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PURPOSE Pembrolizumab and pembrolizumab-chemotherapy demonstrated efficacy in recurrent/metastatic head and neck squamous cell carcinoma in KEYNOTE-048. Post hoc analysis of long-term efficacy and progression-free survival on next-line therapy (PFS2) is presented. METHODS Patients were randomly assigned (1:1:1) to pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy. Efficacy was evaluated in programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥ 20, CPS ≥ 1, and total populations, with no multiplicity or alpha adjustment. RESULTS The median study follow-up was 45.0 months (interquartile range, 41.0-49.2; n = 882). At data cutoff (February 18, 2020), overall survival improved with pembrolizumab in the PD-L1 CPS ≥ 20 (hazard ratio [HR], 0.61; 95% CI, 0.46 to 0.81) and CPS ≥ 1 populations (HR, 0.74; 95% CI, 0.61 to 0.89) and was noninferior in the total population (HR, 0.81; 95% CI, 0.68 to 0.97). Overall survival improved with pembrolizumab-chemotherapy in the PD-L1 CPS ≥ 20 (HR, 0.62; 95% CI, 0.46 to 0.84), CPS ≥ 1 (HR, 0.64; 95% CI, 0.53 to 0.78), and total (HR, 0.71; 95% CI, 0.59 to 0.85) populations. The objective response rate on second-course pembrolizumab was 27.3% (3 of 11). PFS2 improved with pembrolizumab in the PD-L1 CPS ≥ 20 (HR, 0.64; 95% CI, 0.48 to 0.84) and CPS ≥ 1 (HR, 0.79; 95% CI, 0.66 to 0.95) populations and with pembrolizumab-chemotherapy in the PD-L1 CPS ≥ 20 (HR, 0.64; 95% CI, 0.48 to 0.86), CPS ≥ 1 (HR, 0.66; 95% CI, 0.55 to 0.81), and total (HR, 0.73; 95% CI, 0.61 to 0.88) populations. PFS2 was similar after pembrolizumab and longer after pembrolizumab-chemotherapy on next-line taxanes and shorter after pembrolizumab and similar after pembrolizumab-chemotherapy on next-line nontaxanes. CONCLUSION With a 4-year follow-up, first-line pembrolizumab and pembrolizumab-chemotherapy continued to demonstrate survival benefit versus cetuximab-chemotherapy in recurrent/metastatic head and neck squamous cell carcinoma. Patients responded well to subsequent treatment after pembrolizumab-based therapy.

ObjectivesInduction chemotherapy (ICT) followed by definitive treatment is an accepted non-surgical approach for locoregionally advanced head and neck squamous cell carcinoma (LA-HNSCC). However, ICT remains a challenge for cisplatin-unfit patients. We evaluated paclitaxel and cetuximab (P-C) as ICT in a cohort of LA-HNSCC patients unfit for cisplatin.Materials and MethodsThis is a retrospective analysis of patients with newly diagnosed LA-HNSCC considered unfit for cisplatin-based chemotherapy (age >70 and/or ECOG≥2 and/or comorbidities) treated with weekly P-C followed by definitive radiotherapy and cetuximab (RT-C) between 2010 and 2017. Toxicity and objective response rate (ORR) to ICT and RT-C were collected. Median overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan–Meier method. Cox regression analysis was performed to determine baseline predictors of OS and PFS.ResultsA total of 57 patients were included. Grade 3–4 toxicity rate to ICT was 54.4%, and there was a death deemed treatment-related (G5). P-C achieved an ORR of 66.7%, including 12.3% of complete responses (CR). After P-C, 45 patients (78.9%) continued with concomitant RT-C. Twenty-six patients (45.6%) achieved a CR after definitive treatment. With a median follow-up of 21.7 months (range 1.2–94.6), median OS and PFS were 22.9 months and 10.7 months, respectively. The estimated 2-year OS and PFS rates were 48.9% and 33.7%, respectively. Disease stage had a negative impact on OS (stage IVb vs. III–IVa: HR = 2.55 [1.08–6.04], p = 0.03), with a trend towards worse PFS (HR = 1.92 [0.91–4.05], p = 0.09). Primary tumor in the larynx was associated with improved PFS but not OS (HR = 0.45 [0.22–0.92], p = 0.03, and HR = 0.69 [0.32–1.54], p = 0.37, respectively).ConclusionP-C was a well-tolerated and active ICT regimen in this cohort of LA-HNSCC patients unfit for cisplatin-based chemotherapy. P-C might represent a valid ICT option for unfit patients and may aid patient selection for definitive treatment.

Quimioteràpia; Carcinoma de cèl·lules escamoses de cap i coll Quimioterapia; Carcinoma de células escamosas de cabeza y cuello Chemotherapy; Head and neck squamous cell carcinoma PURPOSE The phase III KEYNOTE-048 (ClinicalTrials.gov identifier: NCT02358031) trial of pembrolizumab in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) included planned efficacy analyses in the total population and in participants with programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 1 and CPS ≥ 20. To further characterize the predictive value of PD-L1 expression on outcome, we conducted efficacy analyses in the PD-L1 CPS < 1 and CPS 1-19 subgroups in KEYNOTE-048. METHODS Participants with R/M HNSCC and no prior systemic therapy for R/M disease were randomly assigned 1:1:1 to pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy. Post hoc efficacy analyses of the PD-L1 CPS < 1 and CPS 1-19 subgroups were performed. RESULTS Of 882 participants enrolled, 128 had PD-L1 CPS < 1 and 373 had CPS 1-19. For pembrolizumab versus cetuximab-chemotherapy, the median overall survival was 7.9 versus 11.3 months in the PD-L1 CPS < 1 subgroup (hazard ratio [HR], 1.51 [95% CI, 0.96 to 2.37]) and 10.8 versus 10.1 months in the CPS 1-19 subgroup (HR, 0.86 [95% CI, 0.66 to 1.12]). For pembrolizumab-chemotherapy versus cetuximab-chemotherapy, the median overall survival was 11.3 versus 10.7 months in the PD-L1 CPS < 1 subgroup (HR, 1.21 [95% CI, 0.76 to 1.94]) and 12.7 versus 9.9 months in the CPS 1-19 subgroup (HR, 0.71 [95% CI, 0.54 to 0.94]). CONCLUSION Increased efficacy of pembrolizumab or pembrolizumab-chemotherapy was observed with increasing PD-L1 expression. PD-L1 CPS < 1 subgroup analysis was limited by small participant numbers. Results from the PD-L1 CPS 1-19 subgroup support previous findings of treatment benefit with pembrolizumab monotherapy and pembrolizumab-chemotherapy in patients with PD-L1 CPS ≥ 1 tumors. Although PD-L1 expression is informative, exploration of additional predictive biomarkers is needed for low PD-L1–expressing HNSCC. Funding for this research was provided by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co Inc, Kenilworth, NJ.

Head and Neck Squamous Cell Carcinoma (HNSCC) remains among the most aggressive human cancers. Tumor progression and aggressiveness in SCC are largely driven by Tumor Propagating Cells (TPCs). Aerobic glycolysis, also known as the Warburg Effect, represents a characteristic of many cancers, yet whether this adaptation is functionally important in SCC, and at which stage, remains poorly understood. Here, we show that the NAD+-dependent histone deacetylase Sirtuin 6 (SIRT6) is a robust tumor suppressor in SCC, acting as a modulator of glycolysis in these tumors. Remarkably, rather than a late adaptation, we find enhanced glycolysis specifically in TPCs. More importantly, using single cell RNA sequencing of TPCs, we identify a subset of TPCs with higher glycolysis and enhanced pentose phosphate pathway and glutathione metabolism, characteristics that are strongly associated with a better antioxidant response. Altogether, our studies uncover enhanced glycolysis as a main driver in SCC, and, more importantly, identify a subset of TPCs as the cell-of-origin for the Warburg effect, defining metabolism as a key feature of intra-tumor heterogeneity.

Mechanisms related to the potential beneficial effects of statins on cancer are mainly related to the inhibition of the mevalonate pathway. The purpose of this study was to assess the association between prior use of statins and the risk of head and neck cancer. A hospital-based case–control study was conducted at the Dentistry Hospital of the University of Barcelona, including 101 incident cases of head and neck cancer and 101 controls matched to cases by age and sex. Multivariate logistic regression models were used to assess the association between prior statin exposure and head and neck cancer risk. Of the 202 patients included in total, 28.2% had previously received prescriptions for statins. Prior use of statins was found in 25.7% of cases and 30.7% of controls. Exposure to statins was not associated with head and neck cancer risk (OR = 0.72; 95% CI 0.28–1.84; p = 0.49). There was also no time- or dose-dependent association. Similar trends were observed when analyzed by subsites of cancer and recurrence rate. Our findings do not support a beneficial effect of prior statin exposure on head and neck cancer risk. Future research relying on observational data should emulate randomized clinical trials before clinical implications for repurposing drugs can be drawn.

Immunotherapy; Pembrolizumab; Quality of life Inmunoterapia; Pembrolizumab; Calidad de vida Immunoteràpia; Pembrolizumab; Qualitat de vida Objectives To assess health-related quality of life (HRQoL) with first-line pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) in the phase 3 KEYNOTE-048 trial (NCT02358031). Materials and Methods HRQoL was measured using the European Organisation for Research and Treatment of Cancer 30-question quality-of-life (EORTC QLQ-C30), the EORTC 35-question quality-of-life head and neck cancer–specific module (EORTC QLQ-H&N35), and the EuroQol 5-dimension 3-level instruments (EQ-5D-3L). Secondary endpoints included mean change from baseline in EORTC QLQ-C30 global health status/quality of life (GHS/QoL) at week 15 and time to deterioration (TTD) in EORTC QLQ-C30 GHS/QoL and EORTC QLQ-H&N35 pain and swallowing. Results Of 882 enrolled participants, 844 received ≥ 1 dose of study treatment and completed ≥ 1 HRQoL assessment; adherence was ≥ 79% at week 15 across treatment groups. At week 15, EORTC QLQ-C30 GHS/QoL scores remained stable; no clinically meaningful between-group differences were observed (least squares mean difference, pembrolizumab vs cetuximab-chemotherapy, 0.24; 95% CI, −3.34 to 3.82; pembrolizumab-chemotherapy vs cetuximab-chemotherapy, 0.40; 95% CI, −3.46 to 4.26). Median TTD in EORTC QLQ-C30 GHS/QoL and EORTC QLQ-H&N35 pain and swallowing scores was not reached over 51 weeks across groups, showing stable HRQoL. TTD was similar between groups for EORTC QLQ-C30 GHS/QoL (pembrolizumab vs cetuximab-chemotherapy: HR, 1.38; 95% CI, 0.95–2.00; pembrolizumab-chemotherapy vs cetuximab-chemotherapy: HR, 1.37; 95% CI, 0.94–2.00), as was TTD in EORTC QLQ-H&N35 pain and swallowing scores. Conclusions Pembrolizumab monotherapy and pembrolizumab-chemotherapy extended OS while maintaining HRQoL, further supporting first-line use for R/M HNSCC. Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

© The Author(s) 2020., Regenerative proliferation capacity and poor differentiation are histological features usually linked to poor prognosis in head and neck squamous cell carcinoma (hnSCC). However, the pathways that regulate them remain ill-characterized. Here, we show that those traits can be triggered by the RHO GTPase activator VAV2 in keratinocytes present in the skin and oral mucosa. VAV2 is also required to maintain those traits in hnSCC patient-derived cells. This function, which is both catalysis- and RHO GTPase-dependent, is mediated by c-Myc- and YAP/TAZ-dependent transcriptomal programs associated with regenerative proliferation and cell undifferentiation, respectively. High levels of VAV2 transcripts and VAV2-regulated gene signatures are both associated with poor hnSCC patient prognosis. These results unveil a druggable pathway linked to the malignancy of specific SCC subtypes., We thank M. Blázquez and CIC facilities’ personnel for lab work and core unit technical assistance, respectively. X.R.B. is supported by grants from Worldwide Cancer Research (14-1248), the Castilla-León Government (CSI049U16, CLC-2017-01), the Spanish Ministry of Science and Innovation (MSI) (SAF2015-64556-R, RTI2018-096481-B-I00), the Ramón Areces Foundation, and the Spanish Association against Cancer (GC16173472GARC). X.R.B.’s institution is supported by the Programa de Apoyo a Planes Estratégicos de Investigación de Estructuras de Investigación de Excelencia of the Ministry of Education of the Castilla-León Government (CLC-2017-01). J.M.P. is supported by MSI grants (SAF2015-66015-R, PIE15/00076). S.A.B. was supported by the European Research Council, the Spanish MSIU, and the IRB-Barcelona. S.R.-F. and L.F. L.-M. contracts have been supported by funding from the MSI (BES-2013-063573) and the Spanish Ministry of Education, Culture, and Sports (L.F.L.-M., FPU13/02923), respectively. Both Spanish and Castilla-León government-associated funding is partially supported by the European Regional Development Fund.

Background: Identification of screening tests for the detection of head and neck cancer (HNC) at an early stage is an important strategy to improving prognosis. Our objective was to identify plasma circulating miRNAs for the diagnosis of HNC (oral and laryngeal subsites), within a multicenter International Head and Neck Cancer Epidemiology consortium. Methods: A high-throughput screening phase with 754 miRNAs was performed in plasma samples of 88 cases and 88 controls, followed by a validation phase of the differentially expressed miRNAs, identified in the screening, in samples of 396 cases and 396 controls. Comparison of the fold changes (FC) was carried out using the Wilcoxon rank-sum test and the Dunn multiple comparison test. Results: We identified miR-151-3p (FC = 1.73, P = 0.007) as differentially expressed miRNAs in the screening and validation phase. The miR-151-3p was the only overexpressed miRNA in validation sample of patients with HNC with early stage at diagnosis (FC = 1.81, P = 0.008) and it was confirmed upregulated both in smoker early-stage cases (FC = 3.52, P = 0.024) and in nonsmoker early-stage cases (FC = 1.60, P = 0.025) compared with controls. Conclusions: We identified miR-151-3p as an early marker of HNC. This miRNA was the only upregulated in patients at early stages of the disease, independently of the smoking status. Impact: The prognosis for HNC is still poor. The discovery of a new diagnostic biomarker could lead to an earlier tumor discovery and therefore to an improvement in patient prognosis.

Head and neck cancer; Outcome measurement; Patient-centered care Cáncer de cabeza y cuello; Medición de resultados; Atención centrada en el paciente Càncer de cap i coll; Mesura del resultat; Atenció centrada en el pacient Purpose: A systematic, standardized collection of health outcomes during patient treatment and follow-up, relevant from the perspective of all stakeholders, is a crucial step toward effective and efficient disease management. This project aimed to define a standard set of health outcomes for patients with squamous cell carcinoma of the head and neck (SCCHN). Methods: The project was led and coordinated by a scientific committee (SC). It comprised: (1) a literature review (to identify variables used during SCCHN management); (2) 1st-SC meeting (to select the variables for presentation during nominal groups-NG); (3) five NG (n=42 experts) and four interviews with patients (to reach consensus on the variables for inclusion); and (4) final-SC meeting (to review the results of NG ensuring consensus on the variables where consensus was not reached). Results: Experts agreed to include the following variables in the standard set: treatment-related (treatment intent and type, response to treatment, treatment toxicity/complication, treatment completion), degree of health (performance status, patient-reported health status, pain, dysphonia, feeding and speech limitations, body image alteration, tracheotomy), survival (overall and progression-free survival, cause of death), nutritional (weight, nutritional intervention), other variables (smoking status, alcohol consumption, patient satisfaction with aftermath care, employment status), and case-mix variables (demographic, tumor-related, clinical and nutritional factors). Conclusions: This project may pave the way to standardizing the collection of health outcomes in SCCHN and promote the incorporation of patients’ perspective in its management. The information provided through the systematic compilation of this standard set may define strategies to achieve high-quality, patient-centered care. The project was sponsored by Bristol Myers Squibb.

[eng] The use of imaging techniques routinely used for diagnosis and the assessment for treatment response in oncology allow us to analyze the changes in body composition that occur during treatment and how these changes impact on oncologic outcomes such as survival or toxicity. In addition, we can observe the efficacy of nutritional support through these images. My main objective for this thesis was to evaluate the nutritional and body composition changes affecting patients with head and neck squamous cell carcinoma (HNSCC) during cancer treatment. Initially we designed a prospective study to analyze the body composition and nutritional changes that occur during conservative treatment in patients with locally advanced HNSCC at different time points. All patients were closely monitored throughout the treatment implementing nutritional support according to clinical practice guidelines. We observed that 30% of patients were malnourished at diagnosis. However, after the induction chemotherapy, there was an increase in weight and muscle mass with a significant improvement in nutrition impact symptoms such as dysphagia and odynophagia. Nevertheless, a significant nutritional deterioration occurred by the end of concomitant treatment with bio-radiotherapy or chemo- radiotherapy with 95% of patients becoming severely/moderately malnourished. Our findings suggest that induction chemotherapy may help improve nutritional status by ameliorating nutrition impact symptoms. This improvement could contribute to minimize the significant deterioration that occurs despite an intensive nutritional support along the oncological treatment. An additional aimed was to describe the changes in muscle and fat mass during the chemo- radiation in locally advanced HNSCC patients and evaluate the clinical predictors implicated in this loss. A longitudinal retrospective study was carried out focusing in the analysis of CT images pre-treatment and at the evaluation of tumor response at 3 months after finishing radiotherapy, to quantify muscle and adipose tissue. Nutritional support was provided according to ESPEN guidelines and adjusted body weight (ABW) was used in overweight/obese patients to define their nutritional targets. Patients lost a significant amount of weight, muscle and fat mass during the concomitant treatment. Patients with higher body mass index tended to lose more fat mass but also more muscle. In multivariate regression, only ABW independently predicted muscle and fat loss suggesting that the use of ABW to set nutrition targets in overweight/obese patients may be insufficient. It should be highlighted the urgent need for the development of nutritional guidelines to treat obese cancer patients in order to improve oncological outcomes. We used the repeated images at baseline and after treatment in same cohort of patients to describe the changes in skeletal muscle and fat over time at different anatomical levels to determine whether those changes are systemic or localized. Precision testing was performed calculating the % coefficient of variation, the root-mean-square standard deviation and the corresponding 95% least significant change values for four anatomical levels: upper arm, thigh, chest and abdomen. The median time between scans was 224 (SD 31 days). The least significant change values for muscle varied from 0.7 to 2.4% depending on anatomic level; with the lowest precision error to detect change in the thigh. Muscle wasting appears to be systemic and while present in limbs and trunk is significant higher in the thigh that in the chest abdomen and upper arm. As reduced muscle mass has been associated with increased treatment complications worsening survival in several tumor types, we evaluated the impact of reduced skeletal muscle on prognosis and immune-related adverse events (IrAEs) in patients of recurrent/metastatic HNSCC treated with immune checkpoints inhibitors (ICI). Skeletal muscle was quantified using a CT scan at diagnosis. We observed that low skeletal muscle mass was an independent factor for overall survival in the univariate and multivariate analysis. There was no association between low skeletal muscle and IrAEs of any grade., [spa] El uso de técnicas de imagen utilizadas habitualmente para el diagnóstico y la valoración de respuesta al tratamiento oncológico permite analizar los cambios en la composición corporal (CoC) que se producen durante el tratamiento y cómo estos cambios repercuten en los resultados oncológicos, como la supervivencia o la toxicidad. Además, podemos observar la eficacia del soporte nutricional a través de estas imágenes. El principal objetivo de esta tesis ha sido evaluar los cambios nutricionales y de CoC que afectan a los pacientes con carcinoma escamoso de cabeza y cuello (CECC) durante el tratamiento oncológico. Inicialmente diseñamos un estudio prospectivo para analizar la CoC y los cambios nutricionales que se producen durante el tratamiento conservador en pacientes con CECC localmente avanzado. Todos los pacientes tuvieron seguimiento nutricional implementando el soporte nutricional de acuerdo con las guías de práctica clínica. Hemos observado que el 30% de los pacientes estaban desnutridos en el momento del diagnóstico. Sin embargo, tras la quimioterapia de inducción, aumentó el peso y la masa muscular con una mejora significativa de los síntomas de que limitaban la ingesta (disfagia y odinofagia). No obstante, se produjo un deterioro nutricional significativo al final del tratamiento concomitante (bio-radioterapia o quimio- radioterapia), con un 95% de desnutrición grave/moderada. Nuestros hallazgos sugieren que la quimioterapia de inducción puede ayudar a mejorar el estado nutricional mejorando aquellos síntomas que limitan la ingesta. Esta mejora podría contribuir a minimizar el importante deterioro que se produce a pesar del soporte nutricional intensivo a lo largo del tratamiento oncológico. Un objetivo adicional ha sido describir los cambios en la masa muscular y la grasa durante la quimio-radioterapia concomitante en pacientes con CECC localmente avanzado y evaluar los predictores clínicos implicados en esta pérdida. Se realizó un estudio longitudinal retrospectivo centrado en el análisis de las imágenes de TC previas al tratamiento y en la valoración de respuesta a los 3 meses tras finalizar el tratamiento, para cuantificar músculo y grasa. Se proporcionó soporte nutricional según las guías ESPEN utilizando el peso ajustado (PA) en los pacientes con sobrepeso/obesidad para definir sus objetivos nutricionales. Los pacientes perdieron una cantidad significativa de peso, masa muscular y grasa durante el tratamiento concomitante. Aquellos pacientes con un mayor índice de masa corporal (IMC) tendían a perder más grasa, pero también más músculo. En el análisis multivariado, sólo el IMC predijo de forma independiente la pérdida muscular y grasa, lo que sugiere que el uso del PA para establecer objetivos nutricionales en pacientes con sobrepeso/obesidad puede ser insuficiente. Cabe destacar la necesidad urgente de desarrollar guías nutricionales para el tratamiento nutricional de pacientes obesos con cáncer con el fin de mejorar los resultados oncológicos. Además, hemos utilizado las imágenes del diagnóstico y tras el tratamiento concomitante de esta misma cohorte de pacientes para describir los cambios de CoC a lo largo del tiempo en diferentes niveles anatómicos para determinar si estos cambios son sistémicos o localizados. Se realizaron pruebas de precisión calculando el % de coeficiente de variación y los correspondientes valores del mínimo cambio significativo al 95% para cuatro niveles anatómicos: brazo, muslo, tórax y abdomen. La mediana del tiempo transcurrido entre las exploraciones fue de 224 (DE 31 días). Los valores del mínimo cambio significativo para el músculo variaron entre el 0,7 y el 2,4% según el nivel anatómico; el error de precisión más bajo para detectar el cambio se produjo en el muslo. El deterioro muscular parece ser sistémico y, aunque está presente en las extremidades y el tronco, es significativamente mayor en el muslo que en el tórax, el abdomen y el brazo. Por otro lado, se ha evaluado el impacto de la reducción del músculo esquelético en el pronóstico y los efectos adversos inmuno-relacionados (EAI) en pacientes con CECC recurrente/metastásico tratados con inmunoterapia. El músculo esquelético se cuantificó mediante TC al diagnóstico. Hemos observado que la baja masa muscular era un factor independiente de supervivencia global en el análisis univariante y multivariante. No hubo asociación entre la baja masa muscular y los EAI.

Treballs Finals de Grau de Nutrició Humana i Dietètica, Facultat de Farmàcia i Ciències de l'Alimentació, Campus de l'Alimentació de Torribera, Universitat de Barcelona. Curs: 2020-2021. Tutor: Mercedes Berlanga Herranz, [cat] En l’actualitat el càncer és una de les principals causes de mort arreu del món. Concretament, el càncer de cap i coll es troba com el desè càncer més freqüent a Espanya. L’estat del pacient i el tipus de tractament poden afectar principalment a la zona bucal, què complica l’alimentació per via oral i això causa deficiències nutricionals en els pacients. S’estima que un 10% dels pacients hospitalitzats rebran nutrició enteral, aquest tipus d’alimentació té conseqüències a llarg termini, entre elles, el canvi en la composició de la microbiota, i aquesta en la salut. L’objectiu d’aquesta revisió és detallar la intervenció nutricional en aquests pacients amb càncer de cap i coll, incloent-hi productes com probiòtics o prebiòtics, per a comprovar el seu efecte en l’àmbit clínic per tal de pal·liar els efectes de la nutrició enteral en la microbiota intestinal dels pacients. Una millor intervenció farà que l’estat del pacient millori i amb ell la resposta al tractament oncològic., [eng] Cancer is currently one of the leading causes of death worldwide, specifically, head and neck cancer is the tenth most common cancer in Spain. The state of the patient and the type of treatment can affect mainly the mouth, which complicates food orally and this causes nutritional deficiencies in patients. It is estimated that 10% of hospitalized patients will receive enteral nutrition, this type of diet has long term consequences, including a change in the composition of the microbiota and that of health. The aim of this review is to detail the nutritional intervention in these patients with head and neck cancer, including products such as probiotics or prebiotics, to check its effect in the clinical setting in order to mitigate the effects. of enteral nutrition in the intestinal microbiota of patients. A better intervention will progress the patient's and an improved response to cancer treatment.

BackgroundReduced muscle mass has been associated with increased treatment complications in several tumor types. We evaluated the impact of skeletal muscle index (SMI) on prognosis and immune-related adverse events (IrAEs) in a cohort of recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) treated with immune checkpoints inhibitors (ICI).MethodsA single-institutional, retrospective study was performed including 61 consecutive patients of R/M HNSCC diagnosed between July 2015 and December 2018. SMI was quantified using a CT scan at L3 to evaluate body composition. Median baseline SMI was used to dichotomize patients in low and high SMI. Kaplan-Meier estimations were used to detect overall survival (OS) and progression-free survival (PFS). Toxicity was recorded using Common Terminology Criteria for Adverse Event v4.3.ResultsPatients were 52 men (85.2%) with mean of age 57.7 years (SD 9.62), mainly oral cavity (n = 21; 34.4%). Low SMI was an independent factor for OS in the univariate (HR, 2.06; 95% CI, 1.14–3.73, p = 0.017) and multivariate Cox analyses (HR, 2.99; 95% CI, 1.29–6.94; p = 0.011). PFS was also reduced in patients with low SMI (PFS HR, 1.84; 95% CI, 1.08–3.12; p = 0.025). IrAEs occurred in 29 (47.5%) patients. There was no association between low SMI and IrAEs at any grade (OR, 0.56; 95% CI, 0.20–1.54; p = 0.261). However, grades 3 to 4 IrAEs were developed in seven patients of whom three had low SMI.ConclusionsLow SMI before ICI treatment in R/M HNSCC patients had a negative impact on OS and PFS. Further prospective research is needed to confirm the role of body composition as a predictive biomarker in ICI treatment.

Simple Summary The utility of a diagnostic algorithm for the detection of HPV-driven oral cavity (OCC), oropharyngeal (OPC), and laryngeal (LC) carcinomas using HPV-DNA testing followed by p16(INK4a) immunohistochemistry, taking E6*I mRNA detection as the reference standard, was assessed in HPV-DNA-positive formalin-fixed paraffin-embedded samples from 29 countries. The concordance of p16(INK4a) and E6*I mRNA among 78, 257, and 51 HPV-DNA-positive OCC, OPC, and LC, respectively, was moderate to substantial in OCC and OPC but only fair in LC. A different p16(INK4a) expression pattern was observed in those cases HPV-DNA-positive for types other than HPV16, as compared to HPV16-positive cases. We concluded that the diagnostic algorithm of HPV-DNA testing followed by p16(INK4a) immunohistochemistry might be helpful in the diagnosis of HPV-driven OCC and OPC, but not LC. Our study provides new insights into the use HPV-DNA, p16(INK4a), and HPV-E6*I mRNA for diagnosing an HPV-driven head and neck carcinoma. Background: Tests or test algorithms for diagnosing HPV-driven oral cavity and laryngeal head and neck carcinomas (HNC) have not been yet validated, and the differences among oral cavity and laryngeal sites have not been comprehensively evaluated. We aimed to assess the utility of a diagnostic algorithm for the detection of HPV-driven oral cavity (OCC), oropharyngeal (OPC) and laryngeal (LC) carcinomas using HPV-DNA testing followed by p16(INK4a) immunohistochemistry, taking E6*I mRNA detection as the reference standard. Methods: Formalin-fixed paraffin-embedded OCC, OPC, and LC carcinomas were collected from pathology archives in 29 countries. All samples were subjected to histopathological evaluation, DNA quality control, and HPV-DNA detection. All HPV-DNA-positive samples (including 78 OCC, 257 OPC, and 51 LC out of 3680 HNC with valid HPV-DNA results) were also tested for p16(INK4a) immunohistochemistry and E6*I mRNA. Three different cutoffs of nuclear and cytoplasmic staining were evaluated for p16(INK4a): (a) >25%, (b) >50%, and (c) >= 70%. The concordance of p16(INK4a) and E6*I mRNA among HPV-DNA-positive OCC, OPC, and LC cases was assessed. Results: A total of 78 OCC, 257 OPC, and 51 LC were HPV-DNA-positive and further tested for p16(INK4a) and E6*I mRNA. The percentage of concordance between p16(INK4a) (cutoff >= 70%) and E6*I mRNA among HPV-DNA-positive OCC, OPC, and LC cases was 79.5% (95% CI 69.9-89.1%), 82.1% (95% CI 77.2-87.0%), and 56.9% (95% CI 42.3-71.4%), respectively. A p16(INK4a) cutoff of >50% improved the concordance although the improvement was not statistically significant. For most anatomical locations and p16(INK4a) cutoffs, the percentage of discordant cases was higher for HPV16- than HPV-non16-positive cases. Conclusions: The diagnostic algorithm of HPV-DNA testing followed by p16(INK4a) immunohistochemistry might be helpful in the diagnosis of HPV-driven OCC and OPC, but not LC. A different p16(INK4a) expression pattern was observed in those cases HPV-DNA-positive for types other than HPV16, as compared to HPV16-positive cases. Our study provides new insights into the use HPV-DNA, p16(INK4a), and HPV-E6*I mRNA for diagnosing an HPV-driven HNC, including the optimal HPV test or p16(INK4a) cutoffs to be used. More studies are warranted to clarify the role of p16(INK4a) and HPV status in both OPC and non-OPC HNC.

New key estimates of oral human papillomavirus (HPV) infection and insights on the relationship between oral infection and HPV-associated oropharyngeal cancer are presented. Observed differences in HPV-attributable fractions in oropharyngeal cancer cannot be explained by difference in the prevalence of oral HPV infection across healthy populations., Background Differences in oral human papillomavirus (HPV) prevalence and contrasts in HPV-attributable fractions (AFs) in oropharyngeal cancer (OPC) have not been evaluated in depth. Methods A systematic review was performed to identify studies in which at least 50 healthy individuals were tested for oral HPV infection. Information on sex, age, tobacco/alcohol consumption, sex practices, specimen collection, HPV detection, and population type was extracted. Prevalences were pooled using random-effects models for meta-analyses of binomial data. Correlations were assessed by the Spearman test. Results Forty-eight reports comprising 28 544 individuals fulfilled inclusion criteria. Global oral HPV prevalence was 4.9%. Estimates were highest in Europe, although regional differences were not statistically significant. HPV16 prevalence was 1.0% globally, and regional differences became statistically significant. A lifetime history of >6 sex partners showed a higher risk of oral HPV infection. The age-specific HPV distribution revealed a prevalence of ≥5% over 40 years of age and a lower prevalence at younger ages. There was no association between oral HPV prevalence and HPV-AFs or age-standardized rates (ASRs) of OPC, genital HPV in healthy women, or tobacco use. Conclusions Differences in HPV-AFs or ASRs of OPC cannot be explained by differences in the prevalence of oral HPV infection across healthy populations. Consistent research on determinants of oral HPV prevalence, acquisition, clearance, and persistence is warranted.

Simple Summary Stage of the disease at diagnosis has been recognized as one of the most important prognostic markers for oral cancer. Unfortunately, still two thirds of patients are diagnosed at an advanced stage of disease with a 5-year survival rate of 50% or less. Although the detection of oral cancer at an early stage is the most effective means to improve survival and reduce morbidity, in the past years, there has been little change in the diagnosis of oral cancer at early stages, which is believed to be a result of delays in diagnosis and treatment of oral cancer, among other independent factors. Following the Aarhus statement, developed in effort to standardize the design, methods and reporting of studies concerning time-intervals in early diagnosis research, the review assessed the causes that influence the patient, diagnosis and pre-treatment intervals in the pathway of time-to-treatment in oral cancer and its impact on survival. Abstract The purpose of this review was to identify and describe the causes that influence the time-intervals in the pathway of diagnosis and treatment of oral cancer and to assess its impact on prognosis and survival. The review was structured according to the recommendations of the Aarhus statement, considering original data from individual studies and systematic reviews that reported outcomes related to the patient, diagnostic and pre-treatment intervals. The patient interval is the major contributor to the total time-interval. Unawareness of signs and/or symptoms, denial and lack of knowledge about oral cancer are the major contributors to the process of seeking medical attention. The diagnostic interval is influenced by tumor factors, delays in referral due to higher number of consultations and previous treatment with different medicines or dental procedures and by professional factors such as experience and lack of knowledge related to the disease and diagnostic procedures. Patients with advanced stage disease, primary treatment with radiotherapy, treatment at an academic facility and transitions in care are associated with prolonged pre-treatment intervals. An emerging body of evidence supports the impact of prolonged pre-treatment and treatment intervals with poorer survival from oral cancer.

Head and neck cancers (HNC) are defined as malignant tumours located in the upper aerodigestive tract and represents 5% of oncologic cases in adults in Spain. More than 90% of these tumours have squamous histology. In an effort to incorporate evidence obtained since 2017 publication, the Spanish Society of Medical Oncology (SEOM) presents an update of the squamous cell HNC diagnosis and treatment guideline. Most relevant diagnostic and therapeutic changes from the last guideline have been updated: introduction of sentinel node biopsy in early oral/oropharyngeal cancer treated with surgery, concomitant radiotherapy with weekly cisplatin 40 mg/m2 in the adjuvant setting, new approaches for HPV-related oropharyngeal cancer and new treatments with immune-checkpoint inhibitors in recurrent/metastatic disease. Supplementary Information The online version contains supplementary material available at 10.1007/s12094-020-02533-1.

Simple Summary Emerging evidence points to succinate as an important oncometabolite in cancer development; however, the contribution of the succinate-SUCNR1 axis to cancer progression remains unclear. Head and neck squamous cell carcinoma (HNSCC) is associated with disease and treatment-related morbidity so there is an urgent need for innovation in treatment and diagnosis practices. Our aim was to evaluate the potential of the succinate-related pathway as a diagnostic and prognostic biomarker in HNSCC. The circulating succinate levels are increased in HNSCC, being a potential noninvasive biomarker for HNSCC diagnosis. Moreover, the succinate receptor (SUCNR1) and genes related to succinate metabolism, which are predominantly expressed in the tumoral mucosa as compared with healthy tissue, are positively associated with plasma succinate. Remarkably, we found that SUCNR1 and SDHA expression levels predict prognosis. Head and neck squamous cell carcinoma (HNSCC) is characterized by high rates of mortality and treatment-related morbidity, underscoring the urgent need for innovative and safe treatment strategies and diagnosis practices. Mitochondrial dysfunction is a hallmark of cancer and can lead to the accumulation of tricarboxylic acid cycle intermediates, such as succinate, which function as oncometabolites. In addition to its role in cancer development through epigenetic events, succinate is an extracellular signal transducer that modulates immune response, angiogenesis and cell invasion by activating its cognate receptor SUCNR1. Here, we explored the potential value of the circulating succinate and related genes in HNSCC diagnosis and prognosis. We determined the succinate levels in the serum of 66 pathologically confirmed, untreated patients with HNSCC and 20 healthy controls. We also surveyed the expression of the genes related to succinate metabolism and signaling in tumoral and nontumoral adjacent tissue and in normal mucosa from 50 patients. Finally, we performed immunohistochemical analysis of SUCNR1 in mucosal samples. The results showed that the circulating levels of succinate were higher in patients with HNSCC than in the healthy controls. Additionally, the expression of SUCNR1, HIF-1 alpha, succinate dehydrogenase (SDH) A, and SDHB was higher in the tumor tissue than in the matched normal mucosa. Consistent with this, immunohistochemical analysis revealed an increase in SUCNR1 protein expression in tumoral and nontumoral adjacent tissue. High SUCNR1 and SDHA expression levels were associated with poor locoregional control, and the locoregional recurrence-free survival rate was significantly lower in patients with high SUCNR1 and SDHA expression than in their peers with lower levels (77.1% [95% CI: 48.9-100.0] vs. 16.7% [95% CI: 0.0-44.4], p = 0.018). Thus, the circulating succinate levels are elevated in HNSCC and high SUCNR1/SDHA expression predicts poor locoregional disease-free survival, identifying this oncometabolite as a potentially valuable noninvasive biomarker for HNSCC diagnosis and prognosis.

Matemàtiques i informàtica; Neurologia; Oncologia Matemáticas e informática; Neurología; Oncología Mathematics and computing; Neurology; Oncology Glioblastoma is the most common primary brain tumor. Standard therapy consists of maximum safe resection combined with adjuvant radiochemotherapy followed by chemotherapy with temozolomide, however prognosis is extremely poor. Assessment of the residual tumor after surgery and patient stratification into prognostic groups (i.e., by tumor volume) is currently hindered by the subjective evaluation of residual enhancement in medical images (magnetic resonance imaging [MRI]). Furthermore, objective evidence defining the optimal time to acquire the images is lacking. We analyzed 144 patients with glioblastoma, objectively quantified the enhancing residual tumor through computational image analysis and assessed the correlation with survival. Pathological enhancement thickness on post-surgical MRI correlated with survival (hazard ratio: 1.98, p

Background TORS has become one of the latest surgical alternatives in the treatment of oropharynx squamous cell carcinomas (OPSCC) and has become increasingly accepted by surgeons as a treatment option. Surgical robots were designed for various purposes, such as allowing remote telesurgery, and eliminating human factors like trembling. The study aimed to compare systematic review of the available literature in order to evaluate the safety and efficacy of Transoral Robotic Surgery (TORS) compared with open surgery. Material and Methods We performed a systematic review of the available literature in order to evaluate the safety and effectiveness of TORS compared with open surgery. We compared TORS and open surgery based on 16 outcomes divided in to 3 groups: intra-operative complications, post-operative complications, and functional and oncologic outcomes. An electronic search of observational studies was carried out using the following databases: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Oral Health Group Trials Register, and Scielo. Data analysis was carried out in accordance to Preferred Reporting Items for Systematic Reviews and Metanalysis (PRISMA) and the quality of the studies were evaluated using the Newcastle-Ottawa Scale. No language restrictions were imposed. Results From the 4 studies identified (Newcastle-Ottawa Scale mean score 6.5), 371 patients were revised (186 patients were treated with TORS and 185 with conventional surgery). Overall, TORS, when compared with open surgery, appears to have better functional results (less hospital time, decannulation) and fewer intraoperative and post-operative complications. There is no significant difference when assessing the oncological outcomes (positive margins, survival rate) when comparing both techniques. Conclusions TORS has an overall better functional outcome, and less intraoperative and postoperative complications with no difference in positive margins and survival rate when compared with conventional therapy. Key words:Transoral Robotic Surgery, TORS, open surgery, conventional surgery, head and neck cancer, oral cancer.

BackgroundThe association between socioeconomic disadvantage (low education and/or income) and head and neck cancer is well established, with smoking and alcohol consumption explaining up to three-quarters of the risk. We aimed to investigate the nature of and explanations for head and neck cancer risk associated with occupational socioeconomic prestige (a perceptual measure of psychosocial status), occupational socioeconomic position and manual-work experience, and to assess the potential explanatory role of occupational exposures.MethodsPooled analysis included 5818 patients with head and neck cancer (and 7326 control participants) from five studies in Europe and South America. Lifetime job histories were coded to: (1) occupational social prestige—Treiman’s Standard International Occupational Prestige Scale (SIOPS); (2) occupational socioeconomic position—International Socio-Economic Index (ISEI); and (3) manual/non-manual jobs.ResultsFor the longest held job, adjusting for smoking, alcohol and nature of occupation, increased head and neck cancer risk estimates were observed for low SIOPS OR=1.88 (95% CI: 1.64 to 2.17), low ISEI OR=1.74 (95% CI: 1.51 to 1.99) and manual occupations OR=1.49 (95% CI: 1.35 to 1.64). Following mutual adjustment by socioeconomic exposures, risk associated with low SIOPS remained OR=1.59 (95% CI: 1.30 to 1.94).ConclusionsThese findings indicate that low occupational socioeconomic prestige, position and manual work are associated with head and neck cancer, and such risks are only partly explained by smoking, alcohol and occupational exposures. Perceptual occupational psychosocial status (SIOPS) appears to be the strongest socioeconomic factor, relative to socioeconomic position and manual/non-manual work.

The core function of a multidisciplinary team (MDT) is to bring together a group of healthcare professionals from different fields in order to determine patients' treatment plan. Most of head and neck cancer (HNC) units are currently led by MDTs that at least include ENT and maxillofacial surgeons, radiation and medical oncologists. HNC often compromise relevant structures of the upper aerodigestive tract involving functions such as speech, swallowing and breathing, among others. The impairment of these functions can significantly impact patients' quality of life and psychosocial status, and highlights the crucial role of specialized nurses, dietitians, psycho-oncologists, social workers, and onco-geriatricians, among others. Hence, these professionals should be integrated in HNC MDTs. In addition, involving translational research teams should also be considered, as it will help reducing the existing gap between basic research and the daily clinical practice. The aim of this comprehensive review is to assess the role of the different supportive disciplines integrated in an MDT and how they help providing a better care to HNC patients during diagnosis, treatment and follow up.

234 diagnostic formalin-fixed paraffin-embedded (FFPE) blocks from homogeneously treated patients with locally advanced head and neck squamous cell carcinoma (HNSCC) within a multicentre phase III clinical trial were characterised. The mutational spectrum was examined by next generation sequencing in the 26 most frequent oncogenic drivers in cancer and correlated with treatment response and survival. Human papillomavirus (HPV) status was measured by p16INK4a immunohistochemistry in oropharyngeal tumours. Clinicopathological features and response to treatment were measured and compared with the sequencing results. The results indicated TP53 as the most mutated gene in locally advanced HNSCC. HPV-positive oropharyngeal tumours were less mutated than HPV-negative tumours in TP53 (p, This research was funded by the health research program of the “Instituto de Salud Carlos III” (PI14/00071) co financed with FEDER founds and for the Health Regional Management of the Junta de Castilla y León (GRS1385/A/16). J. Fernández-Mateos was partially supported by a predoctoral research grant from the Consejería de Educación—Junta de Castilla y León and the European Social Fund to CC-B (EDU/1084/2012).

Head and neck squamous cell carcinoma (HNSCC) is among the 10 most common cancers worldwide, with increasing incidence.1 Approximately 10% of patients with HNSCC will be diagnosed with metastatic disease, and even when treated early, around half will have disease recurrence.2,3 The platinum-based doublet chemotherapy with cetuximab regimen has been the most widely-used therapy and considered standard of care (SoC) since it was proven effective in 2007 for recurrent/metastatic (R/M) HNSCC in the first-line setting.3,4 However, patients typically progress even after aggressive first-line therapy, and, until recently, the available options (e.g. cetuximab, methotrexate, and taxanes) have delivered limited survival benefits.3 Durvalumab is an immunotherapeutic agent that blocks the interaction between programmed cell death ligand 1 (PD-L1) and its receptors.5 Durvalumab demonstrated encouraging response rates and duration of response (DoR) with a manageable safety profile in patients with HNSCC.6 Although monotherapy agents that block the programmed cell death protein 1 (PD-1)/PD-L1 axis have shown clinical activity, immunotherapy combinations have the potential to improve upon monotherapy activity.7e9 Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and PD-L1/PD-1 pathways have largely non-redundant roles, suggesting that blockade of both could have additive or synergistic effects.10 Indeed, the combination of durvalumab and tremelimumab, an anti-CTLA-4 monoclonal antibody, was explored based on improved efficacy over monotherapy in other solid tumor types.7 This observation, in addition to the activity demonstrated by durvalumab in earlier R/M HNSCC studies, served as the rationale to evaluate durvalumab and tremelimumab in patients with R/M HNSCC. Several studies, including the EAGLE study, were initiated to evaluate combination immunotherapy regimens in various patient groups.11,12 The EAGLE study was the first phase III study to investigate durvalumab and tremelimumab in patients with R/M HNSCC who had progressed after platinumbased therapy. During the conduct of the EAGLE study, anti-PD-1 monoclonal antibodies were approved for use for R/M HNSCC progression following a platinum-based regimen. Treatment with these immunotherapies resulted in a median overall survival (OS) of 7.5e8.4 months.13,14 These immunotherapies are now recommended for second-line treatment as monotherapies for patients with R/M HNSCC.3,13,14 More recently, immunotherapy alone or in combination with platinum-based chemotherapy has shown improvements in OS in the first-line setting, underscoring the clinical utility of immunotherapy in HNSCC.15 Here, we report the results of the randomized phase III EAGLE trial evaluating durvalumab and durvalumab plus tremelimumab versus SoC therapies in patients with R/M HNSCC who have progressed following a platinumcontaining regimen.

Anti-programmed cell death protein 1 (PD-1) agents have become the standard of care for platinum-refractory recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) and are currently being evaluated in various disease settings. However, despite the gain in overall survival seen in some of the clinical trials, the majority of patients display primary resistance and do not benefit from these agents. Taking into consideration the potentially severe immune-related toxicities and their high cost, the search for predictive biomarkers of response is crucial. Besides Programmed death ligand-1 (PD-L1) expression, other biomarkers such as immune infiltration, tumor mutational burden or immune-gene expression profiling have been explored, but none of them has been validated in this disease. Among these, the microbiota has recently garnered tremendous interest since it has proven to influence the efficacy of PD-1 blockade in some tumor types. With the accumulating evidence on the effect of the microbiota in HNSCC tumorigenesis and progression, the study of its potential role as a predictive immune biomarker is warranted. This review examines the available evidence on emerging immune predictive biomarkers of response to anti-PD-1/PD-L1 therapy in HNSCC, introducing the microbiota and its potential use as a predictive immune biomarker in this disease.

© 2019 by the authors., Despite classical environmental risk factors like tobacco, alcohol or viral infection, not all individuals develop head and neck cancer. Therefore, identification of the genetic susceptibility produced by single nucleotide polymorphisms (SNPs) is an important task. A total of 296 human papillomavirus negative head and neck cancer (HNC) patients (126 laryngeal, 100 pharyngeal and 70 oral cavity) were included in the study, involving 29 candidate SNPs in genes within important carcinogenic pathways (oncogenesis and tumour suppression, DNA repair, inflammation, oxidation and apoptosis). Genotyping was performed using TaqMan probes or restriction fragment length assays in peripheral blood DNA. In addition, 259 paired controls were also evaluated with the same risk factors for each specific location. Nine SNPs in DNA repair (ERCC1 rs11615, ERCC2 rs13181), inflammatory (IL2 rs2069762, IL6 rs1800795), oxidative (NFE2L2 rs13035806 and rs2706110) and apoptotic genes (TP53 rs1042522, MDM2 rs2279744, BCL2 rs2279115) were differently associated with HNSCC susceptibility by location. Some of these SNPs were not described before in this tumour type. In conclusion, we describe several SNPs associated with HNC in a Spanish population, This study was supported by the health research program of the “Instituto de Salud Carlos III” (Spanish Ministry of Economy and Competitiveness, PI11/00519, PI13/01741 and PIE14/00066) cofunded with FEDER founds and by the Health Regional Management of the Junta de Castilla y León (GRS630/A11). J. Fernández-Mateos was partially supported by a predoctoral research grant from the Consejería de Educación—Junta de Castilla y León and the European Social Fund to CC-B (EDU/1084/2012).

Anticossos; Immunoteràpia; Càncer de cap i coll Anticuerpos; Inmunoterapia; Cáncer de cabeza y cuello Antibodies; Immunotherapy; Head and neck cancer Background Patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) progressing on platinum-based chemotherapy have poor prognoses and limited therapeutic options. Programmed cell death-1 (PD-1) and its ligand 1 (PD-L1) are frequently upregulated in HNSCC. The international, multi-institutional, single-arm, phase II HAWK study ( NCT02207530 ) evaluated durvalumab monotherapy, an anti-PD-L1 monoclonal antibody, in PD-L1-high patients with platinum-refractory R/M HNSCC. Patients and methods Immunotherapy-naïve patients with confirmed PD-L1-high tumour cell expression (defined as patients with ≥25% of tumour cells expressing PD-L1 [TC ≥ 25%] using the VENTANA PD-L1 [SP263] Assay) received durvalumab 10 mg/kg intravenously every 2 weeks for up to 12 months. The primary end-point was objective response rate; secondary end-points included progression-free survival (PFS) and overall survival (OS). Results Among evaluable patients (n = 111), objective response rate was 16.2% (95% confidence interval [CI], 9.9–24.4); 29.4% (95% CI, 15.1–47.5) for human papillomavirus (HPV)-positive patients and 10.9% (95% CI, 4.5–21.3) for HPV-negative patients. Median PFS and OS for treated patients (n = 112) was 2.1 months (95% CI, 1.9–3.7) and 7.1 months (95% CI, 4.9–9.9); PFS and OS at 12 months were 14.6% (95% CI, 8.5–22.1) and 33.6% (95% CI, 24.8–42.7). Treatment-related adverse events were 57.1% (any grade) and 8.0% (grade ≥3); none led to death. At data cut-off, 24.1% of patients remained on treatment or in follow-up. Conclusion Durvalumab demonstrated antitumour activity with acceptable safety in PD-L1-high patients with R/M HNSCC, supporting its ongoing evaluation in phase III trials in first- and second-line settings. In an ad hoc analysis, HPV-positive patients had a numerically higher response rate and survival than HPV-negative patients. This study was supported by AstraZeneca.

Cetuximab remains to date the only targeted therapy approved for the treatment of head and neck squamous cell carcinoma (HNSCC). The EGFR pathway plays a key role in the tumorigenesis and progression of this disease as well as in the resistance to radiotherapy (RT). While several anti-EGFR agents have been tested in HNSCC, cetuximab, an IgG1 subclass monoclonal antibody against EGFR, is the only drug with proven efficacy for the treatment of both locoregionally-advanced (LA) and recurrent/metastatic (R/M) disease. The addition of cetuximab to radiotherapy is a validated treatment option in LA-HNSCC. However, its use has been limited to patients who are considered unfit for standard of care chemoradiotherapy (CRT) with single agent cisplatin given the lack of direct comparison of these two regimens in randomized phase III trials and the inferiority suggested by metanalysis and phase II studies. The current use of cetuximab in HNSCC is about to change given the recent results from randomized prospective clinical trials in both the LA and R/M setting. Two phase III studies evaluating RT-cetuximab vs. CRT in Human Papillomavirus (HPV)-positive LA oropharyngeal squamous cell carcinoma (De-ESCALaTE and RTOG 1016) showed inferior overall survival and progression-free survival for RT-cetuximab combination, and therefore CRT with cisplatin remains the standard of care in this disease. In the R/M HNSCC, the EXTREME regimen has been the standard of care as first-line treatment for the past 10 years. However, the results from the KEYNOTE-048 study will likely position the anti-PD-1 agent pembrolizumab as the new first line treatment either alone or in combination with chemotherapy in this setting based on PD-L1 status. Interestingly, cetuximab-mediated immunogenicity through antibody dependent cell cytotoxicity (ADCC) has encouraged the evaluation of combined approaches with immune-checkpoint inhibitors in both LA and R/M-HNSCC settings. This article reviews the accumulated evidence on the role of cetuximab in HNSCC in the past decade, offering an overview of its current impact in the treatment of LA and R/M-HNSCC disease and its potential use in the era of immunotherapy.

Background: Monitoring and improving quality of cancer care has become pivotal today. This is especially relevant for head and neck cancers since the disease is complex, it needs multi therapy, patients tend to be older, they tend to have comorbidities and limited social support. However, information on quality of care for head and neck cancers is scarce. In the context of the project "Information Network on Rare Cancers" we aimed to identify indicators of quality of care specific for the head and neck cancers management and to measure the quality of care for head and neck cancers in different EU Member States. Methods: We defined indicators of quality of care for head and neck cancers based on a multidisciplinary and expert-based consensus process at a European level. To test the proposed indicators, we performed an observational population-based retrospective study in four countries (Ireland, Italy, Netherlands, and Slovenia) in the years 2009-2011. Results: The main quality indicators identified are: availability of formalized multidisciplinary team, participation in clinical and translational research; timeliness of care, high quality of surgery and radiotherapy, and of pathological reporting. For head and neck cancers, the quality of care did not reach the optimal standards in most of the countries analyzed. A high proportion of patients was diagnosed at an advanced disease stage, showed delays in starting treatment (especially for radiotherapy), and there was only a very limited use of multi therapy. Conclusions: According to the achieved consensus, indicators of quality of care for head and neck cancers have to cover the patient journey (i.e., diagnosis and treatment). Our results, showed suboptimal quality of care across countries and call for solutions for ensuring good quality of care for head and neck cancer patients in all EU countries. One possible option might be to refer head and neck cancer patients to specialized centers or to networks including specialized centers.

[cat] El carcinoma escatós de cap i coll (CECC) és el tipus histològic més comú en les neoplàsies de cap i coll. El 60% dels pacients amb CECC es diagnostiquen en un estadi avançat, fet que empitjora el pronòstic. La taxa de supervivència en tumors en estadi avançat es manté al voltant del 50%. Aquestes són xifres similars a les de fa 30 anys. A l’any 2000 Hanahan et al. van descriure les sis característiques o capacitats biològiques adquirides del càncer, una d’elles era la capacitat de Neoangiogènesi i en base a aquesta característica i a la necessitat de detecció precoç del càncer es va desenvolupar la Llum de Banda Estreta (LBE). La LBE és una tecnologia que fa servir filtres òptics en la llum blanca (LB) i selecciona només 415 nm (llum blava) i 540 nm (llum verda), les dues longituds d’ona que absorbeix l’hemoglobina. La hipòtesi principal és que la tècnica endoscòpica LBE és una tècnica fiable que millora la capacitat diagnòstica i de seguiment de lesions malignes i premalignes de cap i coll. Els objectius primaris són determinar el valor de la LBE en el diagnòstic i seguiment de lesions malignes i premalignes de cap i coll i avaluar la consistència de la tècnica LBE mitjançant l’estudi de la concordança inter i intraobservador en la valoració de lesions de cap i coll. Per tal d’assolir aquest objectiu es van realitzar tres estudis amb els següents materials i mètodes. En el primer estudi es van avaluar quatre-centes vuitanta lesions amb endoscòpia amb LB i LBE previ a realitzar biòpsia/exèresi de la lesió. Per altra banda es va realitzar seguiment de cent cinquanta-una lesions sense biòpsia. Es va calcular la supervivència lliure de malaltia i es va analitzar la corba d’aprenentatge. En el segon estudi es van avaluar cinc-centes trenta lesions de cap i coll amb LB seguit de LBE. Posteriorment es va realitzar una biòpsia i es van estudiar els falsos positius i falsos negatius de la tècnica. En el tercer estudi es van recollir vuitanta-set imatges de lesions de cap i coll amb LB i LBE. Un grup de 3 otorrinolaringòlegs experimentats i un de 3 estudiants de medicina van avaluar les imatges després d’una breu formació. No se’ls va proporcionar informació addicional dels pacients. A les tres setmanes es va repetir el mateix protocol. Es va calcular la concordança inter i intraobservador amb l’índex kappa. Els resultats derivats dels tres estudis són: la precisió diagnòstica global va millorar de 74.1% amb LB a 88.9% amb LBE. Aquesta millora era rellevant en totes les sublocalitzacions. La precisió del LBE augmentava de manera significativa amb l’experiència (àrea sota la corba de >0.9). Després d’un seguiment de 25 mesos, 14 de 151 lesions (9,3%) van progressar a carcinoma. La taxa de supervivència lliure de carcinoma eren significativament diferents entre les lesions considerades benignes/displàsia lleu versus aquelles que es presentaven com displàsia moderada/severa (88,9% vs 73.5%; P = 0,018). Els falsos negatius (7,36%) estaven representats per carcinomes escatosos submucosos i tumors no escatosos. Entre les 25 lesions no escatoses el 72% no mostrava cap patró vascular sospitós amb LBE. Els falsos positius (6,04%) eren sobretot canvis mucosos post RDT, úlceres i infeccions. Pel que fa als papil·lomes la precisió diagnòstica arribava als 95,32%, tot i que aquells casos amb displàsia eren difícils de distingir del CECC. La concordança intraobservador amb LBE era substancial (κ = 0,62), millor que amb LB sola que era moderada (κ =0,57) en ambdós grups. La concordança interobservador era moderada amb LB (κ = 0,58) i substancial amb LBE (κ = 0,63). Ambdós grups van millorar la concordança intraobservador i interobservador amb la implementació de la LBE. Les conclusions generals d’aquesta tesi doctoral són que la LBE va proporcionar una millor precisió que la LB i mostrava gran utilitat en el seguiment de lesions premalignes. Que la LBE associada a la LB millora la precisió diagnòstica però no totes les lesions es poden avaluar amb els patrons definits fins ara. Una anamnesi precisa és obligatòria, perquè, en alguns casos, pot ser més rellevant que el patró LBE. I, finalment, que la concordança intra i interobservador de la LBE per l’avaluació de lesions de cap i coll és substancial i millora els resultats de la LB aïllada tant en professionals com en estudiants., [eng] Narrow band imaging (NBI) in combination with white light endoscopy (WLE) is an endoscopic technique that identifies changes in the vascular patterns of the mucosa. The purpose of this study was to evaluate the value of narrow band imaging (NBI) examination in the office for the diagnosis and follow-up of upper airway premalignant and malignant lesions. Four hundred eighty lesions were evaluated with white light endoscopy (WLE) and NBI before a biopsy/excision. Additionally, 151 premalignant lesions were followed up without proven biopsy. Carcinoma-free survival was calculated. The learning curve was analyzed. Overall, the accuracy improved from 74.1% with WLE to 88.9% with NBI, being relevant in all anatomic subsites. The accuracy of NBI increased significantly with increasing experience (area under the curve [AUC] >0.9). After a follow-up of 25 months, 14 of 151 lesions (9.3%) converted into carcinoma. The 4-year carcinoma-free survival rate was 86.4%. The 4-year carcinoma-free survival rate differed significantly between lesions classified as benign/mild dysplasia versus those presenting as moderate/severe dysplasia (88.9% vs 73.5%; P 5 .018). After that, in a second study, we evaluated the characteristics of the falsenegative and false positive cases. Five hundred thirty lesions of the upper airways were evaluated. The WLE was followed by NBI examination before performing a biopsy. The false negative lesions (7.36%) were represented by submucosal and non-SCC tumors. Among the 25 non-SCC tumors, 72% did not show any suspicious vascular pattern under NBI. The false-positive lesions (6.04%) were mainly represented by postradiotherapy mucosal changes, ulcers, and infections. Regarding papillomas, NBI accuracy reached 95.32%, although cases with dysplasia were difficult to distinguish from SCC. Finally in the third study we assessed the intra and interobserver agreement of NBI and WLE at the office, under local anaesthesia, by either experienced or non-experienced observers. Eighty-seven images of head and neck lesions were routinely collected under WLE and NBI. A group of three experienced otolaryngologists and three medical students assessed the images after a brief training. No additional patient nformation was provided. The same protocol was repeated after three weeks. NBI intraobserver agreement was substantial (κ = 0.62) and better than with WLE alone, which was moderate (κ = 0.57) in both groups. Interobserver agreement was moderate with WLE (κ = 0.58) and substantial with NBI (κ = 0.63). Both groups improved intraobserver and interobserver agreement with the implementation of NBI. In summary, NBI provided a greater accuracy than WLE and showed promising usefulness for the follow-up of premalignant lesions., however, not all lesions were ideally evaluated with current defined patterns. An accurate anamnesis is mandatory, Finally, intra and interobserver agreement with NBI for the evaluation of head and neck lesions are substantial, and improve the results of WLE alone in both, professionals and trainees

Clear differences have been established between head and neck squamous cell carcinomas (HNSCC) depending on human papillomavirus (HPV) infection status. This study specifically investigated the status of the CTTN, CCND1 and ANO1 genes mapping at the 11q13 amplicon in relation to the HPV status in HNSCC patients. CTTN, CCND1 and ANO1 protein expression and gene amplification were respectively analyzed by immunohistochemistry and real-time PCR in a homogeneous cohort of 392 surgically treated HNSCC patients. The results were further confirmed using an independent cohort of 279 HNSCC patients from The Cancer Genome Atlas (TCGA). The impact on patient survival was also evaluated. CTTN, CCND1 and ANO1 gene amplification and protein expression were frequent in HPV-negative tumors, while absent or rare in HPV-positive tumors. Using an independent validation cohort of 279 HNSCC patients, we consistently found that these three genes were frequently co-amplified (28%) and overexpressed (39&ndash, 46%) in HPV-negative tumors, whereas almost absent in HPV-positive tumors. Remarkably, these alterations (in particular CTTN and ANO1 overexpression) were associated with poor prognosis. Taken together, the distinctive expression and amplification of these genes could cooperatively contribute to the differences in prognosis and clinical outcome between HPV-positive and HPV-negative tumors. These findings could serve as the basis to design more personalized therapeutic strategies for HNSCC patients.

There is strong evidence supporting the role of the plasminogen activator system in head and neck squamous cell carcinoma (HNSCC), particularly of its uPA (urokinase plasminogen activator) / uPAR (urokinase plasminogen activator receptor) and SERPINE1 components. Overexpression of uPA/uPAR and SERPINE1 enhances tumor cell migration and invasion and plays a key role in metastasis development, conferring poor prognosis. The apparent paradox of uPA/uPAR and its inhibitor SERPINE1 producing similar effects is solved by the identification of SERPINE1 activated signaling pathways independent of uPA inhibition. Both uPA/uPAR and SERPINE1 are directly linked to the induction of epithelial-to-mesenchymal transition, the acquisition of stem cell properties and resistance to antitumor agents. The aim of this review is to provide insight on the deregulation of these proteins in all these processes. We also summarize their potential value as prognostic biomarkers or potential drug targets in HNSCC patients. Concomitant overexpression of uPA/uPAR and SERPINE1 is associated with a higher risk of metastasis and could be used to identify patients that would benefit from an adjuvant treatment. In the future, the specific inhibitors of uPA/uPAR and SERPINE1, which are still under development, could be used to design new therapeutic strategies in HNSCCs.

Importance Dual blockade of programmed death ligand 1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) may overcome immune checkpoint inhibition. It is unknown whether dual blockade can potentiate antitumor activity without compromising safety in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) and low or no PD-L1 tumor cell expression. Objective To assess safety and objective response rate of durvalumab combined with tremelimumab. Design, Setting, and Participants The CONDOR study was a phase 2, randomized, open-label study of Durvalumab, Tremelimumab, and Durvalumab in Combination With Tremelimumab in Patients With R/M HNSCC. Eligibility criteria included PD-L1–low/negative disease that had progressed after 1 platinum-containing regimen in the R/M setting. Patients were randomized (N = 267) from April 15, 2015, to March 16, 2016, at 127 sites in North America, Europe, and Asia Pacific. Interventions Durvalumab (20 mg/kg every 4 weeks) + tremelimumab (1 mg/kg every 4 weeks) for 4 cycles, followed by durvalumab (10 mg/kg every 2 weeks), or durvalumab (10 mg/kg every 2 weeks) monotherapy, or tremelimumab (10 mg/kg every 4 weeks for 7 doses then every 12 weeks for 2 doses) monotherapy. Main Outcomes and Measures Safety and tolerability and efficacy measured by objective response rate. Results Among the 267 patients (220 men [82.4%]), median age (range) of patients was 61.0 (23-82) years. Grade 3/4 treatment-related adverse events occurred in 21 patients (15.8%) treated with durvalumab + tremelimumab, 8 (12.3%) treated with durvalumab, and 11 (16.9%) treated with tremelimumab. Grade 3/4 immune-mediated adverse events occurred in 8 patients (6.0%) in the combination arm only. Objective response rate (95% CI) was 7.8% (3.78%-13.79%) in the combination arm (n = 129), 9.2% (3.46%-19.02%) for durvalumab monotherapy (n = 65), and 1.6% (0.04%-8.53%) for tremelimumab monotherapy (n = 63); median overall survival (95% CI) for all patients treated was 7.6 (4.9-10.6), 6.0 (4.0-11.3), and 5.5 (3.9-7.0) months, respectively. Conclusions and Relevance In patients with R/M HNSCC and low or no PD-L1 tumor cell expression, all 3 regimens exhibited a manageable toxicity profile. Durvalumab and durvalumab + tremelimumab resulted in clinical benefit, with minimal observed difference between the two. A phase 3 study is under way. Trial Registration clinicaltrials.gov Identifier:NCT02319044

Treball Final de Grau d'Odontologia, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Curs: 2016-2017, Director: Helena Viñals Iglesias, Introducció: La pèrdua del sentit del gust és una causa important de morbilitat entre els pacients sotmesos a radioteràpia de cap i coll. L’objectiu d’aquest estudi pilot és avaluar el grau de pèrdua de percepció gustativa en aquest tipus de pacients per als cinc gustos descrits així com la seva evolució al llarg del temps. Materials i mètodes: Es van seleccionar 10 pacients de la branca d’Otorinolaringologia que havien d’iniciar el tractament de radioteràpia en l’Institut Català d’Oncologia de l’Hospitalet de Llobregat. Es van realitzar un total de tres registres per a cada gust: un previ a l’inici de la radioteràpia, a la tercera i a la sisena setmana després d’haver-la començat. Per la valoració dels quatre gustos bàsics (dolç, salat, àcid i amarg) es van emprar tires de paper de filtre impregnades en una substància específica per a cada gust, col·locades a la llengua; mentre que per l’umami les solucions es dipositaven directament a la boca amb una pipeta. Es va valorar també l’estat de la mucosa oral i la salivació (objectiva i subjectiva) en el primer i últim registre. Resultats: Els quatre gustos bàsics van experimentar un augment en el seu llindar de reconeixement al comparar el registre previ a la radioteràpia amb el de la setmana 3. El dolç i l’amarg van manifestar el mateix comportament al comparar la setmana 3 amb la 6, a diferència del salat i l’àcid, en els que no es van observar diferències significatives entre aquests últims registres. Pel que fa a l’umami, no es van registrar canvis significatius entre mesures. L’estat de la mucosa i la salivació sí van experimentar un empitjorament important. Conclusions: Els quatre gustos bàsics tenen un patró d’afectació similar des de l’inici fins la tercera setmana de radioteràpia. L’umami és més fàcilment reconegut tot i ser difícil de descriure. Malgrat que l’estat de la mucosa i la salivació també s’afecten no es pot establir una influència clara d’aquestes en la pèrdua del gust.

Squamous cell carcinoma is the most common malignant tumour of the head and neck. The initial TNM staging, the evaluation of the tumour response during treatment, and the long-term surveillance are crucial moments in the approach to head and neck squamous cell carcinoma (HNSCC). Thus, at each of these moments, the choice of the best diagnostic tool providing the more precise and larger information is crucial. Positron emission tomography with fluorine-18 fludeoxyglucose integrated with CT ((18)F-FDG-PET/CT) rapidly gained clinical acceptance, and it has become an important imaging tool in routine clinical oncology. However, controversial data are currently available, for example, on the role of (18)F-FDG-PET/CT imaging during radiotherapy planning, the prognostic value or its real clinical impact on treatment decisions. In this article, the role of (18)F-FDG-PET/CT imaging in HNSCC during pre-treatment staging, radiotherapy planning, treatment response assessment, prognosis and follow-up is reviewed focusing on current evidence and controversial issues. A proposal on how to integrate (18)F-FDG-PET/CT in daily clinical practice is also described.

Most mouthwashes contain alcohol, a known cause of head and neck cancer (oral cavity, pharynx, larynx), likely through the carcinogenic activity of acetaldehyde, formed in the oral cavity from alcohol. We carried out a pooled analysis of 8981 cases of head and neck cancer and 10 090 controls from 12 case-control studies with comparable information on mouthwash use in the International Head and Neck Cancer Epidemiology Consortium. Logistic regression was used to assess the association of mouthwash use with cancers of the oral cavity, oropharynx, hypopharynx, and larynx, adjusting for study, age, sex, pack-years of tobacco smoking, number of alcoholic drinks/day, and education. Compared with never users of mouthwash, the odds ratio (OR) of all head and neck cancers was 1.01 [95% confidence interval (CI): 0.94-1.08] for ever users, based on 12 studies. The corresponding ORs of cancer of the oral cavity and oropharynx were 1.11 (95% CI: 1.00-1.23) and 1.28 (95% CI: 1.06-1.56), respectively. OR for all head and neck cancer was 1.15 (95% CI: 1.01-1.30) for use for more than 35 years, based on seven studies (P for linear trend=0.01), and OR 1.31 (95% CI: 1.09-1.58) for use more than one per day, based on five studies (P for linear trend

The aim of the present study was to examine the patterns of complementary and alternative medicine (CAM) use in a sample of head and neck cancer patients, forming part of a larger study. A cross-sectional survey design was used collecting data through a descriptive 27-item questionnaire in nine countries in Europe. The participants were 75 patients with head and neck cancers. The prevalence rate of CAM use was 22.7%. The most common therapies used were herbal medicine (47%), medicinal teas (23.5%), use of vitamins/minerals (11.8%) and visualization (11.8%). Use of CAM dramatically increased after the diagnosis with cancer (i.e. eightfold increase in the use of herbs). A profile of CAM users was not evident in this sample. Patients used CAM for a variety of reasons together, with counteracting the ill effects from cancer and its treatment being the most common one. Information about CAM was obtained mostly from friends and family. As one in five head and neck cancer patients use CAM it is important that clinicians explore practices with their patients, improve communication about CAM with them and assist those who want to use CAM in using appropriate and safe therapies.

Chuang, Shu-Chun Jenab, Mazda Heck, Julia E Bosetti, Cristina Talamini, Renato Matsuo, Keitaro Castellsague, Xavier Franceschi, Silvia Herrero, Rolando Winn, Deborah M La Vecchia, Carlo Morgenstern, Hal Zhang, Zuo-Feng Levi, Fabio Dal Maso, Luigino Kelsey, Karl McClean, Michael D Vaughan, Thomas Lazarus, Philip Muscat, Joshua Ramroth, Heribert Chen, Chu Schwartz, Stephen M Eluf-Neto, Jose Hayes, Richard B Purdue, Mark Boccia, Stefania Cadoni, Gabriella Zaridze, David Koifman, Sergio Curado, Maria Paula Ahrens, Wolfgang Benhamou, Simone Matos, Elena Lagiou, Pagona Szeszenia-Dabrowska, Neonilla Olshan, Andrew F Fernandez, Leticia Menezes, Ana Agudo, Antonio Daudt, Alexander W Merletti, Franco Macfarlane, Gary J Kjaerheim, Kristina Mates, Dana Holcatova, Ivana Schantz, Stimson Yu, Guo-Pei Simonato, Lorenzo Brenner, Hermann Mueller, Heiko Conway, David I Thomson, Peter Fabianova, Eleonora Znaor, Ariana Rudnai, Peter Healy, Claire M Ferro, Gilles Brennan, Paul Boffetta, Paolo Hashibe, Mia eng K07CA104231/CA/NCI NIH HHS/ P01CA068384/CA/NCI NIH HHS/ P30 CA015704/CA/NCI NIH HHS/ P30ES010126/ES/NIEHS NIH HHS/ P50CA90388/CA/NCI NIH HHS/ R01 CA100679/CA/NCI NIH HHS/ R01 CA100679-09/CA/NCI NIH HHS/ R01 ES014843/ES/NIEHS NIH HHS/ R01CA048996/CA/NCI NIH HHS/ R01CA078609/CA/NCI NIH HHS/ R01CA100679/CA/NCI NIH HHS/ R01CA30022/CA/NCI NIH HHS/ R01CA51845/CA/NCI NIH HHS/ R01CA61188/CA/NCI NIH HHS/ R01DA11386/DA/NIDA NIH HHS/ R01DE012609/DE/NIDCR NIH HHS/ R01DE13158/DE/NIDCR NIH HHS/ R03CA113157/CA/NCI NIH HHS/ R03CA77954/CA/NCI NIH HHS/ R03DE016611/DE/NIDCR NIH HHS/ R21ES011667/ES/NIEHS NIH HHS/ R24 HD050924/HD/NICHD NIH HHS/ T32CA09142/CA/NCI NIH HHS/ U01CA96134/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Netherlands 2011/11/01 06:00 Cancer Causes Control. 2012 Jan;23(1):69-88. doi: 10.1007/s10552-011-9857-x. Epub 2011 Oct 29.; International audience; We investigated the association between diet and head and neck cancer (HNC) risk using data from the International Head and Neck Cancer Epidemiology (INHANCE) consortium. The INHANCE pooled data included 22 case-control studies with 14,520 cases and 22,737 controls. Center-specific quartiles among the controls were used for food groups, and frequencies per week were used for single food items. A dietary pattern score combining high fruit and vegetable intake and low red meat intake was created. Odds ratios (OR) and 95% confidence intervals (CI) for the dietary items on the risk of HNC were estimated with a two-stage random-effects logistic regression model. An inverse association was observed for higher-frequency intake of fruit (4th vs. 1st quartile OR = 0.52, 95% CI = 0.43-0.62, p (trend) < 0.01) and vegetables (OR = 0.66, 95% CI = 0.49-0.90, p (trend) = 0.01). Intake of red meat (OR = 1.40, 95% CI = 1.13-1.74, p (trend) = 0.13) and processed meat (OR = 1.37, 95% CI = 1.14-1.65, p (trend) < 0.01) was positively associated with HNC risk. Higher dietary pattern scores, reflecting high fruit/vegetable and low red meat intake, were associated with reduced HNC risk (per score increment OR = 0.90, 95% CI = 0.84-0.97).

Introduction Activation status of the phosphatidylinositol 3-kinase (PI3K) pathway in breast cancer brain metastases (BCBMs) is largely unknown. We examined expression of phospho(p)-AKT, p-S6, and phosphatase and tensin homologue (PTEN) in BCBMs and their implications for overall survival (OS) and survival after BCBMs. Secondary analyses included PI3K pathway activation status and associations with time to distant recurrence (TTDR) and time to BCBMs. Similar analyses were also conducted among the subset of patients with triple-negative BCBMs. Methods p-AKT, p-S6, and PTEN expression was assessed with immunohistochemistry in 52 BCBMs and 12 matched primary BCs. Subtypes were defined as hormone receptor (HR)+/HER2-, HER2+, and triple-negative (TNBC). Survival analyses were performed by using a Cox model, and survival curves were estimated with the Kaplan-Meier method. Results Expression of p-AKT and p-S6 and lack of PTEN (PTEN-) was observed in 75%, 69%, and 25% of BCBMs. Concordance between primary BCs and matched BCBMs was 67% for p-AKT, 58% for p-S6, and 83% for PTEN. PTEN- was more common in TNBC compared with HR+/HER2- and HER2+. Expression of p-AKT, p-S6, and PTEN- was not associated with OS or survival after BCBMs (all, P > 0.06). Interestingly, among all patients, PTEN- correlated with shorter time to distant and brain recurrence. Among patients with TNBC, PTEN- in BCBMs was associated with poorer overall survival. Conclusions The PI3K pathway is active in most BCBMs regardless of subtype. Inhibition of this pathway represents a promising therapeutic strategy for patients with BCBMs, a group of patients with poor prognosis and limited systemic therapeutic options. Although expression of the PI3K pathway did not correlate with OS and survival after BCBM, PTEN- association with time to recurrence and OS (among patients with TNBC) is worthy of further study.

The incidence of head and neck squamous cell carcinoma (HNSCC) has been gradually increasing over the last three decades. Recent data have now attributed a viral aetiology to a subset of head and neck cancers. Several studies indicate that oral human papillomavirus (HPV) infection is likely to be sexually acquired. The dominance of HPV 16 in HPV+ HNSCC is even greater than that seen in cervical carcinoma of total worldwide cases. Strong evidence suggests that HPV+ status is an important prognostic factor associated with a favourable outcome in head and neck cancers. Approximately 30 to 40% of HNSCC patients with present with early stage I/II disease. These patients are treated with curative intent using single modality treatments either radiation or surgery alone. A non-operative approach is favored for patients in which surgery followed by either radiation alone or radiochemotherapy may lead to severe functional impairment. Cetuximab, a humanized mouse anti-EGFR IgG1 monoclonal antibody, improved locoregional control and overall survival in combination with radiotherapy in locally advanced tumours but at the cost of some increased cardiac morbidity and mortality. Finally, the improved prognosis and treatment responses to chemotherapy and radiotherapy by HPV+ tumours may suggest that HPV status detection is required to better plan and individualize patient treatment regimes.

The rapid Golgi method, combined with current optical and electronmicroscopica1 techniques, was used in three central gangliogliomas and in one dysplastic gangliocytoma of the cerebellum to study the morphology of ganglionic cells. Gangliogliomas were composed of bipolar, fusiform and radiate cells with dense core and clear vesicles in the perikaryon and cellular processes, the number of each cellular type varying from one case to another. These features, together with the fact that isodendritic neurons are considered to be phylogenetically old neurons, suggest that these tumours are composed of «primitive» neurons that are not homogeneous with regard to their morphology. In contrast, ganglionic cells in dysplastic gangliocytoma are huge cells with long, stereotyped neurites that establish unique asymmetric contacts with neighbouring perikarya and neurites by means of claw-shaped processes covered with synaptic buttons. These morphological characteristics are different from those of any other neuron of the CNS.