Reprogramming Chromosome Ends by Functional Histone Acetylation.

Cancers harness embryonic programs to evade aging and promote survival. Normally, sequences at chromosome ends called telomeres shorten with cell division, serving as a countdown clock to limit cell replication. Therefore, a crucial aspect of cancerous transformation is avoiding replicative aging by activation of telomere repair programs. Mouse embryonic stem cells (mESCs) activate a transient expression of the gene Zscan4, which correlates with chromatin de-condensation and telomere extension. Head and neck squamous cell carcinoma (HNSCC) cancers reactivate ZSCAN4, which in turn regulates the phenotype of cancer stem cells (CSCs). Our study reveals a new role for human ZSCAN4 in facilitating functional histone H3 acetylation at telomere chromatin. Next-generation sequencing indicates ZSCAN4 enrichment at telomere chromatin. These changes correlate with ZSCAN4-induced histone H3 acetylation and telomere elongation, while CRISPR/Cas9 knockout of ZSCAN4 leads to reduced H3 acetylation and telomere shortening. Our study elucidates the intricate involvement of ZSCAN4 and its significant contribution to telomere chromatin remodeling. These findings suggest that ZSCAN4 induction serves as a novel link between 'stemness' and telomere maintenance. Targeting ZSCAN4 may offer new therapeutic approaches to effectively limit or enhance the replicative lifespan of stem cells and cancer cells.

Disease and toxicity outcomes for a modern cohort of patients with squamous cell carcinoma of cutaneous origin involving the parotid gland: Comparison of volumetric modulated arc therapy and pencil beam scanning proton therapy.

OBJECTIVES: We sought to describe outcomes for locally advanced cutaneous squamous cell carcinoma (SCC) involving the parotid treated with volumetric modulated arc therapy (VMAT) versus pencil beam scanning proton beam therapy (PBT). MATERIALS AND METHODS: Patients were gathered from 2016 to 2022 from 5 sites of a large academic RT department; included patients were treated with RT and had parotid involvement by: direct extension of a cutaneous primary, parotid regional spread from a previously or contemporaneously resected but geographically separate cutaneous primary, or else primary parotid SCC (with a cutaneous primary ostensibly occult). Acute toxicities were provider-reported (CTCAE v5.0) and graded at each on treatment visit. Statistical analyses were conducted. RESULTS: Median follow-up was 12.9 months (1.3 - 72.8); 67 patients were included. Positive margins/extranodal extension were present in 34 cases; gross disease in 17. RT types: 39 (58.2 %) VMAT and 28 (41.8 %) PBT. Concurrent systemic therapy was delivered in 10 (14.9 %) patients. There were 17 treatment failures (25.4 %), median time of 168 days. Pathologically positive neck nodes were associated with locoregional recurrence (p = 0.015). Oral cavity, pharyngeal constrictor, and contralateral parotid doses were all significantly lower for PBT. Median weight change was -3.8 kg (-14.1 - 5.1) for VMAT and -3 kg (-16.8 - 3) for PBT (p = 0.013). Lower rates of ≥ grade 1 xerostomia (p = 0.002) and ≥ grade 1 dysguesia (p < 0.001) were demonstrated with PBT. CONCLUSIONS: Cutaneous SCC involving the parotid can be an aggressive clinical entity despite modern multimodal therapy. PBT offers significantly lower dose to organs at risk compared to VMAT, which seemingly yields diminished acute toxicities.

Regionalization of Head and Neck Oncology Tumor Boards: Perspectives of Collaborating Physicians.

Objectives: To survey academic and community physician preferences regarding the virtual multidisciplinary tumor board (MTB) for further improvement and expansion. Study Design: This anonymous 14-question survey was sent to individuals that participated in the head and neck virtual MTBs. The survey was sent via email beginning August 3, 2021, through October 5, 2021. Setting: The University of Maryland Medical Center and regional practices in the state of Maryland. Methods: Survey responses were recorded and presented as percentages. Subset analysis was performed to obtain frequency distributions by facility and provider type. Results: There were 50 survey responses obtained with a response rate of 56%. Survey participants included 11 surgeons (22%), 19 radiation oncologists (38%), and 8 medical oncologists (16%), amongst others. More than 96% of participants found the virtual MTB to be useful when discussing complex cases and impactful to future patient care. A majority of respondents perceived a reduction in time to adjuvant care (64%). Community and academic physician responses strongly agreed that the virtual MTB improved communication (82% vs 73%), provided patient-specific information for cancer care (82% vs 73%), and improved access to other specialties (66% vs 64%). Academic physicians, more so than community physicians, strongly agreed that the virtual MTB improves access to clinical trial enrollment (64% vs 29%) and can be useful in obtaining CME (64% vs 55%). Conclusion: Academic and community physicians view the virtual MTB favorably. This platform can be adapted regionally and further expanded to improve communication between physicians and improve multidisciplinary care for patients.

Gross tumor volume margin and local control in p16-positive oropharynx cancer patients treated with intensity modulated proton therapy.

BACKGROUND: To determine if the extent of high-dose gross tumor volume (GTV) to clinical target volume (CTV) expansion is associated with local control in patients with p16-positive oropharynx cancer (p16+ OPC) treated with definitive intensity modulated proton therapy (IMPT). METHODS: We performed a retrospective analysis of patients with p16+ OPC treated with IMPT at a single institution between 2016 and 2021. Patients with a pre-treatment PET-CT and restaging PET-CT within 4 months following completion of IMPT were analyzed. RESULTS: Sixty patients were included for analysis with a median follow-up of 17 months. The median GTV to CTV expansion was 5 mm (IQR: 2 mm). Thirty-three percent of patients (20 of 60) did not have a GTV to CTV expansion. There was one local failure within the expansion group (3%). CONCLUSION: Excellent local control was achieved using IMPT for p16+ OPC independent of GTV expansion. IMPT with minimal target expansions represent a potential harm-minimization technique for p16-positive oropharynx cancer.

Human Papillomavirus Impact on Temporal Treatment Trends in Oropharyngeal Carcinoma: 2010-2016.

INTRODUCTION: The study objective was to identify practice patterns in oropharyngeal cancer management from 2010 to 2016 among human papillomavirus (HPV)-associated and non-HPV-associated oropharyngeal squamous-cell carcinoma (OPSCC) patients. METHODS: The National Cancer Database was utilized to identify OPSCC patients from 2010 to 2016. Frequency distributions and multivariable analyses were generated to identify practice patterns and predictors of treatment modality. RESULTS: A total of 35,956 patients with nonmetastatic OPSCC were included. HPV status was not associated with a treatment modality preference. At academic centers, the proportion of HPV-associated OPSCC patients versus non-HPV-associated OPSCC patients undergoing surgical management was similar (35.7%; 35.9%). Community cancer programs treated patients less often surgically but with no significant treatment preference based on HPV status. Within each facility type, HPV status was not a predictor of surgical or nonsurgical management. CONCLUSION: HPV association does not appear to significantly influence treatment modality preference among OPSCC patients. The proportion of OPSCC patients undergoing surgical treatment declined from 2010 to 2016.

Comparison of efficacy and toxicity of chemoradiation regimens for head and neck squamous cell carcinoma primary treatment.

BACKGROUND: The best chemoradiation regimen to treat locally and regionally advanced head and neck squamous cell carcinoma (HNSCC) is yet to be established. METHODS: We compared overall survival (OS) and adverse events following chemoradiation regimens (high-dose [HDC] or low-dose [LDC] cisplatin, or carboplatin [CB]) in HNSCC cases selected from SEER-Medicare linked database. RESULTS: Of the 1335 cases who underwent radiotherapy, 264 received HDC, 259 received LDC, and 353 received CB, concurrently. Compared to chemoradiation with HDC, using LDC or CB, or radiotherapy alone were associated with an increasingly worse OS; hazard ratios were 1.33, p = 0.03; 1.35, p = 0.02; and 2.12, p < 0.001; respectively. There were no differences in the rates of adverse events between the three chemoradiation regimens. CONCLUSION: Chemoradiation regimen using HDC appears to be the best primary treatment for locally and regionally advanced HNSCC. Nonetheless, prospective large studies are warranted to further determine its absolute benefit.

Impact of the Novel Coronavirus 2019 (COVID-19) Pandemic on Head and Neck Cancer Care.

OBJECTIVE: The study aimed to assess the impact of the coronavirus disease 2019 (COVID-19) pandemic on head and neck oncologic care at a tertiary care facility. STUDY DESIGN: This was a cross-sectional study conducted between March 18, 2020, and May 20, 2020. The primary planned outcome was the rate of treatment modifications during the study period. Secondary outcome measures were tumor conference volume, operative volume, and outpatient patient procedure and clinic volumes. SETTING: This single-center study was conducted at a tertiary care academic hospital in a large metropolitan area. METHODS: The study included a consecutive sample of adult subjects who were presented at a head and neck interdepartmental tumor conference during the study period. Patients were compared to historical controls based on review of operative data, outpatient procedures, and clinic volumes. RESULTS: In total, 117 patients were presented during the review period in 2020, compared to 69 in 2019. There was an 8.4% treatment modification rate among cases presented at the tumor conference. There was a 61.3% (347 from 898) reduction in outpatient clinic visits and a 63.4% (84 from 230) reduction in procedural volume compared to the prior year. Similarly, the operative volume decreased by 27.0% (224 from 307) compared to the previous year. CONCLUSION: Restrictions related to the COVID-19 pandemic resulted in limited treatment modifications. Transition to virtual tumor board format observed an increase in case presentations. While there were reductions in operative volume, there was a larger proportion of surgical cases for malignancy, reflecting the prioritization of oncologic care during the pandemic.

The association of active and passive tobacco smoke exposure with chronic rhinosinusitis symptom severity: A cross-sectional study.

BACKGROUND: Chronic rhinosinusitis (CRS) causes a great deal of morbidity. There are a multitude of causal factors, though their precise contribution to symptom severity has yet to be defined.  We hypothesized that exposure to both primary and secondhand tobacco smoke would correlate with more severe symptoms of CRS. METHODS: This is a prospective cross-sectional study performed at an academic tertiary care medical center from 2010 to 2013. A total of 85 consecutive patients with chronic sinusitis were screened; 70 with medically refractory CRS requiring functional Endoscopic sinus surgery (FESS) were enrolled. Recent tobacco exposure was assessed using serum cotinine levels. Sinonasal mucosa was biopsied to assess ciliary architecture. Demographics, medical history, tobacco and environmental exposures, and computed tomography (CT) imaging were also collected. Two quality of life (QOL) surveys were administered: one disease specific, Sinonasal Outcomes Test-20 (SNOT-20), and one general, Short Form-12 (SF-12). Results were correlated with the aforementioned exposures. RESULTS: The 70 patients had an average age of 46 years, and 42% were male.  Variables that correlated with worse SNOT-20 scores included serum cotinine (r = 0.43, p = 0.002), number of cigarettes smoked daily (r = 0.27, p = 0.03), and number of secondhand cigarettes exposed to per day (r = 0.29, p = 0.04). There were no significant correlations between SNOT-20 scores and Lund-MacKay or axonemal ultrastructural abnormalities (AUA)-ciliary scores. The two five-variable models best predicted disease-specific QOL. CONCLUSIONS: Increased amounts of serum cotinine and primary and secondhand smoke exposure were associated with worse sinonasal QOL. This study establishes an objective relationship between smoke exposure and patient-perceived severity of CRS, emphasizing the importance of tobacco cessation counseling as part of management.

Direct differentiation of tonsillar biopsy-derived stem cells to the neuronal lineage.

BACKGROUND: Neurological disorders are considered one of the greatest burdens to global public health and a leading cause of death. Stem cell therapies hold great promise for the cure of neurological disorders, as stem cells can serve as cell replacement, while also secreting factors to enhance endogenous tissue regeneration. Adult human multipotent stem cells (MSCs) reside on blood vessels, and therefore can be found in many tissues throughout the body, including palatine tonsils. Several studies have reported the capacity of MSCs to differentiate into, among other cell types, the neuronal lineage. However, unlike the case with embryonic stem cells, it is unclear whether MSCs can develop into mature neurons. METHODS: Human tonsillar MSCs (T-MSCs) were isolated from a small, 0.6-g sample, of tonsillar biopsies with high viability and yield as we recently reported. Then, these cells were differentiated by a rapid, multi-stage procedure, into committed, post-mitotic, neuron-like cells using defined conditions. RESULTS: Here we describe for the first time the derivation and differentiation of tonsillar biopsy-derived MSCs (T-MSCs), by a rapid, multi-step protocol, into post-mitotic, neuron-like cells using defined conditions without genetic manipulation. We characterized our T-MSC-derived neuronal cells and demonstrate their robust differentiation in vitro. CONCLUSIONS: Our procedure leads to a rapid neuronal lineage commitment and loss of stemness markers, as early as three days following neurogenic differentiation. Our studies identify biopsy-derived T-MSCs as a potential source for generating neuron-like cells which may have potential use for in vitro modeling of neurodegenerative diseases or cell replacement therapies.

Survival outcomes of lateral skull base tumors following temporal bone resection.

BACKGROUND: Lateral skull base tumors often necessitate temporal bone resection (TBR), although clinical outcomes can be unfavorable. Factors influencing survival and recurrence after TBR for cutaneous and salivary malignancies were evaluated. METHODS: Twenty-six TBR subjects were included. Survival and recurrence outcomes were estimated at 1, 2, and 5 years postresection. Prognostic factors were analyzed using univariate and multivariate Cox regression. RESULTS: Two years postresection, the overall survival (OS), disease-specific survival (DSS) and recurrence-free survival (RFS) rates were 61%, 74%, and 49%, respectively, and 51%, 63%, and 45% at 5 years. On univariate analysis, preoperative facial nerve dysfunction and intraoperative nerve sacrifice worsened OS, DSS, and RFS. Prior surgery and adjuvant radiation independently predicted reduced OS, DSS, and RFS on multivariate analysis. CONCLUSIONS: Mortality is highest in the first 2 years following resection. Preoperative facial nerve dysfunction, facial nerve sacrifice, and prior radiation are negative predictors of survival and recurrence.

ZSCAN4 facilitates chromatin remodeling and promotes the cancer stem cell phenotype.

Cancer stem cells (CSCs) are cells within tumors that maintain the ability to self-renew, drive tumor growth, and contribute to therapeutic resistance and cancer recurrence. In this study, we investigate the role of Zinc finger and SCAN domain containing 4 (ZSCAN4) in human head and neck squamous cell carcinoma (HNSCC). The murine Zscan4 is involved in telomere maintenance and genomic stability of mouse embryonic stem cells. Our data indicate that the human ZSCAN4 is enriched for, marks and is co-expressed with CSC markers in HNSCC. We show that transient ZSCAN4 induction for just 2 days increases CSC frequency both in vitro and in vivo and leads to upregulation of pluripotency and CSC factors. Importantly, we define for the first time the role of ZSCAN4 in altering the epigenetic profile and regulating the chromatin state. Our data show that ZSCAN4 leads to a functional histone 3 hyperacetylation at the promoters of OCT3/4 and NANOG, leading to an upregulation of CSC factors. Consistently, ZSCAN4 depletion leads to downregulation of CSC markers, decreased ability to form tumorspheres and severely affects tumor growth. Our study suggests that ZSCAN4 plays an important role in the maintenance of the CSC phenotype, indicating it is a potential therapeutic target in HNSCC.

A Novel Device for Placement of a Secondary Tracheoesophageal Voice Prosthesis: A Preliminary Feasibility Study.

BACKGROUND: Tracheoesophageal puncture (TEP) for post-laryngectomy speech rehabilitation can be performed at the time of laryngectomy (primary) or at a subsequent time (secondary). Traditionally, the secondary procedure is performed using a rigid esophagoscope. Diseases like esophageal stricture, limited neck extension, and soft-tissue fibrosis can make this procedure technically challenging or impossible. We developed a novel device to perform a secondary tracheoesophageal puncture using a flexible esophagoscope. OBJECTIVE: To test the feasibility of a novel device used to create a secondary TEP in post-laryngectomy cadavers. METHODS: In this study, we performed a total laryngectomy on 3 fresh cadavers to establish the feasibility of our prototype. In each cadaver, a flexible esophagoscope was passed into the pharynx with the prototype. The prototype was passed through a working port and deployed to distend the esophagus. The puncture was visualized and a wire was passed via the newly established fistula. The device was activated, securing the wire, and then the esophagoscope and device were removed. RESULTS: There was 100% successful deployment of the prototype device, allowing rapid creation of the puncture and security of the guide wire in each cadaver. There was no evidence of collateral mucosal injury or esophageal perforation. CONCLUSIONS: The prototype device offers an alternative method to safely and efficiently perform a secondary TEP without the requirement of rigid esophagoscopy which can sometimes be technically impossible in this patient population.

Harvesting multipotent progenitor cells from a small sample of tonsillar biopsy for clinical applications.

BACKGROUND: Human adult stem cells hold the potential for the cure of numerous conditions and degenerative diseases. They possess major advantages over pluripotent stem cells as they can be derived from donors at any age, and therefore pose no ethical concerns or risk of teratoma tumor formation in vivo. Furthermore, they have a natural ability to differentiate and secrete factors that promote tissue healing without genetic manipulation. However, at present, clinical applications of adult stem cells are limited by a shortage of a reliable, standardized, and easily accessible tissue source which does not rely on specimens discarded from unrelated surgical procedures. METHOD: Human tonsil-derived mesenchymal progenitor cells (MPCs) were isolated from a small sample of tonsillar tissue (average 0.88 cm3). Our novel procedure poses a minimal mechanical and enzymatic insult to the tissue, and therefore leads to high cell viability and yield. We characterized these MPCs and demonstrated robust multipotency in vitro. We further show that these cells can be propagated and maintained in xeno-free conditions. RESULTS: We have generated tonsillar biopsy-derived MPC (T-MPC) lines from multiple donors across a spectrum of age, sex, and race, and successfully expanded them in culture. We characterized them by cell surface markers, as well as in vitro expansion and differentiation potential. Our procedure provides a robust yield of tonsillar biopsy-derived T-MPCs. CONCLUSIONS: Millions of MPCs can be harvested from a sample smaller than 1 g, which can be collected from a fully awake donor in an outpatient setting without the need for general anesthesia or hospitalization. Our study identifies tonsillar biopsy as an abundant source of adult MPCs for regenerative medicine.

Ex vivo antibody-dependent cellular cytotoxicity inducibility predicts efficacy of cetuximab.

We conducted in vitro studies and a clinical trial for patients with squamous cell carcinoma of the head and neck (SCCHN) to study the relationship between FcγRIIIa polymorphisms and antibody-dependent cellular cytotoxicity (ADCC). In vitro, FcγRIIIa genotype was correlated with ADCC and innate cytotoxicity using natural killer (NK) cells harvested from healthy donors. In the phase II study, patients with recurrent or metastatic SCCHN were treated with cetuximab (500 mg/m(2) i.v. every 2 weeks) and lenalidomide (25 mg daily). FcγRIIIa genotype and ex vivo ADCC were correlated with clinical response, progression-free survival (PFS), and overall survival (OS). In vitro, healthy donors with a FcγRIIIa 158-V allele demonstrated more effective ADCC against two colon cancer cell lines HT29 and SW480, mean cytotoxicity: FF 16.1%, VF/VV 24.3% (P = 0.015) and FF 11.7%, VF/VV 21.0% (P = 0.008), respectively. We observed a linear relationship between ADCC response and innate cytotoxicity. In the phase II trial, 40 patients received cetuximab and lenalidomide with median PFS of 7.2 weeks and OS of 16.4 weeks. Thirty-six patients had FcγRIIIa genotype: VV (2), VF (20), and FF (14), and 25 patients had sufficient NK-cell yield to perform ex vivo ADCC. FcγRIIIa genotype was not associated with any clinical outcomes. Patients mounting ex vivo ADCC response had a higher likelihood of stable disease (P = 0.01) and showed a trend toward increased PFS: 14 weeks versus 6.8 weeks, respectively (P = 0.13). Enhanced ex vivo ADCC and innate immunity responses were more predictive of clinical response than FcγRIIIa and may offer a functional assay to select patients suitable for cetuximab therapy.

Use of Dyna CT in evaluation and treatment of pseudoaneurysm secondary to craniofacial tumor resection: Case report and diagnostic implications.

BACKGROUND: Digital subtraction angiography (DSA) is considered the gold standard for the evaluation of head and neck vascular abnormalities. It serves as a useful diagnostic and, in many cases, therapeutic tool for treatment of acute head and neck bleeding. CASE DESCRIPTION: We report the case of a patient who presented with life threatening, uncontrollable epistaxis several weeks after resection of a large recurrent chondrosarcoma of the nasal cavity and anterior skull base. A DSA study, with an adjunctive C-arm computed tomography (CT) (Dyna CT), was ultimately helpful in revealing and precisely localizing a large anterior ethmoidal artery pseudoaneurysm adjacent to the tumor resection cavity. CONCLUSION: This additional information helped define the arterial anatomy in postoperative region, allowed precise localization and direct ligation of the pseudoaneurysm to resolve the bleeding with a favorable patient outcome.

Evaluation of superficial musculoaponeurotic system flap and fat graft outcomes for benign and malignant parotid disease.

OBJECTIVE: (1) To evaluate the effectiveness of the superficial musculoaponeurotic system (SMAS) flap and free fat graft in reconstructing the parotidectomy defect. (2) To evaluate the long-term viability of the free fat graft following parotidectomy for benign and malignant disease, including in the postradiation setting. STUDY DESIGN: Prospective study of consecutive patients. SETTING: Academic tertiary care medical center. Subjects and Methods Thirty-one consecutive patients underwent parotidectomy with SMAS flap and free fat graft reconstruction from 2006 to 2012. Data were compiled through a manual chart review. RESULTS: Twenty-three of the 31 total patients had benign disease, including pleomorphic adenoma, oncocytoma, and Warthin tumor. The 8 remaining patients (9 parotidectomies) underwent surgery for malignant disease, followed by postoperative radiation. The average age was 56 years (range, 16-84 years). The mean follow-up was 22.5 months. Satisfactory volumetric symmetry was achieved in all procedures for benign and malignant disease. Magnetic resonance imaging confirmed long-term fat graft viability in the postradiation setting. There was 1 case of Frey syndrome and no cases of unexpected, permanent facial nerve weakness among the patients. CONCLUSION: The combined technique of SMAS flap and free fat graft is effective for immediate reconstruction of the parotidectomy defect with minimal morbidity and low complication rates. This study demonstrates long-term viability of the free fat graft even in the setting of postoperative radiation.

Epitope mapping of a chimeric CD137 mAb: a necessary step for assessing the biologic relevance of non-human primate models.

Antibody based manipulation of the CD137 (4-1BB) co-signaling pathway is an attractive option for the treatment of cancer and autoimmune disease. We developed a chimeric anti-human CD137 monoclonal antibody (GG) and characterized its function. As a component of planned preclinical studies, we evaluated the binding of GG to activated peripheral blood mononuclear cells (PBMCs) from cynomolgus macaque and baboon against human. Interestingly, GG only recognized human CD137, while a commercial anti-CD137 mAb (4B4-1), recognized activated PBMCs from both human and non-human primates (NHP). Subsequent analysis revealed that the amino acid sequence of CD137 is largely conserved between primate species ( approximately 95% identical), with the extracellular domain differing by only 9-10 amino acids. Based on these data, we generated mutant constructs in the extracellular domain, replacing NHP with human CD137 sequences, and identified 3 amino acids critical for GG binding. These residues are likely part of a conformational epitope, as a peptide spanning this region is unable to block mAb binding. These data demonstrate that subtle sequence variations of defined co-stimulatory molecules amongst primate species can be employed as a strategy for mapping residues necessary for antibody binding to conformational epitopes.

FcgammaRIIIa polymorphisms and cetuximab induced cytotoxicity in squamous cell carcinoma of the head and neck.

PURPOSE: The interaction of Fc fragments of antibodies with the Fcgamma receptors is an essential checkpoint in antibody-dependent cellular cytotoxicity (ADCC). Specific polymorphisms at position 158 enhance FcgammaRIIIa affinity for IgG1 and are associated with improved clinical outcome in lymphoma patients treated with IgG1 anti-CD20 antibody. The role of ADCC in the therapeutic effects of the alpha-epidermal growth factor receptor (EGFR) mAb, cetuximab, in patients with squamous cell carcinoma of the head and neck (SCCHN) is poorly defined. We employed three SCCHN cell lines to test two hypotheses: (1) SCCHN is susceptible to cetuximab-mediated ADCC, (2) efficacy of ADCC is associated with polymorphisms at position 158 of FcgammaRIIIa. EXPERIMENTAL DESIGN: FcgammaRIIIa-158 polymorphisms were determined for healthy donors, and their purified NK cells were used as effector cells against three SCCHN cell lines in ADCC assays. Cytotoxicity levels were compared for each polymorphism class. Proliferation and cell cycle assays were done to examine the direct effects of cetuximab. RESULTS: Our results indicate that SCCHN is susceptible to cetuximab-mediated ADCC in vitro. NK cytotoxic efficiency correlates with donor 158-polymorphisms in FcgammaRIIIa. Overall cytotoxicity was greatest for individuals having a single V allele when compared to homozygous F/F individuals; the cumulative percent cytotoxicity for each polymorphism among the cell lines was 58.2% V/V, 50.6% V/F, and 26.1% F/F (P < 0.001). Additionally, the presence of a V allele correlated with superior natural cytotoxicity against NK sensitive targets. CONCLUSION: These data have both prognostic and therapeutic relevance and support the design of a prospective trial to determine the influence of FcgammaRIIIa polymorphisms on the clinical outcome of patients with SCCHN treated with alpha-EGFR mAbs.

Pure laparoscopic donor nephrectomy: 3-year experience and analysis of a refined technique to maximize graft function.

PURPOSE: Strategies for vascular control and limiting warm ischemia time (WIT) vary between institutions for laparoscopic live donor nephrectomy (LLDN). We refined our technique and retrospectively determined whether it safely provides an allograft of comparable quality to published series. PATIENTS AND METHODS: Fifty consecutive LLDN between February 2003 and November 2006 were reviewed. Key technical aspects include placing the perfused kidney and transected ureter entirely within an endocatch bag, with the string externalized through an extended lateral port site incision. Vessels are then controlled with clips, or a Satinsky clamp for right sided veins. The extraction incision is completed and the bag immediately withdrawn and placed on ice. WIT ends with perfusion with cold UW solution. RESULTS: The series includes 42 left and 8 right kidneys. 13/50 (26%) demonstrated anatomical complexity (more than one artery, vein and/or ureter). Average operative time was 178 minutes. Average WIT was 128 seconds. Conversion to open surgery occurred in two patients, one to define challenging anatomy, and another for hemorrhage from the renal artery stump. Average blood loss was 76 ml. Average length of stay was 3.6 days. Average recipient creatinine was 1.26 mg/dl at discharge. Delayed graft function occurred in three recipients. ATN/slow normalization of creatinine occurred in four. Graft survival at one year was 96%. CONCLUSIONS: The refined technique of LLDN mimics important principles of open donor nephrectomy. Controllable variables which may impact graft function are optimized. WIT is amongst the lowest reported for pure laparoscopy, without increasing complication rates, blood loss, or operative time.

Supraglottoplasty for laryngomalacia with obstructive sleep apnea.

OBJECTIVES/HYPOTHESIS: To determine if supraglottoplasty (SGP) is effective in reversing abnormal respiratory parameters in children with laryngomalacia and obstructive sleep apnea (OSA). STUDY DESIGN: Retrospective case series at a tertiary referral children's hospital. METHODS: Ten patients with laryngomalacia and OSA as documented by polysomnography underwent SGP between 2005 and 2007. Data collected included age, findings on flexible and rigid endoscopy, type of procedure performed, and postoperative course. The postoperative polysomnographies were reviewed to identify changes in obstructive apnea index, obstructive apnea/hypopnea index, respiratory disturbance index, and low arterial oxygen saturation (O2 nadir) after SGP. RESULTS: All 10 patients were successfully extubated after SGP. There were no peri- or postoperative complications, and no patient required a subsequent airway procedure. Each patient had a postoperative nocturnal polysomnography performed after SGP at 11 weeks (range 2-29 weeks). Caregivers reported mild improvement (10%), significant improvement (70%), and complete resolution (20%) of stridor and nocturnal snoring at a follow-up visit 4 weeks after discharge. Marked improvements were observed in obstructive apnea index, obstructive apnea/hypopnea index, respiratory disturbance index and O2 nadir, all of which were statistically significant (P < .05). CONCLUSIONS: Polysomnography should be considered in the initial evaluation of infants with moderate laryngomalacia to rule out OSA. SGP is an effective treatment for infants with laryngomalacia and OSA. The significant benefits of the procedure outweigh thelow morbidity. Improvement after surgery was reliably confirmed by polysomnography in this study.