Practical guides to understanding sample size and minimal clinically important difference (MCID).
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Humans↗
Biomedical subjects
Brian Nussenbaum
Publications and source records attributed to Brian Nussenbaum.
The role of gene therapy for craniofacial and dental tissue engineering.
Basic science advances in bone tissue engineering using osteoinductive protein therapy have already been translated to the use in patients with selected orthopedic problems. The story of the development of bone morphogenetic protein (BMP) osteoinductive therapy, from the discovery of this class of molecules in 1965 to the publication of randomized clinical trials in 2001 for tibial non-unions and 2002 for spinal fusion, is truly fascinating. Both clinical studies showed healing equivalence of the BMP-bioimplant compared to a free non-vascularized bone graft but without the associated donor site morbidity. These advances unfortunately have not lead to rapid application of using BMP osteoinductive protein therapy for reconstructing most craniofacial bone defects, with clinical case series beginning to be reported only for limited small-sized defects. This is a reflection of the complexity and unique characteristics of most craniofacial defects, which will likely require a more robust osteoinductive signal than delivering recombinant protein on a scaffold for clinically meaningful bone regeneration. Gene therapy approaches are promising for overcoming the unique challenges that are characteristic of craniofacial and dental defects.
Animals↗
Practical guides to efficient life-long learning.
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Education, Medical, Continuing↗
Bone regeneration in cranial defects previously treated with radiation.
OBJECTIVES/HYPOTHESIS: Bone reconstruction in the head and neck region is frequently performed in the context of previous radiation treatment. Thus, the effectiveness of tissue engineering approaches for regenerating bone in radiated defects needs to be determined before considering application to patients. Incomplete healing is described when using osteoinductive protein therapy alone for bone defects previously treated with radiation. We hypothesized that a different approach using ex vivo gene therapy can heal these severely compromised defects. STUDY DESIGN: Animal study using Fisher rats. METHODS: Two weeks before surgery, rats received either no radiation or a 12 Gray radiation dose to the calvarium. Syngeneic dermal fibroblasts were transduced ex vivo using an adenoviral vector containing the cDNA for bone morphogenetic protein (BMP)-7. Critical-sized calvarial defects were created, and either a transduced cell-seeded scaffold or an autologous bone graft was placed into the defect. Nonradiated defects were harvested 4 weeks later for both groups. Radiated defects treated with bone grafts were harvested at 4 weeks, and those treated with gene therapy were harvested either at 4 or 8 weeks. Gross inspection and histology were used to evaluate wound healing. RESULTS: None of the bone grafts had gross or histologic evidence of healing at the wound margins. The nonradiated gene therapy treated defects revealed gross and histologic near-100% bone regeneration by 4 weeks after surgery. By gross inspection, the radiated defects had soft tissue admixed with islands of bone at both 4 and 8 weeks. The histologic appearance revealed areas of dense bone in a nonconfluent pattern admixed with adjacent cells having the morphologic appearance of hypertrophic chondrocytes, suggesting continued endochondral ossification. CONCLUSIONS: Preoperative radiation significantly impairs the ability of BMP-7 ex vivo gene therapy to heal rat critical-sized cranial defects. This finding has significant implications for translating this tissue engineering approach to patients with cancer-related segmental bone defects.
Animals↗
Caspase inhibition enhances ischemic tolerance of fasciocutaneous flaps.
OBJECTIVES/HYPOTHESIS: To demonstrate the significance of apoptosis in ischemia-reperfusion injury in revascularized fasciocutaneous flaps and test the hypothesis that pharmacologic inhibition of caspases prolongs the allowable primary ischemia time of these flaps. STUDY DESIGN: Animal study using the epigastric flap in adult male Sprague-Dawley rats. METHODS: Fifty-nine rats were treated with the caspase inhibitor (Q-VD-OPH) reconstituted in dimethylsulfoxide (DMSO) (n = 20, 8 mg/kg:0.8 mL/kg), DMSO alone (n = 19, 0.8 mL/kg), or saline (n = 20, 0.8 mL/kg). Treatment was given as a single intraperitoneal injection 30 minutes before starting primary ischemia. Epigastric flaps were subjected to increasing ischemia times followed by reperfusion. The flaps were harvested and analyzed 7 days later, and viability was assessed. Probit statistical analysis was used to determine the critical ischemia time. This was defined as the time point when 50% of the flaps in each group were expected to survive. RESULTS: The calculated critical ischemia times were 8.92 hours (95% confidence interval 7.19-10.47 h) for the saline group, 16.35 hours (95% confidence interval 11.82-19.89 h) for the DMSO group, and 21.73 hours (95% confidence interval 19.39-25.37 h) for the DMSO with Q-VD-OPH group. These differences were significantly different from each other. CONCLUSIONS: Pretreatment of fasciocutaneous flaps with a free radical scavenger alone or in combination with a caspase inhibitor significantly increases the flap's tolerance of primary ischemia. The added benefit of the caspase inhibitor suggests that apoptosis plays an important role in ischemia-reperfusion injury in soft tissue flaps.
Animals↗
Tissue engineering: the current status of this futuristic modality in head neck reconstruction.
PURPOSE OF REVIEW: To define tissue engineering and describe the components that are involved in engineering tissue. To provide examples of the most recent developments in tissue engineering as they apply to the otolaryngologist. To provide a general overview of selected exciting advances outside the field of general otolaryngology but of general interest to the reconstructive community. RECENT FINDINGS: Tissue engineering is a rapidly evolving field that can be defined as the regeneration of new tissues through the use of biologic mediators and matricis. The three components required are scaffolds, signaling molecules, and cells. A significant amount of work has been done to generate bone, cartilage, cornea, and vascular grafts. Tissue engineered bone is the only tissue type that has been evaluated in Phase III clinical trials and is in routine clinical use. Engineered bone from BMP-2 and BMP-7 is used in orthopedics for lumbar fusions and long bone nonunions. Clinical application of bone tissue engineering in the head and neck is limited to case reports. There has been success in tissue engineering with cartilage for the nose and ear in immune incompetent animal models but there has been difficulty with generating scaffolds that do not incite an immune reaction in an immune competent model. The most advanced organ engineered is a bladder that has been successful in a canine model. SUMMARY: Tissue engineering holds the promise of "off the shelf" parts for reconstruction of tissues and organs. The widest clinical application is with bone in orthopedics. Applications in the head and neck are limited, at present, due to the immunogenicity of the scaffolds and the challenging wounds encountered in both cancer and cosmetic patients.
Animals↗
Ex vivo gene therapy for skeletal regeneration in cranial defects compromised by postoperative radiotherapy.
Because radiation remains a common postoperative treatment for head and neck cancers, it is critical to determine whether new bone-regenerative approaches are effective for healing craniofacial defects challenged by therapeutic doses of radiation. The objective of this study was to determine whether the deleterious effects of radiotherapy could be overcome by ex vivo gene therapy to heal craniofacial defects. Rat calvarial critical-sized defects were treated with either an inlay calvarial bone graft or syngeneic dermal fibroblasts transduced ex vivo with an adenovirus engineered to express bone morphogenetic protein 7 (BMP-7), a morphogen known to stimulate bone formation. Two weeks postoperatively, either no radiation or a single 12-Gy radiation dose was delivered to the operated area and the tissue was harvested 4 weeks later. None of the inlay bone grafts healed at the wound margins of either the radiated or nonradiated sites. In contrast, bone was successfully regenerated when using an ex vivo gene therapy approach. More bone formed in the nonradiated group as determined by the percentage of defect surface covered (87 +/- 4.1 versus 65 +/- 4.7%; p = 0.003) and percentage of defect area filled by new bone (60 +/- 5.9 versus 32 +/- 2.7%; p = 0.002). Although the effects of radiation on the wound were not completely overcome by the gene therapy approach, bone regeneration was still successful despite the radiation sensitivity of the fibroblasts. These results indicate that BMP-7 ex vivo gene therapy is capable of successfully regenerating bone in rat calvarial defects even after a therapeutic dose of radiation. This approach may represent a new strategy for regenerating skeletal elements lost due to head and neck cancer.
Adenoviridae↗
Reliability of sentinel lymph node mapping with biopsy for head and neck cutaneous melanoma.
OBJECTIVES: To determine (1) the reliability of sentinel lymph node mapping with biopsy (SLNB) in head and neck cutaneous melanoma to accurately stage nodal basins and (2) the safety of SLNB in both the neck and parotid regions. DESIGN: Retrospective cohort study with a median follow-up of 25 months. All patients had a minimum follow-up of 1 year. SETTING: Academic medical center. PATIENTS: Eighty evaluable patients diagnosed as having head and neck cutaneous melanoma and staged using SLNB. INTERVENTIONS: Sentinel lymph nodes were identified using preoperative lymphoscintigraphy and a combination of intraoperative gamma probe and isosulfan blue dye. Patients with a SLN positive for melanoma underwent therapeutic lymphadenectomy followed by an evaluation for adjuvant therapies. Patients with a negative SLNB result were followed up clinically. MAIN OUTCOME MEASURES: Percentage of positive SLNs, regional recurrence in the setting of a negative SLNB result (false-negative rate), and procedure complications. RESULTS: The mean Breslow depth was 2.35 mm. A SLN was identified in 77 (96.3%) of cases, with an average of 2.18 nodes per patient. Of the sentinel nodes identified, 74% were from the neck region. The remaining 26% were from the parotid basin. No facial nerve complications occurred. Of the patients, 14 (18%) were SLN positive for metastatic melanoma. The regional failure rate in the setting of a negative SLNB result was 4.5%. CONCLUSIONS: Sentinel lymph node mapping with biopsy is a reliable technique to diagnose regional spread from head and neck cutaneous melanoma. This procedure can be performed in both neck and parotid nodal basins with safety and accuracy similar to non-head and neck sites.
Adolescent↗
Reconstruction of complex parotidectomy defects using the lateral arm free tissue transfer.
OBJECTIVES: The study goal was to show that the lateral arm flap is a viable reconstructive option for complex parotidectomy defects.Study design and setting We studied a case series at a tertiary care medical center from March 1997 to March 2002. The lateral arm flap was used to reconstruct parotidectomy defects that included a composite resection of adjacent tissue in 30 patients. There were 19 men and 11 women (mean age, 62 years; mean follow-up, 19 months). The mean flap area was 114 cm(2), and the mean flap volume was 172 cm(3). The posterior cutaneous nerve of the forearm (PCNF) was used as a facial nerve cable graft in 14 patients. Facial disability outcomes were measured using the Facial Clinimetric Evaluation scale. RESULTS: The major and minor complication rates with use of this reconstructive approach were low: 16.7% (5 of 30) and 26.7% (8 of 30), respectively. Donor site morbidity was minimal, with no patient having a major donor site complication and 23.3% (7 of 30) having minor complications. Functional recovery of the facial nerve occurred in 6 of 8 evaluable patients who underwent facial nerve grafting using the PCNF. Controlling for degree of facial nerve paralysis, Facial Clinimetric Evaluation scale scores of our patients were not statistically different than those of a historic population with a facial paralysis and no surgical defect. CONCLUSIONS: The lateral arm free flap effectively restores facial appearance when used for reconstruction of complex parotidectomy defects. The PCNF, a nerve harvested with the lateral arm flap, can be used as a facial nerve cable graft with a high rate of success. SIGNIFICANCE: The lateral arm flap is successful as a single donor site for reconstructing facial contour and the facial nerve after major ablative defects in the parotid region.
Adult↗
Laryngeal duplication cyst.
Benign congenital laryngeal cysts are rare. Infants and children with these lesions can present with chronic or intermittent airway obstructive symptoms, hoarseness, aspiration, chronic cough, or failure to thrive. The most common congenital laryngeal cysts include saccular cysts, laryngoceles, and ductal cysts. Other more unusual laryngeal lesions, such as hamartomas, choristomas, and teratomas, can also present with these symptoms. We describe a unique congenital cyst that arose in continuity with the larynx in a child with hoarseness and intermittent stridor. The features of this lesion are similar to those of bronchogenic duplication cysts of the trachea, but with histopathological features of the larynx.
Abnormalities, Multiple↗
Leech therapy for patients with surgically unsalvageable venous obstruction after revascularized free tissue transfer.
OBJECTIVE: To assess the efficacy and associated complications of a leech therapy protocol used for patients with a head and neck free tissue transfer in whom flap viability is threatened because of surgically unsalvageable venous obstruction. DESIGN: Medical record review of a prospective protocol. SETTING: Tertiary care academic medical center. PATIENTS: Of the 450 free tissue transfers to the head and neck region performed by our microvascular program from January 1, 1995, to October 31, 2000, 8 patients (1.8%) developed venous obstruction not considered salvageable by conventional surgical or thrombolytic therapy. INTERVENTIONS: All 8 patients were placed on a protocol using leeches (Hirudo medicinalis), intensive care unit monitoring, antithrombotic pharmacotherapy, frequent hematologic evaluation, blood transfusions as needed, and antibiotic prophylaxis for Aeromonas hydrophila. MAIN OUTCOME MEASURES: Flap salvage rate, number of leeches used per patient, time needed for inosculation, duration of intensive care unit admission, transfusion requirement per patient, and complications during leech therapy. RESULTS: All 8 flaps survived with the application of this protocol. An average of 215 leeches were used per patient, and the average time needed for inosculation was 6.6 days. The average duration in the intensive care unit was 9.6 days. The morbidity of our protocol was substantial, with intensive care unit psychosis, prerenal azotemia, and large transfusion requirements being the most frequent complications. An average of 13 U of packed red blood cells per patient was necessary. CONCLUSIONS: Aggressive application of the presented leech therapy protocol can salvage free tissue transfers with venous obstruction that are otherwise unsalvageable. The associated morbidity can be marked. Thus, judicious application of this protocol for flap preservation is essential.
Aged↗
Management of sphenoid sinus cerebrospinal fluid rhinorrhea: making use of an extended approach to the sphenoid sinus.
OBJECTIVES: Specific information addressing the management of cerebrospinal fluid (CSF) fistulas that originate from within the sphenoid sinus remains scant. The objective of this study was to review the cause and management of CSF rhinorrhea arising from the sphenoid sinus. STUDY DESIGN AND SETTING: This is a retrospective chart review of 12 cases of CSF rhinorrhea arising from the sphenoid sinus that occurred in 11 patients. All patients were treated at a single institution between 1994 and 1999. RESULTS: All patients were managed surgically with sphenoid sinus fat obliteration using an endoscopic sublabial, transseptal approach. This approach was successful for all 12 cases, with median duration of follow-up of 18 months. CONCLUSIONS: Endoscopically assisted transseptal repair of CSF fistulas that originate within the sphenoid sinus offers an alternate approach to previously described methods of repair in this region. Advantages include wide access to the entire sphenoid sinus, improved access to laterally pneumatized regions within the sphenoid sinus, and rostral mucosal closure over the repair within the sinus.
Adult↗
Clinical presentation of allergic fungal sinusitis in children.
OBJECTIVE: To compare the differences in the clinical and radiographic presentation of allergic fungal sinusitis in children and adults. STUDY DESIGN: Retrospective chart and computed tomography review. METHODS: The settings included a tertiary care children's hospital, adult academic private hospital, and academic affiliated county hospital. All patients with documented allergic fungal sinusitis who underwent computed tomography evaluation and had surgical treatment of their disease from 1988 to 1999 were included in the study. In total, 151 patients aged 5 to 75 years; 44 of these patients were less than or equal to 17 years of age (children) and 107 were greater than 17 years of age (adults). Main outcome measures included 1) the presence of obvious bony facial abnormalities on presentation, 2) bilateral or unilateral sinus disease on presentation, 3) the presence of asymmetrical disease on presentation, 4) the presence of bony extension on computed tomography scan, and 5) type of fungus present. RESULTS: Fifteen of 36 (42%) pediatric patients and 10 of 103 (10%) adult patients had obvious alteration of their facial skeleton (proptosis, telecanthus, or malar flattening) on presentation (P <.05). Proptosis was the most common facial abnormality in both groups and was seen more often in children (8 of 36 [22%]) than in adults (9 of 103 [9%]) (P <.05). Twenty-eight of 40 (70%) pediatric patients and 37 of 100 (37%) adult patients presented with unilateral sinus disease (P <.05). Thirty-five of 40 (88%) pediatric patients and 58 of 100 (58%) adults presented with asymmetrical disease (P <.05). Computed tomography scans showed that 10 of 40 (25%) pediatric patients and 23 of 100 (23%) adult patients had bony erosion with extension of disease into surrounding structures (P >.05). Cultures from both adults and children showed mainly Bipolaris and Curvilaria species in equal amounts (P >.05). Adults had a greater incidence of Aspergillus species. CONCLUSIONS: Presentation in pediatric patients with allergic fungal sinusitis is different from that in adults, with children having obvious abnormalities of their facial skeleton, unilateral sinus disease, and asymmetrical disease more often. Findings on computed tomography scan show an equal amount of bony erosion with extension of disease. The types of fungus cultured in the sinus cavities are similar in both groups.
Adolescent↗
Paranasal sinus malignancies: an 18-year single institution experience.
OBJECTIVES: To characterize a single institution experience with management of paranasal sinus malignancies during an 18-year time period, report long-term survival rates, and identify prognostic factors. STUDY DESIGN: Retrospective chart review. METHODS: Studied were 141 patients treated for a paranasal sinus malignancy at a single institution from 1980 to 1997 with a minimum 3-year follow-up. Gender, age, TNM stage, anatomic site, pathology, treatment, and recurrence rates were reviewed. Multivariate analysis was performed to determine factors affecting survival. RESULTS: The male to female ratio was 1.6:1, and the median patient age was 60 years. Most patients presented with T3/T4 or locally advanced disease (88%), N0 status (96%), and M0 status (96%). The maxillary sinus was the most commonly affected site (70%), followed by the ethmoid sinus (26%). The most common malignancy was squamous cell carcinoma (51%), followed by adenoid cystic carcinoma (12%) and adenocarcinoma (11%). Sixty-two percent of this study group underwent surgery as part of a multimodality curative treatment plan or alone as curative treatment. Eighteen patients (13%) had unresectable local disease and received non-surgical palliative treatment. Kaplan-Meier analysis revealed the 5-year and 10-year disease-specific survival was 52% and 35%, respectively. Multivariate analysis revealed T4 stage (P =.005), N-positive stage (P =.009), and M-positive stage (P =.018) negatively impacted survival. Seventy-two patients (51%) developed recurrent disease at a median time of 336 days after initial treatment. CONCLUSIONS: Most patients with paranasal sinus malignancies presented with locally advanced disease. Advanced T stage, regional, and distant metastasis are highly predictive of poor survival. Recurrence rate is high and typically occurs within the first year after treatment.
Adolescent↗
Bone morphogenetic protein 7 ex vivo gene therapy.
Acquired and congenital skeletal defects arise from trauma and developmental abnormalities as well as ablative cancer surgery. Reconstructive surgery to repair the functional limitations and aesthetic concerns caused by these defects can be complex and extensive, and therapeutic restoration of structure and function is often difficult. Currently, autologous bone grafts are the "gold standard" method for surgical repair. Protein therapy, whereby recombinant or naturally sourced bone morphogenetic proteins are surgically implanted in a defect, has recently been approved for limited clinical use. Yet protein therapy and other methods including allografting, alloplastic implants and cell therapy have significant limitations. Recent advances in bone morphogenetic protein 7 ex vivo gene therapy for localized skeletal regeneration address these limitations.
Animals↗