Harms reporting by systematic reviews for functional endoscopic sinus surgery: a cross-sectional analysis.

OBJECTIVES: To evaluate the completeness of harms reporting in systematic reviews (SRs) pertaining to functional endoscopic sinus surgery (FESS). METHODS: Using a cross-sectional study design, we performed a comprehensive search using MEDLINE (PubMed and Ovid), EMBASE, Epistemonikos, and the Cochrane Database of Systematic Reviews databases for SRs regarding FESS on May 15th, 2022. Returns were screened and data were extracted in a masked, duplicate manner. Following established methodology, we extracted general study characteristics, harms items, and overall methodological quality for each SR in our sample. Corrected covered area (CCA) was calculated for SR dyads. For data analysis, using Stata 16.1 we performed a bivariate analysis between variables. RESULTS: Fifty-five SR's were included in our sample after excluding 375 studies that did not meet our inclusion criteria. Of the included SRs, 19 (19/55, 34.5%) did not report harms and 39 (39/55, 70.9%) reported half of the harms items or fewer. Our study found that 23 (23/55, 41.8%) of SRs demonstrated a method of harms data collection, 26 (26/55, 47.3%) of SRs had patients available for harms analysis in their results, and 25 (25/55, 45.5%) of SRs had a balanced discussion of harms and benefits of FESS. Fifty-two SRs were appraised as "critically low" quality using AMSTAR-2. A significant association was found between completeness of harms reporting (Mahady) and whether harms were listed as a primary outcome. No other associations were statistically significant. Two SR dyads had CCAs between 20% and 50% overlap and were compared for unique and shared harms. CONCLUSIONS: Our study demonstrates gaps in harms reporting regarding FESS in SRs. We recommend future studies implement guidelines such as the STROCCS guidelines or the harms extension of the PRISMA guidelines to improve harms reporting. Accurate harms reporting may advance patient safety and promote a more objective risk-benefit analysis for physicians and patients.

The impact of COVID-19 on otolaryngology research: a cross-sectional analysis of discontinued trials.

CONTEXT: The COVID-19 pandemic has reduced the capacity to conduct medical research due to recruitment difficulties, supply chain shortages, and funding deficits. The clinical practice of otolaryngology was especially impacted due to a reduction in elective procedures, such as facial plastic surgeries and vocal fold injections. OBJECTIVES: The primary objective was to examine the extent of clinical trial (CTs) disruption secondary to the COVID-19 pandemic in the field of otolaryngology. METHODS: On August 1, 2021, we conducted a systematic search utilizing ClinicalTrials.gov for CTs related to common otolaryngology disorders. We utilized the date range January 1, 2020 through August 1, 2021 to identify all trials potentially affected by the COVID-19 pandemic. Investigators performed screening and data extraction in a duplicate, masked fashion. Trials resulting from the search were extracted for trial status, condition treated, enrollment number, funding, study type, study design, last update posted date, and trial location. Trials that explicitly mentioned COVID-19 as a reason for discontinuation or suspension were coded as such. For trials that did not explicitly mention COVID-19, we coded the reason provided from ClinicalTrials.gov. The Oklahoma State University Center for Health Science Institutional Review Board determined that this project did not qualify as human subject research. RESULTS: A total of 1,777 CTs met the inclusion criteria, and 223 CTs were discontinued between January 1, 2020 and August 1, 2021. Thirty-three (14.8%) of the 223 CTs reported discontinuation explicitly due to the COVID-19 pandemic. The 33 studies had 1,715 participants enrolled in total. Among the primary interventions, 11 (33.3%) were devices, 10 (30.3%) were drugs, 5 (15.2%) were behavioral, 4 (12.1%) were diagnostic tests, 1 (3.0%) was dietary, and 2 (6.1%) were labeled as "other." Regarding the CT location, 20 (60.6%) were conducted in the United States, and 13 (39.4%) were conducted internationally. Of the 33 CTs, 19 (57.6%) were suspended, 9 (27.3%) were terminated, and 5 (15.2%) were withdrawn. The overall most common reason for trial disruption was recruitment difficulties (24.2%). Median enrollment for discontinued trials due to COVID-19 was 37 (interquartile range [IQR], 19-71) and for other reasons was 6 (IQR, 0-27), for which the Mann-Whitney test showed a statistically significant difference between the two (z=-3.913, p<0.001). There were no significant associations between trial location, funding source, randomization, or whether a study involved masked vs unmasked participants. CONCLUSIONS: The COVID-19 pandemic has incited an impact on clinical research in the field of otolaryngology. To preserve trial continuation amid future threats to participant interaction and communication, we recommend further exploration of remote monitoring practices and virtual procedures-those that will maintain the effectiveness and accuracy needed to establish novel therapeutics. We encourage future trials to gauge which remote assessments show the greatest validity, with the long-term goal of establishing innovative study designs resilient to future pandemics.

The Use of Person-centered Language in Medical Research Articles Focusing on Hearing Loss or Deafness.

BACKGROUND: Hearing loss represents one of the most common disabilities worldwide. Despite its prevalence, there is a degree of stigmatization within the public's perception of, or attitude toward, individuals diagnosed with hearing loss or deafness. This stigmatization is propagated by the way hearing loss is referenced, especially in writing. Although the medical community is familiar with hearing loss, medical research is not consistently compliant with nonstigmatizing terminology, like person-centered language (PCL). This study aims to quantify the use of PCL in medical research related to hearing loss. METHODS: A cross-sectional analysis of articles related to hearing loss was performed using PubMed as the primary search engine. The search encompassed articles from January 1, 2016, to November 17, 2020. Journals had to have at least 20 search returns to be included in this study. The primary search resulted in 2392 articles from 31 journals. The sample was then randomized and the first 500 articles were chosen for data extraction. Article screening was performed systematically. Each article was evaluated for predetermined non-PCL terminology to determine adherence to the American Medical Association Manual of Style (AMAMS) guidelines. Articles were included if they involved research with human participants and were available in English. Commentaries and editorials were excluded. RESULTS: Four hundred eighty-two articles were included in this study. Results from this study indicate that 326 articles were not adherent to AMAMS guidelines for PCL (326/482; 68%). Emotional language (i.e., burden, suffer, afflicted) was employed to reference hearing loss in 114 articles (114/482; 24%). Non-PCL adherent labels (i.e., impaired and handicapped) were identified in 46% (221/482) of articles related to hearing loss or deafness. Sixty-seven articles (67/482; 14%) used person-first language in reference to the word "deaf" and 15 articles (15/482; 3%) used "deaf" as a label. CONCLUSIONS: Based on the findings from this cross-sectional analysis, the majority of medical research articles that address hearing loss contain terminology that does not conform to PCL guidelines, as established by AMAMS. Many respected organizations, like the American Medical Association, have encouraged the use of PCL in interactions between patient and medical provider. This encompasses communication in person and in writing. This recommendation stems from the understood role that language plays in how we build impressions of others, especially in a medical context. Implementing PCL to destigmatize language used in reference to deafness or hearing loss is essential to increase advocacy and protect the autonomy of these individuals.

Evaluation of Spin in the Abstracts of Systematic Reviews and Meta-Analyses Focused on Tinnitus.

HYPOTHESIS: The objective was to investigate the prevalence of spin in abstracts of systematic reviews and meta-analyses covering the treatment of tinnitus. We hypothesized that spin would be present in these articles and a significant relationship would exist between spin usage and extracted study characteristics. BACKGROUND: Spin, the misrepresentation of study findings, can alter a clinician's interpretation of a study's results, potentially affecting patient care. Previous work demonstrates that spin is present in abstracts of randomized clinical trials. METHODS: Using a cross-sectional analysis, we conducted a systematic search using MEDLINE and Embase databases on June 2, 2020, for systematic reviews focused on tinnitus treatment. Investigators performed screening and data extraction in a masked, duplicate fashion. RESULTS: Forty systematic reviews met inclusion criteria, and spin was identified in four of them. Spin in abstracts most frequently occurred when conclusions claimed the beneficial effect of the experimental treatment despite high risk of bias in primary studies (n = 3). The other form of spin found was the conclusion claims safety based on nonstatistically significant results with a wide confidence interval (n = 1). There was no significant association between spin and any of our extracted study characteristics. CONCLUSION: Spin was observed in 10% of abstracts of systematic reviews and meta-analyses covering the treatment of tinnitus. Although this percentage may be small, we recommend that medical journals provide a more detailed framework for abstract structure and require the inclusion of risk of bias assessment results in abstracts to prevent the incorporation of spin.

Spin the Abstracts of Systematic Reviews and Meta-Analyses Regarding the Treatment of Ménière's Disease.

OBJECTIVES: To identify, quantify, and characterize the presence of spin-specific strategies leading to misrepresentation of study results-in the abstracts of systematic reviews and meta-analyses of Ménière's disease treatment. METHODS: Using a cross-sectional design, we searched MEDLINE and Embase on May 28, 2020, for systematic reviews and meta-analyses focused on Ménière's disease treatment. Returned searches were screened, and data were extracted in a masked, duplicate fashion. RESULTS: Our sample included 36 systematic reviews and meta-analyses. Of the 36 included studies, 22 (61.1%) abstracts contained spin while 14 (38.9%) did not. The most common spin types were selective reporting of benefit (10/36, 27.8%) or harm (8/36, 22.2%). Other types of spin occurred when findings were extrapolated to the global improvement of the disease (5/36, 13.9%), beneficial effects were reported with high risk of bias in primary studies (3/36, 8.3%), and when beneficial effects were extrapolated to an entire class of interventions (1/36, 2.8%). No instances of other spin types occurred. Abstracts containing spin were substantively associated with studies of critically low methodological quality compared with studies with low and moderate quality. No studies had a methodological rating of high quality. No associations were observed between spin and intervention types, journal recommendation of adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses, or funding. We found a negative correlation (r = -.31) between abstract word limit and presence of spin. CONCLUSIONS: Our study highlights that spin in the abstracts of systematic reviews of Ménière's disease is common, and it further enhances the discussion surrounding spin in abstracts of scientific research. Spin in an abstract does not discredit a study's findings; however, its occurrence should be eliminated.

Endemic North American Plants as Potentially Suitable Agents for Wound Cleaning Under Resource Scarce Conditions.

INTRODUCTION: Skin and subcutaneous infections are dangerous sequelae of soft tissue injuries, especially in austere situations where medical technology is not available. Numerous plant species endemic to North America have been described as having antibacterial properties. Of these, St. John's wort (Hypericum perforatum), chamomile (Matricaria chamomilla), and white oak (Quercus alba) were selected for testing against Staphylococcus aureus. Our objective was to assess the suitability of all 3 plants as potential antiseptic agents using methods easily replicated in a resource-scarce environment. METHODS: Water-soluble natural products were extracted from different concentrations of each plant part using either mechanical agitation at ambient temperature or boiling in unsterilized tap water. Antibacterial activity of each extract against S aureus was assessed using a conventional agar well diffusion bioassay. Zones of inhibition were measured using electronic calipers and were compared to tap water as the negative control. RESULTS: Aqueous extracts of St. John's wort and white oak bark displayed antibacterial effects against S aureus, with St. John's wort being more potent. Chamomile displayed no inhibitory properties at the concentrations examined. CONCLUSIONS: These data suggest that both St. John's wort and white oak are potential candidates for infection prophylaxis and therapy in austere wilderness scenarios, with St. John's wort being the more potent agent. White oak may be more logistically feasible because the larger surface area of a white oak tree allows for harvesting a larger quantity of bark compared to the smaller surface area of the St. John's wort plant.

The relationship between nicotine metabolism and nicotine and carcinogen exposure among American Indian commercial cigarette smokers and electronic nicotine delivery system users.

BACKGROUND: In American Indian (AI) tobacco users from the southern plains region of the US, we examined the relationship between nicotine and carcinogen exposure and nicotine metabolism. METHODS: Smokers (n = 27), electronic nicotine delivery system (ENDS) users (n = 21), and dual users (n = 25) of AI descent were recruited from a southern plains state. Urinary biomarkers of nicotine metabolism (nicotine metabolite ratio [NMR]), nicotine dose (total nicotine equivalents [TNE]), and a tobacco-specific lung carcinogen (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides [total NNAL] were measured. RESULTS: The geometric mean of NMR was 3.35 (95% Confidence Interval(CI): 2.42, 4.65), 4.67 (95% CI: 3.39, 6.43), and 3.26 (95% CI: 2.44, 4.37) among smokers, ENDS users, and dual users. Each of the three user groups had relatively low levels of TNE, indicative of light tobacco use. Among smokers, there were inverse relationships between NMR and TNE (r = -0.45) and between NMR and NNAL (r = -0.50). Among dual users, NMR and TNE, and NMR and NNAL were not associated. Among ENDS users, NMR and TNE were not associated. CONCLUSIONS: AI tobacco users with higher NMR did not have higher TNE or NNAL exposure than those with lower NMR. This supports prior work among light tobacco users who do not alter their tobacco consumption to account for nicotine metabolism. IMPACT: The high prevalences of smoking and ENDS among AI in the southern plains may not be related to nicotine metabolism. Environmental and social cues may play a more important role in light tobacco users and this may be particularly true among AI light tobacco users who have strong cultural ties.

An analysis of the literature addressing tonsillectomy knowledge gaps.

IMPORTANCE: The ability of clinical practice guidelines to improve patient outcomes depends on the quality of evidence that they are built upon. Research into tonsillectomy in children is lacking, and the gaps in evidence were identified by guideline authors. OBJECTIVE: The objective of this study is to evaluate the extent that new research is addressing the gaps identified in the AAO-HNS Tonsillectomy in Children Guideline. DESIGN: For each recommendation in the AAO-HNS guideline Tonsillectomy In Children, we created PICO (Participants, Intervention, Comparator, Outcome) questions and search strings. PubMed was searched to locate studies undertaken after the final literature search performed by the AAO-HNS work group. These studies were then extracted and analyzed. SETTING: This study is relevant to all invested in focusing otolaryngological research on questions which currently lack strong evidence. PARTICIPANTS: Trials in tonsillectomy that started after the development of the AAO-HNS clinical practice guidelines. MAIN OUTCOME MEASURES: The main outcome measures of this study is the extent to which tonsillectomy research is addressing the evidence gaps listed in the clinical practice guideline. RESULTS: Of the 2519 studies included in our sample, 276 (11%) were relevant to the 18 recommendations made within the Tonsillectomy in Pediatric Patients clinical practice guideline. All but one of the recommendations was met by at least one study. CONCLUSIONS: and Relevance: Our findings indicate that knowledge gaps within the guideline at publication may have since been addressed and a guideline update may thus be warranted. LEVEL OF EVIDENCE: NA.

Biomarkers of Exposure in ENDS Users, Smokers, and Dual Users of American Indian Descent.

Objectives: We measured biomarkers of exposure among American Indian (AI) ENDS users, smokers, and dual users. Methods: Urine was analyzed for total nicotine equivalents (TNE) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol(NNAL). Expired-air carbon monoxide (CO) was collected. Two analyses were performed. "CO analysis" included smokers and dual users whose CO was ≥ 6 ppm and ENDS users whose CO was < 6 ppm. "NNAL analysis" included smokers and dual users whose NNAL was ≥ 47.3 pg/mg, and ENDS users whose NNAL was < 47.3 pg/mg. Biomarkers were summarized by geometric means (GM) and compared with nonparametric tests. Results: In both analyses, TNE was no different across the groups, and NNAL and CO were lower in ENDS users. In the NNAL analysis the GM of NNAL was 261.4, 6.1, and 228.0 pg/mg among smokers, ENDS users, and dual users (p < .001). Also in the NNAL analysis, the GM of CO was 14.7, 2.4, and 16.8 ppm among smokers, ENDS users, and dual users (p < .001). Conclusions: ENDS users did not differ in nicotine and had lower exposure to a lung carcinogen and a cardiovascular toxicant than smokers or dual users. Dual users and smokers did not differ in biomarker levels. Results should be used to inform tribal regulations and to educate the AI community on ENDS.

Community-Based Study Recruitment of American Indian Cigarette Smokers and Electronic Cigarette Users.

Data on the effectiveness of strategies for the recruitment of American Indians (AIs) into research is needed. This study describes and compares methods for identifying and recruiting AI tobacco users into a pilot study. Community-based strategies were used to recruit smokers (n = 35), e-cigarette users (n = 28), and dual users (n = 32) of AI descent. Recruitment was considered proactive if study staff contacted the individual at a pow wow, health fair, or vape shop and participation on-site or reactive if the individual contacted the study staff and participation occurred later. Screened, eligible, participated and costs and time spent were compared with Chi square tests. To understand AI descent, the relationship between number of AI grandparents and AI blood quantum was examined. Number of participants screened via the proactive strategy was similar to the reactive strategy (n = 84 vs. n = 82; p-value = 0.8766). A significantly greater proportion of individuals screened via the proactive than the reactive strategy were eligible (77 vs. 50%; p-value = 0.0002) and participated (75 vs. 39%; p-value = < 0.0001). Per participant cost and time estimated for the proactive strategy was $89 and 87 min compared to $79 and 56 min for the reactive strategy. Proportion at least half AI blood quantum was 32, 33, and 70% among those with 2, 3, and 4 AI grandparents, respectively (p = 0.0017). Proactive strategies resulted in two-thirds of the sample, but required more resources than reactive strategies. Overall, we found both strategies were feasible and resulted in the ability to reach sample goals. Lastly, number of AI biological grandparents may be a good, non-invasive indicator of AI blood quantum.

Electronic cigarette aerosols suppress cellular antioxidant defenses and induce significant oxidative DNA damage.

BACKGROUND: Electronic cigarette (EC) aerosols contain unique compounds in addition to toxicants and carcinogens traditionally found in tobacco smoke. Studies are warranted to understand the public health risks of ECs. OBJECTIVE: The aim of this study was to determine the genotoxicity and the mechanisms induced by EC aerosol extracts on human oral and lung epithelial cells. METHODS: Cells were exposed to EC aerosol or mainstream smoke extracts and DNA damage was measured using the primer anchored DNA damage detection assay (q-PADDA) and 8-oxo-dG ELISA assay. Cell viability, reactive oxygen species (ROS) and total antioxidant capacity (TAC) were measured using standard methods. mRNA and protein expression were evaluated by RT-PCR and western blot, respectively. RESULTS: EC aerosol extracts induced DNA damage in a dose-dependent manner, but independently of nicotine concentration. Overall, EC aerosol extracts induced significantly less DNA damage than mainstream smoke extracts, as measured by q-PADDA. However, the levels of oxidative DNA damage, as indicated by the presence of 8-oxo-dG, a highly mutagenic DNA lesion, were similar or slightly higher after exposure to EC aerosol compared to mainstream smoke extracts. Mechanistically, while exposure to EC extracts significantly increased ROS, it decreased TAC as well as the expression of 8-oxoguanine DNA glycosylase (OGG1), an enzyme essential for the removal of oxidative DNA damage. CONCLUSIONS: Exposure to EC aerosol extracts suppressed the cellular antioxidant defenses and led to significant DNA damage. These findings emphasize the urgent need to investigate the potential long-term cancer risk of exposure to EC aerosol for vapers and the general public.

Oral Cavity and Oropharyngeal Cancer: Changing Trends in Incidence in the United States and Oklahoma.

Oral cavity cancer (OC) has steadily decreased in the United States (US) since 1973 whereas oropharyngeal cancer (OP) has increased. We analyzed OC and OP cases from the Oklahoma Central Cancer Registry and Surveillance, Epidemiology, and End Results program comparing those diagnosed from 1997-1999 to those diagnosed from 2010-2012. We compared the incidence of OC and OP cases between Oklahoma and the US and by demographic factors. We observed an increase in OP cases, but no change in OC cases in both the US and in Oklahoma, and observed some differences between Oklahoma and the US by race, gender, and age group. A possible explanation for the increasing incidence of OP cancers may be the increasing prevalence of HPV. This study highlighted the differences in temporal trends of OC and OP cancers and the importance of changing risk factors for these cancers.

Lifestyle behaviors among US cancer survivors.

PURPOSE: We describe and compare lifestyle behaviors, including smoking, physical activity, alcohol consumption, and nutrition, among cancer survivors to individuals with no cancer. METHODS: Data from the 2013 Behavior Risk Factor Surveillance System were used for this cross-sectional study. Weighted analysis was performed, and associations were examined by adjusted prevalence ratios (APRs) and 95 % confidence intervals (CIs). RESULTS: Comparing survivors to individuals with no cancer history, differences were found for a smoking quit attempt (APR 1.08; CI 1.04, 1.12), physical inactivity (APR 1.11; CI 1.07, 1.15), and binge drinking (APR 0.89; CI 0.83, 0.95). An interaction with gender was observed when examining smoking and heavy drinking. Smoking was lower (APR 0.85; CI 0.79, 0.92) among male survivors than males with no cancer history, while higher (APR 1.25; CI 1.18, 1.32) among female survivors compared to females with no cancer history. Heavy drinking (APR 0.85; CI 0.73, 0.98) was lower among male survivors than males with no cancer history, while cancer survivorship was not associated with heavy drinking among females. No differences existed for fruit and vegetable consumption or body mass index. CONCLUSIONS: US cancer survivors are not more likely than the general population to engage in all healthy lifestyle behaviors. Interventions, including improved physician communication, to reduce physical inactivity among all cancer survivors and cigarette smoking among female survivors are needed. IMPLICATIONS FOR CANCER SURVIVORS: Cancer survivors are at increased risk for comorbid conditions, and acceptance of healthy behaviors may reduce dysfunction and improve long-term health. Ultimately, opportunities exist for clinicians to promote lifestyle changes that may improve the length and quality of life of their patients.

Linking γ-aminobutyric acid A receptor to epidermal growth factor receptor pathways activation in human prostate cancer.

Neuroendocrine (NE) differentiation has been attributed to the progression of castration-resistant prostate cancer (CRPC). Growth factor pathways including the epidermal growth factor receptor (EGFR) signaling have been implicated in the development of NE features and progression to a castration-resistant phenotype. However, upstream molecules that regulate the growth factor pathway remain largely unknown. Using androgen-insensitive bone metastasis PC-3 cells and androgen-sensitive lymph node metastasis LNCaP cells derived from human prostate cancer (PCa) patients, we demonstrated that γ-aminobutyric acid A receptor (GABA(A)R) ligand (GABA) and agonist (isoguvacine) stimulate cell proliferation, enhance EGF family members expression, and activate EGFR and a downstream signaling molecule, Src, in both PC-3 and LNCaP cells. Inclusion of a GABA(A)R antagonist, picrotoxin, or an EGFR tyrosine kinase inhibitor, Gefitinib (ZD1839 or Iressa), blocked isoguvacine and GABA-stimulated cell growth, trans-phospohorylation of EGFR, and tyrosyl phosphorylation of Src in both PCa cell lines. Spatial distributions of GABAAR α1 and phosphorylated Src (Tyr416) were studied in human prostate tissues by immunohistochemistry. In contrast to extremely low or absence of GABA(A)R α1-positive immunoreactivity in normal prostate epithelium, elevated GABA(A)R α1 immunoreactivity was detected in prostate carcinomatous glands. Similarly, immunoreactivity of phospho-Src (Tyr416) was specifically localized and limited to the nucleoli of all invasive prostate carcinoma cells, but negative in normal tissues. Strong GABAAR α1 immunoreactivity was spatially adjacent to the neoplastic glands where strong phospho-Src (Tyr416)-positive immunoreactivity was demonstrated, but not in adjacent to normal glands. These results suggest that the GABA signaling is linked to the EGFR pathway and may work through autocrine or paracine mechanism to promote CRPC progression.

Expression of aldo-keto reductase family 1 member C3 (AKR1C3) in neuroendocrine tumors & adenocarcinomas of pancreas, gastrointestinal tract, and lung.

Human aldo-keto reductase family 1 member C3 (AKR1C3) was initially identified as an enzyme in reducing 5α-dihydrotestosterone (5α-DHT) to 5α-androstane-3α, 17ß-diol (3α-diol) and oxidizing 3α-diol to androsterone. It was subsequently demonstrated to possess ketosteroid reductase activity in metabolizing other steroids including estrogen and progesterone, 11-ketoprostaglandin reductase activity in metabolizing prostaglandins, and dihydrodiol dehydrogenase x (DDx) activity in metabolizing xenobiotics. AKR1C3 was demonstrated in sex hormone-dependent tissues including testis, breast, endometrium, and prostate; in sex hormone-independent tissues including kidney and urothelium. Our previous study described the expression of AKR1C3 in squamous cell carcinoma and adenocarcinoma but not in small cell carcinoma. In this report, we studied the expression of AKR1C3 in normal tissue, adenocarcinomas (43 cases) and neuroendocrine (NE) tumors (40 cases) arising from the aerodigestive tract and pancreas. We demonstrated wide expression of AKR1C3 in superficially located mucosal cells, but not in NE cells. AKR1C3-positive immunoreactivity was detected in 38 cases (88.4%) of adenocarcinoma, but only in 7 cases (17.5%) of NE tumors in all cases. All NE tumors arising from the pancreas and appendix and most tumors from the colon and lung were negative. The highest ratio of positive AKR1C3 in NE tumors was found in tumors arising from the small intestine (50%). These results raise the question of AKR1C3's role in the biology of normal mucosal epithelia and tumors. In addition, AKR1C3 may be a useful adjunct marker for the exclusion of the NE phenotype in diagnostic pathology.

Aldo-keto reductase family 1 member C3 (AKR1C3) is expressed in adenocarcinoma and squamous cell carcinoma but not small cell carcinoma.

Human aldo-keto reductase family 1 member C3 (AKR1C3) was initially identified as a critical enzyme in reducing 5α-dihydrotestosterone (5α-DHT) to 5α-androstane-3α,17ß-diol (3α-diol) and oxidizing 3α-diol to androsterone. Based on these enzymatic activities, AKR1C3 was originally named type 2 3α-hydroxysteroid dehydrogenase (HSD)/type 5 17ß-HSD. Additionally, AKR1C3 was demonstrated to be capable of metabolizing other steroids including estrogen and progesterone. Subsequently, AKR1C3 was shown to possess 11-ketoprostaglandin reductase activity in metabolizing prostaglandins and dihydrodiol dehydrogenase x (DDx) activity in metabolizing xenobiotics. Tissue distribution of AKR1C3 has been detected in both sex hormone-dependent organs such as the testis, breast, endometrium, and prostate as well as sex hormone-independent organs including the kidney and urothelium. Although prominent expression of AKR1C isozymes has been reported in human non-small cell lung carcinoma (NSCLC), the expression of AKR1C3 in small cell carcinoma of the lung has not been described. Also, the expression of AKR1C3 in normal lung has not been described. In this study, we demonstrated strong AKR1C3 immunoreactivity in bronchial epithelium but not in bronchial glands or alveolar pneumocytes. Strong AKR1C3 immunoreactivity was also demonstrated in columnar epithelium but only weak immunoreactivity in squamous epithelium of the gastrointestinal junction. Although AKR1C3 immunoreactivity was absent in small cell carcinoma of the lung, positive AKR1C3 immunoreactivity was extensively present in both adenocarcinoma and squamous cell carcinoma arising from the lung and the gastroesophageal junction. AKR1C3 may serve as an adjunct marker for differentiating small cell carcinoma from NSCLC. However, roles of AKR1C3 in adenocarcinoma, squamous cell carcinoma, and small cell carcinoma pathogenesis require further studies.