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PD-L1 in small bowel adenocarcinoma is associated with etiology and tumor-infiltrating lymphocytes, in addition to microsatellite instability.
Giuffrida, P, Arpa, G, Grillo, F, Klersy, C, Sampietro, G, Ardizzone, S, Fociani, P, Fiocca, R, Latella, G, Sessa, F, et al
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2020;(7):1398-1409
Abstract
Small bowel adenocarcinomas (SBAs) are often associated with poor prognosis and have limited therapeutic options. Programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway blockade is an effective treatment in many microsatellite instability-high (MSI-H) solid tumors. We aimed at investigating PD-L1 and PD-1 expression in non-hereditary, non-ampullary SBAs, associated with celiac disease (CeD), Crohn's disease (CrD), or sporadic, recruited through the Small Bowel Cancer Italian Consortium. We assessed PD-L1 and PD-1 by immunohistochemistry in a series of 121 surgically resected SBAs, including 34 CeD-SBAs, 49 CrD-SBAs, and 38 sporadic SBAs. PD-L1 and PD-1 expression was correlated with several clinico-pathological features, such as the etiology, microsatellite instability status, and tumor-infiltrating lymphocyte (TIL) density. The prevalence of PD-L1 positivity according to combined positive score (CPS) was 26% in the whole cohort of SBAs, with significantly (p = 0.001) higher percentage (35%) in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs (5%). CPS ≥ 1 SBAs were significantly (p = 0.013) more frequent in MSI-H cases (41%) than in non-MSI-H ones (18%); however, 15 CPS ≥ 1 microsatellite stable SBAs were also identified. CPS ≥ 1 SBAs showed higher TIL and PD-1+ immune cell density, more frequently medullary histotype, as well as a better outcome in comparison with CPS < 1 cases. This study demonstrates an increased proportion of PD-L1+ cases in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs. In addition, the identification of a subset of PD-L1+ microsatellite stable SBAs supports the need to ascertain additional biomarkers of response to immune checkpoint inhibitors along with MSI-H.
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Evaluating and optimizing oral formulations of live bacterial vaccines using a gastro-small intestine model.
de Barros, JM, Costabile, A, Charalampopoulos, D, Khutoryanskiy, VV, Edwards, AD
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V. 2016;:115-22
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Abstract
Gastrointestinal (GI) models that mimic physiological conditions in vitro are important tools for developing and optimizing biopharmaceutical formulations. Oral administration of live attenuated bacterial vaccines (LBV) can safely and effectively promote mucosal immunity but new formulations are required that provide controlled release of optimal numbers of viable bacterial cells, which must survive gastrointestinal transit overcoming various antimicrobial barriers. Here, we use a gastro-small intestine gut model of human GI conditions to study the survival and release kinetics of two oral LBV formulations: the licensed typhoid fever vaccine Vivotif comprising enteric coated capsules; and an experimental formulation of the model vaccine Salmonella Typhimurium SL3261 dried directly onto cast enteric polymer films and laminated to form a polymer film laminate (PFL). Neither formulation released significant numbers of viable cells when tested in the complete gastro-small intestine model. The poor performance in delivering viable cells could be attributed to a combination of acid and bile toxicity plus incomplete release of cells for Vivotif capsules, and to bile toxicity alone for PFL. To achieve effective protection from intestinal bile in addition to effective acid resistance, bile adsorbent resins were incorporated into the PFL to produce a new formulation, termed BR-PFL. Efficient and complete release of 4.4×10(7) live cells per dose was achieved from BR-PFL at distal intestinal pH, with release kinetics controlled by the composition of the enteric polymer film, and no loss in viability observed in any stage of the GI model. Use of this in vitro GI model thereby allowed rational design of an oral LBV formulation to maximize viable cell release.
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Coeliac disease in children.
Paul, SP, Kirkham, EN, Pidgeon, S, Sandmann, S
Nursing standard (Royal College of Nursing (Great Britain) : 1987). 2015;(49):36-41
Abstract
Coeliac disease is an immune-mediated systemic disorder caused by ingestion of gluten. The condition presents classically with gastrointestinal signs including diarrhoea, bloating, weight loss and abdominal pain, but presentations can include extra-intestinal symptoms such as iron-deficiency anaemia, faltering growth, delayed puberty and mouth ulcers. Some children are at higher risk of developing coeliac disease, for example those with a strong family history, certain genetic disorders and other autoimmune conditions. If coeliac disease is suspected, serological screening with anti-tissue transglutaminase titres should be performed and the diagnosis may be confirmed by small bowel biopsy while the child remains on a normal (gluten-containing) diet. Modified European guidelines recommend that symptomatic children with anti-tissue transglutaminase titres more than ten times the upper limit of normal, and positive human leucocyte antigen (HLA)-DQ2 or HLA-DQ8 status, do not require small bowel biopsy for diagnosis of coeliac disease. Management of the disease involves strict adherence to a lifelong gluten-free diet, which should lead to resolution of symptoms and prevention of long-term complications. Healthcare professionals should be aware of the varied presentations of coeliac disease to ensure timely screening and early initiation of a gluten-free diet.
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Environmental and lifestyle influences on disorders of the large and small intestine: implications for treatment.
Hall, EH, Crowe, SE
Digestive diseases (Basel, Switzerland). 2011;(2):249-54
Abstract
There is growing evidence that many aspects of our lifestyle and the environment we now live in contribute to the development of disease. The luminal digestive tract is a clear target of the influence of dietary components, alcohol, microbial organisms, and other ingested materials. External factors including obesity, lack of physical exercise, and tobacco consumption also impact diseases of the luminal gastrointestinal (GI) tract. A growing understanding of the microbiome which forms an integral part of the human organism indicates that this is another important external force that impacts human health and disease. The luminal GI tract conditions that arise, at least in part, from these external factors range from malignancies (squamous cell esophageal cancer, Barrett's esophagus and associated esophageal adenocarcinoma, gastric cancer, and colorectal cancer), idiopathic inflammatory disorders such as inflammatory bowel diseases, and post-infectious syndromes including post-infectious irritable bowel syndrome, post-infectious dyspepsia and other functional GI disorders. Of particular interest, given their increase in prevalence in much of the world, are immune-mediated conditions in which food antigens are the driving force behind disease development. These entities include celiac disease, eosinophilic esophagitis, and food allergies. Celiac disease is a prime example of a condition mediated by dietary factors whose pathogenesis has only recently been determined, providing opportunities for developing treatment options beyond the gluten-free diet. While a genetic basis for this disease clearly exists, it is believed that environmental factors such as an increase in gluten in the human diet account for its rising prevalence, now roughly 1% of genetically susceptible populations in all continents. Proposed therapeutic strategies span from preventing disease by modulating the time of gluten introduction in infants, to reducing exposure to gluten by developing strains of wheat with lower levels of gluten, degrading ingested gluten peptides within the intestinal lumen via endopeptidases or modulating uptake of these peptides across intestinal tight junctions. Other novel treatments in development focus on interfering with the immune events that lead to disease once gluten accesses the lamina propria including altering the immune milieu from a Th1-predominant response via hookworm infection, inhibiting tissue transglutaminase, and blocking antigen presentation and/or T-cell responses to gluten peptides. While new treatment options for celiac disease reflect the complex interaction of diet, genetic factors and the host immune response, the implications for treatment of many conditions of the large and small intestine that arise from environmental and lifestyle are as basic as ensuring adequate nutrition, regular exercise and cessation of tobacco use. Much more needs to be learned about the microbiome, dietary and other factors and their interaction with the human host in order to develop potential new treatment strategies for diseases that result from the environment and lifestyle.
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Laparoscopic versus Open surgery for small bowel Crohn's disease.
Dasari, BV, McKay, D, Gardiner, K
The Cochrane database of systematic reviews. 2011;(1):CD006956
Abstract
BACKGROUND Crohn's disease (CD) is a chronic inflammatory bowel disease that most commonly involves the terminal ileum and colon (55 percent). Surgical treatment is required in approximately 70 percent of patients. Multiple procedures and repeat operations are required in 30 - 70 percent of all patients (Duepree 2002) but the disease remains incurable.Laparoscopy has gained wide acceptance in gastrointestinal surgery with potential advantages of faster return to normal activity and diet, reduced hospital stay, reduced postoperative pain, better cosmesis (Duepree 2002, Dunker 1998, Milsom 2001, Reissman 1996), improved social and sexual interaction (Albaz 2000) and its use is accepted in benign and malignant colorectal diseases. Laparoscopic surgery offers additional advantage of smaller abdominal fascial wounds, low incidence of hernias, and decreased rate of adhesive small-bowel obstruction (Albaz 2000) compared with conventional surgery reducing the need for non-disease-related surgical procedures in CD population.There are concerns about missing occult segments of disease and critical proximal strictures due to limited tactile ability, earlier recurrence due to possible reduced immune response induced by laparoscopy, technical difficulty due to fragile inflamed bowel and mesentery and the existence of adhesions, fistulas, and abscesses (Uchikoshi 2004). It is therefore important to evaluate the potential benefits and risks of laparoscopic surgery versus open surgery in patients with small bowel CD (Lowney 2005). OBJECTIVES To determine if there is a difference in the perioperative outcomes and re-operation rates for disease recurrence following laparoscopic surgery compared to open surgery in small bowel CD. SEARCH STRATEGY Published and unpublished randomised controlled trials were searched for in the following electronic databases: The Cochrane Central Register of Controlled Trials (CENTRAL) 2010 issue 2 The Cochrane Database of Systematic Reviews, and Database of Abstracts of Reviews of Effects (DARE) 2010 issue 2 The Cochrane Colorectal Cancer Group Controlled Trials Register Ovid MEDLINE (1990 to 2010) EMBASE (1990 to 2010) Health Technology Assessment (HTA) Database (1990 to 2010) SELECTION CRITERIA Randomised controlled trials (RCT) comparing laparoscopic and open surgery for small bowel CD were included. DATA COLLECTION AND ANALYSIS Two reviewers independently assessed the studies and extracted data. RevMan 5.0 was used for statistical analysis. MAIN RESULTS Two RCTs comparing laparoscopic and open surgery for small bowel CD were identified. Long term outcomes of the patients in both the trials were published separately and these were included in the review.Laparoscopic surgery appeared to be associated with reduced number of wound infections (1/61 vs 9/59), reoperation rates for non disease related complications (3/57 vs 7/54 ) but the difference was not statistically significant [p values were 0.23 and 0.19 respectively]. There was no statistically significant difference between any of the compared outcomes between laparoscopic and open surgery in the management of small bowel CD. AUTHORS' CONCLUSIONS Laparoscopic surgery for small bowel CD may be as safe as the open operation. There was no significant difference in the perioperative outcomes and the long term reoperation rates for disease-related or non-disease related complications of CD.
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Small bowel transplantation.
O'Keefe, SJ, Matarese, L
Current gastroenterology reports. 2006;(5):360-6
Abstract
Until very recently, outcomes from small bowel transplantation (SBTx) lagged behind those in liver, heart, and kidney transplantation because of the magnitude of the immunologic burden; the strong expression of histocompatibility antigens; and the contamination in grafts by bacterial organisms. With novel techniques of immune-induction therapies, such as recipient "preconditioning" with lymphocyte reduction, followed by the more subtle use of immunosuppression-based single-agent tacrolimus, graft and host 1-year survival is now over 90% in the most active US centers, a finding that parallels the outcomes in liver and kidney transplantation. In contrast to the alternative therapy for permanent intestinal failure, home total parenteral nutrition (TPN), SBTx improves quality of life and restores digestive and absorptive function, making patients nutritionally autonomous. With survival beyond 1 to 3 years, the procedure is cost-effective. Current results support expansion of the indications for SBTx from use as salvage therapy for patients with TPN failure to preemptive therapy for patients at risk of developing TPN failure.
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Advances in small-intestine transplantation.
Langnas, AN
Transplantation. 2004;(9 Suppl):S75-8
Abstract
Intestinal transplantation has become the treatment of choice for patients who are experiencing life-threatening complications of intestinal failure. Early attempts with intestinal transplantation were unsuccessful as a consequence of both technical and immunologic failures. The introduction of tacrolimus provided the immunologic foundation needed for the field to advance. Guidelines for patient selection combined with standardization of operative procedures and postoperative management has allowed for improved patient and graft survival. There has been a gradual improvement in patient survival over the past 10 years, most notably in the past 3 years. Nutritional autonomy has been achieved in hundreds of patients worldwide. Further advancements in the understanding of the immune response to the transplanted intestine are still needed and will allow the use of new antirejection medications, resulting in improved outcomes.
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Small bowel transplantation.
Ghanekar, A, Grant, D
Current opinion in critical care. 2001;(2):133-7
Abstract
Small bowel transplantation has become the treatment of choice for patients with chronic gut failure whose illness cannot be maintained on home parenteral nutrition. Outcomes have improved as a result of refinements in patient selection, surgical techniques, and the prevention, diagnosis, and treatment of graft rejection. Early listing is important because of the shortage of organ donors. Rejection rates are still 50% or more, despite the use of potent immune suppression. Sepsis rates are also higher for patients who have had small bowel transplantation than for those who have received other organs because of bacterial translocation from the gut secondary to preservation injury and graft rejection. Graft and patient survival rates after small bowel transplantation are comparable to rates after lung transplantation. Successful transplant recipients resume unrestricted oral diets.
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Clinical aspects of small-bowel transplantation.
Veenendaal, RA, Ringers, J, Baranski, A, van Hoek, B, Lamers, CB
Scandinavian journal of gastroenterology. Supplement. 2000;(232):65-8
Abstract
AIM: To update clinical aspects of small-bowel transplantation. METHODS Critical review of the literature. RESULTS The two major functions of the small bowel are absorption of food and protection of the body against ingested pathogens. The highly developed immune system of the bowel, necessary for the latter function, prevented successful small-bowel transplantation during the 1960s and 1970s by provoking early and severe rejection of the graft. The introduction of cyclosporin in the 1980s enabled small-bowel transplantation with a moderate success rate. Further improvement of immunosuppressive regimens, especially the introduction of tacrolimus and aggressive surveillance for and treatment of infections, has resulted in a slow but steady improvement of transplant results during the past decade. At this moment, however, long-term parenteral nutrition is still the first-line treatment of the short-bowel syndrome world-wide because of the excellent results with regard to patient survival. CONCLUSION Although results of small-bowel transplantation are steadily improving, especially due to better immunosuppressive regimens, long-term parenteral nutrition is still the first-line treatment of short-bowel syndrome.