Susan F. Rudy

Gene therapy of human cancer using genetically engineered lymphocytes is dependent on the identification of highly reactive T-cell receptors (TCRs) with antitumor activity. We immunized transgenic mice and also conducted high-throughput screening of human lymphocytes to generate TCRs highly reactive to melanoma/melanocyte antigens. Genes encoding these TCRs were engineered into retroviral vectors and used to transduce autologous peripheral lymphocytes administered to 36 patients with metastatic melanoma. Transduced patient lymphocytes were CD45RA(-) and CD45RO(+) after ex vivo expansion. After infusion, the persisting cells displayed a CD45RA(+) and CD45RO(-) phenotype. Gene-engineered cells persisted at high levels in the blood of all patients 1 month after treatment, responding patients with higher ex vivo antitumor reactivity than nonresponders. Objective cancer regressions were seen in 30% and 19% of patients who received the human or mouse TCR, respectively. However, patients exhibited destruction of normal melanocytes in the skin, eye, and ear, and sometimes required local steroid administration to treat uveitis and hearing loss. Thus, T cells expressing highly reactive TCRs mediate cancer regression in humans and target rare cognate-antigen-containing cells throughout the body, a finding with important implications for the gene therapy of cancer. This trial was registered at www.ClinicalTrials.gov as NCI-07-C-0174 and NCI-07-C-0175.

Altered immune, inflammatory, and angiogenesis responses are observed in patients with head and neck squamous cell carcinoma (HNSCC), and many of these responses have been linked with aggressive malignant behavior and a decrease in prognosis. In this study, we examined the hypothesis that HNSCC cells produce cytokines that regulate immune, inflammatory, and angiogenesis responses. We identified important regulatory cytokines in supernatants of well-defined and freshly cultured HNSCC cell lines by ELISA and determined whether these cytokines are detected in tumor cell lines and tissue specimens by immunohistochemistry. The serum concentration of the cytokines and cytokine-dependent acute phase inflammatory responses (i.e., fibrinogen, C-reactive protein, and erythrocyte sedimentation rate) from patients with HNSCC was determined, and the potential relationship of serum cytokine levels to tumor volume was analyzed. Cytokines interleukin (IL)-1alpha, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor were detected in similar concentration ranges in the supernatants of a panel of established University of Michigan squamous cell carcinoma (UM-SCC) cell lines and supernatants of freshly isolated primary HNSCC cultures. Evidence for the expression of IL-1alpha, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor, and VEGF in HNSCC cells within tumor specimens in situ was obtained by immunohistochemistry. In a prospective comparison of the cytokine level and cytokine-inducible acute-phase proteins in serum, we report that cytokines IL-6, IL-8, and VEGF were detected at higher concentrations in the serum of patients with HNSCC compared with patients with laryngeal papilloma or age-matched control subjects (at P < 0.05). The serum concentrations of IL-8 and VEGF were found to be weakly correlated with large primary tumor volume (R2 = 0.2 and 0.4, respectively). Elevated IL-1- and IL-6-inducible acute-phase responses were also detected in cancer patients but not in patients with papilloma or control subjects (at P < 0.05). We therefore conclude that cytokines important in proinflammatory and proangiogenic responses are detectable in cell lines, tissue specimens, and serum from patients with HNSCC. These cytokines may increase the pathogenicity of HNSCC and prove useful as biomarkers or targets for therapy.

No conventional therapy exists for salivary hypofunction in surviving head and neck cancer patients with Radiation Therapy Oncology Group late grade 2-3 toxicity. We conducted a phase I clinical trial to test the safety and biologic efficacy of serotype 5, adenoviral-mediated aquaporin-1 cDNA transfer to a single previously irradiated parotid gland in 11 subjects using an open label, single-dose, dose-escalation design (AdhAQP1 vector; four dose tiers from 4.8 × 10(7) to 5.8 × 10(9) vector particles per gland). Treated subjects were followed at scheduled intervals. Multiple safety parameters were measured and biologic efficacy was evaluated with measurements of parotid salivary flow rate. Symptoms were assessed with a visual analog scale. All subjects tolerated vector delivery and study procedures well over the 42-d study period reported. No deaths, serious adverse events, or dose-limiting toxicities occurred. Generally, few adverse events occurred, and all were considered mild or moderate. No consistent changes were found in any clinical chemistry and hematology parameters measured. Objective responses were seen in six subjects, all at doses <5.8 × 10(9) vector particles per gland. Five of these six subjects also experienced subjective improvement in xerostomia. AdhAQP1 vector delivery to a single parotid gland was safe and transfer of the hAQP1 cDNA increased parotid flow and relieved symptoms in a subset of subjects.

To examine the effects the proteasome inhibitor bortezomib (VELCADE) on transcription factor nuclear factor-kappaB (NF-kappaB) and target genes and the feasibility of combination therapy with reirradiation in patients with recurrent head-and-neck squamous cell carcinoma (HNSCC).The tolerability and response to bortezomib 0.6 mg/m2 and 0.9 mg/m2 given twice weekly concurrent with daily reirradiation to 50-70 Gy was explored. Blood proteasome inhibition and NF-kappaB-modulated cytokines and factors were measured. Proteasome inhibition, nuclear localization of NF-kappaB phospho-p65, apoptosis, and expression of NF-kappaB-modulated mRNAs were compared in serial biopsies from accessible tumors.The maximally tolerated dose was exceeded, and study was limited to 7 and 2 patients, respectively, given bortezomib 0.6 mg/m2 and 0.9 mg/m2/dose with reirradiation. Grade 3 hypotension and hyponatremia were dose limiting. Mucositis was Grade 3 or less and was delayed. The mean blood proteasome inhibition at 1, 24, and 48 h after 0.6 mg/m2 was 32%, 16%, and 7% and after 0.9 mg/m2 was 56%, 26%, and 14%, respectively. Differences in proteasome and NF-kappaB activity, apoptosis, and expression of NF-kappaB-modulated cell cycle, apoptosis, and angiogenesis factor mRNAs were detected in 2 patients with minor tumor reductions and in serum NF-kappaB-modulated cytokines in 1 patient with a major tumor reduction.In combination with reirradiation, the maximally tolerated dose of bortezomib was exceeded at a dose of 0.6 mg/m2 and the threshold of proteasome inhibition. Although this regimen with reirradiation is not feasible, bortezomib induced detectable differences in NF-kappaB localization, apoptosis, and NF-kappaB-modulated genes and cytokines in tumor and serum in association with tumor reduction, indicating that other schedules of bortezomib combined with primary radiotherapy or reirradiation may merit future investigation.

Aging is associated with loss of muscle mass and strength, reduced satellite cell number, and lower regenerative potential. Testosterone increases muscle mass, strength, and satellite cell number in humans; however, the effects of testosterone on the regenerative potential of skeletal muscle are unclear. Here, we investigated the effect of testosterone on the skeletal muscle regeneration of young (2-month-old) and aged (24-month-old) male mice. We show that testosterone increases the number of proliferating satellite cells in regenerating “tibialis anterior” muscle of young and aged castrated mice 2 and 4 days postinjury. Testosterone supplementation increases the number and the cross-sectional area of regenerating fibers in both classes of age 4 days postinjury. Testosterone increases satellite cell activation and proliferation and the regeneration of both young and aged mouse muscle. These data suggest prospective application of androgens to improve the regenerating potential of the aged human skeletal muscle.

Congenitally missing teeth and poorly developed or absent alveolar ridges are signs often associated with various types of ectodermal dysplasia. Endosseous dental implants may be used to support fixed mandibular prostheses in patients with ectodermal dysplasia. Anatomical factors and age considerations require careful attention to treatment planning.

Abstract Purpose: Nonselective cyclooxygenase (COX) inhibitors have been reported to decrease the frequency of upper aerodigestive cancers. Ketorolac tromethamine oral rinse has been shown to resolve another COX-dependent process, periodontal disease, without incurring gastrointestinal side effects. This trial evaluated if a topically delivered oral rinse containing ketorolac was as safe as and more effective than oral rinse alone in reducing the area of oral leukoplakia. Experimental Design: 57 patients were randomized (2:1 ratio) in a double-blind, placebo-controlled study of ketorolac (10 ml of a 0.1% ketorolac rinse solution; n = 38) or placebo (10 ml of rinse solution; n = 19) given twice daily for 30 s over 90 days. Primary end point was evaluated visually obtaining bidimensional measurement of the size of leukoplakia lesion(s) at entry and at 90 days. Secondary end point was histological assessment of the leukoplakia as sampled by serial punch biopsy and independently reviewed by three pathologists. Results: The patients included 67% males, 11% non-Caucasian, and 86% used tobacco with no significant differences between the two arms. Both rinses were well tolerated with good compliance, and there was no significant difference in adverse events (P = 0.27). Major response rate (complete response and partial response) was 30% for ketorolac and 32% for the placebo arm. There was no significant difference in change in histology between the two arms. Conclusion: Local delivery of a COX-containing oral rinse was well tolerated but produced no significant reduction in the extent of leukoplakia compared with the placebo. However, the favorable response rate to placebo arm remains unexplained and additional investigation of the tissue penetration with ketorolac is warranted.

Head and neck squamous cell carcinomas (HNSCCs) were previously shown to express a repertoire of cytokines and angiogenesis factors that contribute to malignant pathogenesis and are detectable in serum. Pretreatment and posttreatment serum levels of cytokines and angiogenesis factors were evaluated as markers for outcome in patients with HNSCC.Baseline cytokine and factor levels of 29 patients with HNSCC were compared with those of 15 age-matched and sex-matched controls, and pretreatment and posttreatment levels of 22 of the patients eligible for treatment and followed for a median of 37 months were compared.Mean serum concentrations of interleukin (IL)-6, IL-8, hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and growth regulated oncogene 1 (GRO-1) were increased in patients with HNSCC, but elevation of these factors was not associated with clinical outcome. However, changes in first posttreatment serum cytokine levels were observed for many of the patients consistent with response, progression, and survival. Later increases in IL-6 or HGF were observed in patients who had a relapse and inflammatory or infectious complications. A relationship between the change in the pretreatment and first posttreatment cytokine measurement with survival was detected for HGF, IL-8, IL-6, and VEGF using a Cox-proportional hazards model (p = .004, p = .06, p = .10, and p = .11). The association between longitudinal decreases in IL-6, IL-8, VEGF, and HGF throughout the follow-up with survival was detected with a time-dependent Cox model (p = .01, .07, .08, and .05, respectively).Longitudinal changes in serum HGF, IL-6, IL-8, and VEGF were detected with treatment response, relapse, or complications in individual patients and were associated with survival, with HGF showing the strongest relationship with survival. HGF, IL-6, IL-8, and VEGF merit investigation as markers of response, survival, and recurrence in larger prospective studies.

We investigated auditory perception and cognitive processing in individuals with chronic tinnitus or hearing loss using functional magnetic resonance imaging (fMRI). Our participants belonged to one of three groups: bilateral hearing loss and tinnitus (TIN), bilateral hearing loss without tinnitus (HL), and normal hearing without tinnitus (NH). We employed pure tones and frequency-modulated sweeps as stimuli in two tasks: passive listening and active discrimination. All subjects had normal hearing through 2 kHz and all stimuli were low-pass filtered at 2 kHz so that all participants could hear them equally well. Performance was similar among all three groups for the discrimination task. In all participants, a distributed set of brain regions including the primary and non-primary auditory cortices showed greater response for both tasks compared to rest. Comparing the groups directly, we found decreased activation in the parietal and frontal lobes in the participants with tinnitus compared to the HL group and decreased response in the frontal lobes relative to the NH group. Additionally, the HL subjects exhibited increased response in the anterior cingulate relative to the NH group. Our results suggest that a differential engagement of a putative auditory attention and short-term memory network, comprising regions in the frontal, parietal and temporal cortices and the anterior cingulate, may represent a key difference in the neural bases of chronic tinnitus accompanied by hearing loss relative to hearing loss alone.

Abstract Purpose: A phase I clinical trial and molecular correlative studies were conducted to evaluate preclinical evidence for combinatorial activity of the proteasome inhibitor bortezomib, the epidermal growth factor receptor (EGFR) inhibitor cetuximab, and radiation therapy. Experimental Design: Patients with radiotherapy-naive stage IV or recurrent squamous cell carcinoma of the head and neck (SCCHN) were studied. Escalating doses of bortezomib (0.7, 1.0, and 1.3 mg/m2) were given intravenously twice weekly on days 1, 4, 8, and 11, every 21 days, with weekly cetuximab beginning 1 week prior and concurrently with intensity-modulated radiotherapy, delivered in 2 Gy fractions to 70 to 74 Gy. Molecular effects were examined in serial serum and SCCHN tumor specimens and the cell line UMSCC-1. Results: Seven patients were accrued before the study was terminated when five of six previously untreated patients with favorable prognosis oropharyngeal SCCHN progressed within 1 year (progression-free survival = 4.8 months; 95% CI, 2.6–6.9). Three patients each received bortezomib 0.7 or 1.0 mg/m2, without dose-limiting toxicities; one patient treated at 1.3 mg/m2 was taken off study due to recurring cetuximab infusion reaction and progressive disease (PD). Expected grade 3 toxicities included radiation mucositis (n = 4), dermatitis (n = 4), and rash (n = 1). SCCHN-related cytokines increased in serial serum specimens of patients developing PD (P = 0.029). Bortezomib antagonized cetuximab- and radiation-induced cytotoxicity, degradation of EGFR, and enhanced prosurvival signal pathway activation in SCCHN tumor biopsies and UMSCC-1. Conclusions: Combining bortezomib with cetuximab and radiation therapy showed unexpected early progression, evidence for EGFR stabilization, increased prosurvival signaling, and SCCHN cytokine expression, warranting avoidance of this combination. Clin Cancer Res; 17(17); 5755–64. ©2011 AACR.

Purpose: Electronic nicotine delivery systems (ENDS) use poses significant and avoidable health risks to young people.Until recently, seizures were most often associated with cases of liquid nicotine ingestion.Methods: We examined 122 voluntary reports of seizures (n ¼ 114) and neurological symptoms (syncope, n ¼ 7; and tremor, n ¼ 1) in 123 ENDS users (one report contained information on two users) received by the Food and Drug Administration between December 1, 2010, and June 30, 2019.Results: The median age (interquartile range) of users was 20 years (17e27); 67% of reports were in youth and young adults aged 14e24 years.Fifty-one (41%) reported other underlying medical conditions, including previous history of anxiety (n ¼ 11), attention deficit hyperactivity disorder (n ¼ 7), seizure (n ¼ 6), and depression (n ¼ 5).Of the 79 reports with available information, 67 (85%) reported seizure occurred within 24 hours of last use; 49 (62%) reported seizure within 30 minutes.The potential impact of concomitant use of marijuana or cannabidiol oil could not be evaluated from the eight reports that mentioned concomitant use.Conclusions: Findings suggest an association between ENDS use and seizures.Additional information will help to clarify the relationship between ENDS use and seizures and to understand how product attributes such as nicotine content, formulation, quantity, and other ingredients or contaminants may contribute to seizures.It is important that health care providers ask about ENDS use when evaluating neurological symptoms and that users, parents, school personnel, and health care providers report adverse experiences involving tobacco products to Food and Drug Administration via the Safety Reporting Portal (www.safetyreporting.hhs.gov).

Purpose To report the long-term outcomes and toxicity of a regimen of infusion paclitaxel delivered concurrently with radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck. Patients and Methods Between 1995 and 1999, 35 patients with nonmetastatic, Stage III or IV squamous cell carcinoma of the head and neck were treated with three cycles of paclitaxel as a 120-h continuous infusion beginning on Days 1, 21, and 42, concurrent with radiotherapy. The initial 16 patients received 105 mg/m2/cycle, and the subsequent 19 patients received 120 mg/m2/cycle. External beam radiotherapy was delivered to a dose of 70.2–72 Gy at five fractions weekly. Patients were followed to evaluate the disease outcomes and late toxicity of this regimen. Results The median follow-up for all patients was 56.5 months. The median survival was 56.5 months, and the median time to local recurrence was not reached. Of the 35 patients, 15 (43%) developed hypothyroidism. Of the 33 patients who underwent percutaneous endoscopic gastrostomy tube placement, 11 were percutaneous endoscopic gastrostomy tube dependent until death or their last follow-up visit. Also, 5 patients (14%) required a tracheostomy until death, and 3 (9%) developed a severe esophageal stricture. All evaluated long-term survivors exhibited salivary hypofunction. Fibrosis in the radiation field occurred in 24 patients (69%). Conclusion The results of our study have shown that concurrent chemoradiotherapy with a 120-h infusion of paclitaxel provides long-term local control and survival in patients with squamous cell carcinoma of the head and neck. Xerostomia, hypothyroidism, esophageal and pharyngeal complications, and subcutaneous fibrosis were common long-term toxicities; however, the vast majority of toxicities were grade 1 or 2. To report the long-term outcomes and toxicity of a regimen of infusion paclitaxel delivered concurrently with radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck. Between 1995 and 1999, 35 patients with nonmetastatic, Stage III or IV squamous cell carcinoma of the head and neck were treated with three cycles of paclitaxel as a 120-h continuous infusion beginning on Days 1, 21, and 42, concurrent with radiotherapy. The initial 16 patients received 105 mg/m2/cycle, and the subsequent 19 patients received 120 mg/m2/cycle. External beam radiotherapy was delivered to a dose of 70.2–72 Gy at five fractions weekly. Patients were followed to evaluate the disease outcomes and late toxicity of this regimen. The median follow-up for all patients was 56.5 months. The median survival was 56.5 months, and the median time to local recurrence was not reached. Of the 35 patients, 15 (43%) developed hypothyroidism. Of the 33 patients who underwent percutaneous endoscopic gastrostomy tube placement, 11 were percutaneous endoscopic gastrostomy tube dependent until death or their last follow-up visit. Also, 5 patients (14%) required a tracheostomy until death, and 3 (9%) developed a severe esophageal stricture. All evaluated long-term survivors exhibited salivary hypofunction. Fibrosis in the radiation field occurred in 24 patients (69%). The results of our study have shown that concurrent chemoradiotherapy with a 120-h infusion of paclitaxel provides long-term local control and survival in patients with squamous cell carcinoma of the head and neck. Xerostomia, hypothyroidism, esophageal and pharyngeal complications, and subcutaneous fibrosis were common long-term toxicities; however, the vast majority of toxicities were grade 1 or 2.

<h3>Background</h3> Electronic nicotine delivery system (ENDS)-associated overheating, fire or explosion (OH/F/EXP) events have occurred since at least 2009. <h3>Objective</h3> To identify the number and nature of ENDS OH/F/EXP events in the USA. <h3>Methods</h3> Center for Tobacco Products (CTP) scientists searched for event reports among five US federal agencies, scientific literature and media outlets. <h3>Findings</h3> 100 reference sources identified 92 OH/F/EXP events in the USA, of which 45 (49%) injured 47 people, and 67 (73%) involved property damage beyond the product. Events were identified in media outlets (n=50; 54%) and reported to four agencies (n=42; 46%). The report rate peaked at an average of six reports per month in late 2013 with a smaller peak of three to four reports per month in the second quarter of 2015. All reports were incomplete and events exhibited variability. International events in three countries are mentioned, and international responses to events are summarised. <h3>Conclusions</h3> The scope, causes and trajectory of ENDS OH/F/EXP events remain incompletely defined. Some events have resulted in life-threatening injury, permanent disfigurement or disability, and major property damage, suggesting the need for ongoing surveillance and risk mitigation. More comprehensive reporting could assist future analyses and may help to identify root causes and contributors to the OH/F/EXP events.

PURPOSE: To determine the feasibility of an organ preservation regimen consisting of infusional paclitaxel administered concurrently with radiotherapy to patients with locally advanced head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: Thirty-three previously untreated patients with stage III or IV tumors were enrolled onto the study. Paclitaxel was administered as a 120-hour continuous infusion every 3 weeks during the course of radiation therapy. Sixteen patients received a paclitaxel dose of 105 mg/m 2 , and 17 patients received 120 mg/m 2 . Radiation was delivered in a standard format at 1.8 Gy/d to a total dose of 70.2 to 72 Gy. RESULTS: Three months after therapy, a 76% complete response (CR) at the primary site and a 70% overall CR was achieved. At 36 months, locoregional control was 55.7%, overall survival was 57.8%, and disease-free survival was 51.1%. The median survival duration for all 33 patients was greater than 50 months at the time of this report. Local toxicities including mucositis, dysphagia, and skin reactions were severe but tolerable. All patients retained functional speech, and all but four patients were swallowing food 3 months after treatment. Steady-state plasma concentrations for paclitaxel were not achieved during a 120-hour infusion, suggesting a nonlinear process. Tumor volume quantified by pretreatment computerized tomography imaging was associated with likelihood of response and survival. CONCLUSION: Paclitaxel administered as a 120-hour continuous infusion in combination with radiotherapy is a feasible and promising treatment for patients with advanced HNSCC.

Pallister-Hall syndrome (PHS) comprises hypothalamic hamartoma, polydactyly, pituitary dysfunction, laryngotracheal cleft, imperforate anus, and other anomalies. Some patients with PHS have a bifid epiglottis, a rare malformation. Greig cephalopolysyndactyly syndrome (GCPS) comprises polydactyly with craniofacial malformations without the PHS malformations. Both disorders are caused by mutations in the GLI3 gene. Laryngoscopy on 26 subjects with PHS showed that 15 had a bifid or cleft epiglottis (58%) and none of 14 subjects with GCPS had a cleft epiglottis. The malformed epiglottis was asymptomatic in all of the prospectively evaluated subjects. One additional PHS subject was found to have bifid epiglottis and a posterior laryngeal cleft on autopsy. We conclude that bifid epiglottis is common in PHS but not GCPS. Posterior laryngeal clefts are an uncommon manifestation of PHS and are identified only in severely affected patients. The diagnosis of a bifid epiglottis should prompt a thorough search for other sometimes asymptomatic anomalies of PHS to provide better medical care and recurrence risk assessment for affected individuals and families.

To characterize the natural history and possible mechanisms of hearing loss in Stickler syndrome (OMIM 108300; or hereditary progressive arthro-ophthalmopathy) and to determine if the auditory phenotype is a useful discriminating feature for the differential diagnosis of this group of disorders.Multifamily study.Outpatient audiology and otolaryngology clinics at the Warren Grant Magnuson Clinical Center of the National Institutes of Health, Rockville, Md.Forty-six affected individuals from 29 different families segregating Stickler syndrome.Clinical audiologic and otolaryngological examinations were performed on all individuals, including pure-tone audiometry, speech audiometry, and middle ear immittance testing. Otoacoustic emissions, auditory brainstem response, infrared video electronystagmography, and temporal bone computed tomography were performed on a subset of participants.The hearing loss was most often sensorineural in adults, and approximately 28 (60%) of the 46 adult patients had 2 or more thresholds greater than the corresponding 95th percentile values for an age-matched, otologically normal population. The hearing loss most often affected high frequencies (4000-8000 Hz) and was generally no more progressive than that due to age-related hearing loss. Type A(D) tympanograms (classification using the Jerger model), indicating hypermobile middle ear systems, were observed in 21 (46%) of the 46 affected individuals. Computed tomography of the temporal bones revealed no inner ear malformations in 19 affected individuals.The hypermobile middle ear systems observed in ears with normal-appearing tympanic membranes represent a novel finding for Stickler syndrome and are likely to be a useful diagnostic feature for this disorder. The overall sensorineural hearing loss in type I Stickler syndrome is typically mild and not significantly progressive. It is less severe than that reported for types II and III Stickler syndrome linked to COL11A2 (OMIM 120290) and COL11A1 (OMIM 120280) mutations, respectively, or the closely related Marshall syndrome. This difference will be a useful discriminatory feature in the differential diagnosis of this group of disorders.

Epidermal growth factor receptor (EGFR) overexpression in head-and-neck squamous cell carcinoma (HNSCC) stimulates tumor cell proliferation, inhibits apoptosis, and increases chemotherapy and radiation resistance. We examined the toxicity, safety and the effects on EGFR signaling in tumor biopsy samples from patients with locally advanced HNSCC treated with the EGFR signaling inhibitor gefitinib (GEF) combined with weekly intravenous paclitaxel (PAC) and radiation therapy (RT).This was a pilot Phase I dose-escalation study. Eligibility included Stage III to IVB HNSCC, age >or=18 years, no prior RT or chemotherapy, adequate organ function, and informed consent. Endpoints included determination of maximum tolerated dose (MTD) and analysis of treatment effect on EGFR signaling, tumor cell proliferation, and apoptosis in biopsy samples.Ten patients were treated. The MTD of this combination was GEF 250 mg/d with PAC 36 mg/m(2) intravenously weekly x 6 with concurrent RT. Grade 3/4 toxicities included prolonged (>8 weeks) stomatitis (7 patients), infection (2 patients), and interstitial pneumonitis (1 patient). There were five complete responses (CR) and two partial responses (PR). Of 7 patients undergoing serial biopsies, only 1 patient demonstrated a reduction in phosphorylated EGFR, decreased downstream signaling, and reduced cellular proliferation after initiating GEF.Inhibition of EGFR by GEF was observed in only one of seven tumors studied. The addition of GEF to PAC and RT did not appear to improve the response of locally advanced HNSCC compared with our prior experience with PAC and RT alone. This treatment appeared to delay recovery from stomatitis.

To understand the audiologic and vestibular toxicities associated with adoptive cell immunotherapy (ACI) targeting pigment-pathway antigens on melanoma and to investigate the use of intratympanic steroid injections in the treatment of these toxicities.Prospective nonrandomized study.Tertiary clinical research center.Thirty-two patients with progressive metastatic melanoma who failed conventional therapy underwent ACI with T cells genetically modified to target MART-1 (n = 18) or gp100 (n = 14). All patients received serial audiometric testing. Vestibular testing was performed on patients with vestibular complaints. Patients with significant deficits received intratympanic steroid injections.Of 32 patients, 15 had no hearing change, 9 had mild hearing loss, and 8 had moderate hearing loss following treatment. Ten patients received intratympanic steroid injections for mild (n = 2) or moderate (n = 7) hearing loss or for significant imbalance (n = 1). Of those with mild hearing loss (n = 9), all but 1 recovered to pretreatment hearing levels. Four of 8 patients with moderate hearing loss recovered to baseline hearing levels, and 4 had partial recovery. All 7 patients with posttreatment vestibular complaints had demonstrable vestibular dysfunction. Three of these patients demonstrated recovery to normal vestibular function. The number of modified T cells infused for therapy correlated with the degree of audiovestibular deficit.Adoptive cell immunotherapy targeting pigment-pathway cell proteins, a novel therapy for melanoma, can induce hearing loss and vestibular dysfunction. The presumed mechanism of autoimmune attack on normal melanocytes in the cochlear stria vascularis and in the vestibular organs demonstrates the importance of melanocytes in normal inner ear function.

A systematic review was conducted to evaluate the impact of human factors (HF) on the risks associated with electronic cigarettes (e-cigarettes) and to identify research gaps. HF is the evaluation of human interactions with products and includes the analysis of user, environment and product complexity. Consideration of HF may mitigate known and potential hazards from the use and misuse of a consumer product, including e-cigarettes.Five databases were searched through January 2014 and publications relevant to HF were incorporated. Voluntary adverse event (AE) reports submitted to the US Food and Drug Administration (FDA) and the package labelling of 12 e-cigarette products were analysed.No studies specifically addressing the impact of HF on e-cigarette use risks were identified. Most e-cigarette users are smokers, but data on the user population are inconsistent. No articles focused specifically on e-cigarette use environments, storage conditions, product operational requirements, product complexities, user errors or misuse. Twelve published studies analysed e-cigarette labelling and concluded that labelling was inadequate or misleading. FDA labelling analysis revealed similar concerns described in the literature. AE reports related to design concerns are increasing and fatalities related to accidental exposure and misuse have occurred; however, no publications evaluating the relationship between AEs and HF were identified.The HF impacting e-cigarette use and related hazards are inadequately characterised. Thorough analyses of user-product-environment interfaces, product complexities and AEs associated with typical and atypical use are needed to better incorporate HF engineering principles to inform and potentially reduce or mitigate the emerging hazards associated with e-cigarette products.

Flavored non-cigarette tobacco product use is widespread in the U.S. The availability of flavor options could be playing a role in recent increases in use, especially for non-cigarette tobacco products, among youth and young adults. Little is known about specific flavor preferences of youth and adult flavored tobacco product users, as well as how preferences may change over time. This study analyzes PATH Study data from completed Wave 2 (2014–2015) and Wave 3 (2015–2016) youth (12–17 years), and adult (18 + years) interviews to estimate the prevalence of flavored non-cigarette tobacco product use. We assess flavor switching by examining changes between flavors and characteristics of those who changed flavors between waves. Across age groups, and at both waves, fruit-flavored products were the most frequently used flavor by past 30-day electronic nicotine delivery systems (ENDS), cigar, cigarillo, and hookah users. In the past 30 days, a higher proportion of youth and young adults used candy/sweets-flavored ENDS than adults. Among adult ENDS users, the odds of changing flavors were highest among younger users and decreased with increasing age. Flavored tobacco product use is prevalent across non-cigarette tobacco products. Stability in the number of flavors used, as well as specific flavors, is higher among adult tobacco users, while the use of multiple flavors, and change in specific flavor, is more prevalent among youth tobacco users. Additional longitudinal research can further examine the role flavors play in appeal, product trial, and switching.

The parasite Leishmania donovani is one of the species causing visceral leishmaniasis in humans, a deadly infection claiming up to 40,000 lives each year. The current drugs for leishmaniasis treatment have severe drawbacks and there is an urgent need to find new anti-leishmanial compounds. However, the search for drug candidates is complicated by the intracellular lifestyle of Leishmania. Here, we investigate the use of human induced pluripotent stem cell (iPS)-derived macrophages (iMACs) as host cells for L. donovani. iMACs obtained through embryoid body differentiation were infected with L. donovani promastigotes, and high-content imaging techniques were used to optimize the iMACs seeding density and multiplicity of infection, allowing us to reach infection rates up to 70% five days after infection. IC50 values obtained for miltefosine and amphotericin B using the infected iMACs or mouse peritoneal macrophages as host cells were comparable and in agreement with the literature, showing the potential of iMACs as an infection model for drug screening.

The author presents the first comprehensive study of liquid absolute return funds (i.e., mutual funds that have absolute return targets and at least weekly liquidity) and shows that their higher liquidity compared with traditional hedge funds may be offset, in part, by fees that are generally substantially higher than those of traditional equity or hybrid funds. The author constructs the Liquid Absolute Return Indexes (LARI) as a benchmark against which the performance of individual liquid absolute return funds can be measured. Klement performs factor regressions of these indexes and fi nds that their factor exposures differ materially from those of hedge funds. In the article, he also analyzes the effect of adding liquid absolute return funds to a diversifi ed portfolio of stocks and bonds and investigates whether these instruments can be an alternative to traditional alternative investments, such as hedge funds. <b>TOPICS:</b>Mutual funds/passive investing/indexing, real assets/alternative investments/private equity, statistical methods, performance measurement

Objectives Sensory methods use human senses to evaluate product attributes. This review provides an overview of the types of sensory methods used to evaluate the perception of flavour in tobacco and other nicotine-containing (ToNic) products and to discuss how sensory data could inform flavoured ToNic product policy. Data sources PubMed, Embase and Web of Science. Study selection All peer-reviewed studies evaluating ToNic products using a sensory method published before 23 May 2020. Data extraction Two independent coders completed title/abstract and full-text screening to choose articles for inclusion (Cohen’s kappa=0.85, strong agreement). Each coder completed data extraction on half the articles, recording relevant information (eg, sensory methods used, results). The coders categorised sensory methods and generated overarching themes. Data synthesis Of 110 articles identified, we included 29 articles containing 35 studies that used sensory methods to investigate ToNic products. The sensory methods included analytic methods such as discrimination and descriptive tests and hedonic methods such as liking tests. Six themes emerged regarding how sensory methods can be used to understand consumer perception and liking of ToNic products and to inform ToNic product policy. Conclusions The identified studies highlight that sensory data can inform ToNic product policy. Analytic and sensory hedonic ratings can be used to assess a ToNic product’s ability to promote addiction in the user (ie, abuse liability). Lastly, hedonic ratings can provide information to assess potential use behaviours.

Caregiving is an important component in the management of patients with a tracheostomy or laryngectomy. The purpose of this integrative research literature review was to gain a better understanding of the impact of caregiving for adults and children with laryngectomy or tracheostomy on the patient, the family, and the caregiver. Patients who had undergone laryngectomy or tracheostomy included those with and without cancer. This integrated review of the literature on caregiving in this population demonstrates the dearth of studies on this subject. Despite the significance of the caregiving role, few studies have addressed caregiving, and those that have are primarily descriptive. Studies are needed that develop and test interventions to assist caregivers in adaptation to their role, identification of methods of decreasing caregiver burden and strain, and coordination of resources to support patients and caregivers of patients with tracheostomies and laryngectomies.

"Comment on “Does vaping cause seizures? The need for comprehensive drug testing”." Clinical Toxicology, 58(5), pp. 435–436

Successful osseointegration of endosseous titanium implants is thought to be dependent upon close apposition of bone to the implant surface. The integration of implants in this patient was achieved despite the lipid-laden histiocytic infiltration of the bone marrow. Presumably, enough unaffected stromal cells were present to allow sufficient bone formation for osseointegration of the implant fixtures. This result invites speculation regarding both the mechanism of osseointegration and the minimum surface area of bone-implant interface necessary for achieving and maintaining osseointegration of titanium implants. This patient is periodically examined to determine if the loaded fixtures will remain clinically immobile for a prolonged period.

16526 Background: The over expression of EGFR in HNSCC stimulates tumor cell proliferation, inhibits apoptosis, and increases resistance to chemotherapy and radiation. We examined the toxicity and maximum tolerated dose (MTD), and the downstream signaling and cellular effects in tumor biopsies in locally advanced HNSCC patients (Pts.) treated with GEF+PAC and RT. Methods: Pilot phase I dose escalation study initiated at GEF 250 mg/d + PAC 45 mg/m 2 weekly x 6 with concurrent RT to 72 Gy. Eligibility: Stage III-IVB HNSCC, age=18 years, no prior RT or chemotherapy, ECOG =2, adequate organ function and informed consent. Endpoints: MTD determination, analysis of tumor biopsies for treatment effect on phospho-EGFR, Akt, Erk1/2, STAT3, NF-κB p65, Ki67 expression, TUNEL assay, serial measurement of serum IL-6, IL-8, VEGF, HGF and GROa. Results: 10 Pts., median age 60.7 yrs. (range, 41–83), 7 men and 3 women were treated. The MTD was GEF 250 mg/d + PAC 36 mg/m 2 weekly x 6 with concurrent RT. Grade 3/4 toxicities included prolonged (&gt;8 wk duration) mucositis in 7 Pts., infection (1) and interstitial pneumonitis (1). Two Pts. experienced protracted painful oral dysesthesia. There were 5 CR's and 1 PR. Of 7 Pts. undergoing serial biopsy, 1 Pt. showed a significant decrease in phosphorylated-EGFR expression, decreased downstream phosphoprotein signaling and cellular proliferation within 8 days of initiating GEF. Conclusions: Severe and prolonged mucositis was dose-limiting for this schedule of GEF+PAC and RT in locally advanced HNSCC. Inhibition of EGFR activation and downstream signaling by GEF was observed in a minority of Pts. on serial tumor biopsy specimens obtained during treatment. No significant financial relationships to disclose.

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&lt;div&gt;Abstract&lt;p&gt;&lt;b&gt;Purpose:&lt;/b&gt; A phase I clinical trial and molecular correlative studies were conducted to evaluate preclinical evidence for combinatorial activity of the proteasome inhibitor bortezomib, the epidermal growth factor receptor (EGFR) inhibitor cetuximab, and radiation therapy.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Experimental Design:&lt;/b&gt; Patients with radiotherapy-naive stage IV or recurrent squamous cell carcinoma of the head and neck (SCCHN) were studied. Escalating doses of bortezomib (0.7, 1.0, and 1.3 mg/m&lt;sup&gt;2&lt;/sup&gt;) were given intravenously twice weekly on days 1, 4, 8, and 11, every 21 days, with weekly cetuximab beginning 1 week prior and concurrently with intensity-modulated radiotherapy, delivered in 2 Gy fractions to 70 to 74 Gy. Molecular effects were examined in serial serum and SCCHN tumor specimens and the cell line UMSCC-1.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; Seven patients were accrued before the study was terminated when five of six previously untreated patients with favorable prognosis oropharyngeal SCCHN progressed within 1 year (progression-free survival = 4.8 months; 95% CI, 2.6–6.9). Three patients each received bortezomib 0.7 or 1.0 mg/m&lt;sup&gt;2&lt;/sup&gt;, without dose-limiting toxicities; one patient treated at 1.3 mg/m&lt;sup&gt;2&lt;/sup&gt; was taken off study due to recurring cetuximab infusion reaction and progressive disease (PD). Expected grade 3 toxicities included radiation mucositis (&lt;i&gt;n&lt;/i&gt; = 4), dermatitis (&lt;i&gt;n&lt;/i&gt; = 4), and rash (&lt;i&gt;n&lt;/i&gt; = 1). SCCHN-related cytokines increased in serial serum specimens of patients developing PD (&lt;i&gt;P&lt;/i&gt; = 0.029). Bortezomib antagonized cetuximab- and radiation-induced cytotoxicity, degradation of EGFR, and enhanced prosurvival signal pathway activation in SCCHN tumor biopsies and UMSCC-1.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; Combining bortezomib with cetuximab and radiation therapy showed unexpected early progression, evidence for EGFR stabilization, increased prosurvival signaling, and SCCHN cytokine expression, warranting avoidance of this combination. &lt;i&gt;Clin Cancer Res; 17(17); 5755–64. ©2011 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;

&lt;div&gt;Abstract&lt;p&gt;&lt;b&gt;Purpose:&lt;/b&gt; A phase I clinical trial and molecular correlative studies were conducted to evaluate preclinical evidence for combinatorial activity of the proteasome inhibitor bortezomib, the epidermal growth factor receptor (EGFR) inhibitor cetuximab, and radiation therapy.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Experimental Design:&lt;/b&gt; Patients with radiotherapy-naive stage IV or recurrent squamous cell carcinoma of the head and neck (SCCHN) were studied. Escalating doses of bortezomib (0.7, 1.0, and 1.3 mg/m&lt;sup&gt;2&lt;/sup&gt;) were given intravenously twice weekly on days 1, 4, 8, and 11, every 21 days, with weekly cetuximab beginning 1 week prior and concurrently with intensity-modulated radiotherapy, delivered in 2 Gy fractions to 70 to 74 Gy. Molecular effects were examined in serial serum and SCCHN tumor specimens and the cell line UMSCC-1.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; Seven patients were accrued before the study was terminated when five of six previously untreated patients with favorable prognosis oropharyngeal SCCHN progressed within 1 year (progression-free survival = 4.8 months; 95% CI, 2.6–6.9). Three patients each received bortezomib 0.7 or 1.0 mg/m&lt;sup&gt;2&lt;/sup&gt;, without dose-limiting toxicities; one patient treated at 1.3 mg/m&lt;sup&gt;2&lt;/sup&gt; was taken off study due to recurring cetuximab infusion reaction and progressive disease (PD). Expected grade 3 toxicities included radiation mucositis (&lt;i&gt;n&lt;/i&gt; = 4), dermatitis (&lt;i&gt;n&lt;/i&gt; = 4), and rash (&lt;i&gt;n&lt;/i&gt; = 1). SCCHN-related cytokines increased in serial serum specimens of patients developing PD (&lt;i&gt;P&lt;/i&gt; = 0.029). Bortezomib antagonized cetuximab- and radiation-induced cytotoxicity, degradation of EGFR, and enhanced prosurvival signal pathway activation in SCCHN tumor biopsies and UMSCC-1.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; Combining bortezomib with cetuximab and radiation therapy showed unexpected early progression, evidence for EGFR stabilization, increased prosurvival signaling, and SCCHN cytokine expression, warranting avoidance of this combination. &lt;i&gt;Clin Cancer Res; 17(17); 5755–64. ©2011 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;

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Abstract The parasite Leishmania donovani is one of the species causing visceral leishmaniasis in humans, a deadly infection claiming up to 40,000 lives each year. The current drugs for leishmaniasis treatment have severe drawbacks and there is an urgent need to find new anti-leishmanial compounds. However, the search for drug candidates is complicated by the intracellular lifestyle of Leishmania . Here, we investigate the use of human induced pluripotent stem cell (iPS)-derived macrophages (iMACs) as host cells for L. donovani . iMACs obtained through embryoid body differentiation were infected with L. donovani promastigotes, and high-content imaging techniques were used to optimise the iMACs seeding density and multiplicity of infection, allowing us to reach infection rates up to 70% five days after infection. IC 50 values obtained for miltefosine and amphotericin B using the infected iMACs or mouse peritoneal macrophages as host cells were comparable and in agreement with the literature, showing the potential of iMACs as an infection model for drug screening. Author Summary Yearly, up two million people in poverty-stricken areas contract leishmaniasis, a disease caused by parasites of the genus Leishmania . When an infected sandfly takes a blood meal, Leishmania parasites enter the host where they are taken up by macrophages. Inside the macrophage, Leishmania parasites establish a niche where they can proliferate. Although this infection often leads to disability or death, the drugs currently available are lacking due to toxic side effects, high expenses or difficulties in usage. Drug screening assays that are currently used for compound screening often rely on mouse peritoneal macrophages. We have generated human induced pluripotent stem cell derived macrophages and used these as new host cells for Leishmania donovani in the testing of anti-leishmanial compounds. This model has many advantages. For one, it allows us to work with human cells, mimicking the natural infection more closely than possible with murine cells. Secondly, it allows to obtain bigger batches of uniform cells for screening campaigns. Finally, this approach aligns with the principle of 3R, replacing the use of animals for cultivation of Leishmania and drug screening purposes.

2603 Background: B demonstrated antitumor and radiosensitizing activity in preclinical solid tumor models. Methods: A phase I trial was designed to assess escalating doses of B 0.6, 0.9 or 1.2 mg/m2 IV twice weekly concurrent with re-RT 2Gy/5 days/wk to 60-70 Gy. Evaluations included standard measures for adverse events (CTC v3.0), tumor response (RECIST), progression-free survival (PFS) and overall survival (OS). Baroreceptor reflex testing was initiated in a subset of patients to assess the potential cause of observed orthostatic hypotension. Results: 25 patients with recurrent SCCHN were treated: 19 men, 6 women, median age 57 yrs, ECOG performance status∼1, prior surgery and chemotherapies∼1 and > 6 mos since prior RT. All were evaluable for toxicity and 19 for response. B 0.6 or 0.9 mg/m2 + re-RT given 2x/wk for 6-7 wks without breaks was associated with dose-limiting orthostatic hypotension and/or hyponatremia. Amended schedules with a mid-course 2-wk break from B and re-RT, or B alone, were better tolerated. B 0.9 mg/m2 2x/wk with a 2-wk mid- course break was established as the MTD and schedule, based on a dose-limiting neuropathy. Pre-existing and treatment-associated baroreceptor reflex dysfunction was seen in several subjects. Radiation mucositis was less than expected at doses and schedules studied. 5/5 pts given B 0.6 mg/m2 2x/wk without break had early progressive disease, while 5 PRs and 1 SD were seen in 10 subjects treated at the same dose with a 2 wk break. At 0.9 mg/m2, 3 SD and 3 PD were seen. The median PFS and OS of ∼2 + 4 mos in subjects treated without break was inferior to that of ∼4 + 11 months seen in patients treated with breaks. Conclusions: Decreased response in patients treated with B+re-RT without break or at higher doses suggests that proteasome inhibition may confer radioprotection in SCCHN. Peripheral or baroreceptor reflex neuropathy is dose-limiting in some heavily pretreated HNSCC patients. Supported by NIH Intramural Project ZIADC-000016 and a CRADA with Millennium Pharmaceuticals. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Millennium

On April 3, 2019, US Food and Drug Administration's (FDA's) Center for Tobacco Products alerted the public to a potential association between seizure and e-cigarette use, or “vaping,” after reviewing 35 reports of seizure following e-cigarette use.1 After the announcement, there was an increase in voluntary reports to FDA on this topic.2 As of March 1, 2021, more than 250 reports of e-cigarette–associated seizures have been submitted, mostly by consumers or concerned citizens, with approximately two thirds of cases occurring in youth or young adults.

Hearing experts and public health organizations have longstanding hearing safety concerns about personal handheld audio devices, which are growing in both number and popularity. This paper reviews the maximum sound levels of handheld compact disc players, MP3 players, and an iPod. It further reviews device factors that influence the sound levels produced by these audio devices and ways to reduce the risk to hearing during their use.

This is a companion paper to two previous publications on recommended practices for cleaning and reprocessing flexible endoscopes used in Otolaryngology (Burlingame, Arcilla, & McDermott, 2008; Adams & Baker, 2010). In this paper we capture and expand upon the audience question and answer session in which the Society of Otorhinolaryngology and Head-Neck Nurse (SOHN)--endorsed the Association of periOperative Registered Nurses (AORN) recommended practices were presented to the SOHN membership (Adams & Waddington, September, 2010). We include additional background information to assist readers in understanding some of the science behind the recommendations and share successful implementation strategies from Otorhinolaryngology (ORL) outpatient nurses and published references.

This chapter argues that Caroline Bergvall’s multi-media, multilingual, transhistorical work explores a hyphenated practice based on an interdependent relation between reader and text. Drawing on Jessica Benjamin, who argues that in the mother-child bond we find an alternative theory of the production of meaning, Rudy argues that the mother-child relation also offers an affective theory of the reception of experiemental work, since such work offers spaces where readers can also become ‘different, new’. Rudy approaches the queer texts in this ‘expanded field’ as a queer literary critic, drawing on the work of Lisa Ruddick and other practices of intersubjecvitity, she explores the notion that, through such practices, Bergvall’s writing has become a ‘public project’ into which we are invited to enter.

This paper discusses trismus (mandibular hypomobility), addressing its etiologies, relevant anatomy and pathophysiology, with the medical and nursing care of trismic patients commonly seen in the otolaryngology setting. It aims to raise awareness among ORL nurses about the sometimes subtle presentation of trismus and about the important role ORL specialists can play in detecting and treating this debilitating disorder.

This descriptive cross-sectional study examines cathexis, or satisfaction, with the body and the orofacial region in relationship to eight major demographic and health status variables in a nonprobability sample of 34 male and 47 female edentulous subjects aged 36 to 77 years. Kiyak's 27-item Body Cathexis Scale (BCS), including an innovative five-item Orofacial Cathexis Scale (OFCS), was shown to be reliable for use in elderly clients at least to age 77 (Cronbach's alpha = .95). More research is needed to validate the OFCS. Overall scores were in the neutral range, with teeth being the most negatively cathected body part. Longer periods of edentulism were associated with more dissatisfaction with the teeth. Body and orofacial cathexis were highly positively correlated. Chronic illness, education level, race, and religion were not significantly related to cathexis. Edentulism, especially recent edentulism in the elderly, female gender, and divorced marital status could be important indicators for body image disturbance.

2575 Background: Preclinical studies combining proteasome inhibitor B and epidermal growth factor receptor (EGFR) inhibitor C, or B and RT, provided evidence for anti-tumor and radiosensitizing activity. These observations provided a rationale for a first-in-human phase I study combining B with standard concurrent C and IMRT in patients with advanced SCCHN. Methods: Cohorts of patients with chemo +RT naive stage IV or recurrent SCCHN were treated with escalating doses of B, (0.7, 1.0 and 1.3 mg/m2), given IV twice weekly on days 1, 4, 8 + 11 every 3 weeks. B + C 400 mg/m2 was started 1 week before, followed by B + weekly C 250 mg/m2 concurrent with IMRT 2Gy/5 days per week to 70 Gy. Results: 6 patients with stage IV and 1 with recurrent neck SCCHN were accrued; 6 had oropharyngeal and 1 had a laryngeal primary. 3 patients each received B 0.7 or 1.0 mg/m2, without dose-limiting toxicities, and 1 patient treated with B 1.3 mg/m2 was taken off study in week 5 due to recurring Gr 2 infusion reaction to C and progressive disease (PD). Expected Gr 3 toxicities included radiation mucositis (4), dermatitis (4), and rash (1). The study was terminated after 5/6 of the previously untreated patients had PD within one year, 2 in the lung and 3 locoregionally, despite 5 having better prognosis oropharyngeal SCCHNs (3 testing HPV+ before and 2 testing p16+ at the site of PD). The patient with a laryngeal primary had a CR and remains disease-free >10 months, and 1 patient each with PD were salvaged by surgery, or cisplatin and RT. In SCCHN cells, B was found to inhibit C and RT-induced degradation of EGFR, and enhance ERK1/2 pathway signaling and cell survival. Conclusions: The combination of B, C, and IMRT was well tolerated but resulted in a median progression free survival of <12 mos, which compared unfavorably to 17 mos reported for C+RT. Translational studies reveal B unexpectedly prevents C+RT induced EGFR degradation, enhancing tumor prosurvival signaling and radioprotection. Supported by NIHIntramural Project ZIADC-000016 and Millennium Pharmaceuticals. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Millennium

Serious adverse health effects have been reported with the use of vaping products, including neurologic disorders and e-cigarette or vaping product use-associated lung injury (EVALI). Vitamin E acetate, likely added as a diluent to cannabis-containing products, was linked to EVALI. Literature searches were performed on vitamin E and vitamin E acetate-associated neurotoxicity. Blood brain barrier (BBB) penetration potential of vitamin E and vitamin E acetate were evaluated using cheminformatic techniques. Review of the literature showed that the neurotoxic potential of inhalation exposures to these compounds in humans is unknown. Physico-chemical properties demonstrate these compounds are lipophilic, and molecular weights indicate vitamin E and vitamin E acetate have the potential for BBB permeability. Computational models also predict both compounds may cross the BBB via passive diffusion. Based on literature search, no experimental nonclinical studies and clinical information on the neurotoxic potential of vitamin E via inhalation. Neurotoxic effects from pyrolysis by-product, phenyl acetate, structurally analogous to vitamin E acetate, suggests vitamin E acetate has potential for central nervous system (CNS) impairment. Cheminformatic model predictions provide a theoretical basis for potential CNS permeability of these inhaled dietary ingredients suggesting prioritization to evaluate for potential hazard to the CNS.

This study was initiated by the Society of Otorhinolaryngology and Head-Neck Nurses, Inc. (SOHN) to establish research priorities for the specialty. Otorhinolaryngology (ORL) Nurses were asked to identify, rate, and rank priorities for ORL nursing research. The survey sample was gleaned from attendees at the 20th Annual SOHN Congress and Nursing Symposium plus a follow-up mailing to active SOHN members who did not attend. A decision-making method, the reactive delphi technique, was employed. Four rounds of soliciting opinions by questionnaires were completed. Data from each round were reviewed and analyzed by three ORL nurse investigators. The respondents were largely actively employed, female SOHN members who were seasoned nurses, experienced in ORL nursing. The majority were Registered Nurses (RN) or held Bachelor of Science (BSN) degrees. They were primarily employed as staff nurses in outpatient settings and working with a general otorhinolaryngology patient population of all ages. The fourteen priorities identified fall in the areas of patient outcomes (three), patient education (three), symptom management (two), patient self-care (two), psychosocial issues (two), and nursing care delivery (two), spanning the practice spectra of all ORL nurse generalists and subspecialists. The top five research priorities identified are; care of neck stomas and related equipment, quality of life in head and neck cancer patients, impact of managed care on ORL nursing care delivery, value of ORL specialty nurses/nursing units, and effective techniques to promote cessation of substance abuse in adolescents. This priority identification provides a baseline for the newly forming SOHN Foundation.

Purpose/Objective(s)We report the long-term outcomes of 33 patients with locally advanced squamous cell carcinoma of the head and neck treated with concurrent paclitaxel and radiation therapy.Materials/MethodsBetween 1995 and 1999, 33 patients with biopsy proven stage III or IV squamous cell carcinoma of the head and neck who were either ineligible for curative resection or refused surgery were treated on an IRB-approved protocol. Radiation was delivered to 70.2–72 Gy in 5 fractions per week using 3-D treatment planning. A three-field technique with lateral and low-anterior neck fields was typically used with a shrinking field technique. Three patients with oral tongue lesions received a brachytherapy boost. Chemotherapy consisted of 3 cycles of paclitaxel administered as a 120-hour continuous intravenous infusion beginning days 1, 21, and 42. The initial 16 patients received a dose of 105 mg/m2/cycle, and the subsequent 17 patients received 120 mg/m2/cycle after no significant toxicity seen at the lower dose. Patient records were reviewed for treatment toxicity and outcome. Toxicity was graded with the RTOG late radiation morbidity scoring criteria.ResultsMedian follow-up is 4.9 years for all patients and 8.2 years for surviving patients, with no patients lost to follow-up. The median survival for all patients was 54 months, and the median time to local recurrence or death was 52 months. In regards to toxicity, most (9/10) surviving patients had xerostomia at last follow-up, with 50% having grade 2 and 40% having grade 1 xerostomia. Fibrosis in the local-regional radiation field was seen in 67% of patients, with 45% of the patients with grade 2 or higher and 6% of patients with grade 3 or higher neck fibrosis. Twelve (36%) patients developed hypothyroidism post-treatment requiring medical supplementation. Three patients (10%) with recurrent or persistent disease developed a local fistula. The median duration of percutaneous endoscopic gastrostomy tube (PEG) usage in the 31 patients that underwent placement was 11.6 months; eleven patients (33%) were PEG-dependent until death or last follow-up with 1 surviving PEG-dependent patient. Twelve patients (36%) developed distant metastases, 5 patients (15%) had a tracheostomy until death, while 3 patients (10%) had severe esophageal strictures.ConclusionsConcurrent chemo-radiation with concurrent paclitaxel in a 120-hour infusion for 3 cycles can provide long term local control and survival in patients with locally advanced head and neck cancers. Xerostomia, hypothyroidism, and fibrosis were common long-term toxicities but the vast majorities were grade I or II. Purpose/Objective(s)We report the long-term outcomes of 33 patients with locally advanced squamous cell carcinoma of the head and neck treated with concurrent paclitaxel and radiation therapy. We report the long-term outcomes of 33 patients with locally advanced squamous cell carcinoma of the head and neck treated with concurrent paclitaxel and radiation therapy. Materials/MethodsBetween 1995 and 1999, 33 patients with biopsy proven stage III or IV squamous cell carcinoma of the head and neck who were either ineligible for curative resection or refused surgery were treated on an IRB-approved protocol. Radiation was delivered to 70.2–72 Gy in 5 fractions per week using 3-D treatment planning. A three-field technique with lateral and low-anterior neck fields was typically used with a shrinking field technique. Three patients with oral tongue lesions received a brachytherapy boost. Chemotherapy consisted of 3 cycles of paclitaxel administered as a 120-hour continuous intravenous infusion beginning days 1, 21, and 42. The initial 16 patients received a dose of 105 mg/m2/cycle, and the subsequent 17 patients received 120 mg/m2/cycle after no significant toxicity seen at the lower dose. Patient records were reviewed for treatment toxicity and outcome. Toxicity was graded with the RTOG late radiation morbidity scoring criteria. Between 1995 and 1999, 33 patients with biopsy proven stage III or IV squamous cell carcinoma of the head and neck who were either ineligible for curative resection or refused surgery were treated on an IRB-approved protocol. Radiation was delivered to 70.2–72 Gy in 5 fractions per week using 3-D treatment planning. A three-field technique with lateral and low-anterior neck fields was typically used with a shrinking field technique. Three patients with oral tongue lesions received a brachytherapy boost. Chemotherapy consisted of 3 cycles of paclitaxel administered as a 120-hour continuous intravenous infusion beginning days 1, 21, and 42. The initial 16 patients received a dose of 105 mg/m2/cycle, and the subsequent 17 patients received 120 mg/m2/cycle after no significant toxicity seen at the lower dose. Patient records were reviewed for treatment toxicity and outcome. Toxicity was graded with the RTOG late radiation morbidity scoring criteria. ResultsMedian follow-up is 4.9 years for all patients and 8.2 years for surviving patients, with no patients lost to follow-up. The median survival for all patients was 54 months, and the median time to local recurrence or death was 52 months. In regards to toxicity, most (9/10) surviving patients had xerostomia at last follow-up, with 50% having grade 2 and 40% having grade 1 xerostomia. Fibrosis in the local-regional radiation field was seen in 67% of patients, with 45% of the patients with grade 2 or higher and 6% of patients with grade 3 or higher neck fibrosis. Twelve (36%) patients developed hypothyroidism post-treatment requiring medical supplementation. Three patients (10%) with recurrent or persistent disease developed a local fistula. The median duration of percutaneous endoscopic gastrostomy tube (PEG) usage in the 31 patients that underwent placement was 11.6 months; eleven patients (33%) were PEG-dependent until death or last follow-up with 1 surviving PEG-dependent patient. Twelve patients (36%) developed distant metastases, 5 patients (15%) had a tracheostomy until death, while 3 patients (10%) had severe esophageal strictures. Median follow-up is 4.9 years for all patients and 8.2 years for surviving patients, with no patients lost to follow-up. The median survival for all patients was 54 months, and the median time to local recurrence or death was 52 months. In regards to toxicity, most (9/10) surviving patients had xerostomia at last follow-up, with 50% having grade 2 and 40% having grade 1 xerostomia. Fibrosis in the local-regional radiation field was seen in 67% of patients, with 45% of the patients with grade 2 or higher and 6% of patients with grade 3 or higher neck fibrosis. Twelve (36%) patients developed hypothyroidism post-treatment requiring medical supplementation. Three patients (10%) with recurrent or persistent disease developed a local fistula. The median duration of percutaneous endoscopic gastrostomy tube (PEG) usage in the 31 patients that underwent placement was 11.6 months; eleven patients (33%) were PEG-dependent until death or last follow-up with 1 surviving PEG-dependent patient. Twelve patients (36%) developed distant metastases, 5 patients (15%) had a tracheostomy until death, while 3 patients (10%) had severe esophageal strictures. ConclusionsConcurrent chemo-radiation with concurrent paclitaxel in a 120-hour infusion for 3 cycles can provide long term local control and survival in patients with locally advanced head and neck cancers. Xerostomia, hypothyroidism, and fibrosis were common long-term toxicities but the vast majorities were grade I or II. Concurrent chemo-radiation with concurrent paclitaxel in a 120-hour infusion for 3 cycles can provide long term local control and survival in patients with locally advanced head and neck cancers. Xerostomia, hypothyroidism, and fibrosis were common long-term toxicities but the vast majorities were grade I or II.

Purpose: Recent data from the Centers for Disease Control and Prevention identify electronic cigarettes as the tobacco products most commonly used by youth. In 2016, more than 2 million US middle and high school students had used electronic nicotine delivery systems (ENDS) in the past 30 days. The role of ENDS in the initiation of nicotine use by youth is a serious concern; nicotine can harm the developing brain and is addictive. Research demonstrates ENDS use also increases the risk that youth and young adults will subsequently try cigarettes. FDA’s …

It is essential that authors involved in biomedical publication be aware of basic guidelines for the ethical publication of their scientific work. The undersigned editors have taken a consortium approach to a concern facing several major journals that relates to duplicate publication. We aim to maintain the integrity of our scientific journals. Reports that claim original information must contain original information. We believe the priority placed on this tenet is appropriately reflective of its importance to patient care.

Tobacco cessation intervention is a primary therapy for treating many conditions encountered in an otolaryngology practice. This paper presents the latest billing, coding, and insurance information to use in providing tobacco cessation services. It further guides the appropriate applications of these codes to patient encounters.

In March, 2002, the Society of Otorhinolaryngology and Head-Neck Nurses, Inc. (SOHN) conducted a web-based survey of members' knowledge of and satisfaction with its portfolio of products and services. This paper reports on the process of developing and conducting the survey, as well as its findings. A new "Volunteer Agreement/Code of Conduct", piloted for this team's work is introduced. General and specific recommendations are put forth for SOHN members and leaders, including useful information to facilitate work for future survey teams.

Educational objectives : To conceptualize the decision‐making process involved in employing a physician extender and to identify the multiple facets of the physician extender role in otolaryngology.