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Management of functional intrathoracic sympathetic paragangliomas in succinate dehydrogenase subunit D (SDHD) mutation carriers is challenging, and there is no uniform guideline for treatment to date. The risks of potential malignant behavior and long-term cardiovascular morbidity have to be weighed against the risks of treatment complications. We report the multidisciplinary and shared decision-making approach that resulted in successful surgical removal of 3 paragangliomas in a SDHD mutation carrier. [ABSTRACT FROM AUTHOR]

This systematic review and meta-analysis aim to investigate the prevalence rates of various types of sleep disturbances among head and neck cancer (HNC) patients before, during, and after cancer treatment. We performed a systematic search on PubMed, Embase, CINAHL, and PsycINFO to find studies that reported the prevalence of any type of sleep disturbance among adult HNC patients. Meta-analyses of prevalence were performed using random effects models, with I2 values to indicate the extent of heterogeneity. In total, 29 studies of accumulatively 2315 HNC patients were included. The quality of the studies was fairly low and the heterogeneity was high. Studies on three types of sleep disturbances were found: insomnia (17 studies), hypersomnolence (12 studies), and sleep-related breathing disturbances (14 studies). The prevalence of insomnia was 29% (95% CI 20-41%) before treatment, 45% (95% CI 33-58%) during treatment, and 40% (95% CI 24-58%) after treatment, while for hypersomnolence the prevalence was 16% (95% CI 7-32%) before treatment and 32% (95% CI 20-48%) after treatment. The prevalence of sleep-related breathing disturbances before and after treatment was 66% (95% CI 44-82%) and 51% (95% CI 34-67%), respectively. These results imply that sleep disturbances are highly prevalent among HNC patients before, during, and after treatment. [ABSTRACT FROM AUTHOR]

Objective: To explore the possibility of shortening the length of follow-up from 5 to 3 years in patients who have undergone curative treatment of an oral squamous cell carcinoma.Study Design: The medical records of 225 patients who had undergone initial curative treatment at the VU University Medical Center in Amsterdam, the Netherlands, between 2004 and 2009 were analyzed.Results: In 96 patients (42.7%) a secondary event occurred. Eighty-six percent of the secondary events were detected within 3 years. In the fourth and fifth years, 14% of the secondary events were found, consisting mainly of second primary tumors.Conclusions: Most secondary events occurred within the first 3 years of follow-up. Therefore, the case can be made for an altered regimen of follow-up beyond 3 years based on certain risk factors unique to the patient as well as the patient's ability to adequately report symptoms that may be associated with recurrent disease. [ABSTRACT FROM AUTHOR]

The infrahyoid flap is a myocutaneous pedicled flap mainly nourished by the superior thyroid vessels through the perforators of theinfrahyoidmuscles. This thin and pliableflap provides a skin island of about 7 by 4cm from the central part of the anterior neck. Theflapcan be transferred on its pedicle of superior thyroid artery and vein to reconstruct medium sized head and neck defects created aftercancer ablation. We have successfully used this flap in a series of 40 cases with no total flap loss and with 1 case of superficial skin necrosis. The aim of this review is to highlight the clinical usefulness of this pedicled flap even in the microvascular free flap era. A comprehensive review of the available literature reporting on the infrahyoid flap has been carried out using a web search. The history of the infrahyoid flap, the surgical technique with technical innovations, the clinical utility and limitations of this flap, are reported and discussed. Among the 7 larger series (cohort larger than 50 cases) a total of 956 flaps were performed, and the global success rate was 91.7%, with failures being mainly related to partial skin necrosis, as the rate of total (skin and muscle) flap necrosis was only 1%. This flap is reliable, easy to harvest during neck dissection, oncologically safe, it does carry a negligible donor site morbidity. This paper highlights how the infrahyoid flap can represent an excellent reconstructive solution in selected patients and head and neck sites. [ABSTRACT FROM AUTHOR]

Summary: Background: Incidence and survival trends of head and neck squamous cell carcinoma (HNSCC) are essential knowledge for guiding policy making and research. Methods: The total population of the Netherlands was studied covering 1989–2011. Two-and five-year survival and age-standardized incidence rates of HNSCC were assessed in relation to site, gender and age (15years-of-age categories). Results: We recorded a statistically significant increase of oral, oropharyngeal and hypopharyngeal carcinoma for males and females of all ages, varying from 0.6% (hypopharynx in males) to 2.7% (oropharynx in females) per year. The incidence of laryngeal carcinoma significantly decreased for males with 2.3% per year; for females the situation was stable. In young adults (below 45years of age) the incidence figures were different: significant decreasing incidence trends were seen for both genders for carcinomas of the oropharynx, hypopharynx and larynx. Regarding oral carcinoma, no change was observed for the young patient group, but for subsites trends were divergent. Carcinoma of the floor or mouth decreased for both genders, but carcinoma of the tongue rose by a significant 2.8% per year for young males. Five-year survival trends for all ages showed no change for laryngeal carcinoma, a small improvement for oral and hypopharyngeal carcinoma, and a substantial and significant improvement of survival from 36% to 47% survival over the total period for oropharyngeal carcinoma. Conclusion: In the Netherlands for the last two decades, the incidence of oral, oropharyngeal and hypopharyngeal squamous cell carcinoma has increased and survival has improved. The incidence of laryngeal carcinoma has decreased in males, and remained unchanged in females; survival from laryngeal carcinoma has not changed. [Copyright &y& Elsevier]

Summary: Background and aims: We performed a systematic review to examine the effect of nutritional interventions on nutritional status, quality of life (QoL) and mortality in patients with head and neck squamous cell cancer (HNSCC) receiving radiotherapy or chemoradiotherapy. Methods: We searched Pubmed, EMBASE, CENTRAL and Cinahl from inception through January 3rd, 2012 to identify randomized controlled trials (RCTs) from a broad range of nutritional interventions in patients with HNSCC during (chemo)radiotherapy. Two reviewers independently assessed study eligibility and risk of bias, and extracted data. Results: Of 1141 titles identified, 12 study reports were finally included, describing 10 different studies with 11 interventions. Four out of 10 studies examined the effects of individualized dietary counseling, and showed significant benefits on nutritional status and QOL compared to no counseling or general nutritional advice by a nurse (p < 0.05). Three studies on oral nutritional supplements (ONS) were inconsistent about the effect on nutritional status compared with no supplementation. One study showed that nasogastric tube feeding had beneficial effects on nutritional status compared to ONS, but not in all patient groups (p < 0.04). One study showed benefits of percutaneous endoscopic gastronomy (PEG) feeding on nutritional status shortly after RT compared with nasogastric feeding (p = 0.001). Two studies showed that prophylactic PEG feeding was not superior over tube feeding if required. Conclusions: This review shows beneficial effects of individualized dietary counseling on nutritional status and QoL, compared to no counseling or standard nutritional advice. Effects of ONS and tube feeding were inconsistent. [Copyright &y& Elsevier]

Summary: Background & aims: Weight loss is a frequently observed problem in patients with head and neck cancer (HNC) during radiotherapy. It is still to be assessed whether hypermetabolism is contributing to this problem. The aim of this study was to investigate hypermetabolism before radiotherapy, and changes in resting energy expenditure (REE) in HNC patients during radiotherapy. Methods: REE was measured by indirect calorimetry in 71 patients with HNC before radiotherapy, after 3 and 6 weeks of radiotherapy, and 3 months after radiotherapy. The association between REE and tumour stage, CRP, and prior tumour surgery was analyzed by linear regression analyses. Forty healthy control subjects were one-to-one matched to 40 patients by gender, age and fat free mass (FFM) index to compare REE. Results: Before radiotherapy, REE was not significantly different between patients and controls, neither in absolute values (1568 ± 247 vs. 1619 ± 244 kcal/d; p = 0.29), nor after weight-adjustment (22.1 ± 3.5 vs. 21.5 ± 3.3 kcal/kg, p = 0.42) or FFM-adjustment (31.5 ± 4.9 vs. 30.7 ± 4.5 kcal/kg, p = 0.38). REE was independent of tumour stage, CRP, and prior tumour surgery. REE (kcal/d) decreased during radiotherapy and thereafter by 9% from pre-radiotherapy (p < 0.01). Weight and FFM also decreased significantly over time (p < 0.001). REE adjusted for FFM decreased in the first 3 weeks of radiotherapy with 4% (B = −1.39 kcal/kg FFM, p < 0.01), increased at the end of radiotherapy and decreased again 3 months after radiotherapy (B = −1.31 kcal/kg FFM, p = 0.04). Conclusions: Head and neck cancer patients had normal REE before radiotherapy. During radiotherapy, REE decreased continuously with ongoing weight loss. However, weight loss is not the only explaining factor, since REE expressed per kg FFM showed a much more divergent course which is currently unexplained. [Copyright &y& Elsevier]

Summary: In this study, we present a case of parotid gland de novo carcinosarcoma. Salivary gland carcinosarcoma (or true malignant mixed tumor) is a rare biphasic neoplasm, composed of both malignant epithelial and malignant mesenchymal components. It is yet unclear whether these two phenotypes occur by collision of two independent tumors or if they are of clonal origin. To analyze the clonality of the different morphologic tumor components, oligonucleotide microarray-based comparative genomic hybridization (oaCGH) was performed on the carcinoma and the sarcoma entity separately. This technique enables a high-resolution, genome-wide overview of the chromosomal alterations in the distinct tumor elements. Analysis of both fractions showed a high number of DNA copy number changes. Losses were more prevalent than gains (82 and 49, respectively). The carcinomatous element displayed more chromosomal aberrations than the sarcomatous component. Specific amplifications of MUC20 (in mesenchymal element) and BMI-1 (in both elements) loci were observed. Overall homology between the two genomic profiles was 75%. DNA copy number profiles of the epithelial and mesenchymal components in this salivary gland carcinosarcoma displayed extensive overlap, indicating a monoclonal origin. Since losses are shared to a larger extent than gains, they seem to be more essential for initial oncogenic events. Furthermore, specific amplifications of a mucin and a Polycomb group gene imply these proteins in the tumorigenesis of carcinosarcomas. [Copyright &y& Elsevier]

Purpose: The purpose of this study was to evaluate the clinical, pathological, and therapeutic experience of a group of patients with primary oral malignant melanoma (OMM) in Amsterdam, The Netherlands. Patients and Methods: Fourteen patients (5 males, 9 females, mean age 57.9 years) with histopathologic diagnosis of OMM were treated at the Department of Oral and Maxillofacial Surgery/Oral Pathology of the Vrije University Medical Center in Amsterdam between 1978 and 2005. A pigmented, flat or swollen, irregularly bordered lesion of oral mucosa was detected in most patients during the first clinical examination. Pain was the most commonly referred symptom; the palate was the most frequently affected subsite. Following the mucosal melanoma microstaging system, all patients staged as stage I (T any N0M0) could be subclassified as microstage II (invasion up to the lamina propria), except for 1 patient microstaged as stage III (deep skeletal tissue invasion into skeletal muscle, bone, or cartilage). Where possible, surgery was the treatment of choice. Postoperative radiotherapy, using fractions of 6 Gy twice a week for a total dose of 30 Gy, was given to 3 patients. Three patients were treated primarily with radiotherapy alone. Results: Five patients developed local recurrence within 4 to 72 months, and 10 patients developed distant metastases within 6 to 78 months. Ten patients died of their disease within an average interval of 40 months, with a range of 12 to 80 months. Of the 10 patients who qualified for evaluation of the 5-year-survival rate, 1 was alive with disease and 2 were alive without evidence of disease, resulting in a 5-year survival rate of 30%. However, all patients died of their disease before the end of the 10-year follow-up period. Conclusion: Our study confirms that OMM is a rare and aggressive malignancy with a low 5-year survival rate. An evidence-based protocol for the best therapeutic approach is not yet available. [Copyright &y& Elsevier]

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. 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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

• Platinum-based CRT for HPV-neg HNSCC has unique treatment course and outcome pattern. • CRT is often too toxic, in ∼35% of patients the cisplatin-dose plan needed changes. • Switching to carboplatin when cisplatin is too toxic seems not beneficial for OS (HR 1.49 vs HR 1.59). • Development of DM was strongly associated with boosting method (SEQ vs SIB; OR 1.91). Definitive concomitant cisplatin-based chemoradiotherapy (CRT) is the current gold standard for most patients with advanced stage head and neck squamous cell carcinoma (HNSCC) of the pharynx and larynx. Since previous meta-analysis on CRT outcomes in HNSCC have been reported, advances have been made in radiotherapy techniques and clinical management, while HPV-status has been identified as a strong confounding prognostic factor in oropharyngeal cancer. Here, we present real-world outcome data from a large multicenter cohort of HPV-negative advanced stage HNSCC treated with CRT using contemporary IMRT-based techniques. Retrospective data were collected from a multicenter cohort of 513 patients treated with definitive concurrent platinum-based CRT with curative intent between January 2009 and August 2017. Only patients with HPV-negative advanced stage (III-IV) HNSCC were included. A prognostic model for outcome was developed based on clinical parameters and compared to TNM. Nearly half of the 513 patients (49%) had an oropharyngeal tumor, often locally advanced (73.3% T3-T4b) and with involvement of the regional lymph nodes (84%). Most patients (84%) received cisplatin as single agent. In total 66% received the planned number of cycles and 75% reached a cumulative cisplatin dose of ≥200 mg/m2. Locoregional control was achieved in 324 (63%) patients during follow-up, and no association with tumor sites was observed (p = 0.48). Overall survival at 5 year follow-up was 47%, with a better survival for laryngeal cancer (p = 0.02) compared to other sites. A model with clinical variables (gender, high pre-treatment weight loss, N2c/N3-stage and <200 mg/m2 dose of cisplatin) provided a noticeably stronger association with overall survival than TNM-staging (C- index 0.68 vs 0.55). Simultaneous Integrated Boosting (SIB) significantly outperformed Sequential Boosting (SEQ) to reduce the development of distant metastasis (SEQ vs SIB: OR 1.91 (1.11–3.26; p = 0.02). Despite advances in clinical management, more than a third of patients with HPV-negative HNSCC do not complete CRT treatment protocols due to cisplatin toxicity. A model that consists of clinical variables and treatment parameters including cisplatin dose provided the strongest association with overall survival. Since cisplatin toxicity is a major obstacle in completing definitive CRT, the development of alternative and less toxic radiosensitizers is therefore warranted to improve treatment results. The association of RT-boost technique with distant metastasis is an important finding and requires further study. [ABSTRACT FROM AUTHOR]

Summary: The relatively modest survival of patients surgically treated for advanced HNSCC can partly be explained by the development of local relapse. It is important that surgeons are able to predict which patients are at high risk to develop local relapse, since clinical management can be tailored. Local relapse after resection of a primary HNSCC is easily explained, when tumour is detected in the surgical margins and thus residual tumour is likely to remain in the patient, but the pathobiology is more complex in cases where the margins are histologically tumour-free. Molecular studies indicate that there are two different mechanisms responsible in these cases. First, small clusters of residual tumour cells that are undetectable on routine histopathological examination (known as minimal residual cancer: MRC) proliferate and this forms the basis of recurring cancer. A second cause of relapse is a remaining field of preneoplastic cells that is struck by additional genetic hits leading to invasive cancer. It is likely that within this field, that can be over 7cm in diameter, the primary carcinoma has also emerged. Despite careful histopathological examination of the surgical margins of the primary carcinoma, it is at present not reliably possible to predict which patient will develop local relapse. Herein we focus on new developments regarding the analysis of margins, causes of local relapse, and how novel molecular techniques can be of help in a more accurate risk assessment. Critical analysis of the studies that have been published thus far shows that there is a list of promising markers, based on protein expression (immuno-histochemistry) and nucleic acid analysis. Further studies should be focused on validation and assessment of the clinical utility of these markers. Margin analysis should reveal whether one is dealing with residual cancer cells that might be treated by post-operative radiotherapy or with preneoplastic fields that remained behind. For this latter entity, there is no intervention available at present, except for a more intensive surveillance. [Copyright &y& Elsevier]

Summary: The detection of distant metastases and second primary tumours at the time of initial evaluation changes the prognosis and influences the selection of treatment modality in patients with HNSCC. Until recently chest CT was the single most effective test to screen for distant metastases in HNSCC patients. In this observational cohort study we prospectively compared the yield of whole body 18FDG-PET and chest CT to detect distant metastases and synchronous primary tumours. The results of whole body 18FDG-PET and chest CT were analysed in 34 consecutive HNSCC patients with previously established risk factors for the presence of distant metastases. Four patients were diagnosed with distant metastases or second primary tumours: CT as well as 18FDG-PET identified one patient with lung metastases and another with primary lung cancer. In addition, 18FDG-PET detected second primary tumours in two patients (hepatocellular carcinoma and abdominal adenocarcinoma). However increased uptake sites at 18FDG-PET in lung, liver and pelvis in five patients were not confirmed by other imaging modalities. The added value of whole body 18FDG-PET versus chest CT was to identify unknown malignancy in 6% of the patients. Confirmation of positive 18FDG-PET findings is feasible and necessary. [Copyright &y& Elsevier]

To report the functional and oncologic results of larynx preservation surgery with free flap reconstruction for posterior pharyngeal wall carcinoma. Retrospective medical chart review. Tertiary care referral center. We present a series of seven patients, who were treated for an advanced stage posterior pharyngeal wall carcinoma between 1995 and 1998. All patients underwent posterior pharyngectomy with larynx preservation via a suprahyoidal approach for carcinoma of the posterior pharyngeal wall, with radial forearm free flap reconstruction. Complications occurred in three patients with grade 3 comorbidity, one of whom suffered flap loss. After a mean follow-up of 48 months, three patients are alive without disease. One patient is alive with a second primary tongue carcinoma. Two patients died of disease, whereas one patient died of another cause. All patients could be decannulated and maintain their voice. Six out of seven patients were able to take oral nutrition, although four patients needed additional PEG-tube feeding. Posterior pharyngectomy with larynx preservation and radial forearm free flap reconstruction is feasible in selected patients, with acceptable functional results and survival. However, the patient must be aware of the risk of chronic aspiration and the possibility of long-term PEG feedings. [Copyright &y& Elsevier]

The emerge of improved personalized treatment adaptations and outcome prediction is accompanied with increasing non-invasive assessments in early treatment phase, leading to increased patient burden. This study assessed the adherence of patients with head and neck squamous cell carcinoma (HNSCC) to undergo pretreatment and research-related intratreatment imaging, and assessed which factors caused drop-out. Between 2013 and 2019, advanced-staged HNSCC patients were prospectively included, underwent (chemo) radiotherapy with curative intent and planned for both pre-treatment and intratreatment sequential 18F-FDG-PET/CT, 18F-FDG-PET/MRI and thereafter MRI (including DWI/DCE). Drop-out-factors were described as healthcare-related (logistics and imaging-system defects) and patient-related (psychological, physical, not-specified). Common Toxicity Criteria (CTC) were routinely scored by radiation/medical oncologists throughout the first 3 weeks, and compared between patient drop-outs and who complete imaging. Ninety-seven patients (mean age 61 ± 6.8 years) were included; 95 patients (97.9%) underwent pretreatment imaging and 63 (64.9%) intratreatment imaging. For 18F-FDG-PET/CT, 18F-FDG-PET/MRI and MRI pretreatment drop-outs were 2, 10 and 3 patients and for intratreatment drop-outs were 34, 39 and 35 patients, respectively. Patient-related drop-out-factors were physical (n = 16, e.g. dysphagia), psychological (n = 6, e.g. claustrophobia) and non-specified (n = 12). Healthcare-related drop-out-factors were logistics (n = 6) and 18F-FDG-PET/CT-/MRI-system defects (n = 2). The CTC mucosal toxicity was significantly higher (p = 0.023) at week 2 of (chemo)radiotherapy in patient drop-outs than with complete imaging. The drop-out frequency of advanced-staged HNSCC patients for imaging during (chemo)radiotherapy in a research-setting was high and mainly patient-related. Treatment of patient-related inconveniences, communication of rationale and healthcare-related imaging protocol efficiency improvements may contribute to improved adherence. • Patient drop-outs were due to patient-related or healthcare-related factors. • Physical treatment discomfort (pain, dysphagia, psychological anxiety) caused most drop-outs. • Drop-out reduction can be realised by early identification and addressing drop-out-factors, such as preemptive discussion or medication, and improving healthcare-related factors. • Early treatment phase mucosal toxicity was found predictive for patient drop-out. [ABSTRACT FROM AUTHOR]

• Mesenchymal characteristics are associated with poor prognosis in HPV-negative HNSCC. • Multiple EMT signatures confirm poor prognosis association. • Novel HNSCC-specific EMT prediction models predict patient outcomes. • Early metastatic disease prior to treatment linked to mesenchymal HNSCC. The prognosis of patients with HPV-negative advanced stage head and neck squamous cell carcinoma (HNSCC) remains poor. No prognostic markers other than TNM staging are routinely used in clinic. Epithelial-to-mesenchymal transition (EMT) has been shown to be a strong prognostic factor in other cancer types. The purpose of this study was to determine the role of EMT in HPV-negative HNSCC outcomes. Pretreatment tumor material from patients of two cohorts, totalling 174 cisplatin-based chemoradiotherapy treated HPV-negative HNSCC patients, was RNA-sequenced. Seven different EMT gene expression signatures were used for EMT status classification and generation of HNSCC-specific EMT models using Random Forest machine learning. Mesenchymal classification by all EMT signatures consistently enriched for poor prognosis patients in both cohorts of 98 and 76 patients. Uni- and multivariate analyses show important HR of 1.6–5.8, thereby revealing EMT's role in HNSCC outcome. Discordant classification by these signatures prompted the generation of an HNSCC-specific EMT profile based on the concordantly classified samples in the first cohort (cross-validation AUC > 0.98). The independent validation cohort confirmed the association of mesenchymal classification by the HNSCC-EMT model with poor overall survival (HR = 3.39, p < 0.005) and progression free survival (HR = 3.01, p < 0.005) in multivariate analysis with TNM. Analysis of an additional HNSCC cohort from PET-positive patients with metastatic disease prior to treatment further supports this relationship and reveals a strong link of EMT to the propensity to metastasize. EMT in HPV-negative HNSCC co-defines patient outcome after chemoradiotherapy. The generated HNSCC-EMT prediction models can function as strong prognostic biomarkers. [ABSTRACT FROM AUTHOR]

Rationale: This study evaluates the lymphatic drainage patterns and determines the accuracy of the sentinel lymph node biopsy (SLNB) in patients diagnosed with a cT1-2N0 OSCC and a history of neck surgery or radiotherapy in three Dutch head and neck centers.Materials and Methods: Retrospective analysis of 53 cT1-2N0 OSCC patients, who underwent SLNB between 2007 and 2016, after a history of neck surgery or radiotherapy. Ten patients had previous treatment of the neck only contralateral from the current tumour. These ten patients were not used for the analysis of lymphatic drainage patterns. The 43 patients with previous ipsilateral or bilateral treatment of the neck had a history of ipsilateral SLN extirpation (n = 9; 21%), neck dissection (n = 16; 37%), radiotherapy (n = 10; 23%), or combined neck dissection and radiotherapy (n = 8; 19%).Results: SLNs were detected in 45 patients, resulting in an identification rate of 85% (45/53). Three patients (7%) had at least one positive SLN. One patient (1/45; 2%) was diagnosed with regional recurrence during the follow-up after a negative SLNB (sensitivity 75%, negative predictive value 98%). The first SLN was detected in level I-III in 58% of the patients, unexpected drainage patterns were observed in 30% (first SLN level IV 9% and level V 5% and contralateral neck in well-lateralized tumours 16%). In 12% no lymphatic drainage pattern was visible.Conclusions: SLNB seems to be a reliable procedure for neck staging of cT1-2N0 OSCC patients with a previously treated neck. SLNB determines the individual lymphatic drainage patterns, enabling visualization of unexpected drainage pattern variability in 30% of these patients. [ABSTRACT FROM AUTHOR]

Background and Purpose: In head and neck squamous cell carcinoma (HNSCC) (chemo)radiotherapy is increasingly used to preserve organ functionality. The purpose of this study was to identify predictive pretreatment DWI- and 18F-FDG-PET/CT-parameters for treatment failure (TF), locoregional recurrence (LR) and death in HNSCC patients treated by (chemo)radiotherapy.Materials and Methods: We retrospectively included 134 histologically proven HNSCC patients treated with (chemo)radiotherapy between 2012-2017. In 58 patients pre-treatment DWI and 18F-FDG-PET/CT were performed, in 31 patients DWI only and in 45 patients 18F-FDG-PET/CT only. Primary tumor (PT) and largest lymph node (LN) metastasis were quantitatively assessed for TF, LR and death. Multivariate analysis was performed for 18F-FDG-PET/CT and DWI separately and thereafter combined. In patients with both imaging modalities, positive and negative predictive value in TF and differences in LR and death, were assessed.Results: Mean follow-up was 25.6 months (interquartile-range; 14.0-37.1 months). Predictors of treatment failure, corrected for TNM-stage and HPV-status, were SUVmax-PT, ADCmax-PT, total lesion glycolysis (TLG-LN), ADCp20-LN (P = 0.049, P = 0.024, P = 0.031, P = 0.047, respectively). TLG-PT was predictive for LR (P = 0.003). Metabolic active tumor volume (MATV-PT) (P = 0.003), ADCGTV-PT (P < 0.001), ADCSD (P = 0.048) were significant predictors for death. In patients with both imaging modalities SUVmax-PT remained predictive for treatment failure (P = 0.049), TLG-LN for LR (P = 0.003) and ADCGTV-PT for death (P < 0.001). Higher predictive value for treatment failure was found for the combination of SUVmax-PT and ADCmax-PT, compared to either one separately.Conclusion: Both DWI- and 18F-FDG-PET/CT-parameters appear to have predictive value for treatment failure, locoregional recurrence and death. Combining SUVmax-PT and ADCmax-PT resulted in better prediction of treatment failure compared to single parameter assessment. [ABSTRACT FROM AUTHOR]

This systematic review gives an extensive overview of the current state of functional imaging during (chemo)radiotherapy to predict locoregional control (LRC) and overall survival (OS) for head and neck squamous cell carcinoma. MEDLINE and EMBASE were searched for literature until April 2018 assessing the predictive performance of functional imaging (computed tomography perfusion (CTp), MRI and positron-emission tomography (PET)) within 4 weeks after (chemo)radiotherapy initiation. Fifty-two studies (CTp: n = 4, MRI: n = 19, PET: n = 26, MRI/PET: n = 3) were included involving 1623 patients. Prognostic information was extracted according the PRISMA protocol. Pooled estimation and subgroup analyses were performed for comparable parameters and outcome. However, the heterogeneity of included studies limited the possibility for comparison. Early tumoral changes from (chemo)radiotherapy can be captured by functional MRI and 18F-FDG-PET and could allow for personalized treatment adaptation. Lesions showed potentially prognostic intratreatment changes in perfusion, diffusion and metabolic activity. Intratreatment ADCmean increase (decrease of diffusion restriction) and low SUVmax (persistent low or decrease of 18F-FDG uptake) were most predictive of LRC. Intratreatment persistent high or increase of perfusion on CT/MRI (i.e. blood flow, volume, permeability) also predicted LRC. Low SUVmax and total lesion glycolysis (TLG) predicted favorable OS. The optimal timing to perform functional imaging to predict LRC or OS was 2-3 weeks after treatment initiation. [ABSTRACT FROM AUTHOR]

Head and neck squamous cell carcinoma (HNSCC) is typically regarded as a disease of elderly people. However, increasing numbers of patients worldwide with HNSCC at younger age (defined as <45 years old) have been reported in recent years. To assess geographical variations and trends worldwide in incidence of oral and oropharyngeal cancer in young patients, a systematic review was conducted in PubMed and Google scholar databases from 1975 to June 2016. Seventy-eight studies were selected for further study. Nineteen population-based studies on incidence rate were available from 13 countries, showing a prominent increase over time except for the Netherlands. A notable rise of oral (mobile) tongue cancer among white women and oropharyngeal cancer in white men was observed. Data suggest that cancer in young patients may be a distinct clinical entity and characterised by different aetiology and pathogenesis. Additionally, the relative proportion of oral and oropharyngeal cancer in young patients to total incidence revealed a significant difference between estimates from North America (5.5%) and both Africa (17.2%) and Middle East (14.5%). It is concluded that (i) a rising trend in oral and oropharynx cancers is observed in young patients worldwide; (ii) incidence studies should properly define outcomes in age cohorts and use a consensus cut-off for young patients; (iii) more population-based studies should be performed in non-Western regions to get accurate global measures of incidence for these cancers in young subpopulations and (iv) there is an urge to identify new aetiological factors in these young patients. [ABSTRACT FROM AUTHOR]

Intravoxel incoherent motion (IVIM) imaging is increasingly applied in the assessment of head and neck cancer (HNC). Our purpose was to determine the diagnostic and prognostic performance of IVIM in HNC by performing a critical review of the literature. Pubmed and EMBASE were searched until May 2016. Study and patients characteristics, imaging protocol and diagnostic or prognostic outcomes were extracted by 2 independent reviewers. The studied IVIM parameters were diffusion coefficient (D), pseudodiffusion coefficient (D∗), and perfusion fraction (f). We included 10 diagnostic studies, 5 prognostic studies and 2 studies assessing both. Studies were very heterogeneous in terms of applied b-values, imaging protocols, outcome measurements and reference standards; therefore we did not perform a meta-analysis. The most commonly used sequence was "spin-echo planar imaging". A median of 10.5 b-values (range, 3-17) were used. All but three studies included at least 4 b-values below b=200s/mm2. By combining IVIM-parameters squamous cell carcinomas, lymphomas, malignant salivary gland tumors, Warthin's tumors and pleomorphic adenomas could be differentiated with a sensitivity of 85-87% and specificity of 80-100%. Low pre-treatment D or f and an increase in D during treatment were associated with a favorable response to treatment. D∗ appeared to be the parameter with the lowest prognostic value. Future research should focus on finding the optimal IVIM protocol, using uniformly accepted study methods and larger patient populations. [ABSTRACT FROM AUTHOR]

• Predictive models based on MR-radiomic features were able to predict HPV status. • The study outcomes support the role of MR-radiomics as potential imaging biomarker. • Survival prediction improved by combining clinical features with MRI-based radiomics. 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. 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. 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). 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. [ABSTRACT FROM AUTHOR]

Survivors of head and neck cancer can experience long-term consequences of the cancer and subsequent treatments even after the cancer has resolved. Increasingly clinicians are aware of the social, psychological, financial, and emotional impacts of these cancers, in addition to the support required for the physical symptoms. This review provides recommendations on the long-term management and support required for survivors of head and neck cancer in the European healthcare setting. [ABSTRACT FROM AUTHOR]

Summary: Ameloblastoma is a histologically almost always benign odontogenic tumor with a high rate of recurrence if not removed completely. Therefore, radical surgery is the treatment of choice of a primary ameloblastoma. Of 18 patients with a recurrent ameloblastoma, previously treated by enucleation, radical surgery was deemed impossible in three because of the extent of the tumor or because of a poor general condition of the patient. Of the remaining 15 patients three refused to undergo radical surgery and have been treated for their recurrence by enucleation again. In none of the twelve remaining patients treated by radical surgery a recurrence was observed in a mean follow-up period of 10.5years. In one of these patients a metastatic cervical lymph node was detected during the primary reconstruction of the mandibular defect. The absence of recurrences in patients treated by radical surgery should be looked at with some reservation, since recurrences may still show up after 10.5years. The three patients who refused radical surgery all developed one or more new recurrences. [ABSTRACT FROM AUTHOR]

Purpose The purpose of this study is to evaluate the efficacy of 18 F-FDG-PET as first-line diagnostic investigation, prior to performing a direct laryngoscopy with biopsy under general anesthesia, in patients suspected of recurrent laryngeal carcinoma after radiotherapy. Patients and methods 150 patients suspected of recurrent T2–4 laryngeal carcinoma at least two months after prior (chemo)radiotherapy with curative intent for resectable disease were randomized to direct laryngoscopy (CWU: conventional workup strategy) or to 18 F-FDG-PET only followed by direct laryngoscopy if PET was assessed ‘positive’ or ‘equivocal’ (PWU: PET based workup strategy), to compare the effectiveness of these strategies. Primary endpoint was the number of indications for direct laryngoscopies classified as unnecessary based on absence of recurrence, both on direct laryngoscopy and on six month follow up. Safety endpoints comprised resectability of recurrent lesions and completeness of surgical margins following salvage laryngectomy. Results Intention-to-treat analyses were performed on all randomized patients (CWU: n = 74, PWU: n = 76). Tumor recurrence was similar in both groups: 45 patients (30%; 21 CWU, 24 PWU) within six months. In 53 patients in the CWU arm (72%, 95% CI: 60–81) unnecessary direct laryngoscopies were performed compared to 22 in the PWU arm (29%, 95% CI: 19–40) ( p < 0·0001). The percentage of salvage laryngectomies (resectability) and positive surgical margins were similar between CWU and PWU (81%, 63% respectively, p = 0·17, and 29%, 7%, respectively, p = 0.20). The prevalence of the combination of local unresectability and positive margins is in the CWU group 24% and in the PWU group 8%. No difference ( p = 0.32) in disease specific survival between both groups was found. Conclusion In patients with suspected laryngeal carcinoma after radiotherapy, PET as the first diagnostic procedure can reduce the need for direct laryngoscopy by more than 50% without jeopardizing quality of treatment. [ABSTRACT FROM AUTHOR]

Objectives: Patients with head and neck cancer (HNC) frequently encounter weight loss with multiple negative outcomes as a consequence. Adequate treatment is best achieved by early identification of patients at risk for critical weight loss. The objective of this study was to detect predictive factors for critical weight loss in patients with HNC receiving (chemo)radiotherapy ((C)RT).Materials and Methods: In this cohort study, 910 patients with HNC were included receiving RT (±surgery/concurrent chemotherapy) with curative intent. Body weight was measured at the start and end of (C)RT. Logistic regression and classification and regression tree (CART) analyses were used to analyse predictive factors for critical weight loss (defined as >5%) during (C)RT. Possible predictors included gender, age, WHO performance status, tumour location, TNM classification, treatment modality, RT technique (three-dimensional conformal RT (3D-RT) vs intensity-modulated RT (IMRT)), total dose on the primary tumour and RT on the elective or macroscopic lymph nodes.Results: At the end of (C)RT, mean weight loss was 5.1±4.9%. Fifty percent of patients had critical weight loss during (C)RT. The main predictors for critical weight loss during (C)RT by both logistic and CART analyses were RT on the lymph nodes, higher RT dose on the primary tumour, receiving 3D-RT instead of IMRT, and younger age.Conclusion: Critical weight loss during (C)RT was prevalent in half of HNC patients. To predict critical weight loss, a practical prediction tree for adequate nutritional advice was developed, including the risk factors RT to the neck, higher RT dose, 3D-RT, and younger age. [ABSTRACT FROM AUTHOR]

Summary Background Pretreatment screening on distant metastases is particularly useful in head and neck squamous cell carcinoma (HNSCC) patients with high risk factors. Methods In a retrospective study of 88 patients with previously identified clinical high risk factors the predictive value of standardized uptake value (SUV) of 18F - fluorodeoxyglucose (FDG) in the primary tumor and in the lymph node metastases for the development of distant metastases was examined. Different SUVs corrected for plasma glucose levels and body mass index were calculated and analysed in different patient groups: all patients ( n = 88), patients with a follow up >6 months ( n = 73), not previously treated patients ( n = 51) and not previously treated patients with a follow up >6 months ( n = 40). Results Twenty-four of the 88 (27%) high risk HNSCC patients were diagnosed with distant metastases during screening and follow up. No correlation was found between different SUVs of the primary tumor and lymph nodes metastases and the development of distant metastases. Conclusion SUVs of primary tumor and lymph node on FDG-PET are not predictive for distant metastases in a (selected) group of patients with already high risk factors for distant metastases. [ABSTRACT FROM AUTHOR]

Summary Objectives Evaluation of accuracy and interobserver variation of diffusion-weighted magnetic resonance imaging (DW-MRI) and 18F-fluorodeoxyglucose positron emission tomography–computed tomography (18F-FDGPET–CT) to detect residual lymph node metastases after chemoradiotherapy (CRT) in advanced staged head and neck squamous cell carcinoma (HNSCC). Materials and methods Retrospectively, routinely performed DW-MRI ( n = 73) and 18F-FDG-PET–CT ( n = 58) 3 months after CRT in HNSCC-patients with advanced nodal disease (N2–N3) were assessed by two radiologists and two nuclear medicine physicians (individually and in consensus). Imaging was scored dichotomously and on a five-point Likert scale. We also explored different scenarios for the potential added value of DW-MRI to PET–CT using the consensus Likert scale. Histopathology and a follow-up of 9 months after CRT served as reference standard. Results Five patients (7%) had residual regional disease. DW-MRI showed a sensitivity of 60% and a specificity of 93%, vs. 100% and 84% for PET–CT, respectively. DW-MRI and PET–CT observers had ‘moderate’ and ‘substantial’ interobserver agreement ( κ = 0.58 and κ = 0.64, respectively) with the dichotomous system. The combination of PET–CT and DW-MRI showed a sensitivity of 100% and a specificity of 95%. Conclusion The high sensitivity of PET–CT authorizes a neck dissection in all patients with a positive test result and the high specificity of DW-MRI justifies avoidance of invasive neck dissections if the test is negative. Interobserver agreement varied as a function of test positivity criteria. Adding DW-MRI to PET–CT seemed to increase the specificity of PET–CT alone, thereby ensuring that less patients are exposed to unnecessary neck dissections. [ABSTRACT FROM AUTHOR]

Summary Background and purpose Previously identified high risk factors for development of distant metastases are: three or more lymph node metastases, bilateral lymph node metastases, lymph nodes larger than 6 cm, low jugular lymph node metastases, locoregional tumor recurrence and second primary tumors. The aims of this study were to validate these specific risk factors and to investigate the impact of time (i.e. during screening or follow-up) of detection of distant metastases on survival. Material and methods From a total of 301 HNSCC patients with high risk factors who were scheduled for extensive treatment and underwent pretreatment screening on distant metastases using chest CT and/or whole body PET(-CT) (in some patients combined with whole body MRI), the high risk factors, the development and time point of distant metastases and survival were analyzed. Results Forty-four percent developed distant metastases. Multivariate analysis revealed that bilateral lymph node metastases is the strongest predictive factor. Locoregional recurrence and second primary tumor were the risk factors associated with the lowest cumulative incidence. However, if the risk factor locoregional recurrence was split into local and regional recurrences, regional recurrence became a high risk factor. The more high risk factors a patient had the lower the 5-year distant metastases free survival was. Patients with distant metastases detected pretreatment has a significant worse survival (corrected for lead time bias) compared to patients with distant metastases diagnosed during follow-up. Conclusions The validity of three or more lymph node metastases, bilateral lymph node metastases, lymph nodes larger than 6 cm, low jugular lymph node metastases and regional recurrence as high risk factors for the development of distant metastases was confirmed. If more high risk factors are present the cumulative incidence of distant metastases increases significantly. The detection of distant metastases by pretreatment screening worsens the overall survival as compared to distant metastases detected during follow-up. [ABSTRACT FROM AUTHOR]

The aim of this study was to systematically review available evidence on the association between health-related quality of life (HRQoL) and survival in patients with head and neck cancer (HNC), adjusted for important clinical, demographic and lifestyle-related factors. A systematic literature search in four electronic bibliographic databases was conducted in January 2014. We included studies that provided data on HRQoL, survival, and the association between HRQoL and survival among HNC patients. Two researchers independently rated the quality of the included studies. A best evidence synthesis was applied to draw conclusions. Nineteen studies were included, of which twelve focused on all subscales of a HRQoL questionnaire and seven focused on selected subscales. The mean (SD) quality score was 72 (17)% and 11 (58)% studies were of high quality. According to the best evidence synthesis, we found strong evidence for a positive association between pre-treatment physical functioning and survival and between change in global QoL from pre-treatment to 6 months after treatment and survival. Due to inconsistent findings, we found insufficient evidence for an association with survival of other HRQoL domains, including role, emotional, cognitive and social functioning, mental health and well-being. Future high quality studies with a longitudinal design are needed to examine the complex association between HRQoL and survival. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Results of the Dutch multi-institutional trial on sentinel lymph node (SLN) biopsy in oral cancer. PATIENTS AND METHODS: Patients were consecutively enrolled from 4 institutions, with T1/T2 oral cancer and cN0 neck based on palpation and ultrasound guided fine needle aspiration cytology. Lymphatic mapping consisted of preoperative lymphoscintigraphy. For intraoperative SLN detection a gamma-probe was used and in some patients additional blue dye. SLN negative patients were carefully observed, SLN positive patients were treated by neck dissection, radiotherapy or a combination of both. Endpoints of the study were risk of occult lymp node metastases, neck control, accuracy, 5-year disease-free survival (DFS), overall survival (OS) and disease-specific survival (DSS). RESULTS: Twenty of 62 patients (32%) had positive SLNs. Macrometastases were found in 9 patients, micrometastases in 8, and isolated tumour cells in 3 patients. Median follow-up was 52.5months. Of the 42 SLN negative patients, 5 developed a regional recurrence of whom 4 patients could be successfully salvaged. DFS, OS and DSS of SLN negative patients were 72.0%, 92.7% and 97.4%, and for SLN positive patients these numbers were 73.7%, 79.7%, 85.0%, respectively (DFS: p=0.916, OS: p=0.134, DSS: p=0.059, respectively). Neck control rate was 97% in SLN negative and 95% in SLN positive patients. Sensitivity was 80% and negative predictive value 88%. CONCLUSION: SLN biopsy is able to reduce the risk of occult lymph node metastases in T1/T2 oral cancer patients from 40% to 8%, and enables excellent control of the neck. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Several hypotheses have been proposed to explain the relatively good prognosis of patients with a human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) and one of these is a higher sensitivity to (chemo)radiation. Previous studies have suggested that treatment failure in OPSCC patients is caused by resistance of cancer stem cells (CSCs). The purpose of this study was to evaluate the association between the number of CSCs and prognosis in HPV-positive OPSCC patients. Experimental design: All OPSCC patients (n =711) treated between 2000 and 2006 in two Dutch university hospitals were included. Presence of HPV in a tumour tissue specimen was tested by p16-immunostaining followed by HPV DNA GP5+/6+polymerase chain reaction (PCR). The presence and intensity of tumour CSC markers CD44 and CD98 were determined by immunohistochemistry and semiquantitative scoring was performed. Overall survival (OS) and progression-free survival (PFS) rates were compared between patients with low and high CD44/CD98 expression in relation to HPV status. Results: HPV-positive tumours showed a lower percentage of cells with CD44 and CD98 expression than HPV-negative tumours (p <0.001, χ 2-test). Within the group of patients with HPV-positive OPSCC, a high percentage of CD98-positive tumour cells was associated with a significantly worse 5-year OS and PFS (OS: 36.4% and PFS: 27.3%) compared to patients with a low percentage of CD98-positive cells (OS: 71.9% and PFS: 70.5%, respectively) (p <0.001). Conclusions: HPV-positive OPSCCs harbour fewer cells expressing the CSC enrichment markers CD44 and CD98. Furthermore, OS and PFS were significantly worse for patients with HPV-positive OPSCC with a high percentage of CD98-positive cells. [Copyright &y& Elsevier]

Abstract: Background and purpose: To evaluate the course of health-related quality of life (HRQOL) from diagnosis to 2years follow-up in patients with head and neck cancer (HNSCC) treated with chemoradiation (CRT). Materials and methods: 164 patients completed the EORTC QLQ-C30 and QLQ-H&N35 questionnaires 1week before and 6weeks and 6, 12, 18, and 24months after CRT. Patients were compared to a reference group. A linear mixed-model analysis was used to assess changes in HRQOL over time, and whether this was associated with age, gender, comorbidity, and tumor sublocation. Results: Significant differences for the majority of HRQOL scales were observed between patient and reference group at baseline, and follow-up. The course of HRQOL was different for survivors compared to non-survivors. In survivors, improvement over time was observed (in global quality of life, physical, role, and social function, fatigue, pain, swallowing, speech, social eating, and social contacts), while in non-survivors the pattern over time was either no changes in HRQOL or a deterioration (in physical function, social eating and contacts). In both survivors and non-survivors, emotional functioning improved after treatment, but deteriorated in the longer term. Patients with comorbidity reported worse physical function, and patients with oral/oropharyngeal cancer (compared to hypopharyngeal/laryngeal cancer) reported more oral pain and sexual problems, but fewer speech problems. Conclusions: The course of HRQOL of HNSCC patients during the first 2years after CRT is different for survivors compared to non-survivors and is associated with comorbidity and tumor subsite. [Copyright &y& Elsevier]

Summary: Objectives: Early detection and treatment of high risk premalignant mucosal changes of the oral cavity, will expectedly improve survival and reduce treatment-related morbidity. Aims of this study were to evaluate a non-invasive screening approach and to assess the value of molecular markers to identify patients at risk for oral cancer. Materials and Methods: Exfoliated cells and biopsies were obtained from oral leukoplakia lesions of 43 patients, of whom six developed oral cancer. All samples were investigated for loss of heterozygosity (LOH) at chromosomes 3p, 9p, 11q and 17p using microsatellite markers. On the biopsy specimen additional immunohistochemical staining for p53, TP53 mutation analysis and histopathological grading were performed. Results: The analytical sensitivity of the non-invasive assay using exfoliated cells to detect genetic changes present in the lesions was 45% (9 of 20), the specificity was 100% (19 of 19), and the positive predictive value was also 100% (9 of 9). LOH was present in 20 of 39 (51%) of the biopsies with uniformly LOH at 9p. Mutated TP53 and LOH at 9p in the biopsy, as single markers and in combination, were significant risk factors for malignant progression of leukoplakia to oral cancer (Kaplan–Meier analysis, p <0.05). Conclusion: A non-invasive genetic screening approach using LOH in exfoliated cells has limited value for monitoring patients with leukoplakia. However, LOH at 9p, but also mutated TP53 in biopsies of oral leukoplakia have a significant association with malignant transformation and are promising candidate biomarkers to predict the risk for malignant progression. [Copyright &y& Elsevier]

Summary: Objectives: The incidences of hypo(para)thyroidism were assessed prospectively in 137 consecutive patients with laryngeal (84.7%) or hypopharyngeal (15.3%) carcinoma who were treated with surgery and/or radiotherapy between 2004 and 2006. Material and methods: Laboratory studies were performed in patients before primary or salvage treatment of a laryngeal or hypopharyngeal carcinoma and were repeated 6, 12, 18 and 24months after treatment. All patients were evaluated for the development of hypo(para)thyroidism, and the presence of autoantibodies. The association of hypothyroidism was analyzed against several patient parameters including tumor and treatment characteristics. Results: The incidence of hypothyroidism following treatment of laryngeal and hypopharyngeal carcinoma was 47.4%: 27.7% subclinical hypothyroidism and 19.7% clinical hypothyroidism. The median time to develop hypothyroidism was 10months. The incidence of hypoparathyroidism was 7.3%. Univariate analysis showed that patients with laryngectomy, hemithyroidectomy, neck dissection, paratracheal lymph node dissection and radiotherapy had a higher risk of developing hypothyroidism. Multivariate analysis showed laryngectomy, hemithyroidectomy, neck dissection and age to be predictive factors for the development of hypothyroidism. The combination of surgery and radiotherapy increased this risk. Hemithyroidectomy was the most important risk factor. Conclusion: The incidence rate of hypothyroidism after treatment for laryngeal or hypopharyngeal cancer in this largest prospective study is high (47.4%), especially after combination treatment. Based on the intervals between treatment and the development of hypothyroidism, thyroid testing before treatment, every 3months during the first year, every 6months the second year and annually thereafter is recommended as screening procedure. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: The purpose of this multicentre prospective study was to investigate the significance of the radiation dose in the major and minor salivary glands, and other pre-treatment and treatment factors, with regard to the development of patient-rated xerostomia and sticky saliva among head and neck cancer (HNC) patients treated with primary (chemo-) radiotherapy ((CH)RT). Methods and materials: The study population was composed of 167 consecutive HNC patients treated with three-dimensional conformal (3D-CRT) (CH) RT. The primary endpoint was moderate to severe xerostomia (XER6m) as assessed by the EORTC QLQ-H&N35 at 6months after completing (CH)RT. The secondary endpoint was moderate to severe sticky saliva at 6months (STIC6m). All organs at risk (OARs) potentially involved in salivary function were delineated on planning-CT, including the parotid, submandibular and sublingual glands and the minor glands in the soft palate, cheeks and lips. Patients with moderate to severe xerostomia or sticky saliva at baseline were excluded. The optimum number of variables for a multivariate logistic regression model was determined using a bootstrapping method. Results: The multivariate analysis showed the mean parotid dose, age and baseline xerostomia (none versus a bit) to be the most important predictors for XER6m. The risk of developing xerostomia increased with age and was higher when minor baseline xerostomia was present in comparison with patients without any xerostomia complaints at baseline. Model performance was good with an area under the curve (AUC) of 0.82. For STIC6m, the mean submandibular dose, age, the mean sublingual dose and baseline sticky saliva (none versus a bit) were most predictive for sticky saliva. The risk of developing STIC6m increased with age and was higher when minor baseline sticky saliva was present in comparison with patients without any sticky saliva complaints at baseline. Model performance was good with an AUC of 0.84. Conclusions: Dose distributions in the minor salivary glands in patients receiving 3D-CRT have limited significance with regard to patient-rated symptoms related to salivary dysfunction. Besides the parotid and submandibular glands, only the sublingual glands were significantly associated with sticky saliva. In addition, reliable risk estimation also requires information from other factors such as age and baseline subjective scores. When these selected factors are included in predictive models, instead of only dose volume histogram parameters, model performance can be improved significantly. [Copyright &y& Elsevier]

Abstract: Background and purpose: The purpose of this large multicentre prospective cohort study was to identify which dose volume histogram parameters and pre-treatment factors are most important to predict physician-rated and patient-rated radiation-induced swallowing dysfunction (RISD) in order to develop predictive models for RISD after curative (chemo) radiotherapy ((CH) RT). Material and methods: The study population consisted of 354 consecutive head and neck cancer patients treated with (CH) RT. The primary endpoint was grade 2 or more swallowing dysfunction according to the RTOG/EORTC late radiation morbidity scoring criteria at 6months after (CH) RT. The secondary endpoints were patient-rated swallowing complaints as assessed with the EORTC QLQ-H&N35 questionnaire. To select the most predictive variables a multivariate logistic regression analysis with bootstrapping was used. Results: At 6months after (CH) RT the bootstrapping procedure revealed that a model based on the mean dose to the superior pharyngeal constrictor muscle (PCM) and mean dose to the supraglottic larynx was most predictive. For the secondary endpoints different predictive models were found: for problems with swallowing liquids the most predictive factors were the mean dose to the supraglottic larynx and radiation technique (3D-CRT versus IMRT). For problems with swallowing soft food the mean dose to the middle PCM, age (18–65 versus >65years), tumour site (naso/oropharynx versus other sites) and radiation technique (3D-CRT versus IMRT) were the most predictive factors. For problems with swallowing solid food the most predictive factors were the mean dose to the superior PCM, the mean dose to the supraglottic larynx and age (18–65 versus >65years). And for choking when swallowing the V60 of the oesophageal inlet muscle and the mean dose to the supraglottic larynx were the most predictive factors. Conclusions: Physician-rated and patient-rated RISD in head and neck cancer patients treated with (CH) RT cannot be predicted with univariate relationships between the dose distribution in a single organ at risk and an endpoint. Separate predictive models are needed for different endpoints and factors other than dose volume histogram parameters are important as well. [Copyright &y& Elsevier]

Summary: The detection of distant metastases is critical for prognostication and for the choice of treatment in patients with head and neck squamous cell carcinoma (HNSCC). Pretreatment screening for distant metastases should be conducted particularly for patients with high risk factors, prior to locoregional treatment decisions. Different diagnostic techniques are discussed. Unfortunately, most studies lack sufficient follow-up to reliably assess false-negative results. Moreover, the designs of most studies vary substantially with regard to homogeneity of groups (tumor types and stages), timing (pretreatment, follow-up) and definition of risk factors (patient selection). Therefore, only a few studies are comparable. The combination of F-18 fluoro-d-glucose-positron emission tomography (FDG-PET) and a dedicated CT (at least of the chest) is the most important imaging protocol at the present time. Eventually, whole-body-MRI (WB-MRI) may possibly replace PET-CT for screening patients for distant metastases. [ABSTRACT FROM AUTHOR]

Summary: Oral leukoplakia is a potentially malignant disorder that will develop into oral cancer at an estimated rate of 1–2% per year. Aim of the present study is to assess the possible predictive value of DNA ploidy for malignant progression of oral leukoplakia. A cohort of 62 leukoplakia patients was studied and their biopsy was examined with standard histopathology and DNA image cytometry. Cox regression analysis was performed to establish the relationship between progression-free survival and the DNA ploidy status. During the follow-up time (median of 69months) 13 patients developed an oral squamous cell carcinoma (OSCC). DNA aneuploidy was observed in 27 (44%) patients and was significantly associated with a shorter progression-free survival [Hazard ratio of 3.7, 95% confidence intervals (CI) of 1.1 and 13.0 and a p-value of 0.04]. Sensitivity and specificity scores were 54% and 60%, respectively. Aneuploidy was not correlated with dysplasia grading (chi-square analysis). DNA aneuploidy in oral leukoplakia is associated with an increased risk of progression to OSCC. However, for the individual leukoplakia patient, DNA ploidy status as single biomarker has limited value to predict progression to cancer. [ABSTRACT FROM AUTHOR]

Summary: Currently, selection of lymph nodes for ultrasound-guided-fine-needle-aspiration cytology (USgFNAC) in patients with HNSCC relies mainly on size of lymph nodes. This retrospective study was undertaken to assess the potential value of size, laterality, level and changes in size as criteria for selection of nodes that need to be aspirated during follow-up of patients. We aim to reduce the number of unnecessary aspirations being performed without decreasing accuracy of USgFNAC. Eighty-one patients with oral cavity carcinoma (OCC) were eligible for observation-policy regarding treatment of the neck and received transoral excision of OCC. Selection of nodes for fine-needle-aspiration-cytology (FNAC) was based on size criterion. Localization (side and level) and size of aspirated lymph nodes were scored. Data on treatment and follow-up were collected and analyzed to assess the value of the used criteria. During follow-up all 17 positive nodes were found, of which 16 were ipsilateral. Contralateral metastasis was found in a patient with ipsilateral metastasis and a tumor crossing the midline. Minimal axial diameter (MAD) of all positive nodes was larger than 5.0mm in level II or 4.0mm in other levels. Follow-up aspirations in patients with OCC performed in the neck by USgFNAC can be reduced by 56% without increasing false-negative lymph nodes if follow-up aspirations would only be performed on the ipsilateral neck in lymph nodes with a MAD of 5mm in level II and 4mm in other levels or larger and in lymph nodes with rapid change of diameter. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: Although patients with early stage (T1/T2) laryngeal cancer (LC) are thought to have a low incidence of malnutrition, severe weight loss is observed in a subgroup of these patients during radiotherapy (RT). The objective of this study was to evaluate weight loss and nutrition-related symptoms in patients with T1/T2 LC during RT and to select predictive factors for early identification of malnourished patients. Methods: Of all patients with T1/T2 LC, who received primary RT between 1999 and 2007, the following characteristics were recorded: sex, age, TNM classification, tumour location, radiation schedule, performance status, quality of life, weight loss, and nutrition-related symptoms. The association between baseline characteristics and malnutrition (>5% weight loss during RT) was investigated by Cox regression analysis. Results: The study population consisted of 238 patients. During RT, 44% of patients developed malnutrition. Tumour location, TNM classification, RT on the neck nodes, RT dose, nausea/vomiting, pain, swallowing, senses problems, trouble with social eating, dry mouth and the use of painkillers were all significantly associated with malnutrition. In the multivariate analysis, RTs on both the neck nodes (HR 4.16, 95% CI 2.62–6.60) and dry mouth (HR 1.72, 95% CI 1.14–2.60) remained predictive. Nevertheless, RT on the neck nodes alone resulted in the best predictive model for malnutrition scores. Conclusions: Patients with early stage laryngeal cancer are at risk of malnutrition during radiotherapy. Radiotherapy on the neck nodes is the best predictor of malnutrition during radiotherapy. Therefore, we suggest to offer nutritional counselling to all the patients who receive nodal irradiation. [ABSTRACT FROM AUTHOR]

Summary: Radiation may cause radiation-induced cancers after a long latency period. In a group of 111 patients surgically treated for hypopharyngeal carcinoma, patients previously treated with radiotherapy for tuberculosis in the neck were compared to patients without previous radiotherapy. Seven patients (7.4%) underwent radiotherapy (median age 15years) and developed a hypopharyngeal carcinoma (median age 70years, median latency period 54.4year). Considering this long latency period and the localisation in the previous radiation field these tumours can be classified as potentially radiation-induced carcinomas. Patients with potentially radiation-induced carcinomas were significantly older when the hypopharyngeal carcinoma was diagnosed (p =0.048), were more frequently females (p =0.05) and had a worse 5-year regional control rate (p =0.048). When radiotherapy is considered in young patients the risk of induction of tumours has to be kept in mind. [ABSTRACT FROM AUTHOR]

Abstract: Recent studies have revealed an important and intriguing role for human papillomavirus (HPV) in head and neck squamous cell carcinoma (HNSCC). There are indications that the prevalence of HPV-positive HNSCC has recently increased, and genetic analyses point to a completely distinct class of HNSCCs. Most studies suggest that patients with this type of tumour have a better prognosis and some argue that an adjusted therapeutic approach is needed. One crucial point in the research of HNSCC–HPV involvement has often been neglected, which is the lack of a standardised assay to detect HPV. This has resulted in a considerable variation in the frequency of HPV-positive tumours between studies reported thus far. Especially for PCR-based tests, the risk exists that the assay is too sensitive and detects virus without implying a causal involvement in HNSCC. A reliable algorithm to detect a clinically relevant HPV infection in formalin-fixed paraffin embedded tissue has recently become available. Here, we address important biological and analytical aspects of HPV involved in the development of HNSCC and it is emphasised that a standardised HPV assay is a prerequisite for assessing the clinical importance of a HPV infection in HNSCC. [Copyright &y& Elsevier]