[Dihydropyrimidine dehydrogenase deficiency screening for management of patients receiving a fluoropyrimidine: Results of two national practice surveys addressed to clinicians and biologists]. / Intérêts et limites de la recherche du déficit en dihydropyrimidine déshydrogénase dans le suivi des patients traités par fluoropyrimidines : résultats de deux enquêtes nationales de pratiques réalisées auprès des médecins et des biologistes.

Dihydropyrimidine dehydrogenase (DPD) deficiency is the main cause of early severe toxicities induced by fluoropyrimidines (FP). The French Group of Clinical Oncopharmacology (GPCO)-Unicancer and the French Pharmacogenetics Network (RNPGx) initiated two surveys, one addressed to oncologists, the other to biologists, in order to evaluate routine practices regarding DPD deficiency screening at national level, as well as compliance, motivations and obstacles for implementation of these tests. These anonymized online surveys were performed with the logistic assistance of the Francophone Federation of Digestive Oncology (FFCD) and the support of numerous medical and biological societies. The surveys were conducted in 2016-2017 before the creation of the French INCa/HAS expert panel, which contributed to the drafting of rules and recommendations for DPD deficiency screening published in December 2018. In all, 554 questionnaires from clinicians were analyzed (23% participation) and 35 from biologists. The main arguments raised by clinicians for justifying the limited practice of DPD deficiency screening were: the lack of recommendations from medical societies or Health Authorities, delays in obtaining results, and the lack of adequate reimbursement by the health insurance system. The goal of these surveys was to provide the French Health Authorities with an overview on nationwide DPD-deficiency screening practices and thus help to design recommendations for the standardization and improvement of the management and safety of cancer patients receiving FP-based chemotherapy.

A Novel External Carotid Arterial Sheath System for Intra-arterial Infusion Chemotherapy of Head and Neck Cancer.

PURPOSE: The purpose of this study was to describe a novel system for treating advanced head and neck cancer consisting of an external carotid arterial sheath (ECAS) and a microcatheter to inject drugs retrogradely into multiple feeding arteries through the superficial temporal artery (STA). MATERIALS AND METHODS: Four consecutive patients with head and neck cancer that had more than one feeding artery were enrolled in this study. The ECAS was made of polyurethane and surface-coated with heparin resin to prevent thrombus formation, allowing it to remain in place for a prolonged period of time. The ECAS was inserted through the STA, and its tip was placed between the maxillary artery and facial artery. The tumor-feeding arteries were selected using a hooked-shaped microcatheter through the ECAS. RESULTS: A total of 13 target arteries were selected in the four patients. The microcatheter inserted via the ECAS was used to catheterize ten arteries (five lingual arteries and five facial arteries). The remaining three lingual arteries were directly selected by the catheter without ECAS. All of the target arteries were able to be catheterized superselectively. The technical success rate was 100%. Vascular occlusion, which might have been caused by the ECAS, was observed in one patient. No neurologic toxicities occurred. CONCLUSION: This ECAS system is a new approach for retrograde superselective intra-arterial chemotherapy that covers the entire tumor with anticancer drugs. It has the potential to increase the effectiveness of therapy for advanced head and neck cancer. LEVEL OF EVIDENCE: Level 4, Case Series.

Predictors of outcome with cetuximab and paclitaxel for head and neck squamous cell carcinoma.

OBJECTIVES: Identify predictors of outcome in patients with recurrent/metastatic head and neck squamous cell carcinoma (RMHNSCC) treated with weekly cetuximab and paclitaxel (CP). STUDY DESIGN: Retrospective analysis. METHODS: Patients with RMHNSCC treated with CP were identified and patient data was recorded. The Kaplan-Meier method was used to estimate outcomes, and Cox regression analysis was used to examine outcome predictors. RESULTS: Fifty-nine patients initiated CP between January 2007 and June 2014. Median age was 56 (range: 39-80) years. The most common primary sites were the oropharynx in 22 (37%) patients, oral cavity in 19 (32%), and larynx in 11 (19%). Eastern Cooperative Oncology Group performance status (ECOG PS) was 0 in seven (12%), 1 in 32 (54%), and 2 in 16 (28%) patients. In 44 (75%) patients, CP was used as a first-line R/M regimen. Median number of cycles was five (range: 1-29). Dose modifications were necessary in 27 (46%) patients. The objective response rate was 47.5%, with 27 (45.8%) partial responses and one (2%) complete response. With a median follow-up of 13.4 months, median progression-free (PFS) and overall survival (OS) were 7.7 and 13.2 months, respectively. On multivariable analysis, an ECOG of 2 of 3 was associated with inferior OS (hazard ratio [HR]: 3.94; P = 0.01; 95% confidence interval [CI]: 1.1-14.04) and PFS (HR: 7.29; P < 0.01; 95% CI: 2.1-26.0) compared to an ECOG 0 of 1. First-line CP administration was associated with superior PFS compared to second line (HR: 2.6; P = 0.02; 95% CI:1.2-5.5). CONCLUSIONS: CP is well tolerated in this population of patients, with favorable tumor efficacy. First-line use and an ECOG 0 of 1 points appears to confer superior outcomes. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:1583-1588, 2017.

Conceptos básicos para el uso racional de antibióticos en otorrinolaringología / Basic concepts for the rational use of antibiotics in otorhinolaryngology

El uso racional de antibióticos es un tema de la mayor importancia en la práctica médica actual. Es fundamental que los médicos conozcan tanto las manifestaciones clínicas de cada proceso infeccioso y sus diagnósticos diferenciales, como también sus características epidemiológicas, prevalencia bacteriana local y patrones de resistencia, así como también la farmacología de los antibióticos disponibles, con el fin de tomar la mejor decisión terapéutica. Al enfrentarnos a un paciente, siempre debemos tener en mente que no todas las enfermedades inflamatorias son infecciosas, no todas las infecciones son bacterianas, y no siempre éstas últimas deben ser tratadas con antibióticos. Las infecciones de la vía aerodigestiva superior están dentro de las patologías infecciosas más frecuentes e involucran a una gran cantidad de especialidades médicas. El objetivo de esta revisión es entregar los conceptos farmacológicos y microbiológicos básicos para una utilización adecuada de los distintos antimicrobianos, y aplicar estos conceptos en el tratamiento de infecciones otorrinolaringológicas frecuentes y relevantes.

Rational use of antibiotics is of major importance in current clinical practice. It is fundamental that physicians know the clinical manifestations of each infectious disease and its differential diagnoses, their epidemiologic characteristics, local bacterial prevalence and resistance patterns, as well as the pharmacology of the different antibiotics, to make the best therapeutic decision. When faced to a patient, we always have to keep in mind that not every inflammatory disease is infectious, not every infectious disease is bacterial, and that the latter not always has to be treated with antibiotics. Upper aerodigestive infections are among the most frequent infectious diseases and involve several different medical specialties. The objective of this review is to give the basic pharmacologic and microbiologic concepts for an appropriate use of the different antimicrobials, and to apply these concepts in the treatment of frequent and relevant otorhinolaryngological infections.

[Proton Pump Inhibitor and High-dose Methotrexate: Two Cases Reports]. / Inhibiteurs de pompe à proton et méthotrexate haute dose : à propos de deux cas.

Methotrexate (MTX) is a cytotoxic agent prescribed at high dose in treatment of malignancy. Association of MTX to proton pump inhibitor (PPI) is not recommended if doses are more than 20 mg per weeks and only to take into account for smaller doses. Review relate some cases of delayed elimination of methotrexate in patients taking PPI, which increase risk of toxic event. However, currently there is no status quo on interaction between PPI and MTX according to available data. We report two clinical cases illustrating one more time a toxic event to MTX in presence of PPI. In absence of risk/benefit ratio set correctly, an assessment of appropriateness of PPI prescription before MTX therapy can limit an iatrogenic risk.

Low PTEN expression is associated with worse overall survival in head and neck squamous cell carcinoma patients treated with chemotherapy and cetuximab.

BACKGROUND: Platinum-based chemotherapy associated with cetuximab is the first-line treatment for inoperable recurrence or metastatic head and neck squamous cell carcinoma (HNSCC). There is no established biomarker for cetuximab efficacy in HNSCC. The PI3K pathway is one of the most frequently altered pathways in HNSCC. Loss of phosphatase and tensin homolog (PTEN) expression occurs in up to 30 % of cases. METHODS: This was a retrospective analysis of data from 61 patients with inoperable recurrence or metastatic HNSCC treated with cetuximab. PTEN, epidermal growth factor receptor and p16 expression were analyzed by immunohistochemistry and tested for association with clinical outcomes. RESULTS: Median overall survival was 11.4 months and progression-free survival was 6.9 months. Low PTEN expression was present in 26.2 % of patients and identified patients with worse prognosis. p16 was positive in only 8.5 % of tumors. CONCLUSIONS: Low PTEN expression in patients treated with cetuximab plus chemotherapy emerged as a prognostic biomarker and should be evaluated for its predictive role for cetuximab efficacy.

Xerostomia after radiotherapy. What matters--mean total dose or dose to each parotid gland?

PURPOSE: Xerostomia is a debilitating side effect of radiotherapy in patients with head and neck cancer. We undertook a prospective study of the effect on xerostomia and outcomes of sparing one or both parotid glands during radiotherapy for patients with squamous cell carcinoma of the head and neck. METHODS AND MATERIALS: Patients with locally advanced squamous cell carcinoma of the head and neck received definitive (70 Gy in 2 Gy fractions) or adjuvant (60-66 Gy in 2 Gy fractions) curative-intent radiotherapy using helical tomotherapy with concurrent chemotherapy if appropriate. Group A received < 26 Gy to the left and right parotids and group B received < 26 Gy to either parotid. RESULTS: The study included 126 patients; 114 (55 in group A and 59 in group B) had follow-up data. There were no statistically significant differences between groups in disease stage. Xerostomia was significantly reduced in group A vs. group B (p = 0.0381). Patients in group A also had significantly less dysphagia. Relapse-free and overall survival were not compromised in group A: 2-year relapse-free survival was 86% vs. 72% in group B (p = 0.361); 2-year overall survival was 88% and 76%, respectively (p = 0.251). CONCLUSION: This analysis suggests that reducing radiotherapy doses to both parotid glands to < 26 Gy can reduce xerostomia and dysphagia significantly without compromising survival. Sparing both parotids while maintaining target volume coverage and clinical outcome should be the treatment goal and reporting radiotherapy doses delivered to the individual parotids should be standard practice.

The evolving role of selective neck dissection for head and neck squamous cell carcinoma.

Neck dissection is an important part of the surgical treatment of head and neck squamous cell carcinoma (HNSCC). The historical concept of neck dissection implied the removal of all lymph node-bearing tissue in the neck, which began in the late nineteenth century. However, more conservative variations of neck dissection have been performed and promoted as well. Anatomic, pathologic, clinical investigations, and prospective studies have demonstrated that the lymphatic dissemination of HNSCC occurs in predictable patterns. Supported by these studies, selective neck dissection (SND), which consists of the removal of select levels of lymph nodes in the neck that have the highest risk of harboring undetected metastases, has become widely accepted in the treatment of the clinically uninvolved neck. More recently, evidence supports using SND in a therapeutic setting in selected cases of HNSCC with limited metastatic disease. Additionally, even more targeted dissections referred to as super-selective neck dissection have been explored for selected patients undergoing elective node dissection for supraglottic cancer and as an adjuvant therapy for salvage of residual lymphadenopathy confined to a single neck level following chemoradiation. In the future, the trend to tailor treatment to individual patients and to limit toxicity and morbidity may further increase the use of SND. The indications have to be guided by further research, in relation with non-surgical treatment options while optimizing oncological effectiveness.

[MIF in head and neck cancer: a new therapeutic target ?]. / Le MIF dans les cancers des voies aéro-digestives supérieures: une nouvelle thérapie ciblée?

Macrophage migration inhibitory factor is a critical proinflammatory cytokine produced by cells of innate and adaptive immune system. MIF plays a key role in cell cycle regulation and in the pathogenesis of many cancers. Recently, MIF has been studied in the upper aerodigestive tract cancer for its involvement in tumor progression, invasion, proliferation and cell motility. In addition, MIF appears to be a mediator in angiogenesis and in the development of metastasis and locoregional lymph node, which are often associated with a poor prognosis. The mechanisms of action responsible for MIF involvement in tumor progression are not completely elucidated. However, the main effects of MIF are mediated by the CD74 receptor. MIF binding to its receptor is responsible for the activation of several signaling pathways (ERK1/2 - MAPK, JAB1 - CSN5, PI3K - Akt), the inhibition of p53 and the stimulation of angiogenic factors including VEGF and IL-8. The overexpression of MIF also causes a reduction of the anti-tumor activity of the immune system. Finally, MIF could be an interesting biomarker in the diagnosis and monitoring of upper aerodigestive tract cancers. In this paper, we assess the state of knowledge of MIF involvement in upper aero-digestive tract cancers and we analyze the therapeutic perspectives.

[Capillary ENT hemangioma].

Capillary hemangioma is considered to be one of the most widespread (frequently occurring) vascular ENT tumours. These neoplasms are usually localized in the nasal cavity, sometimes in the larynx or pharynx, and rarely in the outer or middle ear. The principal method for the treatment of this pathology is surgical intervention. Tumour destruction by laser and radiowave radiation finding wide application for the removal of hemangiomas does not substantially lighten the work of a surgeon; moreover the use of these tools is fraught with a high risk of serious intra- and postoperative complications. In an attempt to avoid or reduce bleeding in the course of surgical intervention we used for the first time hemostatic TachoComb and a Fibro-Vein solution. The mode of using these preparations is described in much detail because it determines to a large degree the efficacy and safety of the treatment. The possibility to combine the surgical intervention with the application of TachoComb and a Fibro-Vein solution is considered; also, the advantages of radiowave-induced destruction of hemangiomas are emphasized.

[Current strategies in radiotherapy of head- and neck cancer]. / Aktuelle Fortschritte in der Strahlentherapie von Kopf-Hals-Tumoren.

Over the last 20 years there was a dramatic change in therapeutic options for head and neck tumors mainly due to improvements in surgical and radiotherapeutic techniques and in the increasing use of multimodal therapy. Especially for locally advanced tumors, one can achieve long lasting disease free intervals in a large proportion of patients. The following article will focus on the novel techniques in radiation oncology and combined radiochemotherapy giving an overview without too many technical details.

[Nanomedicine in otorhinolaryngology--future prospects]. / Nanomedizin in der HNO-Heilkunde--ein Ausblick.

BACKGROUND: Nanotechnology becomes more and more important in the world of today. Equally, it does generally in medicine and of course specifically in otorhinolaryngology. Essentially, there are the following fields: Diagnostics, new therapies and agents, drug delivery and medical implants. MATERIAL AND METHODS: An extensive literature research on nanomedicine in otorhinolaryngology was carried out in the standard online medical reference databases "PubMed/Medline" and "Web of Science". Furthermore, we are giving an overview of the work of the Department of Otorhinolaryngology, Head and Neck Surgery, Section of Experimental Oncology and Nanomedicine (SEON), University Hospital Erlangen. RESULTS: A lot of new and innovative studies on nanotechnology in diagnostics and therapy were recovered. Depending on the variety in otorhinolaryngology, there are numerous versatile approaches, according to the different areas. The main part is engaged in drug delivery. CONCLUSIONS: The efforts to exploit the potential of nanotechnology in otorhinolaryngology are multifaceted, innovative and seminal. The best perspective of success is attributed to nanoparticulate drug delivery systems.

[First experiences with ultrasound guided subclavian vein port placement in ENT]. / Erste Erfahrungen in der sonografisch kontrollierten Portanlage der V. subclavia in der HNO.

BACKGROUND: Description of ultrasound guided port placement in the subclavian vein in ENT and discussion of clinical advantages and disadvantages. MATERIALS AND METHODS: 50 Patients underwent ultrasound guided port placement. The catheter tip was placed over subclavian vein or jugular vein between the superior vena cava and the right atrium. Correct placement was confirmed radiographically. All patients received ports prior to chemotherapy and were followed up in our institution. RESULTS: Port placement was successful in all 50 cases. In 2 cases the suclavian vein could not be punctured. The internal and external jugular veins were used as alternatives in one case each. Subcutaneous hematoma was observed in 4 cases, in 2 cases revision was required. In one case a discrete pneumothorax was observed in radiographic imaging. However, further treatment was not required. During the application of chemotherapy one case of catheter infection was observed and one case of catheter thrombosis. Thrombosis followed incorrect use of the catheter in an external department. In both cases the port catheter was removed. In one further case removal of the catheter was performed after completion of the chemotherapy. In total 3 different port catheter systems were used. CONCLUSION: Ultrasound guided placement of port catheters in the subclavian vein is a simple procedure for ENT settings. Complication rates were very low, application of chemotherapy is simple and quality of life for the oncologic patient is increased.

Functional outcome in patients with advanced head and neck cancer: surgery and reconstruction with free flaps versus primary radiochemotherapy.

The objective was to compare functional outcome in patients with advanced head and neck cancer (HNC) treated with (a) surgical resection and reconstruction with microvascular free flaps (MVFF) followed by radiochemotherapy versus (b) primary radiochemotherapy (RCT) on the basis of the International Classification of Functioning, Disability and Health (ICF) from WHO. This was a cross-sectional, multi-institutional study. The outcome measures included ICF Core Sets for HNC, the EORTC-QLQ, modules c30 + hn35 and the University of Washington-Quality of life Questionnaire (UW-QOL). Analyses included descriptive statistics, ranking exercises, and regression analyses in a cumulative logit model; 27 patients were treated with MVFF and 22 with RCT. Global Quality of life scores suggested a slightly better functional outcome for the surgical approach. The majority of ICF categories (81/93, 87%) did not show a difference in functional outcome between the two treatment approaches. In the remaining 12 ICF categories, n = 3 body structures were more affected in the MVFF group, while n = 3 body functions, and n = 6 activities/participations were more problematic in the RCT group. This included oral swallowing and weight maintenance functions as well as social relationships, acquiring a job, and economic self-sufficiency. In addition, nine contextual environmental factors were more relevant to the RCT group. Both treatment approaches seemed appropriate to advanced HNC from the perspective of functional outcome. The influence of treatment modalities on the social and economic lives of cancer survivors needs to be explored further. In order to guide rehabilitation according to patients' needs, the ICF offers a multidimensional view comprising body structures, body functions, and activities and participation in life.

Dysphagia. Impact on quality of life after radio(chemo)therapy of head and neck cancer.

BACKGROUND: In the past, xerostomia was considered one of the most important determining factors of quality of life (QoL) after radiotherapy (RT) of the head and neck region. In addition, more recent studies have shown that RT-induced dysphagia has an essential influence on the QoL. PATIENTS AND METHODS: Between September 2005 and August 2007, 35 patients with locally advanced squamous cell carcinoma of the head and neck region were included in the prospective study. Patients were treated by IMAT (intensity-modulated arc therapy) or IMRT (intensity-modulated radiotherapy) planned on 3D imaging. A total of 28 patients (80%) received concomitant chemotherapy. The evaluation of QoL (EORTC QLQ-C30, H&N C-35) and toxicities (CTC 2.0) were assessed at the beginning of, during, and after RT as well as up to 12 months after the end of therapy. RESULTS: At the end of therapy, 86% of the patients experienced difficulties in swallowing (62% CTC II-III°). Twelve months after the end of treatment, 15% still suffered from dysphagia CTC II-III°. Concomitant chemotherapy exacerbated the incidence and gravity of dysphagia, resulting in increasing dietary problems. QoL (EORTC) was significantly affected by dysphagia. In particular, the global state of health and QoL were influenced at the end of treatment (p=0.033) and at a later stage (p=0.050). CONCLUSION: The findings of this study suggest that more emphasis should be placed on structured clinical diagnostics, therapy, and rehabilitation of deglutition problems. This means in particular to not only spare the parotids while planning the irradiation, but also to take into consideration the important structures for deglutition, like the retropharyngeal muscles.

[Treatment related swallowing dysfunction and the potentialities of IMRT]. / Schluckstörungen nach Kopf-Hals-Tumortherapie und die Möglichkeiten der IMRT.

Altered fractionated radiotherapy and concurrent chemoradiation could improve local control and survival for patients with locally advanced head and neck cancer. However, intensified treatment seems to increase late toxicity. Late swallowing dysfunction is common and has a large impact on quality of life and can get life-threatening character. Recent studies could show interrelations between the radiation dose to certain anatomical structures involved in the swallowing process and the risk of swallowing dysfunction. Important structures seem to be the pharyngeal constrictors and the supraglottic and glottic larynx. Further prospective clinical validations using standardized diagnostic protocols for dysphagia are necessary to establish dose constraints to anatomical structures involved in swallowing.