John C. Wong

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.

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 (λ∥) or perpendicular to (λ⊥) fiber tracts were measured along the intracranial course of the CST. Results: FA and λ∥ increased, and ADC and λ⊥ 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. λ∥ 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.

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 NPM1s 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.

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. Clin Cancer Res; 17(12); 4167–76. ©2011 AACR.

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

BACKGROUNDnEctopic 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.nnnMETHODSnA 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.nnnRESULTSnMRCP 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.nnnCONCLUSIONnIn 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.

A Case of Rothia dentocariosa Bacteremia in a Patient Receiving Infliximab for Ulcerative Colitis

A Case of Rothia dentocariosa Bacteremia in a Patient Receiving Infliximab for Ulcerative Colitis

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.

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.

Mo1940 Prevalence and Risk Factors of Colonic Adenomas Among 1133 40-49 Years Old Undergoing Screening Colonoscopy

Growing evidence suggests that metabolic syndrome is not only a cluster of risk factors for cardiovascular disease and type 2 diabetes, but also for some cancer including a colorectal cancer. We have previously shown that insulin resistance, an increased visceral fat, hypoadiponectinemia and low-grade systemic inflammation assessed by serum IL-6 levels are linked to the risk of colorectal adenoma. Recently, it has been reported that chemerin, as a novel adipokine, can act as a chemoattractant for immune cells. And obesity, insulin resistance and inflammation have shown to have elevated serum levels of chemerin. However, the role of chemerin in human colorectal adenoma is still unknown. Therefore, we investigated the relationship between serum chemerin levels and the incidence of colorectal adenoma. Methods: We conducted a total colonoscopy-based cross-sectional case-control study. 76 male individuals with an endoscopically diagnosed colorectal adenoma were enrolled along with 72 age-matched male for our control group. Both cohort groups underwent health checkups, between 2007 and 2009, at Tohoku Central Hospital. Serum levels of chemerin were measured in samples of venous blood obtained from the participants after an overnight fast. The risk for colorectal adenoma was evaluated by logistic regression analysis. Results: In the colorectal adenoma group, the mean levels of serum insulin, fasting, plasma glucose, value of HOMA-IR and HbA1c were higher than those in the control group. There were no differences between the groups in the proportions of current smokers, alcohol consumers, mean BMI, bold pressure and serum triglyceride. The mean concentration of serum chemerin was significantly higher in the colorectal adenoma group than in the control group (791±354 ng/ml vs. 538±401 ng/ml, p<0.001). In multivariate analysis, high chemerin level (above the median) was associated with the incidence of colorectal adenoma (OR 2.9, 95%CI; 1.456.09) after adjustment for age, blood pressure, BMI, triglyceride, HOMA-IR and HbA1c. In conclusion, the present study suggests that increased serum levels of chemerin are positively associated with the incidence of colorectal adenoma in men. Our study indicates that chemerin may play an important role in the development of human colorectal adenoma. To confirm our findings in this study, further replication and research are required to elucidate the underlying the mechanisms. This will enable us to gain a better understanding of the link between metabolic syndrome and colorectal adenoma.