Assessing the need for adaptive radiotherapy in head and neck cancer patients using an automatic planning tool.

BACKGROUND: Unbiased analysis of the impact of adaptive radiotherapy (ART) is necessary to evaluate dosimetric benefit and optimize clinics' workflows. The aim of the study was to assess the need for adaptive radiotherapy (ART) in head and neck (H&N) cancer patients using an automatic planning tool in a retrospective planning study. MATERIALS AND METHODS: Thirty H&N patients treated with adaptive radiotherapy were analysed. Patients had a CT scan for treatment planning and a verification CT during treatment according to the clinic's protocol. Considering these images, three plans were retrospectively generated using the iCycle tool to simulate the scenarios with and without adaptation: 1) the optimized plan based on the planning CT; 2) the optimized plan based on the verification CT (ART-plan); 3) the plan obtained by considering treatment plan 1 re-calculated in the verification CT (non-ART plan). The dosimetric endpoints for both target volumes and OAR were compared between scenarios 2 and 3 and the SPIDERplan used to evaluate plan quality. RESULTS: The most significant impact of ART was found for the PTVs, which demonstrated decreased D98% in the non-ART plan. A general increase in the dose was observed for the OAR but only the spinal cord showed a statistical significance. The SPIDERplan analysis indicated an overall loss of plan quality in the absence of ART. CONCLUSION: These results confirm the advantages of ART in H&N patients, especially for the coverage of target volumes. The usage of an automatic planning tool reduces planner-induced bias in the results, guaranteeing that the observed changes derive from the application of ART.

Emergence of abstract sound representations in the ascending auditory system.

Auditory processing begins by decomposing sounds into their frequency components, raising the question of where the representation of sounds as wholes emerges in the auditory system. To address this question, we used stimulus-specific adaptation (SSA), the reduction in the responses of a neuron to a common sound (standard) which does not generalize to another, rare sound (deviant). SSA to tone frequency has been demonstrated in multiple stations of the auditory pathway, including the inferior colliculus (IC), medial geniculate body (MGB) and auditory cortex. We designed wideband stimuli (tone clouds) that have identical frequency components but are nevertheless distinct. Tone clouds evoked early and substantial SSA in primary auditory cortex (A1) but only late and minor SSA in IC and MGB. These results imply that while in IC and MGB sounds are largely represented in terms of their frequency components, in A1 they are represented as abstract entities.

ACE-27 as a prognostic tool of severe acute toxicities in patients with head and neck cancer treated with chemoradiotherapy: a real-world, prospective, observational study.

PURPOSE: To evaluate the association between comorbidities as assessed by the "Adult Comorbidity Evaluation 27" (ACE-27) and the development of severe acute toxicities in patients with head and neck cancer treated with chemoradiotherapy. METHODS: Prospective, single-center cohort of patients with head and neck cancer treated with chemoradiotherapy (cisplatin 100 mg/m2 on days 1, 22, and 43; intensity-modulated radiotherapy 60 to 69.96 gray, in 30 to 33 fractions,) between June 2018 and December 2019. ACE-27 was assessed before the start of treatment. Patients were divided in two groups based on ACE-27 grading (none to mild versus moderate to severe comorbidities). Differences in incidence of severe acute toxicity and change in treatment plan between groups were examined. RESULTS: A total of 101 patients were included: 90.1% were male, and median age was 57 years. ACE-27 grading was none in 6.9% of patients, mild in 52.5%, moderate in 29.7%, and severe in 10.9%. Severe acute toxicities occurred more frequently in patients with moderate to severe comorbidities (75.6% versus 48.3%), with a statically significant difference (p = 0.006, OR 3.314, 95%-CI (1.382-7.944)). In the group with moderate to severe comorbidities, omission of at least one cisplatin cycle (75.6% versus 60.0%) and premature ending of radiotherapy (12.2% versus 5.0%) also occurred more frequently (p ≥ 0.05). CONCLUSION: In patients with head and neck cancer treated with chemoradiotherapy, the presence of moderate to severe comorbidities seems to correlate with higher incidences of severe acute toxicities. ACE-27 may identify patients at higher risk of major toxicities and assist decisions regarding treatment.

Clinical validation of a graphical method for radiation therapy plan quality assessment.

BACKGROUND: This work aims at clinically validating a graphical tool developed for treatment plan assessment, named SPIDERplan, by comparing the plan choices based on its scoring with the radiation oncologists (RO) clinical preferences. METHODS: SPIDERplan validation was performed for nasopharynx pathology in two steps. In the first step, three ROs from three Portuguese radiotherapy departments were asked to blindly evaluate and rank the dose distributions of twenty pairs of treatment plans. For plan ranking, the best plan from each pair was selected. For plan evaluation, the qualitative classification of 'Good', 'Admissible with minor deviations' and 'Not Admissible' were assigned to each plan. In the second step, SPIDERplan was applied to the same twenty patient cases. The tool was configured for two sets of structures groups: the local clinical set and the groups of structures suggested in international guidelines for nasopharynx cancer. Group weights, quantifying the importance of each group and incorporated in SPIDERplan, were defined according to RO clinical preferences and determined automatically by applying a mixed linear programming model for implicit elicitation of preferences. Intra- and inter-rater ROs plan selection and evaluation were assessed using Brennan-Prediger kappa coefficient. RESULTS: Two-thirds of the plans were qualitatively evaluated by the ROs as 'Good'. Concerning intra- and inter-rater variabilities of plan selection, fair agreements were obtained for most of the ROs. For plan evaluation, substantial agreements were verified in most cases. The choice of the best plan made by SPIDERplan was identical for all sets of groups and, in most cases, agreed with RO plan selection. Differences between RO choice and SPIDERplan analysis only occurred in cases for which the score differences between the plans was very low. A score difference threshold of 0.005 was defined as the value below which two plans are considered of equivalent quality. CONCLUSION: Generally, SPIDERplan response successfully reproduced the ROs plan selection. SPIDERplan assessment performance can represent clinical preferences based either on manual or automatic group weight assignment. For nasopharynx cases, SPIDERplan was robust in terms of the definitions of structure groups, being able to support different configurations without losing accuracy.

Case Report: Sarcoidosis mimicking head and neck cancer progression.

Several case reports have been published describing the coexistence of sarcoidosis and cancer. In the literature, simultaneous occurrence of head and neck cancer and sarcoidosis is rarely reported. In this paper we present a case of a 42-year-old man with squamous cell carcinoma of the oral cavity, locally advanced, which after surgery and adjuvant radiotherapy developed local persistence and progression in the mediastinal lymph nodes. The patient was submitted to chemotherapy and after a complete response, new suspicious mediastinal and hilar lymph nodes appeared in the thoracic computed tomography (CT) scan and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) scan. To enroll the patient in a clinical trial, the patient underwent mediastinoscopy with mediastinal lymph node dissection. The histopathological findings were consistent with sarcoidosis and no metastatic disease was found. Since the patient had no symptoms and the levels of serum angiotensin converting enzyme were normal, no further pharmacological intervention was done. After 4 years of follow up the patient remains without evidence of cancer. This case shows that although imagological techniques (CT and FDG-PET scan) are extensively used to assess the tumor response, false-positive cases can occur. Whenever it is possible a biopsy of the suspected metastatic site should always be performed.

Biological dose-escalated definitive radiation therapy in head and neck cancer.

OBJECTIVE: To compare treatment outcome of patients with head and neck (HN) tumours treated with definitive radiation therapy that, mainly owing to differences in the fractionation scheme used with simultaneous integrated boost techniques, resulted in a different biological dose. METHODS: 181 patients with HN cancer, prescribed to about 70.2 Gy in the primary tumour, were included in this study. Population cohort was divided into Group <70 and Group ≥70 when the mean dose converted to a 2 Gy fractionation in the primary tumour was less or higher than 70.2 Gy, respectively. The probability of local control (LC), locoregional control (LRC), disease-free survival (DFS) and overall survival (OS) was determined for both groups. The incidence of acute and late complications was compared between the two groups. RESULTS: At 24 months for Groups <70 and ≥70, LC was 83.2% and 87.5%, LRC was 79.5% and 81.6%, DFS was 56.3% and 66.8% and OS was 63.9% and 71.5% p = ns, respectively. The incidence of acute dysphagia, odynophagia and pain, and late mucositis was significantly higher in Group ≥70 than in Group <70. The rate of xerostomia, dysphonia, radiodermatitis, alopecia, dental complications, hypoacusia and weight loss was comparable between the two groups. CONCLUSION: The biological dose escalation was safe, but an increase in the incidence of the acute side effects: dysphagia, odynophagia and pain and late mucositis, was obtained. Advances in knowledge: Despite the significant biological dose escalation, within the range of doses delivered to this cohort, no clear dose-response effect was observed.

SPIDERplan: A tool to support decision-making in radiation therapy treatment plan assessment.

AIM: In this work, a graphical method for radiotherapy treatment plan assessment and comparison, named SPIDERplan, is proposed. It aims to support plan approval allowing independent and consistent comparisons of different treatment techniques, algorithms or treatment planning systems. BACKGROUND: Optimized plans from modern radiotherapy are not easy to evaluate and compare because of their inherent multicriterial nature. The clinical decision on the best treatment plan is mostly based on subjective options. MATERIALS AND METHODS: SPIDERplan combines a graphical analysis with a scoring index. Customized radar plots based on the categorization of structures into groups and on the determination of individual structures scores are generated. To each group and structure, an angular amplitude is assigned expressing the clinical importance defined by the radiation oncologist. Completing the graphical evaluation, a global plan score, based on the structures score and their clinical weights, is determined. After a necessary clinical validation of the group weights, SPIDERplan efficacy, to compare and rank different plans, was tested through a planning exercise where plans had been generated for a nasal cavity case using different treatment planning systems. RESULTS: SPIDERplan method was applied to the dose metrics achieved by the nasal cavity test plans. The generated diagrams and scores successfully ranked the plans according to the prescribed dose objectives and constraints and the radiation oncologist priorities, after a necessary clinical validation process. CONCLUSIONS: SPIDERplan enables a fast and consistent evaluation of plan quality considering all targets and organs at risk.

Detecting the unexpected.

Sensory input is inherently dynamic and redundant. Humans and animals alike show a remarkable ability to extract regularities from the sensory scene and dynamically update their responses to the environment. This type of short-term plasticity occurs on time scales ranging from seconds to minutes (and possibly longer). Mismatch Negativity (a component of the human event-related potentials, MMN) and Stimulus Specific Adaptation (a single-neuron analogue, SSA) are two examples of this form of short-term plasticity. Conceptually, both are thought to express a form of surprise and to represent predictive processing. MMN and SSA therefore provide us with handles for investigating this important time scale of short-term plasticity.

Assessment and topographic characterization of locoregional recurrences in head and neck tumours.

PURPOSE: To evaluate the differences between three methods of classification of recurrences in patients with head and neck tumours treated with Radiation Therapy (RT). MATERIALS AND METHODS: 367 patients with head and neck tumours were included in the study. Tumour recurrences were delineated in the CT images taken during patient follow-up and deformable registration was used to transfer this volume into the planning CT. The methods used to classify recurrences were: method CTV quantified the intersection volume between the recurrence and the Clinical Target Volume (CTV); method TV quantified the intersection between the Treated Volume and the recurrence (for method CTV and TV, recurrences were classified in-field if more than 95% of their volume were inside the volume of interest, marginal if the intersection was between 20-95% and outfield otherwise); and method COM was based on the position of the Centre Of Mass of the recurrence. A dose assessment in the recurrence volume was also made. RESULTS: The 2-year Kaplan-Meier locoregional recurrence incidence was 10%. Tumour recurrences occurred in 22 patients in a mean time of 16.5 ± 9.4 months resulting in 28 recurrence volumes. The percentage of in-field recurrences for methods CTV, TV and COM was 7%, 43% and 50%, respectively. Agreement between the three methods in characterizing individually in-field and marginal recurrences was found only in six cases. Methods CTV and COM agreed in 14. The percentage of outfield recurrences was 29% using all methods. For local recurrences (in-field or marginal to gross disease) the average difference between the prescribed dose and D 98% in the recurrence volume was -5.2 ± 3.5% (range: -10.1%-0.9%). CONCLUSIONS: The classification of in-field and marginal recurrences is very dependent on the method used to characterize recurrences. Using methods TV and COM the largest percentage of tumour recurrences occurred in-field in tissues irradiated with high doses.

[Secondary hypothyroidism after cervical irradiation: systematic evaluation of thyroid function in follow-up]. / Hipotiroidismo secundário à irradiação cervical: avaliação sistemática da função tiroideia no seguimento.

INTRODUCTION: Sometimes Thyroid dysfunction is an underestimated consequence of radiation exposure. The underlying mechanism is not clearly understood, but it is likely to be multifactorial. As so, the specific risk factors associated with the development of secondary radiotherapy hypothyroidism remain undefined. The direct irradiation of the thyroid gland may result more frequently in hypothyroidism. This is an irreversible condition, requiring lifelong treatment and monitoring. OBJECTIVES: To evaluate the incidence of hypothyroidism in patients with head and neck cancer who underwent neck irradiation on an intensive or adjuvant basis and determine whether it is justifiable to integrate the monitoring of parameters for evaluation of thyroid function (TSH, free fraction T3 e free fraction T4 ) in this patient group on the Institutional follow up protocol. MATERIAL AND METHODS: This is an observational, retrospective descriptive study, which comprises a group of 376 patients with head and neck cancer undergoing radiotherapy, on adjuvant or intensive basis, between the years 2007 and 2012, at Portuguese Institute of Oncology of Coimbra, E.P.E. 145 patients met all the inclusion criteria. Standardized rating scales for the definition of hypothyroidism have been used - LENT-SOMA scales (Late Effects Normal Tissues Subjective Objective Management Analysis). Grade 1 or higher was considered as a complication hypothyroidism. RESULTS: The analysis of a cohort of 145 patients was carried out. The most frequent tumor site was the larynx (26.9%). Thirty-two patients received adjuvant radiotherapy and 113 were treated with intensive schemes. The most used radiotherapy technique was intensity modulated (IMRT), performed in 86.2% patients. The overall incidence rate of hypothyroidism at 12 months was 18.6%. The diagnosis for hypothyroidism was done between 9 and 12 months after treatment radiotherapy in 51.9% of the patients with this complication. DISCUSSION: An analysis of the published literature, hypothyroidism is the most common thyroid complication after irradiation and affects a large percentage of patients undergoing cervical radiotherapy with curative intent. It has been shown that the risk of hypothyroidism increases with time after exposure, but the highest incidence appears to be in the first two years after treatment. From our analysis we obtained at 12 months, a rate of incidence of hypothyroidism of 18.6% (16.55% grade 1 and grade 2, 2.1%). CONCLUSIONS: This study found an incidence of hypothyroidism corresponding to the lowest values reported in other published studies. The short duration of follow-up considered in this analysis, may justify these results. With these results and their correlation with the available literature, the authors consider justified and recommend the inclusion of the systematic evaluation of thyroid function in the follow-up protocol of these patients.

Introdução: A disfunção tiroideia constitui uma consequência, por vezes subestimada, da exposição à radiação. O mecanismo subjacente não está claramente esclarecido, mas terá uma origem multifatorial. Os fatores de risco específicos para o desenvolvimento de hipotiroidismo secundário à radioterapia permanecem indeterminados. A irradiação direta da glândula tiroideia pode resultar, com maior frequência, em hipotiroidismo. Este é uma condição irreversível, requerendo monitorização e tratamento permanente. Objetivos: Avaliar a incidência de hipotiroidismo nos doentes portadores de neoplasias da cabeça e pescoço submetidos a irradiação cervical, a título intensivo ou adjuvante, bem como determinar se é justificável a integração no protocolo de seguimento Institucional, de parâmetros laboratoriais (TSH, T3 Livre e T4 Livre) para avaliação da função tiroideia neste grupo de doentes e qual a sua periodicidade. Material e Métodos: Este é um estudo observacional, descritivo, retrospetivo, que engloba um grupo de 376 doentes portadores de neoplasias da cabeça e pescoço, submetidos a tratamento de radioterapia, a título adjuvante ou intensivo, entre os anos de 2007 e 2012, no Instituto Português de Oncologia de Coimbra Francisco Gentil E.P.E. Cumpriram todos os critérios de inclusão 145 doentes. Foram utilizadas escalas de avaliação padronizadas para a definição de hipotiroidismo ­ LENT-SOMA scales (Late Effects Normal Tissues Subjective Objective Management Analysis). Foi considerada como complicação o hipotiroidismo Grau 1 ou superior. Resultados: Procedeu-se à análise de um grupo de 145 doentes. A localização tumoral mais frequente foi a Laringe (26,9%). Trinta e dois doentes efetuaram radioterapia adjuvante e 113 efetuaram esquemas intensivos. A técnica de radioterapia mais utilizada foi a intensidade modulada (IMRT), efetuada em 86,2% doentes. A taxa de incidência global de hipotiroidismo aos 12 meses foi de 18,6%. Em 51,9% dos doentes foi efetuado o diagnóstico de hipotiroidismo entre os 9 e os 12 meses após o tratamento de radioterapia. Discussão: Da análise da literatura publicada, o hipotiroidismo constitui a complicação tiroideia radioinduzida mais frequente e afeta uma grande percentagem de doentes submetidos a radioterapia cervical com intenção curativa. Foi demonstrado que o risco de hipotiroidismo aumenta com o tempo após a exposição, contudo a incidência mais elevada parece ser nos dois primeiros anos após o tratamento. Da nossa análise obtivemos, aos 12 meses uma taxa de incidência global de hipotiroidismo de 18,6%, (grau 1 de 16,55% e grau 2 de 2,1%). Conclusão: Neste estudo foi encontrada uma incidência de hipotiroidismo correspondente aos valores mais baixos descritos em outros estudos publicados. O curto tempo de follow-up considerado nesta análise poderá justificar os resultados obtidos. Face aos resultados obtidos, e correlacionando-os com a literatura disponível, os autores consideram justificável e recomendável a inserção da avaliação sistemática da função tiroideia no protocolo de follow-up destes doentes.

Neuronal adaptation translates stimulus gaps into a population code.

Neurons in sensory pathways exhibit a vast multitude of adaptation behaviors, which are assumed to aid the encoding of temporal stimulus features and provide the basis for a population code in higher brain areas. Here we study the transition to a population code for auditory gap stimuli both in neurophysiological recordings and in a computational network model. Independent component analysis (ICA) of experimental data from the inferior colliculus of Mongolian gerbils reveals that the network encodes different gap sizes primarily with its population firing rate within 30 ms after the presentation of the gap, where longer gap size evokes higher network activity. We then developed a computational model to investigate possible mechanisms of how to generate the population code for gaps. Phenomenological (ICA) and functional (discrimination performance) analyses of our simulated networks show that the experimentally observed patterns may result from heterogeneous adaptation, where adaptation provides gap detection at the single neuron level and neuronal heterogeneity ensures discriminable population codes for the whole range of gap sizes in the input. Furthermore, our work suggests that network recurrence additionally enhances the network's ability to provide discriminable population patterns.

Impaired auditory temporal selectivity in the inferior colliculus of aged Mongolian gerbils.

Aged humans show severe difficulties in temporal auditory processing tasks (e.g., speech recognition in noise, low-frequency sound localization, gap detection). A degradation of auditory function with age is also evident in experimental animals. To investigate age-related changes in temporal processing, we compared extracellular responses to temporally variable pulse trains and human speech in the inferior colliculus of young adult (3 month) and aged (3 years) Mongolian gerbils. We observed a significant decrease of selectivity to the pulse trains in neuronal responses from aged animals. This decrease in selectivity led, on the population level, to an increase in signal correlations and therefore a decrease in heterogeneity of temporal receptive fields and a decreased efficiency in encoding of speech signals. A decrease in selectivity to temporal modulations is consistent with a downregulation of the inhibitory transmitter system in aged animals. These alterations in temporal processing could underlie declines in the aging auditory system, which are unrelated to peripheral hearing loss. These declines cannot be compensated by traditional hearing aids (that rely on amplification of sound) but may rather require pharmacological treatment.