Surgery versus sclerotherapy versus combined therapy in head and neck lymphatic malformations in the pediatric population: systematic review and meta-analysis.

PURPOSE: To systematically review current literature on the treatment of lymphatic malformations (LMs) of the head and neck to guide treatment strategy. METHODS AND MATERIALS: A systematic review and meta-analysis of literature until 16 November 2021 was performed on treatments of LMs in the head and neck. RESULTS: Out of 9044 articles, 54 studies were eligible for inclusion with 26 studies providing detailed participant data. A total number of 1573 patients with a mean age of 21.22 months were analysed. Comparative meta-analysis did not reveal significant differences two proportions of volume reduction (≥ 50% and 100%) between sclerotherapy and surgical treatment. Regression demonstrated that positive predictors for volume reduction were surgery 17 (95% CI 0.26-34; p = 0.047) and treatment of macrocystic lesions 19 (95% CI 5.5-32; p = 0.006). Treatment of mixed lesions also demonstrated a trend towards achieving a greater volume reduction (p = 0.052). A higher de Serres stage of the lesion had a negative effect on the amount of volume reduction - 3.7 (95% CI - 7.0 to - 0.35; p = 0.030). CONCLUSION: This comprehensive meta-analysis demonstrated no significant difference in volume reduction between various treatment modalities at study level. However, individual patient data indicated that surgery and larger cyst types are associated with a significant higher percentage of volume reduction, whereas a higher de Serres stage negatively impacted the amount of volume reduction. These findings can be used for patient counseling and treatment planning based on cyst type and de Serres stage. However volume reduction constitutes just one objective within a more complex treatment spectrum.

Skull base surgery for malignant tumors: The 2nd international collaborative study (1995-2015).

BACKGROUND: The current study presents the effort of a global collaborative group to review the management and outcomes of malignant tumors of the skull base worldwide. PATIENTS AND METHODS: A total of 28 institutions contributed data on 3061 patients. Analysis evaluated clinical variables, survival outcomes, and multivariable factors associated with outcomes. RESULTS: The median age was 56 years (IQR 44-67). The open surgical approach was used in 55% (n = 1680) of cases, endoscopic resection was performed in 36% (n = 1087), and the combined approach in 9.6% (n = 294). With a median follow-up of 7.1 years, the 5-year OS DSS and RFS were 65%, 71.7% and 53%, respectively. On multivariable analysis, older age, comorbidities, histology, dural/intracranial involvement, positive margins, advanced stage, and primary site were independent prognostic factors for OS, DSS, and RFS. Adjuvant RT was a protective prognostic factor. CONCLUSION: The progress across various disciplines may have contributed to improved OS and DSS in this study compared to previous reports.

Comparative analysis of immune infiltrates in head and neck cancers across anatomical sites.

BACKGROUND: The response rate to immune checkpoint inhibitors targeting programmed cell death 1 (PD-1) receptor is 13%-18% for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Detailed understanding of the tumor immune microenvironment (TIME) is crucial in order to explain and improve this response rate. HNSCCs arise at various anatomical locations including the oral cavity, hypopharynx, larynx and oropharynx. Studies directly comparing immune infiltration between anatomical sites are scarce. Since the distinct locations could drive deviating microenvironments, we questioned whether the immune composition varies across these HNSCC sites. METHODS: Here, we characterized the TIME of 76 fresh tumor specimens using flow cytometry and performed single-cell RNA-sequencing on nine head and neck tumor samples. RESULTS: We found major differences in the composition of the TIME between patients. When comparing anatomical sites: tumors originating from the oral cavity had higher T cell infiltrates than tumors from other anatomical sites. The percentage of tumor-infiltrating T-lymphocytes positive for the immune checkpoint PD-1 varied considerably between patients, with the highest fraction of PD-1+ T cells found in larynx squamous cell carcinomas (SCCs). While we had hypothesized that the anatomical sites of tumor origin would drive sample clustering, our data showed that the type of TIME was more dominant and was particularly driven by the fraction of T cells positive for PD-1. Moreover, a high proportion of PD-1+ CD8+ T cells associated with an improved overall survival. Using single-cell RNA-sequencing, we observed that PD-1 expression was highest in the CD8-ENTPD1 tissue resident memory T cell/exhausted T cell and CD4-CXCL13 type 1 T helper cell clusters. CONCLUSIONS: We found that oral cavity SCCs had the highest frequencies of T cells. We also observed considerable interpatient heterogeneity for PD-1 on T cells, with noticeably higher frequencies of PD-1+ CD4+ T helper cells in larynx SCCs. Within the entire cohort, a higher fraction of CD8+ T cells positive for PD-1 was linked to improved overall survival. Whether the fraction of PD-1+ T cells within the TIME enables immune checkpoint inhibitor response prediction for patients with head and neck cancer remains to be determined.

Mental healthcare utilization among head and neck cancer patients: A longitudinal cohort study.

OBJECTIVE: To investigate utilization of mental healthcare among head and neck cancer (HNC) patients from diagnosis to 2 years after treatment, in relation to psychological symptoms, mental disorders, need for mental healthcare, and sociodemographic, clinical and personal factors. METHODS: Netherlands Quality of life and Biomedical Cohort study data as measured before treatment, at 3 and 6 months, and at 1 and 2 years after treatment was used (n = 610). Data on mental healthcare utilization (iMCQ), psychological symptoms (Hospital Anxiety and Depression Scale, Cancer Worry Scale), mental disorders (CIDI interview), need for mental healthcare (Supportive Care Needs Survey Short-Form 34, either as continuous outcome indicating the level of need or dichotomized into unmet need (yes/no)) and several sociodemographic, clinical and personal factors were collected. Factors associated with mental healthcare utilization were investigated using generalized estimating equations (p < 0.05). RESULTS: Of all HNC patients, 5%-9% used mental healthcare per timepoint. This was 4%-14% in patients with mild-severe psychological symptoms, 4%-17% in patients with severe psychological symptoms, 15%-35% in patients with a mental disorder and 5%-16% in patients with an unmet need for mental healthcare. Among all patients, higher symptoms of anxiety, a higher need for mental healthcare, lower age, higher disease stage, lower self-efficacy and higher social support seeking were significantly associated with mental healthcare utilization. CONCLUSION: Mental health care utilization among HNC patients is limited, and is related to psychological symptoms, need for mental healthcare, and sociodemographic, clinical and personal factors.

Changes in Sexuality and Sexual Dysfunction over Time in the First Two Years after Treatment of Head and Neck Cancer.

The aim of this study was to investigate changes in sexuality and sexual dysfunction in head and neck cancer (HNC) patients in the first two years after treatment, in relation to the type of treatment. Data were used of 588 HNC patients participating in the prospective NETherlands Quality of life and Biomedical Cohort Study (NET-QUBIC) from diagnosis to 3, 6, 12 and 24 months after treatment. Primary outcome measures were the International Index of Erectile Function (IIEF) and the Female Sexual Function Index (FSFI). The total scores of the IIEF and FSFI were dichotomized into sexual (dys)function. In men, type of treatment was significantly associated with change in erectile function, orgasm, satisfaction with intercourse, and overall satisfaction. In women, type of treatment was significantly associated with change in desire, arousal, and orgasm. There were significant differences between treatment groups in change in dysfunctional sexuality. A deterioration in sexuality and sexual dysfunction from baseline to 3 months after treatment was observed especially in patients treated with chemoradiation. Changes in sexuality and sexual dysfunction in HNC patients were related to treatment, with an acute negative effect of chemoradiation. This effect on the various domains of sexuality seems to differ between men and women.

Changes in multidisciplinary team decisions in a high volume head and neck oncological center following those made in its preferred partner.

Objective: Head and neck cancer care is highly complex, and multidisciplinary team meetings (MDTs) are vital for improved outcomes. In the Netherlands, head and neck cancer care is practiced in eight high-volume head and neck oncologic centers (HNOC) and six affiliated hospitals preferred partner (PP) centers. Patients treated in the PP are presented and discussed in the HNOC. To evaluate the importance of these mandatory and decisive steps in decision making, we have assessed the changes in treatment. Materials and methods: Retrospective evaluation of head and neck cancer patients referred between January 2011 and October 2018 for a MDT evaluation to the HNOC was conducted. The differences in MDT recommendation were classified with regards to major and minor changes. Results: Management recommendation(MR) changed after 113 of 515 MDT discussions within the PP (487 patients; 22%), of which 86 cases (16%) were major changes. In 67 cases (59.3%), escalation of management was recommended, while in 43 cases (38.1%) de-escalation was recommended. Conclusion: There was a high rate of change of MRs, when comparing the PP recommendations with the HNOC recommendations. Since patient and tumor characteristics seem unable to predict these changes, we recommend all patients be seen for a clinical presentation, revision of diagnostics, and MDT discussion in a high volume HNOC.

The course of health-related quality of life in the first 2 years after a diagnosis of head and neck cancer: the role of personal, clinical, psychological, physical, social, lifestyle, disease-related, and biological factors.

PURPOSE: The aim of this prospective cohort study was to estimate the relationship between the course of HRQOL in the first 2 years after diagnosis and treatment of head and neck cancer (HNC) and personal, clinical, psychological, physical, social, lifestyle, HNC-related, and biological factors. METHODS: Data were used from 638 HNC patients of the NETherlands QUality of life and BIomedical Cohort study (NET-QUBIC). Linear mixed models were used to investigate factors associated with the course of HRQOL (EORTC QLQ-C30 global quality of life (QL) and summary score (SumSc)) from baseline to 3, 6, 12, and 24 months after treatment. RESULTS: Baseline depressive symptoms, social contacts, and oral pain were significantly associated with the course of QL from baseline to 24 months. Tumor subsite and baseline social eating, stress (hyperarousal), coughing, feeling ill, and IL-10 were associated with the course of SumSc. Post-treatment social contacts and stress (avoidance) were significantly associated with the course of QL from 6 to 24 months, and social contacts and weight loss with the course of SumSc. The course of SumSc from 6 to 24 months was also significantly associated with a change in financial problems, speech problems, weight loss, and shoulder problems between baseline and 6 months. CONCLUSION: Baseline clinical, psychological, social, lifestyle, HNC-related, and biological factors are associated with the course of HRQOL from baseline to 24 months after treatment. Post-treatment social, lifestyle, and HNC-related factors are associated with the course of HRQOL from 6 to 24 months after treatment.

MRI-based radiomic prognostic signature for locally advanced oral cavity squamous cell carcinoma: development, testing and comparison with genomic prognostic signatures.

BACKGROUND: . At present, the prognostic prediction in advanced oral cavity squamous cell carcinoma (OCSCC) is based on the tumor-node-metastasis (TNM) staging system, and the most used imaging modality in these patients is magnetic resonance image (MRI). With the aim to improve the prediction, we developed an MRI-based radiomic signature as a prognostic marker for overall survival (OS) in OCSCC patients and compared it with published gene expression signatures for prognosis of OS in head and neck cancer patients, replicated herein on our OCSCC dataset. METHODS: For each patient, 1072 radiomic features were extracted from T1 and T2-weighted MRI (T1w and T2w). Features selection was performed, and an optimal set of five of them was used to fit a Cox proportional hazard regression model for OS. The radiomic signature was developed on a multi-centric locally advanced OCSCC retrospective dataset (n = 123) and validated on a prospective cohort (n = 108). RESULTS: The performance of the signature was evaluated in terms of C-index (0.68 (IQR 0.66-0.70)), hazard ratio (HR 2.64 (95% CI 1.62-4.31)), and high/low risk group stratification (log-rank p < 0.001, Kaplan-Meier curves). When tested on a multi-centric prospective cohort (n = 108), the signature had a C-index of 0.62 (IQR 0.58-0.64) and outperformed the clinical and pathologic TNM stage and six out of seven gene expression prognostic signatures. In addition, the significant difference of the radiomic signature between stages III and IVa/b in patients receiving surgery suggests a potential association of MRI features with the pathologic stage. CONCLUSIONS: Overall, the present study suggests that MRI signatures, containing non-invasive and cost-effective remarkable information, could be exploited as prognostic tools.

Unmet supportive care needs among informal caregivers of patients with head and neck cancer in the first 2 years after diagnosis and treatment: a prospective cohort study.

OBJECTIVE: Informal caregivers of head and neck cancer (HNC) patients have a high caregiver burden and often face complex practical caregiving tasks. This may result in unmet supportive care needs, which can impact their quality of life (QoL) and cause psychological distress. In this study, we identify caregivers' unmet needs during long-term follow-up and identify caregivers prone to unmet supportive care needs. METHODS: Data were used from the multicenter prospective cohort study NETherlands QUality of life and Biomedical cohort studies In Cancer (NET-QUBIC). The unmet supportive care needs, psychological distress, caregiver burden, and QoL were measured for 234 informal caregivers and their related patients at baseline, 3, 6, 12, and 24 months after. Mixed effect models for repeated measurements were used. RESULTS: At baseline, most caregivers (70.3%) reported at least one unmet supportive care need, with most of the identified needs in the "healthcare & illness" domain. During the follow-up period, caregivers' unmet needs decreased significantly in all domains. Nevertheless, 2 years after treatment, 28.3% were still reporting at least one unmet need. Financial problems were increasingly associated with unmet needs over time. Furthermore, caring for a patient who themselves had many unmet needs, an advanced tumor stage, or severe comorbidity was associated with significantly more unmet needs in caregivers. CONCLUSIONS: The current study shows the strong likelihood of caregivers of HNC patients facing unmet supportive care needs and the interaction between the needs of patients and caregivers. It is important to optimally support informal caregivers by involving them from the start when counseling patients, by providing them with relevant and understandable information, and by referring vulnerable caregivers for (psychosocial) support.

Management of the brachial plexus in head and neck cancer.

PURPOSE OF REVIEW: The brachial plexus is an important anatomical structure that is regularly encountered by head and neck surgeons and radiation oncologists. Surgical or radiation-induced brachial plexus injury have great impact on arm function and quality of life. Anatomical variations and management of the brachial plexus in head and neck cancer treatment are discussed. RECENT FINDINGS: The brachial plexus consists of spinal roots from C5-C8 and T1. The most prevalent anatomical variations in brachial plexus anatomy include the prefixed brachial plexus (additional contribution from C4) in 11%, the roots of C5 and C6 piercing the belly of the anterior scalene muscle in 6.8%, and presence of the scalenus minimus muscle in 4.1-46%. Due to its location, the brachial plexus is at risk of inadvertent division or neuropraxia during surgical procedures such as neck dissection or robot-assisted transaxillary thyroid surgery (RATS). In case of inadvertent division, nerve reconstruction surgery is warranted and may lead to improved function. The risk of radiation-induced brachial plexus injury is dose-dependent and occurs in approximately 12-22%. Currently, no successful treatment options exist for radiation-induced injury. SUMMARY: Knowledge of anatomical variations is important for head and neck surgeons to minimize the risk of brachial plexus injury. Limiting radiation therapy dose to the brachial plexus is desirable to decrease the risk of brachial plexus injury.

The Change in Social Eating over Time in People with Head and Neck Cancer Treated with Primary (Chemo)Radiotherapy: The Role of Swallowing, Oral Function, and Nutritional Status.

This study aimed at investigating the change in social eating problems from diagnosis to 24 months after primary (chemo)radiotherapy and its associations with swallowing, oral function, and nutritional status, in addition to the clinical, personal, physical, psychological, social, and lifestyle dimensions. Adult patients from the NETherlands QUality of life and BIomedical Cohort (NET-QUBIC) treated with curative intent with primary (chemo)radiotherapy for newly-diagnosed HNC and who provided baseline social eating data were included. Social eating problems were measured at baseline and at 3-, 6-, 12-, and 24-month follow-up, with hypothesized associated variables at baseline and at 6 months. Associations were analyzed through linear mixed models. Included patients were 361 (male: 281 (77.8%), age: mean = 63.3, SD = 8.6). Social eating problems increased at the 3-month follow-up and decreased up to 24 months (F = 33.134, p < 0.001). The baseline-to-24 month change in social eating problems was associated with baseline swallowing-related quality of life (F = 9.906, p < 0.001) and symptoms (F = 4.173, p = 0.002), nutritional status (F = 4.692, p = 0.001), tumor site (F = 2.724, p = 0.001), age (F = 3.627, p = 0.006), and depressive symptoms (F = 5.914, p < 0.001). The 6-24-month change in social eating problems was associated with a 6-month nutritional status (F = 6.089, p = 0.002), age (F = 5.727, p = 0.004), muscle strength (F = 5.218, p = 0.006), and hearing problems (F = 5.155, p = 0.006). Results suggest monitoring social eating problems until 12-month follow-up and basing interventions on patients' features.

Prognostic implications of p16 and HPV discordance in oropharyngeal cancer (HNCIG-EPIC-OPC): a multicentre, multinational, individual patient data analysis.

BACKGROUND: p16INK4a (p16) immunohistochemistry is the most widely used biomarker assay for inferring HPV causation in oropharyngeal cancer in clinical and trial settings. However, discordance exists between p16 and HPV DNA or RNA status in some patients with oropharyngeal cancer. We aimed to clearly quantify the extent of discordance, and its prognostic implications. METHODS: In this multicentre, multinational individual patient data analysis, we did a literature search in PubMed and Cochrane database for systematic reviews and original studies published in English between Jan 1, 1970, and Sept 30, 2022. We included retrospective series and prospective cohorts of consecutively recruited patients previously analysed in individual studies with minimum cohort size of 100 patients with primary squamous cell carcinoma of the oropharynx. Patient inclusion criteria were diagnosis with a primary squamous cell carcinoma of oropharyngeal cancer; data on p16 immunohistochemistry and on HPV testing; information on age, sex, tobacco, and alcohol use; staging by TNM 7th edition; information on treatments received; and data on clinical outcomes and follow-up (date of last follow-up if alive, date of recurrence or metastasis, and date and cause of death). There were no limits on age or performance status. The primary outcomes were the proportion of patients of the overall cohort who showed the different p16 and HPV result combinations, as well as 5-year overall survival and 5-year disease-free survival. Patients with recurrent or metastatic disease or who were treated palliatively were excluded from overall survival and disease-free survival analyses. Multivariable analysis models were used to calculate adjusted hazard ratios (aHR) for different p16 and HPV testing methods for overall survival, adjusted for prespecified confounding factors. FINDINGS: Our search returned 13 eligible studies that provided individual data for 13 cohorts of patients with oropharyngeal cancer from the UK, Canada, Denmark, Sweden, France, Germany, the Netherlands, Switzerland, and Spain. 7895 patients with oropharyngeal cancer were assessed for eligibility. 241 were excluded before analysis, and 7654 were eligible for p16 and HPV analysis. 5714 (74·7%) of 7654 patients were male and 1940 (25·3%) were female. Ethnicity data were not reported. 3805 patients were p16-positive, 415 (10·9%) of whom were HPV-negative. This proportion differed significantly by geographical region and was highest in the areas with lowest HPV-attributable fractions (r=-0·744, p=0·0035). The proportion of patients with p16+/HPV- oropharyngeal cancer was highest in subsites outside the tonsil and base of tongue (29·7% vs 9·0%, p<0·0001). 5-year overall survival was 81·1% (95% CI 79·5-82·7) for p16+/HPV+, 40·4% (38·6-42·4) for p16-/HPV-, 53·2% (46·6-60·8) for p16-/HPV+, and 54·7% (49·2-60·9) for p16+/HPV-. 5-year disease-free survival was 84·3% (95% CI 82·9-85·7) for p16+/HPV+, 60·8% (58·8-62·9) for p16-/HPV-; 71·1% (64·7-78·2) for p16-/HPV+, and 67·9% (62·5-73·7) for p16+/HPV-. Results were similar across all European sub-regions, but there were insufficient numbers of discordant patients from North America to draw conclusions in this cohort. INTERPRETATION: Patients with discordant oropharyngeal cancer (p16-/HPV+ or p16+/HPV-) had a significantly worse prognosis than patients with p16+/HPV+ oropharyngeal cancer, and a significantly better prognosis than patients with p16-/HPV- oropharyngeal cancer. Along with routine p16 immunohistochemistry, HPV testing should be mandated for clinical trials for all patients (or at least following a positive p16 test), and is recommended where HPV status might influence patient care, especially in areas with low HPV-attributable fractions. FUNDING: European Regional Development Fund, Generalitat de Catalunya, National Institute for Health Research (NIHR) UK, Cancer Research UK, Medical Research Council UK, and The Swedish Cancer Foundation and the Stockholm Cancer Society.

Minimizing population health loss due to scarcity in OR capacity: validation of quality of life input.

OBJECTIVES: A previously developed decision model to prioritize surgical procedures in times of scarce surgical capacity used quality of life (QoL) primarily derived from experts in one center. These estimates are key input of the model, and might be more context-dependent than the other input parameters (age, survival). The aim of this study was to validate our model by replicating these QoL estimates. METHODS: The original study estimated QoL of patients in need of commonly performed procedures in live expert-panel meetings. This study replicated this procedure using a web-based Delphi approach in a different hospital. The new QoL scores were compared with the original scores using mixed effects linear regression. The ranking of surgical procedures based on combined QoL values from the validation and original study was compared to the ranking based solely on the original QoL values. RESULTS: The overall mean difference in QoL estimates between the validation study and the original study was - 0.11 (95% CI: -0.12 - -0.10). The model output (DALY/month delay) based on QoL data from both studies was similar to the model output based on the original data only: The Spearman's correlation coefficient between the ranking of all procedures before and after including the new QoL estimates was 0.988. DISCUSSION: Even though the new QoL estimates were systematically lower than the values from the original study, the ranking for urgency based on health loss per unit of time delay of procedures was consistent. This underscores the robustness and generalizability of the decision model for prioritization of surgical procedures.

Magnetic resonance imaging based radiomics prediction of Human Papillomavirus infection status and overall survival in oropharyngeal squamous cell carcinoma.

OBJECTIVES: Human papillomavirus- (HPV) positive oropharyngeal squamous cell carcinoma (OPSCC) differs biologically and clinically from HPV-negative OPSCC and has a better prognosis. This study aims to analyze the value of magnetic resonance imaging (MRI)-based radiomics in predicting HPV status in OPSCC and aims to develop a prognostic model in OPSCC including HPV status and MRI-based radiomics. MATERIALS AND METHODS: Manual delineation of 249 primary OPSCCs (91 HPV-positive and 159 HPV-negative) on pretreatment native T1-weighted MRIs was performed and used to extract 498 radiomic features per delineation. A logistic regression (LR) and random forest (RF) model were developed using univariate feature selection. Additionally, factor analysis was performed, and the derived factors were combined with clinical data in a predictive model to assess the performance on predicting HPV status. Additionally, factors were combined with clinical parameters in a multivariable survival regression analysis. RESULTS: Both feature-based LR and RF models performed with an AUC of 0.79 in prediction of HPV status. Fourteen of the twenty most significant features were similar in both models, mainly concerning tumor sphericity, intensity variation, compactness, and tumor diameter. The model combining clinical data and radiomic factors (AUC = 0.89) outperformed the radiomics-only model in predicting OPSCC HPV status. Overall survival prediction was most accurate using the combination of clinical parameters and radiomic factors (C-index = 0.72). CONCLUSION: Predictive models based on MR-radiomic features were able to predict HPV status with sufficient performance, supporting the role of MRI-based radiomics as potential imaging biomarker. Survival prediction improved by combining clinical features with MRI-based radiomics.

Self-efficacy and coping style in relation to psychological distress and quality of life in informal caregivers of patients with head and neck cancer: a longitudinal study.

OBJECTIVE: In order to understand how informal caregivers of head and neck cancer (HNC) patients deal with the consequences of the disease, we investigated their self-efficacy and coping style in relation to symptoms of anxiety and depression (distress) and quality of life (QoL) over time. In addition, factors associated with self-efficacy and coping style were investigated. METHODS: A total of 222 informal caregivers and their related HNC patients were prospectively followed as part from the multicenter cohort NETherlands QUality of life and Biomedical cohort studies In Cancer (NET-QUBIC). Self-efficacy and coping style were measured at baseline, and distress and QoL at baseline and 3, 6, 12, and 24 months after treatment. RESULTS: Informal caregivers had a high level of self-efficacy comparable with patients. Caregivers used "seeking social support," "passive reacting," and "expression of emotions" more often than patients. Factors associated with self-efficacy and coping were higher age and lower education. Higher self-efficacy was related with better QoL and "active tackling" was associated with less depression symptoms. "Passive reacting" and "expression of emotions" were associated with higher psychological distress and reduced QoL. CONCLUSION: Among informal caregivers of HNC patients, higher self-efficacy and "active tackling" were associated with better functioning over time, while "passive reacting" and "expression of negative emotions" were associated with worse functioning. Awareness of the differences in self-efficacy skills and coping and their relationship with QoL and psychological distress will help clinicians to identify caregivers that may benefit from additional support that improve self-efficacy and "active tackling" and reduce negative coping styles.

External validation of an MR-based radiomic model predictive of locoregional control in oropharyngeal cancer.

OBJECTIVES: To externally validate a pre-treatment MR-based radiomics model predictive of locoregional control in oropharyngeal squamous cell carcinoma (OPSCC) and to assess the impact of differences between datasets on the predictive performance. METHODS: Radiomic features, as defined in our previously published radiomics model, were extracted from the primary tumor volumes of 157 OPSCC patients in a different institute. The developed radiomics model was validated using this cohort. Additionally, parameters influencing performance, such as patient subgroups, MRI acquisition, and post-processing steps on prediction performance will be investigated. For this analysis, matched subgroups (based on human papillomavirus (HPV) status of the tumor, T-stage, and tumor subsite) and a subgroup with only patients with 4-mm slice thickness were studied. Also the influence of harmonization techniques (ComBat harmonization, quantile normalization) and the impact of feature stability across observers and centers were studied. Model performances were assessed by area under the curve (AUC), sensitivity, and specificity. RESULTS: Performance of the published model (AUC/sensitivity/specificity: 0.74/0.75/0.60) drops when applied on the validation cohort (AUC/sensitivity/specificity: 0.64/0.68/0.60). The performance of the full validation cohort improves slightly when the model is validated using a patient group with comparable HPV status of the tumor (AUC/sensitivity/specificity: 0.68/0.74/0.60), using patients acquired with a slice thickness of 4 mm (AUC/sensitivity/specificity: 0.67/0.73/0.57), or when quantile harmonization was performed (AUC/sensitivity/specificity: 0.66/0.69/0.60). CONCLUSION: The previously published model shows its generalizability and can be applied on data acquired from different vendors and protocols. Harmonization techniques and subgroup definition influence performance of predictive radiomics models. KEY POINTS: • Radiomics, a noninvasive quantitative image analysis technique, can support the radiologist by enhancing diagnostic accuracy and/or treatment decision-making. • A previously published model shows its generalizability and could be applied on data acquired from different vendors and protocols.

Radiation modulates expression and related activities of c-Met protein in oral tongue squamous cell carcinoma cell lines.

OBJECTIVES: c-Met, a receptor tyrosine kinase, is involved in the growth, invasion and metastasis of a variety of cancers. In a set of cell lines from several solid tumors, a five-fold increase in c-Met expression after irradiation has been reported. This study aimed to assess if c-Met is likewise abundantly expressed in oral tongue squamous cell carcinoma (OTSCC) upon exposure to irradiation, followed by a Met-induced biological response. MATERIALS AND METHODS: Six OTSCC cell lines were exposed to gamma radiation doses of 2, 4, and 6 Gray. The changes in c-Met protein levels were assessed by western blot and flow cytometry. c-Met gene expression, cell migration, proliferation and cell cycle assays were performed as phenotypic readouts. RESULTS: Irradiation resulted in upregulation of c.Met in all cell lines with different time kinetics. On average the cells displayed minimal c-Met expression on their surface ranging from 5 to 30% of total protein. Abrupt downregulation of c-Met surface expression occurred one hour after radiation but recovered 48 h post-radiation. Intracellularly, the highest level of expression was found on day 5 after radiation exposure. Irradiation induced aggressive invasive potential of the cells as determined in cell migration assays, particularly in cell lines with the highest c-Met expression. CONCLUSIONS: These results provide novel insights into both intracellular and extracellular dynamics of c-Met expression profiles upon irradiation of OTSCC cells in vitro. It might also suggest that radiation enhances cell migration, indicative of invasiveness, through c-Met up-regulation, at least for certain types of OTSCC cells.

Caregiver Burden, Psychological Distress and Quality of Life among Informal Caregivers of Patients with Head and Neck Cancer: A Longitudinal Study.

(1) Background: The aim of this study was to investigate caregiver burden among informal caregivers of head and neck cancer patients, in relation to distress and quality of life (QoL), and the relationship between informal caregivers and patients. (2) Methods: Data of 234 dyads from the multicenter prospective cohort study Netherlands Quality of life and Biomedical Cohort studies in cancer was used. Caregiver burden, psychological distress, global QoL, physical and social functioning were measured from baseline until 24 months after treatment. (4) Conclusions: This prospective cohort study shows the high burden of caring for HNC patients, the impact of this burden and the interaction between caregiver and patient. We suggest that healthcare professionals include caregivers in counseling and support.

Immune-based classification of HPV-associated oropharyngeal cancer with implications for biomarker-driven treatment de-intensification.

BACKGROUND: There is significant interest in treatment de-escalation for human papillomavirus-associated (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) patients given the generally favourable prognosis. However, 15-30% of patients recur after primary treatment, reflecting a need for improved risk-stratification tools. We sought to develop a molecular test to risk stratify HPV+ OPSCC patients. METHODS: We created an immune score (UWO3) associated with survival outcomes in six independent cohorts comprising 906 patients, including blinded retrospective and prospective external validations. Two aggressive radiation de-escalation cohorts were used to assess the ability of UWO3 to identify patients who recur. Multivariate Cox models were used to assess the associations between the UWO3 immune class and outcomes. FINDINGS: A three-gene immune score classified patients into three immune classes (immune rich, mixed, or immune desert) and was strongly associated with disease-free survival in six datasets, including large retrospective and prospective datasets. Pooled analysis demonstrated that the immune rich group had superior disease-free survival compared to the immune desert (HR = 9.0, 95% CI: 3.2-25.5, P = 3.6 × 10-5) and mixed (HR = 6.4, 95% CI: 2.2-18.7, P = 0.006) groups after adjusting for age, sex, smoking status, and AJCC8 clinical stage. Finally, UWO3 was able to identify patients from two small treatment de-escalation cohorts who remain disease-free after aggressive de-escalation to 30 Gy radiation. INTERPRETATION: With additional prospective validation, the UWO3 score could enable biomarker-driven clinical decision-making for patients with HPV+ OPSCC based on robust outcome prediction across six independent cohorts. Prospective de-escalation and intensification clinical trials are currently being planned. FUNDING: CIHR, European Union, and the NIH.