David Sauer

Office-Based Unsedated Small-Caliber Endoscopy Is Equivalent to Conventional Sedated Endoscopy in Screening and Surveillance for Barrett's Esophagus: A Randomized and Blinded Comparison

OBJECTIVES:A major limitation to screening and surveillance of Barretts esophagus is the complexity, expense, and risk associated with sedation for upper endoscopy. This study examines the feasibility, accuracy, and patient acceptability of office-based unsedated endoscopy as an alternative.METHODS:Of 274 eligible adults scheduled for endoscopic screening for gastroesophageal reflux symptoms or surveillance of Barretts esophagus at a tertiary care center, 121 underwent unsedated small-caliber endoscopy and conventional endoscopy in a randomized crossover study. The two procedures were compared with regard to histological detection of Barretts esophagus and dysplasia and biopsy size. Patients answered questionnaires assessing the tolerability of the procedures.RESULTS:The prevalence of Barretts esophagus was 26% using conventional endoscopy and 30% using unsedated endoscopy (P = 0.503). The level of agreement between the two approaches was “moderate” (κ = 0.591). Each modality detected four cases of low-grade dysplasia with concordance on one case. The tissue samples collected with unsedated endoscopy were smaller than with conventional endoscopy (P < 0.001). The majority of subjects rated their experience with both procedures as being well tolerated with minimal or no difficulty. When asked which procedure they would prefer in the future, 71% (81/114) chose unsedated small-caliber endoscopy.CONCLUSIONS:Office-based unsedated small-caliber endoscopy is technically feasible, well tolerated, and accurate in screening for Barretts esophagus, despite yielding a smaller biopsy specimen. This approach bears the potential to eliminate the infrastructure and cost required for intravenous sedation in this application.

Relationship between clinical measures and histopathologic findings in chronic rhinosinusitis.

OBJECTIVE: Describe detailed histopathologic findings from a cohort of patients with chronic rhinosinusitis and evaluate whether histologic measures correlate with baseline clinical factors. STUDY DESIGN: Cross-sectional study with planned data collection. SETTING: Tertiary medical center. SUBJECTS AND METHODS: Adult patients with chronic rhinosinusitis were prospectively enrolled and demographic data and medical comorbidities recorded. Disease severity was measured by computed tomography (CT), endoscopy, Smell Identification Test (SIT), the Chronic Sinusitis Survey, Rhinosinusitis Disability Index, and SF-36 General Health Survey. Mucosal specimens were assessed for the presence of mucosal inflammation, including cellular (eosinophils, neutrophils, lymphocytes, mast cells, plasma cells, macrophages), epithelial (squamous metaplasia, basement membrane thickening, goblet cells), and stromal markers (subepithelial edema, fibrosis). Histopathologic findings were correlated to baseline clinical factors. RESULTS: A total of 147 subjects were enrolled with histologic samples available for review. Presence of inflammatory markers was diverse, with lymphocytes present in 100 percent of subjects, eosinophils in 49.7 percent, and neutrophils found in 0.7 percent. Total eosinophil counts correlated with the presence of nasal polyposis (r = −0.367; P < 0.001), asthma (r = 0.264; P = 0.001), and aspirin intolerance (r = 0.279; P = 0.001). Mucosal eosinophilia correlated with worse disease severity on CT (r = 0.414; P < 0.001), endoscopy (r = 0.376; P < 0.001), and SIT (r = −0.253; P = 0.002), with the highest correlations seen in subgroups without nasal polyps. Histopathologic findings did not significantly correlate with any quality-of-life measure. CONCLUSION: Mucosal eosinophilia correlates with objective disease severity as defined by CT, endoscopy, and SIT scores. Although other histologic markers of inflammation are present, none show similar correlations. The presence of mucosal eosinophils does not correlate with quality-of-life scores.

Impact of mucosal eosinophilia and nasal polyposis on quality-of-life outcomes after sinus surgery.

OBJECTIVE: Assess whether the presence of mucosal eosinophilia correlates with surgical outcomes in patients with chronic rhinosinusitis. STUDY DESIGN: Prospective cohort. SETTING: Tertiary medical center. SUBJECTS AND METHODS: Adult patients with chronic rhinosinusitis were prospectively enrolled, and demographic data and medical comorbidities were recorded. Preoperative quality of life (QOL) was measured by the Chronic Sinusitis Survey (CSS), Rhinosinusitis Disability Index (RSDI), and Short Form-36 General Health Survey (SF-36). Sinus mucosal specimens were collected at the time of surgery and the degree of eosinophilia quantified. Postoperative QOL was measured, and differences in QOL improvement were compared between those with and without eosinophilia. RESULTS: A total of 102 patients had both histopathological and QOL outcome data available for review. Follow-up averaged 16.5 months. Patients with eosinophilia showed significantly less improvement in the RSDI total (17.9 vs 25.0; P = 0.044), RSDI functional (5.7 vs 8.8; general health subscale; P = 0.018), CSS medication (3.6 vs 17.3; P = 0.013), SF-36 general health (0.6 vs 9.6; P = 0.008), SF-36 physical role (16.1 vs 34.7; P = 0.036), and SF-36 vitality (11.9 vs 21.2; P = 0.034) scales than those without eosinophilia. The greatest improvement in QOL was seen in patients without eosinophilia or polyps, with the least improvement seen in those with eosinophilia but without polyps. CONCLUSION: The presence of mucosal eosinophilia at the time of surgery consistently predicted less improvement in both disease-specific and general QOL compared with patients without eosinophilia. The impact of eosinophilia on outcomes was greatest for patients without nasal polyposis, a group that demonstrated the least improvement in QOL measures.

M3 muscarinic receptor antagonists inhibit small cell lung carcinoma growth and mitogen-activated protein kinase phosphorylation induced by acetylcholine secretion

The importance of acetylcholine as a neurotransmitter in the nervous system is well established, but little is yet known about its recently described role as an autocrine and paracrine hormone in a wide variety of nonneuronal cells. Consistent with the expression of acetylcholine in normal lung, small cell lung carcinoma (SCLC) synthesize and secrete acetylcholine, which acts as an autocrine growth factor through both nicotinic and muscarinic cholinergic mechanisms. The purpose of this study was to determine if interruption of autocrine muscarinic cholinergic signaling has potential to inhibit SCLC growth. Muscarinic receptor (mAChR) agonists caused concentration-dependent increases in intracellular calcium and mitogen-activated protein kinase (MAPK) and Akt phosphorylation in SCLC cell lines. The inhibitory potency of mAChR subtype-selective antagonists and small interfering RNAs (siRNAs) on acetylcholine-increased intracellular calcium and MAPK and Akt phosphorylation was consistent with mediation by M3 mAChR (M3R). Consistent with autocrine acetylcholine secretion stimulating MAPK and Akt phosphorylation, M3R antagonists and M3R siRNAs alone also caused a decrease in basal levels of MAPK and Akt phosphorylation in SCLC cell lines. Treatment of SCLC cells with M3R antagonists inhibited cell growth both in vitro and in vivo and also decreased MAPK phosphorylation in tumors in nude mice in vivo. Immunohistochemical staining of SCLC and additional cancer types showed frequent coexpression of acetylcholine and M3R. These findings suggest that M3R antagonists may be useful adjuvants for treatment of SCLC and, potentially, other cancers.

Central nodal metastases in papillary thyroid carcinoma based on tumor histologic type and focality.

OBJECTIVE To determine the risk of nodal metastases to the central compartment from differentiated papillary thyroid carcinoma (PTC) relative to known prognostic variables. DESIGN A 7-year single-institutional retrospective review. SETTING Tertiary academic center. PATIENTS A total of 115 patients undergoing central neck dissection (CND) for PTC or follicular variant PTC (FVPTC). MAIN OUTCOME MEASURE Number, location, and positivity of lymph nodes for malignant disease in the central compartment based on patient age, sex, extrathyroidal extension, and primary tumor size, histologic type, and focality. RESULTS Eighty-seven percent of patients had PTC, and 13% had FVPTC. Bilateral (64%) or ipsilateral (36%) CND was performed in patients with PTC. Patients with FVPTC underwent only ipsilateral CND. There was no significant difference in the number of lymph nodes retrieved based on patient age or sex, histologic type of the primary tumor, size or focality, or surgeon or pathologist. Seventy-eight percent of patients with PTC had malignant lymph nodes in the ipsilateral (75%) or bilateral/contralateral (69%) central compartment. Ipsilateral nodal metastases directly correlated with tumor multifocality (r = 0.93; P = .001) and size (r = 0.89; P = .001). Bilateral nodal metastases directly correlated with tumor multifocality (r = 0.92; P = .001) but was independent of size (r = 0.56; P = .001). No malignant lymph nodes were identified in the central compartment of FVPTC. CONCLUSIONS Malignant central nodal metastases occur with high frequency in PTC but not in FVPTC. The risk of metastases correlated with the size and multifocality of the primary tumor. Additional studies are warranted to determine the extent of CND in patients with and without known multifocal disease and to determine the role of CND in patients with FVPTC.

Ethmoid histopathology does not predict olfactory outcomes after endoscopic sinus surgery.

Background Histological inflammation correlates with the degree of baseline olfactory dysfunction in patients with chronic rhinosinusitis (CRS); however, factors associated with improvement in olfactory status after endoscopic sinus surgery (ESS) remain elusive. Our purpose was to compare histopathological findings in CRS patients with olfactory loss and evaluate whether inflammatory markers can predict long-term olfactory improvement after ESS. Methods Adult (≥18 years) patients with CRS were prospectively enrolled after electing ESS due to failed medical management. Mucosal tissue specimens were collected at the time of surgery and underwent pathological review in a blinded fashion. Subjects completed the 40-item Smell Identification Test (SIT) preoperatively and at least 6 months postoperatively. Multivariate logistic regression was used to identify histological factors associated with postoperative improvement in SIT score. Results The final cohort was comprised of 101 patients with a mean follow-up of 16.7 ± 6.0 months. Mean mucosal eosinophil count was higher in patients with hyposmia and anosmia (p < 0.001). Patients with preoperative anosmia were more likely to have greater severity of basement membrane (BM) thickening compared with subjects with hyposmia or normosmia (p = 0.021). In patients with olfactory dysfunction, 54.7% reported olfactory improvement of at least 4 points on postoperative SIT scores. After controlling for nasal polyposis, histological variables were not associated with postoperative improvement in olfaction. Conclusion Patients with severe olfactory dysfunction were more likely to have mucosal eosinophilia and BM thickening on ethmoid histopathological examination compared with normosmic patients. The presence of specific histological inflammatory findings did not, however, predict olfactory improvement after surgery.

Expanded criteria for carcinoid liver debulking: Maintaining survival and increasing the number of eligible patients

BACKGROUND Cytoreduction of carcinoid liver metastases typically aims for ≥ 90% debulking in patients without extrahepatic disease. Data on the impact of less-restrictive resection criteria and other clinical and tumor-specific factors on outcomes are limited. METHODS Records of carcinoid patients undergoing liver debulking from 2007 to 2011 were reviewed. Debulking threshold was 70%, extrahepatic disease did not preclude cytoreduction, and positive margins were allowed. Kaplan-Meier liver progression-free (PFS) and disease-specific (DSS) survival were calculated and compared by log-rank analysis and statistical significance of differences in distributions of factors between patient groups was determined by chi-squared analysis. RESULTS Fifty-two patients were identified. Complete resection of intrahepatic and extrahepatic gross disease was achieved in 12 patients. All primaries reviewed were low grade, but one third of patients had at least one intermediate-grade metastasis. Fifteen patients (29%) had liver progression; median PFS was 72 months. Five-year DSS was 90%, with all deaths from liver failure. Only age was an important prognostic factor for PFS and DSS. Five-year DSS for patients <50 years was 73% and was 97% for patients 50 or older (P = .03). CONCLUSION The use of expanded criteria for debulking resulted in 90% 5-year DSS. Although younger age portends a poorer prognosis, the favorable PFS and DSS justify also using expanded criteria in this subgroup.

Effect of Calcitriol on Prostate-Specific Antigen In vitro and in Humans

Background: Calcitriol, the natural ligand for the vitamin D receptor, has significant potential in prostate cancer treatment. Measurement of its antineoplastic activity in prostate cancer clinical trials may be complicated by effects of calcitriol on prostate-specific antigen (PSA) production. We examined the effects of calcitriol at similar concentration on cell proliferation, androgen receptor (AR) expression, and PSA production in vitro and on PSA concentrations in prostate cancer patients. Experimental Design: LNCaP prostate cancer cell proliferation was examined by cell counts 6 days after exposure to a range of concentrations of calcitriol. AR and PSA protein was quantified in LNCaP cells over 96 hours after exposure to 1 nmol/L calcitriol. Serum PSA and free PSA was serially measured by immunoassay over a period of 8 days in patients with hormone-naïve prostate cancer after a single dose of 0.5 μg/kg calcitriol. Results: Calcitriol treatment resulted in dose-dependent growth inhibition of LNCaP with ∼50% growth inhibition at the clinically achievable concentration of 1 nmol/L. Time-dependent up-regulation of AR expression and of PSA production in LNCaP cells was shown at the same concentration. No significant change in serum PSA or free PSA over 8 days was seen in eight subjects treated with a single dose of 0.5 μg/kg calcitriol. The analysis was powered to detect a 1.23-fold change between the baseline and day 8 serum PSA. Conclusions: At clinically achievable concentrations, calcitriol inhibits growth and induces AR and PSA expression in LNCaP cells. We did not detect similar changes in serum PSA or free PSA in patients exposed to similar concentrations of calcitriol. Thus, a PSA flare, predicted by preclinical systems, is unlikely to occur in patients and therefore unlikely to complicate interpretation of clinical trial outcomes.

Moderate hypoxia suppresses exercise-induced procoagulant changes

Hypoxia has been implicated as a stimulant of coagulation. As exertion is known to affect haemostasis, we sought to control for this by using a standardized protocol. Subjects were exercised both at room air and at 12% oxygen. Exercise produced an increase in procoagulant factors, which was reduced with hypoxic exercise. Room air exercise increased fibrinolytic markers. Hypoxic exercise did not affect the increase in tissue plasminogen activator, but decreased the increase in plasminogen activator inhibitor‐1 expression. Thus, it appears that hypoxia may exert an antithrombotic effect by both damping exercise‐induced procoagulant changes and stimulating fibrinolysis.

Overlapping Morphologic and Immunohistochemical Features of Hashimoto Thyroiditis and IgG4-Related Thyroid Disease

Immunoglobulin G4-related disease (IgG4-RD) is an emerging clinicopathologic entity characterized by both IgG4+ plasma cell infiltration and fibrosis in one or more organs, prototypically pancreas or salivary/lacrimal glands. IgG4-RD in the thyroid (IgG4-RTD) is an area of active study, and the relationship between IgG4-RTD and Hashimoto thyroiditis is not fully delineated due to their overlapping histologic features. Retrospective review was performed of all thyroidectomy cases demonstrating lymphocytic inflammation at a single institution over a 4-year period. Approximately half (23/38) of patients had a clinical diagnosis of Hashimoto thyroiditis (HT). Nine of the 38 patients had increased absolute and relative numbers of IgG4+ plasma cells. Patients with a clinical diagnosis of HT had increased lymphoplasmacytic inflammation, but the relative proportion of IgG4+ plasma cells was not increased compared to patients without HT. There was no correlation between IgG4 levels and the amount of fibrosis in patients with or without HT. Patients identified as having the fibrosing variant of HT were not more likely to have increased levels of IgG4+ plasma cells than those without. There is significant morphologic and immunohistochemical overlap between HT and IgG4-RTD. Future studies to identify specific characteristics of IgG4-RTD involving the thyroid are necessary to accurately define this entity.