Correlation of ex vivo cytokine secretion profiles with scoring indices in ulcerative colitis.

BACKGROUND: In ulcerative colitis, the complexity of mucosal cytokine secretion profiles and how they correlate with endoscopic and clinical scores is still unclear. METHODS: In this study, we collected fresh biopsies from UC patients to investigate which cytokines are produced in ex vivo culture conditions, a platform increasingly used for testing of novel drugs. Then, we correlated cytokine production with several scoring indices commonly used to assess the severity of the disease. RESULTS: Increased levels of IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, TNFα and IFNÉ£ were produced by biopsies of UC patients compared to non-IBD controls. Our results show a better correlation of cytokine levels with Mayo Endoscopic Subscore (MES) and Mayo score, than the more complex Ulcerative Colitis Endoscopic Index of Severity (UCEIS). Out of 10 measured cytokines, eight correlated with MES, six with Mayo score and only three with UCEIS, due to the partial increase in cytokine secretion observed in donors with UCEIS = 7-8. When we analysed individual subscores within the UCEIS, Vascular Network subscore showed a correlation similar to MES (7/10 cytokines), while Bleeding as well as Erosions and Ulcers subscores correlated with only 3/10 cytokines, similarly to the total UCEIS. CONCLUSIONS: Our findings suggest that choosing biopsies from donors with MES = 2-3 and UCEIS = 2-6 from areas with no bleeding and no superficial and/or deep ulcers could enable a deeper insight into the cytokine profile of the inflamed tissue and represent a better tool for studying potential therapeutic targets and evaluation of novel therapies.

Claudins: Beyond Tight Junctions in Human IBD and Murine Models.

Claudins are transmembrane proteins constituting one of three tight junction protein families. In patients with inflammatory bowel disease (IBD), disease activity-dependent changes in expression of certain claudins have been noted, thus making certain claudin family members potential therapy targets. A study was undertaken with the aim of exploring expression of claudins in human disease and two different animal models of IBD: dextrane sulfate sodium-induced colitis and adoptive transfer model of colitis. The expression of sealing claudin-1, claudin-3, claudin-4, and claudin-8, and pore-forming claudin-2 in humans and rodents has been evaluated by immunohistochemistry and quantitative polymerase chain reaction. Claudins were expressed by epithelial and cells of mesodermal origin and were found to be situated at the membrane, within the cytoplasm, or within the nuclei. Claudin expression by human mononuclear cells isolated from lamina propria has been confirmed by Western blot and flow cytometry. The claudin expression pattern in uninflamed and inflamed colon varied between species and murine strains. In IBD and both animal models, diverse alterations in claudin expression by epithelial and inflammatory cells were recorded. Tissue mRNA levels for each studied claudin reflected changes within cell lineage and, at the same time, mirrored the ratio between various cell types. Based on the results of the study, it can be concluded that 1) claudins are not expressed exclusively by epithelial cells, but by certain types of cells of mesodermal origin as well; 2) changes in the claudin mRNA level should be interpreted in the context of overall tissue alterations; and 3) both IBD animal models that were analyzed can be used for investigating claudins as a therapy target, respecting their similarities and differences highlighted in this study.

Small intestinal bacterial overgrowth and non-alcoholic fatty liver disease diagnosed by transient elastography and liver biopsy.

BACKGROUND: We aimed to determine if there was a higher incidence of small intestinal bacterial overgrowth (SIBO) in non-alcoholic fatty liver disease (NAFLD) than in patients without NAFLD. Moreover, we assessed whether patients with significant fibrosis (SF) had a higher incidence of SIBO compared with patients with non-significant or no liver fibrosis. METHODS: NAFLD was diagnosed in 117 patients by using Fibroscan with a controlled attenuation parameter (CAP) as well as liver biopsy (LB). SIBO was defined by esophagogastroduodenoscopy with an aspiration of the descending duodenum. RESULTS: Patients with non-alcoholic steatohepatitis (NASH) and those with SF on LB had a significantly higher incidence of SIBO than patients without NASH and those without SF, respectively (P < .05). According to histological characteristics, there was a higher proportion of patients in the SIBO group with higher steatosis and fibrosis grade, lobular and portal inflammation, and ballooning grade (P < .001). In multivariate analysis, significant predictors associated with SF and NASH were type 2 diabetes mellitus (T2DM) and SIBO. Moreover, in multivariate analysis, significant predictors that were independently associated with SIBO were T2DM, fibrosis stage and ballooning grade (OR 8.80 (2.07-37.37), 2.50 (1.16-5.37) and 27.6 (6.41-119), respectively). The most commonly isolated were gram-negative bacteria, predominantly Escherichia coli and Klebsiella pneumoniae. CONCLUSION: In this relatively large population of patients, we used a gold standard for both SIBO (quantitative culture of duodenum's descending part aspirate) and NAFLD (LB), and we demonstrated that NASH patients and those with SF had a higher incidence of SIBO. Moreover, significant predictors independently associated with SIBO were T2DM, fibrosis stage and ballooning grade. Although TE is a well-investigated method for steatosis and fibrosis detection, in our study, independent predictors of SIBO were histological characteristics of NAFLD, while elastographic parameters did not reach statistical significance.

BURKITT LYMPHOMA IN GASTROINTESTINAL TRACT: A REPORT OF TWO CASES.

Burkitt lymphoma, a type of non-Hodgkin B-cell lymphoma, is the fastest growing human cancer, presenting pathologically with a 'starry sky' pattern. It is most often found in the abdomen and the jaw, however, localization in the abdomen other than the ileocecal area is very rare and described only in a handful of cases. Standard treatment consists of initial tumor cytoreduction followed by intense chemotherapy. Most of the relapses occur within one year of the diagnosis, while the 5-year survival is around 80%. We present two cases which are specific for unusual location of Burkitt lymphoma in the colon and stomach, in immunocompetent patients with negative Epstein-Barr virus tests. Also, one of the patients presented is one of the oldest ever reported with abdominal Burkitt lymphoma, while the other patient is an example of diagnostic difficulties in distinguishing Burkitt lymphoma from similar lymphomas. Due to the rapidly growing tumors and urgent need for cytoreductive surgery, it is crucial to consider the diagnosis of Burkitt lymphoma even in atypical localizations or absence of the common risk factors associated with Burkitt lymphoma.

Physical Exercise: An Evaluation of a New Clinical Biomarker of Survival in Hospice Patients.

PURPOSE: Survival analysis is an important issue in palliative care. However, there is a lack of quality clinical biomarkers for assessing survival, especially in bedridden patients. Recent research supports the benefit of physiotherapy in palliative care, as majority of hospice patients are able to perform physical therapy. We propose the hypothesis that the difference in activity during physical exercise can be used as a biomarker of survival in hospice care. METHODS: We examined 536 consecutive patients who performed physical exercises in our hospice from March 2013 to July 2017. Univariate, multivariate, and Kaplan-Meier analysis were performed to explore the association between the level of physical exercise activity and survival. RESULTS: Physical exercises were performed by almost 70% of our hospice patients. The patients who initially performed active exercises lived longer, on average, compared to patients who only managed passive exercises (15 days vs 6 days, hazard ratio 0.60, 0.49-0.74). Surprisingly, the difference in survival based on the level of physical activity remained consistent regardless of the patient performance score, emphasizing its usefulness as an independent survival biomarker in a hospice setting. This tool also gave us an option to recognize a significant proportion of bedridden patients performing active exercises (30%), previously unrecognized using standard performance scales, exhibiting longer survival compared to others with the same performance score. CONCLUSION: Patients' level of activity during physical exercises has the potential to be a valuable new clinical biomarker in palliative care, whether used individually or combined with commonly used performance scales.

The Impact of Combined Use of Opioids, Antipsychotics, and Anxiolytics on Survival in the Hospice Setting.

CONTEXT: Opioids and sedatives are the cornerstone of symptom management in the end-of-life patients, but undertreatment is a common problem. Although several studies explored the individual effect of opioids, anxiolytics, and antipsychotics on survival, not much is known regarding their combined use. As these drugs share similar and potentially fatal side effects, primarily respiratory depression which occurs more often during night-hours, it is crucial to explore whether their interaction poses a danger for fragile hospice patients. OBJECTIVES: To analyze the relationship of a combination of opioids, anxiolytics, and antipsychotics on survival and the change of night-time death percentage. METHODS: A retrospective study of 765 consecutive patients admitted to hospice in Croatia over the period of four years (2013-2017). The main outcome was the total length of survival of hospice patients regarding different drug combination, along with night-time death percentage. RESULTS: Different combinations of opioids, anxiolytics, and antipsychotics were associated with longer survival in hospice compared with patients using no such drugs. When we included different parameters which affected overall survival into a multivariate analysis, only the patients who had the combination of both opioids, anxiolytics, and antipsychotics in their regular therapy were associated with longer survival in hospice (11 vs. five days, hazard ratio 0.54, P < 0.001). No combination of opioids, anxiolytics, and antipsychotics significantly changed the night-time death percentage. CONCLUSION: This research supports the safety of opioids, anxiolytics, and antipsychotics in the hospice setting when used both individually as well as in combination.

Endogenous erythropoietin and erythropoietin receptors in colorectal cancer; can we answer the questions?

Erythropoietin (Epo) is glycoprotein hormone which binds on erythropoietin receptors (EpoR) promoting proliferation and differentiation. Studies have shown that EpoR, apart from erythrocyte precursors, is expressed on no hematopoietic tissue and various tumor cells. Despite the progress in modern medicine, colorectal carcinoma (CRC) is still the leading cause of increased morbidity and mortality between oncology patients worldwide. Its precursors are benign villous adenomas, which in certain percentage progress to cancer. Anemia of chronic disease is common finding in CRC patients. Some of them are treated with Epo. Epo/EpoR seems to correlate with tumor progression and metastasizing. Therefore, the identification of at-risk group remains a clinical challenge. Vascular endothelial growth factor (VEGF) is a signal protein that stimulates angiogenesis and concentration of VEGF is positive correlated with tumor growth in numerous tumors. The importance of Epo in tumor pathogenesis has led to a growing interest in the potential prognostic value. By our point of view there are many open questions about role of Epo/EpoR in CRC.

Mystery Story about Erythropoietin (Epo) and Erythropoietin Receptor (EpoR) are Disguised?

In this review we would like to focus our attention upon very controversial reports on Erythropoietin (Epo) and Erythropoietin Receptor (EpoR) expression in cancer patients. The effects of Epo on cancerous tissues are poorly understood. Hypoxia results in an increase in the level of the production of both Epo and EpoR via activation of the hypoxia-inducible factor 1 (HIF-1) pathway. HIF-1α, promotes the expression of vascular endothelial growth factor (VEGF). The signaling through VEGF in both a paracrine and an autocrine manner is required for the homeostasis of adult vessels. Macrophages stimulate vessel sprouting via a soluble factor other than VEGF, rather than through direct contact with endothelial cells. The intriguing questions are set about many researches to link Epo/EpoR expression and function in order to establish one of the mechanisms of tumor growth, disease progression of cancer patient. However, it is uncertain role in tumour angiogenesis as promoter and stimulator of tumour growth which should need to be furtherly validated.

Endoscopic diagnostic of chronic pancreatitis.

Chronic pancreatitis is defined as a continuous inflammatory pancreatic disease, one characterized by irreversible morphological changes, often associates with pain and sometimes with the loss of endocrine and exocrine function. As a histological confirmation of chronic pancreatitis is often unavailable, the diagnosis is traditionally based on imaging methods such as computerized tomography (CT) or endoscopic retrograde cholangiopancreatography (ERCP), and recently magnetic resonance cholangiopancreatography (MRCP) as a noninvasive alternative to ERCP. Developments in the classification system of CP include the Marseille classification of 1963 which offered histopathologic criteria for CP, the Cambridge classification of 1984 which introduced imaging features of computed tomography (CT), transabdominal ultrasound (TUS) and endoscopic retrograde cholangiopancreatography (ERCP) for classification of CP as well as Rosemont classification system of 2007 which presented the endoscopic ultrasonography diagnosis of CP. Endoscopic ultra-sonography (EUS) was first introduced as a diagnostic method for evaluation of pancreatic disease in 1986. It has experienced significant improvements since then and allowed for an alternative approach in diagnosing patients with pancreatic diseases. In patients with suspected pancreatic masses EUS-guided fine needle aspiration (EUS-FNA) is the best method for obtaining tissue diagnosis and differentiating CP from pancreatic carcinoma. The recent studies indicate that EUS is the method of choice when compared with other imaging methods such as ERCP because it frequently provides more accurate diagnostics. The aim of this review is to discuss the findings in endoscopic diagnostics up to the present moment and to indicate advantages, limitations and possible complications along with the current recommendations in CP diagnostics.

Nutrition in cancer patients.

Cachexia is defined as an unintended loss of stable weight exceeding 10%. Patients with advanced cachexia express anorexia, early satiety, severe weight loss, weakness, anemia, and edema. Anorexia represents the result of a failure of the usual appetite signals whereas cachexia is the debilitating state of involuntary weight loss. This syndrome, referred to as the cancer anorexia-cachexia syndrome, (CACS) and usually consists of a combination of anorexia, tissue wasting, malnutrition, weight loss and loss of compensatory increase in feeding. CACS represents the result of a complex interaction between cancer growth and host response and is associated with a poor response to chemotherapy and with an increase in drug-related toxicity. In advanced cachexia (mostly in metastatic cancer and terminally disease) any interventions with nutritional suplements are ineffective. Therefore, nutritional support in the reversion of tumor cachexia and in the importance of maintaining patient weight, muscle mass, quality of life, has the exceptional importance, becouse good nutritional status of patients leads to the possibility of more aggressive and longer treatment and thus to longer survival.

Primary gastric mantle cell lymphoma.

Mantle cell lymphoma represents 2.5-7% all of non Hodgkin's lymphomas. Stomach is the most common site of extranodal lymphoma. However, that is not the case with mantle cell lymphoma, which is extremely rare. We present a case of 71-year-old woman admitted to the Internal Clinic of the University Clinical Hospital Center Rijeka, because of stomach discomfort and melena. Endoscopy and computed tomography revealed a polyp in gastric antrum. Histopathologic, immunohistochemic and genetic methods were also performed and the results were consistent with primary gastric mantle cell lymphoma without periepigastric and/or local or distant abdominal lymph node involvement.