Review of Gastrointestinal Motility in Cystic Fibrosis

Gastrointestinal manifestations in patients with cystic fibrosis (CF) are extremely common and have recently become a research focus. Gastrointestinal (GI) dysfunction is poorly understood in the CF population, despite many speculations including the role of luminal pH, bacterial overgrowth, and abnormal microbiome. Nevertheless, dysmotility is emerging as a possible key player in CF intestinal symptoms. Our review article aims to explore the sequelae of defective cystic fibrosis transmembrane conductance regulator (CFTR) genes on the GI tract as studied in both animals and humans, describe various presentations of intestinal dysmotility in CF, review newer diagnostic motility techniques including intraluminal manometry, and review the current literature regarding the potential role of dysmotility in CF-related intestinal pathologies.     

Gastrointestinal side effects of mycophenolic acid in renal transplant patients: a reappraisal.

Patient and graft survival following renal transplantation have improved markedly over the past decade, meaning that physician attention has turned more towards minimizing short- and long-term toxicities associated with immunosuppressive regimens. Gastrointestinal (GI) adverse events are common following renal transplantation and all immunosuppressive regimens have been associated with such events. Mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS) are potential components of immunosuppression regimens, and are associated with the most successful outcomes in kidney transplantation. The effects of MMF and EC-MPS are likely mediated via the active metabolite mycophenolic acid (MPA). The GI events caused by both MMF and EC-MPS may, in part, be related to MPA, independent of the formulation or route of administration. MPA may produce GI events either through direct action or through the action of it metabolites. However, many other factors may cause GI events observed following renal transplantation. These include the surgery itself and concurrent diseases such as diabetes, and bacterial, viral, fungal and parasitical infections. Additionally, numerous concomitant non-immunosuppressive agents, including antibiotics hypoglycaemic and proton-pump inhibitors, can be associated with GI events. In a recent trial in renal transplant patients with severe diarrhoea, approximately 50% of patients achieved resolution of diarrhoea through methods other than altering their immunosuppressive regimens. Indeed altering of the immunosuppressive regimen may lead to the risk of acute rejection. Thus, in order to reduce the risk of rejection and subsequent damage to the graft, it is important to consider other causes of GI events in renal transplant patients before altering immunosuppressive regimens.     

Diabetes-induced mechanophysiological changes in the small intestine and colon

The disorders of gastrointestinal(GI) tract including intestine and colon are common in the patients with diabetes mellitus(DM). DM induced intestinal and colonic structural and biomechanical remodeling in animals and humans. The remodeling is closely related to motor-sensory abnormalities of the intestine and colon which are associated with the symptoms frequently encountered in patients with DM such as diarrhea and constipation. In this review, firstly we review DM-induced histomorphological and biomechanical remodeling of intestine and colon. Secondly we review motor-sensory dysfunction and how they relate to intestinal and colonic abnormalities. Finally the clinical consequences of DMinduced changes in the intestine and colon including diarrhea, constipation, gut microbiota change and colon cancer are discussed. The final goal is to increase the understanding of DM-induced changes in the gut and the subsequent clinical consequences in order to provide the clinicians with a better understanding of the GI disorders in diabetic patients and facilitates treatments tailored to these patients.     

Pharmacokinetic Principles of Immunosuppressive Drugs

A basic tenet of clinical pharmacology is that the pharmacologic activity of an exogenously administered agent is related to the free drug concentration available at its receptor or ligand-binding site. The discipline of pharmacokinetics can be defined as the study of the processes that lead to the availability of an agent to its site of action. In this review we will discuss basic principles of pharmacokinetics that govern the absorption, distribution, metabolism, elimination and binding of immunosuppressive drugs commonly utilized in whole organ transplantation. In a discipline such as organ transplantation, where the agents utilized carry significant toxicity and where failure of efficacy can have dire consequences, knowledge of the pharmacokinetics of the agents utilized has become a basic skill for all transplant professionals. In this review we describe some of the underlying principles that govern the disposition of the agents commonly utilized in solid organ transplantation. In addition, we hope this review will help in understanding some of the basic drug interactions encountered in transplant practice.     

Systemic mastocytosis mimicking inflammatory bowel disease: A case report and discussion of gastrointestinal pathology in systemic mastocytosis

Gastrointestinal (GI) symptoms are present in up to 80% of patients with systemic mastocytosis (SM). GI symptoms include mainly abdominal pain, diarrhea, nausea, and vomiting. It is believed that most of the GI symptoms are due to the secondary effect of mast cell mediators on the GI tract. Direct involvement of the GI tract by neoplastic mast cell infiltration has not been well documented. We report a case of SM that initially mimicked inflammatory bowel disease based on clinical, radiographic, endoscopic, and histopathologic findings. On routine histologic sections of small bowel and colonic mucosal biopsies, there was expansion of the lamina propria by mononuclear inflammatory cells, foci of erosions with associated acute inflammation, and evidence of chronic mucosal injury with architectural distortion and gland foreshortening. Only on repeat biopsies and with ancillary tests for mast cells was a diagnosis of SM made, with extensive involvement of the GI tract. This is the first reported case of SM presenting as and mimicking inflammatory bowel disease. It is critical that clinicians and pathologists are aware that neoplastic mast cells in patients with SM can infiltrate the mucosa throughout the GI tract and that this infiltration can lead to symptoms and findings that can mimic inflammatory bowel disease.     

New immunosuppressive drugs: an update

An increasing number of immunosuppressive drugs became available for clinical use over the past few decades. These include substances with recently recognized immunosuppressive properties, which needed careful evaluation in various trials before they could be approved for use in different diseases. The effectiveness of other agents was already established, but knowledge about their modes of action or the mechanisms that lead to side effects was acquired much later. This understanding also contributed to the development of new drugs that display synergistic effects or lack certain adverse effects. The greater choice afforded by such research endeavours allows us to select the best therapeutic strategy for an individual patient; however, this requires a comprehensive knowledge of the available options. The present review provides an update of current knowledge of the most important substances (including calcineurin and target of rapamycin inhibitors, regulators of gene expression, and inhibitors of purine and pyrimidine synthesis) and surveys some of the novel agents that are expected to play an important role in the future.     

Histopathological findings in the gastrointestinal tract of primate recipients of porcine renal xenografts following different immunosuppressive regimens

BACKGROUND: Cyclophosphamide (CYP) and methotrexate (MTX) have been used as immunosuppressants in induction or maintenance protocols in a large variety of xenotransplantation models. Combining the use of transgenic porcine organs expressing human decay-accelerating factor (hDAF) with immunosuppressive therapy that included the use of CYP or MTX, survival of primate recipients of life-supporting renal xenografts has been prolonged. However, both drugs can cause significant systemic toxicity and, in particular, gastrointestinal (GI) toxicity. To date only limited data have been reported on the histopathological features deriving from the use of such agents in non-human primates. METHODS: Cyclophosphamide or MTX was used as part of the immunosuppressive regimen in 15 bilaterally nephrectomized non-human primate (Macaca fascicularis) recipients of a life-supporting hDAF porcine kidney. At post-mortem, a detailed analysis of the GI tract in animals receiving either CYP or MTX was performed. Paraffin-embedded sections of each portion of the GI tract were prepared and stained with hematoxylin and eosin (H&E). In some animals, additional investigations by immunohistochemistry (CD3, CD5, CD20, CD79 alpha cy, lambda, and kappa light chains) and by in situ hybridization for EBV encoded RNA (EBER) were undertaken. RESULTS: The xenografted animals from the CYP group had a mean survival of 31 days (range: 0 to 90 days); animals from the MTX group survived a median of 14 days (range: 0 to 39 days). GI complications were the most frequent cause of euthanasia after renal failure. In CYP-treated animals GI-tract lesions were primarily characterized by diffuse, severe lymphoplasmocytic mucosal inflammatory infiltrate. Variable degrees of villi atrophy and fusion, gut-associated lymphoid tissue (GALT) and goblet cell hyperplasia were also observed. In MTX-treated primates, findings were consistent with severe villi atrophy associated with mild-to-moderate disseminated lymphoplasmocytic infiltration. CONCLUSIONS: In conclusion, GI tract lesions are an early and consistent finding when CYP or MTX are used as induction agents in this model. The two compounds induce different types of GI tract damage, however, in agreement with their different mechanisms of action. Whilst CYP primarily determines inflammatory lesions, MTX leads to a degenerative type of damage. This study indicates that immunosuppressive drugs can cause severe GI tract damage in primate recipients of renal xenografts and may be responsible for life-threatening lesions.     

肠道菌群在胃肠道肿瘤发生发展及治疗中作用的现状与展望

胃肠道是人体内菌群的储存库。肠道菌群与人体构成共生关系,不仅参与营养物质代谢、机体免疫系统的发育和肠道屏障功能等正常生理过程,也与人体的多种疾病发生进展特别是胃肠道肿瘤的发病密切相关。同时肠道菌群影响着肿瘤的放疗、化疗和免疫治疗的疗效和毒副反应。随着基因测序技术和生物信息学的发展和普及化,探索肠道菌群与胃肠道肿瘤发生发...     

Prospects for personalized immunosuppression: pharmacologic tools--a review

In the last few years, novel immunosuppressive agents and new formulations, including sirolimus, mycophenolic acid (the active metabolite of mycophenolate mofetil), tacrolimus, and microemulsion cyclosporine, have significantly improved the clinical outcome of transplant recipients. However, the majority of immunosuppressive agents need a constant monitoring of drug levels to reduce the risk of graft rejection as well as drug-induced toxicities. Many factors may affect the pharmacokinetic characteristics of immunosuppressive agents, potentially reducing treatment effectiveness. Absorption and metabolism of immunosuppressive drugs are influenced by patient genotype and comedications, while comorbidities (ie, diabetes and cystic fibrosis) are responsible for altered pharmacokinetics. Dose individualization in transplant recipients is performed according to their health status, graft function, and drug therapeutic range. With respect to the last issue, therapeutic drug monitoring (TDM) plays a crucial role in achieving optimal immunosuppression, improving the efficacy of drugs, and lowering toxic effects. Pharmacokinetic analysis allowed the identification of specific parameters, such as plasma or blood levels, immediately before dosing (C(min) or trough levels) or 2 hours after administration (C(2)), which are significantly related to tissue exposure to the drug. More recently, studies have investigated treatment individualization by evaluating drug pharmacogenetics based on the expression level or mutations of their molecular targets, including calcineurin for cyclosporine and tacrolimus, and inosine monophosphate dehydrogenase for mycophenolic acid. Although no conclusive data may be drawn from these preliminary trials, further studies are underway to address the role of pharmacogenetics in clinical decision making.     

Immunosuppressive and metabolic agents that influence allo- and xenograft survival by in vivo expansion of T regulatory cells

The transplanted organs or cells survive if the recipient receives adequate long-term immunosuppressive therapy. Immunosuppressive therapy combined with cell-based strategies (eg, regulatory T cell [Treg]-based therapy) promotes graft survival. A combination of Treg-based therapy and minimal or no immunosuppressive drug therapy would have the potential to minimize the risks of the complications and side effects of these drugs. Fortunately, some immunosuppressive and other agents not only impede the effector T cell response, but also help generate new CD4⁺ Tregs from conventional effector T cells. These agents include IL-2, TGF-β, agents that block the CD40/CD40L costimulation pathway, mTOR inhibitors, and histone deacetylase inhibitors. Consequently, a state of relative unresponsiveness to the transplanted organ may be induced through the expansion of Tregs. We here review the effect of these various agents on expansion of CD4⁺ Tregs in allo- and xenotransplantation. The expansion of Tregs might allow a dose reduction of the standard immunosuppressive drugs.     

Infectious Diseases of the Lower Gastrointestinal Tract

Gastrointestinal (GI) infections are a major cause of morbidity and mortality worldwide. Although infectious organisms are often recovered by microbiological methods, surgical pathologists play an invaluable role in diagnosis. The lower GI tract, including the appendix, large bowel, and anus, harbors a wide variety of pathogens. Some infections are part of disseminated disease, whereas others produce clinicopathologic scenarios that are specific to the lower GI tract. This review focuses on selected infectious disorders of the lower GI tract that may be encountered by the general surgical pathologist, including viral, bacterial, fungal, and parasitic organisms, and including infections caused by food- and water-borne pathogens. Diagnostic gross and histologic features are discussed, as well as useful clinical features and ancillary diagnostic techniques. Pertinent differential diagnoses are also emphasized, including other inflammatory conditions of the gut (such as ischemia or idiopathic inflammatory bowel disease) that can be mimicked by lower GI infections.     

Review of select transplant subpopulations at high risk of failure from standard immunosuppressive therapy

Despite improvements in short-term graft and patient survival rates for solid organ transplants, certain subgroups of transplant recipients experience poorer clinical outcome compared to the general population. Groups including pediatrics, African-Americans, diabetics, cystic fibrosis patients, and pregnant women require special considerations when designing immunosuppressive regimens that optimize transplant outcomes. Problems specific to pediatric transplant recipients include altered pharmacokinetics of immunosuppressive drugs, such as cyclosporine (CsA) and tacrolimus (poor absorption, increased metabolism, rapid clearance), the need to restore growth post-transplantation, and a high incidence of drug-related adverse effects. African-Americans have decreased drug absorption and bioavailability, high immunologic responsiveness, and a high incidence of post-transplant diabetes mellitus. Diabetics and cystic fibrosis patients exhibit poor absorption of immunosuppressive agents, which may lead to underimmunosuppression and subsequent graft rejection. Pregnant women undergo physiologic changes that can alter the pharmacokinetics of immunosuppressives, thus requiring careful clinical management to minimize the risks of either under- or overimmunosuppression to mother and child. To achieve an optimal post-transplant outcome in these high-risk patients, the problems specific to each group must be addressed, and immunosuppressive therapy individualized accordingly. Drug formulation greatly impacts upon pharmacokinetics and the resultant level of immunosuppression. Thus, a formulation with improved absorption (e.g., CsA for microemulsion), higher bioavailability, and less pharmacokinetic variability may facilitate patient management and lead to more favorable outcomes, especially in groups demonstrating low and variable bioavailability. Other strategies aimed at improving transplant outcome include the use of higher immunosuppressive doses, different combinations of immunosuppressive agents, more frequent monitoring, and management of concurrent disease states.     

Cardiotoxicity of systemic agents used in breast cancer

Several breast cancer therapies can lead to cardiovascular toxicity: drugs such anthracyclines can cause permanent damage, anti-HER2 agents may cause transitory and reversible cardiac dysfunction and others, such as those used in endocrine therapy, primarily disturb lipid metabolism. Considering the seriousness of these complications, trials are now being conducted to address cardiotoxicity associated with new drugs; however, to fully understand their toxicity profiles, longer follow-up is needed. In this review, we compile the information available about cardiac toxicity related to well-established systemic breast cancer treatments, as well as newer drugs, including antiangiogenics, mTOR inhibitors and novel anti-HER2 agents. We also describe current and next generation cardiac biomarkers and functional tests that can optimize treatment and reduce and prevent the incidence of treatment-related cardiotoxicity     

Extra-gastrointestinal stromal tumor of the pancreas: case report and a review of the literature

Gastrointestinal (GI) stromal tumors are mesenchymal tumors that arise from the GI tract. In rare cases, these tumors are found in intra-abdominal sites unrelated to the GI tract and are immunohistochemically similar to their GI tract counterparts. Primary pancreatic GI stromal tumors are very rare, with only 4 previous cases reported.     

Reduction of gastrointestinal complications in renal graft recipients after conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium

Gastrointestinal (GI) complications such as diarrhea or indigestion frequently occur in renal graft recipients treated with mycophenolate mofetil (MMF), requiring dose reductions to reduce side effects, thereby increasing the risk of rejection episodes and graft loss. In a prospective clinical trial, the immunosuppressive therapy of renal graft recipients was converted from MMF to enteric-coated mycophenolate sodium (EC-MPS) to identify a strategy to reduce GI symptoms without dose reduction. At baseline and 6-8 weeks later patients filled in 4 questionnaires related to GI symptoms and general and health-related quality of life. In 15 German study centers, 196 renal graft recipients (mean age 49.5 ± 13.5 years; male/female, 120/76) were included; 51.0% of patients suffered from GI complications at baseline. The Gastrointestinal Symptom Rating Scale score decreased significantly (P < .001) in patients with GI complications from 2.61 ± 0.86 at baseline to 2.14 ± 0.86 at visit 2. Health-related and general quality of life improved significantly. Fifty percent of patients with GI symptoms and 34% of the total per protocol population reported an improvement of their physical condition after converting the medication. In conclusion, conversion from MMF to EC-MPS reduces GI complications in renal graft recipients, reduces the patients' physical discomfort, and maintains their quality of life.(ClinicalTrials.gov number NCT00149968.)     

Acute drug toxicity related to drinking herbal tea in a kidney transplant recipient

Calcineurin and mTOR inhibitors are commonly used immunosuppressive agents with narrow therapeutic range. As the drugs are mainly metabolized by the P450 cytochrome system, the interaction between food and herbs are also commonly seen and affect the drug levels. We present a case of a kidney transplant recipient with toxic therapeutic levels of cyclosporine A and sirolimus due to interaction between the immunosuppressive agents and Chinese herbal tea. Ingredients within the herbal tea were reported to have inhibitory effect on cytochrome CYP3A4 in-vitro studies. Transplant recipients should be alert that there may be potent interaction between the immunosuppressive drugs and herbs resulting in adverse effect on allograft function.     

免疫抑制剂的药物基因组学研究进展

患者对药物反应的个体差异,一般是由药物在体内的代谢酶、转运体和靶点编码基因的多态性引起的。因为免疫抑制剂的治疗窗口较窄,患者个体差异导致的不良反应和疗效不佳,都可能引起比较严重的后果,近年人们对于利用药物基因组学进行个体化治疗给予了很高的期待。大量研究已经揭示了多种基因多态性与免疫抑制剂的药代动力学和药效动力学(PK/PD)之间的关联。本文将围绕免疫抑制剂的PK/PD,选择部分具备临床参考意义的研究,简要综述与免疫抑制剂代谢、转运和活化过程相关的药物基因组学进展。     

Alteration in gastrointestinal peptide tissue levels in rejecting small bowel transplants

Gastrointestinal (GI) peptide tissue levels were measured following intestinal transplantation in rats and evaluated as a possible early marker of transplant rejection. Vascularized syngeneic and allogeneic jejunal transplants were performed in rats without immunosuppressive therapy. Serial tissue samples of transplanted intestine were obtained from each group of animals. Baseline levels of peptides were determined in nontransplanted jejunum of the same animals. Results were correlated with histology at all experimental time points. Tissue levels of gut peptides (somatostatin, vasoactive intestinal peptide and substance P) were determined by two methods--immunoperoxidase staining and radioimmunoassay. Normal levels of gut peptides in syngeneic bowel were maintained up to 1 year after transplantation. Allogeneic bowel showed a progressive decline in gut peptide concentrations simultaneously with (or preceding) histologic evidence of rejection. The monitoring of GI peptide tissue levels may prove to be a useful method of detecting small bowel transplant rejection.     

Gastrointestinal growth factors and neoplasia

Gastrointestinal (GI) hormones are chemical messengers that have been recognized for over a century as regulatory factors for normal physiologic functions in the GI tract and pancreas, including absorption, secretion, motility, and digestion. These hormones traditionally act in a true endocrine fashion with release from a distant site to regulate physiologic functions of specific target organs. In general, GI hormones bind to their G-protein-coupled receptors (GPCRs) to produce their endocrine effects. In addition to effects on physiologic functions of the GI tract and pancreas, selected GI hormones can act in an endocrine, paracrine, and/or autocrine fashion to stimulate the proliferation of normal and neoplastic GI tissues as well as non-GI tissues. This review will focus on effects of GI hormones on neoplastic tissues concentrating on the hormones that have been best characterized for these effects.