Staining for p53 and Ki-67 increases the sensitivity of EUS-FNA to detect pancreatic malignancy

AIM: To investigate whether tumor marker staining can improve the sensitivity of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) to diagnose pancreatic malignancy.METHODS: Patients who underwent EUS-FNA were retrospectively identified. Each EUS-FNA specimen was evaluated by routine cytology and stained for tumor markers p53, Ki-67, carcinoembryonic antigen (CEA) and CA19-9. Sensitivity, specificity, positive and negative predictive values (PPV and NPV), and positive and negative likelihood ratios (PLR and NLR) were calculated in order to evaluate the performance of each test to detect malignancy.RESULTS: Sixty-one specimens had complete sets of stains, yielding 49 and 12 specimens from pancreatic adenocarcinomas and benign pancreatic lesions due to pancreatitis, respectively. Cytology alone had sensitivity and specificity of 41% and 100% to detect malignancy, respectively. In 46% of the specimens, routine cytology alone was deemed indeterminate. The addition of either p53 or Ki-67 increased the sensitivity to 51% and 53%, respectively, with perfect specificity, PPV and PLR (100%, 100% and infinite). Both stains in combination increased the sensitivity to 57%. While additional staining with CEA and CA19-9 further increased the sensitivity to 86%, the specificity, PPV and PLR were significantly reduced (at minimum 42%, 84% and 1, respectively). Markers in all combinations performed poorly as a negative test (NPV 26% to 47%, and NLR 0.27 and 0.70).CONCLUSION: Immunohistochemical staining for p53 and Ki-67 can improve the sensitivity of EUS-FNA to diagnose pancreatic adenocarcinoma.     

Prior SARS-CoV-2 infection and COVID-19 vaccine effectiveness against outpatient illness during widespread circulation of SARS-CoV-2 Omicron variant,US Flu VE network

Background

We estimated combined protection conferred by prior SARS-CoV-2 infection and COVID-19 vaccination against COVID-19-associated acute respiratory illness (ARI).

Methods

During SARS-CoV-2 Delta (B.1.617.2) and Omicron (B.1.1.529) variant circulation between October 2021 and April 2022, prospectively enrolled adult patients with outpatient ARI had respiratory and filter paper blood specimens collected for SARS-CoV-2 molecular testing and serology. Dried blood spots were tested for immunoglobulin-G antibodies against SARS-CoV-2 nucleocapsid (NP) and spike protein receptor binding domain antigen using a validated multiplex bead assay. Evidence of prior SARS-CoV-2 infection also included documented or self-reported laboratory-confirmed COVID-19. We used documented COVID-19 vaccination status to estimate vaccine effectiveness (VE) by multivariable logistic regression by prior infection status.

Results

Four hundred fifty-five (29%) of 1577 participants tested positive for SARS-CoV-2 infection at enrollment; 209 (46%) case-patients and 637 (57%) test-negative patients were NP seropositive, had documented previous laboratory-confirmed COVID-19, or self-reported prior infection. Among previously uninfected patients, three-dose VE was 97% (95% confidence interval [CI], 60%–99%) against Delta, but not statistically significant against Omicron. Among previously infected patients, three-dose VE was 57% (CI, 20%–76%) against Omicron; VE against Delta could not be estimated.

Conclusions

Three mRNA COVID-19 vaccine doses provided additional protection against SARS-CoV-2 Omicron variant-associated illness among previously infected participants.     

Mice harboring a defective epidermal growth factor receptor (waved-2) have an increased susceptibility to acute dextran sulfate-induced colitis

BACKGROUND: It has been reported that epithelial growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) play an important role in colonic mucosal defense and repair. Waved-2 (wa-2) mice harboring a defect EGF-R and phenotypically similar to TGF-alpha knockout mice provide a novel approach to study the role of EGF-R ligands in the maintenance and repair of colonic mucosa. METHODS: Acute colonic mucosal injury was induced by oral administration of dextran sodium sulfate (DSS: 5 g%) given for 6 days ad libitum to wa-2 homozygotes and their genetic controls (n = 10, each group), as well as to wa-2 mice with and without exogenous EGF administration. Severity of colonic injury was assessed histologically of the entire colon and graded. A crypt damage score (CDS) reflecting all three grades of mucosal pathology was calculated. Decrease in total body weight, colon length and colonic blood content was determined for all groups. RESULTS: Thirty-eight percent of the entire colonic mucosa was destroyed in wa-2 animals compared to 15% in control mice. The CDS was 16.0 +/- 1.4 and 9.6 +/- 0.8 in wa-2 and control mice, respectively. EGF application to wa-2 mice did not reduce the severity of mucosal injury (CDS: 18.9 +/- 1.7 and 19.4 +/- 2.1 in EGF and vehicle injected mice, respectively). CONCLUSIONS: The increased susceptibility of wa-2 mice to DSS demonstrates the pivotal role of EGF-R ligands such as EGF and TGF-alpha in preserving the integrity of the colonic mucosa against mucosal injury. The missing beneficial effect of exogenous EGF administration in these mice further underlines the importance of an intact ligand/EGF-R pathway.     

Protective role of neurotrophins in experimental inflammation of the rat gut

BACKGROUND & AIMS: Sensory neuropeptides modulate the mucosal response to inflammation in experimental colitis. Because nerve growth factor (NGF) regulates the expression of neuropeptides such as substance P and calcitonin gene-related peptide (CGRP) and is implicated as a link between the nervous system and the immune system in the inflammatory process, we investigated the functional role of NGF and neurotrophin-3 during experimental colitis. METHODS: Immunoneutralizing antibodies specific for NGF and neurotrophin (NT)-3 were used to block their endogenous activity. Mild trinitrobenzene sulfonic acid (TNBS) colitis was induced, and damage scores were assessed after 1 week. Neuropeptide content in the colon and NT messenger RNA (mRNA) expression were determined. RESULTS: The pretreatment with anti-NGF or anti-NT-3 caused a significant 2-3-fold increase in the severity of the experimental inflammation as assessed by a macroscopic damage score, histologic ulceration score, and myeloperoxidase activity in the tissue. CGRP, but not substance P, contents in the colon were significantly reduced by NGF immunoneutralization. NGF mRNA was slightly up-regulated after NGF immunoneutralization, but NT-3 mRNA was unchanged by NT-3 immunoneutralization. CGRP mRNA was not significantly changed after 1 week of colitis by NGF or NT-3 immunoneutralization, whereas beta-preprotachykinin mRNA was up-regulated after immunoneutralization. CONCLUSIONS: These findings suggest a regulatory role for NGF and NT-3 in experimental inflammation of the gut. This effect may be partly caused by the reduction of mucosal CGRP content caused by the NGF blockade.     

Palliation of patients with dysphagia due to advanced esophageal cancer by endoscopic injection of cisplatin/epinephrine injectable gel

BACKGROUND: The aim of therapy for advanced esophageal cancer is relief of dysphagia with minimal treatment-related morbidity. This study assessed the efficacy of endoscopic intratumoral injection of cisplatin/epinephrine gel to relieve obstruction and improve swallowing. The gel is designed to minimize diffusion of active drug away from the tumor injection site. METHODS: Patients with inoperable esophageal cancer and dysphagia caused by exophytic esophageal tumor underwent up to 6 weekly endoscopic injections of the gel. Response was documented objectively (exophytic tumor volume, lumen size, dysphagia grade) and subjectively (achievement of treatment goal). RESULTS: Twenty-four patients were treated. Primary evaluation criteria for 18 evaluable patients were as follows: dysphagia grade improved in 4 (duration 30 to 45 days) and stabilized in 11; lumen patency improved in 6 (duration 29 to 56 days) and stabilized in 10; exophytic tumor volume decreased in 8 (duration 29 to 114 days). Eight patients felt that their ability to swallow improved. One patient with intramural and exophytic tumor developed a tracheoesophageal fistula, possibly related to treatment. Other complications were tolerable and self-limited. No nephrotoxicty or severe nausea/vomiting typical of systemic administration of cisplatin occurred. CONCLUSIONS: Endoscopic injection of cisplatin/epinephrine gel is a straightforward procedure with standard equipment and techniques, which can provide palliation for patients with exophytic malignant tumors of the esophagus. Assessment of this method in conjunction with other therapeutic options such as brachytherapy is warranted.     

Evaluation of fully covered self-expanding metal stents in benign biliary strictures and bile leaks

AIM: To investigate the use of fully covered metal stents in benign biliary strictures (BBS) and bile leaks.METHODS: We studied 17 patients, at Harbor-UCLA Medical center (Los Angeles), with BBS (n = 12) and bile leaks (n = 5) from July 2007 to February 2012 that had received placement of fully covered self-expanding metal stents (FCSEMs). Fourteen patients had endoscopic placement of VIABIL^® (Conmed, Utica, New York, United States) stents and three had Wallflex^® (Boston Scientific, Mass) stents. FCSEMS were 8 mm or 10 mm in diameter and 4 cm to 10 cm in length. Patients were followed at regular intervals to evaluate for symptoms and liver function tests. FCSEMS were removed after 4 or more weeks. Resolution of BBS and leak was documented cholangiographically following stent removal. Stent patency can be defined as adequate bile and contrast flow from the stent and into the ampulla during endoscopic retrograde cholangiopancreatography (ERCP) without clinical signs and/or symptoms of biliary obstruction. Criterion for bile leak resolution at ERCP is defined as absence of contrast extravasation from the common bile duct, cystic duct remanent, or gall bladder fossa. Rate of complications such as migration, and in-stent occlusion were recorded. Failure of endoscopic therapy was defined as persistent biliary stenosis or continuous biliary leakage after 12 mo of stent placement.RESULTS: All 17 patients underwent successful FCSEMS placement and removal. Etiologies of BBS included: cholecystectomies (n = 8), cholelithiasis (n = 2), hepatic artery compression (n = 1), pancreatitis (n = 2), and Whipple procedure (n = 1). All bile leaks occurred following cholecystectomy. The anatomic location of BBS varied: distal common bile duct (n = 7), common hepatic duct (n = 1), hepaticojejunal anastomosis (n = 2), right intrahepatic duct (n = 1), and choledochoduodenal anastomatic junction (n = 1). All bile leaks were found to be at the cystic duct. Twelve of 17 patients had failed prior stent placement or exchange. Resolution of the biliary strictures and bile leaks was achieved in 16 of 17 patients (94%). The overall median stent time was 63 d (range 27-251 d). The median stent time for the BBS group and bile leak group was 62 ± 58 d (range 27-199 d) and 92 ± 81 d (range 48-251 d), respectively. All 17 patients underwent successful FCSEMS removal. Long term follow-up was obtained for a median of 575 d (range 28-1435 d). Complications occurred in 5 of 17 patients (29%) and included: migration (n = 2), stent clogging (n = 1), cholangitis (n = 1), and sepsis with hepatic abscess (n = 1).CONCLUSION: Placement of fully covered self-expanding metal stents may be used in the management of benign biliary strictures and bile leaks with a low rate of complications.     

Action of ethanol and some alcoholic beverages on gastric acid secretion and release of gastrin in humans

The action of intragastric ethanol in various concentrations (1.4%-40% vol/vol) and of beer, white wine, cognac, and whisky on gastric acid secretion and release of gastrin was studied in healthy humans. Ethanol concentrations of 1.4% and 4% (vol/vol), but not higher, significantly (p less than 0.05) increased gastric acid secretion to 23% and 22%, respectively, of incremental maximal acid output [i.e., observed response to pentagastrin (6 micrograms/kg s.c.) minus basal acid output]. The 1-h incremental gastric acid responses to beer and wine were 96% and 61%, respectively, of incremental maximal acid output. Neither cognac nor whisky had any stimulatory effect. The 1-h incremental gastric acid response to an 8% peptone meal was 40% of incremental maximal acid output, and to peptone plus white wine 77%. Plasma gastrin levels were not altered by ethanol, cognac, and whisky. The 1-h integrated plasma gastrin responses to beer and white wine were 119% and 77%, respectively, of the response to the peptone meal. We conclude that (a) the action of pure ethanol on gastric acid secretion is related to its concentration: concentrations of 1.4% and 4% are moderate stimulants; concentrations of 5%-40% have no effect, or rather an inhibitory effect; (b) beer and white wine, but not whisky and cognac, are potent stimulants of gastric acid secretion; (c) the stimulatory mechanism of low ethanol concentrations is unknown; and (d) nonalcoholic constituents of beer and wine are most likely responsible for the stimulatory actions of both beverages on gastric acid secretion and release of gastrin.     

Increased Expression of Epidermal Growth Factor-receptor in an Experimental Model of Colitis in Rats

Corrao G, Aricò S, Zambon A, Torchio P, di Orio F, Collaborative Groups for the Study of Liver Diseases in Italy. Female sex and the risk of liver cirrhosis. Scand J Gastroenterol 1997 32:1174–1180.

Background: Evidence on gender-related differences in susceptibility to alcohol-induced liver diseases is questionable with regard to both methodologic and clinical aspects. With the aim to assess the role of gender in the risk of liver cirrhosis, independently and in combination with known risk factors, data from three case-control studies performed in various Italian areas were analysed. Methods: The cases were 462 cirrhotic patients (300 men and 162 women) admitted for the first time to hospital for liver decompensation. Controls were 651 patients (355 men and 296 women) admitted to the same hospitals during the same period as the cases, for acute diseases unrelated to alcohol. Alcohol consumption was expressed as lifetime daily alcohol intake. Results: A significant and independent associations between alcohol intake, chronic hepatitis B and C virus infections, and the risk of liver cirrhosis was observed. The effect of alcohol intake was multiplicatively increased in women. The odds ratio (OR) increased from 1.0 (reference category: men, lifetime abstainers) to 31.4 (95% confidence interval (CI), 10.3–95.8) in men drinking more than 100 g/day of alcohol, and from 2.2 (95% CI, 1.0–7.1) in abstaining women to 44.8 (95% CI, 8.2–224.0) in women drinking more than 100 g/day of alcohol. An increased risk of liver cirrhosis associated with female gender independently of alcohol consumption and virus infection was also observed. Conclusions: A higher susceptibility to alcohol-induced liver diseases was confirmed for women, and an independent effect of female sex on the risk of cirrhosis was observed. Besides alcohol and viruses, some unknown gender-related factor might then be involved in the occurrence of the disease.