Use of neuromuscular blockade for neck dissection and association with iatrogenic nerve injury.

BACKGROUND: Cranial nerve injury is an uncommon but significant complication of neck dissection. We examined the association between the use of intraoperative neuromuscular blockade and iatrogenic cranial nerve injury during neck dissection. METHODS: This was a single-center, retrospective, electronic health record review. Study inclusion criteria stipulated patients > 18 years who had ≥ 2 neck lymphatic levels dissected for malignancy under general anesthesia with a surgery date between 2008 - 2018. Use of neuromuscular blockade during neck dissection was the primary independent variable. This was defined as any use of rocuronium, cisatracurium, or vecuronium upon anesthesia induction without reversal with sugammadex prior to surgical incision. Univariate tests were used to compare variables between those patients with, and those without, iatrogenic cranial nerve injury. Multivariable logistic regression determined predictors of cranial nerve injury and was performed incorporating Firth's estimation given low prevalence of the primary outcome. RESULTS: Our cohort consisted of 925 distinct neck dissections performed in 897 patients. Neuromuscular blockade was used during 285 (30.8%) neck dissections. Fourteen instances (1.5% of surgical cases) of nerve injury were identified. On univariate logistic regression, use of neuromuscular blockade was not associated with iatrogenic cranial nerve injury (OR: 1.73, 95% CI: 0.62 - 4.86, p = 0.30). There remained no significant association on multivariable logistic regression controlling for patient age, sex, weight, ASA class, paralytic dose, history of diabetes, stroke, coronary artery disease, carotid atherosclerosis, myocardial infarction, and cardiac arrythmia (OR: 1.87, 95% CI: 0.63 - 5.51, p = 0.26). CONCLUSIONS: In this study, use of neuromuscular blockade intraoperatively during neck dissection was not associated with increased rates of iatrogenic cranial nerve injury. While this investigation provides early support for safe use of neuromuscular blockade during neck dissection, future investigation with greater power remains necessary.

Predictors of survival in patients undergoing oropharyngeal surgery for cancer recurrence after radiation therapy.

PURPOSE: The incidence of oropharyngeal squamous cell carcinoma continues to rise with the majority of patients receiving definitive or adjunctive radiation. For patients with locoregional recurrence after radiation, optimal treatment involves salvage surgery. The aim of this study is to identify factors that predict survival to ultimately improve patient selection for salvage surgery. METHODS: Retrospective cohort study at an NCI-designated cancer center. We analyzed patients with a history of head and neck radiation who presented with persistent/recurrent or second primary disease requiring salvage oropharyngeal resection from 1998-2017 (n = 120). Patients were stratified into three classes based on time to recurrence and presence of laryngopharyngeal dysfunction. Primary outcomes were 5-year overall survival (OS) and disease specific survival (DSS). RESULTS: Median OS was 27 months (median follow-up 20 months). Five-year OS was 47% for class I (recurrence > 2 years), 26% for class II (recurrence ≤ 2 years), and 0% for class III (recurrence ≤ 2 years and laryngopharyngeal dysfunction), (p < 0.0001). Five-year DSS showed significant differences between classes (p < 0.0001). On multivariate analysis, class remained predictive of OS (p = 0.04- < 0.001) and DSS (p = 0.04-0.001). Adjuvant radiation after salvage surgery with negative margins showed superior OS (71% vs. 28%, p = 0.01) and DSS (83% vs 37%, p = 0.02) compared to surgery alone and was a significant predictor of improved survival on multivariate analysis (HR 0.1, p = 0.04). CONCLUSION: This study identified a subset of patients with oropharyngeal cancer recurrence within two years of initial treatment and with laryngopharyngeal dysfunction who have poor outcomes for salvage surgery.

Analysis of tumor-infiltrating CD103 resident memory T-cell content in recurrent laryngeal squamous cell carcinoma.

BACKGROUND: Recurrent laryngeal squamous cell carcinomas (LSCCs) are associated with poor outcomes, without reliable biomarkers to identify patients who may benefit from adjuvant therapies. Given the emergence of tumor-infiltrating lymphocytes (TIL) as a biomarker in head and neck squamous cell carcinoma, we generated predictive models to understand the utility of CD4+, CD8+ and/or CD103+ TIL status in patients with advanced LSCC. METHODS: Tissue microarrays were constructed from salvage laryngectomy specimens of 183 patients with recurrent/persistent LSCC and independently stained for CD4+, CD8+, and CD103+ TIL content. Cox proportional hazards regression analysis was employed to assess combinations of CD4+, CD8+, and CD103+ TIL levels for prediction of overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) in patients with recurrent/persistent LSCC. RESULTS: High tumor CD103+ TIL content was associated with significantly improved OS, DSS, and DFS and was a stronger predictor of survival in recurrent/persistent LSCC than either high CD8+ or CD4+ TIL content. On multivariate analysis, an "immune-rich" phenotype, in which tumors were enriched for both CD103+ and CD4+ TILs, conferred a survival benefit (OS hazard ratio: 0.28, p = 0.0014; DSS hazard ratio: 0.09, p = 0.0015; DFS hazard ratio: 0.18, p = 0.0018) in recurrent/persistent LSCC. CONCLUSIONS: An immune profile driven by CD103+ TIL content, alone and in combination with CD4+ TIL content, is a prognostic biomarker of survival in patients with recurrent/persistent LSCC. Predictive models described herein may thus prove valuable in prognostic stratification and lead to personalized treatment paradigms for this patient population.

Completion Lymph Node Dissection or Radiation Therapy for Sentinel Node Metastasis in Merkel Cell Carcinoma.

BACKGROUND: For sentinel lymph node (SLN) metastasis from Merkel cell carcinoma (MCC), the benefit of completion lymph node dissection (CLND) versus radiation therapy (RT) is unclear. This study compares outcomes for patients with SLN metastasis undergoing CLND or RT. We also evaluated positive non-SLNs as a prognostic factor. METHODS: Using a prospective database, we identified MCC patients with SLN metastasis who underwent CLND or RT. At our institution, CLND was recommended for patients with acceptable perioperative risk, while therapeutic RT was offered to those with high perioperative risk. Primary outcomes were MCC-specific survival (MCCSS), disease-free survival (DFS), nodal recurrence-free survival (NRFS), and distant recurrence-free survival (DRFS). RESULTS: From 2006 to 2017, 163 patients underwent CLND (n = 137) or RT (n = 26). Median follow-up was 1.9 years. CLND had no significant differences for MCCSS (5-year survival 71% vs. 64%, p = 1.0), DFS (52% vs. 61%, p = 0.8), NRFS (76% vs. 91%, p = 0.3), or DRFS (65% vs. 75%, p = 0.3) compared with RT. Patients with positive non-SLNs (n = 44) had significantly worse MCCSS (5-year survival 39% vs. 87%, p < 0.001), DFS (35% vs. 60%, p = 0.005), and DRFS (54% vs. 71%, p = 0.03) compared with negative non-SLNs (n = 93). Multivariate analysis showed positive non-SLNs were independently associated with MCCSS, DFS, and DRFS. CONCLUSIONS: CLND and RT may have similar outcomes for MCC patients with SLN metastasis when treatment aligns with our institutional practices. For patients undergoing CLND, positive non-SLNs is an important prognostic factor associated with poor survival and distant recurrence. This high-risk group should be considered for adjuvant systemic therapy trials.

Elective Paratracheal Lymph Node Dissection in Salvage Laryngectomy.

BACKGROUND: Indications for and efficacy of paratracheal nodal dissection (PTND) in patients undergoing laryngectomy (salvage) for persistent or recurrent laryngeal squamous cell carcinoma are not well-defined. METHODS: A retrospective cohort study was performed for patients undergoing salvage laryngectomy with clinically and radiographically negative neck disease between 1998 and 2015 (n = 210). Univariate and multivariate Cox regression analyses were performed. RESULTS: PTND was performed on 77/210 patients (36%). The PTND cohort had a greater proportion of advanced T classification (rT3/rT4) tumors (78%) than subjects without PTND (55%; p = 0.001). There was a 14% rate of occult nodal metastases in the paratracheal basin; of these, 55% did not have pathologic lateral neck disease. Multivariate analysis controlling for tumor site, tumor stage, and pathologic lateral neck disease demonstrated that PTND was associated with improved overall survival [OS] (p = 0.03; hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.38-0.96), disease-free survival [DFS] (p = 0.03; HR 0.55, 95% CI 0.31-0.96), and distant DFS survival (p = 0.01; HR 0.29, 95% CI 0.11-0.77). The rate of hypocalcemia did not differ between subjects who underwent bilateral PTND, unilateral PTND, or no PTND (p = 0.19 at discharge, p = 0.17 at last follow-up). CONCLUSIONS: PTND at the time of salvage laryngectomy was more common in patients with rT3/rT4 tumors and was associated with improved OS and DFS, with no effect on hypocalcemia. In patients undergoing PTND, the finding of occult paratracheal metastases was often independent of lateral neck metastases.

Soy Isoflavone Supplementation Increases Long Interspersed Nucleotide Element-1 (LINE-1) Methylation in Head and Neck Squamous Cell Carcinoma.

AIM: Soy isoflavones have been suggested as epigenetic modulating agents with effects that could be important in carcinogenesis. Hypomethylation of LINE-1 has been associated with head and neck squamous cell carcinoma (HNSCC) development from oral premalignant lesions and with poor prognosis. To determine if neoadjuvant soy isoflavone supplementation could modulate LINE-1 methylation in HNSCC, we undertook a clinical trial. METHODS: Thirty-nine patients received 2-3 weeks of soy isoflavone supplements (300 mg/day) orally prior to surgery. Methylation of LINE-1, and 6 other genes was measured by pyrosequencing in biopsy, resection, and whole blood (WB) specimens. Changes in methylation were tested using paired t tests and ANOVA. Median follow up was 45 months. RESULTS: LINE-1 methylation increased significantly after soy isoflavone (P < 0.005). Amount of change correlated positively with days of isoflavone taken (P = 0.04). Similar changes were not seen in corresponding WB samples. No significant changes in tumor or blood methylation levels were seen in the other candidate genes. CONCLUSION: This is the first demonstration of in vivo increases in tissue-specific global methylation associated with soy isoflavone intake in patients with HNSCC. Prior associations of LINE-1 hypomethylation with genetic instability, carcinogenesis, and prognosis suggest that soy isoflavones maybe potential chemopreventive agents in HNSCC.

The natural history of thin melanoma and the utility of sentinel lymph node biopsy.

BACKGROUND AND OBJECTIVES: Current literature may overestimate the risk of nodal metastasis from thin melanoma due to reporting of data only from lesions treated with SLNB. Our objective was to define the natural history of thin melanoma, assessing the likelihood of nodal disease, in order to guide selection for SLNB. METHODS: Retrospective review. The primary outcome was the rate of nodal disease. Clinicopathologic factors were evaluated to find associations with nodal disease. RESULTS: Five hundred and twelve lesions, follow up available for 488 (median: 48 months). Lesions treated with WLE/SLNB compared to WLE alone were more likely to have high-risk features. The rate of nodal disease was higher in the WLE/SLNB group (24 positive SLNB, five false-negative SLNB with nodal recurrence: 10.2%) compared to WLE alone (four nodal recurrences: 2.0%). Univariate analysis showed age ≤45, Breslow depth ≥0.85 mm, mitotic rate >1 mm2 , and ulceration were associated with nodal disease. Multivariate analysis confirmed the association of age ≤45 and ulceration. CONCLUSIONS: SLNB for melanoma 0.75-0.99 mm should be considered in patients age ≤45, Breslow depth ≥0.85 mm, mitotic rate >1 mm2 , and/or with ulceration. Thin melanoma <0.85 mm without high-risk features may be treated with WLE alone.

NCCN Guidelines implementation in the multidisciplinary Merkel Cell Carcinoma Program at the University of Michigan.

Merkel cell carcinoma (MCC) is a rare malignancy of the skin, and prospective randomized clinical studies on management and treatment are very limited. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for MCC provide up-to-date, best evidence-based, and consensus-driven management pathways with the purpose of providing best care and outcomes. Multidisciplinary management with consensus treatment recommendations to individualize patient care within the framework of these guidelines is optimal. The University of Michigan multidisciplinary MCC program uses NCCN Guidelines in the management and treatment of its patients. This article discusses 4 patient presentations to highlight the implementation of the NCCN Guidelines for MCC at the University of Michigan.

Clinicopathologic features of primary Merkel cell carcinoma: a detailed descriptive analysis of a large contemporary cohort.

BACKGROUND: Little uniformity exists in the clinical and histologic variables reported with primary Merkel cell carcinoma (MCC). OBJECTIVE: To provide a rigorous descriptive analysis of a contemporary cohort and promote the prospective collection of detailed data on MCC for future outcome studies. METHODS AND MATERIALS: A detailed descriptive analysis was performed for clinical and histologic features of 147 patients with 150 primary MCC tumors in a prospectively collected database from 2006 to 2010. RESULTS: The majority (73.5%) of patients were at American Joint Committee on Cancer clinical stage I or II at presentation, 20.4% at stage III, and 6.1% at stage IV. Detailed descriptive clinical and histologic findings are presented. CONCLUSION: Clinical and histologic profiling of primary MCC in the literature is variable and limited. Systematic prospective collection of MCC data is needed for future outcome studies and the ability to compare and share data from multiple sources for this relatively rare tumor.

Sentinel lymph node biopsy is accurate and prognostic in head and neck melanoma.

BACKGROUND: Sentinel lymph node biopsy (SLNB) has emerged as a widely used staging procedure for cutaneous melanoma. However, debate remains around the accuracy and prognostic implications of SLNB for cutaneous melanoma arising in the head and neck, as previous reports have demonstrated inferior results to those in nonhead and neck regions. Through the largest single-institution series of head and neck melanoma patients, the authors set out to demonstrate that SLNB accuracy and prognostic value in the head and neck region are comparable to other sites. METHODS: A prospectively collected database was queried for cutaneous head and neck melanoma patients who underwent SLNB at the University of Michigan between 1997 and 2007. Primary endpoints included SLNB result, time to recurrence, site of recurrence, and date and cause of death. Multivariate models were constructed for analyses. RESULTS: Three hundred fifty-three patients were identified. A sentinel lymph node was identified in 352 of 353 patients (99.7%). Sixty-nine of the 353 (19.6%) patients had a positive SLNB. Seventeen of 68 patients (25%) undergoing completion lymphadenectomy after a positive SLNB result had at least 1 additional positive nonsentinel lymph node. Patients with local control and a negative SLNB failed regionally in 4.2% of cases. Multivariate analysis revealed positive SLNB status to be the most prognostic clinicopathologic predictor of poor outcome; hazard ratio was 4.23 for SLNB status and recurrence-free survival (P < .0001) and 3.33 for overall survival (P < .0001). CONCLUSIONS: SLNB is accurate and its results are of prognostic importance for head and neck melanoma patients.

Impact of Completion Lymphadenectomy on Quality of Life for Head and Neck Cutaneous Melanoma.

OBJECTIVE: Recent randomized data suggest that completion lymph node dissection after a positive sentinel lymph node biopsy (SLNB) improves locoregional control but does not improve survival for melanoma patients. Locoregional recurrences of head and neck cutaneous melanoma (HNCM) may result in significant morbidity. A better understanding of morbidity is thus important to inform decisions about whether to pursue completion neck dissection (ND). STUDY DESIGN: Cross-sectional study. SETTING: Academic tertiary care hospital. METHODS: Clinical data were collected for patients with HNCM seen between 2016 and 2019 who were at least 1-year disease free. Each patient completed the Self-administered Leeds Assessment of Neuropathic Symptoms and Signs (SLANSS), Neck Dissection Impairment Index, and SF-36 (Short Form-36). Scores were compared by surgical treatment: wide local excision (WLE) only, SLNB, and ND. Univariate and multivariable regression was performed. RESULTS: Of 474 patients, 140 returned questionnaires (29.5% response rate; WLE, n = 49; SLNB, n = 76; ND, n = 15). No significant differences in SLANSS or Neck Dissection Impairment Index scores were found between the WLE and SLNB groups. SLANSS scores differed by 2 SD (P = .001) in the ND cohort, which had a 36% rate of neuropathy. Neck impairment was worse by 1 SD (P = .01) in the ND cohort. No differences were found in SF-36 domains. CONCLUSION: Neuropathy and neck impairment are components of morbidity after ND. These risks must be balanced with potential morbidity of locoregional recurrence in HNCM.

Isolation of circulating tumor cells to diagnose melanoma and evaluate the efficacy of surgical resection using melanoma-specific microsystem.

Melanoma is one of the most aggressive skin cancers due to its potential to metastasize widely in the body. The risk of metastasis is increased with later detection and increased thickness of the primary lesion, thus early identification and surgical removal is critical for higher survival rates for patients. However, even with appropriate treatment, some patients will develop recurrence which may be difficult to identify until advanced or causing symptoms. Recent advances in liquid biopsy have proposed less-invasive alternatives for cancer diagnosis and monitoring using minimal/zero invasion at sample collection, and circulating tumor cells(CTCs) have been considered a promising blood-based surrogate marker of primary tumors. However, previous CTC technologies relying on epithelial-cell adhesion molecules have limited to epithelial cells, thus hampering use of CTCs for non-epithelial cancers such as melanoma. Here, we used the Melanoma-specific OncoBean platform(MelanoBean) conjugated with melanoma specific antibodies(MCAM and MCSP). The device was used in comprehensive studies for diagnosing melanoma and evaluating surgery efficacy based on change in the number and characteristics of CTCs and CTC-clusters pre- and post-surgical treatment. Our study demonstrated that melanoma patients(n=45) at all stages(I-IV) have a noticeable number of MCTCs as well as MCTC-clusters compared to healthy donors(n=9)(P=0.0011), and surgical treatment leads to a significant decrease in the number of CTCs(P<0.0001). The CTCs recovered from the device underwent molecular profiling for melanoma-associated genes expression using multiplexed qRT-PCR, demonstrating the ability to monitor molecular signature through treatment. The presented MelanoBean and the comprehensive approach will empower prognostic value of CTCs in melanoma in much larger cohort studies.

Tumor-Infiltrating Lymphocytes in Patients With Advanced Laryngeal Cancer Undergoing Bioselection.

OBJECTIVE: Bioselection to assess tumor response after induction chemotherapy has been introduced as an alternative treatment strategy to total laryngectomy for patients with advanced larynx squamous cell carcinoma (LSCC). Tumor-infiltrating lymphocytes (TILs) have proven to serve as prognostic biomarkers in head and neck cancer but have not been evaluated as a way to select patients for treatment paradigms. The aim of this study is to evaluate the role of pretreatment TILs in patients with advanced LSCC undergoing the bioselection paradigm. STUDY DESIGN: Retrospective study. SETTING: Tertiary care hospital. METHODS: Patients with advanced LSCC treated with bioselection and available tissue were included (N = 76). Patients were stratified into CD8-low and CD8-high cohorts by using the median TIL count. Kaplan-Meier survival analysis and multivariate cox regression were performed with SPSS version 26 (IBM). RESULTS: After controlling for tobacco use, tumor site, and stage, a high CD8 TIL count was an independent predictor of improved 5-year disease-specific survival (hazard ratio, 0.17 [95% CI, 0.03-0.84]; P = .03). CD8 TIL counts did not predict response to induction chemotherapy; however, subgroup analysis of patients treated with chemoradiation therapy revealed that CD8 TIL count was significantly associated with degree of response (P = .012). CONCLUSION: These findings support prior data published by our group showing that TILs are predictive of disease-specific survival in patients with head and neck cancer. CD8 TIL counts were significantly associated with degree of clinical response after induction chemotherapy. These results suggest that pretreatment assessment of tumor-infiltrating CD8 cells could be useful in selecting patients.

Long-term neck and shoulder function among survivors of oropharyngeal squamous cell carcinoma treated with chemoradiation as assessed with the neck dissection impairment index.

BACKGROUND: Of interest is the long-term neck and shoulder impairment of patients treated with primary chemoradiotherapy (CRT). This is important for counseling patients regarding treatment decisions when discussing primary CRT. METHODS: A cross-sectional study to identify factors that contribute to neck and shoulder dysfunction in patients treated with primary CRT. We utilized the neck dissection impairment index (NDII). Eighty-seven patients treated between 2003 and 2010, who were free of disease, responded; 24 of these 87 underwent post-CRT neck dissection. Mean interval since completion of CRT was over 5 years (62.7 months). Mean age, 63.5 years, male:female 75:12. RESULTS: Mean NDII score was 87.4 (SD 22.1, range 5-100). Multiple linear regression revealed worse NDII scores for patients with larger pre-CRT gross tumor nodal volume (GTVnodal), controlled for age, sex, body mass index (BMI), and the presence of neck dissection (p = 0.02). There were significant associations with increasing GTVnodal and "low" scores for components of the NDII that assessed neck pain (p = 0.02), neck stiffness (p = 0.01), lifting heavy objects (p = 0.02), reaching overhead (p = 0.02), and ability to do work (p = 0.02). Physical therapy (PT) was evaluated as an "anchor" but it was prescribed "as needed." Regression revealed participation in PT was associated with higher GTVnodal, lower BMI, presence of neck dissection, and female sex (p = 0.00007). CONCLUSION: GTVnodal was an independent predictor of neck and shoulder impairment. High GTVnodal was associated with increased pain and stiffness, and increased difficulty lifting heavy objects, reaching overhead, overall ability to perform work-related tasks and was associated with participation in post-treatment PT.

Virus-positive Merkel Cell Carcinoma Is an Independent Prognostic Group with Distinct Predictive Biomarkers.

PURPOSE: Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma that can be divided into two classes: virus-positive (VP) MCC, associated with oncogenic Merkel cell polyomavirus (MCPyV); and virus-negative (VN) MCC, associated with photodamage. EXPERIMENTAL DESIGN: We classified 346 MCC tumors from 300 patients for MCPyV using a combination of IHC, ISH, and qPCR assays. In a subset of tumors, we profiled mutation status and expression of cancer-relevant genes. MCPyV and molecular profiling results were correlated with disease-specific outcomes. Potential prognostic biomarkers were further validated by IHC. RESULTS: A total of 177 tumors were classified as VP-MCC, 151 tumors were VN-MCC, and 17 tumors were indeterminate. MCPyV positivity in primary tumors was associated with longer disease-specific and recurrence-free survival in univariate analysis, and in multivariate analysis incorporating age, sex, immune status, and stage at presentation. Prioritized oncogene or tumor suppressor mutations were frequent in VN-MCC but rare in VP-MCC. TP53 mutation developed with recurrence in one VP-MCC case. Importantly, for the first time we find that VP-MCC and VN-MCC display distinct sets of prognostic molecular biomarkers. For VP-MCC, shorter survival was associated with decreased expression of immune markers including granzyme and IDO1. For VN-MCC, shorter survival correlated with high expression of several genes including UBE2C. CONCLUSIONS: MCPyV status is an independent prognostic factor for MCC. Features of the tumor genome, transcriptome, and microenvironment may modify prognosis in a manner specific to viral status. MCPyV status has clinicopathologic significance and allows for identification of additional prognostic subgroups.

CT and FDG-PET radiologic biomarkers in p16+ oropharyngeal squamous cell carcinoma patients treated with definitive chemoradiotherapy.

PURPOSE: To assess associations between imaging biomarkers from standard of care pre-treatment CT and FDG-PET scans and locoregional (LR) and distant metastatic (DM) recurrences in patients with p16+ oropharyngeal squamous cell carcinoma (OPSCC) treated with definitive chemoradiotherapy (CRT). METHODS: An institutional database from a single NCI-designated cancer center identified 266 patients with p16+ OPSCC treated with definitive CRT in our department from 2005 to 2016 with evaluable pre-treatment FDG-PET scans. Quantitative SUV metrics and qualitative imaging metrics were determined from FDG-PET and CT scans, while clinical characteristics were abstracted from the medical record. Associations between clinical/imaging features and time to LR (TTLRF) or DM (TTDMF) failure and overall survival (OS) were assessed using univariable Cox regression and penalized stepwise regression for multivariable analyses (MVA). RESULTS: There were 27 LR and 32 DM recurrences as incident failures. Imaging biomarkers were significantly associated with TTLRF, TTDMF and OS. FDG-PET metrics outperformed CT and clinical metrics for TTLRF, with metabolic tumor volume being the only significant feature selected on MVA: C-index = 0.68 (p = 0.01). Radiographic extranodal extension (rENE), positive retropharyngeal nodes (RPN+), and clinical stage were significant on MVA for TTDMF: C-index = 0.84 (p < 0.001). rENE, group stage, and RPN+ were significant on MVA for OS: C-index = 0.77 (p < 0.001). CONCLUSIONS: In the largest study to date of uniformly treated patients with CRT to evaluate both pretreatment CT and FDG-PET, radiographic biomarkers were significantly associated with TTLRF, TTDMF and OS among patients with p16+ OPSCC treated with CRT. CT metrics performed best to predict TTDMF, while FDG-PET metrics showed improved prediction for LRRFS. These metrics may help identify candidates for treatment intensification or de-escalation of therapy. STATEMENT OF TRANSLATIONAL RELEVANCE: Pre-treatment imaging features from standard-of-care PET/CT imaging show promise for predicting long-term outcomes following HPV-associated oropharynx cancer (HPV-OPC) therapy. This study comprehensively characterizes qualitative and quantitative pre-treatment imaging metrics associated with time to pattern-specific failure in a cohort of 266 patients treated uniformly with definitive chemoradiation. Multivariate analysis (MVA) for time to locoregional failure (TTLRF), time to distant metastatic failure (TTDMF), and overall survival (OS) was performed. FDG-PET metrics outperformed CT and clinical metrics for TTLRF. CT radiographic extranodal extension, positive retropharyngeal nodes, and stage strongly predicted TTDMF (combined C-index = 0.84, log rank p < 0.001). Number of smoking pack-years complemented clinical and imaging features only in patients without radiographic extranodal extension or positive retropharyngeal nodes. Time to pattern-specific failure is important for guiding treatment de-escalation strategies, which intend to reduce treatment-related toxicity in patients with relatively long expected survival times. This study suggests that PET/CT features should play a crucial role in future de-escalation trials and management of HPV-OPC patients.

Dual-Isolation and Profiling of Circulating Tumor Cells and Cancer Exosomes from Blood Samples with Melanoma Using Immunoaffinity-Based Microfluidic Interfaces.

Melanoma is among the most aggressive cancers, and its rate of incidence continues to grow. Early detection of melanoma has been hampered due to the lack of promising markers for testing. Recent advances in liquid biopsy have proposed noninvasive alternatives for cancer diagnosis and monitoring. Circulating tumor cells (CTCs) and cancer-exosomes are gaining influence as promising biomarkers because of their cancer-associated molecular markers and signatures. However, technologies that offer the dual-isolation of CTCs and exosomes using a single sample have not been thoroughly developed. The dual-utilization OncoBean (DUO) device is conjugated with melanoma specific antibodies, MCAM and MCSP, enabling simultaneous CTC and exosome isolations. Using blood samples from patients, CTCs and exosomes are specifically isolated from a single sample and then undergo molecular profiling for comprehensive study. Melanoma patients have 0-17CTCs mL-1 and 299 µg exosomal protein mL-1 while healthy donors display fewer than 2CTCs and 75.6 µg of exosomes mL-1, respectively. It is also demonstrated that both markers express melanoma-associated genes using multiplex qRT-PCR to test for expression pattern of a 96 gene panel. The dual isolation and molecular characterization will allow for further research into melanoma to identify viable markers for disease progression and treatment efficacy.

Sentinel Lymph Node Biopsy in Head and Neck Melanoma: Long-term Outcomes, Prognostic Value, Accuracy, and Safety.

OBJECTIVE: To evaluate the long-term outcomes of sentinel lymph node biopsy (SLNB) for head and neck cutaneous melanoma (HNCM). STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary academic medical center. SUBJECTS AND METHODS: Longitudinal review of a 356-patient cohort with HNCM undergoing SLNB from 1997 to 2007. RESULTS: Descriptive characteristics included the following: age, 53.5 ± 19 years (mean ± SD); sex, 26.8% female; median follow-up, 4.9 years; and Breslow depth, 2.52 ± 1.87 mm. Overall, 75 (21.1%) patients had a positive SLNB. Among patients undergoing completion lymph node dissection following positive SLNB, 20 (27.4%) had at least 1 additional positive nonsentinel lymph node. Eighteen patients with local control and negative SLNB developed regional disease, indicating a false omission rate of 6.4%, including 10 recurrences in previously unsampled basins. Ten-year overall survival (OS) and melanoma-specific survival (MSS) were significantly greater in the negative sentinel lymph node (SLN) cohort (OS, 61% [95% CI, 0.549-0.677]; MSS, 81.9% [95% CI, 0.769-0.873]) than the positive SLN cohort (OS, 31% [95% CI, 0.162-0.677]; MSS, 60.3% [95% CI, 0.464-0.785]) and positive SLN/positive nonsentinel lymph node cohort (OS, 8.4% [95% CI, 0.015-0.474]; MSS, 9.6% [95% CI, 0.017-0.536]). OS was significantly associated with SLN positivity (hazard ratio [HR], 2.39; P < .01), immunosuppression (HR, 2.37; P < .01), angiolymphatic invasion (HR, 1.91; P < .01), and ulceration (HR, 1.86; P < .01). SLN positivity (HR, 3.13; P < .01), angiolymphatic invasion (HR, 3.19; P < .01), and number of mitoses (P = .0002) were significantly associated with MSS. Immunosuppression (HR, 3.01; P < .01) and SLN status (HR, 2.84; P < .01) were associated with recurrence-free survival, and immunosuppression was the only factor significantly associated with regional recurrence (HR, 6.59; P < .01). CONCLUSIONS: Long-term follow up indicates that SLNB showcases durable accuracy, safety, and prognostic importance for cutaneous HNCM.

Cranial nerve outcomes in regionally recurrent head & neck melanoma after sentinel lymph node biopsy.

OBJECTIVE: Characterize long-term cranial nerve (CN) outcomes following sentinel lymph node biopsy (SLNB) based management for head and neck cutaneous melanoma (HNCM). METHODS: Longitudinal review of HNCM patients undergoing SLNB from 1997-2007. RESULTS: Three hundred fifty-six patients were identified, with mean age 53.5 ± 19.0 years, mean Breslow depth 2.52 ± 1.87 mm, and 4.9 years median follow-up. One hundred five (29.4%) patients had SLNB mapping to the parotid basin. Eighteen patients had positive parotid SLNs and underwent immediate parotidectomy / immediate completion lymph node dissection (iCLND), with six possessing positive parotid non-sentinel lymph nodes (NSLNs). Fifty-two of 356 (14.6%) patients developed delayed regional recurrences, including 20 total intraparotid recurrences: five following false negative (FN) parotid SLNB, three following prior immediate superficial parotidectomy, two following iCLND without parotidectomy, and the remaining 12 parotid recurrences had negative extraparotid SLNBs. Parotid recurrences were multiple (4.9 mean recurrent nodes) and advanced (n = 4 extracapsular extension), and all required salvage dissection including parotidectomy. Immediate parotidectomy/iCLND led to no permanent CN injuries. Delayed regional HNCM macrometastasis precipitated 16 total permanent CN injuries in 13 patients: 10 CN VII, five CN XI, and one CN XII deficits. Fifty percent (n = 10) of parotid recurrences caused ≥1 permanent CN deficits. CONCLUSIONS: Regional HNCM macrometastases and salvage dissection confer marked CN injury risk, whereas early surgical intervention via SLNB ± iCLND ± immediate parotidectomy yielded no CN injuries. Further, superficial parotidectomy performed in parotid-mapping HNCM does not obviate delayed intraparotid recurrences, which increase risk of CN VII injury. Despite lack of a published disease-specific survival advantage in melanoma, early disease control in cervical and parotid basins is paramount to minimize CN complications. LEVEL OF EVIDENCE: 4 (retrospective case series) Laryngoscope, 130:1707-1714, 2020.