Emphysematous cystitis as a potential marker of severe Crohn's disease.

BACKGROUND: Emphysematous cystitis (EC) is characterized by the presence of air within the bladder wall, often a complication of urinary tract infection (UTI) by gas-producing organisms. However, EC has also been reported in the setting of infectious colitis suggesting an alternate etiology. We report a rare case of EC in the setting of severe Crohn's colitis with no clinical evidence of UTI. CASE PRESENTATION: A 43-year old female presented with a 2-month history of bloody diarrhea consisting of 8-12 bowel movements a day, weight loss of 10 kg and peripheral edema. She also had multiple ulcerated lesions on her abdominal wall and in the perianal region. Initial CT scan was significant for pancolitis, anasarca and EC. The follow-up CT cystogram, flexible cystoscopy and pelvic MRI confirmed the diagnosis of EC and ruled out any fistulous tracts in the pelvis including enterovesical/colovesical fistula. The patient did not report any urinary symptoms and the urinalysis was within normal limits. An extensive infectious workup was negative. Despite the paucity of infectious findings, the EC was empirically treated with an intravenous third-generation cephalosporin. Colonoscopy was significant for multiple ulcerated and hyperemic areas with pseudopolyps all throughout the right, transverse and left colon. Biopsies confirmed Crohn's colitis with no evidence of granulomata or dysplasia. Immunohistochemistry was negative for CMV. The perianal and abdominal wall lesions were suspected to be pyoderma gangrenosum although biopsies were equivocal. The colitis was initially treated with intravenous steroids followed by biologic therapy with Infliximab. Despite appropriate escalation of therapies, the patient developed colonic perforation requiring subtotal colectomy. CONCLUSION: This is a rare case of EC in a patient with severe Crohn's colitis. There was no evidence of urinary tract infection or fistulising disease. According to our review, this is the first reported incident of EC in a patient with inflammatory bowel disease without any prior intra-abdominal surgeries. While active Crohn's disease alone is a critical illness, we conclude that concomitant EC may be a poor prognostic factor.

Colorectal Polyps in Childhood Cancer Survivors Treated with Radiation Therapy.

BACKGROUND: Cancer survivors treated with abdominal or pelvic radiation therapy (RT) for childhood cancer have an increased risk of colorectal cancer. However, clinical guidelines are inconsistent on recommendations regarding the early initiation of screening in these patients due to the lack of supporting evidence that these patients pass through a pre-invasive phase, in which adenomatous polyps can be detected and removed. AIMS: To determine the prevalence of adenomatous polyps in cancer survivors treated with RT for childhood cancer; the prevalence in average-risk patients aged 17-49; and the prevalence in average-risk patients aged 50-75. METHODS: We conducted a retrospective study comparing the prevalence of adenomatous polyps among three patient groups: childhood cancer survivors aged 17-49 with prior RT who underwent colonoscopy screening from 2006 to 2017; age- and gender-matched patients in the average-risk population; and average-risk patients aged 50-75. RESULTS: One hundred and forty-five patients were included in the study. The proportion of patients with adenomatous polyps in the cancer survivor group was significantly higher than that in the age- and gender-matched average-risk group (58.6 vs 17.2%, p = 0.00) and higher than the average-risk group aged 50-75 (58.6 vs 27.6%, p = 0.009). The prevalence of adenomas with high-risk features was higher in the survivor group compared to patients aged 50-75 (20.7 vs 3.5%, p = 0.015). CONCLUSIONS: Cancer survivors treated with RT for childhood cancer have a higher prevalence of adenomatous polyps compared to the average-risk population. These findings support the early initiation of colonoscopy screening 10 years after radiation therapy, even in patients who have received RT doses below 30 Gy.

Amelioration of dextran sulphate sodium-induced colitis in mice by echinacoside-enriched extract of Cistanche tubulosa.

Echinacoside (ECH) is a major bioactive phenyethanoids in medicinal herba Cistanche and has been reported to have antiinflammatory activity and beneficial effect on wound healing in many experimental studies. This study was to test the efficacy of ECH-enriched extract of Cistanche tubulosa in the treatment of dextran sulphate sodium (DSS)-induced colitis, a preclinical model of ulcerative colitis. Oral administration of ECH extract significantly suppresses the development of acute colitis, indicated by lowering disease activity index (p < 0.0001, n = 8) and preventing colonic damage (p = 0.0336). Histological examinations showed that ECH extract treatment protected intestinal epithelium from inflammatory injury (p = 0.0249) but had less effect on inflammatory cellular infiltration (p = 0.1753). The beneficial effect of ECH extract treatment was associated with upregulation of transforming growth factor (TGF)-ß1 as well as with an increase in the number of Ki67(+) proliferating cells in diseased colons (p < 0.0001). In cultured MODE-K cells, the addition of ECH extract enhanced in vitro wound healing that depended on TGF-ß1 expression. These data suggest that ECH extract possesses a greater efficacy in preventing DSS-induced colitis in mice, implying the potential of ECH or its derivatives for clinically treating inflammatory bowel disease.

Anti-N-Methyl-D Receptor Encephalitis During Long-Term Adalimumab Therapy for Crohn's Disease.

A 46-year-old woman with fistulizing Crohn's disease in clinical remission in the setting of long-term adalimumab therapy presented to hospital and was ultimately diagnosed with anti-N-methyl-D (NMDA) receptor antibody-mediated autoimmune encephalitis (NMDAr-AE). Inflammatory central nervous system and antibody-mediated adverse effects have been found to be associated with anti-tumor necrosis factor agents, with 5 previous case reports noting cases of NMDAr-AE in patients on these medications. The current article reports this case, which is unique for the length of adalimumab therapy before this presentation, as well as a summary of literature regarding anti-tumor necrosis factors and NMDAr-AE.

Requirement of epithelial integrin-linked kinase for facilitation of Citrobacter rodentium-induced colitis.

BACKGROUND: Integrin-linked kinase (ILK) is a serine-threonine kinase that transduces extracellular matrix-related cues into intracellular signals, with fundamental roles in cell motility, development and cancer. Recently ILK been shown to have an important role in bacterial epithelial cell attachment, through ILK-bacterial OspE binding. Here we report on the role of epithelial derived ILK in response to Citrobacter rodentium infection. METHODS: C. rodentium was administered to both control and intestinal epithelial cell ILK knockout mice. Histological inflammatory scores were assessed, and cytokines measured by ELISA as well as RT-PCR, in mouse colons. Bacterial colonization was determined by plating homogenates onto MacConkey agar, and immunofluorescence microscopy performed using anti-LPS and anti-Tir antibodies. RESULTS: ILK-ko mice exhibited reduced weight loss at 15 days post-infection (p < 0.01) and demonstrated reduced histological inflammatory scores (p < 0.01), reduced CCL2 and pro-inflammatory cytokines. This was not due to reduced colonization, but was associated with an altered pattern of C. rodentium bacterial migration. Attenuated fibronectin expression was found in the ILK-ko mice. C. rodentium exposure was shown to increase ILK expression in cell lines, and in murine epithelium in vivo. In ILK-ko mice reduced activation of ser473Akt and reduced crypt proliferation, together with reduced cyclin D1 expression were observed. CONCLUSIONS: ILK influences the host response to C. rodentium -induced infection, independently of reduced colonization in the ILK knockout mice. The reduced inflammation and dramatically attenuated hyperplastic cryptal response to infection in this group, are at least in part the result of, the reduction in CCL2 and cyclin D1 expression respectively.

The importance of integrin-linked kinase in the regulation of bladder cancer invasion.

It is important to understand the molecular mechanisms of bladder cancer progression not only to prevent cancer progression but also to detect new therapeutic targets against advanced bladder cancer. The integrin-linked kinase (ILK) is a major signaling integrator in mammalian cells and plays an important role in epithelial-mesenchymal transition (EMT) of human cancers, but its mechanisms are not completely understood. In this study, we investigated the importance and mechanisms of ILK in bladder cancer progression. When the expression of ILK in bladder cancer cell lines and N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced murine bladder cancer was evaluated, ILK has a tendency to be overexpressed in invasive cell lines and invasive BBN-induced murine bladder cancer. Overexpression of ILK in 253J bladder cancer cells suppressed E-cadherin expression, resulting in the promotion of cell invasion. Conversely, ILK knockdown by siRNA suppresses cell invasion in invasive bladder cancer cells through the regulation of E-cadherin or matrix metalloprotease 9 (MMP-9). To regulate E-cadherin expression, our results showed that the glycogen synthase kinase 3ß (GSK3ß)-Zeb1 pathway may play an important role downstream of ILK. Finally, the results of a human bladder tissue microarray (TMA) showed that ILK expression correlates with the invasiveness of human bladder cancer. Our study suggests that ILK is overexpressed in invasive bladder cancer and plays an important role in the EMT of bladder cancer via the control of E-cadherin and MMP-9 expression. ILK may be a new molecular target to suppress tumor progression in advanced and high-risk bladder cancer patients.

Hypovitaminosis D in adults with inflammatory bowel disease: potential role of ethnicity.

BACKGROUND: Although vitamin D deficiency occurs in inflammatory bowel disease (IBD), it is currently unclear to what extent ethnicity affects vitamin D levels. Our aim was therefore to determine the ethnic variation in serum 25-hydroxyvitamin D status and its association with disease severity in adults with IBD. METHODS: We conducted a prospective cohort study in ambulatory care IBD patients. Clinical disease severity was assessed through validated questionnaires. Serum 25-hydroxyvitamin D levels were used for vitamin D status. C-reactive protein (CRP), ferritin and hemoglobin (Hgb) levels were correlated with serum 25-hydroxyvitamin D levels. RESULTS: Sixty ulcerative colitis (UC) and forty Crohn's disease (CD) patients were enrolled comprising 65 % Caucasians and 29 % South Asians. However, South Asians had consistently lower average serum 25-hydroxyvitamin D levels (All 44.8 ± 18.1 nmol/L, UC 48.2 ± 18.3 nmol/L, CD 24.3 ± 13.3 nmol/L). Hypovitaminosis D was found in 39 % of All, 36.7 % of UC and 42.5 % of CD patients. A significantly higher proportion of South Asians were vitamin D deficient when compared to Caucasians in All and CD groups (58.6 % vs. 30.8 %, p = 0.01 and 85.7 % vs. 32.3 %, p < 0.01, respectively). CONCLUSIONS: A significantly higher percentage of South Asians had hypovitaminosis D when compared to Caucasians. Disease severity trended towards an inverse relationship with vitamin D status in all South Asian and Caucasian CD patients, although most patients in this study had only mild to moderate disease. We suggest that vitamin D supplementation should be considered in all adult IBD patients.

Role of epithelial integrin-linked kinase in promoting intestinal inflammation: effects on CCL2, fibronectin and the T cell repertoire.

BACKGROUND: The role of integrin signaling in mucosal inflammation is presently unknown. Hence, we aimed to investigate the role of epithelial-derived integrin-linked kinase (ILK), a critical integrin signaling intermediary molecule, in colonic inflammation. METHODS: Conditional intestinal epithelial cell ILK knockout mice were used for assessment of acute and chronic dextran sodium sulfate (DSS)-induced colitis. Disease activity was scored using standard histological scoring, mucosal cytokines were measured using ELISA, chemokines were determined using reverse-transcription polymerase chain reaction, as well as Q-PCR, and intracellular cytokine staining performed using FACS analysis. RESULTS: In both acute and chronic DSS-induced colitis, compared to wild-type mice, ILK-ko mice exhibit less weight loss, and have reduced inflammatory scores. In an in vitro model system using HCT116 cells, we demonstrate that si-RNA mediated down-regulation of ILK results in a reduction in monocyte chemoattractant protein 1 (MCP1, CCL2) chemokine expression. A reduction in CCL2 levels is also observed in the tissue lysates of chronically inflamed colons from ILK-ko mice. Examination of mesenteric lymph node lymphocytes from ILK-ko mice reveals that there is a reduction in the levels of IFN gamma using intracellular staining, together with an increase in Foxp3+ T regulatory cells. Immunohistochemistry demonstrates that reduced fibronectin expression characterizes the inflammatory lesions within the colons of ILK-ko mice. Intriguingly, we demonstrate that fibronectin is directly capable of downregulating T regulatory cell development. CONCLUSIONS: Collectively, the data indicate for the first time that ILK plays a pro-inflammatory role in intestinal inflammation, through effects on chemokine expression, the extracellular matrix and immune tolerance.

Ethnic variation in the annual rates of adult inflammatory bowel disease in hospitalized patients in Vancouver, British Columbia.

BACKGROUND: There is currently little available information regarding the impact of ethnicity on the clinical features of inflammatory bowel disease (IBD). Migrating populations and changing demographics in Vancouver, British Columbia (BC) provide a unique opportunity to examine the role of ethnicity in the prevalence, expression and complications of IBD. OBJECTIVES: To determine the demographics of IBD and its subtypes leading to hospitalization in the adult population of BC. METHODS: A one-year retrospective study was performed for all patients who presented acutely with IBD to Vancouver General Hospital from January 1, 2006 to December 31, 2006. Data regarding sex, age, ethnicity, IBD type and extent of disease, complications and management strategies were collected. Clinical data were confirmed by pathology and radiology reports. RESULTS: There were 186 cases of IBD comprising Crohn's disease (CD) 56%, ulcerative colitis (UC) 43% and indeterminate colitis (1%) 1%. The annual rate of IBD cases warranting hospitalization in Caucasians was 12.9 per 100,000 persons (7.9 per 100,000 persons for CD and 5.0 per 100,000 persons for UC). This was in contrast to the annual rate of IBD in South Asians at 7.7 per 100,000 persons (1.0 per 100,000 persons for CD and 6.8 per 100,000 persons for UC) and in Pacific Asians at 2.1 per 100,000 persons (1.3 per 100,000 persons for CD, 0.8 per 100,000 persons for UC). The male to female ratio was higher in South Asians and Pacific Asians than in Caucasians. The extent of disease was significantly different across racial groups, as was the rate of complications. CONCLUSIONS: These early results suggest that there are ethnic disparities in the annual rates of IBD warranting hospitalization in the adult population of BC. There was a significantly higher rate of CD in the Caucasian population than in South Asian and Pacific Asian populations. The South Asian population had a higher rate of UC, with an increased rate of complications and male predominance. Interestingly, the rate of CD and UC was lowest in the Pacific Asian population. These racial differences - which were statistically significant - suggest a role for ethnodiversity and environmental changes in the prevalence of IBD in Vancouver.

End stage liver disease etiology & transplantation referral outcomes of major ethnic groups in British Columbia, Canada: A cohort study.

ABSTRACT: Liver disease etiology and transplantation outcomes may vary by ethnicity. We aimed to determine if disparities exist in our province.We reviewed the provincial database for liver transplant referrals. We stratified cohorts by ethnicity and analyzed disease etiology and outcomes.Four thousand nine hundred sixteen referrals included 220 South Asians, 413 Asians, 235 First Nations (Indigenous), and 2725 Caucasians. Predominant etiologies by ethnicity included alcohol (27.4%) and primary sclerosing cholangitis (PSC) (8.8%) in South Asians, hepatitis B (45.5%) and malignancy (13.9%) in Asians, primary biliary cholangitis (PBC) (33.2%) and autoimmune hepatitis (AIH) (10.8%) in First Nations, and hepatitis C (35.9%) in Caucasians. First Nations had lowest rate of transplantation (30.6%, P = .01) and highest rate of waitlist death (10.6%, P = .03). Median time from referral to transplantation (268 days) did not differ between ethnicities (P = .47). Likelihood of transplantation increased with lower body mass index (BMI) (hazard ratio [HR] 0.99, P = .03), higher model for end stage liver disease (MELD) (HR 1.02, P < .01), or fulminant liver failure (HR 9.47, P < .01). Median time from referral to ineligibility status was 170 days, and shorter time was associated with increased MELD (HR 1.01, P < .01), increased age (HR 1.01, P < .01), fulminant liver failure (HR 2.56, P < .01) or South Asian ethnicity (HR 2.54, P < .01). Competing risks analysis revealed no differences in time to transplant (P = .66) or time to ineligibility (P = .91) but confirmed increased waitlist death for First Nations (P = .04).We have noted emerging trends such as alcohol related liver disease and PSC in South Asians. First Nations have increased autoimmune liver disease, lower transplantation rates and higher waitlist deaths. These data have significance for designing ethnicity specific interventions.

Racial differences in the incidence of colorectal cancer.

BACKGROUND: Colon cancer is one of the most common cancers and the second most common cause of cancer mortality in Western societies. Population screening has been introduced as a means to reducing its impact; however, there are little or no data on the incidence of this disorder in the different populations that comprise the Canadian population. OBJECTIVE: To retrospectively determine the incidence of colorectal cancer in selected racial populations of British Columbia. METHODS: The British Columbia Cancer Agency database was used to retrieve information on the incidence of cancers occurring during the years 1994 to 1998, with the British Columbia and national population censuses used to derive the age-specific and age-standardized incidence rates of colorectal cancers. Surnames were used to identify the origin of individuals from South Asian and Chinese backgrounds. RESULTS: For the Caucasian Canadian (C) population, the weighted age-standardized incidence rate ranged from 51.99 per 100,000 in 1995, to 57.68 per 100,000 in 1998. For Chinese Canadians (CC), the range was 39.2 per 100,000 in 1996, to 31.2 per 100,000 in 1998. For South Asian Canadians (SAC), the range was 7.40 per 100,000 in 1994, to 24.85 per 100,000 in 1998. The RR for the development of cancer were significantly different when comparing C versus CC (RR 1.9; 95% CI 1.58 to 2.31; P<0.001), C versus SAC (RR 7.1; 95% CI 4.20 to 12.0; P<0.0001) and CC versus SAC (RR 3.7; 95% CI 2.14 to 6.5; P<0.0001). CONCLUSIONS: Significant differences in the incidence of colorectal cancers have been defined for the first time in various racial subgroups in British Columbia. This finding may have important implications for both screening and understanding of the environmental factors influencing the biology of these lesions. Because SAC have among the highest incidence of atherosclerotic heart disease and diabetes, it suggests that unidentified genetic and/or environmental protective factors are capable of countering the traditionally recognized risk of high saturated fat intake for the development of colorectal cancer.

Biomarkers for hepatocellular cancer.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. If diagnosed early, curative treatment options such as surgical resection, loco-regional therapies, and liver transplantation are available to patients, increasing their chances of survival and improving their quality of life. Unfortunately, most patients are diagnosed with late stage HCC where only palliative treatment is available. Therefore, biomarkers which could detect HCC early with a high degree of sensitivity and specificity, may play a crucial role in the diagnosis and management of the disease. This review will aim to provide an overview of the different biomarkers of HCC comprising those used in the diagnosis of HCC in at risk populations, as well as others with potential for prognosis, risk predisposition and prediction of response to therapeutic intervention.

Inflammatory bowel disease patients prioritize mucosal healing, symptom control, and pain when choosing therapies: results of a prospective cross-sectional willingness-to-pay study.

BACKGROUND: Given the large armamentarium of therapies for inflammatory bowel disease (IBD), physicians cannot fully describe all treatments to patients and, therefore, make assumptions regarding treatment attributes communicated to patients. This study aimed to assess out-of-pocket willingness-to-pay that IBD patients allocate to treatment attributes. METHODS: Adult patients receiving therapy for IBD were invited to access a cross-sectional web-based discrete-choice experiment (May 22-August 31, 2015) that presented paired medication scenarios with varying efficacy, safety, and administration parameters. Preference weights and willingness-to-pay for each attribute level were assessed by a hierarchical Bayes method including a multinomial logit model. RESULTS: A total of 586 IBD patients were included, 404 (68.9%) with Crohn's disease and 182 (31.1%) with ulcerative colitis. Genders were evenly distributed; the majority of patients (70.1%) were 50 years or younger and had postsecondary education (75.4%), while the median health status was 7 (Likert scale: 1 [poor] - 10 [perfect]). Regarding relative preference-weight estimates, for the average respondent, reducing pain during administration, mucosal healing, and symptom relief were the highest-ranking attributes. Conversely, infusion reactions and risk of hospitalization or surgery were the lowest-ranking attributes. In multivariate analysis, patient sociodemographics did not affect the rank order of attributes although small differences were observed between asymptomatic and symptomatic patients in the previous year. CONCLUSION: This study has important implications related to understanding patient preferences and designing patient-centered strategies. IBD patients prioritize treatments with low administration pain. Additionally, these results concur with treatment guidelines emphasizing patients' preference for mucosal healing and symptom control.

Expression of integrin-linked kinase is not a useful prognostic marker in resected hepatocellular cancer.

BACKGROUND: Hepatocellular cancer (HCC) is one of the most common malignancies worldwide, and is known to be associated with a poor prognosis. Unfortunately there are no available reliable markers of prognosis. The aim of this study was to determine whether integrin-linked kinase (ILK) expression correlates with post-resection survival from HCC. PATIENTS AND METHODS: A tissue microarray was constructed using HCC samples, and immunohistochemical analysis for ILK was then carried out and scored by three independent observers. Clinical chart review was performed to determine survival parameters. RESULTS: Of the 52 cases of HCC, 22 cases were associated with hepatitis B (HBV), 18 with hepatitis C (HCV), 2 with HBV and HCV co-infection; 81% of all patients were male and 19% female. Western immunoblotting showed a highly significant correlation between levels of expression of ILK and ser473-PKBphosphorylation, both in control and tumor sections (Spearman rank correlation, r=0.8155, p=0.0004), however, there was no direct correlation between the levels of expression of ILK with patient survival (log-rank test, p= 0.864). CONCLUSION: ILK expression does not appear to have a role in predicting outcome in patients with resected HCC.

Differential targeting of protein kinase B in cell death induced by sulindac and its metabolite sulindac sulfide.

Non-steroidal anti-inflammatory drugs such as sulindac inhibit human colorectal carcinogenesis through a mechanism involving the direct inhibition of cyclooxygenase (Cox)-2. However, a wealth of recent evidence indicates that these agents might elicit their effects through mechanisms independently of Cox-2. In this study, we investigated the effects of sulindac and its metabolite, sulindac sulfide on modulation of the critical survival kinase, protein kinase B (PKB). Here, we demonstrate for the first time that treatment with either sulindac or sulindac sulfide results in a decrease in PKB activity, and we provide compelling evidence that this occurs through two distinct mechanisms. Additionally, we report that overexpression of, and conditional activation of PKB attenuates the apoptotic effects of sulindac, but not for sulindac sulfide - the metabolic metabolite of sulindac. We also demonstrate that treatment with sulindac sulfide, but not sulindac, results in a very early robust activation of both caspase-8 and -9. Furthermore, we show that the apoptotic effects of sulindac sulfide can be reverted by both the caspase-8 and -9 inhibitors. Evidence is provided to indicate that PKB is targeted by robust caspase activation due to sulindac sulfide. Hence, further investigation into the mechanisms regulating conversion of sulindac to sulindac sulfide (or direct use of the latter compound), may enhance our ability to target cancers with enhanced signaling through the growth factor-->phosphatidylinositol 3-kinase pathway.

Intrahepatic cholangiocarcinoma presenting as the Budd-Chiari syndrome: a case report and literature review.

Intrahepatic cholangiocarcinoma, an increasingly recognized primary tumour of the liver, is associated with a very poor prognosis. A patient with this tumour who presented with Budd-Chiari syndrome (the first to the authors' knowledge in Western literature and only the third patient overall) secondary to extensive thrombosis in his inferior vena cava extending from the right atrium down to his iliac vessels is described. Neither curative nor palliative intervention was deemed to be an option in this patient, who deteriorated rapidly while on anti-coagulants. Postmortem examination confirmed the radiological findings, and histological analysis revealed characteristic appearances of this tumour within the biliary tree and invasion into the inferior vena cava. Furthermore, biliary dysplasia, which can be a precursor to this cancer, was also noted within some of the bile ducts.