Thyroidectomy with and without laryngectomy: Differences in post-operative hypocalcemia and management.

BACKGROUND: Total laryngectomy (TL) with thyroidectomy can pose significant risks to parathyroid function, and variance in rates of post-operative hypocalcemia (POH) based on extent of thyroidectomy have not been previously reported. Our objective is to identify the rates of hypocalcemia and hypoparathyroidism in TL+/-thyroidectomy and compare this to matched thyroidectomy alone cohorts. METHODS: Multi-institutional retrospective chart review of patients treated surgically for laryngeal cancer with TL or benign/malignant thyroid disease with thyroidectomy at regional tertiary care centers in New Orleans and Baton Rouge, Louisiana from 2016 to 2019. Cases were evaluated for post-operative and post-discharge calcium and parathyroid hormone levels, post-operative and long-term calcium supplementation, and intraoperative parathyroid identification and management. RESULTS: 101 TL and 319 thyroidectomy patients' charts were reviewed. Regression analysis revealed increased odds of hypocalcemia and hypoparathyroidism in TL + TT versus TT alone (OR 10.7, OR 16.5, p < 0.001, respectively). TL + HT versus HT alone had increased odds of hypoparathyroidism (OR 1.6, p < 0.001). TL with any thyroidectomy compared to TL alone demonstrated both increased odds of hypocalcemia and hypoparathyroidism (OR 4.4 p = 0.009, and OR 4.5 p = 0.05). Odds of requiring long-term calcium supplementation were significantly increased with the addition of thyroidectomy across all groups. TL + TT was 8 times as likely (p = 0.002) and TL + HT was 5.3 times as likely (p = 0.001) to require long-term calcium supplementation compared to TL alone. CONCLUSIONS: Thyroidectomy combined with TL demonstrates marked increased risk of parathyroid dysfunction and resultant POH. Despite improved visualization of soft tissue anatomy with TL, risk of parathyroid injury in these settings requires special attention to extent of parathyroid dissection and potential devascularization to reduce long-term sequelae of hyperparathyroidism. Therefore, post-operative calcium monitoring after TL is necessary and should resemble the long-standing stringent protocols that already exist for monitoring in thyroidectomy populations.

Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism.

Neuroblastoma is a paediatric malignancy that typically arises in early childhood, and is derived from the developing sympathetic nervous system. Clinical phenotypes range from localized tumours with excellent outcomes to widely metastatic disease in which long-term survival is approximately 40% despite intensive therapy. A previous genome-wide association study identified common polymorphisms at the LMO1 gene locus that are highly associated with neuroblastoma susceptibility and oncogenic addiction to LMO1 in the tumour cells. Here we investigate the causal DNA variant at this locus and the mechanism by which it leads to neuroblastoma tumorigenesis. We first imputed all possible genotypes across the LMO1 locus and then mapped highly associated single nucleotide polymorphism (SNPs) to areas of chromatin accessibility, evolutionary conservation and transcription factor binding sites. We show that SNP rs2168101 G>T is the most highly associated variant (combined P = 7.47 × 10(-29), odds ratio 0.65, 95% confidence interval 0.60-0.70), and resides in a super-enhancer defined by extensive acetylation of histone H3 lysine 27 within the first intron of LMO1. The ancestral G allele that is associated with tumour formation resides in a conserved GATA transcription factor binding motif. We show that the newly evolved protective TATA allele is associated with decreased total LMO1 expression (P = 0.028) in neuroblastoma primary tumours, and ablates GATA3 binding (P < 0.0001). We demonstrate allelic imbalance favouring the G-containing strand in tumours heterozygous for this SNP, as demonstrated both by RNA sequencing (P < 0.0001) and reporter assays (P = 0.002). These findings indicate that a recently evolved polymorphism within a super-enhancer element in the first intron of LMO1 influences neuroblastoma susceptibility through differential GATA transcription factor binding and direct modulation of LMO1 expression in cis, and this leads to an oncogenic dependency in tumour cells.

Common variants upstream of MLF1 at 3q25 and within CPZ at 4p16 associated with neuroblastoma.

Neuroblastoma is a cancer of the developing sympathetic nervous system that most commonly presents in young children and accounts for approximately 12% of pediatric oncology deaths. Here, we report on a genome-wide association study (GWAS) in a discovery cohort or 2,101 cases and 4,202 controls of European ancestry. We identify two new association signals at 3q25 and 4p16 that replicated robustly in multiple independent cohorts comprising 1,163 cases and 4,396 controls (3q25: rs6441201 combined P = 1.2x10-11, Odds Ratio 1.23, 95% CI:1.16-1.31; 4p16: rs3796727 combined P = 1.26x10-12, Odds Ratio 1.30, 95% CI: 1.21-1.40). The 4p16 signal maps within the carboxypeptidase Z (CPZ) gene. The 3q25 signal resides within the arginine/serine-rich coiled-coil 1 (RSRC1) gene and upstream of the myeloid leukemia factor 1 (MLF1) gene. Increased expression of MLF1 was observed in neuroblastoma cells homozygous for the rs6441201 risk allele (P = 0.02), and significant growth inhibition was observed upon depletion of MLF1 (P < 0.0001) in neuroblastoma cells. Taken together, we show that common DNA variants within CPZ at 4p16 and upstream of MLF1 at 3q25 influence neuroblastoma susceptibility and MLF1 likely plays an important role in neuroblastoma tumorigenesis.

The functional variant rs34330 of CDKN1B is associated with risk of neuroblastoma.

The genetic aetiology of sporadic neuroblastoma is still largely unknown. We have identified diverse neuroblastoma susceptibility loci by genomewide association studies (GWASs); however, additional SNPs that likely contribute to neuroblastoma susceptibility prompted this investigation for identification of additional variants that are likely hidden among signals discarded by the multiple testing corrections used in the analysis of genomewide data. There is evidence suggesting the CDKN1B, coding for the cycle inhibitor p27Kip1, is involved in neuroblastoma. We thus assess whether genetic variants of CDKN1B are associated with neuroblastoma. We imputed all possible genotypes across CDKN1B locus on a discovery case series of 2101 neuroblastoma patients and 4202 genetically matched controls of European ancestry. The most significantly associated rs34330 was analysed in an independent Italian cohort of 311 cases and 709 controls. In vitro functional analysis was carried out in HEK293T and in neuroblastoma cell line SHEP-2, both transfected with pGL3-CDKN1B-CC or pGL3-CDKN1B-TT constructs. We identified an association of the rs34330 T allele (-79C/T) with the neuroblastoma risk (Pcombined = 0.002; OR = 1.17). The risk allele (T) of this single nucleotide polymorphism led to a lower transcription rate in cells transfected with a luciferase reporter driven by the polymorphic p27Kip1 promoter (P < 0.05). Three independent sets of neuroblastoma tumours carrying -79TT genotype showed a tendency towards lower CDKN1B mRNA levels. Our study shows that a functional variant, associated with a reduced CDKN1B gene transcription, influences neuroblastoma susceptibility.

Sample size under the additive hazards model.

BACKGROUND: The additive hazards model can be easier to interpret and in some cases fits better than the proportional hazards model. However, sample size formulas for clinical trials with time to event outcomes are currently based on either the proportional hazards assumption or an assumption of constant hazards. AIMS: The goal is to provide sample size formulas for superiority and non-inferiority trials assuming an additive hazards model but no specific distribution, along with evaluations of the performance of the formulas. METHODS: Formulas are presented that determine the required sample size for a given scenario under the additive hazards model. Simulations are conducted to ensure that the formulas attain the desired power. For illustration, the non-inferiority sample size formula is applied to the calculations in the SPORTIF III trial of stroke prevention in atrial fibrillation. CONCLUSION: Simulation results show that the sample size calculations lead to the correct power. Sample size is easily calculated using a tool that is available on the web at http://leemcdaniel.github.io/samplesize.html.

NCBI Epigenomics: a new public resource for exploring epigenomic data sets.

The Epigenomics database at the National Center for Biotechnology Information (NCBI) is a new resource that has been created to serve as a comprehensive public resource for whole-genome epigenetic data sets (www.ncbi.nlm.nih.gov/epigenomics). Epigenetics is the study of stable and heritable changes in gene expression that occur independently of the primary DNA sequence. Epigenetic mechanisms include post-translational modifications of histones, DNA methylation, chromatin conformation and non-coding RNAs. It has been observed that misregulation of epigenetic processes has been associated with human disease. We have constructed the new resource by selecting the subset of epigenetics-specific data from general-purpose archives, such as the Gene Expression Omnibus, and Sequence Read Archives, and then subjecting them to further review, annotation and reorganization. Raw data is processed and mapped to genomic coordinates to generate 'tracks' that are a visual representation of the data. These data tracks can be viewed using popular genome browsers or downloaded for local analysis. The Epigenomics resource also provides the user with a unique interface that allows for intuitive browsing and searching of data sets based on biological attributes. Currently, there are 69 studies, 337 samples and over 1100 data tracks from five well-studied species that are viewable and downloadable in Epigenomics.

Differential Regulation of Tachykinin and Opioid System Gene Expression in Brain and Immune Cells of Chronic Binge Alcohol-Treated Simian Immunodeficiency Virus-Infected Macaques.

People living with HIV have a high likelihood of at-risk alcohol use and are at increased risk for neurocognitive decline. The underlying mechanisms involved in HIV-associated neurocognitive disorder (HAND) are not completely understood. Previously, we showed that chronic binge alcohol (CBA) administration produced behavioral deficits in non antiretroviral therapy (ART)-treated simian immunodeficiency virus (SIV)-infected macaques. Moreover, we observed that CBA/SIV enhanced neuroinflammatory gene expression and attenuated growth factor signaling in the frontal cortex (FC) and basal ganglia, effects that were partially ameliorated by ART. We hypothesized that the neuroinflammatory and growth factor changes observed could be associated with alterations in opioid, tachykinin, and endocannabinoid gene expression. Furthermore, we proposed that gene expression patterns in peripheral blood mononuclear cells (PBMCs) could serve as an indicator of expression changes in the brain (FC). We examined gene expression patterns of opioid, tachykinin, and endocannabinoid systems in FC and PBMCs isolated from CBA/SIV macaques. Expression of targeted genes as determined by reverse transcription-quantitative polymerase chain reaction was analyzed in relation to CBA, ART, plasma, and brain viral loads (PVL and BVL, respectively) and compared with baseline (PBMC) or FC from SIV- controls. FC expression of ORM1, POMC, and TACR1 was negatively associated with PVL (p = .03, .002, .05 respectively). FC expression of TAC1 was positively associated with CBA exposure (p = .05). PBMC expression of DAGLA was positively associated with CBA exposure; but negatively associated with combined CBA/ART exposure (p = .03). Our findings reflect the complex interactions of SIV, CBA, and ART in modulating opioid and tachykinin system gene expression. Contrary to our prediction, results did not reveal parallel changes (in magnitude or direction) in PBMC and FC gene expression. Further studies are warranted to determine the relevance of these transcriptional changes in modulating HAND-related behaviors resulting from at-risk alcohol use and HIV/SIV exposure.

Healing Touch: A Strategy for Acute Care Nurses' Stress Reduction.

The purpose of the study is to determine whether administering healing touch (HT) is more effective than deep breathing (DB) for reducing acute care nurses' stress during a shift. A randomized cluster trial assessed 150 nurses' vital signs and Visual Analog Scale for Stress (VASS) levels pre, post, and at follow-up to achieve a power of .7 and medium affect size. Open-ended questions following the intervention enriched quantitative findings describing the experience, facilitators, and barriers to potential use in nursing. The generalized estimating equation 1 (GEE1) comparisons of mean change over time, found that nurses in the HT intervention, had significantly lower VASS stress scores at posttreatment (-0.95, p = .0002) and at follow-up (-0.73, p = .0144) than the DB group, and the respiratory rate (RR) rate differences were nearly significant at post-intervention and significant at follow-up, respectively (1.36, p = .0568 and -2.28, p = .0011), indicating lower RR after HT. These findings support the use of HT as an effective stress reduction strategy as a relevant strategy to sustain a viable nurse work force post-COVID-19.

Impact of Alcohol on Bone Health in People Living With HIV: Integrating Clinical Data From Serum Bone Markers With Morphometric Analysis in a Non-Human Primate Model.

People living with HIV (PLWH) represent a vulnerable population to adverse musculoskeletal outcomes due to HIV infection, antiretroviral therapy (ART), and at-risk alcohol use. Developing measures to prevent skeletal degeneration in this group requires a grasp of the relationship between alcohol use and low bone mass in both the PLWH population and its constituents as defined by sex, age, and race. We examined the association of alcohol use with serum biochemical markers of bone health in a diverse cohort of PLWH enrolled in the New Orleans Alcohol Use in HIV (NOAH) study. To explore the effects of alcohol on bone in the context of HIV and ART and the role of estrogen, we conducted a parallel, translational study using simian immunodeficiency virus (SIV)+/ART+ female rhesus macaques divided into four groups: vehicle (Veh)/Sham; chronic binge alcohol (CBA)/Sham; Veh/ovariectomy (OVX); and CBA/OVX. Clinical data showed that both osteocalcin (Ocn) and procollagen type I N-propeptide (PINP) levels were inversely associated with multiple measures of alcohol consumption. Age (>50 years) significantly increased susceptibility to alcohol-associated suppression of bone formation in both female and male PLWH, with postmenopausal status appearing as an additional risk factor in females. Serum sclerostin (Scl) levels correlated positively with measures of alcohol use and negatively with Ocn. Micro-CT analysis of the macaque tibias revealed that although both CBA and OVX independently decreased trabecular number and bone mineral density, only OVX decreased trabecular bone volume fraction and impacted cortical geometry. The clinical data implicate circulating Scl in the pathogenesis of alcohol-induced osteopenia and suggest that bone morphology can be significantly altered in the absence of net change in osteoblast function as measured by serum markers. Inclusion of sophisticated tools to evaluate skeletal strength in clinical populations will be essential to understand the impact of alcohol-induced changes in bone microarchitecture. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Anatomic Considerations of Perinasal Musculature for Improved Dental Show During Smile in Facial Synkinesis.

Introduction: There is an anatomic explanation for upper lip and midfacial tethering resulting in lack of motion in facial synkinesis. Objective: To measure the effect of perinasal chemodenervation on dental show in the synkinetic population and clarify the anatomic relationship of perinasal musculature. Methods: Literature search was performed on anatomy of the perinasal modiolus, and anatomic evaluation was performed through human anatomic specimen dissection. Photographic outcomes were observed in synkinetic patients receiving chemodenervation to smile antagonists with and without perinasal muscle injections and assessed through naive observer survey. Retrospective outcomes for all patients receiving perinasal chemodenervation was collected utilizing Facial Clinimetric Evaluation Scale, Sunnybrook Facial Grading System (FGS), Facial Disability Index (FDI), and the Synkinesis Assessment Questionnaire. Results: Anatomic dissections demonstrated muscular confluence spanning the nasal sidewall and upper lip tethering the soft tissue to bone. Thirty-four of 53 chemodenervation patients received perinasal Botox experiencing improvement in synkinetic symptoms of the upper lip, nose, and improved dental show as noted on paired t-test for FGS (p = 0.00096), and FDI social p = 0.015) also supported by naive observer surveys (p = 0.03). Conclusions: Human anatomic specimen dissections support a perinasal confluence of musculature with bony attachments that can be successfully treated with chemodenervation in facial synkinesis patients.

Effect of Mirtazapine on Nausea in Children with Functional Nausea and Functional Dyspepsia Postprandial Distress Syndrome.

OBJECTIVE: The objective of this study was to assess the clinical response and safety of mirtazapine in the pediatric population with a diagnosis of functional nausea and nausea associated with functional dyspepsia postprandial distress syndrome. METHODS: This was a retrospective chart review to evaluate the safety and efficacy of mirtazapine for pediatric nausea and nausea associated with functional dyspepsia postprandial distress syndrome. Clinical response was classified as complete response, partial response, and no response. We also identified the prescribed doses, side effects, and weight changes during mirtazapine therapy. RESULTS: Among the 57 total patients, 67% were females and ages ranged from 7 to 19 years with a mean of 14 ± 3 years. Clinical (complete and partial) response was reported in 82% of patients. Nausea resolved in 82% and insomnia in 77% of the patients. Eighty-four percent gained weight with a mean of 4 ± 7 kg. Sixty-five percent did not report adverse effects. The most common adverse effects were undesired weight gain (16%) and dysphoria (9%). Two patients discontinued the medicine after the first dose because of adverse effects. There was a significant correlation between the initial dose and weight (rs = 0.478; p = 0.0002). The median initial and final doses were 15 mg, respectively. CONCLUSIONS: Mirtazapine is an option for treating children and adolescents with functional nausea and nausea associated with functional dyspepsia post-prandial distress syndrome, especially for a select group of patients with concurrent weight loss, anxiety, and insomnia.

Referral Patterns of Outpatient Palliative Care among the Head and Neck Cancer Population.

Introduction Patients with head and neck cancer (HNC) experience unique physical and psychosocial challenges that impact their health and quality of life. Early implementation of palliative care has been shown to improve various health care outcomes. Objective The aim of the present study was to evaluate the patterns of referral of patients with HNC to outpatient palliative care as they relate to utilization of resources and end-of-life discussions. Methods We performed a retrospective review of 245 patients with HNC referred to outpatient palliative care services at two Louisiana tertiary care centers from June 1, 2014, to October 1, 2019. The control group consisted of those that were referred but did not follow-up. Reasons for referral were obtained, and outcome measures such as emergency department (ED) visits, hospital readmissions, and advance care planning (ACP) documentation were assessed according to predictive variables. Results There were 177 patients in the treatment group and 68 in the control group. Patients were more likely to follow up to outpatient palliative care services if referred for pain management. Hospital system, prior inpatient palliative care, and number of outpatient visits were associated with an increased likelihood for ED visits and hospital readmissions. Those in the palliative care treatment group were also more likely to have ACP discussions. Conclusion Early implementation of outpatient palliative care among patients with HNC can initiate ACP discussions. However, there are discrepancies in referral reasons to palliative care and continued existing barriers to its effective utilization.

A machine learning algorithm with subclonal sensitivity reveals widespread pan-cancer human leukocyte antigen loss of heterozygosity.

Human leukocyte antigen loss of heterozygosity (HLA LOH) allows cancer cells to escape immune recognition by deleting HLA alleles, causing the suppressed presentation of tumor neoantigens. Despite its importance in immunotherapy response, few methods exist to detect HLA LOH, and their accuracy is not well understood. Here, we develop DASH (Deletion of Allele-Specific HLAs), a machine learning-based algorithm to detect HLA LOH from paired tumor-normal sequencing data. With cell line mixtures, we demonstrate increased sensitivity compared to previously published tools. Moreover, our patient-specific digital PCR validation approach provides a sensitive, robust orthogonal approach that could be used for clinical validation. Using DASH on 610 patients across 15 tumor types, we find that 18% of patients have HLA LOH. Moreover, we show inflated HLA LOH rates compared to genome-wide LOH and correlations between CD274 (encodes PD-L1) expression and microsatellite instability status, suggesting the HLA LOH is a key immune resistance strategy.

Predicting Need for Surgery in Recurrent Laryngotracheal Stenosis Using Changes in Spirometry.

OBJECTIVES/HYPOTHESIS: We sought to identify changes that occur in spirometric values between surgical interventions in patients with recurrent laryngotracheal stenosis and assess the utility of tracking those changes in predicting the need to return to surgery. METHODS: This is a retrospective, case-control study of laryngotracheal stenosis. Charts from a 10 year period were reviewed, and 80 patients were identified with recurrent laryngotracheal stenosis and serial spirometry. Recorded forced expiratory volume in 1 second (FEV1 ), forced inspiratory volume in 1 second (FIV1 ), peak expiratory flow (PEF), and peak inspiratory flow (PIF), and body mass index (BMI) were tabulated. Calculations were then performed to determine deviations in spirometric measurements from maximums. Comparing the patients who required intervention to those who did not, we used a regression analysis to generate a decision tree based on factors with the strongest predictive power. We then calculated receiver operating characteristic (ROC) curves for all calculated variables. RESULTS: Deviations in PEF, PIF, and FIV1 from each patient's maximums had strong predictive power in determining return to surgery. PIF was the only fixed measurement found to have a statistically significant role in predicting return to surgery. BMI did not play a role. CONCLUSION: For each patient, the deviation from their overall spirometric maximums had the statistically strongest predictive power in determining need to return to surgery. This suggests the importance of the trends in spirometric measures for each individual, and implies these trends have greater import than fixed measures alone. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:2199-2203, 2021.

Antiretroviral therapy administration reduces neuroinflammation without restoring brain-derived neurotrophic factor signaling in alcohol-administered simian immunodeficiency virus-infected macaques.

OBJECTIVE: The present study examined interactions between simian immunodeficiency virus (SIV), chronic binge alcohol (CBA), and antiretroviral therapy (ART) on growth factor signaling, neuroinflammatory markers, viral loads (VL), and CD4+ cell counts. DESIGN: Adult male rhesus macaques were administered CBA (13-14 g ethanol (EtOH)/kg per week) or sucrose (SUC) 3 months prior to SIVmac251 infection until the study endpoint. At viral setpoint, a subset of CBA/SIV+ and SUC/SIV+ macaques were randomized to receive daily ART (9-[2-Phosphonyl-methoxypropyly]adenine [PMPA] 20 mg/kg, 2',3'-dideoxy-5-fluoro-3'-thiacytidine (FTC), 30 mg/kg). Frontal cortex (FC) and basal ganglia (BG) were collected for gene and protein expression. METHODS: Relationships between brain and plasma VL or CD4+ cell counts were determined using linear regression. Effects of SIV, CBA, and ART on markers of neuroinflammation and brain-derived neurotrophic factor (BDNF) signaling were determined by ANOVA and linear regression. RESULTS: SIV increased FC and BG neuroinflammatory and glial cell gene expression (CX3CR1, B2M), and reduced FC protein kinase B phosphorylation. CBA decreased FC and BG tropomyosin receptor kinase B (TrkB) phosphorylation, and increased full-length TrkB (TrkB-FL) and SLC1A3 expression in FC and BG, respectively. ART suppressed plasma and brain VL, reduced neuroinflammatory gene expression in FC (IBA1, CX3CR1, and GFAP), and BG (CD74 and CD11ß), and did not restore FC or BG BDNF signaling deficits. CONCLUSIONS: Results show ART-mediated reduction in VL and neuroinflammatory gene expression, irrespective of CBA administration. ART did not attenuate SIV- and CBA-mediated BDNF signaling deficits, suggesting these deficits, despite effective neuroinflammation suppression, may explain CBA- and SIV-associated neurocognitive deficits. Therapeutics targeting growth factor signaling may be important adjuvants in treating HIV-associated neurocognitive decline.

Examining the relationship of immunotherapy and wound complications following flap reconstruction in patients with head and neck cancer.

BACKGROUND: Immunotherapy agents are used to treat advanced head and neck lesions. We aim to elucidate relationship between immunotherapy and surgical wound complications. METHODS: Retrospective multi-institutional case series evaluating patients undergoing ablative and flap reconstructive surgery and immunotherapy treatment. MAIN OUTCOME: wound complications. RESULTS: Eight-two (62%) patients received preoperative therapy, 89 (67%) postoperative, and 33 (25%) in both settings. Forty-one (31%) patients had recipient site complications, 12 (9%) had donor site. Nineteen (14%) had major recipient site complications, 22 (17%) had minor. There was no statistically significant difference in complications based on patient or tumor-specific variables. Preoperative therapy alone demonstrated increased major complications (odds ratio [OR] 3.7, p = 0.04), and trend to more donor site complications (OR 7.4, p = 0.06), however treatment in both preoperative and postoperative therapy was not. CONCLUSIONS: Preoperative immunotherapy may be associated with increased wound complications. Controlled studies are necessary to delineate this association and potential risks of therapy.

Prediction of Immunotherapy Response in Melanoma through Combined Modeling of Neoantigen Burden and Immune-Related Resistance Mechanisms.

PURPOSE: While immune checkpoint blockade (ICB) has become a pillar of cancer treatment, biomarkers that consistently predict patient response remain elusive due to the complex mechanisms driving immune response to tumors. We hypothesized that a multi-dimensional approach modeling both tumor and immune-related molecular mechanisms would better predict ICB response than simpler mutation-focused biomarkers, such as tumor mutational burden (TMB). EXPERIMENTAL DESIGN: Tumors from a cohort of patients with late-stage melanoma (n = 51) were profiled using an immune-enhanced exome and transcriptome platform. We demonstrate increasing predictive power with deeper modeling of neoantigens and immune-related resistance mechanisms to ICB. RESULTS: Our neoantigen burden score, which integrates both exome and transcriptome features, more significantly stratified responders and nonresponders (P = 0.016) than TMB alone (P = 0.049). Extension of this model to include immune-related resistance mechanisms affecting the antigen presentation machinery, such as HLA allele-specific LOH, resulted in a composite neoantigen presentation score (NEOPS) that demonstrated further increased association with therapy response (P = 0.002). CONCLUSIONS: NEOPS proved the statistically strongest biomarker compared with all single-gene biomarkers, expression signatures, and TMB biomarkers evaluated in this cohort. Subsequent confirmation of these findings in an independent cohort of patients (n = 110) suggests that NEOPS is a robust, novel biomarker of ICB response in melanoma.

A regression based phase I clinical trial for late-onset toxicities without clinician elicitation.

An extension of the isotonic regression based phase I clinical trial design is presented that incorporates partial follow-up times into estimation of the raw toxicity probabilities. This phase I clinical trial design, called the TITE-IR design, drastically decreases average trial duration by allowing patients to be treated immediately after being enrolled in a phase I clinical trial. The TITE-IR design does not require specification of a prior skeleton of toxicity probabilities like the continual reassessment method, has an additional trial parameter for controlling aggressiveness of dose escalation, and has an easily understood formula for estimating toxicity probabilities. An R statistical software package is described in detail in the appendix for simulating and implementing the design. A simulation study shows that the TITE-IR design outperforms the 3 + 3 design in terms of selecting the true maximum tolerated dose and results in shorter trial times, without a large loss in efficiency, compared to the isotonic regression design and Storer's up-and-down design D. These properties make the TITE-IR design a more appealing option to clinicians than the two most commonly used 3 + 3 designs and the isotonic regression design with larger follow-up windows for toxicity.

Facial Nerve Translocation for Low Tension Neurorrhaphy to Masseteric Nerve.

INTRODUCTION: The techniques of facial reanimation are continually evolving in search of the ideal method for rehabilitating the paralyzed face. In the past, alternative cranial nerve motor nuclei have been used to power facial musculature. The trigeminal nerve is gaining popularity as a promising nerve to drive facial motion, particularly in the lower face. OBJECTIVES: This article describes a low-tension technique of using the transposed facial nerve to the trigeminal nerve (masseteric branch) for facial reanimation. METHODS: Six patients over 2.5 years were treated with facial nerve translocation with division at the geniculate and direct neurorrhaphy to the motor branch of the masseter. Patients were evaluated by physical examination, measurement of oral commissure excursion using MEEI FACE-gram software, video assessment, Sunnybrook Facial Grading System, Facial Disability Index, and Facial Clinimetric Evaluation Scale (FaCE). RESULTS: Patients demonstrated early motion within 4 months postoperatively and were placed into facial physical therapy. All demonstrated improvements in oral competence, strong oral commissure excursion with good symmetry, speech improvements, and variable results in facial tone. Synkinesis to the smile antagonists in the lower face was noted and treated with chemodenervation in three of six. No upper division synkinesis was noted. CONCLUSION: The motor branch of the trigeminal nerve is an effective option for facial reanimation via facial nerve translocation and end-to-end neurorrhaphy. Variable results in facial tone were noted with excellent oral commissure excursion. This procedure is safe in the reoperated mastoid.