Doublecortin-like kinase 1 is a therapeutic target in squamous cell carcinoma.

Doublecortin like kinase 1 (DCLK1) plays a crucial role in several cancers including colon and pancreatic adenocarcinomas. However, its role in squamous cell carcinoma (SCC) remains unknown. To this end, we examined DCLK1 expression in head and neck SCC (HNSCC) and anal SCC (ASCC). We found that DCLK1 is elevated in patient SCC tissue, which correlated with cancer progression and poorer overall survival. Furthermore, DCLK1 expression is significantly elevated in human papilloma virus negative HNSCC, which are typically aggressive with poor responses to therapy. To understand the role of DCLK1 in tumorigenesis, we used specific shRNA to suppress DCLK1 expression. This significantly reduced tumor growth, spheroid formation, and migration of HNSCC cancer cells. To further the translational relevance of our studies, we sought to identify a selective DCLK1 inhibitor. Current attempts to target DCLK1 using pharmacologic approaches have relied on nonspecific suppression of DCLK1 kinase activity. Here, we demonstrate that DiFiD (3,5-bis [2,4-difluorobenzylidene]-4-piperidone) binds to DCLK1 with high selectivity. Moreover, DiFiD mediated suppression of DCLK1 led to G2/M arrest and apoptosis and significantly suppressed tumor growth of HNSCC xenografts and ASCC patient derived xenografts, supporting that DCLK1 is critical for SCC growth.

Evaluation of the safety and effectiveness of robot-assisted neck dissections.

BACKGROUND: Robot-assisted neck dissection (RAND) for the management of the regional lymphatic basin offers the potential for improved cosmesis and reduced lymphedema. While RAND has been previously described, functional outcome and oncologic control rates need further elucidation. METHODS: A retrospective, matched cohort study of neck dissections completed at UPMC from 2017 to 2021 was conducted. RAND was identified and matched to open neck dissections (open) in a 1:2 ratio. Matching characteristics included primary cancer site, pre-operative clinical N-stage, age at time of surgery, HPV status, and previous chemoradiation treatment (salvage vs. nonsalvage procedure). Additional information was collected on patient demographics, surgery characteristics, and outcomes. Comparisons were made using t-test, chi-square test, Fisher's exact test, and Kaplan-Meier Wilcoxon (KMW) test with p < 0.05 indicating significance. RESULTS: Overall, RAND and open groups had similar distributions of age, gender, BMI, primary site of cancer, HPV status, clinical N-stage, clinical T-stage, known neck disease prior to procedure, prior chemoradiation therapy, and level(s) of neck dissection. Surgically, RAND procedures yielded less drainage on average (124 mL in RAND vs. 220 mL in open approaches; p = 0.01). There was no difference in the rates of complications, estimated blood loss, or number of lymph nodes obtained. There were also no differences in the rates of adjuvant therapy. Long term, there were no differences in the rates of local, locoregional, and distant recurrence of primary disease between RAND and open procedures. There were also no differences in postprocedure disease-free survival time (KMW p-value = 0.32; HR [of RAND compared with open] = 0.62). Similarly, there were no statistical differences in the overall survival of RAND patients when compared with the open group (75 vs. 58.9 months; HR = 0.11, p = 0.87). CONCLUSION: This study is the first to report the long-term effectiveness of robot-assisted surgery compared with the traditional, open approach. In addition to well-known cosmetic benefits, robot-assisted surgery may also offer patients a reduction in uncomfortable drains and improved effects from lymphedema. Overall, this study provides initial data that the RAND may be considered as an alternative approach to open surgery.

Advances in Facial Reanimation.

Facial nerve paralysis is a debilitating clinical entity that presents as a complete or incomplete loss of facial nerve function. The etiology of facial nerve palsy and sequelae varies tremendously. The most common cause of facial paralysis is Bell's palsy, followed by malignant or benign tumors, iatrogenic insults, trauma, virus-associated paralysis, and congenital etiologies.

Pediatric peanut aspirations before and after 2015 recommendation for early peanut exposure.

OBJECTIVES: To investigate if there has been an increase in peanut foreign body aspirations (FBA) in children since the publication of the Learning Early About Peanut Allergy (LEAP) trial, which revealed that early exposure to peanut-containing foods prevented peanut allergies in children at risk of atopic disease. METHODS: Retrospective chart reviews were conducted separately at two pediatric institutions. Institutions One and Two reviewed children less than 7 years old who underwent bronchoscopy for FBA over ten-year periods between January 2007 and September 2017 and November 2008 and May 2018, respectively. The proportion of FBAs attributed to peanuts was compared before and after the publication LEAP. RESULTS: Out of 515 reviewed cases, there was no change in pediatric peanut aspirations prior to and following the LEAP trial and AAP guideline change (33.5% vs 31.4%, p = 0.70). At Institution One, 317 patients met inclusion criteria. When comparing FBAs before and after LEAP, there were no significant changes in the rate of peanut aspiration (53.5% vs. 45.1%, p = 0.17). Institution Two also found no significant increase in the rate of peanut aspirations before and after the Addendum Guidelines (41.4% vs. 28.6%, p = 0.65) upon review of 198 cases. CONCLUSIONS: Multiple institutions demonstrated a non-significant change in the rate of peanut FBAs following the AAP recommendation. Given that peanuts comprise a large proportion of FBAs, it is important to continue to track peanut aspirations. Longer term data tracking is needed from more institutions to further understand how recommendations from other specialties and the media impacts pediatric aspiration outcomes.

Longitudinal Analysis of Caregiver Burden in Head and Neck Cancer.

Importance: Despite the critical role of caregivers in head and neck cancer (HNC), there is limited literature on caregiver burden (CGB) and its evolution over treatment. Research is needed to address evidence gaps that exist in understanding the causal pathways between caregiving and treatment outcomes. Objective: To evaluate the prevalence of and identify risk factors for CGB in HNC survivorship. Design, Setting, and Participants: This longitudinal prospective cohort study took place at the University of Pittsburgh Medical Center. Dyads of treatment-naive patients with HNC and their caregivers were recruited between October 2019 and December 2020. Eligible patient-caregiver dyads were 18 years or older and fluent in English. Patients undergoing definitive treatment identified a caregiver as the primary, nonprofessional, nonpaid person who provided the most assistance to them. Among 100 eligible dyadic participants, 2 caregivers declined participation, resulting in 96 enrolled participants. Data were analyzed from September 2021 through October 2022. Main Outcomes and Measures: Participants were surveyed at diagnosis, 3 months postdiagnosis, and 6 months postdiagnosis. Caregiver burden was evaluated with the 19-item Social Support Survey (scored 0-100, with higher scores indicating more support), Caregiver Reaction Assessment (CRA; scored 0-5, with higher scores on 4 subscales [disrupted schedule, financial problems, lack of family support, and health problems] indicating negative reactions, and higher scores on the fifth subscale [self-esteem] indicating favorable influence); and 3-item Loneliness Scale (scored 3-9, with higher scores indicating greater loneliness). Patient health-related quality of life was assessed using the University of Washington Quality of Life scale (UW-QOL; scored 0-100, with higher scores indicating better QOL). Results: Of the 96 enrolled participants, half were women (48 [50%]), and a majority were White (92 [96%]), married or living with a partner (81 [84%]), and working (51 [53%]). Of these participants, 60 (63%) completed surveys at diagnosis and at least 1 follow-up. Of the 30 caregivers, most were women (24 [80%]), White (29 [97%]), married or living with a partner (28 [93%]), and working (22 [73%]). Caregivers of nonworking patients reported higher scores on the CRA subscale for health problems than caregivers of working patients (mean difference, 0.41; 95% CI, 0.18-0.64). Caregivers of patients with UW-QOL social/emotional (S/E) subscale scores of 62 or lower at diagnosis reported increased scores on the CRA subscale for health problems (UW-QOL-S/E score of 22: CRA score mean difference, 1.12; 95% CI, 0.48-1.77; UW-QOL-S/E score of 42: CRA score mean difference, 0.74; 95% CI, 0.34-1.15; and UW-QOL-S/E score of 62: CRA score mean difference, 0.36; 95% CI, 0.14-0.59). Woman caregivers had statistically significant worsening scores on the Social Support Survey (mean difference, -9.18; 95% CI, -17.14 to -1.22). The proportion of lonely caregivers increased over treatment. Conclusions and Relevance: This cohort study highlights patient- and caregiver-specific factors that are associated with increased CGB. Results further demonstrate the potential implications for negative health outcomes for caregivers of patients who are not working and have lower health-related quality of life.

Prevalence of Multidrug-Resistant Organisms in Patients Undergoing Free Flap Reconstruction.

OBJECTIVES/HYPOTHESIS: The purpose of this study is to evaluate the relationship between antibiotic prophylaxis and prevalence of multidrug-resistant organisms (MDRO) in patients undergoing head and neck cancer reconstruction. STUDY DESIGN: Retrospective Chart Review. METHODS: Retrospective review of patients who underwent head and neck free flap reconstruction at our institution between 2009 to 2016. RESULTS: Of the 145 patients that underwent head and neck tumor removal surgery using free tissue flaps to cover the defect and therafter received antibiotic prophylaxis, 30 (20.7%) developed postoperative surgical site (n = 17, 55.7%) or distant (n = 13, 43.4%) infections. Seven had a multidrug-resistant infection, the most common with Methicillin-Resistant Staphylococcus aureus (MRSA). There was no significant relationship between antibiotic spectrum or duration to the development of postoperative infections or MDRO. Pseudomonas and MRSA infections were low overall with only one multidrug-resistant Pseudomonas infection. CONCLUSIONS: The choice of antibiotic prophylaxis should cover organisms these patients are at highest risk for including anaerobes and Gram-negative organisms. A shorter duration of antibiotic prophylaxis should be considered given no increased risk of postoperative infection nor MDRO. Finally, one must be aware of the potential threat of multidrug-resistant Pseudomonas and MRSA amongst this vulnerable population and identity these with culture driven treatment. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E1881-E1887, 2021.

PET/CT Poorly Predicts AJCC 8th Edition Pathologic Staging in HPV-Related Oropharyngeal Cancer.

OBJECTIVE: The American Joint Committee on Cancer (AJCC) 8th edition introduced distinct clinical and pathological staging paradigms for human papilloma virus positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC). Treatment planning for OPSCC often utilizes positron emission tomography/computed tomography (PET/CT) to assess clinical stage. We hypothesize that PET/CT will accurately predict final pathologic AJCC 8th edition staging in patients with HPV+ OPSCC. METHODS: All patients with primary HPV+ OPSCC with preoperative PET/CT who underwent transoral robotic surgery and neck dissection between 2011 and 2017 were identified. Data were collected via chart review. Two neuroradiologists performed blinded re-evaluation of all scans. Primary tumor size and cervical nodal disease characteristics were recorded and TNM staging was extrapolated. Cohen's kappa statistic was used to assess interrater reliability. Test for symmetry was performed to analyze discordance between radiologic and pathologic staging. RESULTS: Forty-nine patients met inclusion criteria. Interrater reliability was substantial between radiologists for nodal (N) and overall staging (OS) (κ = 0.715 and 0.715). Radiologist A review resulted in identical OS for 67% of patients, overstaging for 31%, and understaging for 2%. Radiologist B review resulted in 61% identical OS, 39% overstaging, and 0% understaging. In misclassified cases, the test of symmetry shows strong bias toward overstaging N stage and OS (P < .001). Radiologic interpretation of extracapsular extension showed poor interrater reliability (κ = 0.403) and poor accuracy. CONCLUSION: PET/CT predicts a higher nodal and overall stage than pathologic staging. PET/CT should not be relied upon for initial tumor staging, as increased FDG uptake is not specific for nodal metastases. PET/CT is shown to be a poor predictor of ECE. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:1535-1541, 2021.

Consensus of free flap complications: Using a nomenclature paradigm in microvascular head and neck reconstruction.

BACKGROUND: We aim to define a set of terms for common free flap complications with evidence-based descriptions. METHODS: Clinical consensus surveys were conducted among a panel of head and neck/reconstructive surgeons (N = 11). A content validity index for relevancy and clarity for each item was computed and adjusted for chance agreement (modified kappa, K). Items with K < 0.74 for relevancy (i.e., ratings of "good" or "fair") were eliminated. RESULTS: Five out of nineteen terms scored K < 0.74. Eliminated terms included "vascular compromise"; "cellulitis"; "surgical site abscess"; "malocclusion"; and "non- or mal-union." Terms that achieved consensus were "total/partial free flap failure"; "free flap takeback"; "arterial thrombosis"; "venous thrombosis"; "revision of microvascular anastomosis"; "fistula"; "wound dehiscence"; "hematoma"; "seroma"; "partial skin graft failure"; "total skin graft failure"; "exposed hardware or bone"; and "hardware failure." CONCLUSION: Standardized reporting would encourage multi-institutional research collaboration, larger scale quality improvement initiatives, the ability to set risk-adjusted benchmarks, and enhance education and communication.

Cancer Stem Cell Metabolism and Potential Therapeutic Targets.

Malignant tumors contain heterogeneous populations of cells in various states of proliferation and differentiation. The presence of cancer stem or initiating cells is a well-established concept wherein quiescent and poorly differentiated cells within a tumor mass contribute to drug resistance, and under permissive conditions, are responsible for tumor recurrence and metastasis. A number of studies have identified molecular markers that are characteristic of tissue-specific cancer stem cells (CSCs). Isolation of CSCs has enabled studies on the metabolic status of CSCs. As metabolic plasticity is a hallmark of cancer cell adaptation, the intricacies of CSC metabolism and their phenotypic behavior are critical areas of research. Unlike normal stem cells, which rely heavily on oxidative phosphorylation (OXPHOS) as their primary source of energy, or cancer cells, which are primarily glycolytic, CSCs demonstrate a unique metabolic flexibility. CSCs can switch between OXPHOS and glycolysis in the presence of oxygen to maintain homeostasis and, thereby, promote tumor growth. Here, we review key factors that impact CSC metabolic phenotype including heterogeneity of CSCs across different histologic tumor types, tissue-specific variations, tumor microenvironment, and CSC niche. Furthermore, we discuss how targeting key players of glycolytic and mitochondrial pathways has shown promising results in cancer eradication and attenuation of disease recurrence in preclinical models. In addition, we highlight studies on other potential therapeutic targets including complex interactions within the microenvironment and cellular communications in the CSC niche to interfere with CSC growth, resistance, and metastasis.

Potent Antitumor Effects of a Combination of Three Nutraceutical Compounds.

Head and neck squamous cell carcinoma (HNSCC) is associated with low survival, and the current aggressive therapies result in high morbidity. Nutraceuticals are dietary compounds with few side effects. However, limited antitumor efficacy has restricted their application for cancer therapy. Here, we examine combining nutraceuticals, establishing a combination therapy that is more potent than any singular component, and delineate the mechanism of action. Three formulations were tested: GZ17-S (combined plant extracts from Arum palaestinum, Peganum harmala and Curcuma longa); GZ17-05.00 (16 synthetic components of GZ17-S); and GZ17-6.02 (3 synthetic components of GZ17S; curcumin, harmine and isovanillin). We tested the formulations on HNSCC proliferation, migration, invasion, angiogenesis, macrophage viability and infiltration into the tumor and tumor apoptosis. GZ17-6.02, the most effective formulation, significantly reduced in vitro assessments of HNSCC progression. When combined with cisplatin, GZ17-6.02 enhanced anti-proliferative effects. Molecular signaling cascades inhibited by GZ17-6.02 include EGFR, ERK1/2, and AKT, and molecular docking analyses demonstrate GZ17-6.02 components bind at distinct binding sites. GZ17-6.02 significantly inhibited growth of HNSCC cell line, patient-derived xenografts, and murine syngeneic tumors in vivo (P < 0.001). We demonstrate GZ17-6.02 as a highly effective plant extract combination and pave the way for future clinical application in HNSCC.