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ItemAssessment of p63 expression in the salivary gland neoplasms adenoid cystic carcinoma, polymorphous low-grade adenocarcinoma, and basal cell and canalicular adenomas(2004-05) Edwards, Paul C.; Bhuiya, Tawfiqul; Kelsch, Robert DPurpose The purpose of this study was to determine the extent of p63 immunoreactivity in the malignant salivary gland neoplasms adenoid cystic carcinoma (ACC) and polymorphous low-grade adenocarcinoma (PLGA) and to compare this to the expression of this marker in the benign salivary gland tumors canalicular adenoma and basal cell adenoma. Few studies on the expression of p63 in head and neck salivary gland tumors have been published to date. P63, a selective immunohistochemical marker of basal/stem cells of stratified epithelium and of myoepithelial cells, is a p53 homologue that plays an essential role in both morphogenesis of epidermis and limb development. P63 immunoreactivity has been demonstrated in squamous cell and urothelial carcinomas. It is generally absent in most nonsquamous cell carcinomas. Study design Formalin-fixed paraffin-embedded sections from 49 salivary gland neoplasms, representing 6 canalicular adenomas, 11 basal cell adenomas, 17 PLGA and 15 ACC accessioned from 1989 to 2002 by the Department of Pathology, Long Island Jewish Medical Center, New Hyde Park, NY, were stained with an anti-p63 monoclonal antibody. Results Nuclear p63 reactivity was uniformly positive in PLGA (17/17, 100%). Positive reactivity was also identified in the majority of cases of ACC (13/15, 87%), primarily in the nonluminal myoepithelial-like cells surrounding luminal cells. Canalicular adenoma did not exhibit any p63 immunoreactivity. All basal cell adenomas of parotid origin stained strongly for p63, with staining localized to the peripheral tumor cells situated adjacent to the connective tissue stroma. None of the basal cell adenomas originating in the upper lip stained with p63. In native adjacent salivary gland tissue, p63 reactivity was identified focally in the nuclei of myoepithelial and basal duct cells. Conclusions P63 is strongly expressed in basal cell adenoma of parotid origin, and in ACC and PLGA. Canalicular adenoma did not demonstrate p63 staining, consistent with this tumor's putative luminal ductal cell differentiation. Our results suggest that the neoplastic cells in PLGA may represent either a population of p63-positive epithelial stem/reserve cells similar to the basal cells of stratified epithelium, or modified myoepithelial cells. Given the staining pattern of the tumors examined, p63 does not appear to be an ideal marker for distinguishing between ACC, PLGA, and basal cell adenoma. ItemAssessment of Salivary Adipokines Resistin, Visfatin, and Ghrelin as Type 2 Diabetes Mellitus Biomarkers(Hindawi Publishing Corporation, 2018-02-01) Srinivasan, Mythily; Meadows, Melinda L.; Maxwell, Lisa; Oral Pathology, Medicine and Radiology, School of DentistryType 2 diabetes mellitus (T2DM) is emerging as a metabolic epidemic worldwide. Pathologically, dysregulation of many biological pathways precedes hyperglycemia and the clinical diagnosis of T2DM. Changing trajectories along the process of T2DM development necessitates frequent measurement of biomarkers for early identification of at-risk individuals and successful prevention. Increase in circulating inflammatory adipokines has been suggested as predictive of T2DM. Human saliva is an easily accessible biospecimen amenable for painless frequent collection and possesses nearly 50% of serum proteome. In this study, we measured the adipokines resistin, visfatin, TNF-α, and ghrelin as markers for T2DM in unstimulated whole saliva (UWS) using specific assay kits. Resistin and visfatin concentrations were significantly higher in T2DM saliva. Although the concentration of acylated or unacylated ghrelin was lower in diabetic saliva, the decrease was not significant. Since resistin and visfatin are biomarkers integral to T2DM pathology, their salivary assessments may receive clinical acceptance. ItemBilateral Central Giant Cell Granulomas of the Mandible in An Eight Year-Old Girl with Noonan Syndrome (Noonan-Like/Multiple Giant Cell Lesions Syndrome)(2005-03) Edwards, Paul C.; Fox, Joyce; Fantasia, John E; Goldberg, Jeff; Kelsch, Robert DA number of conditions can present with lesions that histologically are indistinguishable from the central giant cell granuloma (CGCG) of bone, including brown tumors of hyperparathyroidism, cherubism, and, less commonly, a number of inherited syndromes. We report a case of an eight-year girl who presented with bilateral CGCGs of the posterior mandible. Characteristic facial features, reported increased post-operative bleeding and history of pulmonary stenosis led us to suspect a diagnosis of Noonan syndrome. A medical geneticist confirmed this on further evaluation. This case report will discuss the salient features of this diagnosis. ItemBisphosphonates Inhibit Expression of p63 by Oral Keratinocytes(2011-07) Scheller, E L; Baldwin, C M; Kuo, S; D'Silva, N J; Feinberg, S E; Krebsbach, P H; Edwards, Paul C.Osteonecrosis of the jaw (ONJ), a side-effect of bisphosphonate therapy, is characterized by exposed bone that fails to heal within eight weeks. Healing time of oral epithelial wounds is decreased in the presence of amino-bisphosphonates; however, the mechanism remains unknown. We examined human tissue from individuals with ONJ and non-bisphosphonate-treated controlindividuals to identify changes in oral epithelium and connective tissue. Oral and intravenous bisphosphonate-treated ONJ sites had reduced numbers of basal epithelial progenitor cells, as demonstrated by a 13.8 ± 1.1% and 31.9 ± 5.8% reduction of p63 expression, respectively. No significant differences in proliferation rates, vessel density, or macrophage number were noted. In vitro treatment of clonal and primary oral keratinocytes with zoledronic acid (ZA) inhibited p63, and expression was rescued by the addition of mevalonate pathway intermediates. In addition, both ZA treatment and p63 shRNA knock-down impaired formation of 3D Ex Vivo Produced Oral Mucosa Equivalents (EVPOME) and closure of an in vitro scratch assay. Analysis of our data suggests that bisphosphonate treatment may delay oral epithelial healing by interfering with p63-positive progenitor cells in the basal layer of the oral epithelium in a mevalonate-pathway-dependent manner. This delay in healing may increase the likelihood of osteonecrosis developing in already-compromised bone. ItemC-kit expression in the salivary gland neoplasms adenoid cystic carcinoma, polymorphous low-grade adenocarcinoma, and monomorphic adenoma(2003-05) Edwards, Paul C.; Bhuiya, Tawfigul; Kelsch, Robert DObjective. Differentiating between adenoid cystic carcinomas (ACCs), polymorphous low-grade adenocarcinomas (PLGAs), and the monomorphic adenomas (including canalicular adenomas, trabecular adenomas, and basal cell adenomas) can present a diagnostic challenge, especially when examining tissue obtained from small incisional or fragmented biopsies. Recent studies have revealed that overexpression of the tyrosine kinase receptor protein c-kit occurs in a narrow subset of malignant neoplasms, including gastrointestinal stromal tumors, myeloid leukemias, seminomas, and ACCs. C-kit reportedly is not expressed in PLGAs. We compared the expression of the c-kit antigen in the malignant salivary gland neoplasms ACC and PLGA with its expression in salivary gland monomorphic adenoma (including canalicular adenoma and basal cell adenoma). Study design. Formalin-fixed paraffin-embedded sections of 49 salivary gland neoplasms (17 monomorphic adenomas, 17 PLGAs, and 15 ACCs) accessioned between 1989 and 2002 were retrieved from the files of the Department of Pathology, Long Island Jewish Medical Center, and were stained with an anti-c-kit polyclonal antibody. Results. C-kit reactivity was uniformly positive in the cytoplasm of luminal neoplastic cells in ACCs (15/15, 100%). Positive reactivity was also identified in the majority of PLGAs (16/17, 94%), with at least 25% of the tumor cells being positive. Similar reactivity was seen in monomorphic adenomas (16/17, 94%). Conclusions. In contrast to previous reports, we find that c-kit expression was not restricted to ACC but was expressed in all 3 tumor types evaluated (ACC, PLGA, and monomorphic adenoma). Therefore, c-kit does not appear to be a useful marker for distinguishing between either ACC and PLGA in equivocal cases, or in benign and malignant salivary gland neoplasms. ItemCERE-120 Prevents Irradiation-Induced Hypofunction and Restores Immune Homeostasis in Porcine Salivary Glands(Elsevier, 2020-09-11) Lombaert, Isabelle M. A.; Patel, Vaishali N.; Jones, Christina E.; Villier, Derrick C.; Canada, Ashley E.; Moore, Matthew R.; Berenstein, Elsa; Zheng, Changyu; Goldsmith, Corinne M.; Chorini, John A.; Martin, Daniel; Zourelias, Lee; Trombetta, Mark G.; Edwards, Paul C.; Meyer, Kathleen; Ando, Dale; Passineau, Michael J.; Hoffman, Matthew P.; Oral Pathology, Medicine and Radiology, School of DentistrySalivary gland hypofunction causes significant morbidity and loss of quality of life for head and neck cancer patients treated with radiotherapy. Preventing hypofunction is an unmet therapeutic need. We used an adeno-associated virus serotype 2 (AAV2) vector expressing the human neurotrophic factor neurturin (CERE-120) to treat murine submandibular glands either pre- or post-irradiation (IR). Treatment with CERE-120 pre-IR, not post-IR, prevented hypofunction. RNA sequencing (RNA-seq) analysis showed reduced gene expression associated with fibrosis and the innate and humoral immune responses. We then used a minipig model with CERE-120 treatment pre-IR and also compared outcomes of the contralateral non-IR gland. Analysis of gene expression, morphology, and immunostaining showed reduced IR-related immune responses and improved secretory mechanisms. CERE-120 prevented IR-induced hypofunction and restored immune homeostasis, and there was a coordinated contralateral gland response to either damage or treatment. CERE-120 gene therapy is a potential treatment for head and neck cancer patients to influence communication among neuronal, immune, and epithelial cells to prevent IR-induced salivary hypofunction and restore immune homeostasis. ItemChronic fibrosing osteomyelitis of the jaws: an important cause of recalcitrant facial pain. A clinicopathologic study of 331 cases in 227 patients(Elsevier, 2017) Goldblatt, Lawrence I.; Adams, William R.; Spolnik, Kenneth J.; Deardorf, Kevin A.; Parks, Edwin T.; Department of Oral Pathology, Medicine and Radiology, School of DentistryObjective This was a retrospective and follow-up analysis of 331 cases of chronic fibrosing osteomyelitis of the jaws (CFOJ) in 227 patients. Study Design Demographic, clinical, surgical, and microscopic characteristics were tabulated for all patients. A follow-up mail survey was used to determine the degree of symptom relief experienced after surgery. Results The female to male ratio approached 7:1, and mean age of patients was 53 years. The most common sites were the mandibular posterior region, followed by the maxillary posterior region. Consistent clinical findings included intractable jaw pain mimicking that of odontogenic origin but unresponsive to usual therapies, minimal or undetectable radiographic abnormalities on plain films but dramatic radiolucencies detected on cone beam computed tomography, and large cavities that were either empty or filled with blood mixed with lipid globules encountered at surgery. The most common histomorphologic findings were vital lamellar bone, prominent resting and reversal lines, microshards and splaying of trabeculae, rounded trabeculae, marrow fibrosis, and pools of erythrocytes and lipid globules, often together. Moderate to complete relief of symptoms for periods up to 108 months after surgery were reported by 83% of the 70 patients who returned the survey. Conclusions On the basis of the findings of this study, CFOJ can be considered a unique entity with consistent clinicopathologic features. Its features suggest a pathogenesis based on bone marrow ischemia. CFOJ can be treated on a rational basis with a justifiable expectation of success and probable cure. ItemClinically aggressive central giant cell granulomas in two patients with neurofibromatosis 1(2006-12) Edwards, Paul C.; Fantasia, John E; Saini, Tamjit; Rosenberg, Tracey J; Sachs, Stephen A; Ruggiero, SalvatoreBackground Neurofibromatosis 1 (NF1) is an autosomal dominantly inherited disorder caused by a spectrum of mutations affecting the Nf1 gene. Affected patients develop benign and malignant tumors at an increased frequency. Clinical findings include multiple cutaneous café-au-lait pigmentations, neurofibromas, axillary freckling, optic gliomas, benign iris hamartomas (Lisch nodules), scoliosis, and poorly defined soft tissue lesions of the skeleton. Kerl first reported an association of NF1 with multiple central giant cell granulomas (CGCGs) of the jaws. There have since been 4 additional published cases of NF1 patients with CGCGs of the jaws. Clinical cases We report on 2 patients who presented with NF1 and aggressive CGCGs of the jaws. In both cases, the clinical course was characterized by numerous recurrences despite mechanical curettage and surgical resection. Conclusions We review proposed mechanisms to explain the apparent association between NF1 and an increased incidence of CGCGs of the jaws. While the presence of CGCGs of the jaws in patients with NF1 could represent either a coincidental association or a true genetic linkage, we propose that this phenomenon is most likely related to NF1-mediated osseous dysplasia. Compared to normal bone, the Nf1-haploinsufficient bone in a patient with NF1 may be less able to remodel in response to as of yet unidentified stimuli (e.g. excessive mechanical stress and/or vascular fragility), and consequently may be more susceptible to developing CGCG-like lesions. Alternatively, the CGCG in NF1 patients could represent a true neoplasm, resulting from additional, as of yet unidentified, genetic alterations to Nf1-haploinsufficient bone. ItemComparison of Anesthesia for Dental/Oral Surgery by Office-based Dentist Anesthesiologists versus Operating Room-based Physician Anesthesiologists(Allen Press, 2017) Saxen, Mark A.; Urman, Richard D.; Yepes, Juan F.; Gabriel, Rodney A.; Jones, James E.; Oral Pathology, Medicine and Radiology, School of DentistryFew studies have examined the practice characteristics of dentist anesthesiologists and compared them to other anesthesia providers. Using outcomes from the National Anesthesia Clinical Outcomes Registry and the Society for Ambulatory Anesthesia Clinical Outcomes Registry for dental/oral surgery procedures, we compared 7133 predominantly office-based anesthetics by dentist anesthesiologists to 106,420 predominantly operating room anesthetics performed by physician anesthesia providers. These encounters were contrasted with 34,191 previously published encounters from the practices of oral and maxillofacial surgeons. Children younger than 6 years received the greatest proportion of general anesthetic services rendered by both dentist anesthesiologists and hospital-based anesthesia providers. These general anesthesia services were primarily provided for complete dental rehabilitation for early childhood caries. Overall treatment time for complete dental rehabilitation in the office-based setting by dentist anesthesiologists was significantly shorter than comparable care provided in the hospital operating room and surgery centers. The anesthesia care provided by dentist anesthesiologists was found to be separate and distinct from anesthesia care provided by oral and maxillofacial surgeons, which was primarily administered to adults for very brief surgical procedures. Cases performed by dentist anesthesiologists and hospital-based anesthesia providers were for much younger patients and of significantly longer duration when compared with anesthesia administered by oral and maxillofacial surgeons. Despite the limited descriptive power of the current registries, office-based anesthesia rendered by dentist anesthesiologists is clearly a unique and efficient mode of anesthesia care for dentistry. ItemCone beam CT evaluation of the presence of anatomic accessory canals in the jaws(2014-05) Eshak, M; Brooks, S; Abdel-Wahed, N; Edwards, Paul C.Objectives: To assess the prevalence, location and anatomical course of accessory canals of the jaws using cone beam CT. Methods: A retrospective analysis of 4200 successive cone beam CT scans, for patients of both genders and ages ranging from 7 to 88 years, was performed. They were exposed at the School of Dentistry, University of Michigan, Ann Arbor, MI. After applying the exclusion criteria (the presence of severe ridge resorption, pre-existing implants, a previously reported history of craniofacial malformations or syndromes, a previous history of trauma or surgery, inadequate image quality and subsequent scans from the same individuals), 4051 scans were ultimately included in this study. Results: Of the 4051 scans (2306 females and 1745 males) that qualified for inclusion in this study, accessory canals were identified in 1737 cases (42.9%; 1004 females and 733 males). 532 scans were in the maxilla (13.1%; 296 females and 236 males) and 1205 in the mandible (29.8%; 708 females and 497 males). Conclusions: A network of accessory canals bringing into communication the inner and outer cortical plates of the jaws was identified. In light of these findings, clinicians should carefully assess for the presence of accessory canals prior to any surgical intervention to decrease the risk for complications.