Volumetric laser endomicroscopy features of dysplasia at the gastric cardia in Barrett's oesophagus: results from an observational cohort study.

OBJECTIVE: Volumetric laser endomicroscopy (VLE) is an advanced imaging modality used in Barrett's oesophagus (BE) to help identify dysplasia in the oesophagus. VLE criteria exist for oesophageal dysplasia but not for dysplasia in the gastric cardia. The aim of this study was to determine if there are in vivo VLE features that can predict gastric cardia dysplasia in BE. DESIGN: This was a single-centre observational cohort study from August 2016 to August 2018. Patients were included if they had BE, were undergoing a VLE exam as standard of care, and had a suspicious target laser marked at the gastric cardia. The following VLE features were correlated to histology to determine if an association existed between histology subtype and VLE feature: wide crypts, irregular surface, one large isolated gland, multiple glands, and complex glands. RESULTS: A total of 110 in vivo gastric cardia targets in 77 patients with BE were analysed. The following abnormalities were identified: 61 wide crypts, 34 isolated glands, 16 irregular surfaces, 15 multiple glands, and 11 complex glands. Complex glands were the only VLE feature that correlated to any histology subtype. They were present in 71% of targets with high-grade dysplasia (HGD), T1a cancer or T1b cancer and had a sensitivity, specificity, and accuracy of 71%, 99%, and 85%, respectively. Of the 10 patients with complex glands on VLE and HGD/cancer on histology, 4 had a normal-appearing mucosa (40%) on endoscopy. CONCLUSION: Identification of complex glands on VLE may aid in detection of HGD or early cancer in the gastric cardia in BE. This is particularly important, as dysplasia at the gastric cardia can be difficult to see endoscopically.

Carrying the Weight: Athletics and Obesity in High School Football Players.

This article determines the prevalence of obesity among high school football players nationwide and compares obesity between position groups of football players and across team sports. We calculate body mass index (BMI) for 391 212 males participating in baseball, basketball, football, lacrosse, and soccer, then stratify BMI into commonly accepted categories and subdivide football players by position played, comparing BMI across position groups and sports. A total of 47.4% of high school football players are healthy weight (BMI = 18.5-24.9 kg/m2), 18.0% have obesity (BMI = 30-34.9 kg/m2: 12.4%) or class 2 obesity (BMI >34.9 kg/m2: 5.6%). Among linemen, 14.8% are healthy weight, 14.6% have class 2 obesity, and another 29.3% have obesity. Among non-linemen, the combined prevalence of obesity and class 2 obesity is 2.7%, comparable to other team sports. Obesity is common among high school football players, more so than among other high school athletes. Obesity and class 2 obesity are only common among linemen.

Elite athletes and anticoagulant therapy: an intermittent dosing strategy.

Traditionally, the athlete who requires long-term anticoagulation has been told to forgo participation in contact and collision sports. However, a strategy of short-term interruption of anticoagulant therapy may be designed for some athletes, allowing them return to full athletic activity. A personalized pharmacokinetic/pharmacodynamic study of a direct oral anticoagulant (DOAC) may allow athletic participation when plasma drug concentration is minimal and resumption of treatment after the risk of bleeding sufficiently normalizes. Scientific data and uncertainties regarding this approach, as well as practical challenges in the implementation, will be discussed.

Declining use of combination infliximab and immunomodulator for inflammatory bowel disease in the community setting.

AIM: To describe trends of combination therapy (CT) of infliximab (IFX) and immunomodulator (IMM) for inflammatory bowel disease (IBD) in the community setting. METHODS: A retrospective study was conducted of all IBD patients referred for IFX infusion to our community infusion center between 04/01/01 and 12/31/14. CT was defined as use of IFX with either azathioprine, 6-mercaptopurine, or methotrexate. We analyzed trends of CT usage overall, for Crohn's disease (CD) and ulcerative colitis (UC), and for the subgroups of induction patients. We also analyzed the trends of CT use in these groups over the study period, and compared the rates of CT use prior to and after publication of the landmark SONIC trial. RESULTS: Of 258 IBD patients identified during the 12 year study period, 60 (23.3%) received CT, including 35 of 133 (26.3%) induction patients. Based on the Cochran-Armitage trend test, we observed decreasing CT use for IBD patients overall (P < 0.0001) and IBD induction patients, (P = 0.0024). Of 154 CD patients, 37 (24.68%) had CT, including 20 of 77 (26%) induction patients. The Cochran Armitage test showed a trend towards decreasing CT use for CD overall (P < 0.0001) and CD induction, (P = 0.0024). Overall, 43.8% of CD patients received CT pre-SONIC vs 7.4% post-SONIC (P < 0.0001). For CD induction, 40.0% received CT pre-SONIC vs 10.8% post-SONIC (P = 0.0035). Among the 93 patients with UC, 19 (20.4%) received CT. Of 50 induction patients, 14 (28.0%) received CT. The trend test of the 49 patients with a known year of induction again failed to demonstrate any significant trends in the use of CT (P = 0.6). CONCLUSION: We observed a trend away from CT use in IBD. A disconnect appears to exist between expert opinion and evidence favoring CT with IFX and IMM, and evolving community practice.

Efficacy of liquid nitrogen cryotherapy for Barrett's esophagus after endoscopic resection of intramucosal cancer: A multicenter study.

BACKGROUND AND AIM: Liquid nitrogen cryotherapy (LNC) allows increased depth of ablation compared with radiofrequency ablation in Barrett's esophagus (BE). Expert centers may use LNC over radiofrequency ablation to ablate Barrett's esophagus after endoscopic resection of intramucosal cancer (IMCA). The aim of our study was to (1) evaluate the safety and efficacy of LNC ablation in patients with BE and IMCA and (2) to evaluate the progression to invasive disease despite therapy. METHODS: This was a multicenter, retrospective study of consecutive patients with BE who received LNC following endoscopic mucosal resection (EMR) of IMCA. The outcomes evaluated were complete eradication of dysplasia and intestinal metaplasia and development of invasive cancer during follow up. The follow-up period was at least 1 year from initial LNC. RESULTS: Twenty-seven patients were identified. The median Prague score was C3M5 (range C0M1-C14M14). After EMR+LNC, the median Prague score was C0M1 (range C0M0-C9M10); 22/27 patients (82%) achieved complete eradication of dysplasia after cryotherapy, and 19/27 patients (70%) achieved complete eradication of intestinal metaplasia. One out of 27 patients (4%) developed invasive cancer (disease beyond IMCA) over the study period. CONCLUSION: Cryotherapy is an effective endoscopic tool for eradication of BE dysplasia after EMR for IMCA. Development of invasive cancer is low for this high-risk group.

Combination therapy for inflammatory bowel disease.

Biologic therapies such as infliximab and adalimumab have become mainstays of treatment for inflammatory bowel disease. Early studies suggested that combination therapy (CT) with infliximab and an immunomodulator drug such as azathioprine may help optimize biologic pharmacokinetics, minimize immunogenicity, and improve outcomes. The landmark SONIC trial in Crohn's disease and the UC SUCCESS trial in ulcerative colitis demonstrated CT with infliximab and azathioprine to be superior to monotherapy with either agent alone at inducing clinical remission in treatment naïve patients with moderate to severe disease. However, many unanswered questions linger. The role of CT in non-naive patients as well as the optimal duration of CT remains unknown. The effectiveness of CT with alternate biologics and/or alternate immunomodulators is not as clear, and it is unknown whether SONIC's conclusions can be extrapolated beyond infliximab and azathioprine. Also looming are the risks of CT including opportunistic infection and malignancy; specifically, lymphoma. This review lays out the evidence as it pertains to the risks and benefits of CT as well as the areas that require further research. With this information in hand, the practitioner may develop a treatment strategy that best suits each individual patient.

Feasibility of liquid nitrogen cryotherapy after failed radiofrequency ablation for Barrett's esophagus.

BACKGROUND AND AIM: Radiofrequency ablation (RFA) for dysplastic Barrett's esophagus (BE) is highly effective. RFA failures are infrequent but can be a challenging cohort to manage. There are limited data on the feasibility of liquid nitrogen cryospray ablation for complete eradication of dysplasia (CE-D) and/or intestinal metaplasia (CE-IM) after RFA has failed to achieve CE-IM in patients with dysplastic BE. METHODS: This is a retrospective review from two medical centers of prospectively maintained databases looking at patients that underwent liquid nitrogen cryospray ablation for refractory intestinal metaplasia post failed RFA. RESULTS: Eighteen patients were identified that met inclusion criteria. Eleven patients had persistent dysplasia and IM following RFA and seven had persistent non-dysplastic IM. More than 80% of patients were male with long-segment BE (median length 8 cm). Seventy two percent of patients with dysplasia achieved CE-D after cryotherapy. Fifty percent (9/18) of all RFA failures achieved CE-IM with cryotherapy. In comparison, RFA has a CE-IM of 78% in a less challenging treatment naïve cohort from a large-scale meta-analysis of 3802 patients. No adverse events occurred in our cohort. CONCLUSION: Cryospray ablation is feasible and safe for achieving CE-D and CE-IM after RFA failure. The CE-D rates are high with cryotherapy in this population. CE-IM with cryotherapy is acceptable in this difficult-to-treat cohort when compared to CE-IM rates with RFA in dysplastic BE treatment naïve patients (50% vs 78%).

Downhill Esophageal Varices Associated With Central Venous Catheter-Related Thrombosis Managed With Endoscopic and Surgical Therapy.

Downhill esophageal varices are a rare cause of upper gastrointestinal hemorrhage. We present a case of downhill variceal bleeding due to superior vena cava thrombosis resulting from a prior central venous catheter. The patient was managed with endoscopic band ligation and later with surgical axillary vein to right atrium bypass grafting. Successful long-term resolution of varices was achieved at 1 year of follow-up. This is the longest follow-up described for combined endoscopic and surgical management in the existing literature for catheter-associated downhill varices.

Volumetric laser endomicroscopy can target neoplasia not detected by conventional endoscopic measures in long segment Barrett's esophagus.

Methods and study aims: The incidence of esophageal cancer is rising despite increased surveillance efforts. Volumetric laser endomicroscopy (VLE) is a new endoscopic imaging tool that can allow for targeted biopsy of neoplasia in Barrett's esophagus. We report a series of 6 patients with long-segment Barrett's esophagus ( > 3 cm), who underwent a session of endoscopy with volumetric laser endomicroscopy, after a separate prior session of standard high-definition endoscopy with narrow band imaging (NBI) and random biopsies that did not reveal neoplasia. In all six patients, the first endoscopy was the index endoscopy diagnosing the Barrett's esophagus. All VLE exams were performed within 6 months of the previous endoscopy. In five patients, VLE-targeted biopsy resulted in upstaged disease/diagnosed dysplasia that then qualified the patient for endoscopic ablation therapy. In one patient, VLE localized a focus of intramucosal cancer that allowed for curative endoscopic mucosal resection. This case series shows that endoscopy with VLE can target neoplasia that cannot be localized by high-definition endoscopy with NBI and random biopsies.

Decompensated cirrhosis may be a risk factor for adverse events in endoscopic retrograde cholangiopancreatography.

BACKGROUND AND AIMS: There are limited data regarding the safety of endoscopic retrograde cholangiopancreatography (ERCP) in cirrhosis. The current literature consists of small series totalling less than 225 patients. METHODS: Retrospective matched cohort study of the National Inpatient Sample (NIS) for 2009. We compared adverse events of cirrhotic patients who underwent ERCP (n = 1930) with a matched control group that consisted of randomly selected non-cirrhotic patients who underwent ERCP (n = 5790). An additional control group, to measure cirrhosis-related adverse events, consisted of cirrhotic patients undergoing non-pancreaticobiliary endoscopy. RESULTS: ERCP-associated adverse events of post-ERCP pancreatitis (PEP) (8.3% vs. 5.5%) and bleeding (2.3% vs. 1.0%) were more common in the cirrhosis cohort vs. the non-cirrhosis cohort (all P < 0.05). In subgroup analysis, compensated cirrhotic patients (n = 1308) had a similar adverse event profile to non-cirrhotic controls except for a slightly higher rate of PEP (7.7% vs. 5.5%; P < 0.05). However, decompensated cirrhotic patients (n = 622) had statistically significant higher rates of PEP (9.7% vs. 5.5%) and bleeding (4.3% vs. 1.0%), compared with non-cirrhotic controls respectively (P < 0.05). In regard to cirrhosis-related adverse events, cirrhotic patients undergoing ERCP were more likely to develop bacterial peritonitis vs. cirrhotic patients undergoing non-pancreaticobiliary endoscopy (2.2% vs. 1.1%; P < 0.005). CONCLUSION: ERCP adverse events were statistically higher among patients with decompensated cirrhosis. This increased risk needs to be confirmed with prospective studies. A thorough risk/benefit assessment should be performed prior to performing ERCP in decompensated cirrhotic patients.

Prostate Cancer: assessing the effects of androgen-deprivation therapy using quantitative diffusion-weighted and dynamic contrast-enhanced MRI.

PURPOSE: To investigate the effects of androgen-deprivation therapy (ADT) on MRI parameters and evaluate their associations with treatment response measures. MATERIALS AND METHODS: The study included 30 men with histopathologically confirmed prostate cancer who underwent MRI before and after initiation of ADT. Thirty-four tumours were volumetrically assessed on DW-MRI (n = 32) and DCE-MRI (n = 18), along with regions of interest in benign prostatic tissue, to calculate apparent diffusion coefficient (ADC) and transfer constant (K(trans)) values. Changes in MRI parameters and correlations with clinical parameters (change in prostate-specific antigen [PSA], treatment duration, PSA nadir) were assessed. RESULTS: Prostate volume and PSA values decreased significantly with therapy (p < 0.001). ADC values increased significantly in tumours and decreased in benign prostatic tissue (p < 0.05). Relative changes in ADC and absolute post-therapeutic ADC values differed significantly between tumour and benign tissue (p < 0.001). K(trans) decreased significantly only in tumours (p < 0.001); relative K(trans) changes and post-therapeutic values were not significantly different between tumour and benign tissue. The relative change in tumour ADC correlated significantly with PSA decrease. No changes were associated with treatment duration or PSA nadir. CONCLUSIONS: Multi-parametric MRI shows significant measurable changes in tumour and benign prostate caused by ADT and may help in monitoring treatment response. KEY POINTS: • Androgen-deprivation therapy caused changes of ADC, K (trans) in tumour and benign prostate. • Prostate volume and PSA values decreased significantly with therapy. • ADC values may be helpful for monitoring treatment response.

Gleason 7 prostate cancer treated with low-dose-rate brachytherapy: lack of impact of primary Gleason pattern on biochemical failure.

UNLABELLED: What's known on the subject? and What does the study add? There appears to be a clear difference in cancer control outcomes for patients with Gleason scores of 3+4 and those with scores of 4+3 after radical prostatectomy. It has been documented that patients with Gleason 4+3 prostate cancer have higher incidences of non-organ-confined disease than those with primary pattern 3. Higher rates of extracapsular extension, seminal vesicle invasion and positive margins have been found to be associated with primary pattern 4 over 3. These higher rates of non-organ-confined disease can lead to increased biochemical failure, which, in turn, can lead to higher mortality rates. This study provides information on the prognostic significance of primary Gleason pattern in the brachytherapy management of prostate cancer. Study Type - Prognosis (case series) Level of Evidence 4. OBJECTIVES: • To report the biochemical outcomes for Gleason 7 prostate cancer treated with brachytherapy. • To analyse the impact of the primary Gleason pattern as well as other disease- and treatment-related factors on outcome. PATIENTS AND METHODS: • A total of 560 patients with Gleason 7 prostate cancer were treated between 1990 and 2008 with brachytherapy, alone or in combination with hormonal therapy and/or external beam radiation therapy. • There were 352 patients with Gleason pattern 3+4 and 208 with Gleason pattern 4+3. • The mean (range) presenting PSA level was 11.2 (1-300) ng/mL, and the median was 7.8 ng/mL. • The presenting clinical stages were T1b in 1%, T1c in 33%, T2a in 16%, T2b in 32%, T2c in 16% and T3 in 2% of patients. RESULTS: • The actuarial freedom from biochemical failure rate at 10 years was 82%. • There was no significant difference between 10-year freedom from biochemical failure rates for patients with Gleason scores of 3+4 (79%) and those with scores of 4+3 (82%). • Biologically effective dose and presenting PSA level were both significant predictors of biochemical failure in multivariate analysis. CONCLUSIONS: • The primary Gleason pattern in Gleason 7 prostate cancer shows no significant effect on biochemical failure when treated with brachytherapy. • These results are different from those found after radical prostatectomy and are probably attributable to the enhanced local control afforded by a brachytherapy approach to this disease subset.

Thyroid-stimulating hormone induces a Wnt-dependent, feed-forward loop for osteoblastogenesis in embryonic stem cell cultures.

We have shown that the anterior pituitary hormone, thyroid-stimulating hormone (TSH), can bypass the thyroid to exert a direct protective effect on the skeleton. Thus, we have suggested that a low TSH level may contribute to the bone loss of hyperthyroidism that has been attributed traditionally to high thyroid hormone levels. Earlier mouse genetic, cell-based, and clinical studies together have established that TSH inhibits osteoclastic bone resorption. However, the direct influence of TSH on the osteoblast has remained unclear. Here, we have used a model system developed from murine ES cells, induced to form mature mineralizing osteoblasts, and show that TSH stimulates osteoblast differentiation primarily through the activation of protein kinase Cδ and the up-regulation of the noncanonical Wnt components frizzled and Wnt5a. We predict that a TSH-induced, fast-forward short loop in bone marrow permits Wnt5a production, which, in addition to enhancing osteoblast differentiation, also stimulates osteoprotegerin secretion to attenuate bone resorption by neighboring osteoclasts. We surmise that this loop should uncouple bone formation from bone resorption with a net increase in bone mass, which is what has been observed upon injecting TSH.

Synthesis and structure-activity relationship of a novel series of heterocyclic sulfonamide gamma-secretase inhibitors.

gamma-Secretase inhibitors have been shown to reduce the production of beta-amyloid, a component of the plaques that are found in brains of patients with Alzheimer's disease. A novel series of heterocyclic sulfonamide gamma-secretase inhibitors that reduce beta-amyloid levels in cells is reported. Several examples of compounds within this series demonstrate a higher propensity to inhibit the processing of amyloid precursor protein compared to Notch, an alternative gamma-secretase substrate.

Lipid-lowering effects of ethyl 2-phenacyl-3-aryl-1H-pyrrole- 4-carboxylates in rodents.

A series of substituted 2-phenacyl-3-phenyl-1H-pyrrole-4-carboxylates were prepared from substituted acetophenones in 6 steps. The final condensations between a chloroenal and an aminoketone were carried out under neutral conditions in parallel to yield the series listed below. Selected pyrrole derivatives proved to be potent hypolipidemic agents lowering serum triglyceride concentrations in CF-1 male mice after 14 days of I.P. administration. One agent orally lowered serum cholesterol in Sprague-Dawley male rats at 2mg/kg/day after 14 days. The agents demonstrated a lowering of mouse serum LDL- cholesterol levels and selected compounds showed an elevation of serum HDL-cholesterol levels. The cholesterol concentrations in the liver were raised while the cholesterol and triglyceride contents of the aorta were significantly lowered by the selected trisubstituted pyrrole.

Synthesis and cytotoxicity of substituted ethyl 2-phenacyl-3-phenylpyrrole-4-carboxylates.

The substituted ethyl-2-phenacyl-3-phenylpyrrole-4-carboxylates were synthesized by a condensation of a beta-chloroenal and an alpha-aminoketone under neutral conditions. They proved to be potent cytotoxic agents against the growth of murine L1210 and P388 leukemias and human HL-60 promyelocytic leukemia, HuT-78 lymphoma, and HeLa-S(3) uterine carcinoma. Selective compounds were active against the growth of Tmolt(3) and Tmolt(4) leukemias and THP-1 acute monocytic leukemia, liver Hepe-2, ovary 1-A9, ileum HCT-8 adenocarcinoma, and osteosarcoma HSO. A mode of action study in HL-60 cells demonstrated that DNA and protein syntheses were inhibited after 60 min at 100 microM. DNA and RNA polymerases, PRPP-amido transferase, dihydrofolate reductase, thymidylate synthase, and TMP kinase activities were interfered with by the agent with reduction of d[NTP] pools. Nonspecific interaction with the bases of DNA and cross-linking of the DNA may play a role in the mode of action of these carboxylates.

Synthesis and cytotoxicity of cyanoborane adducts of n6-benzoyladenine and 6-triphenylphosphonylpurine.

N6-Benzoyladenine-cyanoborane (2), and 6-triphenylphosphonylpurine-cyanoborane (3) were selected for investigation of cytotoxicity in murine and human tumor cell lines, effects on human HL-60 leukemic metabolism and DNA strand scission to determine the feasibility of these compounds as clinical antineoplastic agents. Compounds 2 and 3 both showed effective cytotoxicity based on ED(50) values less than 4 mug/ml for L1210, P388, HL-60, Tmolt(3), HUT-78, HeLa-S(3) uterine, ileum HCT-8, and liver Hepe-2. Compound 2 had activity against ovary 1-A9, while compound 3 was only active against prostate PL and glioma UM. Neither compound was active against the growth of lung 549, breast MCF-7, osteosarcoma HSO, melanoma SK2, KB nasopharynx, and THP-1 acute monocytic leukemia. In mode of action studies in human leukemia HL-60 cells, both compounds demonstrated inhibition of DNA and protein syntheses after 60 min at 100 muM. These compounds inhibited RNA synthesis to a lesser extent. The utilization of the DNA template was suppressed by the compounds as determined by inhibition of the activities of DNA polymerase alpha, m-RNA polymerase, r-RNA polymerase and t-RNA polymerase, which would cause adequate inhibition of the synthesis of both DNA and RNA. Both compounds markedly inhibited dihydrofolate reductase activity, especially in compound 2. The compounds appeared to have caused cross-linking of the DNA strands after 24 hr at 100 muM in HL-60 cells, which was consistent with the observed increased in ct-DNA viscosity after 24 hr at 100 muM. The compounds had no inhibitory effects on DNA topoisomerase I and II activities or DNA-protein linked breaks. Neither compound interacted with the DNA molecule itself through alkylation of the nucleotide bases nor caused DNA interculation between base pairs. Overall, these antineoplastic agents caused reduction of DNA and protein replication, which would lead to killing of cancer cells.