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True malignant mixed tumors, also known as salivary gland carcinosarcoma (SCS), are uncommon yet highly aggressive lesions associated with a poor prognosis. These tumors exhibit a distinctive biphasic structure characterized by both epithelial and mesenchymal components. Recent research has shown that the majority of SCS cases stem from pre-existing pleomorphic adenomas (PAs), suggesting a stepwise developmental pattern. In this report, we present a case of a 73-year-old female with SCS and describe the clinical, radiographic, and pathologic observations. Notably, the SCS was associated with a residual PA. The SCS displayed a CTNNB1::PLAG1 gene rearrangement, providing a molecular basis for its origin from the PA. Further DNA genomic analysis exposed mutations in BAP1, PER1, and LRPB1. Our findings provide support to the theory that SCS emerges from a pre-existing PA while highlighting the multiple genetic changes that could contribute to malignant transformation. [ABSTRACT FROM AUTHOR]

Oral squamous cell carcinoma (OSCC) is worldwide health problem associated with high morbidity and mortality. From both the patient and socioeconomic perspectives, prevention of progression of premalignant oral intraepithelial neoplasia (OIN) to OSCC is clearly the preferable outcome. Optimal OSCC chemopreventives possess a variety of attributes including high tolerability, bioavailability, efficacy and preservation of an intact surface epithelium. Terminal differentiation, which directs oral keratinocytes leave the proliferative pool to form protective cornified envelopes, preserves the protective epithelial barrier while concurrently eliminating growth-aberrant keratinocytes. This study employed human premalignant oral keratinocytes and an OSCC cell line to evaluate the differentiation-inducing capacity of the synthetic retinoid, fenretinide (4HPR). Full-thickness oral mucosal explants were evaluated for proof of concept differentiation studies. Results of this study characterize the ability of 4HPR to fulfill all requisite components for keratinocyte differentiation, i.e. nuclear import via binding to cellular RA binding protein-II (molecular modeling), binding to and subsequent activation of retinoic acid nuclear receptors (receptor activation assays), increased expression and translation of genes associated with keratinocyte differentiation [Reverse transcription polymerase chain reaction (RT-PCR), immunoblotting] upregulation of a transglutaminase enzyme essential for cornified envelope formation (transglutaminase 3, functional assay) and augmentation of terminal differentiation in human oral epithelial explants (image-analyses quantified corneocyte desquamation). These data build upon the chemoprevention repertoire of 4HPR that includes function as a small molecule kinase inhibitor and inhibition of essential mechanisms necessary for basement membrane invasion. An upcoming clinical trial, which will assess whether a 4HPR-releasing mucoadhesive patch induces histologic, clinical and molecular regression in OIN lesions, will provide essential clinical insights. [ABSTRACT FROM AUTHOR]

Purpose/objectives: Clinical teaching in dentistry has cycled through specialty‐based "departmental" teaching to group practice scenarios. The aims of this study were to ascertain third‐year dental students' perceptions of a specialty‐based rotation supplemented by online educational tools and to compare their Objective Structured Clinical Exam (OSCE) scores to those of the students in the previous year. Methods: This retrospective research design included the analysis of OSCE scores, and student responses to survey questions regarding their perceptions of the clinical oral pathology (COP) rotation. This study was completed in 2022. It included data from 2020 to 2021 and 2021 to 2022 corresponding to input from the Classes of 2022 and 2023, respectively. The response rate was 100%. Results: The students evaluated the focused COP rotation and the online teaching modules as a positive experience. The results of the OSCE were similar to those of the previous class and showed a high average score. Conclusions: This study shows that students had a positive perception to specialty‐based learning with online educational tools and that it enhanced the education they received in the comprehensive care clinic. The OSCE scores were similar to those of the previous class. These findings suggest a method of maintaining high‐quality dental education through challenges as it continues evolving. [ABSTRACT FROM AUTHOR]

Basement membrane invasion defines malignant transformation of surface premalignancy. Treatment of oral squamous cell carcinoma (OSCC) cells with the synthetic vitamin A derivative, fenretinide (4HPR), induces numerous cancer-preventive effects including suppression of basement membrane invasion, elimination of anchorage-independent growth, disruption of actin cytoskeletal components and inhibition of the invasion-enabling focal adhesive kinase. The purpose of this study was to elucidate 4HPR's effects on additional invasion-relevant mechanisms including matrix metalloproteinase (MMP) activation and function, cell–extracellular matrix (ECM) attachments and interaction with a kinase that is essential for the epithelial–myoepithelial transformation i.e. c-Jun NH2-terminal kinase (JNK). Our data revealed that 4HPR binds with high affinity to the ATP-binding site of all three JNK isoforms with concurrent suppression of kinase function. Additional studies showed 4HPR treatment inhibited both OSCC cell–ECM adhesion and MMP activation and function. JNK downregulation and induced expression studies confirmed that the JNK3 isoform conveyed that largest impact on OSCC migration and invasion. Biodegradable polymeric implants formulated to preserve 4HPR's function and bioavailability were employed to assess 4HPR's chemopreventive impact on an OSCC tumor induction model. These studies revealed 4HPR local delivery significantly inhibited OSCC tumor size, mitotic indices and expression of the endothelial marker, erythroblast transformation-specific-related gene with concurrent increases in tumor apoptosis (cleaved caspase-3). Collectively, these data show that 4HPR suppresses invasion at multiple sites including 'outside-in' signaling, cell–ECM interactions and suppression of MMPs. These functions are also essential for physiologic function. Regulation is therefore essential and reinforces the pharmacologic advantage of local delivery chemopreventive formulations.. [ABSTRACT FROM AUTHOR]

BACKGROUND: Black raspberries (BRB) inhibit a broad range of cancers in preclinical models, including in vivo models of oral, esophageal, colon, breast and skin cancer. Promising preclinical results have led to clinical evaluations in cancer patients or patients at increased risk for cancer development. OBJECTIVE: To summarize clinical investigations targeting cancer or precancerous lesions with BRB and discuss future directions. METHODS: A thorough literature search was conducted through December 1, 2015 to identify all published studies evaluating BRB in cancer focused clinical trials. RESULTS: Research investigating BRB in clinical settings report positive effects on preneoplastic lesions or cancers of the oral cavity, esophagus and colon. BRB treatment resulted in: histologic regression of oral intraepithelial neoplasia associated with improved histologic grade and significantly reduced loss of heterozygosity at tumor suppressor gene loci, modulated genes linked to RNA processing and growth factor recycling; in the colon, BRB inhibited FAP-associated polyp progression, demethylated tumor suppressor genes and improved plasma cytokine profiles; in Barrett's patients, BRB consumption increased tissue levels of GST-pi and decreased 8-isoprostane, a marker of lipid peroxidation/oxidative stress. CONCLUSIONS: The precise dose, duration and optimum mode of BRB delivery for cancer inhibition remains to be fully elucidated. Common themes across studies support that BRB are anti-proliferative, anti- inflammatory, reduce oxidative stress and restore tumor suppressive activity. Future directions are included in the conclusions section. [ABSTRACT FROM AUTHOR]

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on macronutrients, dietary patterns, and risk of adenocarcinoma in Barrett’s esophagus; micronutrients, trace elements, and risk of Barrett’s esophagus and esophageal adenocarcinoma; the role of mate consumption in the development of squamous cell carcinoma; the relationship between energy excess and development of esophageal adenocarcinoma; and the nutritional management of the esophageal cancer patient. [ABSTRACT FROM AUTHOR]

Purpose: Bone regeneration through distraction osteogenesis (DO) is promising but remarkably slow. To accelerate it, autologous mesenchymal stem cells have been directly injected to the distraction site in a few recent studies. Compared to direct injection, a scaffold-based method can provide earlier cell delivery with potentially better controlled cell distribution and retention. This pilot project investigated a scaffold-based cell-delivery approach in a porcine mandibular DO model. Materials and Methods: Eleven adolescent domestic pigs were used for two major sets of studies. The in-vitro set established methodologies to: aspirate bone marrow from the tibia; isolate, characterize and expand bone marrow-derived mesenchymal stem cells (BM-MSCs); enhance BM-MSC osteogenic differentiation using FGF-2; and confirm cell integration with a gelatin-based Gelfoam scaffold. The in-vivo set transplanted autologous stem cells into the mandibular distraction sites using Gelfoam scaffolds; completed a standard DO-course and assessed bone regeneration by macroscopic, radiographic and histological methods. Repeated-measure ANOVAs and t-tests were used for statistical analyses. Results: From aspirated bone marrow, multi-potent, heterogeneous BM-MSCs purified from hematopoietic stem cell contamination were obtained. FGF-2 significantly enhanced pig BM-MSC osteogenic differentiation and proliferation, with 5 ng/ml determined as the optimal dosage. Pig BM-MSCs integrated readily with Gelfoam and maintained viability and proliferative ability. After integration with Gelfoam scaffolds, 2.4–5.8×107 autologous BM-MSCs (undifferentiated or differentiated) were transplanted to each experimental DO site. Among 8 evaluable DO sites included in the final analyses, the experimental DO sites demonstrated less interfragmentary mobility, more advanced gap obliteration, higher mineral content and faster mineral apposition than the control sites, and all transplanted scaffolds were completely degraded. Conclusion: It is technically feasible and biologically sound to deliver autologous BM-MSCs to the distraction site immediately after osteotomy using a Gelfoam scaffold to enhance mandibular DO. [ABSTRACT FROM AUTHOR]

The article evaluates the cell cycle regulatory genes for homozygous deletion, loss of heterozygosity, and mutation events in 20 proliferative verrucous leukoplakia (PVL) cases. It illustrates that molecular alterations, even within a specific genetic region, are associated with distinct histologic types of oral premalignancy.

Background. As part of ongoing studies aimed at identifying the molecular events involved in head and neck squamous cell carcinoma progression, we recently isolated a novel serine protease, DESC1. This study was conducted to further characterize DESC1. Methods. Specimens of normal, dysplastic, and carcinomatous oropharyngeal mucosa (n = 31) were evaluated for DESC1 immunoreactivity using standard streptavidin-biotin immunoperoxidase techniques. Between-lesion stain intensity values were analyzed using multiple Wilcoxon tests. DESC1 expression was also evaluated in cultured human keratinocytes after induction of differentiation by calcium challenge, with subsequent real-time reverse transcriptase-polymerase chain reaction quantification. Results. DESC1 immunoreactivity decreased as lesions approached a malignant phenotype. Post hoc testing comparing the different lesion types and DESC1 staining values showed significance between “normal” and “carcinoma” (p = .0017) groups. Induction of normal keratinocyte differentiation by calcium challenge was accompanied by an increase in DESC1 expression (p = .002). Conclusions. These results suggest downregulation of DESC1 during squamous cell carcinoma progression and upregulation during normal epithelial differentiation. © 2005 Wiley Periodicals, Inc. Head Neck28: 432–440, 2006 [ABSTRACT FROM AUTHOR]

Abstract: Despite focused efforts to improve therapy, 5-yr survival rates for persons with advanced-stage oral squamous cell carcinoma (SCC) remain discouragingly low. Clearly, early detection combined with strategies for local intervention, such as chemoprevention prior to SCC development, could dramatically improve clinical outcomes. Previously conducted oral cavity human chemoprevention trials, however, have provided mixed results. Although some therapies showed efficacy, they were often accompanied by either significant toxicities or circulating antiadenoviral antibodies. It is clearly apparent that identification of nontoxic, effective treatments is essential to prevent malignant transformation of oral epithelial dysplasias. This study employed cell lines isolated from human oral SCC tumors to investigate the effects of a freeze-dried black raspberry ethanol extract (RO-ET) on cellular growth characteristics often associated with a transformed phenotype such as sustained proliferation, induction of angiogenesis, and production of high levels of reactive species. Our results demonstrate that RO-ET suppresses cell proliferation without perturbing viability, inhibits translation of the complete angiogenic cytokine vascular endothelial growth factor, suppresses nitric oxide synthase activity, and induces both apoptosis and terminal differentiation. These data imply that RO-ET is a promising candidate for use as a chemopreventive agent in persons with oral epithelial dysplasia. [ABSTRACT FROM AUTHOR]

To evaluate the direct effect of human cyclooxygenase-2 (hCox-2) on human breast tumor cell proliferation, invasion, and angiogenesis, hCox-2 cDNA was transfected into slow growing, non-metastatic MCF-7 human breast tumor cells that express low levels of Cox-2. Two stable transfectant clones, designated MCF-7/hCox-2 clones 8 and 10, had significantly decreased (P<0.05) doubling time, with two-fold greater number of cells during exponential growth compared to the MCF-7/vector control. Proliferation of both of the MCF-7/hCox-2 clones was significantly inhibited in a time- and dose-dependent manner by celecoxib. The MCF-7/hCox-2 clones 8 and 10 formed larger and greater numbers of colonies in soft agar than the MCF-7/vector control, with a corresponding increased invasion across an artificial Matrigel basement membrane in response to recombinant human epidermal growth factor (hEGF). The MCF-7/hCox-2 clones 8 and 10 had higher mRNA levels of two splice variants of vascular endothelial growth factor (VEGF), V145 and V165. These results demonstrate that hCox-2 directly increases breast tumor cell proliferation, stimulates invasion across a basement membrane, and induces synthesis of specific heparin binding splice variants of VEGF. [Copyright &y& Elsevier]

AIDS-related Kaposi's sarcoma (AIDS-KS), the most prevalent HIV-associated malignancy, is a debilitating, potentially fatal disease. Currently, there is a need for development of AIDS-KS therapies that are not only well tolerated, but also capable of providing sustained remission. Preclinical assessment of pharmacological parameters and therapeutic efficacies are dependent upon in vivo parameters. However, there are currently no animal KS models and mucocutaneous KS cell isolates have proved to be non-tumorigenic in animal hosts. This report describes the development of a murine model that enables in vivo transplantation of `native' low population doubling level AIDS-KS cells from biopsy-confirmed mucocutaneous lesions. The angiogenic phenotype of in situ AIDS-KS lesions is reconstituted via controlled release of a complete angiogenic peptide, recombinant human basic fibroblast growth factor (bFGF), from locally injectable, biodegradable polylactide–co-glycolide implants. Consequential to the sustained local release of bioactive bFGF, a murine vascular network is established, which facilitates the in vivo transplantation of AIDS-KS cells. Desirable aspects of this model include: low cost murine species, transplantation of non-selected patient cells and use of animal hosts that are T cell-deficient. The transplanted human AIDS-KS cells and extensive murine vascular network create lesions that retain a striking resemblance, at both the gross and microscopic levels, to in situ AIDS-KS tumors. Because the bFGF-induced murine vascular network is analogous to the abundant vascularity present in AIDS-KS lesions, this murine model should provide an excellent vehicle for numerous clinically relevant studies, such as assessment of drug clearance at AIDS-KS lesional sites. Finally, applicability of this method is not restricted to AIDS-related malignancies. Establishment and maintenance of an extensive host vascular network should augment success rates for in vivo transplantation of numerous other human cell strains or lines. [ABSTRACT FROM PUBLISHER]

Controlled release from biodegradable polymers is a novel approach to replace daily painful injections of protein drugs. A major obstacle to development of these polymers is the need to retain the structure and biological activity of encapsulated proteins during months of incubation under physiological conditions. We encapsulated bovine serum albumin (BSA) in injectable poly(DL-lactide-co-glycolide) (PLGA) 50/50 cylindrical implants and determined the mechanism of BSA instability. Simulations of the polymer microclimate revealed that moisture and acidic pH (<3) triggered unfolding of encapsulated BSA, resulting in peptide bond hydrolysis and noncovalent aggregation. To neutralize the acids liberated by the biodegradable lactic/glycolic acid-based polyester, we coincorporated into the polymer an antacid, Mg(OH)[SUB2], which increased microclimate pH and prevented BSA structural losses and aggregation for over one month. We successfully applied this stabilization approach in both cylinder- and microsphere-injectable configurations and for delivery of angiogenic basic fibroblast growth factor and bone-regenerating bone morphogenetic protein-2. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Key points Plain language summary Calcifying odontogenic cysts (Gorlin cysts) most commonly present centrally and have only rarely been reported in peripheral locations. The purpose of this report is to describe a new case of peripheral calcifying odontogenic cyst (PCOC) occurring in the anterior maxillary gingiva and to review the management and differential diagnosis of such a lesion.A 37‐year‐old female presented with a long‐standing submucosal nodule on the gingiva between the maxillary central incisors, with asymptomatic growth over the last three years. Following an initial incisional biopsy, a diagnosis of PCOC was established. To exclude the possibility of a central process, a corresponding small field of view cone beam CT scan was obtained and the patient returned for a 6 mm excisional biopsy to the depth of the periosteum.Results of these additional assessments supported the original diagnosis of PCOC. Following uneventful healing of the second biopsy, no recurrence or other clinical findings were noted at 1‐year follow‐up.While rare, the peripheral variant of calcifying odontogenic cyst, and other peripheral counterparts to recognized central cysts and tumors, should be considered in a differential diagnosis for a benign gingival nodule. Gingival tissue should be submitted for histologic evaluation to ensure a neoplastic process is not present. Various lesions may present on the gingiva as a “bump”; these can represent common clinical entities, such as pyogenic granuloma, peripheral ossifying fibroma, peripheral giant cell granuloma, and fibroma, or more rare conditions that may not be adequately considered in the differential diagnosis. A rarely documented case of peripheral calcifying odontogenic cyst (PCOC; Gorlin cyst) on the maxillary anterior gingiva of an adult female is reported here and compared with the few other similar PCOC cases in the literature. A biopsy of gingival lesions is always necessary to establish the correct diagnosis and provide the appropriate treatment. Various lesions may present on the gingiva as a “bump”; these can represent common clinical entities, such as pyogenic granuloma, peripheral ossifying fibroma, peripheral giant cell granuloma, and fibroma, or more rare conditions that may not be adequately considered in the differential diagnosis.A rarely documented case of peripheral calcifying odontogenic cyst (PCOC; Gorlin cyst) on the maxillary anterior gingiva of an adult female is reported here and compared with the few other similar PCOC cases in the literature.A biopsy of gingival lesions is always necessary to establish the correct diagnosis and provide the appropriate treatment.Several different lesions can appear on the gingiva (gums). Some are quite common, and some are rare. This report documents the occurrence of a new case of calcifying odontogenic cyst (Gorlin cyst), a type of cyst that has been rarely found outside the jawbone, presenting as a “bump” on the gingiva between the maxillary central incisor teeth of an adult female. Because of the patient history, a peripheral calcifying odontogenic cyst (PCOC) was not initially suspected. Following a biopsy, a PCOC diagnosis was given. The possibility of a lesion within the bone was then excluded by an X‐ray (cone beam CT) scan examination. A second, more extensive biopsy confirmed the diagnosis and the removal of the lesion. The patient had no complications or recurrence for the following 12 months. This case highlights the need to always biopsy lesions presenting on the gums to obtain a proper diagnosis and provide the correct treatment. [ABSTRACT FROM AUTHOR]

The purpose of this study was to develop solid dispersions of fenretinide(4HPR), incorporate them into poly(lactic-co-glycolic)(PLGA) millicylindrical implants, and evaluate the resulting implants in vitro and in vivo for future applications in oral cancer chemoprevention. Due to the extreme hydrophobicity of 4HPR, 4HPR-polyvinylpyrrolidone (PVP) amorphous solid dispersions(ASDs) were prepared for solubility enhancement. The optimal PVP-4HPR ratio of 9/1(w/w) provided a 50-fold solubility enhancement in aqueous media, which was sustained over 1 week. PVP-4HPR ASD particles were loaded into PLGA millicylinders and drug release was evaluated in vitro in PBST and in vivo by recovery from subcutaneous injection in rats. While initial formulations of PLGA PVP-4HPR millicylinders only released 10% 4HPR in vitro after 28 days, addition of the plasticizer triethyl-o-acetyl-citrate(TEAC) into PVP-4HPR ASDs resulted in a 5.6-fold total increase in drug release. Remarkably, the TEAC-PVP-4HPR PLGA implants demonstrated slow, continuous, and nearly complete release over 1 month in vivo compared to a 25% release for our previously reported formulation incorporating solubilizers and pore-forming agents. Hence, a combination of PLGA plasticizer and ASD formation provides an avenue for long-term controlled release in vivo for the exceptionally difficult drug to formulate, 4HPR, and a suitable formulation for future evaluation in rodent models of oral cancer. [ABSTRACT FROM AUTHOR]

Summary: Studies show an association between sanguinarine, the active ingredient in Viadent® oral health care products, and oral premalignant lesions. The study was undertaken to quantitatively compare the staining profiles of sanguinarine-associated leukoplakia to normal and dysplastic specimens. Archived oral mucosal specimens were stained for tumor markers p16, p53, cyclin D1, Ki-67, and Bcl-x and analyzed through Simple PCI® image analysis software. Quantitative analyses showed trends towards intermediate staining in Viadent®-related specimens (Ki-67: normal: 18.12±2.15, Viadent®: 16.12±2.16, dysplasia: 14.53±2.04, p>0.05; cyclin D1: normal: 15.65±3.68, Viadent®: 12.52±3.57, dysplasia: 1.94±3.93, p<0.05; p16: normal: 55.04±4.16, Viadent®: 49.74±4.16, dysplasia: 45.03±4.45; p>0.05; p53:normal: 2.65±1.37, Viadent®: 4.64±1.52, dysplasia: 8.71±1.37; p<0.05 Kruskal Wallace, Tukey/Kramer). Our Viadent® profiles, intermediate between normal and dysplasia, support a preneoplastic nature of this process. [Copyright &y& Elsevier]