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.

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.

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.

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.

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.

Genetic association of DLG5 R30Q with familial and sporadic inflammatory bowel disease in men.

BACKGROUND: The association of DLG5 R30Q with IBD has been replicated in several populations, but is not statistically significant in others. We studied the incidence of DLG5 alleles in a population of IBD patients from Pennsylvania. METHODS: DLG5 R30Q (rs1248696) and G1066G (rs1248634) were analyzed with PCR-based RFLP methods in a total of 521 subjects, that included 105 individuals with IBD and 139 without IBD from a familial IBD registry, 107 with sporadic IBD, and 170 unrelated healthy controls. R30Q was further analyzed with SNPlex Genotyping System in 473 samples. RESULTS: RFLP genotyping data showed that, DLG5 R30Q was significantly associated with IBD overall (p=0.006), and separately with CD (p=0.009) and UC (p=0.024). The association of R30Q with IBD was entirely due to a male-associated effect (male vs female p=0.015 vs 0.241 (IBD), p=0.024 vs 0.190 (CD), and p=0.019 vs 0.575 (UC)). The frequency of the A allele carriage was elevated in both affected and unaffected members in the familial IBD cohort compared to healthy controls (p=0.037). In the family pedigrees, we observed differences in the expression of IBD in individuals carrying the A allele between families. CONCLUSIONS: In the studied population, DLG5 R30Q was associated with all forms of IBD. An elevated presence of the R30Q variant was observed in all members of a familial IBD registry. This association of the R30Q variant with IBD was male-specific.

Both human SP-A1 and Sp-A2 genes are expressed in small and large intestine.

The human SP-A locus consists of two functional genes and one pseudogene, and SP-A is shown to play a role in local host defense and the regulation of inflammation in lung. Because the intestine, like the lung, is constantly exposed to foreign and potentially harmful substances, we investigated the hypothesis that both human SP-A genes are expressed in intestine. We demonstrate that both SP-A genes are expressed in human small and large intestine. The presence of SP-A mRNA in human intestine was detected by reverse transcription polymerase chain reaction (RT-PCR), Northern blot analysis, and immunohistochemistry. The size of intestinal SP-A mRNA is the same as that in human lung, but the level of expression, compared with that in the lung, is very low in both the small and large intestine. Immunohistochemical analysis revealed positive reactivity for SP-A in a subgroup of epithelial cells in the intestine. Expression of both SP-A1 and SP-A2 genes was established by gene-specific PCR amplification, PCR-based converted RFLP discrimination, and direct sequencing of RT-PCR products. We speculate that SP-A in the intestine plays a role in local host defense and inflammation.

Cd1d-restricted cellular lysis by peripheral blood lymphocytes: relevance to the inflammatory bowel diseases.

The CD1d molecule has been implicated to play a role in inflammatory bowel diseases (IBD), possibly through its presentation of an intestinal antigen trigger. To understand the role of the CD1d class I-like protein in IBD, we investigated the molecule's expression in diseased intestinal tissue and determined its potential to undergo specific recognition by intraepithelial and peripheral blood lymphocytes (PBLs) derived from IBD patients. We have observed an increase in precipitable CD1d in inflamed tissues, which suggests CD1d up-regulation in IBD; this was not accompanied by the occurrence of CD1d-specific cytotoxicity by lymphocytes isolated from the same tissue sites. In contrast, we have observed CD1d-specific cytotoxicity by PBLs from both patients and normal controls mediated by a possibly unique type of lymphocytic cell. These observations support a model in which intestinal inflammation may be initiated by circulating PBLs following the tissue-specific upregulation of CD1d. These activated PBLs may then be the source of the extraintestinal manifestations observed with IBD. We therefore propose that the cells responsible for this activity may play a role in regulating immune responses through the specific recognition of CD1d-specific antigen(s).

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.

Bowel permeability is improved in Crohn's disease after ileocolectomy.

PURPOSE: Numerous investigators have shown increased bowel permeability in patients with Crohn's disease. It is unclear whether this is a precondition affecting the entire intestine or a consequence of the inflammation and, therefore, only affecting the diseased bowel. The present study tested the hypothesis that resection of diseased bowel in patients with ileocolonic Crohn's disease would correct abnormalities in bowel permeability. METHODS: Ten patients (5 females; mean age, 33 +/- 2 years) with ileocolonic Crohn's disease who underwent elective ileocolic resections had bowel permeability measured preoperatively and postoperatively by the relative urinary clearance of orally consumed lactulose and rhamnose. RESULTS: Mean preoperative bowel permeability in patients with Crohn's disease was significantly elevated relative to healthy volunteers (0.172 +/- 0.04 vs. 0.046 +/- 0.01; P < 0.05, unpaired t-test). After ileocolectomy, bowel permeability decreased in patients with Crohn's disease and reached a normal range by postoperative day 30. CONCLUSIONS: Bowel permeability is increased in patients with ileocolic Crohn's disease because of the presence of diseased bowel and decreases to a normal range in these patients after resection of gross intestinal disease. This suggests that bowel permeability may be a quantitative and clinically effective method with which to assess the presence and severity of diseased bowel in patients with Crohn's disease.

Cytomegalovirus enteritis: a highly lethal condition requiring early detection and intervention.

UNLABELLED: Cytomegalovirus infection causing symptomatic enteritis is most usually associated with immunosuppressed transplant patients or patients positive for human immunodeficiency virus. Most reports studying this illness are small and do not clearly define the risk factors or mortality rates. METHODS: The present study retrospectively reviewed the charts of 67 patients with biopsy-proven cytomegalovirus enteritis (esophageal, gastric, small bowel, and colonic) to define and to investigate factors that influence survival. Patients were classified into four groups based on underlying medical condition: 1) patients positive for human immunodeficiency virus; 2) transplant patients receiving immunosuppressive medications; 3) immunosuppressed nontransplant patients; and 4) otherwise healthy individuals. Mortality rates based on underlying medical condition, location of intestinal cytomegalovirus infection, cytomegalovirus therapy, age, and average days to institution of treatment were defined and statistically assessed. RESULTS: Mortality was significantly greater in the normal patient group (80 percent) than in the transplant (21 percent), other immunosuppressed (44 percent), or human immunodeficiency virus-positive (75 percent) groups (P = 0.0006, Cochran-Mantel-Haenszel statistics). There was no difference in mortality based on intestinal location of disease or treatment modality (surgery, medical therapy, or both). Cohorts of patients older than 65 years had a statistically higher mortality rate vs. those younger than 65 years old (68 vs. 38 percent; P = 0.05, Cochran-Mantel-Haenszel statistics). Statistically increased mortality was also associated with increased time from hospital admission to institution of cytomegalovirus treatment, whether therapy was medication alone or medication and surgery (P < 0.05, exact Wilcoxon's test). CONCLUSIONS: 1) Lethal cytomegalovirus enteritis can arise in patient populations not typically identified as being at risk for this disorder, including normal individuals. 2) Mortality in cytomegalovirus enteritis is adversely associated with age older than 65 years and increased time to institution of therapy but is not affected by anatomic site of infection or particular form of treatment. Paradoxically, in this study, normal patients had the highest mortality, which we attribute to a low index of suspicion and relatively late institution of therapy.

Increased LFA-1 expression in intestines of rats with GVHD after small bowel transplantation.

Experimental graft-versus-host disease (GVHD) causes immune-mediated intestinal injury. The adhesion molecule lymphocyte function associated antigen-1 (LFA-1) is involved in leukocyte homing to areas of inflammatory injury. Our hypothesis was that LFA-1 is increased in the GVHD injured small bowel and colon. We found that animals with GVHD caused by auxiliary small bowel transplantation displayed significantly increased expression of intestinal LFA-1alpha at times of clinical illness when compared to controls. The staining pattern progressed from a few discretely stained cells in the lamina propria on day 5 to diffuse confluent staining of lamina propria on day 13 and was statistically significantly increased from controls at days 10 and 13. CyA-treated animals had intermediate staining between control and day 13 GVHD animals. There was no difference between sham-operated control animals and SBTx animals with GVHD in the amount of staining for LFA-1 in extraintestinal organs normally affected by GVHD. We conclude that: (1) LFA-1 expression in the small bowel and colon progressively increased during GVHD after SBTx; and (2) CyA treatment is associated with decreased LFA-1 expression in the small bowel and colon of GVHD animals after SBTx. LFA-1 may play an important role in immune-mediated injury of the intestine.

Monoclonal antibody to lymphocyte function associated antigen-1 improves graft-versus-host disease.

UNLABELLED: We previously showed that intestinal tissue expression of lymphocyte function associated antigen-1 is increased in animals with graft-versus-host disease after small-bowel transplantation. HYPOTHESIS: Treatment of rats with monoclonal antibody to lymphocyte function associated antigen-1 after small-bowel transplantation will lessen the severity of graft-versus-host disease. METHODS: Graft-versus-host disease was created in Lewis X Brown-Norway F1 rats by heterotopic vascularized small-bowel transplantation from Lewis donors. Transplanted rats were treated with either saline or various regimens of monoclonal antibody to lymphocyte function associated antigen-1. Clinical characteristics, weight loss, spleen index, white blood cell counts, native intestinal histology, bowel permeability, and survival were then compared between groups and appropriate sham-operated and lymphocyte function associated antigen-1-treated controls. RESULTS: Lymphocyte function associated antigen-1-treated rats lost less weight, had larger spleen indexes, more normal white blood cell counts, more normal native intestinal histology, less alteration in bowel permeability, and longer survival than untreated small-bowel transplantation rats. CONCLUSIONS: In this model of graft-versus-host disease after small-bowel transplantation, monoclonal antibody to lymphocyte function associated antigen-1 treatment decreased the severity of graft-versus-host disease and prolonged rat survival.

Amelioration of graft versus host disease with anti-ICAM-1 therapy.

We have previously demonstrated an increase in the adhesion molecule lymphocyte function-associated antigen-1 (LFA-1) in GVHD after small bowel transplantation (SBTx) and a therapeutic effect for the monoclonal antibody (MoAb) to LFA-1 in the same model. The present study evaluated the role of MoAb to LFA-1's ligand, intercellular adhesion molecule-1 (ICAM-1) in GVHD. Methods. GVHD was created in LBNF1 rats by heterotopic vascularized SBTx from Lewis donors. Saline treated SBTx-GVHD and sham-operated control animals were compared to animal groups treated with MoAb to ICAM-1 or MoAb to ICAM-1 and LFA-1. GVHD was evaluated by measuring spleen index, white blood cell count, bowel permeability, weight loss, and animal survival. RESULTS. Animals treated with the MoAb to ICAM-1 appeared clinically to have almost as severe GVHD as untreated animals; however, they had improved spleen indices, less neutropenia and weight loss, and survived longer than untreated animals (range 15-22 days in treated animals vs 12-16 days in untreated animals, P < 0. 01). Treatment with MoAb to both ICAM-1 and LFA-1 appeared to have a synergistic beneficial effect on GVHD (range 19-29 days, P < 0.001 vs untreated animals). Conclusion. MoAb to ICAM-1 alone or in combination with MoAb to LFA-1 ameliorates GHVD after SBTx and prolongs survival.

Coinfection of human foreskin fragments with multiple human papillomavirus types (HPV-11, -40, and -LVX82/MM7) produces regionally separate HPV infections within the same athymic mouse xenograft.

The athymic mouse xenograft system was used to prepare infectious stocks of two additional anogenital tissue-targeting human papillomaviruses (HPVs) in a manner similar to that for the development of infectious stocks of HPV-11. An anal condyloma from a transplant patient was used as material for extraction of infectious virus, and human foreskin fragments were incubated with the virus suspension and transplanted subrenally into athymic mice. Partial viral sequencing indicated that two rare HPV types (HPV-40 and HPVLVX82/MM7) were concurrently present in both the patient condyloma and the foreskin xenografts, and passage of both types was achieved as a mixed infection with HPV-40 predominating. Xenografts that developed from simultaneous infection of human foreskin fragments with HPV-11, -40, and -LVX82/MM7 virions produced regionally separate areas of HPV-11 and -40 infection as determined by in situ hybridization. In addition, in situ hybridization with HPV-40 and HPVLVX82/MM7 DNA probes demonstrated that both of these HPV types were present as adjacent but separate infections within the same anal condyloma of the transplant patient. These studies indicate that multiple HPV types can simultaneously infect genital tissue and that each HPV type predominantly maintains regional separation within the same papilloma.

Decreased expression of LFA-1 on peripheral blood lymphocytes in graft versus host disease.

We have previously demonstrated an increase in lymphocyte function associated antigen-1 (LFA-1) expression in the native intestines of animals with graft versus host disease (GVHD) after small bowel transplantation (SBTx). The present study evaluated LFA-1 expression on peripheral blood lymphocytes (PBLs) during GVHD. GVHD was created in LBNF1 rats by heterotopic vascularized SBTx from Lewis donors and compared to sham-op controls and cyclosporine-treated SBTx rats (SBTx-CyA, 10 mg/kg/day). PBLs were harvested on Postop Day 13 when signs of severe GVHD were present and PBLs were stained for LFA-1, CD3 (T-cell marker), and CD45 (B cell marker) and analyzed on an Epics 5 flow cytometer. Mesenteric lymph node (MLN) lymphocytes from the native intestines were also harvested for each group and stained for LFA-1. There were significant decreases in LFA-1, CD3, and CD45 PBL expression in rats with GVHD. CyA treatment corrected the abnormal CD3 and CD45 ratios, but not LFA-1 expression. It is concluded that: (1) The proportion of PBLs expressing LFA-1 is depressed in animals with clinical GVHD consistent with their recruitment into the host's inflamed tissues. (2) CyA treatment corrects the abnormalities in T and B cell ratios but not the decreased expression of LFA-1 on PBLs and may relate to its known imperfect ability to treat GVHD.

An increased gamma delta T cell population in the intestine of thymus-leukemia antigen transgenic mice.

In an approach to study thymic leukemia antigen's (TL's) function, we have developed transgenic mice that express T18d on virtually all somatic cells; in such mice, we initially observed changes in T cells within the thymus and lymph nodes as well as the ability of TL to undergo recognition by splenic T cells. As phase II of our study, we now present the results on the composition of gut T cell populations which may be a better measure of TL's true function. We have demonstrated an increase in the number of gamma delta T cells as well as the increase in gamma delta T cells expressing the V gamma 2 chain. These cells appear to be both CD4 and CD8 negative. This suggests that TL may select for a subset of gamma delta T cells within the gut and bolsters earlier reports implicating an H-2T regional gene product as the major histocompatibility complex ligand for gamma delta T cells.

Stoma creation through the stoma site: a rapid, safe technique.

UNLABELLED: Stoma creation often involves a separate laparotomy incision. Recently, laparoscopy was suggested to minimize the morbidity associated with conventional open stomal techniques. We describe and evaluate a technique of stoma creation done directly through the stoma site, avoiding both laparotomy and laparoscopy. METHODS: Charts of 36 patients who underwent attempted stoma creation using this closed technique were retrospectively reviewed. RESULTS: A total of 32 patients had stomas successfully created in this fashion (closed group); although four patients failed and required laparotomy (open group), there was an overall success rate of 89 percent. Blood loss (17 +/- 5 vs. 350 +/- 130 ml; P < .001), operative time (52 +/- 8 vs. 169 +/- 35 minutes; P < 0.001), and complications (3/32 vs. 4/4; P < 0.001) favored the closed group. No factors, including diagnosis, obesity, or previous abdominal surgery were identified that contraindicated use of the closed technique. CONCLUSIONS: Stomas can be safely made in a high proportion of patients without the need for laparotomy or laparoscopy. Failure of the closed technique identifies a group of patients who have a high associated operative time, blood loss, and morbidity when laparotomy is used for stoma creation and in whom laparoscopic procedures may improve results.