Faculty Bibliography

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: 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: The authors previously described the generation of vascularized bone in a pig model, using a hemimandibular allograft scaffold, adipose-derived stem cells, recombinant human bone morphogenetic protein-2, and periosteum. This study tests the hypothesis that this "allograft revitalization" technique is as effective as vascularized autograft for repairing critical bony defects. METHODS: Three groups of pigs had 3-cm defects created in their bilateral tibial diaphyses for repair using rigid fixation and one of three modalities. Negative control tibias were repaired with allograft tibia alone. To simulate repair using vascularized autograft, the osteotomized bone in positive control animals was left in situ, with the posterior periosteum intact. Experimental animals' defects were repaired with allograft tibia packed with autologous adipose-derived stem cells and recombinant human bone morphogenetic protein-2, with native periosteum intact. After 8 weeks, unilateral midgraft osteotomies were performed to assess graft healing potential. Serial radiographs and terminal micro-computed tomography and histology enabled evaluation of healing. RESULTS: At week 7 after ostectomy, no negative control tibias had healed (zero of six) whereas most positive control (five of six) and all experimental tibias (six of six) had healed. Unilateral midgraft osteotomies were performed at 8 weeks to assess graft ability to heal. As expected, no negative control tibias (three of three) had radiographic union 7 weeks later. However, all positive control (two of two; p = 0.05) and experimental (three of three; p = 0.01) tibias had healed their repeated osteotomies by this time. CONCLUSION: Similar to vascularized autograft, revitalized allograft successfully repaired a critical tibial defect, including after refracture, suggesting that this technique may be an alternative to osseous free flaps.

BACKGROUND: Face lifting is one of the most common operative procedures for facial aging and perhaps the procedure most synonymous with plastic surgery in the minds of the lay public, but no verifiable documentation of patient satisfaction exists in the literature. This study is the first to examine face-lift outcomes and patient satisfaction using a validated questionnaire. METHODS: One hundred five patients undergoing a face lift performed by the senior author (C.H.T.) using a high, extended-superficial musculoaponeurotic system with submental platysma approximation technique were asked to complete anonymously the FACE-Q by e-mail. FACE-Q scores were assessed for each domain (range, 0 to 100), with higher scores indicating greater satisfaction with appearance or superior quality of life. RESULTS: Fifty-three patients completed the FACE-Q (50.5 percent response rate). Patients demonstrated high satisfaction with facial appearance (mean +/- SD, 80.7 +/- 22.3), and quality of life, including social confidence (90.4 +/- 16.6), psychological well-being (92.8 +/- 14.3), and early life impact (92.2 +/- 16.4). Patients also reported extremely high satisfaction with their decision to undergo face lifting (90.5 +/- 15.9). On average, patients felt they appeared 6.9 years younger than their actual age. Patients were most satisfied with the appearance of their nasolabial folds (86.2 +/- 18.5), cheeks (86.1 +/- 25.4), and lower face/jawline (86.0 +/- 20.6), compared with their necks (78.1 +/- 25.6) and area under the chin (67.9 +/- 32.3). CONCLUSION: Patients who responded in this study were extremely satisfied with their decision to undergo face lifting and the outcomes and quality of life following the procedure.

BACKGROUND: Inadvertent intra-arterial injection of illicit substances is a known complication of injection drug use and can lead to severe complications, including infection, ischemia and compartment syndrome. Identifying complications of intra-arterial injection can be difficult, as clinical manifestations overlap with other more common conditions such as cellulitis and soft tissue infection, and a history of injection drug use is frequently not disclosed. METHODS: A 37-year-old male patient presented with 24 hours of right hand pain, erythema and swelling. Despite classic "track marks", he denied a history of injection drug use, and vascular insults were not initially considered. After failing to respond to three days of aggressive treatment for suspected deep-space infection, an arteriogram demonstrated findings consistent with digital ischemia of embolic etiology. RESULTS: As a result of the delay in diagnosis, the lesion was not amenable to reperfusion and the patient required amputation of the distal digit. CONCLUSION: Practitioners should be alert to the possibility of intra-arterial injection and resulting complications when evaluating unusual extremity infections or unexplained ischemic symptoms, even in the absence of a definite history of injection drug use.

BACKGROUND: Microvascular reconstruction of the pediatric mandible, particularly when necessitated by severe, congenital hypoplasia, presents a formidable challenge. Complex cases, however, may be simplified by computer-aided design/computer-aided manufacturing (CAD/CAM) assisted surgical planning. This series represents the senior authors' preliminary experiences with CAD/CAM assisted, microvascular reconstruction of the pediatric mandible. METHODS: Presented are two patients with hemifacial/bifacial microsomia, both with profound mandibular hypoplasia, who underwent CAD/CAM assisted reconstruction of their mandibles with vascularized fibula flaps. Surgical techniques, CAD/CAM routines employed, complications, and long-term outcomes are reported. RESULTS: Successful mandibular reconstructions were achieved in both patients with centralization of their native mandibles and augmentation of deficient mandibular subunits. No long-term complications were observed. CONCLUSIONS: CAD/CAM technology can be utilized in pediatric mandibular reconstruction, and is particularly beneficial in cases of profound, congenital hypoplasia requiring extensive, multi-planar, bony reconstructions.

BACKGROUND: The use of autologous adipose tissue harvested through liposuction techniques for soft-tissue augmentation has become commonplace among cosmetic and reconstructive surgeons alike. Despite its longstanding use in the plastic surgery community, substantial controversy remains regarding the optimal method of processing harvested lipoaspirate before grafting. This evidence-based review builds on prior examinations of the literature to evaluate both established and novel methods for lipoaspirate processing. METHODS: A comprehensive, systematic review of the literature was conducted using Ovid MEDLINE in January of 2015 to identify all relevant publications subsequent to the most recent review on this topic. Randomized controlled trials, clinical trials, and comparative studies comparing at least two of the following techniques were included: decanting, cotton gauze (Telfa) rolling, centrifugation, washing, filtration, and stromal vascular fraction isolation. RESULTS: Nine articles comparing various methods of processing human fat for autologous grafting were selected based on inclusion and exclusion criteria. Five compared established processing techniques (i.e., decanting, cotton gauze rolling, centrifugation, and washing) and four publications evaluated newer proprietary technologies, including washing, filtration, and/or methods to isolate stromal vascular fraction. CONCLUSIONS: The authors failed to find compelling evidence to advocate a single technique as the superior method for processing lipoaspirate in preparation for autologous fat grafting. A paucity of high-quality data continues to limit the clinician's ability to determine the optimal method for purifying harvested adipose tissue. Novel automated technologies hold promise, particularly for large-volume fat grafting; however, extensive additional research is required to understand their true utility and efficiency in clinical settings.