Associations between context and affect within the daily lives of cancer caregivers.

PURPOSE: This study used ecological momentary assessment (EMA) to test the association between activity, location, and social company contexts with cancer caregivers' in-the-moment affect to identify precisely when and where to deliver psychological interventions for caregivers. METHODS: Current cancer caregivers (N = 25) received 8 EMA prompts per day for 7 consecutive days. At each prompt, caregivers reported their current positive affect and negative affect, as well as what they were doing, where they were located, and who they were with. Multilevel logistic regressions tested the associations between caregivers' contexts with their own person-mean-centered state (concurrent momentary level) and trait (overall weekly average) positive or negative affect. RESULTS: Caregivers reported lower state negative affect, as well as higher state positive affect, when socializing (ps < .001), when at a public location (ps < .03), and when around their friends, family, spouse/partner, or care recipient (i.e., person with cancer, ps < .02), relative to when not endorsing the context. Caregivers also reported lower state negative affect when eating/drinking or engaging in leisure (ps < .01; but no parallel effects for state positive affect). Caregivers reported higher state negative affect while working, when at their workplace, or when around work colleagues (ps < .001) and lower state positive affect when at home or alone (ps < .03). CONCLUSIONS: Results suggest the pertinence of a behavioral activation framework to mitigate the emotional strain of caregiving. Interventions that facilitate caregivers' ability to socialize with a range of friends and family, including their loved one with cancer, outside of the home may have the strongest positive emotional impact.

The Clinical Utility and Cost of Routine Staging Exam under Anesthesia for Oral Cavity Squamous Cell Carcinoma.

INTRODUCTION: The standard complete evaluation of patients with head and neck squamous cell carcinoma (HNSCC) has included a staging exam under anesthesia (EUA) since the 1970s. The EUA for all sites of HNSCC has historically consisted of panendoscopy for the purpose of diagnostic biopsy, accurate staging of primary disease, and identification of second primary tumors. However, due to the accessibility of the oral cavity, the sole purpose of EUA for tumors of this site is to identify second primary tumors. Since the EUA became the gold standard for evaluation of HNSCC, there have been significant advancements in less invasive technologies such as CT, PET-CT, MRI, and fiberoptic examination. In this study, we sought to determine the value to patient care and cost-effectiveness of EUA in patients with oral cavity squamous cell carcinoma (OCSCC). METHODS: A retrospective chart review identified 77 patients who underwent EUA for OCSCC. RESULTS: The most common subsites were the oral tongue and floor of mouth (59.7% and 24.7% respectively). All underwent direct laryngoscopy, 94.8% underwent esophagoscopy, and 20.8% underwent flexible transnasal examination in clinic prior to EUA. For 90.9% of patients, the EUA did not change initial T-staging based on clinical examination and imaging. The remaining 9.1% of patients were upstaged after EUA, however this change did not impact the treatment plan. Second primary tumors were identified in 3.9% of patients, all were found in either the oral cavity or oropharynx, and were also identified with clinical examination or imaging. Analysis of patient charges determined an average cost of $8,022.93 per patient under the current paradigm involving EUA, however with a new algorithm eliminating mandatory EUA average cost decreases to $1,448.44. CONCLUSION: Formal EUA has historically been the gold standard for all HNSCC tumors. However, when performed for cases of oral cavity carcinoma, it is safe and cost effective to limit its use to select clinical scenarios.

An Internally Validated Prognostic Risk-Score Model for Disease-Specific Survival in Clinical Stage I and II Merkel Cell Carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare cutaneous malignancy for which factors predictive of disease-specific survival (DSS) are poorly defined. METHODS: Patients from six centers (2005-2020) with clinical stage I-II MCC who underwent sentinel lymph node (SLN) biopsy were included. Factors associated with DSS were identified using competing-risks regression analysis. Risk-score modeling was established using competing-risks regression on a training dataset and internally validated by point assignment to variables. RESULTS: Of 604 patients, 474 (78.5%) and 128 (21.2%) patients had clinical stage I and II disease, respectively, and 189 (31.3%) had SLN metastases. The 5-year DSS rate was 81.8% with a median follow-up of 31 months. Prognostic factors associated with worse DSS included increasing age (hazard ratio [HR] 1.03, p = 0.046), male sex (HR 3.21, p = 0.021), immune compromise (HR 2.46, p = 0.013), presence of microsatellites (HR 2.65, p = 0.041), and regional nodal involvement (1 node: HR 2.48, p = 0.039; ≥2 nodes: HR 2.95, p = 0.026). An internally validated, risk-score model incorporating all of these factors was developed with good performance (AUC 0.738). Patients with ≤ 4.00 and > 4.00 points had 5-year DSS rates of 89.4% and 67.2%, respectively. Five-year DSS for pathologic stage I/II patients with > 4.00 points (n = 49) was 79.8% and for pathologic stage III patients with ≤ 4.00 points (n = 62) was 90.3%. CONCLUSIONS: A risk-score model, including patient and tumor factors, based on DSS improves prognostic assessment of patients with clinically localized MCC. This may inform surveillance strategies and patient selection for adjuvant therapy trials.

Predictors of False Negative Sentinel Lymph Node Biopsy in Clinically Localized Merkel Cell Carcinoma.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is routinely recommended for clinically localized Merkel cell carcinoma (MCC); however, predictors of false negative (FN) SLNB are undefined. METHODS: Patients from six centers undergoing wide excision and SLNB for stage I/II MCC (2005-2020) were identified and were classified as having either a true positive (TP), true negative (TN) or FN SLNB. Predictors of FN SLNB were identified and survival outcomes were estimated. RESULTS: Of 525 patients, 28 (5.4%), 329 (62.7%), and 168 (32%) were classified as FN, TN, and TP, respectively, giving an FN rate of 14.3% and negative predictive value of 92.2% for SLNB. Median follow-up for SLNB-negative patients was 27 months, and median time to nodal recurrence for FN patients was 7 months. Male sex (hazard ratio [HR] 3.15, p = 0.034) and lymphovascular invasion (LVI) (HR 2.22, p = 0.048) significantly correlated with FN, and increasing age trended toward significance (HR 1.04, p = 0.067). The 3-year regional nodal recurrence-free survival for males >75 years with LVI was 78.5% versus 97.4% for females ≤75 years without LVI (p = 0.009). Five-year disease-specific survival (90.9% TN vs. 51.3% FN, p < 0.001) and overall survival (69.9% TN vs. 48.1% FN, p = 0.035) were significantly worse for FN patients. CONCLUSION: Failure to detect regional nodal microscopic disease by SLNB is associated with worse survival in clinically localized MCC. Males, patients >75 years, and those with LVI may be at increased risk for FN SLNB. Consideration of increased nodal surveillance following negative SLNB in these high-risk patients may aid in early identification of regional nodal recurrences.

Feasibility of ecological momentary assessment to study depressive symptoms among cancer caregivers.

OBJECTIVE: Ecological momentary assessment (EMA) may help with the development of more targeted interventions for caregivers' depression, yet the use of this method has been limited among cancer caregivers. This study aimed to demonstrate the feasibility of EMA among cancer caregivers and the use of EMA data to understand affective correlates of caregiver depressive symptoms. METHODS: Caregivers (N = 25) completed a depressive symptom assessment (Patient Health Questionnaire-8) and then received eight EMA survey prompts per day for 7 days. EMA surveys assessed affect on the orthogonal dimensions of valence and arousal. Participants completed feedback surveys regarding the EMA protocol at the conclusion of the week-long study. RESULTS: Of 32 caregivers approached, 25 enrolled and participated (78%), which exceeded the a priori feasibility cutoff of 55%. The prompt completion rate (59%, or 762 of 1,286 issued) did not exceed the a priori cutoff of 65%, although completion was not related to caregivers' age, employment status, physical health quality of life, caregiving stress, or depressive symptoms or the patients' care needs (ps > 0.22). Caregivers' feedback about their study experience was generally positive. Mixed-effects location scale modeling showed caregivers' higher depressive symptoms were related to overall higher reported negative affect and lower positive affect, but not to affective variability. CONCLUSIONS: Findings from this feasibility study refute potential concerns that an EMA design is too burdensome for distressed caregivers. Clinically, findings suggest the potential importance of not only strategies to reduce overall levels of negative affect, but also to increase opportunities for positive affect.

Accuracy of MRI for the diagnosis of metastatic cervical lymphadenopathy in patients with thyroid cancer.

PURPOSE: The aim of this study was to systematically compare a comprehensive array of magnetic resonance (MR) imaging features in terms of their sensitivity and specificity to diagnose cervical lymph node metastases in patients with thyroid cancer. MATERIALS AND METHODS: The study included 41 patients with thyroid malignancy who underwent surgical excision of cervical lymph nodes and had preoperative MR imaging ≤4weeks prior to surgery. Three head and neck neuroradiologists independently evaluated all the MR images. Using the pathology results as reference, the sensitivity, specificity and interobserver agreement of each MR imaging characteristic were calculated. RESULTS: On multivariate analysis, no single imaging feature was significantly correlated with metastasis. In general, imaging features demonstrated high specificity, but poor sensitivity and moderate interobserver agreement at best. CONCLUSIONS: Commonly used MR imaging features have limited sensitivity at correctly identifying cervical lymph node metastases in patients with thyroid cancer. A negative neck MR scan should not dissuade a surgeon from performing a neck dissection in patients with thyroid carcinomas.

Utility of abdominal imaging to assess for liver metastasis in patients with head and neck cancer and abnormal liver function tests.

PURPOSE: To determine the utility of abdominal imaging to further evaluate abnormal pre-operative liver function tests (LFTs) in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: Records of patients evaluated by the head and neck surgery service from January 2004 through December 2009 were reviewed. For patients with abnormal alkaline phosphatase, alanine transaminase, or aspartate transaminase, subsequent abdominal imaging was assessed. RESULTS: Of the 862 patients with HNSCC who had documented LFTs, 109 (12.6%) had one or more abnormal values. In the same time period, LFTs were also obtained on 361 patients with benign head and neck tumors; of these, 40 (11.1%) had abnormalities. Of the 109 patients with HNSCC and abnormal LFTs, 78 (71.6%) underwent abdominal imaging (ultrasound, CT, MRI, or PET/CT). Overall, liver metastasis was demonstrated in only 1 of 109 patients with abnormal LFTs (0.92%) and in only 1 of 862 patients with HNSCC (0.12%). CONCLUSIONS: While HNSCC patients rarely present with liver metastasis, they often have abnormal LFTs. Although the presence of liver metastasis can dramatically change patient management, the yield of follow-up liver imaging for all patients with elevated LFTs is exceedingly low. Thus, the use of risk-stratified abdominal imaging may be prudent and cost effective in a select group of patients in whom distant metastasis is more likely. However, characteristics of this group are difficult to define given the rarity of liver metastasis in HNSCC.

Diagnostic Delay in HPV-Related Oropharyngeal Squamous Cell Carcinoma.

Introduction Human papillomavirus-related (HPV + ) oropharyngeal squamous cell carcinoma (OPSCC) is increasing in incidence and presents diagnostic challenges given its unique clinical presentation. Objective The purpose of the present study is to characterize the impact of the unique clinical presentation of HPV-related OPSCC on delays in diagnosis. Methods Retrospective review of presenting symptoms and clinical characteristics of 284 patients with OPSCC treated from 2002-2014. Delay in diagnosis was defined as the presence of any of the following: multiple non-diagnostic fine needle aspirate (FNA) biopsies; two or more courses of antibiotic therapy; surgery with incorrect preoperative diagnosis; evaluation by an otolaryngologist without further workup; or surgery without definitive postoperative diagnosis. Results p16+ tumors demonstrated a distinct clinical presentation that more commonly involved a neck mass (85.1% versus 57.3% of p16-; p < 0.001) and less frequently included odynophagia (24.6% versus 51.7% of p16-; p < 0.001). Patients who experienced diagnostic delay were more likely to have p16+ tumors (77.7% delayed versus 62.8% not delayed; p = 0.006). p16+ primary tumors were more likely to be undetectable by physical examination of the head and neck including flexible laryngoscopy (19.0% versus 6.7% of p16-; p = 0.007) and more frequently associated with nondiagnostic FNA biopsies of a cervical nodal mass (11.8% versus 3.4% of p16-, p = 0.03). Conclusions Compared with non-HPV related OPSCC, the unique clinical presentation and characteristics of HPV+ OPSCC are associated with an increased incidence of diagnostic delay. Targeted education of appropriate care providers may improve time to diagnosis and treatment.

Activation of the insulin-like growth factor-1 receptor alters p27 regulation by the epidermal growth factor receptor in oral squamous carcinoma cells.

BACKGROUND: Although oral squamous cell carcinomas (OSCCs) commonly overexpress the epidermal growth factor receptor (EGFR), EGFR tyrosine kinase inhibitors (TKIs) exhibit poor efficacy clinically. Activation of the insulin-like growth factor-1 receptor (IGF1R) induces resistance of OSCC cells to EGFR-TKIs in vitro. This study seeks to evaluate the changes in cell cycle status in OSCC cells in response to gefitinib and IGF1R activation. METHODS: SCC-25 OSCC cells were used for in vitro analyses. RESULTS: Gefitinib caused a 50% reduction in S-phase population, and IGF1R activation caused a 2.8-fold increase; combined treatment yielded a baseline S-phase population. Gefitinib treatment increased the cyclin-dependent kinase inhibitor p27, and this was not abrogated by IGF1R activation. pT157-p27 was noted by immunoblot to be decreased on gefitinib treatment, but this was reversed with IGF1R activation. T157 phosphorylation contributes to cytoplasmic localization of p27 where it can promote cell proliferation and cell motility. Using both subcellular fractionation and immunofluorescence microscopy techniques, IGF1R stimulation was noted to increase the relative cytoplasmic localization of p27; this persisted when combined with gefitinib. CONCLUSIONS: IGF1R activation partially reverses the cell cycle arrest caused by gefitinib in OSCC cells. While IGF1R stimulation does not eliminate the gefitinib-induced increase in total p27, its phosphorylation state and subcellular localization are altered. This may contribute to the ability of the IGF1R to rescue OSCC cells from EGFR-TKI treatment and may have important implications for the use of p27 as a biomarker of cell cycle arrest and response to therapy.

Lymph Node Dissection: Principles and Postoperative Imaging.

The management of neck nodes in head and neck cancer is critical, given a markedly increased poor prognosis in patients with nodal metastasis. The surgical management of neck nodes has undergone radical changes secondary to a paradigm shift from curative surgery to nonsurgical organ and function-preserving options, such as radiation therapy. In the neck after treatment, radiologists should be familiar with imaging findings in various types of neck dissections and post-chemoradiation changes, along with signs of residual or recurrent disease. A multidisciplinary approach is essential with well-designed evidence-based surveillance imaging protocols and standardized reporting.

A Telemedicine-Delivered Nursing Intervention for Cancer-Related Distress in Rural Survivors.

OBJECTIVES: To evaluate preliminary efficacy, fidelity, and integrity of data collection of a nurse-led, telemedicine-delivered video visit intervention aimed at improving management of rural survivors' cancer-related distress symptoms. SAMPLE & SETTING: 21 rural survivors participated in a nurse-led telemedicine intervention delivered six weeks after the end of active cancer treatment. METHODS & VARIABLES: Participants' symptom management was measured with the Short Form Survivor Unmet Needs Survey, a four-factor, 30-item instrument that measures the unmet needs of adult survivors. Data were collected preintervention and six weeks postintervention. RESULTS: The mean difference between pre- and postintervention survey scores was -0.24, representing an overall improvement in management of unmet needs. The unmet emotional needs domain had the highest mean preintervention score and the largest mean reduction. All effect sizes were small. IMPLICATIONS FOR NURSING: A nurse-led, telemedicine-delivered video visit intervention may improve rural survivors' symptom management during early survivorship. Comparison with a control group using a sample size powered to detect clinically meaningful differences is an important next step to fully evaluate the impact of this model of care.

Self-reliance, Social Norms, and Self-stigma as Barriers to Psychosocial Help-Seeking Among Rural Cancer Survivors With Cancer-Related Distress: Qualitative Interview Study.

BACKGROUND: Even when technology allows rural cancer survivors to connect with supportive care providers from a distance, uptake of psychosocial referrals is low. Fewer than one-third of participants in a telemedicine intervention for identifying rural survivors with high distress and connecting them with care accepted psychosocial referral. OBJECTIVE: The purpose of this research was to examine the reasons for which rural cancer survivors did not accept a psychosocial referral. METHODS: We utilized a qualitative design to address the research purpose. We interviewed participants who had been offered psychosocial referral. Semistructured interviews were conducted 6 weeks later (n=14), and structured interviews were conducted 9 months later (n=6). Data were analyzed descriptively using an inductive approach. RESULTS: Ultimately, none of the rural cancer survivors (0/14, 0%) engaged with a psychosocial care provider, including those who had originally accepted referrals (0/4, 0%) for further psychosocial care. When explaining their decisions, survivors minimized their distress, emphasizing their self-reliance and the need to handle distress on their own. They expressed a preference for dealing with distress via informal support networks, which was often limited to close family members. No survivors endorsed public stigma as a barrier to accepting psychosocial help, but several suggested that self-stigma associated with not being able to handle their own distress was a reason for not seeking care. CONCLUSIONS: Rural cancer survivors' willingness to accept a psychosocial referral may be mediated by the rural cultural norm of self-reliance and by self-stigma. Interventions to address referral uptake may benefit from further illumination of these relationships as well as a strength-based approach that emphasizes positive aspects of the rural community and individual self-affirmation.

Redesigning Journal Club to Improve Participant Satisfaction and Education.

OBJECTIVE: Journal clubs are a fundamental part of medical training that allow residents and faculty to critically analyze literature, keep up-to-date with new advancements, and implement evidence-based medicine. The aim of this study was to describe one otolaryngology residency program's efforts towards reformatting its journal club, evaluate how well the re-designed format enabled participants to achieve journal club goals compared to the prior format, and assess faculty and resident qualitative perceptions of both formats. DESIGN: An 11-question survey was sent to all department faculty and residents to obtain feedback regarding the original journal club format. The results of this initial survey were then used to redesign the journal club format, which consisted of 3 rotating session types: evidence-based, deep-dive, and landmark. A 6-month pilot program using the redesigned format was implemented, and surveys were sent at the halfway mark and at the conclusion of the pilot to evaluate the effectiveness of these format changes. SETTING: A single academic center with an otolaryngology residency program PARTICIPANTS: : Residents and faculty in the department of otolaryngology RESULTS: Compared to the original format, the 6-month pilot demonstrated a more consistent attainment of journal club goals and a near-unanimous preference for the new format. This preference was consistent among both faculty (90.9%) and residents (89%). All respondents agreed that the intended goals of journal club were more frequently met under the revamped format, and statistically significant differences in approval rate were observed in the specific areas of critically assessing the literature, highlighting new findings, and translating forefront knowledge. The overall time required to prepare for sessions was lower for faculty, and higher for residents. CONCLUSIONS: The findings from this study help to support programmatic efforts towards redesigning journal clubs with the goals of improving participant satisfaction and educational benefit. With the paucity of data in the literature evaluating journal club format overhauls, this study provides compelling evidence for programs to perform similar assessments and consider redesigns if warranted.

Examination of a distress screening intervention for rural cancer survivors reveals low uptake of psychosocial referrals.

PURPOSE: To determine the impact of a telemedicine-delivered intervention aimed at identifying unmet needs and cancer-related distress (CRD) following the end of active treatment on supportive care referral patterns. METHODS: We used a quasi-experimental design to compare supportive care referral patterns between a group of rural cancer survivors receiving the intervention and a control group (N = 60). We evaluated the impact of the intervention on the number and type of referrals offered and whether or not the participant accepted the referral. CRD was measured using a modified version of the National Comprehensive Cancer Network Distress Thermometer and Problem List. RESULTS: Overall, 30% of participants received a referral for further post-treatment supportive care. Supporting the benefits of the intervention, the odds of being offered a referral were 13 times higher for those who received the intervention than those in the control group. However, even among the intervention group, only 28.6% of participants who were offered a referral for further psychosocial care accepted. CONCLUSIONS: A nursing telemedicine visit was successful in identifying areas of high distress and increasing referrals. However, referral uptake was low, particularly for psychosocial support. Distance to care and stigma associated with seeking psychosocial care may be factors. Further study to improve referral uptake is warranted. IMPLICATIONS FOR CANCER SURVIVORS: Screening for CRD may be inadequate for cancer survivors unless patients can be successfully referred to further supportive care. Strategies to improve uptake of psychosocial referrals is of high importance for rural survivors, who are at higher risk of CRD.

Phase II randomized study of preoperative calcitriol to prevent hypocalcemia following thyroidectomy.

BACKGROUND: A prospective, stratified, randomized, double-blind, placebo-controlled study was conducted to observe the impact of preoperative calcitriol supplementation on serum calcium levels following total thyroidectomy. METHODS: Subjects were randomized 1:1 to receive 1 µg calcitriol or placebo for 1 week preceding thyroidectomy. The primary outcome measure was change in serum calcium from baseline to 18 h post-thyroidectomy. Subjects were also assessed for incidence of symptomatic hypocalcemia, length of stay, readmission for hypocalcemia, and intravenous calcium supplementation. RESULTS: Forty-seven patients underwent thyroidectomy; 23 received preoperative calcitriol supplementation, and 24 received placebo. Repeated measures regression demonstrated no difference in postoperative serum calcium over time (p = 0.22). There were no occurrences of hypocalcemia, intravenous calcium supplementation, or readmission in either group. No difference was observed in length of stay (p = 0.38). One patient in the calcitriol group developed Grade 3 hypercalcemia. CONCLUSIONS: Preoperative calcitriol supplementation had no impact on postoperative serum calcium levels compared to placebo.

Non-HPV-Related Head and Neck Squamous Cell Carcinoma in a Young Patient Cohort.

OBJECTIVES: Head and neck squamous cell carcinoma (HNSCC) is rare in patients younger than 40 years. Many practitioners suspect HNSCC is a more aggressive disease in this age group, and perhaps increasing in incidence; however, there are scant and conflicting data to support this assertion. We sought to compare outcomes for young patients with non-human papillomavirus (HPV)-related HNSCC to those of older patients. METHODS: A retrospective chart review of patients with HNSCC treated from 2004 to 2016 at 2 tertiary referral centers. Patients aged 18 to 40 with p16-negative HNSCC were included in the young patient cohort (n = 59). A randomly selected stage- and subsite-matched cohort aged 55 to 65 was analyzed for comparison (n = 114). RESULTS: When considering all patients with HNSCC, patients younger than 40 were more likely to have oral tongue cancer (62.7%) compared to patients age 55 to 65 (16.9%). When an older patient cohort was stage- and subsite-matched to the young patient cohort, there were more never smokers (49.2% vs 17.5% of older patients, P < .01) and females (40.7% vs 24.6% of older patients, P = .028) in the young patient group. The young patient cohort had better average overall survival than the older group (14.4 vs 8.1 years, respectively, P = .02), but similar average disease-free survival (6.2 years vs 6.6 years, respectively, P = .67); 50.9% of young patients had tumors with adverse histologic features versus 42.0% of older patients (P = .28). The young patients demonstrated a superior average conditional survival after recurrence (9.8 years vs 3.2 years for older patients, P < .01). CONCLUSIONS: Despite the limitations of study design, these data suggest that young patients who develop non-HPV-related HNSCC tend to have similarly aggressive disease, but longer overall survival and better survival after recurrence. These findings may be attributable to better overall health as evidenced by fewer comorbidities.

2015 American Thyroid Association guidelines and thyroid-stimulating hormone suppression after thyroid lobectomy.

BACKGROUND: 2015 American Thyroid Association (ATA) guidelines recommended more conservative treatment in low-risk well-differentiated thyroid cancer (WDTC), stating that lobectomy alone may be sufficient. The guidelines further recommend mild thyroid-stimulating hormone (TSH) level suppression (0.5-2 mU/L) for this population. Our goal is to evaluate the natural history of patients undergoing lobectomy to determine the percentage that would require postoperative levothyroxine supplementation under these guidelines. METHODS: Retrospective chart review of 168 patients that underwent lobectomy between 2010 and 2019 was performed. Preoperative and postoperative TSH values and the rate of patients prescribed levothyroxine were analyzed. RESULTS: Thirty-five percent of patients were prescribed levothyroxine postoperatively. At 6 weeks postoperatively, 66% had TSH value of >2; this increased to 76% by 6 to 12 months. CONCLUSION: To adhere to ATA guidelines for WDTC managed with lobectomy alone, the majority of patients (76%) would require postoperative levothyroxine supplementation. Low preoperative TSH was found to be the most significant predictor for postoperative TSH < 2.

IGF1R and Src inhibition induce synergistic cytotoxicity in HNSCC through inhibition of FAK.

Head and neck cancer is the sixth most common cancer worldwide with a 5-year survival of only 65%. Targeting compensatory signaling pathways may improve therapeutic responses and combat resistance. Utilizing reverse phase protein arrays (RPPA) to assess the proteome and explore mechanisms of synergistic growth inhibition in HNSCC cell lines treated with IGF1R and Src inhibitors, BMS754807 and dasatinib, respectively, we identified focal adhesion signaling as a critical node. Focal Adhesion Kinase (FAK) and Paxillin phosphorylation were decreased as early as 15 min after treatment, and treatment with a FAK inhibitor, PF-562,271, was sufficient to decrease viability in vitro. Treatment of 3D spheroids demonstrated robust cytotoxicity suggesting that the combination of BMS754807 and dasatinib is effective in multiple experimental models. Furthermore, treatment with BMS754807 and dasatinib significantly decreased cell motility, migration, and invasion in multiple HNSCC cell lines. Most strikingly, treatment with BMS754807 and dasatinib, or a FAK inhibitor alone, significantly increased cleaved-PARP in human ex-vivo HNSCC patient tissues demonstrating a potential clinical utility for targeting FAK or the combined targeting of the IGF1R with Src. This ex-vivo result further confirms FAK as a vital signaling node of this combinatorial treatment and demonstrates therapeutic potential for targeting FAK in HNSCC patients.