDSA/SHEA guidelines was associated with a decreased risk of mortality and LOS in hospitalized patients with CDI.

Hernia incidence following single-site vs standard laparoscopic colorectal surgery.

AIM: Compared with standard laparoscopic (SDL) approaches, less is known about the incidence of hernias after single-site laparoscopic (SSL) colorectal surgery. This study hypothesized that SSL colorectal surgery was associated with an increased risk of hernia development. METHOD: Institutional retrospective chart review (September 2008-June 2013) identified 276 evaluable patients who underwent laparoscopic colorectal procedures. The following data were collected: demographic data, risk factors for the development of a hernia, operative details and postoperative course including the development of a hernia. Patients were stratified by laparoscopic technique to compare the characteristics of those undergoing SDL and SSL. Patients were subsequently stratified by the presence or absence of a hernia to identify associated factors. RESULTS: One hundred and nineteen patients (43.1%) underwent SDL and 157 patients (56.9%) underwent SSL surgery. The development of an incisional hernia was observed in 7.6% (9/119) of SDL patients compared with 17.0% (18/106) of SSL patients (P = 0.03) over a median 18-month follow-up. Similar proportions of patients developed parastomal hernias in both groups [SDL 16.7% (10/60) vs SSL 15.9% (13/80)]. Hernias were diagnosed at a median of 8.1 (SDL) and 6.5 (SSL) months following the index operation and were less likely to be incarcerated in the SSL group [SDL 38.9% (7/18) vs SSL 6.5% (2/31), P = 0.01]. CONCLUSION: SSL colorectal surgery is associated with an increase in the incidence of incisional hernias but not parastomal hernias. Site of specimen extraction in SSL may contribute to the development of an incisional hernia.

Decreased efficacy of twice-weekly intravaginal dehydroepiandrosterone on vulvovaginal atrophy.

OBJECTIVE: While daily intravaginal administration of 0.50% (6.5 mg) dehydroepiandrosterone (DHEA, prasterone) for 12 weeks has shown clinically and statistically significant effects on moderate to severe (MS) dyspareunia as the most bothersome symptom (MBS), the present study analyzes the effect of a reduced dosing regimen on MBS vaginal dryness. METHOD: Daily intravaginal 0.50% prasterone for 2 weeks followed by twice weekly for 10 weeks versus placebo. RESULTS: Maximal beneficial changes in vaginal parabasal and superficial cells and pH were observed at 2 weeks as observed for intravaginal 10 µg estradiol (E2). This was followed by a decrease or lack of efficacy improvement after switching to twice-weekly dosing. The decrease in percentage of parabasal cells, increase in percentage of superficial cells and decrease in vaginal pH were all highly significant (p < 0.0001 to 0.0002 over placebo) at 12 weeks. In parallel, the statistical significance over placebo (p value) on MBS vaginal dryness at 6 weeks was 0.09 followed by an increase to 0.198 at 12 weeks. For MBS dyspareunia, the p value of 0.008 at 6 weeks was followed by a p value of 0.077 at 12 weeks, thus illustrating a decrease of efficacy at the lower dosing regimen. The improvements of vaginal secretions, color, epithelial integrity and epithelial surface thickness were observed at a p value < 0.01 or 0.05 over placebo at 2 weeks, with a similar or loss of statistical difference compared to placebo at later time intervals. No significant adverse event was observed. Vaginal discharge related to the melting of Witepsol was reported in 1.8% of subjects. CONCLUSION: The present data show that daily dosing with 0.50% DHEA for 2 weeks followed by twice-weekly dosing is a suboptimal treatment of the symptoms/signs of vulvovaginal atrophy resulting from a substantial loss of the efficacy achieved at daily dosing.

Identification of disease-associated DNA methylation in intestinal tissues from patients with inflammatory bowel disease.

Overwhelming evidence supports the theory that inflammatory bowel disease (IBD) is caused by a complex interplay between genetic predispositions of multiple genes, combined with an abnormal interaction with environmental factors. It is becoming apparent that epigenetic factors can have a significant contribution in the pathogenesis of disease. Changes in the methylation state of IBD-associated genes could significantly alter levels of gene expression, potentially contributing to disease onset and progression. We have explored the role of DNA methylation in IBD pathogenesis. DNA methylation profiles (1505 CpG sites of 807 genes) of matched diseased (n = 26) and non-diseased (n = 26) intestinal tissues from 26 patients with IBD [Crohn's disease (CD) n = 9, ulcerative colitis (UC) n = 17] were profiled using the GoldenGate™ methylation assay. After an initial identification of a panel of 50 differentially methylated CpG sites from a training set (14 non-diseased and 14 diseased tissues) and subsequent validation with a testing set (12 non-diseased and 12 diseased tissues), we identified seven CpG sites that are differentially methylated in intestinal tissues of IBD patients. We have also identified changes in DNA methylation associated with the two major IBD subtypes, CD and UC. This study reports IBD-associated changes in DNA methylation in intestinal tissue, which may be disease subtype-specific.

Review article: the pathogenesis of pouchitis.

BACKGROUND: A total proctocolectomy followed by ileal pouch-anal anastomosis is a potentially curative surgery for ulcerative colitis or familial adenomatous polyposis. About 5-35% of patients with ulcerative colitis and 0-11% of patients with familial adenomatous polyposis develop subsequent inflammation of the ileal pouch termed pouchitis. AIM: To provide a comprehensive analysis of the research studying the possible pathogenesis of pouchitis. The goals were to identify promising areas of investigation, to help focus clinicians, researchers and patients on how to better understand and then potentially manage ileal pouchitis, and to provide avenues for future research investigations. METHODS: This review examined manuscripts from 1981 to 2015 that discussed and/or proposed hypotheses with supportive evidence for the potential underlying pathogenic mechanism for pouchitis. RESULTS: The pathogenesis of pouchitis is not definitively understood, but various hypotheses have been proposed, including (i) recurrence of ulcerative colitis, (ii) dysbiosis of the ileal pouch microbiota, (iii) deprivation of nutritional short-chain fatty acids, (iv) mucosal ischaemia and oxygen-free radical injury, (v) host genetic susceptibility and (vi) immune dysregulation. However, none of these alone are able to fully explain pouchitis pathogenesis. CONCLUSIONS: Pouchitis, similar to inflammatory bowel disease, is a complex disorder that is not caused by any one single factor. More likely, pouchitis occurs through a combination of both dysregulated host inflammatory mechanisms and interaction with luminal microbiota.

The effect of anti-interleukin-2 receptor monoclonal antibody on allograft rejection.

During immune response to an allograft, activated T cells express a number of cell surface activation antigens, among them the membrane receptor for the lymphokine interleukin 2 (IL-2). As the IL-2 receptor is not present on resting T cells, it offers an attractive target for potentially specific immunosuppressive therapy. The rat monoclonal antibody M7/20, which binds to the murine IL-2 receptor, was studied for its effect on allograft survival in two H-2-incompatible strain combinations in inbred mice. Treatment with M7/20 for 10 days markedly prolonged survival of vascularized, heterotopic heart allografts in both strain combinations, with indefinite graft survival in 50% of recipients. The same treatment significantly prolonged skin allograft survival in one of the two combinations. The results support the important role of the IL-2 receptor in the mechanism of graft rejection and confirm its suitability as a target for immunosuppressive therapy in transplantation.

Absence of GNAI2 codon 179 oncogene mutations in inflammatory bowel disease.

The human GNAI2 gene coding for G protein, Galphai2, is located on chromosome 3p21 in proximity to the region where an inflammatory bowel disease (IBD) locus has been suggested. Galphai2-deficient mice develop a lethal diffuse colitis that resembles human ulcerative colitis (UC) and frequently progresses to colon adenocarcinoma. Furthermore, the human GNAI2 gene is subject to point mutations at certain positions, including three at codon 179, all of which have been reported in human endocrine tumors. In order to evaluate the possible involvement of this gene in IBD pathogenesis, we have examined GNAI2 codon 179 sequences in 28 familial IBD patients, including 13 UC, 15 Crohn's disease (CD), and 7 patients with colon cancer/dysplasia, from 12 multiplex IBD families. The wildtype codon 179, CGC for arginine, plus the first G of the codon 180 engender a sequence recognizable by the enzyme BstUI. Mutations, therefore, can result in the abrogation of BstUI digestion of polymerase chain reaction (PCR) products containing the codon 179. Using the PCR-restriction fragment length polymorphism technique, all 28 IBD patients, including those with colon cancer, and 14 non-IBD family members show a BstUI-cleavable PCR-banding pattern indicating the presence of wildtype codon 179. We conclude that, in the familial IBD and colon cancer/dysplasia patients studied, there is no detectable mutation in the codon 179 of the GNAI2 gene.

Thrombolysis in the treatment of peripheral arterial vascular occlusions.

The efficacy of thrombolytic agents in the management of peripheral arterial disease remains unclear. We reviewed our experience with 64 consecutive episodes of limb-threatening graft or native vessel occlusions. The overall success rate was 59%, with a major complication/mortality rate of 28%. Thrombolytic therapy in patients with occluded vascular grafts required identification of a causative lesion and subsequent adjunctive management with percutaneous transluminal angioplasty or surgery for sustained patency (64%). In contrast, approximately 70% of native vessel occlusions maintained patency whether a causative lesion was identified and corrected or not. Patients who failed thrombolytic therapy had a worse prognosis overall, with 38% undergoing primary amputation, although patients with reconstructable occlusions still had a 64% salvage rate at six months. The review demonstrated that thrombolytic therapy continues to be a useful adjunct in treating the patient with peripheral vascular occlusion, although a significant risk of major complications persists. Patients with graft occlusions successfully treated with thrombolysis require correction of any precipitating lesions for long-term limb salvage, while careful management of patients failing thrombolysis can still achieve significant limb salvage in selected cases.

Decrease in neostriatal blood flow after D-amphetamine administration or electrical stimulation of the substantia nigra.

Local blood flow was measured in the caudate nuclei and, in some cases, other areas of rat and monkey brain by the hydrogen clearance technique. Resting values for caudate blood flow in the rat were similar to those reported elsewhere, i.e., 69 +/- 4 ml/min/100 g in the caudate. Administering D-amphetamine sulfate (0.5 mg/kg, i.p.) to rats reduced caudate flow by a maximum of about 33% after 30 min; this effect could be blocked by pretreatment with haloperidol (5.0 mg/kg, i.p.), a drug that blocks dopamine receptors. D-Amphetamine sulfate (1.5 mg/kg) also reduced caudate but not cortical blood flow in unanesthetized monkeys. Electrical stimulation of the pars compacta of the substantia nigra reduced ipsilateral caudate flow by about 25% without affecting flow in the contralateral caudate. This effect varied with the frequency and intensity of stimulation. These studies suggest that the intraparenchymal release of brain dopamine may modify intraparenchymal (local) blood flow.

The incidence, management, and outcome of patients with gastrointestinal carcinoids and second primary malignancies.

BACKGROUND: A higher than expected incidence of second primary malignancies in patients with gastrointestinal carcinoids has been reported. How patients with such concurrent neoplasms should be managed and whether or not the discovery of an incidental carcinoid at the time of operation for another malignancy affects patient management or outcome, has never been previously addressed. STUDY DESIGN: We retrospectively reviewed our 20-year experience with gastrointestinal carcinoid tumors with the purpose of determining the appropriate management and eventual outcome of patients with these multiple malignancies. RESULTS: Sixty-nine patients with carcinoids of the gastrointestinal tract were discovered, of whom 29 (42 percent) had second synchronous tumors and three (4 percent) had metachronous tumors. The gastrointestinal tract accounted for 42.9 percent of the tumors, and carcinoma of the colon and rectum was found in seven (21.9 percent) of 32 patients. None of the 29 patients with a second synchronous tumor presented with symptoms referable to their carcinoid, each of which was incidentally discovered: nine at autopsy and 20 at laparotomy for the treatment of other tumors. All of the 20 surgical patients had the gastrointestinal carcinoids resected for cure, although three had histopathologic criteria for invasion. None of the 29 patients died as a result of, had recurrence of, or had their postoperative therapy altered by the carcinoid diagnosis. CONCLUSIONS: Gastrointestinal carcinoid is associated with a high incidence of second primary malignancy, 46 percent in this study. The most common site for the second primary malignancy in these patients is the gastrointestinal tract, suggesting a site specific predisposition to malignant degeneration. Most gastrointestinal carcinoids are incidentally discovered at laparotomy or autopsy. The discovery of an asymptomatic gastrointestinal carcinoid during the operative treatment of another malignancy will usually only require resection without additional treatment and will have little affect on the prognosis of the individual.

Treatment of acute gynecologic infections with trovafloxacin. Trovafloxacin Surgical Group.

BACKGROUND: Trovafloxacin, a broad-spectrum fourth-generation quinolone with gram-positive and gram-negative aerobic and anaerobic bacterial activity, is available in oral and intravenous formulations. The objective of this prospective, multicenter, double-blind, randomized study was to compare the efficacy of trovafloxacin with that of cefoxitin, an approved drug for treatment of acute gynecologic infections, together with amoxicillin/clavulanic acid as oral follow-on treatment. METHODS: Patients with a clinical diagnosis of acute pelvic infection received either intravenous alatrofloxacin with oral trovafloxacin follow-on (trovafloxacin) or a combined regimen of cefoxitin followed by amoxicillin/clavulanic acid for a maximum of 14 days. The primary endpoint was clinical response to therapy on follow-up at day 30. RESULTS: Clinical success rates were comparable between the trovafloxacin (n = 107) and comparative (n = 119) groups at study end (90% vs. 86%, respectively; 95% confidence interval, -4.5, 12.5). Among clinically evaluable patients, clinical success rates for infections involving Enterococcus species were higher with trovafloxacin than with the comparative regimen at the end of treatment (96% and 85%) and at study end (96% and 86%). CONCLUSION: Intravenous alatrofloxacin followed by oral trovafloxacin for a maximum of 14 days of total therapy was efficacious in the treatment of acute pelvic infections.

Awake epidural anesthesia is associated with improved natural killer cell cytotoxicity and a reduced stress response.

BACKGROUND: Laparotomy under general anesthesia is associated with depressed natural killer cell cytotoxicity (NKCC) and compromised clearance of tumor cells. We tested the hypothesis that awake epidural anesthesia (AEA) improves NKCC compared to conventional general endotracheal anesthesia (GEA). PATIENTS AND METHODS: Preoperative, perioperative, and postoperative (day 3) NKCC, plasma epinephrine, norepinephrine, cortisol levels, and 24-hour urinary cortisol levels were measured in 20 patients undergoing open colectomy under either AEA or GEA. RESULTS: Preoperative and postoperative measurements were not significantly different in the two groups. Patients receiving GEA had a significant reduction in NKCC from 36% +/- 4% preoperatively to 22% +/- 4% perioperatively (P = 0.02). Patients receiving AEA had no significant change in NKCC. Perioperative plasma epinephrine and cortisol levels were higher with GEA than AEA. The perioperative 24-hour urinary cortisol excretion values were significantly higher in the group receiving GEA, suggesting a greater stress hormone response in this group compared to AEA patients. CONCLUSIONS: Compared to GEA, AEA appears to preserve perioperative NKCC. This effect may be related to an attenuated stress hormone response associated with AEA. Cancer patients may have improved killing of embolized tumor cells during surgery performed under AEA.

Gastric duplication cyst. Endoscopic presentation as an ulcerated antral mass.

A case of a 53-year-old man who presented with epigastric pain and weight loss is described. Endoscopy showed a smooth antral mass with what appeared to be a central overlying ulcer. Computerized tomography and upper gastrointestinal series confirmed the presence of a gastric mass. Laparotomy and local resection showed a gastric duplication comprised of two cysts, one with communication to the stomach lumen. Gastric duplication is a rare entity, especially in the adult. Though generally benign, local ulceration or fistula formation can cause symptoms and may suggest a more malignant process that warrants investigation.

Local cerebral blood flow in the dog during intravenous infusion of dopamine.

Local cerebral blood flow was measured in anaesthetized beagle dogs by the hydrogen clearance method. Dopamine was administered as a continuous intravenous infusion of varying doses. The changes in local cerebral blood flow induced by dopamine were similar at the different locations; i.e., the caudate nucleus, thalamus, frontal and parietal cortex. Blood flow responded to dopamine in the following ways: low dose (less than 2 micrograms/kg/min): blood flow decreased or remained unchanged; moderate doses (2--6 micrograms/kg/min): blood flow increased at all electrodes; high doses (7--20 micrograms/kg/min): blood flow decreased once again. The decrease in blood flow could be inhibited by the alpha-adrenergic receptor antagonist phentolamine or by the serotonin receptor antagonist methysergide. This indicates that the constrictor effect of dopamine on cerebral blood vessels is mediated via alpha-adrenergic receptors as well as via serotonin receptors. The increase in cerebral flow could be inhibited by the dopamine receptor antagonist haloperidol, indicating vascular dopamine receptors in the brain with a dilating effect. When the vasoconstrictor activity of dopamine is blocked, the single response to a dopamine infusion is a blood flow increase. This might be beneficial in the clinical situation of symptomatic vasospasm.

The cancer "fear" in IBD patients: is it still REAL?

Increased rates of colorectal cancer (CRC) with high rates of progression from dysplasia to CRC are well documented in the inflammatory bowel disease (IBD) population. This increased risk in the presence of currently improving but still inadequate surveillance techniques confirms that the cancer "fear" in IBD patients is still real. The majority of data on the cancer risk in IBD has been gathered from ulcerative colitis (UC) patients as these patients are generally better studied. Thus surveillance and treatment protocols for Crohn's disease (CD) are frequently modeled on UC paradigms. Dysplasia in the IBD cohort frequently is a harbinger of local, distant, or metachronous neoplasia. Therefore, frequent surveillance and referral for surgical intervention when dysplasia is detected are justified in both the CD and UC patient.