Pegylated insulin-like growth factor-1 biotherapeutic delivery promotes rotator cuff regeneration in a rat model.

Tears in the rotator cuff are challenging to repair because of the complex, hypocellular, hypovascular, and movement-active nature of the tendon and its enthesis. Insulin-like Growth Factor-1 (IGF-1) is a promising therapeutic for this repair. However, its unstable nature, short half-life, and ability to disrupt homeostasis has limited its clinical translation. Pegylation has been shown to improve the stability and sustain IGF-1 levels in the systemic circulation without disrupting homeostasis. To provide localized delivery of IGF-1 in the repaired tendons, we encapsulated pegylated IGF-1 mimic and its controls (unpegylated IGF-1 mimic and recombinant human IGF-1) in polycaprolactone-based matrices and evaluated them in a pre-clinical rodent model of rotator cuff repair. Pegylated-IGF-1 mimic delivery reestablished the characteristic tendon-to-bone enthesis structure and improved tendon tensile properties within 8 weeks of repair compared to controls, signifying the importance of pegylation in this complex tissue regeneration. These results demonstrate a simple and scalable biologic delivery technology alternative to tissue-derived grafts for soft tissue repair.

Exercise-induced piezoelectric stimulation for cartilage regeneration in rabbits.

More than 32.5 million American adults suffer from osteoarthritis, and current treatments including pain medicines and anti-inflammatory drugs only alleviate symptoms but do not cure the disease. Here, we have demonstrated that a biodegradable piezoelectric poly(L-lactic acid) (PLLA) nanofiber scaffold under applied force or joint load could act as a battery-less electrical stimulator to promote chondrogenesis and cartilage regeneration. The PLLA scaffold under applied force or joint load generated a controllable piezoelectric charge, which promoted extracellular protein adsorption, facilitated cell migration or recruitment, induced endogenous TGF-ß via calcium signaling pathway, and improved chondrogenesis and cartilage regeneration both in vitro and in vivo. Rabbits with critical-sized osteochondral defects receiving the piezoelectric scaffold and exercise treatment experienced hyaline-cartilage regeneration and completely healed cartilage with abundant chondrocytes and type II collagen after 1 to 2 months of exercise (2 to 3 months after surgery including 1 month of recovery before exercise), whereas rabbits treated with nonpiezoelectric scaffold and exercise treatment had unfilled defect and limited healing. The approach of combining biodegradable piezoelectric tissue scaffolds with controlled mechanical activation (via physical exercise) may therefore be useful for the treatment of osteoarthritis and is potentially applicable to regenerating other injured tissues.

Proliferative Verrucous Leukoplakia: An Expert Consensus Guideline for Standardized Assessment and Reporting.

The many diverse terms used to describe the wide spectrum of changes seen in proliferative verrucous leukoplakia (PVL) have resulted in disparate clinical management. The objective of this study was to produce an expert consensus guideline for standardized assessment and reporting by pathologists diagnosing PVL related lesions. 299 biopsies from 84 PVL patients from six institutions were selected from patients who had multifocal oral leukoplakic lesions identified over several years (a minimum follow-up period of 36 months). The lesions demonstrated the spectrum of histologic features described in PVL, and in some cases, patients developed oral cavity squamous cell carcinoma (SCC). An expert working group of oral and maxillofacial and head and neck pathologists reviewed microscopic features in a rigorous fashion, in combination with review of clinical photographs when available. The working group then selected 43 single slide biopsy cases for whole slide digital imaging (WSI) review by members of the consensus conference. The digital images were then reviewed in two surveys separated by a washout period of at least 90 days. Five non-PVL histologic mimics were included as controls. Cases were re-evaluated during a consensus conference with 19 members reporting on the cases. The best inter-observer diagnostic agreement relative to PVL lesions were classified as "corrugated ortho(para)hyperkeratotic lesion, not reactive" and "SCC" (chi-square p = 0.015). There was less than moderate agreement (kappa < 0.60) for lesions in the "Bulky hyperkeratotic epithelial proliferation, not reactive" category. There was ≥ moderate agreement (> 0.41 kappa) for 35 of 48 cases. This expert consensus guideline has been developed with support and endorsement from the leadership of the American Academy of Oral and Maxillofacial Pathology and the North American Society of Head and Neck Pathologists to recommend the use of standardized histopathologic criteria and descriptive terminology to indicate three categories of lesions within PVL: (1) "corrugated ortho(para)hyperkeratotic lesion, not reactive;" (2) "bulky hyperkeratotic epithelial proliferation, not reactive;" and (3) "suspicious for," or "squamous cell carcinoma." Classification of PVL lesions based on a combination of clinical findings and these histologic descriptive categories is encouraged in order to standardize reporting, aid in future research and potentially guide clinical management.

Use of Simulated Patient Encounters to Teach Residents to Respond to Patients Who Discriminate Against Health Care Workers.

BACKGROUND: Previous studies indicate that medical trainees frequently experience discrimination by patients. Little is known about effective strategies to teach trainees to respond to this discrimination. AIM: To create a workshop for first-year residents utilizing standardized patients to improve skills in responding to patients exhibiting discrimination towards members of the health care team. SETTING: The Patient Safety Training Center at Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire. PARTICIPANTS: First-year residents in the Internal Medicine Residency Program. PROGRAM DESCRIPTION: An introductory didactic session including a communication skills framework was followed by simulated encounters with four standardized patients. Learners received feedback from a trained facilitator, peers, and the standardized patients. PROGRAM EVALUATION: One hundred percent of the 19 learners who participated agreed that the simulated exercises were realistic and improved their readiness to address patient bias. The proportion of learners who reported being somewhat or very confident in their preparedness to respond to patients exhibiting discrimination increased from 74% before the workshop to 100% (p = 0.07) after the workshop. DISCUSSION: A workshop incorporating standardized patients may improve resident confidence in responding to patients with discriminatory behaviors. The workshop could be modified to incorporate other learners and staff, or for inter-disciplinary training.

Curcumin, a turmeric extract, for oral lichen planus: A systematic review.

OBJECTIVE: Conduct a PROSPERO registered (CRD42018105227) systematic review of the efficacy of curcumin in the treatment of oral lichen planus (OLP). DATA SOURCES: Medline from the earliest possible date to the present (December 18, 2018) using the terms "turmeric" OR "curcumin" OR "curcuma" AND "oral lichen planus". STUDY SELECTION AND DATA EXTRACTION: Studies assessing patient outcomes in OLP. There were four trials assessing the comparative efficacy of topical curcumin vs. topical corticosteroids and three trials assessing the efficacy of oral curcumin vs. placebo. DATA SYNTHESIS: Clinical and methodological heterogeneity precluded statistical pooling. There were many limitations in the literature weakening the strength and applicability of evidence. Topical curcumin provided reductions in pain, burning, and clinical manifestations of OLP versus baseline, effects similar or inferior to topical corticosteroids. In oral curcumin trials, there were no significant benefits of curcumin therapy versus placebo but there were some potential benefits and reasonable safety in an observational extension study. CONCLUSIONS: It is difficult to determine whether topical or oral curcumin is a viable therapy for oral lichen planus. Topically applied curcumin in particular shows promising preliminary data but would likely not supplant topical corticosteroids as the modality of choice for most patients.

Impact of numeracy on understanding of prostate cancer risk reduction in PSA screening.

Prostate-specific antigen (PSA) screening for prostate cancer in men of average risk remains controversial. Patients' ability to incorporate risk reduction data into their decision-making may depend on their numeracy. We assessed the impact of patients' numeracy on their understanding of the risk reduction benefits of PSA screening. Men attending a general internal medicine clinic were invited to complete a survey. Four versions of the survey each included a three-item numeracy test and PSA risk reduction data, framed one of four ways: absolute (ARR) versus relative risk reduction (RRR), with or without baseline risk (BR). Respondents were asked to adjust their perceived risk of prostate-cancer mortality using the data presented. Accuracy of risk reduction was evaluated relative to how risk data were framed. Among a total of 200 respondents, a majority incorrectly answered one or more of the numeracy items. Overall accuracy of risk adjustment was only 20%. Accuracy varied with data framing: when presented with RRR, respondents were 13% accurate without BR and 31% accurate with BR; when presented with ARR, they were 0% accurate without BR and 35% accurate with BR. Including BR data significantly improved accuracy for both RRR (P = 0.03) and ARR groups (P < 0.01). Accuracy was significantly related to numeracy; numeracy scores of 0, 1, 2, and 3 were associated with accuracy rates of six, five, nine, and 36 percent, respectively (P < 0.01). Overall, numeracy was significantly associated with the accuracy of interpreting quantitative benefits of PSA screening. Alternative methods of communicating risk may facilitate shared decision-making in the use of PSA screening for early detection of prostate cancer.

Contemporary concepts in the diagnosis of oral cancer and precancer.

This article addresses several issues in the approach to diagnosis of oral cancer. The term oral cancer is clarified. Key aspects of the biologic basis of development of oral cancer and the known risk factors associated with the disease are summarized. The clinical presentation of oral cancers and precancerous lesions and their histopathologic correlates is discussed. The importance of conventional tissue biopsy as the prevailing gold standard for diagnosis is emphasized. Other current technologies available for detecting and diagnosing oral cancer and premalignant lesions are acknowledged, and their respective strengths and weaknesses are discussed.

Smoking and drinking in relation to depressive symptoms among persons with oral cancer or oral epithelial dysplasia.

BACKGROUND: We examined whether smoking or drinking during or before the diagnosis-year of oral cancer or oral epithelial dysplasia (OED) was related to "subsequent depression" measured months after the oral diagnosis. METHODS: Incident cases of oral cancer or OED were identified via 3 oral pathology laboratories. A telephone-administered questionnaire included questions on smoking/drinking history through the diagnosis-year and measured depressive symptoms using the Center for Epidemiologic Studies-Depression Scale (CES-D); scores of 16+ indicated clinical depression. "Subsequent depression" was defined as a CES-D score of 16+, measured at the time of assessment several months after the diagnosis of oral cancer or OED. RESULTS: Patients who smoked during their diagnosis-year had twice the odds of subsequent depression relative to former/never smokers. Diagnosis-year (vs never/former) drinking was not associated with depression; however, average alcohol consumption of >1.5 drinks/week was negatively associated with subsequent depression for both diagnosis-year and ex-drinkers (past reported drinking) even among heavy drinkers. CONCLUSION: Our findings suggest that subsequent depression is positively associated with diagnosis-year smoking and negatively associated with alcohol consumption of >1.5 drinks/week among both diagnosis-year and ex-drinkers.

Cyclin D1 overexpression increases susceptibility to 4-nitroquinoline-1-oxide-induced dysplasia and neoplasia in murine squamous oral epithelium.

The cyclin D1 oncogene is frequently amplified/overexpressed in oral squamous cell carcinomas. Mice with overexpression of cyclin D1 targeted to the stratified squamous epithelia of the tongue, esophagus, and forestomach develop a phenotype of epithelial dysplasia at these sites. In this study, we examined the effect of cyclin D1 overexpression on susceptibility of mice to carcinogen-induced tumorigenesis, using 4-nitroquinoline-1-oxide (4NQO), an established potent oral carcinogen in mice. Cyclin D1 overexpressing mice and nontransgenic littermates were administered 4NQO (20 or 50 parts per million (ppm) in the drinking water) for 8 wk and monitored for an additional 16 wk. Histopathological analyses of the tongue revealed significantly higher severity of dysplasia in the cyclin D1 overexpression mice, compared with nontransgenic controls and with untreated controls. Moreover, only the cyclin D1 overexpression mice developed neoplastic lesions in the oro-esophageal epithelia. Examination of the dysplastic and neoplastic lesions revealed abnormal proliferation. Our findings suggest that cyclin D1 overexpression enhances susceptibility to carcinogen-induced oral tumorigenesis. These results underscore the importance of cyclin D1 in the process of oral neoplastic development. Further, they emphasize the value of this transgenic model to study the pathogenesis of oral precancer and cancer and establish it as a model system to test candidate agents for chemoprevention of upper aero-digestive cancer.

Peripheral complex odontoma in a pediatric dental patient: a case report.

Odontomas are the most commonly occurring benign odontogenic tumors of the jaws. Although a majority of odontomas are intraosseous, there are case reports of odontomas that erupted into the oral cavity. Even less common are peripheral or soft-tissue odontomas, only a few of which have been reported to date. We report a peripheral odontoma that arose in the alveolar mucosa of the posterior maxilla in a young child. The diagnosis, complications, treatment, and prognosis of this entity will be discussed.

Smoking and drinking in relation to oral cancer and oral epithelial dysplasia.

OBJECTIVE: Risks associated with smoking and drinking are not necessarily constant over the multistage pathway to oral cancer. We investigated whether smoking and drinking patterns differ for persons with oral cancer (OC) relative to those with oral epithelial dysplasia (OED), a precancerous condition. METHODS: Incident cases of OC and OED were interviewed using a questionnaire containing questions on smoking and drinking. Odds ratios (ORs) compared the odds of smoking and drinking among persons with OC relative to OED. RESULTS: No adjusted ORs for smoking achieved statistical significance; however, most were <1.0. The odds of OC relative to OED increased with drinking level; the adjusted OR for 19+ drinks/week was 3.03 (1.56-5.87). Age drinking began and years of drinking were not notably different for OC and OED cases; a higher proportion of OC cases reported discontinuing alcohol for 9+ years before diagnosis. CONCLUSIONS: The relationship between smoking and OED was at least as strong as that for smoking and OC, suggesting that smoking may have its greatest impact on oral carcinogenesis prior to malignant transformation. Drinking was more strongly associated with OC than OED, particularly at elevated consumption levels; the role of alcohol does not appear limited to a late-stage effect.

Oral lichen planus and oral lichenoid lesions: diagnostic and therapeutic considerations.

Several therapeutic agents have been investigated for the treatment of oral lichen planus (OLP). Among these are corticosteroids, retinoids, cyclosporine, and phototherapy, in addition to other treatment modalities. A systematic review of clinical trials showed that particularly topical corticosteroids are often effective in the management of symptomatic OLP lichen planus. Systemic corticosteroids should be only considered for severe widespread OLP and for lichen planus involving other mucocutaneous sites. Because of the ongoing controversy in the literature about the possible premalignant character of OLP, periodic follow-up is recommended. There is a spectrum of oral lichen planus-like ("lichenoid") lesions that may confuse the differential diagnosis. These include lichenoid contact lesions, lichenoid drug reactions and lichenoid lesions of graft-versus-host disease. In regard to the approach to oral lichenoid contact lesions the value of patch testing remains controversial. Confirmation of the diagnosis of an oral lichenoid drug reaction may be difficult, since empiric withdrawal of the suspected drug and/or its substitution by an alternative agent may be complicated. Oral lichenoid lesions of graft-versus-host disease (OLL-GVHD) are recognized to have an association with malignancy. Local therapy for these lesions rests in topical agents, predominantly corticosteroids.

Management of oral epithelial dysplasia: a review.

One of the goals of the fourth meeting of The World Workshop on Oral Medicine (WWOM IV) included a review of the pathophysiology and future directions for the clinical management of patients with oral epithelial dysplasia, excluding the lips and oropharynx. In the pathophysiology review of dysplasia since WWOM III (1998-2006), a wide range of molecular changes associated with progression of dysplasia to squamous cell carcinoma were found. These include loss of heterozygosity, dysregulation of apoptosis, aberrant DNA expression, and altered expression of numerous tissue markers. Based on the literature search, no single molecular pathway has been identified as the primary factor in progression of dysplasia to squamous cell carcinoma. A systematic review of medical (i.e., nonsurgical) management strategies for the treatment of dysplastic lesions has shown promising results in short-term resolution of dysplasia in the small number of studies that met eligibility criteria for review. However, because of the limited periods of follow-up reported in these studies, it remains unclear as whether resolution of dysplasia would actually be a long-term benefit of these interventions. This question is particularly germane when it is considered in the context of prevention of future development of squamous cell carcinoma. Because of the lack of randomized controlled trials that have shown effectiveness in the prevention of malignant transformation, no recommendations can be provided for specific surgical interventions of dysplastic oral lesions either.

Sociodemographic risk indicators for depressive symptoms among persons with oral cancer or oral epithelial dysplasia.

PURPOSE: We report findings from a study that measured associations between sociodemographic risk indicators and depressive symptoms among individuals diagnosed with either oral cancer or a premalignant lesion. MATERIALS AND METHODS: Incident cases of oral cancer and oral epithelial dysplasia (OED) were identified by reviewing pathology reports generated by 3 oral pathology laboratories serving primarily community-based oral and maxillofacial surgeons. Subjects were interviewed by telephone to collect information on sociodemographic characteristics, depressive symptoms using the Center for Epidemiologic Studies-Depression (CES-D) Scale, and social support using the Berkman Social Network Inventory. RESULTS: The analysis included 167 oral cancer and 234 OED cases. Nineteen percent of the subjects had a CES-D score indicative of clinical depression (CES-D > or =16). Forward and backward stepwise logistic regression identified diagnosis (cancer/OED), age, social support, employment status, and gender as sociodemographic indicators of CES-D scores of 16+. In the final model, which also controlled for smoking and drinking, the odds of having elevated CES-D scores (16+) were 79% higher among oral cancer relative to OED cases. The odds of high CES-D scores were significantly reduced in persons over the age of 50 compared with those aged 50 years and younger as well as in persons with higher, relative to low, levels of social support and in persons employed outside the home compared with those who were not. Although not statistically significant, men were more likely to have CES-D scores indicative of clinical depression. CONCLUSIONS: Knowledge of sociodemographic characteristics may assist the clinician in identifying those individuals with an elevated risk of concomitant depressive symptoms.