Faculty Bibliography

Endothelin-1 (ET-1) produced by various cancers is known to be responsible for inducing pain. While ET-1 binding to ETAR on peripheral nerves clearly mediates nociception, effects from binding to ETBR are less clear. The present study assessed the effects of ETBR activation and the role of endogenous opioid analgesia in carcinoma pain using an orthotopic cancer pain mouse model. mRNA expression analysis showed that ET-1 was nearly doubled while ETBR was significantly down-regulated in a human oral SCC cell line compared to normal oral keratinocytes (NOK). Squamous cell carcinoma (SCC) cell culture treated with an ETBR agonist (10(-4)M, 10(-5)M, and 10(-6) M BQ-3020) significantly increased the production of beta-endorphin without any effects on leu-enkephalin or dynorphin. Cancer inoculated in the hind paw of athymic mice with SCC induced significant pain, as indicated by reduction of paw withdrawal thresholds in response to mechanical stimulation, compared to sham-injected and NOK-injected groups. Intratumor administration of 3mg/kg BQ-3020 attenuated cancer pain by approximately 50% up to 3h post-injection compared to PBS-vehicle and contralateral injection, while intratumor ETBR antagonist BQ-788 treatment (100 and 300microg/kg and 3mg/kg) had no effects. Local naloxone methiodide (500microg/kg) or selective mu-opioid receptor antagonist (CTOP, 500microg/kg) injection reversed ETBR agonist-induced antinociception in cancer animals. We propose that these results demonstrate that peripheral ETBR agonism attenuates carcinoma pain by modulating beta-endorphins released from the SCC to act on peripheral opioid receptors found in the cancer microenvironment

Mediators involved in the generation of pain in patients with cancer are poorly understood. Using a combined molecular, pharmacologic, behavioral, and genetic approach, we have identified a novel mechanism of cancer-dependent allodynia induced by protease-activated receptor 2 (PAR2). Here we show that human head and neck carcinoma cells have increased levels of proteolytic activity compared to normal human cell controls. Supernatant from human carcinoma cells, but not controls, caused marked and prolonged mechanical allodynia in mice, when administered into the hindpaw. This nociceptive effect was abolished by serine protease inhibition, diminished by mast cell depletion and absent in PAR2-deficient mice. In addition, non-contact co-culture of trigeminal ganglion neurons with human head and neck carcinoma cells increased the proportion of neurons that exhibited PAR2-immunoreactivity. Our results point to a direct role for serine proteases and their receptor in the pathogenesis of cancer pain. This previously unrecognized cancer pain pathway has important therapeutic implications wherein serine protease inhibitors and PAR2 antagonists may be useful for the treatment of cancer pain

BACKGROUND: Critical defects of the craniomaxillofacial region are often treated with vascularized osteocutaneous free flaps. These lengthy operations may be associated with considerable donor-site morbidity and suboptimal functional and aesthetic results. To overcome these issues, this study investigates an engineered vascularized bone flap using allograft bone, adipose-derived stem cells, and recombinant human bone morphogenic protein (rhBMP)-2 and compares two alternative blood supplies. METHODS: Edentulous porcine hemimandibles were commercially sterilized, packed with rhBMP-2-soaked absorbable collagen sponge and autologous, culture-expanded adipose-derived stem cells, and implanted into two locations within 10 pigs: (1) an intercostal-based periosteal envelope (thoracic) and (2) within the rectus abdominis muscle with insertion of the superficial inferior epigastric vascular pedicle into the medullary cavity (abdominal). The constructs were incubated in vivo for 7 to 8 weeks and harvested to assess de novo bone formation. RESULTS: Radiographic, micro-computed tomographic, and histologic assessments of harvested constructs were performed. Abdominal constructs had a thin rim of new, cancellous bone surrounding a fibrotic core with little allograft remaining. Thoracic allografts were absorbed completely and replaced with new, full-thickness, cancellous bone. Calcitic tissue content was significantly higher in thoracic (474.16 +/- 75.93 ml) compared with abdominal (143.20 +/- 46.39 ml) constructs (p < 0.006). New bone in both groups contained Haversian systems, but only thoracic constructs contained marrow elements and blood vessels resembling normal bone. CONCLUSIONS: These data demonstrate revitalization of large-volume allograft bone, and have positive implications for bone tissue engineering. Allograft revitalization in thoracic but not abdominal constructs reinforces the critical role of the periosteum in the process.

BACKGROUND: Half of the patients with head and neck squamous cell carcinoma (HNSCC) can be expected to fail therapy, indicating that more aggressive treatment is warranted for this group. We have developed a novel risk model that can become a basis for developing new treatment paradigms. Here we report on the performance of our model in a new multicenter cohort. DESIGN: Eligible patients from 3 institutions (Montefiore Medical Center, University of Manitoba, and New York University Medical Center) were identified and pathology slides from their resection specimens were reviewed by Margaret Brandwein-Gensler; risk category was assigned as previously published. Kaplan-Meier analysis was performed for disease progression and survival. Cox proportional hazards regression was performed, adjusted for potential confounders. A teaching module was also developed; attending pathologists were asked to score coded slides after a lecture and multiheaded microscope teaching session. Agreement was assessed by calculating Cohen unweighted kappa coefficients. RESULT: The validation cohort consisted of 305 patients, from the above institutions, with 311 primary HNSCC of the oral cavity, oropharynx, and larynx. The median follow-up period for all patients was 27 months. Risk category predicts time to disease progression (P=0.0005), locoregional recurrence (P=0.013), and overall survival (P=0.0000) by Kaplan-Meier analysis. High-risk status is significantly associated with decreased time to disease progression, adjusted for clinical confounders (P=0.015, hazard ratio 2.32, 95% confidence interval 1.18-4.58) compared with collapsed intermediate and low-risk groups. We also demonstrate substantial interrater agreement (kappa=0.64), and very good rater agreement when compared with the standard (kappa=0.87). CONCLUSIONS: We demonstrate significant predictive performance of the risk model in a new cohort of patients with primary HNSCC, adjusted for confounders. Our training experience also supports the feasibility of adapting the risk model in clinical practice

The purpose of this project was to study the effect of a subimmunosuppressive dose of FK506 (0.7 mg/kg per day) on nerve regeneration along a long nerve gap (4 cm), using the contralateral C7 nerve root transfer model for musculocutaneous nerve neurotization. Two types of tubes were applied to the nerve gap: a polycaprolactone tube and a collagen tube. Twenty adult male Sprague-Dawley rats were divided into 4 groups (n = 5). A polycaprolactone was used in groups 1 and 3 and a collagen tube in groups 2 and 4. Groups 1 and 2 were daily administered a subimmunosuppressive dose of FK506. Animals were euthanized on day 30. Evaluation consisted of behavioral assessment, needle electromyography studies, biceps muscle weight measurements, and qualitative and quantitative morphometry. Groups 1 and 2 showed higher mean values for fiber counts, axon diameters, myelin thickness and myelin area in C7, better functional evaluation results, and higher biceps weight left to right ratio than groups 3 and 4. There was no evidence of reinnervation potentials, and there were no axons detectable inside the tube lumen in any of the study groups. The present study demonstrated that there was nonsignificant improvement of the functional recovery, after systemic administration of a low dose of FK506. This was attributed to 3 factors: length of nerve gap; duration of follow up; and dose of FK506. However, FK506-treated animals tended to be in a more advanced stage of nerve regeneration compared with the control groups

The critical length of 30 mm beyond which nerve regeneration was not possible limited up to now the use of tubulization. In this pilot study, a novel animal model is introduced using tubulization techniques for long-nerve defects (40 mm) in brachial plexus surgery. Twelve Sprague-Dawley rats were divided into 3 groups. A poly-DL-lactide-epsilon-caprolactone tube (group 1), a collagen tube (group 2), and a nerve graft (group 3) were, respectively, used to bridge a 40-mm gap between the right C7 root and the left musculocutaneous nerve. Animals were euthanized on day 30. Evaluation consisted of behavioral assessment, needle electromyography studies, biceps muscle weight measurements, qualitative, and quantitative morphometry. Only group 3 demonstrated axon regeneration and reinnervation potentials. There was statistical significant difference for biceps weight left/right ratio (P = 0.010) but not for behavioral results (P = 0.10) between group 3 and groups 1 and 2. This study introduced a novel rat model for the studying of nerve regeneration along long-nerve gaps (4 cm). Although using an autologous nerve graft regeneration achieved, the use of synthetic conduits failed to show regeneration. This may be attributed to gap length; duration of follow-up; and to no administration of a neurotrophic factor

OBJECTIVE: To evaluate the early bone response to plateau root form dental implants with 4 different surface treatments. STUDY DESIGN: Surface treatments comprised (n = 12 each): as-machined (M), alumina-blasted/acid-etched (AB/AE), alumina-blasted/acid-etched + nanothickness bioceramic coating (Nano), and plasma-sprayed calcium phosphate (PSCaP). Implants were placed in the radius diaphyses of 12 beagle dogs, remaining in vivo for 3 and 5 weeks. After euthanasia, the implants were subjected to torque to interface fracture and subsequently nondecalcified for histomorphology. Statistical analysis was performed by a GLM analysis of variance model at 5% significance level. RESULTS: Torque to interface fracture was significantly greater for the PSCaP group than for other groups (P < .001). Histomorphologic analysis showed woven bone formation around all implant surfaces at 3 weeks, and its replacement by lamellar bone at 5 weeks. Time in vivo did not affect torque measures. CONCLUSION: The PSCaP surface increased the early bone biomechanical fixation of plateau root form implants.