Adenoma detection rates in colonoscopies for positive fecal immunochemical tests versus direct screening colonoscopies.

BACKGROUND AND AIMS: Recent guidelines propose higher adenoma detection rate (ADR) benchmarks for colonoscopies performed for positive results for fecal immunochemical tests (FIT), but this is based on low-quality evidence. We aimed to compare ADR, advanced ADR (AADR), and number of adenomas per colonoscopy (APC) in direct screening colonoscopy (DSC) versus FIT-positive colonoscopy (FITC) in a multicenter Asia-Pacific cohort to justify differential targets. METHODS: Asymptomatic average-risk patients ≥50 years of age who underwent screening colonoscopy directly or as follow-up for positive OC-Sensor FIT results were identified from 8 sites across the Asia-Pacific region. Overall, sex-specific ADR, overall AADR, and overall APC were compared between the 2 screening methods. Multivariable logistic regression was performed to adjust for confounding by differences in patient characteristics. Linear regression was used to correlate ADR with APC and to propose APC benchmarks. RESULTS: A total of 2901 (mean age, 60.1 years; 57% men) individuals had DSC, and 2485 (mean age, 62.8 years; 57% men) underwent FITC. Overall ADR (53.6% vs 37.5%; odds ratio [OR], 1.93; P < .001), male-specific ADR (61.6% vs 44.6%; OR, 2; P < .001), female-specific ADR (43.2% vs 28.2%; OR, 1.94; P < .001) and overall AADR (29.9% vs 4.9%; OR, 8.2; P < .001) in FITC were significantly higher than the corresponding values for DSC. Differences remained significant after adjustment for patient characteristics. ADR was strongly and positively correlated to APC, with an ADR of 45% and 35% correlating to an APC of ∼1 and ∼0.65. CONCLUSIONS: Results from this international multicenter cohort study provide early evidence that newly proposed higher ADR targets are justified as quality indicators for FITC.

Lower Relative Contribution of Positive Family History to Colorectal Cancer Risk with Increasing Age: A Systematic Review and Meta-Analysis of 9.28 Million Individuals.

OBJECTIVES: Existing algorithms predicting the risk of colorectal cancer (CRC) assign a fixed score for family history of CRC. Whether the increased CRC risk attributed to family history of CRC was higher in younger patients remains inconclusive. We examined the risk of CRC associated with family history of CRC in first-degree relative (FDR) according to the age of index subjects (<40 vs. ≥40; <50 vs. ≥50; and <60 vs. ≥60 years). METHODS: Ovid Medline, EMBASE, and gray literature from the reference lists of all identified studies were searched from their inception to March 2017. We included case-control/cohort studies that investigated the relationship between family history of CRC in FDR and prevalence of CRC. Two reviewers independently selected articles according to the PRISMA guideline. A random effects meta-analysis pooled relative risks (RR). RESULTS: We analyzed 9.28 million subjects from 63 studies. A family history of CRC in FDR confers a higher risk of CRC (RR = 1.76, 95% CI = 1.57-1.97, p < 0.001). This increased risk was higher in younger individuals (RR = 3.29, 95% CI = 1.67-6.49 for <40 years versus RR = 1.42, 95% CI = 1.24-1.62 for ≥40 years, p = 0.017; RR = 2.81, 95% CI = 1.94-4.07 for <50 years versus RR = 1.47, 95% CI = 1.28-1.69 for ≥50 years, p = 0.001). No publication bias was identified, and the findings are robust in subgroup analyses. CONCLUSIONS: The increase in relative risk of CRC attributed to family history was found to be higher in younger individuals. Family history of CRC could be assigned a higher score for younger subjects in CRC risk prediction algorithms. Future studies should examine if such approach may improve their predictive capability.

Prevalence, distribution, and risk factor for colonic neoplasia in 1133 subjects aged 40-49 undergoing screening colonoscopy.

BACKGROUND AND AIM: Colorectal cancer (CRC) incidence is rising among <50-year olds. The objective of this study was to determine screening colonoscopy outcomes among 40- to 49-year olds, which are currently limited. METHODS: Asymptomatic 40- to 49-year olds underwent one time CRC screening colonoscopy at The Chinese University of Hong Kong between 2007 and 2011. Screening outcomes, including prevalence, distribution, and predictive factors for overall and specifically proximal colorectal neoplasia were determined. RESULTS: Among 1133 ethnic Chinese, colorectal neoplasia prevalence was 20.5%. In men, distal adenomas were associated with proximal colorectal neoplasia. Men, advancing age, a first degree relative (FDR) with CRC, and diabetes mellitus were independently associated with colorectal neoplasia. A colorectal neoplasia was three times more likely to be found in a 45- to 49-year-old man with FDR of CRC compared with a 40- to 44-year-old woman without a FDR of CRC. The numbers needed to screen one colorectal neoplasia, and one advanced neoplasm in the highest risk group of 45- to 49-year-old men with FDR with CRC were 2.8 (95% CI: 2.2-4.4) and 18.5 (95% CI: 8.9-39.2), respectively. CONCLUSIONS: Colorectal neoplasia prevalence in this 40- to 49-year-old Chinese cohort was higher than previous studies. Men, advancing age, FDR with CRC, and diabetes mellitus, can be used to risk stratify for neoplasia development. Men 45-49 years old with FDR with CRC represented the highest risk subgroup, with the lowest number needed to screen.

Nucleophosmin 1, upregulated in adenomas and cancers of the colon, inhibits p53-mediated cellular senescence.

Dysregulation of nucleophosmin 1 (NPM1) has been found in numerous solid and hematological malignancies. Our previous meta-analysis of colorectal cancer (CRC) high throughput gene expression profiling studies identified it as a consistently reported up-regulated gene in the malignant state. Our aims were to compare NPM1 expression in normal colon, adenoma and CRC, to correlate their expressions with clinico-pathological parameters, and to assess the biological role of aberrant NPM1 expression in CRC cells. NPM1 transcript levels were studied in human CRC cell lines, whereas a tissue microarray of 57 normal human colon, 40 adenoma and 185 CRC samples were used to analyze NPM1 protein expression by immunohistochemistry. CRC cell lines were subjected to transient siRNA-mediated knockdown to study NPM1's roles on cell viability and senescence. NPM1 transcript levels were 7-11-folds higher in three different human CRC cell lines compared to normal colon cells. NPM1 protein expression was found to be progressively and significantly upregulated in CRC compared to adenomas and in adenomas compared to normal mucosa. Reducing NPM1 expression by siRNA had caused a significant decrease in cell viability, a concomitant increase in cellular senescence and cell cycle arrest. Cellular senescence induced under conditions of forced NPM1 suppression could be prevented by knocking down p53. The differential expression of NPM1 along the normal colon-adenoma-carcinoma progression and its involvement in resisting p53 related senescent growth arrest in CRC cell lines implicate its role in supporting CRC tumorigenesis.

Recurrent ectopic pancreatitis of the jejunum and mesentery over a 30-year period.

BACKGROUND: Ectopic pancreas is defined as pancreatic tissue found outside its usual anatomical position, with no ductal or vascular communication with the native pancreas. We describe a case of ectopic pancreas of the small bowel and mesentery causing recurrent episodes of pancreatitis, initially suspected on computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP), and confirmed on histological review of the resection. METHODS: A 67-year-old woman presented with clinical symptoms and biochemical evidence of pancreatitis. She had similar episodes over the past 30 years with unrevealing investigations, and was concluded to have idiopathic pancreatitis. She underwent CT and MRCP, with findings suggestive of ectopic pancreas, a diagnosis confirmed on histology of the resection. RESULTS: MRCP identified a mass in the proximal small bowel mesentery isointense to the native pancreas, with a small duct draining into a proximal jejunal loop. The resected specimen consisted of normal parenchyma with lobulated acinar tissue with scattered islets of Langerhans, an occasional ductular structure, and admixed areas of adipose tissue. The patient remained asymptomatic with normal biochemistry six months post-operatively. CONCLUSION: In an individual with abdominal pain, elevated serum amylase/lipase, but imaging findings of a normal native pancreas, ectopic pancreatitis should be considered, and can be evaluated by CT and MRCP.

Combined structural and neurochemical evaluation of the corticospinal tract in amyotrophic lateral sclerosis.

Our objective was to characterize the structural and metabolic changes of the corticospinal tract (CST) in ALS patients using combined diffusion tensor imaging (DTI) and magnetic resonance spectroscopic imaging (MRSI). Fourteen patients (male:female, 6:8; mean age, 54 years) and 14 controls (male:female, 8:6; mean age, 53 years) underwent imaging. Four regions of the CST were evaluated: precentral gyrus, corona radiata, posterior limb of the internal capsule, and cerebral peduncle. DTI and MRSI indices tested included fractional anisotropy (FA), apparent diffusion coefficient (ADC), and the ratio of N-acetylaspartate to choline (NAA/Cho) and creatine (NAA/Cr). In the precentral gyrus, NAA/Cho was reduced 18% (p<0.001), NAA/Cr was reduced 9% (p=0.01), and FA was reduced 3% (p=0.02). NAA/Cho and NAA/Cr were reduced in the corona radiata (p<0.001). Reduced NAA/Cho in the precentral gyrus correlated with shorter symptom duration (r=0.66, p=0.02) and faster disease progression (r=-0.65, p=0.008). Increased spasticity correlated with higher ADC in the precentral gyrus (R=0.52, p=0.005). In conclusion, both MRSI and DTI provided in vivo evidence of intracranial degeneration of the CST in ALS that was most prominent rostrally in the precentral gyrus.

AI-doscopist: a real-time deep-learning-based algorithm for localising polyps in colonoscopy videos with edge computing devices.

We have designed a deep-learning model, an "Artificial Intelligent Endoscopist (a.k.a. AI-doscopist)", to localise colonic neoplasia during colonoscopy. This study aims to evaluate the agreement between endoscopists and AI-doscopist for colorectal neoplasm localisation. AI-doscopist was pre-trained by 1.2 million non-medical images and fine-tuned by 291,090 colonoscopy and non-medical images. The colonoscopy images were obtained from six databases, where the colonoscopy images were classified into 13 categories and the polyps' locations were marked image-by-image by the smallest bounding boxes. Seven categories of non-medical images, which were believed to share some common features with colorectal polyps, were downloaded from an online search engine. Written informed consent were obtained from 144 patients who underwent colonoscopy and their full colonoscopy videos were prospectively recorded for evaluation. A total of 128 suspicious lesions were resected or biopsied for histological confirmation. When evaluated image-by-image on the 144 full colonoscopies, the specificity of AI-doscopist was 93.3%. AI-doscopist were able to localise 124 out of 128 polyps (polyp-based sensitivity = 96.9%). Furthermore, after reviewing the suspected regions highlighted by AI-doscopist in a 102-patient cohort, an endoscopist has high confidence in recognizing four missed polyps in three patients who were not diagnosed with any lesion during their original colonoscopies. In summary, AI-doscopist can localise 96.9% of the polyps resected by the endoscopists. If AI-doscopist were to be used in real-time, it can potentially assist endoscopists in detecting one more patient with polyp in every 20-33 colonoscopies.

The interaction between SPARC and GRP78 interferes with ER stress signaling and potentiates apoptosis via PERK/eIF2α and IRE1α/XBP-1 in colorectal cancer.

Therapy-refractory disease is one of the main contributors of treatment failure in cancer. In colorectal cancer (CRC), SPARC can function as a sensitizer to conventional chemotherapy by enhancing apoptosis by interfering with the activity of Bcl-2. Here, we examine a novel mechanism by which SPARC further potentiates apoptosis via its modulation of the unfolded protein response (UPR). Using mass spectrometry to identify SPARC-associated proteins, GRP78 was identified as a protein partner for SPARC in CRC. In vitro studies conducted to assess the signaling events resulting from this interaction, included induction of ER stress with tunicamycin, 5-fluorouracil (5-FU), and irinotecan (CPT-11). We found that the interaction between GRP78 and SPARC increased during exposure to 5-FU, CPT-11, and tunicamycin, resulting in an attenuation of GRP78's inhibition of apoptosis. In addition, we also show that SPARC can sensitize CRC cells to PERK/eIF2α and IRE1α/XBP-1 UPR signaling by interfering with ER stress following binding to GRP78, which leads to ER stress-associated cell death in CRC cells. In line with these findings, a lower expression of GRP78 relative to SPARC in CRC is associated with a lower IC50 for 5-FU in either sensitive or therapy-refractory CRC cells. Interestingly, this observation correlates with tissue microarray analysis of 143 human CRC, where low GRP78 to SPARC expression level was prognostic of higher survival rate (P = 0.01) in individuals with CRC. This study demonstrates that modulation of UPR signaling by SPARC promotes ER stress-associated death and potentiates apoptosis. This may be an effective strategy that can be combined with current treatment options to improve therapeutic efficacy in CRC.

Spatial profiling of the corticospinal tract in amyotrophic lateral sclerosis using diffusion tensor imaging.

BACKGROUND AND PURPOSE: Diffusion tensor imaging (DTI) was used as a noninvasive method to evaluate the anatomy of the corticospinal tract (CST) and the pattern of its degeneration in amyotrophic lateral sclerosis (ALS). METHODS: Fourteen patients with ALS and 15 healthy controls underwent DTI. Parameters reflecting coherence of diffusion (fractional anisotropy, FA), bulk diffusion (apparent diffusion coefficient, ADC), and directionality of diffusion (eigenvalues) parallel to (lambda( parallel)) or perpendicular to (lambda( perpendicular)) fiber tracts were measured along the intracranial course of the CST. RESULTS: FA and lambda( parallel) increased, and ADC and lambda( perpendicular) decreased progressively from the corona radiata to the cerebral peduncle in all subjects. The most abnormal finding in patients with ALS was reduced FA in the cerebral peduncle contralateral to the side of the body with the most severe upper motor neuron signs. lambda( parallel) was increased in the corona radiata. Internal capsule FA correlated positively with symptom duration, and cerebral peduncle ADC positively with the Ashworth spasticity score. CONCLUSION: There is a spatial dependency of diffusion parameters along the CST in healthy individuals. Evidence of intracranial CST degeneration in ALS was found with distinct diffusion changes in the rostral and caudal regions.

Inactivation of the Kinase Domain of CDK10 Prevents Tumor Growth in a Preclinical Model of Colorectal Cancer, and Is Accompanied by Downregulation of Bcl-2.

Cyclin-dependent kinase 10 (CDK10), a CDC2-related kinase, is highly expressed in colorectal cancer. Its role in the pathogenesis of colorectal cancer is unknown. This study examines the function of CDK10 in colorectal cancer, and demonstrates its role in suppressing apoptosis and in promoting tumor growth in vitro and in vivo Modulation of CDK10 expression in colorectal cancer cell lines demonstrates that CDK10 promotes cell growth, reduces chemosensitivity and inhibits apoptosis by upregulating the expression of Bcl-2. This effect appears to depend on its kinase activity, as kinase-defective mutant colorectal cancer cell lines have an exaggerated apoptotic response and reduced proliferative capacity. In vivo, inhibiting CDK10 in colorectal cancer following intratumoral injections of lentivirus-mediated CDK10 siRNA in a patient-derived xenograft mouse model demonstrated its efficacy in suppressing tumor growth. Furthermore, using a tissue microarray of human colorectal cancer tissues, the potential for CDK10 to be a prognostic biomarker in colorectal cancer was explored. In tumors of individuals with colorectal cancer, high expression of CDK10 correlates with earlier relapse and shorter overall survival. The findings of this study indicate that CDK10 plays a role in the pathogenesis in colorectal cancer and may be a potential therapeutic target for treatment. Mol Cancer Ther; 16(10); 2292-303. ©2017 AACR.

Endoscopic ultrasound of pancreatic lesions.

Endoscopic ultrasound (EUS) is a well-established tool for the evaluation of pancreatic lesions. Due to the closer proximity of EUS to the pancreas, EUS offers a high sensitivity for detection of small pancreatic mass and is the preferred modality for obtaining tissue for diagnosis of pancreatic mass. Contrast-enhanced EUS and/or elastography provide additional information to the fundamental B-mode ultrasound images, leading to more accurate diagnosis. The aim of this video-article is to show the different steps in performing EUS on pancreatic lesions and to provide some tips and tricks to improve and facilitate the execution of EUS on pancreatic lesions.

Pharmacological Treatment in Upper Gastrointestinal Bleeding.

Acute upper gastrointestinal bleeding (AUGIB) is a common medical emergency. Bleeding peptic ulcers account for the majority of causes in patients presenting with AUGIB, whereas variceal bleeding in cirrhotic patients represents a more severe form of bleeding. Endoscopic therapy is the mainstay of treatment in patients with active bleeding, as it achieves hemostasis and improves patient outcomes. Pharmacotherapy is an important adjunct to endoscopic hemostasis. In the management of patients with bleeding peptic ulcers, acid suppression after endoscopic hemostasis reduces rates of further bleeding and interventions. In patients with stable hemodynamics awaiting endoscopy, acid suppression starts ulcer healing and downstages stigmata of bleeding, thereby reducing the need for endoscopic therapy. In managing patients with variceal bleeding, early administration of vasoactive drugs lowers splanchnic blood flow, promotes hemostasis, and makes subsequent endoscopic treatment easier. The use of vasoactive agents and antibiotics have both been shown to reduce mortality. In this review article, strategies of acid suppression therapy for peptic ulcer bleeds, vasoactive agents, and antibiotics for variceal bleeding, together with recent evidence on the use of tranexamic acid in gastrointestinal bleeding, are discussed.

Development of testicular germ cell cancer following successful infliximab induction therapy for ulcerative colitis.

Antitumor necrosis factor alpha (anti-TNFα) agents have substantially altered the management of inflammatory bowel diseases (IBD). Their benefits must however be weighed against increased risks for infections, lymphoma, and possibly other malignancies. We report on a 27-year-old man, with a six-year history of ulcerative colitis maintained on mesalamine suppositories, presenting with clinical, radiographic and biopsy evidence of an acute colitis flare. Due to the refractory nature of his disease, infliximab was started, resulting in induction of remission within six weeks. Three months after the first dose of infliximab, the patient was diagnosed with a testicular mixed germ cell tumor requiring orchiectomy. Four cases of testicular cancer development among patients using anti-TNFα agents have been identified. Given the prevalence of IBD in young men and recent suggestions for "top-down therapy," testicular cancer as a potential complication of anti-TNFα agents should be further explored on a population basis.

Absence of MMP2 expression correlates with poor clinical outcomes in rectal cancer, and is distinct from MMP1-related outcomes in colon cancer.

PURPOSE: Treatments for colorectal cancer (CRC) are primarily disease stage based. However, heterogeneity in outcome within even a single stage highlights its limitations in predicting disease behavior. Recently, the role of gene expression as predictive and prognostic markers has been explored. Our objectives were to identify consistently differentially expressed genes through meta-analysis of high-throughput gene-expression studies, and evaluate their predictive and prognostic significance in colon (CC) and rectal (RC) cancers. EXPERIMENTAL DESIGN: Publications applying high-throughput gene- expression technologies to specific CRC stages were identified. A vote counting strategy was used to identify the most significant differentially expressed genes. Their predictive and prognostic values were independently assessed in a tissue microarray of 191 cases of stage II-IV CC/RC from two tertiary care centers. Their biological effects were also examined in vitro. RESULTS: MMP1 and MMP2 were identified as consistently underexpressed in liver metastasis compared with primary CRC. Shorter time to distant metastasis and overall survival occurred in stage III CC lacking MMP1 expression, and in stage III RC lacking MMP2. MMP1 levels in stage II and III CC were associated with increased likelihood of distant metastasis, whereas the risk of local recurrence in stage III RC could be stratified by MMP2. Promotion of cell invasion of CRC cell lines exposed to MMP1/2 inhibitors were confirmed in vitro. CONCLUSIONS: MMP1 and MMP2 may be useful biomarkers that can help stratify patients at higher risk of developing recurrence in colorectal cancer, and guide individualized treatment decisions to achieve better outcomes.