The peroxisome proliferator-activated receptor (PPAR) gamma is one member of the nuclear receptor superfamily that contains in excess of 80 described receptors. PPARgamma activators are a diverse ...group of agents that range from endogenous fatty acids or derivatives (linolenic, linoleic, and 15-deoxy-Delta(12,14)-prostaglandin J(2)) to Food and Drug Administration-approved thiazolidinedione drugs pioglitazone (Actos) and rosiglitazone (Avandia) for the treatment of diabetes. Once activated, PPARgamma will preferentially bind with retinoid X receptor alpha and signal antiproliferative, antiangiogenic, and prodifferentiation pathways in several tissue types, thus making it a highly useful target for down-regulation of carcinogenesis. Although PPAR-gamma activators show many anticancer effects on cell lines, their advancement into human advanced cancer clinical trials has met with limited success. This article will review translational findings in PPARgamma activation and targeting in carcinogenesis prevention as they relate to the potential use of PPARgamma activators clinically as cancer chemoprevention strategies.
Scribes in medical practice enable more efficient documentation requirements but insufficient analyses have occurred to fully evaluate their efficacy in otolaryngology. We analyzed pre/post metrics ...of scribe implementation that may aid practitioners in determining feasibility for use in their practices.
1808 patient charts were analyzed in The Epic Electronic Medical Record system (EMR) (903 pre and 905 post scribe implementation). We measured: clinic volumes, time saved in documentation, chart billing level, and lag days of chart closure.
Patient volumes increased by 3.02% with an 11–17% decrease in time spent in clinic/day and lag days for billing. The distribution of visits for new patients was 17.75% level 2, 51.45% level 3, 29.71% level 4 before the scribe and was 6.83% level 2, 89.21% level 3, 3.96% level 4 after the scribe. For established patients it was 3.97% level 2, 84.92% level 3, 8.93% level 4 before and 0.34% level 2, 91.76% level 3, 7.73% level 4 after. The change in level of documentation for established and new patients pre and post scribe implementation was not statistically significant (p = 0.821, 0.063, respectively). Charts were closed within 0 to 7 days with the implementation of a scribe instead of 7–21 days when awaiting dictations for transcription.
The implementation of a scribe in an academic otolaryngology clinic facilitated more rapid completion of documentation while decreasing provider hours/day in clinic. We feel the analysis can be generalized to otolaryngology practitioners in general and the data structures we implemented are usable for others.
Epidemiologic studies of diabetic patients treated with metformin identified significantly lower incidences of cancer. From this, there is growing interest in the use of metformin to treat and ...prevent cancer. Studies have investigated chemopreventive mechanisms including alterations in calorie intake, cancer metabolism, and cell signaling. Repurposing the drug is challenging due to its metabolic effects and non-uniform effects on different types of cancer. In our previously published studies, we observed that benzoapyrene treated mice receiving metformin significantly reduced lung adenomas; however, mice had reduced weight gain. In this study, we compared chemoprevention diets with and without metformin to evaluate the effects of diet vs. effects of metformin. We also performed tandem mass spectrometry on mouse serum to assess metabolomic alterations associated with metformin treatment. In metformin cohorts, the rate of weight gain was reduced, but weights did not vary between diets. There was no weight difference between diets without metformin. Interestingly, caloric intake was increased in metformin treated mice. Metabolomic analysis revealed metabolite alterations consistent with metformin treatment. Based on these results, we conclude that previous reductions in lung adenomas may have been occurred from anticancer effects of metformin rather than a potentially toxic effect such as calorie restriction.
Oral cancers lack standardized monitoring systems. Our institution has developed an active surveillance system which provides detailed monitoring and follow up of patients with oral preneoplastic ...lesions (OPL). We examined a historic cohort of patients with OPL seen by regional dental professionals and a current cohort of clinic patients. The major aim was to examine follow up practices for biopsy proven dysplasia to gauge appropriateness of an active monitoring system for oral carcinoma.
Questionnaires regarding patients with OPL were sent to 285 dentists who had requested oral pathology services from our institution. The follow up practices of 141 dentists were evaluated for patients with OPL. We then examined our current clinic referral patterns for the number of dental referrals after the creation of an oral carcinoma active surveillance clinic.
There were 76.5% (108/141) of patients who received follow up after diagnosis of preneoplastic oral lesions with 14.1% who underwent repeat biopsy. There was a malignant transformation rate of 11.3% including transformation of 42.8% of severe dysplasias into carcinoma within 2 years. After establishment of a dental referral clinic, 21.8% of tumor visits in a six-week period were referred from the regional dental community.
A high rate of transformation of OPL to cancer in this cohort may support a role for joint dental and otolaryngology surveillance of dysplasia with longitudinal follow up.
Large cell neuroendocrine carcinoma (LCNEC) of the larynx is an exceedingly rare cancer of the head and neck that is difficult to diagnose. Few case reports of laryngeal LCNEC exist within the ...literature, and it was not until recently that LCNEC was recognized as a discrete subtype of neuroendocrine carcinoma. Given its recent recognition as a distinct subtype, histologic characteristics distinguishing LCNEC from other poorly differentiated carcinomas remain under investigation. Various reports have shown genetic alterations such as p53 and/or p16 overexpression, which are typically associated with infection by human papilloma virus (HPV). However, some reports have shown p53 and/or p16 overexpression in HPV negative samples. In this case, we discuss a 67-year-old patient with a history of extensive alcohol and tobacco use with a newly diagnosed T4N0M0, high grade, LCNEC of the subglottic larynx. Tumor pathology demonstrated positive staining for typical neuroendocrine (NE) markers like synaptophysin and chromogranin A; however, there was diffuse CK34βE12 and p16 expression. LCNEC is a newly classified subtype of poorly differentiated neuroendocrine (NE) tumors, and the diagnosis requires consideration of the clinical presentation, microscopic features, and immunostaining markers.
Extra‐esophageal reflux is suspected to cause a wide range of clinical symptoms in the upper airways. Diagnosis and treatment has focused on acid, but realization of the role of nonacid reflux has ...resulted in research investigating the use of pepsin as a biomarker for gastric reflux and aspiration. Pepsin analysis can complement the use of questionnaires and office‐based diagnosis and lessen the dependency on invasive and expensive diagnostic tests. Furthermore, pepsin as a first‐line diagnostic biomarker has been shown to improve the accuracy of reflux diagnosis. In addition to its use as a diagnostic biomarker, pepsin has been shown to cause inflammation independent of the pH of the refluxate and thus despite acid suppression therapy. Research is ongoing to develop new therapies for airway reflux that specifically target pepsin.
Diagnosis and treatment of extra‐esophageal reflux (EER), which is suspected of causing a range of symptoms in the upper airways, has focused on acid. However, realization of the role of nonacid reflux has resulted in research investigating the use of pepsin as a biomarker for gastric reflux and aspiration. Pepsin analysis improves the accuracy of reflux diagnosis and reduces the need for invasive and expensive diagnostic tests.
Peroxisome proliferator-activated receptor gamma (PPAR γ) is activated by thiazolidinedione drugs (TZDs) and can promote anti-cancer properties. We used three TZDs (pioglitazone, rosiglitazone, and ...ciglitazone) to target cervical cancer cell lines and a nude mouse animal model. Each agent increased activation of PPAR γ, as judged by a luciferase reporter gene assay in three HPV-associated cell lines (CaSki, SiHa, and HeLa cells) while decreasing cellular proliferation in a dose-dependent manner. They also promoted Oil Red O accumulation in treated cell lines and upregulated the lipid differentiation marker adipsin. Interestingly, xenograft HeLa tumors in nude mice treated with 100mg/kg/day pioglitazone exhibited decreased growth compared to control mice or mice treated with standard cervical chemotherapy. In conclusion, TZDs slow tumor cell growth in vitro and in vivo with decreases in cell proliferation and increases in PPAR γ and adipsin. These agents may be interesting treatments or treatment adjuncts for HPV-associated cancers or perhaps even precancerous conditions.
•Thiazolidinediones decreases cervical cancer proliferation.•Pioglitazone increases cervical cancer differentiation.•Pioglitazone decreases tumor growth in mice.•Pioglitazone may be a useful treatment adjunct.
A decrease in the almost fifty percent mortality rate from oral cancer is needed urgently. Improvements in early diagnosis and more effective preventive treatments could affect such a decrease. ...Towards this end, we undertook for the first time an in-depth mass spectrometry-based quantitative shotgun proteomics study of non-invasively collected oral brush biopsies. Proteins isolated from brush biopsies from healthy normal tissue, oral premalignant lesion tissue (OPMLs), oral squamous cell carcinoma (OSCC) and matched control tissue were compared. In replicated proteomic datasets, the secretory leukocyte protease inhibitor (SLPI) protein stood out based on its decrease in abundance in both OPML and OSCC lesion tissues compared to healthy normal tissue. Western blotting in additional brushed biopsy samples confirmed a trend of gradual decreasing SLPI abundance between healthy normal and OPML tissue, with a larger decrease in OSCC lesion tissue. A similar SLPI decrease was observed in-vitro comparing model OPML and OSCC cell lines. In addition, exfoliated oral cells in patients' whole saliva showed a loss of SLPI correlated with oral cancer progression. These results, combined with proteomics data indicating a decrease in SLPI in matched healthy control tissue from OSCC patients compared to tissue from healthy normal tissue, suggested a systemic decrease of SLPI in oral cells correlated with oral cancer development. Finally, in-vitro experiments showed that treatment with SLPI significantly decreased NF-kB activity in an OPML cell line. The findings indicate anti-inflammatory activity in OPML, supporting a mechanistic role of SLPI in OSCC progression and suggesting its potential for preventative treatment of at-risk oral lesions. Collectively, our results show for the first time the potential for SLPI as a mechanism-based, non-invasive biomarker of oral cancer progression with potential in preventive treatment.
Oral cancer survival rates increase significantly when it is detected and treated early. Unfortunately, clinicians now lack tests which easily and reliably distinguish pre-malignant oral lesions from ...those already transitioned to malignancy. A test for proteins, ones found in non-invasively-collected whole saliva and whose abundances distinguish these lesion types, would meet this critical need.
To discover such proteins, in a first-of-its-kind study we used advanced mass spectrometry-based quantitative proteomics analysis of the pooled soluble fraction of whole saliva from four subjects with pre-malignant lesions and four with malignant lesions. We prioritized candidate biomarkers via bioinformatics and validated selected proteins by western blotting. Bioinformatic analysis of differentially abundant proteins and initial western blotting revealed increased abundance of myosin and actin in patients with malignant lesions. We validated those results by additional western blotting of individual whole saliva samples from twelve other subjects with pre-malignant oral lesions and twelve with malignant oral lesions. Sensitivity/specificity values for distinguishing between different lesion types were 100%/75% (p = 0.002) for actin, and 67%/83% (p<0.00001) for myosin in soluble saliva. Exfoliated epithelial cells from subjects' saliva also showed increased myosin and actin abundance in those with malignant lesions, linking our observations in soluble saliva to abundance differences between pre-malignant and malignant cells.
Salivary actin and myosin abundances distinguish oral lesion types with sensitivity and specificity rivaling other non-invasive oral cancer tests. Our findings provide a promising starting point for the development of non-invasive and inexpensive salivary tests to reliably detect oral cancer early.
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