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Oral mucosal injury caused by mammalian target of rapamycin inhibitors: emerging perspectives on pathobiology and impact on clinical practice

Peterson, Douglas E; O'Shaughnessy, Joyce A; Rugo, Hope S; Elad, Sharon; Schubert, Mark M; Viet, Chi T; Campbell-Baird, Cynthia; Hronek, Jan; Seery, Virginia; Divers, Josephine; Glaspy, John; Schmidt, Brian L; Meiller, Timothy F
In recent years oral mucosal injury has been increasingly recognized as an important toxicity associated with mammalian target of rapamycin (mTOR) inhibitors, including in patients with breast cancer who are receiving everolimus. This review addresses the state-of-the-science regarding mTOR inhibitor-associated stomatitis (mIAS), and delineates its clinical characteristics and management. Given the clinically impactful pain associated with mIAS, this review also specifically highlights new research focusing on the study of the molecular basis of pain. The incidence of mIAS varies widely (2-78%). As reported across multiple mTOR inhibitor clinical trials, grade 3/4 toxicity occurs in up to 9% of patients. Managing mTOR-associated oral lesions with topical oral, intralesional, and/or systemic steroids can be beneficial, in contrast to the lack of evidence supporting steroid treatment of oral mucositis caused by high-dose chemotherapy or radiation. However, steroid management is not uniformly efficacious in all patients receiving mTOR inhibitors. Furthermore, technology does not presently exist to permit clinicians to predict a priori which of their patients will develop these lesions. There thus remains a strategic need to define the pathobiology of mIAS, the molecular basis of pain, and risk prediction relative to development of the clinical lesion. This knowledge could lead to novel future interventions designed to more effectively prevent mIAS and improve pain management if clinically significant mIAS lesions develop.
PMCID:4971919
PMID: 27334013
ISSN: 2045-7634
CID: 2158872

The Effect of Laser-Etched Surface Design on Soft Tissue Healing of Two Different Implant Abutment Systems: An Experimental Study in Dogs

Neiva, Rodrigo; Tovar, Nick; Jimbo, Ryo; Gil, Luiz F; Goldberg, Paula; Barbosa, Joao Pm; Lilin, Thomas; Coelho, Paulo G
This study describes the early soft tissue morphology around two different implant systems that received either smooth or laser-etched abutments in a beagle dog model. Implants were placed in the healed mandibular molar region of eight beagle dogs and allowed to heal for 7 weeks. When the most apical aspect of the junctional epithelium (JE) was above or within the upper half of the laser-etched region, fibers were oriented perpendicular to the abutment surface. In contrast, JE positioned within the lower half of the laser-etched region or within or below the implant-abutment gap level presented fibers oriented parallel to the abutment surface.
PMID: 27560671
ISSN: 1945-3388
CID: 2240692

Implant design and its effects on osseointegration over time within cortical and trabecular bone

Beutel, Bryan G; Danna, Natalie R; Granato, Rodrigo; Bonfante, Estevam A; Marin, Charles; Tovar, Nick; Suzuki, Marcelo; Coelho, Paulo G
Healing chambers present at the interface between implant and bone have become a target for improving osseointegration. The objective of the present study was to compare osseointegration of several implant healing chamber configurations at early time points and regions of interest within bone using an in vivo animal femur model. Six implants, each with a different healing chamber configuration, were surgically implanted into each femur of six skeletally mature beagle dogs (n = 12 implants per dog, total n = 72). The implants were harvested at 3 and 5 weeks post-implantation, non-decalcified processed to slides, and underwent histomorphometry with measurement of bone-to-implant contact (BIC) and bone area fraction occupied (BAFO) within healing chambers at both cortical and trabecular bone sites. Microscopy demonstrated predominantly woven bone at 3 weeks and initial replacement of woven bone by lamellar bone by 5 weeks. BIC and BAFO were both significantly increased by 5 weeks (p < 0.001), and significantly higher in cortical than trabecular bone (p < 0.001). The trapezoidal healing chamber design demonstrated a higher BIC than other configurations. Overall, a strong temporal and region-specific dependence of implant osseointegration in femurs was noted. Moreover, the findings suggest that a trapezoidal healing chamber configuration may facilitate the best osseointegration. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2015.
PMID: 26034012
ISSN: 1552-4981
CID: 1615912

Effect of Simplified One-Step Drilling Protocol on Osseointegration

Patel, Arpita; Gil, Luiz F; Castellano, Arthur; Freitas, Gileade; Navarro, Daniel; Peredo, Ana P; Tovar, Nick; Coelho, Paulo
This study was designed to compare the combined effect of two different drilling techniques (conventional expansion and one-step) and four different implant geometries in a beagle dog model. The nondecalcified bone-implant samples underwent histologic/metric analysis at 2 and 6 weeks. Morphologic analysis showed similarities between different drilling technique groups and implant geometries. Histomorphometric parameters, bone-to-implant contact (BIC), and bone area fraction occupancy (BAFO) were analyzed, and no statistical difference between drilling groups and/or implant geometry was found. Time was the only variable that affected BIC and BAFO, suggesting that the two protocols are equally biocompatible and osseoconductive.
PMID: 27560682
ISSN: 1945-3388
CID: 2240682

Microvascular Free Flap for Total Eyelid Reconstruction With a Visually Useful Eye

Ghadiali, Larissa K; Patel, Payal; Levine, Jamie P; Gold, Katherine G; Lisman, Richard D
Total eyelid loss, full thickness loss of the upper and lower eyelids, is uncommon and surgically challenging. Eyelid reconstruction after such injuries can be further complicated by loss of adjacent tissue. When tissue for local flaps is unavailable, free flaps must be considered. Few cases of total eyelid reconstruction via microvascular free flap have been reported, especially with an intact globe and good visual acuity. In this report, we describe the use of a microvascular free flap based on the radial artery for total eyelid reconstruction in a patient with an intact globe and useful visual acuity.
PMID: 25299739
ISSN: 0740-9303
CID: 1300122

Learned intermediary [Editorial]

Jerrold, Laurance
PMID: 27476372
ISSN: 1097-6752
CID: 2198702

Functional assessment of the ex vivo vocal folds through biomechanical testing: A review

Dion, Gregory R; Jeswani, Seema; Roof, Scott; Fritz, Mark; Coelho, Paulo G; Sobieraj, Michael; Amin, Milan R; Branski, Ryan C
The human vocal folds are complex structures made up of distinct layers that vary in cellular and extracellular composition. The mechanical properties of vocal fold tissue are fundamental to the study of both the acoustics and biomechanics of voice production. To date, quantitative methods have been applied to characterize the vocal fold tissue in both normal and pathologic conditions. This review describes, summarizes, and discusses the most commonly employed methods for vocal fold biomechanical testing. Force-elongation, torsional parallel plate rheometry, simple-shear parallel plate rheometry, linear skin rheometry, and indentation are the most frequently employed biomechanical tests for vocal fold tissues and each provide material properties data that can be used to compare native tissue to diseased or treated tissue. Force-elongation testing is clinically useful, as it allows for functional unit testing, while rheometry provides physiologically relevant shear data, and nanoindentation permits micrometer scale testing across different areas of the vocal fold as well as whole organ testing. Thoughtful selection of the testing technique during experimental design to evaluate a hypothesis is critical to optimize biomechanical testing of vocal fold tissues.
PMCID:4851737
PMID: 27127075
ISSN: 1873-0191
CID: 2092662

The drivers of academic success in cleft and craniofacial centers: A ten year analysis of over 2000 publications [Meeting Abstract]

Plana, N; Massie, J; Stern, M; Alperovich, M; Runyan, C; Staffenberg, D; Koniaris, L; Shetye, P; Grayson, B; Diaz-Siso, J R; Flores, R
Background/Purpose: Multidisciplinary Cleft and Craniofacial Centers require significant investment and maintenance by medical schools and/or departments, and yet the variables contributing to their academic productivity remain unknown. This study characterizes the elements that result in high academic productivity in Cleft and Craniofacial Centers. Methods/Descriptions: All cleft and craniofacial centers accredited by American Cleft Palate-Craniofacial Association were included. Vari-ables such as university affiliation (UNI); resident training (RES); number of active surgical and orthodontic faculty (FAC); and investment in a craniofacial surgery (CF) or craniofacial orthodontics (CO) fellowship program, or both (CF+CO), were obtained for each center. All craniofacial and cleft-related research published between July 2005 and June 2015 was identified using the National Library of Medicine database; for each article, journal of publication and impact factor were also recorded. A stepwise multivariable linear regression analysis was performed on the listed variables to outcome measures of total publications, summative impact factor, and basic science publications. Results: A total of 160 centers were identified, comprising 690 active faculty, 29 craniofacial fellowships and 9 orthodontic fellowships; 2,093 articles were published in 199 journals within the study period. Variables most positively associated to a high number of publications were, in order: CF+CO (beta, CF+CO = 0.555, p < 0.001), CF (beta, CF= 0.248, p < 0.001), RES (beta, RES = 0.198, p = 0.003). Variables most positively associated to a high summative impact factor are, in order: CF+CO (beta, CF+CO = 0.551, p < 0.001), CF (beta, CF = 0.313, p < 0.001), FAC (beta, FAC = 0.183, p = 0.006). Variables most positively associated to basic science publications are, in order: CF+CO (beta, CF+CO=0.491, p < 0.001), CF (beta, CF=0.322, p < 0.001), and RES (beta, RES = 0.164, p = 0.032). Conclusions: Participation in both craniofacial surgery and orthodontic fellowships demonstrate the strongest association with academic success; craniofacial fellowship alone, residency programs and number of active faculty are also predictive. Cleft and Craniofacial Centers interested in academic performance should allocate funds and resources into these variables, particularly interdisciplinary partnerships between surgery and dentistry
EMBASE:611868357
ISSN: 1545-1569
CID: 2241242

Feasibility and cost analysis of outpatient alveolar bone graft surgery [Meeting Abstract]

Runyan, C; Stern, M; Massie, J; Flores, R
Background/Purpose: Patients with cleft lip and palate commonly require an alveolar bone graft (ABG) at approximately 8 years old to allow for tooth descent in the location of the alveolar cleft. This procedure was previously performed with at least one post-operative overnight stay due to hip pain. Upon transitioning from an open iliac crest bone harvesting technique to an Acumed drill, we observed that most patients had limited hip pain and were treatable as outpatients. We report feasibility and cost analysis of performed ABG surgery as an outpatient using the Acumed drill technique. Methods/Descriptions: Under IRB-approval, a 3-year retrospective review was conducted of all subjects born with a cleft lip/palate (CLP) and who had an alveolar bone graft performed between 2012 and 2015. Patients were categorized based upon hospital stay: inpatient (overnight stay), observation (23-hour), or outpatient. Prior to April 2013, patients underwent ABG surgery as a planned inpatient procedure (Group 1). After April 2013, patients underwent ABG surgery as a planned outpatient procedure (Group 2). Cost data acquired included: total direct cost (costs associated directly with patient care), total variable direct cost (costs which vary according to the needs of each patient), fixed direct cost (charges that do not fluctuate depending on what is done), and the sum of total direct costs for both medical/surgical supplies and operating room costs. T-tests were used to determine differences in various cost categories between groups of patients. Results: 58 patients were enrolled with a total of 62 procedures (4 patients had 2 ABGs), and with a mean age of 10 years at the time of surgery. 7 procedures were inpatient, 16 were observation, and 39 were outpatient. 7 of 14 Group 1 patients (50%) were admitted as inpatients, whereas 0 of 48 Group 2 patients were inpatients. The total direct costs averaged $4,536 for inpatients, $3,222 for the observation group, and $3,340 for the outpatient group. These inpatient and outpatient costs were significantly different (p<.001). There were significantly reduced total variable direct costs (p<0.05) and fixed direct costs (p<0.001) when comparing the outpatient to inpatient groups. Costs for the observation group were significantly lower in all three cost categories than inpatient costs, but were not significantly different than outpatient costs. Of the 39 outpatient procedures, no patients visited urgent care within 30 days postoperatively, and observation group had two patients visit urgent care. None were readmitted in any group. Conclusions: In ABG surgery done on patients born with a CLP, the costs for an inpatient stay are significantly higher than those of patients discharged the same day or who stay in the hospital for less than 23 hours on observational status. The Acumed drill technique results in improved pain control with no appreciable harms to the outpatient group, allowing for same day discharge
EMBASE:611868406
ISSN: 1545-1569
CID: 2241182

Total Face, Eyelids, Ears, Scalp, and Skeletal Subunit Transplant: A Reconstructive Solution for the Full Face and Total Scalp Burn

Sosin, Michael; Ceradini, Daniel J; Levine, Jamie P; Hazen, Alexes; Staffenberg, David A; Saadeh, Pierre B; Flores, Roberto L; Sweeney, Nicole G; Bernstein, G Leslie; Rodriguez, Eduardo D
BACKGROUND: Reconstruction of extensive facial and scalp burns can be increasingly challenging, especially in patients that have undergone multiple procedures with less than ideal outcomes resulting in restricting neck and oral contractures, eyelid dysfunction, and suboptimal aesthetic appearance. METHODS: To establish a reconstructive solution for this challenging deformity, a multidisciplinary team was assembled to develop the foundation to a facial vascularized composite allotransplantation program. The strategy of developing and executing a clinical transplant was derived on the basis of fostering a cohesive and supportive institutional clinical environment, implementing computer software and advanced technology, establishing a cadaveric transplant model, performing a research facial procurement, and selecting an optimal candidate with the aforementioned burn defect who was well informed and had the desire to undergo face transplantation. RESULTS: Approval from the institutional review board and organ procurement organization enabled our face transplant team to successfully perform a total face, eyelids, ears, scalp, and skeletal subunit transplant in a 41-year-old man with a full face and total scalp burn. CONCLUSIONS: The culmination of knowledge attained from previous experiences continues to influence the progression of facial vascularized composite allotransplantation. This surgical endeavor methodically and effectively synchronized the fundamental principles of aesthetic, craniofacial, and microvascular surgery to restore appearance and function to a patient suffering from failed conventional surgery for full face and total scalp burns. This procedure represents the most extensive soft-tissue clinical face transplant performed to date. CLINICAL QUESTION/LEVEL OF EVIDEMCE: Therapeutic, V.
PMID: 27348652
ISSN: 1529-4242
CID: 2165512