Faculty Bibliography

Purpose: Oral squamous cell carcinoma (SCC) invasion and metastasis result in treatment failure and correlate with increased pain. We have previously shown that the "endothelin axis," consisting of endothelin A and B receptors (ETAR and ETBR), mediates oral SCC pain, and that inhibiting ETAR with macitentan alleviates pain. We now hypothesize that the endothelin axis also mediates oral SCC growth and metastasis. We explore the therapeutic effect of concurrent ETAR antagonism (with macitentan) and ETBR re-expression on oral SCC growth and invasion in vitro and in vivo. Methods: We quantified the effect of macitentan treatment and targeted ETBR re-expression on oral SCC cell invasion and proliferation, in vitro indices of metastasis and growth, using a Matrigel invasion chamber assay and the Real Time Cell Analyzer (RTCA). We then created an oral SCC mouse model to determine the effect of macitentan treatment on oral SCC growth. Results: Macitentan treatment or ETBR re-expression alone significantly inhibited oral SCC proliferation and invasion in a dose-dependent manner; macitentan combined with ETBR re-expression had the strongest inhibitory effect on cancer proliferation and invasion. In the oral SCC mouse model, macitentan treatment and ETBR re-expression had significant anti-proliferative and anti-metastatic effects compared to control treatment. Conclusion: Our strategy of targeting the endothelin axis inhibited cancer growth and invasion in vitro and in a preclinical model. These results establish the therapeutic potential of macitentan, an orally available ETAR antagonist, for oral SCC metastasis

Reconstruction of large maxillary and mandibular defects following ablative surgery has posed a challenge to the head and neck surgeon due to the high functional and esthetic demands requiring precise three-dimensional reconstruction. Previous issues with maxillofacial reconstruction have included poor facial contour, unfavorable orthognathic relationships, and inability to provide adequate dental rehabilitation. The advent of the fibula flap along with (3D) facial analysis and virtual surgical simulation has revolutionized surgical interventions of the head and neck. Recent reports on the long-term success of dental implants in fibula reconstructions have made dental rehabilitation a reality. However, the loading and restoration of these implants are usually delayed prior to final prosthodontic rehabilitation leading to adverse functional, esthetic and psychological effects. Rohner et al. has documented the success of a two-stage surgery of fibula harvest and dental implant placement (Stage 1) followed by ablative surgery, inset and immediate loading with a dental prosthesis (Stage 2)⁽²⁾; this procedure is a two stage process that involves a 10-week delay between each surgery and will leave the patient edentulous. At our institution, computer-aided surgery and CAD/CAM technologies have enabled us to virtually plan complex surgery and have afforded our group the opportunity of providing a "Jaw in a Day '¹ This technique is a one-stage complete surgery including ablation, free flap, implant, and prosthetic reconstruction. A retrospective chart review was conducted for all patients who received immediate dental implants with a dental prosthesis in a fibular free flap following mandibular resection due to benign tumors. "Jaw in a Day 'procedures were completed at two of our affiliated hospitals (Bellevue Hospital Center and NYU Langone Medical Center) from January 2011 to January 2015. We looked at success rate of flaps, implants, and prostheses. We also looked at primary and long-term complications. Of the 8 patients who underwent the above procedure, a total of 35 immediate implants were placed along with a fixed prosthesis. Patients received maxillary/mandibular resection, fibula free flap reconstruction with immediate implant and dental prosthesis placement. All patients treated were diagnosed with benign mandibular (7) and maxillary (1) tumors, including ameloblastoma (6), odontogenic myxoma (1), and AV malformation (1). Of the 35 implants placed, 1 implant failed and was removed. The cumulative survival of fibular-free flaps was 100%. The cumulative implant success rate was 97%. Complications included soft tissue perimplantitis (2), plate exposure (2), and (1) prosthesis that did not adequately fit. The followup of the 8 patients was from January 2011 to January 2015. Single-stage maxillofacial reconstruction with virtual surgical planning has greatly impacted the field of maxillofacial reconstruction allowing for precision and accuracy while improving patient's function and quality of life. The above study shows its feasibility and low complication rates. Immediate implant and dental prosthesis placement has helped reduce the time for dental prosthetic rehabilitation and avoid the traditional 3- to 6-month delay period. Reconstruction with a MVFFF and immediate dental rehabilitation has revolutionized the treatment of benign tumor following ablative surgery

With the advent of the microvascular fibula free flap (MVFFF), maxillofacial reconstruction following ablative surgery has been a viable solution for patients with large maxillary or mandibular defects. Furthermore, total maxillofacial reconstruction in a two-stage process, where the fibula is harvested and dental implants placed (Stage I) followed by ablative surgery, inset and immediate loading with a dental prosthesis (Stage 2) has been well documented.1 This procedure, however, requires two separate surgical procedures and a delay of at least 10 weeks between each stage where the patient is often left partially or completely edentulous. The incorporation of computer-aided surgical simulation (CASS) and computer-aided design/computer-aided manufacturing (CAD/CAM) has made it possible to not only complete total maxillofacial reconstruction from tumor ablationto immediate insertion of an implant-retained dental prosthesis in a single OR procedure, butithas also increased the predictability and accuracy of maxillofacial reconstruction and decreased intraoperative time.2 Patients requiring more complex maxillofacial reconstruction heavily benefit from increased precision of the final surgical outcome as the accuracy of each osteotomy influences subsequent steps. The aim of our study is to assess the predictability and accuracy of virtually planned, single-stage total maxillofacial reconstruction, also known as 'Jaw in a Day'.³ We conducted a retrospective chart review of all patients who underwent maxillofacial tumor ablation, MVFFF reconstruction, implant placement and immediate implant loading with a dental prosthesis in a single OR procedure. These procedures were completed at Bellevue Hospital Center and NYU Langone Medical Center from January 2011 to January 2015. All cases were virtually planned with Medical Modeling (Golden, CO), and stereolithographic models, osteotomy guides, implant guides, and dental prosthesis were fabricated via CAD/CAM technology. To determine the precision and accuracy of the post-surgical outcomes, we compared the final positions of the implants and fibula on postoperative CT imaging with the planned positions of the implants and fibula based on preoperative virtual planning with Medical Modeling. A total of 8 patients underwent tumor ablation, MVFFF reconstruction, implant placement and immediateimplant loading with a dental prosthesis in a single OR procedure. All patients were diagnosed with benign mandibular (7) and maxillary (1) tumors, including ameloblastoma (6), odontogenic myxoma (1), and AVmalformation (1).Atotal of 35implants were placed with satisfactory primary stability at the time of surgery. On average, the final positions of the implants placed were within 2mm of the virtually treatment planned positions within the fibula. To date, there have been no flap failures and only one implant has failed osseointegration into the MVFFF. Total maxillofacial reconstruction via CASS and CAD/CAM technology has made it possible for surgeons to complete these procedures with high precision and accuracy while minimizing intraoperative time. Additionally, immediate dental rehabilitation is possible at the time of ablation, eliminating the period of edentulism for these patients. Given the highly predictable and accurate postoperative outcomes and low complications rates of virtually planned total maxillofacial reconstruction with a MVFFF and immediate dental rehabilitation, this technique is quickly becoming the standard of care for patients requiring complex maxillofacial reconstruction

INTRODUCTION: Fractures of the orbital-maxillo-zygomatic complex are among the most common fractures affecting the facial skeleton. Goal of surgical treatment is the realignment of fracture lines for a complete functional and aesthetic rehabilitation. MATERIALS AND METHODS: From January 2008 to January 2011 in the Department of Maxillofacial Surgery of Complesso Integrato Columbus of the Universita Cattolica del Sacro Cuore in Rome, 25 patients, affected by comminute fractures of the anterior wall of the maxillary sinus associated with fractures of the orbital-maxillary complex were selected. The synthesis of the larger fracture fragments was performed by plates and screws (1.5 mm) while a biocompatible glue (N-Butyl-2-Cyanoacrylate-Glubran2((R))) was applied to treat the comminute fractures of the anterior wall of the maxillary sinus. RESULTS AND CONCLUSION: The aim of our article is to report our experience and a review of the literature on application of-Butyl-2-Cyanoacrylate for treatment of comminute fractures of the anterior wall of the maxillary sinus. According to the results achieved in our study the N-Butyl-2-Cyanoacrylate can be indicated to treat comminuted fractures of the anterior wall of the maxillary sinus which could not easily be treated with internal rigid fixation.

Background: Comparison of long-term survival of patients with clinical Stage I non-smallcell lung cancer (NSCLC) with and without mediastinal lymph node resection (MLNR) in the International Early Lung Cancer Action Program, a large prospective cohort in a lowdose CT screening program. Methods: All instances of thoracic surgery for first solitary primary non-small-cell lung cancer prompted by low-dose CT screening, performed under an IRB approved common protocol at each of the participating institutions since 1992 to 2014, are included. Follow-up time was calculated from diagnosis to death from lung cancer, last contact, or December 31, 2014, whichever came first. Univariate logistic regression analysis of the demographic, CT, and surgical findings for those with and without MLNR was performed. Kaplan-Meier (K-M) survival rates and Cox regression analysis was performed using all significant univariate variables. Results: The 10-year Kaplan-Meier (K-M) NSCLC-specific survival rate for the 225 patients manifesting as a subsolid nodule was 100%, regardless of whether they had MLNR (N = 169) or not (N = 56). For the 373 NSCLC patients manifesting as a solid nodule, for those who had MLNR (N = 285) and those who did not (N = 88), the K-M NSCLC-survival rate was not significantly different (86 % vs. 93%, P = 0.23). The rate was 95% vs. 96% (P = 0.86) for those whose pathologic tumor diameter was <= 10 mm; 83% vs. 94% (P = 0.19) for 11-20 mm, and 79% vs. 86% (P = 0.67) for 21-20 mm. Cox regression analysis comparing MLNR with no MLNR showed that survival rates were not significantly different (P = 0.33), but significantly survival decreased when the tumor diameter was above 20 mm (HR= 5.1, 95% CI: 1.6-15.7). Conclusion: Lymph node evaluation is not necessary for resection of subsolid nodules in patients with screen-detected lung cancer

Background: Tumor hypoxia is associated with chemo- and radioresistance and is a prevalent characteristic in tumors of patients with non-small cell lung cancer (NSCLC). Evofosfamide (previously known as TH-302) is a hypoxia-activated prodrug designed to release the bis-alkylating DNA crosslinker bromo-isophosphoramide mustard (Br-IPM) when reduced in severe hypoxia. In a Phase 1/2 study (NCT00743379) that included a single arm evofosfamide in combination with pemetrexed in 18 patients with relapsed/ refractory non-squamous NSCLC, median PFS was 7.0 months and median OS was 14.9 months. Response in 15 evaluable patients: 6 partial responses (4 confirmed), 6 stable disease and 3 progressive disease. The most common adverse events were fatigue, anemia, stomatitis and nausea. Methods: An international, multicenter, randomized, double-blind, placebo-controlled trial was initiated to evaluate evofosfamide in combination with pemetrexed versus placebo and pemetrexed as a potential secondline treatment for patients with non-squamous NSCLC (NCT02093962). Approximately 440 patients will be enrolled with histologically confirmed stage IIIB or IV NSCLC with non-squamous histology, measurable disease according to RECIST 1.1, and ECOG performance status 0-1. Eligible patients have recurrent or progressive disease after one prior platinum-based non-pemetrexed chemotherapy treatment for advanced disease with or without maintenance. EGFR-activating and ALK rearrangements status must be known, and if identified, patients must have received a targeted kinase inhibitor. Evofosfamide (400 mg/m²) or matched placebo is administered by IV infusion over 30 - 60 minutes on Day 1 and Day 8 of a 21-day cycle. Pemetrexed (500 mg/m²) is administered by IV infusion 2 to 4 hours after evofosfamide administration on Day 1. Overall survival (OS) is the primary endpoint; secondary endpoints include safety, progression-free survival and RECIST response rate. The study design has 85% power to detect a 40% improvement in OS with a one-sided alpha of 0.025. The first patient was enrolled in June 2014; recruitment is ongoing

BACKGROUND:Nonsteroidal anti-inflammatory drugs have become an important component of narcotic-sparing postoperative pain management protocols. However, conflicting evidence exists regarding the adverse association of nonsteroidal anti-inflammatory drug use with intestinal anastomotic healing in colorectal surgery. OBJECTIVE:This study compares patients receiving nonsteroidal anti-inflammatory drugs on postoperative day 1 with patients who did not receive nonsteroidal anti-inflammatory drugs with regard to the occurrence of anastomotic leaks. DESIGN/METHODS:This is a retrospective study from a protocol-driven prospectively collected statewide database. A propensity score model was used to adjust for differences between the groups in patient demographics, characteristics, comorbidities, and laboratory values. SETTINGS/METHODS:The multicenter data set used in this analysis represents a variety of academic and community hospitals within the state of Michigan from July 2012 through February 2014. PATIENTS/METHODS:Nonpregnant patients over the age of 18 who underwent colon and rectal surgery with bowel anastomosis were selected. MAIN OUTCOME MEASURES/METHODS:Occurrence of anastomotic leak, composite surgical site infection, sepsis, and death within 30 days of surgery were the primary outcomes measured. RESULTS:A total of 4360 patients met inclusion criteria, of which 1297 (29.7%) received nonsteroidal anti-inflammatory drugs and 3063 (70.3%) did not receive nonsteroidal anti-inflammatory drugs. There was no statistically significant difference between the 2 groups in the proportion of cases with anastomotic leak (OR, 1.33; CI, 0.86-2.05; p = 0.20), composite surgical site infection (OR, 1.26; CI, 0.96-1.66; p = 0.09), or death within 30 days (OR, 0.58; CI, 0.28-1.19; p = 0.14). There was a significantly greater risk of sepsis for patients given nonsteroidal anti-inflammatory drugs than for those patients not given nonsteroidal anti-inflammatory drugs (OR, 1.47; CI, 1.05-2.06; p = 0.03). LIMITATIONS/CONCLUSIONS:This is a nonrandomized study performed retrospectively, and it is based on data collected only within a subset of hospitals in the state of Michigan. CONCLUSIONS:No statistically significant increase in the proportion of patients with anastomotic leak was observed when prescribing nonsteroidal anti-inflammatory drugs for analgesia in the early postoperative period for patients undergoing elective colorectal surgery. Unexpectedly, there was an increased risk of sepsis that warrants further investigation (see video, Supplemental Digital Content 1, http://links.lww.com/DCR/A192, for a synopsis of this study).

Perioperative infection is the most common and dreaded complication associated with tissue expander (TE) breast reconstruction. Historically, the expansion period was thought to be the time of greatest hazard to the implant. However, recent institutional observations suggest infectious complications occur prior to expansion. This investigation, therefore, was conducted to determine the timing of infectious complications associated with two-stage TE breast reconstructions. Following IRB approval, a retrospective review of all consecutive two-stage immediate TE breast reconstructions at a single institution from November 2007 to November 2011 was conducted. Reconstructions were then divided into two cohorts: those suffering infectious complications and those that did not. Infectious complications including minor cellulitis, major cellulitis, abscess drainage, and explantation were identified. Various operative and patient variables were evaluated in comparison. Eight hundred ninety immediate two-stage TE breast reconstructions met inclusion criteria. Patients suffering infection were older (55.4 years versus 49.3 years; p < 0.001), and more likely to have therapeutic mastectomy (94% versus 61%; p < 0.0001), the use of acellular dermal matrix (ADM; 72.5% versus 54.9%; p = 0.001), and greater initial TE fill (448.6 mL versus 404.7 mL; p = 0.0078). The average time to developing of infectious symptoms was 29.6 days (range 9-142 days), with 94.6% (n = 87) of infections prior to the start of expansion. Perioperative infections in immediate two-stage TE to implant breast reconstructions are significant and occur mostly prior to the start of expansion. Thus, challenging the conventional wisdom that instrumentation during expander filling as the primary cause of implant infections. Possible etiologic factors include greater age, therapeutic mastectomy versus prophylactic mastectomy, larger initial TE fill, and the use of ADM.

PURPOSE: Implant design and the implant-abutment interface have been regarded as key influences on crestal bone maintenance over time. The aim of the present study was to determine crestal bone changes around implants placed at different depths in a dog model. MATERIALS AND METHODS: Thirty-six two-piece dental implants with a medialized implant-abutment interface and Morse taper connection (Ankylos, Dentsply) were placed in edentulous areas bilaterally in six mongrel dogs. On each side of the mandible, three implants were placed randomly at the bone crest, 1.5 mm subcrestally, or 3.0 mm subcrestally. After 3 months, the final abutments were torqued into place. At 6 months, the animals were sacrificed and samples taken for microcomputed tomographic (micro-CT) and histologic evaluations. RESULTS: Micro-CT analysis revealed similar crestal or marginal bone loss among groups. Both subcrestal implant groups lost significantly less crestal and marginal bone than the equicrestal implants. Bone loss was greatest on the buccal of the implants, regardless of implant placement depth. Histologically, implants placed subcrestally were found to have bone in contact with the final abutment and on the implant platform. CONCLUSION: Implants with a centralized implant-abutment interface and Morse taper connection can be placed subcrestally without significant loss of crestal or marginal bone. Subcrestal placement of this implant system appears to be advantageous in maintaining bone height coronal to the implant platform.

Although preclinical and sparse human histology retrieval studies have shown that the interface between implant and bone is constantly remodeling, no human retrieval database has been developed to determine the effect of functional loading time and other clinical/implant design variables on osseointegration. The present study tested the hypothesis that bone-to-implant contact (BIC) and bone area fraction occupancy (BAFO) increase over functional loading time around dental implants. Due to prosthetic retreatment reasons, 93 human implant retrievals from the same manufacturer (Bicon LLC, Boston, MA, USA) were obtained over a period of approximately 15 years. The retrieved implants were under functional loading from 120 days to approximately 18 years and were histomorphologic/metrically evaluated. BIC/BAFO were assessed as a function of multiple independent variables: implant surface type, diameter, length, jaw (maxilla/mandible), region (anterior/posterior), and time of functional loading. The results showed that both BIC and BAFO increased over time independently of implant design/clinical variables, supporting the postulated hypothesis. (c) 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2014.