Tratamiento y supervivencia de pacientes con melanoma en el Instituto Nacional de Oncología y Radiobiología / Treatment and survival of patients with melanoma at the National Institute of Oncology and Radiobiology

RESUMEN Introducción: El melanoma es una enfermedad potencialmente mortal, asociada a una alta morbilidad y mortalidad, por el alto riesgo de metástasis nodal regional y a distancia. Objetivo: Describir las características demográficas, clínico-patológicas, terapéutica, instaurada en la serie estudiada y la supervivencia en los pacientes evaluados. Material y Métodos: Se realizó un estudio descriptivo y retrospectivo, en 79 pacientes con melanoma localmente avanzado estadio III, en el período de 2003 a 2018. Se realizó una revisión documental de historias clínicas e informes de anatomía patológica para la obtención de los datos. Resultados: En relación con las variables clínico-patológicas de los pacientes, 51,9 % fueron hombres y el subtipo histológico de extensión superficial representó 44,1 % de la muestra. Un 64,6 % se diagnosticó en etapa IIIB y 35,4 % en etapa IIIC. La exéresis de la lesión primaria como único tratamiento se realizó en 35,1 % de los pacientes y el uso del Interferón alfa en 80 % para los que recibieron inmunoterapia. Hasta el momento del análisis 67 pacientes, 84,8 %, habían progresado y un 83,5 % fallecieron. La mediana de supervivencia libre de progresión se estimó en 1,0 año y la de la supervivencia global en 1,10 años. Conclusiones: En la serie de pacientes evaluados predominó el subtipo extensión superficial. Predominó discretamente el sexo masculino y la etapa IIIB. La modalidad terapéutica más indicada fue la exéresis de la lesión primaria; tanto la supervivencia libre de progresión como la global fueron bajas.

ABSTRACT Introduction: Melanoma is a potentially lethal disease that is associated with a high morbidity and mortality rates due to the high risk of regional or distant nodal metastasis. Objective: To describe the demographic and clinical-pathological characteristics and the therapeutic procedure, as well as to determine the survival in the patients evaluated in the study. Material and Methods: A descriptive and retrospective study was carried out in a group of seventy-nine patients suffering from locally advanced stage III melanoma during 2003-2018 period. Data were taken from the documentary review of clinical histories and the records of the Department of Pathological Anatomy. Results: Regarding the clinical-pathological variables, men comprised 51,9 % of the sample, and the superficial extension in the histological subtype represented 44,1 % of the sample. About 64,6 % and 35,4 % of patients were diagnosed in stage IIIB and stage IIIC, respectively. The removal of the primary lesion was performed as the only treatment option in 35,1 % of the patients, and Interferon Alfa was used in 80 % of those who received immunotherapy. Up until the analysis of 67 patients, it was demonstrated that 84,8 % of them had improved while 83,5 % had died. The median progression-free survival was 1,0 years and the global survival was 1,10 years. Conclusions: The superficial subtype predominated in the group of patients studied. There was a discrete prevalence of males and stage IIIB. The most commonly indicated therapeutic procedure was the removal of the primary lesion. Both the median progression-free survival and the global one were low.

Novel biological strategies to enhance the radiation therapeutic ratio

Successful anticancer strategies require a differential response between tumor and normal tissue (i.e., a therapeutic ratio). In fact, improving the effectiveness of a cancer therapeutic is of no clinical value in the absence of a significant increase in the differential response between tumor and normal tissue. Although radiation dose escalation with the use of intensity modulated radiation therapy has permitted the maximum tolerable dose for most locally advanced cancers, improvements in tumor control without damaging normal adjacent tissues are needed. As a means of increasing the therapeutic ratio, several new approaches are under development. Drugs targeting signal transduction pathways in cancer progression and more recently, immunotherapeutics targeting specific immune cell subsets have entered the clinic with promising early results. Radiobiological research is underway to address pressing questions as to the dose per fraction, irradiated tumor volume and time sequence of the drug administration. To exploit these exciting novel strategies, a better understanding is needed of the cellular and molecular pathways responsible for both cancer and normal tissue and organ response, including the role of radiation-induced accelerated senescence. This review will highlight the current understanding of promising biologically targeted therapies to enhance the radiation therapeutic ratio.

Proteção radiológica: conhecimento e métodos dos cirurgiões-dentistas / Radiological protection: knowledge and methods of dentist

Objetivo: Avaliar o conhecimento de cirurgiões-dentistas da cidade de Patos-PB acerca da biossegurança em radiologia odontológica e métodos de proteção utilizados. Métodos: Foi utilizada uma abordagem indutiva com procedimento estatístico descritivo e técnica de documentação direta através da pesquisa de campo, utilizando o formulário como instrumento. Participaram do estudo 50 cirurgiões-dentistas que trabalhavam em consultórios particulares com aparelho de raios X intraoral na cidade de Patos-PB. Após a assinatura do Termo de Consentimento Livre e Esclarecido pelos profissionais, foram aplicados questionários para avaliação do conhecimento dos mesmos sobre biossegurança em radiologia e práticas de proteção utilizadas. Os dados foram tabulados e foi feita análise descritiva das variáveis qualitativas pelas medidas de proporção, frequências e porcentagens. Resultados: Observou-se que todos os profissionais mostraram preocupação em relação à radioproteção e que buscavam realizar os exames radiográficos seguindo os princípios de cada técnica radiográfica a fim de se evitar a repetição das mesmas. Para proteção do paciente, a maioria relatou utilizar avental de chumbo, incluindo protetor de tireóide, além de reduzir o tempo de exposição. Acerca da proteção própria, a maior parte afirmou possuir paredes com revestimento de chumbo. Conclusão: Observouse que a maioria dos profissionais tem conscientização acerca dos aspectos de radioproteção, contudo, alguns cirurgiões-dentistas ainda desconhecem os mesmos e não praticam a biossegurança em radiologia, colocando em risco sua própria saúde e a dos pacientes.(AU)

Aim: To assess the knowledge of dentists in the city of Patos, PB, Brazil, about biosafety in radiology and applied protection methods. Methods: This study involved an inductive approach with a descriptivestatistical procedure and a research technique for direct documentation in the field, using a questionnaire as the main instrument. This study included 50 dentists who work in private practices with intraoral X-ray units in Patos, PB. After the professionals had signed the Free and Informed Consent Form, questionnaires were applied to evaluate the dentists' knowledge about biosafety in radiology and their protection practices. The data were tabulated, and a descriptive analysis was performed regarding the qualitative variables measured by proportion, frequencies, and percentages. Results: It was observed that all of the staff were concerned about their own radioprotection and that they sought to comply with the principles of each radiographic technique in order to avoid repeating radiographs. For patient protection, the majority reported using lead aprons, including a thyroid shield, in addition to reducing exposure time. Regarding their own protection, most facilities have walls with lead casing. Conclusion: It was observed that most professionals are aware of the aspects of radiological protection; however, some are still unfamiliar with these procedures and do not practice biosafety in radiology, putting their own health and that of their patients at risk.(AU)

statistical quantification of radiobiological metrics in intensity modulated radiation therapy evaluation

The dosimetric parameters from the DVH cannot predict the amount of tumor kill and normal tissue complications directly but it can assess the conformity and homogeneity of the physical dose distributions. For example, the D-V parameter V20 [Percentage of lung volume receiving 20Gy] is used to gauge the incidence of grade >/=2 or grade >/=3 radiation pneumonitis with the plan. But the complication can be correlated to more than one point in the DVH [eg. V5, V40, D50] and it is treatment technique dependent. The aim of this study is to quantify the uncertainty of physical dose metrics to predict the clinical outcomes of the radiotherapy treatments. The radiobiological estimates such as TCP and NTCP were made for a cohort of 50 patients [15-Brain; 20-H and N; 15-Pelvis] using the D-V parameters. A statistical analysis based on Spearman ranking coefficient correlation was performed to determine the correlation of the physical plan quality indicators with that of radiobiological estimates. The correlation between the Conformity Index and the Tumor Control probability was found to be good and the dosimetric parameters for optic nerves, optic chiasm, brain stem, normal brain and parotids correlated well with the Normal Tissue Complication Probability estimates compared to other normal structures. A follow up study [median duration: 28 Months] was also performed. There was no grade 3 or grade 4 normal tissue complications observed. Local tumor control was found to be higher in brain [90%] and pelvic cases [95%] whereas a decline of 75% was noted with Head and Neck cases. The EUD concept of radiobiological model used in the software determines the TCP and NTCP values which can predict precise outcomes with the use of dose volume data in the voxel level. The uncertainty of using physical dose metrics for plan evaluation is quantified with the statistical analysis. It is also helpful in ranking rival treatment plans

Radiobiological mechanisms of stereotactic body radiation therapy and stereotactic radiation surgery

Despite the increasing use of stereotactic body radiation therapy (SBRT) and stereotactic radiation surgery (SRS) in recent years, the biological base of these high-dose hypo-fractionated radiotherapy modalities has been elusive. Given that most human tumors contain radioresistant hypoxic tumor cells, the radiobiological principles for the conventional multiple-fractionated radiotherapy cannot account for the high efficacy of SBRT and SRS. Recent emerging evidence strongly indicates that SBRT and SRS not only directly kill tumor cells, but also destroy the tumor vascular beds, thereby deteriorating intratumor microenvironment leading to indirect tumor cell death. Furthermore, indications are that the massive release of tumor antigens from the tumor cells directly and indirectly killed by SBRT and SRS stimulate anti-tumor immunity, thereby suppressing recurrence and metastatic tumor growth. The reoxygenation, repair, repopulation, and redistribution, which are important components in the response of tumors to conventional fractionated radiotherapy, play relatively little role in SBRT and SRS. The linear-quadratic model, which accounts for only direct cell death has been suggested to overestimate the cell death by high dose per fraction irradiation. However, the model may in some clinical cases incidentally do not overestimate total cell death because high-dose irradiation causes additional cell death through indirect mechanisms. For the improvement of the efficacy of SBRT and SRS, further investigation is warranted to gain detailed insights into the mechanisms underlying the SBRT and SRS.

From microdosimetry to nanodosimetry--the link between radiobiology and radiation physics / 生物医学工程学杂志

The link between micro- and macro-parameters for radiation interactions that take place in living biological systems is described in this paper. Meanwhile recent progress and development in microdosimetry and nanodosimetry are introduced, including the methods to measure and calculate these micro- or nano-parameters. The relationship between radiobiology and physical quantities in microdosimetry and nanodosimetry was presented. Both the current problems on their applications in radiation protection and radiotherapy and the future development direction are proposed.

Indicadores citogenéticos para la identificación de exposición a radiación ionizante en humanos / Cytogenetic indicators for the identification of ionizing radiation exposure in humans

La biodosimetría citogenética se aplica en la evaluación médica de las personas involucradas en situaciones radiológicas anormales, con el fin de evaluar las dosis recibidas, el peligro inminente para la salud y aplicar los tratamientos médicos más adecuados. Además, contribuye al esclarecimiento de sucesos cuando existen dudas respecto a los resultados de la dosimetría física por dosímetros defectuosos, no calibrados o ausentes. Es el método más preciso de dosimetría biológica, ya que existe una relación matemática que permite calcular la dosis, establecer el grado de homogenidad de la exposición y, en caso de exposiciones no homogéneas, establecer la fracción del cuerpo irradiada y la dosis que recibió esa fracción mediante la cuantificación del número y tipos de aberraciones cromos¢micas y de micronúcleos y su distribución en los linfocitos de la sangre periférica. Para este análisis se establecen las relaciones dosis-efecto y un sistema automatizado para el cálculo de las dosis de radiación recibidas. Actualmente se está desarrollando un proyecto conjunto Universidad de Costa Rica-Hospital San Juan de Dios, con el objetivo de explorar los efectos cromosómicos de la radiación, en pacientes expuestos por razones el objetivo de explorar los efectos cromosómicos de la radiación, en pacientes expuestos por razones terapéuticas y atendidos en este hospital. De igual modo, se hará la curva de calibración dosis-respuesta in vitro para rayos gama y se validar  mediante la intercomparación con el Laboratorio de Dosimetría Citogenética de Centro para la Protección e Higiene de las Radiaciones de Cuba...

Mathematical model of tumor evolution in radiotherapy / 生物医学工程学杂志

The schemes of dose fractionation play an important role in tumor radiotherapy. We used mathematical methods to describe the process of tumor cells evolution during radiotherapy, trying to find how the schemes of dose fractionation affect tumor cells. In clinical radiobiology, linear-quadratic (LQ) model is frequently used to describe radiation effects of tumor cells. We integrated LQ model with effect of oxygen, and with the phenomenon of repopulation and reoxygenation in the theory of radiation biology. While we considered the disappearing progress of doomed cells in tumor, we established the mathematical model of tumor evolution in radiotherapy. We simulated some common treatment schedules, and studied the change role of tumor cells during radiotherapy. These results can serve for the optimization of dose fractionation scheme based on tumor radiobiological characteristics.

Repercussões da radioterapia na região orofacial e seu tratamento / Impact of radiotherapy on the orofacial region and management of related conditions

A radioterapia em região de cabeça e pescoço provoca inúmeras sequelas ao paciente irradiado, afetando o sistema estomatognático e com repercussões sistêmicas importantes. As sequelas da radiação ionizante podem ser extensas e, algumas vezes, permanentes, em especial nas glândulas salivares e no tecido ósseo. É relevante que o cirurgião dentista tenha conhecimento das reações adversas e das formas adequadas de prevenção e tratamento para amenizar o desconforto e melhorar a condição de vida do paciente irradiado. Portanto, a conscientização e motivação deste paciente, com a promoção de saúde oral através da adequação do meio bucal e orientações sobre ações preventivas, são essenciais para se obter o melhor prognóstico.

Head and neck radiotherapy causes countless sequelae in irradiated patients, affecting the stomatognathic system, with significant systemic implications. Sequelae of exposure to ionizing radiation may be extensive and sometimes permanent, particularly in the salivary glands and bone tissue. It is of utmost importance that the surgeon dentist be aware of adverse reactions and appropriate forms of treatment to alleviate discomfort and improve the quality of life of the irradiated patient. Therefore, awareness and motivation of the patient, with promotion of oral health through the adaptation of the oral environment and guidance on preventive measures are essential to get a better prognosis.

Efeito da radiação ionizante sobre o paladar em pacientes submetidos a radioterapia para a região da cabeça e pescoço / Effect of ionizing radiation on the taste function of patients submitted to head and neck radiotherapy

OBJETIVO: Avaliar os efeitos da radiação ionizante sobre o paladar, em pacientes que foram submetidos a radioterapia na região de cabeça e pescoço. MATERIAIS E MÉTODOS: Foram selecionados 20 pacientes que possuíam diagnóstico de tumor na região de cabeça e pescoço, que iniciaram tratamento no Setor de Radioterapia da Santa Casa de Misericórdia de Belo Horizonte, MG, Brasil. Para testes do paladar, foram manipuladas quatro soluções (salgada - NaCl; doce - sacarose; azeda - ácido cítrico; amarga - ureia) em três concentrações diferentes (fraca, média e forte), administradas por meio de conta-gotas, três gotas de cada solução de maneira aleatória, respeitando a ordem das concentrações fracas, médias e fortes. Após a aplicação de cada solução, o paciente relatava o sabor que sentia. O procedimento foi realizado semanalmente durante as três primeiras semanas de radioterapia. RESULTADOS: Foi observada diferença estatisticamente significante na perda do paladar dos pacientes em tratamento radioterápico, quando se compararam a 1ª e 4ª semanas de tratamento na solução salgada, nas três concentrações, na solução doce nas concentrações fracas e médias e nas soluções azedas e amargas, apenas quando se testaram as concentrações fracas. CONCLUSÃO: A radiação ionizante altera o paladar de pacientes submetidos a radioterapia de cabeça e pescoço.

OBJECTIVE: To evaluate the effects of ionizing radiation on the taste function in patients submitted to radiotherapy in the head and neck region. MATERIALS AND METHODS: Twenty patients diagnosed with head and neck tumors and undergoing treatment in the Division of Radiotherapy at Santa Casa de Misericórdia de Belo Horizonte, MG, Brazil, were selected. For their taste function testing, four solutions were manipulated with salt (NaCl), sugar (sucrose), citric acid (for acidity), and urea (for bitterness), at three different (low, medium and high) concentrations. Weekly tests were performed during the first three weeks of radiotherapy, with random administration of the solutions (three drops each) respecting the order of their concentration levels (low, medium and high). After the application of each solution, the patient reported which flavor he/she tasted. RESULTS: A statistically significant difference was observed in the loss of taste function as the results in the 1st and 4th weeks of treatment were compared, with salty solution at the three concentration levels, with the sweet solution at low and medium concentrations, and with the sour and bitter solutions, only at low concentration. CONCLUSION: Ionizing radiation alters the taste function of patients submitted to head and neck radiotherapy.

Efeitos biológicos da radioterapia na expressão do fator de crescimento epidérmico (EGF) durante a odontotogênese em camundongos (Mus musculus) / Biological effects of the radiotherapy in the expression of the epidermal growth factor (EGF) during odontogenesis in mice (Mus musculus)

Pacientes portadores de câncer na região de cabeça e pescoço quando submetidos à radioterapia podem apresentar vários tipos de manifestações clínicas, dentre elas a diminuição dos níveis salivares do fator de crescimento epidérmico (EGF). O EGF é uma pequena proteína (53 aminoácidos) que estimula a proliferação de células dos mamíferos, sendo encontrada em vários órgãos em desenvolvimento. Pode também exercer um papel fisiológico na erupção dentária ao interagir com outras moléculas como o fator de crescimento transformante _ (TGF-_), a interleucina 1 (IL-1) e do fator de estimulação de colônia 1 (CSF-1), aumentando a reabsorção óssea e estimulando a quimiotaxia de células mononucleares. O objetivo deste trabalho foi verificar, por meio de reações de imuno-histoquímica, se a expressão do fator de crescimento epidérmico (EGF) pode ser alterada na odontogênese do primeiro molar superior de camundongos Mus musculus, após exposição de fêmeas prenhes a radioterapia, na dose de 3 Gray (Gy) ao décimo dia de gestação. Foram avaliados os germes dentários dos embriões aos 14, 16 e 18 dias de desenvolvimento pré-natal. As análises morfológica microscópica óptica e histomorfométrica demonstraram que o número de células epiteliais periféricas do órgão do esmalte imunopositivas para o EGF foi significativamente menor no grupo 3 Gy em relação ao grupo controle nos períodos de 14º (P<0,0001), 16º (P<0,0001<0,05) e 18º (P<0,0008) dias pré-natais.

CyberKnife(TM) for the Treatment of Non-Metastatic Prostate Cancer

PURPOSE: The radiobiology of prostate cancer favors a hypofractionated dose regimen. We report here our experience with the CyberKnife(TM), demonstrating its efficacy, safety, and feasibility as a treatment modality for non-metastatic prostate cancer. MATERIALS AND METHODS: Between October 2002 and April 2006, 20 patients with biopsy-proven prostate cancer were treated with the CyberKnife(TM). The distribution of clinical risks, as assessed by using D'Amico's definition for risk grouping, was as follows: low (4), intermediate (5), and high (11). Three patients received 32 Gy, 7 patients received 34 Gy, and 10 patients received 36 Gy. All patients received the radiation doses in 4 fractions. The rectal and bladder toxicities were graded by using the criteria set forth by the Radiation Therapy Oncology Group (RTOG). RESULTS: The mean patient age was 71.4 years (range, 52-79 years), and the mean follow-up period was 35.5 months (range, 8-74 months). There were 2 acute and 1 late grade 2 gastrointestinal toxicities, and 1 acute and 2 late grade 2 urinary toxicities. The 5-year overall survival rate was 100%, respectively. The 5-year biochemical failure-free rate of the low-risk, intermediate-risk, and high-risk patients was 100%, 100%, and 90.9%, respectively. CONCLUSIONS: CyberKnife(TM) is a safe, well-tolerated, and rather effective treatment for non-metastatic prostate cancer. We obtained a 100% 5-year biochemical failure-free rate in low-risk and intermediate-risk patients. CyberKnife(TM) is a viable option for the treatment of non-metastatic prostate cancer.

Introduction to Radiosurgery

Radiosurgery, or stereotactic radiosurgery, is a minimally invasive modality to treat a lesion with stereotactically focused ionizing radiation without surgical incision. Because there are no incision procedures, general anesthesia or transfusion is not required, and complications related to incisional procedures do not occur in radiosurgery. As a result, radiosurgery shows much low rates of complications than conventional open surgery with comparable cure rates. In the beginning, radiosurgery was applied only to a few intracranial diseases because a stereotactic frame was applied to the skull. Along with the development of technologies and accumulation of knowledge on radiosurgery such as medical imaging, computer, radiation physics, and radiobiology, indications of radiosurgery have been expanded in various ways. Nowadays, radiosurgery is accepted as an adjuvant treatment or a primary treatment option for many neurosurgical diseases and cancers. Cranial nerve schwannomas, brain meningiomas, pituitary adenoma, and other benign brain tumors are good indications for radiosurgery. Intracranial arteriovenous malformation, brain metastases from extracranial cancers, and trigeminal neuralgia are also well controlled by radiosurgery. Spinal metastases and various cancers are emerging indications for extracranial radiosurgery, which has been recently introduced. In this article, the authors summarized the basic concept, history, development, and future of radiosurgery as an introduction to radiosurgery.

Physical and Biological Background of Radiosurgery

Radiosurgery is a highly precise form of radiation therapy for the treatment of vascular lesions, certain primary or metastatic neoplasms, or functional disorders. Either intracranial or extracranial, which are inaccessible or unsuitable for surgical or other management. As the basis of radiation physics for radiosurgery, this article introduces radiation history, the method of radiation production, interaction mode of radiations with human, transfer of radiation energy to the tissue, and dose planning to generate a desirable dose distribution on the target site. Biologically, the goal of radiosurgery is to cause a precise damage only to the limited tissue within the target volume without exceeding the acceptable rate of complications. As the therapeutic ratio is a function of the volume irradiated, the total dose and dose per fraction used, and the level of acceptable risk, radiation oncologists or practitioners should consider various radiobiologic factors when using radiosurgery to obtain the maximum therapeutic ratio.

3-Dimensional conformal radiotherapy versus intensity modulated radiotherapy for localized prostate cancer: dosimetric and radiobiologic analysis

To analyze the dosimetric and radio biologic advantages between intensity modulated radiotherapy [IMRT] and 3 dimensional conformal radiotherapy [3DCRT] and selection of optimal photon energy for IMRT treatments. 24 patients with localized prostate carcinoma were planned for 3DCRT and IMRT techniques. Radiation dose of 54 Gy with 2 Gy/fraction, was planned to Planning target volume [PTV1] [prostate + seminal vesicle + 1 cm margin] and 72 Gy to PTV2 [prostate + 1 cm margin] respectively. 3DCRT planning was done using 15 MV photon beam while IMRT plans were created using 6 MV and 15MV photons. Treatment plans were analyzed using mean, median, dose maximum and cumulative dose volume histogram for PTV1, PTV2, bladder, and rectum. Tumor control probability [TCP] was calculated for prostate. Normal tissue complication probability [NTCP] was calculated for bladder, rectum, and head of femur. Mean dose to prostate was 72.79 +/- 0.18 Gy for IMRT 15 MV, 72.16 +/- 0.27 Gy for 3DCRT and 72.48 +/- 0.19 Gy for IMRT 6 MV. TCP was greater for IMRT 15 MV followed by IMRT 6 MV. The mean value of NTCP was significantly lower [p = 0.0015] for IMRT 6 MV compared to 3DCRT for rectum while for bladder all were comparable. IMRT techniques shows superiority in sparing surrounding critical organs, thus reducing normal tissue complication rates while maintaining the same or higher tumor control probability. No significant difference was observed between IMRT 6 MV and IMRT 15 MV techniques.

Accelerated proliferation correction factors in linear-quadratic and multiple-component models

Study in design to incorporate accelerated proliferation correction factors into linearquadratic and multiple-component models. Accelerated proliferation rate correction factor has been incorporated into the linearquadratic and the multiple component models by applying accelerated exponential cell growth to explain the tumor cell kinetics and estimates proper treatment results. Biological effectiveness and tumor control probability, in terms of BED [LQ model], BRD [MC model], TCP[LQ model] and TCP[MC model], were computed for three conventional and two accelerated hyperfractionated radiation therapy treatment schedules with using a range of accelerated proliferation rate constants to demonstrate the effect of the proliferation process. The results of the study show that the accelerated proliferation rate reduces the effectiveness of a treatment schedule delivered in a prolonged period of time. Care should be taken in the selection of a treatment protocol for a patient of head and neck cancer with an account of the cell kinetics of the tumor