Cemal Yazici

Acute Porphyrias in the USA: Features of 108 Subjects from Porphyrias Consortium

BACKGROUND Recent descriptions of the clinical and laboratory features of subjects with acute porphyrias in the US are lacking. Our aim was to describe clinical, biochemical, and genetic features of 108 subjects. METHODS Between September 2010 and December 2012, 108 subjects with acute porphyrias (90 acute intermittent porphyrias, 9 hereditary coproporphyrias, 9 variegate porphyrias) were enrolled into an observational study. Genetic testing was performed at a central genetic testing laboratory and clinical information entered into a central database. Selected features were compared with data for adults in the US. RESULTS Most subjects (88/108, 81%) were female, with self-reported onset of symptoms in the second through fourth decades of life. The most common symptom was abdominal pain. Appendectomies and cholecystectomies were common before a diagnosis of porphyria. The diagnosis was delayed by a mean of 15 years. Anxiety and depression were common, and 18% complained of chronic symptoms, especially neuropathic and other pains. The incidences of systemic arterial hypertension, chronic kidney disease, seizure disorders, and psychiatric conditions were markedly increased. Mutations of the known causative genes were found in 102/105 of those tested, with novel mutations being found in 37, including in 7/8 subjects with hereditary coproporphyria. Therapy with intravenous hematin was the most effective therapy both for treatment of acute attacks and for prevention of recurrent attacks. CONCLUSIONS Acute porphyrias often remain undiagnosed for more than a decade after first symptoms develop. Intravenous hematin is the treatment of choice, both for treatment of acute attacks and for prevention of recurrent attacks.

Inpatient capsule endoscopy leads to frequent incomplete small bowel examinations

AIM To examine the predictive factors of capsule endoscopy (CE) completion rate (CECR) including the effect of inpatient and outpatient status. METHODS We identified 355 consecutive patients who completed CE at Rush University Medical Center between March 2003 and October 2005. Subjects for CE had either nothing by mouth or clear liquids for the afternoon and evening of the day before the procedure. CE exams were reviewed by two physicians who were unaware of the study hypotheses. After retrospective analysis, 21 cases were excluded due to capsule malfunction, prior gastric surgery, endoscopic capsule placement or insufficient data. Of the remaining 334 exams [264 out-patient (OP), 70 in-patient (IP)], CE indications, findings, location of the patients [IP vs OP and intensive care unit (ICU) vs general medical floor (GMF)] and gastrointestinal transit times were analyzed. Statistical analysis was completed using SPSS version 17 (Chicago, IL). Chi-square, t test or fisher exact-tests were used as appropriate. Multivariate logistic regression analysis was used to identify variables associated with incomplete CE exams. RESULTS The mean age for the entire study population was 54.7 years. Sixty-one percent of the study population was female, and gender was not different between IPs vs OPs (P = 0.07). The overall incomplete CECR was 14% in our study. Overt obscure gastrointestinal bleeding (OGB) was significantly more common for the IP CE (P = 0.0001), while abdominal pain and assessment of IBD were more frequent indications for the OP CE exams (P = 0.002 and P = 0.01, respectively). Occult OGB was the most common indication and arteriovenous malformations were the most common finding both in the IPs and OPs. The capsule did not enter the small bowel (SB) in 6/70 IPs and 8/264 OPs (P = 0.04). The capsule never reached the cecum in 31.4% (22/70) of IP vs 9.5% (25/ 264) of OP examinations (P < 0.001). The mean gastric transit time (GTT) was delayed in IPs compared to OPs, 98.5 ± 139.5 min vs 60.4 ± 92.6 min (P = 0.008). Minimal SB transit time was significantly prolonged in the IP compared to the OP setting [IP = 275.1 ± 111.6 min vs OP = 244.0 ± 104.3 min (P = 0.037)]. CECR was also significantly higher in the subgroup of patients with OGB who had OP vs IP exams (95% vs 80% respectively, P = 0.001). The proportion of patients with incomplete exams was higher in the ICU (n = 7/13, 54%) as compared to the GMF (n = 15/57, 26%) (P = 0.05). There was only a single permanent SB retention case which was secondary to a previously unknown SB stricture, and the remaining incomplete SB exams were due to slow transit. Medications which affect gastrointestinal system motility were tested both individually and also in aggregate in univariate analysis in hospitalized patients (ICU and GMF) and were not predictive of incomplete capsule passage (P > 0.05). Patient location (IP vs OP) and GTT were independent predictors of incomplete CE exams (P < 0.001 and P = 0.008, respectively). CONCLUSION Incomplete CE is a multifactorial problem. Patient location and related factors such as severity of illness and sedentary status may contribute to incomplete exams.

Race-dependent association of sulfidogenic bacteria with colorectal cancer

Objective Colorectal cancer (CRC) incidence is higher in African Americans (AAs) compared with non-Hispanic whites (NHWs). A diet high in animal protein and fat is an environmental risk factor for CRC development. The intestinal microbiota is postulated to modulate the effects of diet in promoting or preventing CRC. Hydrogen sulfide, produced by autochthonous sulfidogenic bacteria, triggers proinflammatory pathways and hyperproliferation, and is genotoxic. We hypothesised that sulfidogenic bacterial abundance in colonic mucosa may be an environmental CRC risk factor that distinguishes AA and NHW. Design Colonic biopsies from uninvolved or healthy mucosa from CRC cases and tumour-free controls were collected prospectively from five medical centres in Chicago for association studies. Sulfidogenic bacterial abundance in uninvolved colonic mucosa of AA and NHW CRC cases was compared with normal mucosa of AA and NHW controls. In addition, 16S rDNA sequencing was performed in AA cases and controls. Correlations were examined among bacterial targets, race, disease status and dietary intake. Results AAs harboured a greater abundance of sulfidogenic bacteria compared with NHWs regardless of disease status. Bilophila wadsworthia-specific dsrA was more abundant in AA cases than controls. Linear discriminant analysis of 16S rRNA gene sequences revealed five sulfidogenic genera that were more abundant in AA cases. Fat and protein intake and daily servings of meat were significantly higher in AAs compared with NHWs, and multiple dietary components correlated with a higher abundance of sulfidogenic bacteria. Conclusions These results implicate sulfidogenic bacteria as a potential environmental risk factor contributing to CRC development in AAs.

Expression of an Oncogenic BARD1 Splice Variant Impairs Homologous Recombination and Predicts Response to PARP-1 Inhibitor Therapy in Colon Cancer

BRCA1-associated RING domain protein 1 (BARD1) stabilizes BRCA1 protein by forming a heterodimeric RING-RING complex, and impacts function of BRCA1, including homologous recombination (HR) repair. Although colon cancer cells usually express wild type BRCA1, presence of an oncogenic BARD1 splice variant (SV) in select cancers may render BRCA1 dysfunctional and allow cells to become sensitive to HR targeting therapies. We previously reported association of loss of full-length (FL) BARD1 with poor prognosis in colon cancer as well as expression of various BARD1 SVs with unknown function. Here we show that loss of BARD1 function through the expression of a BARD1 SV, BARD1β, results in a more malignant phenotype with decreased RAD51 foci formation, reduced BRCA1 E3 ubiquitin ligase activity, and decreased nuclear BRCA1 protein localization. BARD1β sensitizes colon cancer cells to poly ADP ribose polymerase 1 (PARP-1) inhibition even in a FL BRCA1 background. These results suggest that expression of BARD1β may serve as a future biomarker to assess suitability of colon cancers for HR targeting with PARP-1 inhibitors in treatment of advanced colon cancer.

Inhalational exposure to particulate matter air pollution alters the composition of the gut microbiome

Recent studies suggest an association between particulate matter (PM) air pollution and gastrointestinal (GI) disease. In addition to direct deposition, PM can be indirectly deposited in oropharynx via mucociliary clearance and upon swallowing of saliva and mucus. Within the GI tract, PM may alter the GI epithelium and gut microbiome. Our goal was to determine the effect of PM on gut microbiota in a murine model of PM exposure via inhalation. C57BL/6 mice were exposed via inhalation to either concentrated ambient particles or filtered air for 8-h per day, 5-days a week, for a total of 3-weeks. At exposures end, GI tract tissues and feces were harvested, and gut microbiota was analyzed. Alpha-diversity was modestly altered with increased richness in PM-exposed mice compared to air-exposed mice in some parts of the GI tract. Most importantly, PM-induced alterations in the microbiota were very apparent in beta-diversity comparisons throughout the GI tract and appeared to increase from the proximal to distal parts. Changes in some genera suggest that distinct bacteria may have the capacity to bloom with PM exposure. Exposure to PM alters the microbiota throughout the GI tract which maybe a potential mechanism that explains PM induced inflammation in the GI tract.

NFkB is essential for activin-induced colorectal cancer migration via upregulation of PI3K-MDM2 pathway

Colorectal cancer (CRC) remains a common and deadly cancer due to metastatic disease. Activin and TGFB (TGFβ) signaling are growth suppressive pathways that exert non-canonical pro-metastatic effects late in CRC carcinogenesis. We have recently shown that activin downregulates p21 via ubiquitination and degradation associated with enhanced cellular migration independent of SMADs. To investigate the mechanism of metastatic activin signaling, we examined activated NFkB signaling and activin ligand expression in CRC patient samples and found a strong correlation. We hypothesize that activation of the E3 ubiquitin ligase MDM2 by NFkB leads to p21 degradation in response to activin treatment. To dissect the link between activin and pro-carcinogenic NFkB signaling and downstream targets, we found that activin but not TGFB induced activation of NFkB leading to increased MDM2 ubiquitin ligase via PI3K. Further, overexpression of wild type p65 NFkB increased MDM2 expression while the NFkB inhibitors NEMO-binding domain (NBD) and Bay11-7082 blocked the activin-induced increase in MDM2. In conclusion, in colon cancer cell migration, activin utilizes NFkB to induce MDM2 activity leading to the degradation of p21 in a PI3K dependent mechanism. This provides new mechanistic knowledge linking activin and NFkB signaling in advanced colon cancer which is applicable to targeted therapeutic interventions.

Increased Frequency of KRAS Mutations in African Americans Compared with Caucasians in Sporadic Colorectal Cancer

OBJECTIVES: The basis for over‐representation of colorectal cancer (CRC) in African‐American (AA) populations compared with Caucasians are multifactorial and complex. Understanding the mechanisms for this racial disparity is critical for delivery of better care. Several studies have investigated sporadic CRC for differences in somatic mutations between AAs and Caucasians, but owing to small study sizes and conflicting results to date, no definitive conclusions have been reached. METHODS: Here, we present the first systematic literature review and meta‐analysis investigating the mutational differences in sporadic CRC between AAs and Caucasians focused on frequent driver mutations (APC,TP53, KRAS,PI3CA, FBXW7,SMAD4, and BRAF). Publication inclusion criteria comprised sporadic CRC, human subjects, English language, information on ethnicity (AA, Caucasian, or both), total subject number >20, and information on mutation frequencies. RESULTS: We identified 6,234 publications. Meta‐analysis for APC, TP54, FBXW7, or SMAD4 was not possible owing to paucity of data. KRAS mutations were statistically less frequent in non‐Hispanic Whites when compared with AAs (odds ratio, 0.640; 95% confidence interval (CI): 0.5342–0.7666; P=0.0001), while the mutational differences observed in BRAF and PI3CA did not reach statistical significance. CONCLUSIONS: Here, we report the mutational patterns for KRAS, BRAF, and PI3CA in sporadic CRC of AAs and Caucasians in a systematic meta‐analysis of previously published data. We identified an increase in KRAS mutations in sporadic CRC in AAs, which may contribute to worse prognosis and increased mortality of CRC in AAs. Future studies investigating health‐care disparities in CRC in AAs should control for KRAS mutational frequency.

Risk factors for severe or fatal drug‐induced liver injury from amoxicillin–clavulanic acid

To identify risk factors for severe liver injury or mortality from drug‐induced liver injury (DILI) from amoxicillin–clavulanic acid. To determine if co‐administration of potentially hepatotoxic drugs was associated with an increased risk of DILI from amoxicillin–clavulanic acid.

The predictors of mortality and secular changes in management strategies in emphysematous gastritis.

BACKGROUND AND AIMS Emphysematous gastritis (EG) is caused by invasion of the gastric wall by gas-producing organisms and carries mortality rate up to 60%. Our investigation aimed to determine the predictors of survival and the secular trends in survival rates of subjects with EG. METHODS PubMed search was completed to identify previous cases of EG. In addition, we included a recent case from our center. Statistical analysis was completed with two-sided Chi2 tests for categorical data and t-tests for continuous variables using SPSS v. 22.0 (SPSS Inc, Chicago, IL). RESULTS Study cohort included 59 adults. Mean age was 55.5 years; mean LOS was 28.6 days, and 44.1% of subjects were female. Subjects who had EG before 2000 had significantly higher rates of exploratory laparotomy compared to subjects who had EG after 2000 (62.5% vs. 22.2%, P=0.002). In contrast, subjects with EG after 2000 had significantly higher rates of EGD (55.6% vs. 18.8%, P=0.003) and lower rates of mortality (33.3% vs. 59.4%, P=0.046) compared to subjects with EG on or before 2000. In multivariate logistic regression analysis, the only independent predictor of mortality was length of stay (P=0.047). CONCLUSION We showed that previously reported 60% mortality rate of EG has been reduced to 33.3% for cases reported after 2000. EGD has been utilized more often while surgical interventions are used only in carefully selected cases. Our data suggests that early endoscopic evaluation and optimal medical management can perhaps continue to improve survival in subjects with EG.

Evolving role of the endoscopist in management of gastrointestinal neuroendocrine tumors

Neuroendocrine tumors (NETs) are uncommon gastrointestinal neoplasms but have been increasingly recognized over the past few decades. Luminal NETs originate from the submucosa of the gastrointestinal tract and careful endoscopic exam is a key for accurate diagnosis. Despite their reputation as indolent tumors with a good prognosis, some NETs may have aggressive features with associated poor long-term survival. Management of NETs requires full understanding of tumor size, depth of invasion, local lymphadenopathy status, and location within the gastrointestinal tract. Staging with endoscopic ultrasound or cross-sectional imaging is important for determining whether endoscopic treatment is feasible. In general, small superficial NETs can be managed by endoscopic mucosal resection and endoscopic submucosal dissection (ESD). In contrast, NETs larger than 2 cm are almost universally treated with surgical resection with lymphadenectomy. For those tumors between 11-20 mm in size, careful evaluation can identify which NETs may be managed with endoscopic resection. The increasing adoption of ESD may improve the results of endoscopic resection for luminal NETs. However, enthusiasm for endoscopic resection must be tempered with respect for the more definitive curative results afforded by surgical treatment with more advanced lesions.