Principles in the Management of Glioblastoma.

Glioblastoma, the most aggressive and common malignant primary brain tumour, is characterized by infiltrative growth, abundant vascularization, and aggressive clinical evolution. Patients with glioblastoma often face poor prognoses, with a median survival of approximately 15 months. Technological progress and the subsequent improvement in understanding the pathophysiology of these tumours have not translated into significant achievements in therapies or survival outcomes for patients. Progress in molecular profiling has yielded new omics data for a more refined classification of glioblastoma. Several typical genetic and epigenetic alterations in glioblastoma include mutations in genes regulating receptor tyrosine kinase (RTK)/rat sarcoma (RAS)/phosphoinositide 3-kinase (PI3K), p53, and retinoblastoma protein (RB) signalling, as well as mutation of isocitrate dehydrogenase (IDH), methylation of O6-methylguanine-DNA methyltransferase (MGMT), amplification of epidermal growth factor receptor vIII, and codeletion of 1p/19q. Certain microRNAs, such as miR-10b and miR-21, have also been identified as prognostic biomarkers. Effective treatment options for glioblastoma are limited. Surgery, radiotherapy, and alkylating agent chemotherapy remain the primary pillars of treatment. Only promoter methylation of the gene MGMT predicts the benefit from alkylating chemotherapy with temozolomide and it guides the choice of first-line treatment in elderly patients. Several targeted strategies based on tumour-intrinsic dominant signalling pathways and antigenic tumour profiles are under investigation in clinical trials. This review explores the potential genetic and epigenetic biomarkers that could be deployed as analytical tools in the diagnosis and prognostication of glioblastoma. Recent clinical advancements in treating glioblastoma are also discussed, along with the potential of liquid biopsies to advance personalized medicine in the field of glioblastoma, highlighting the challenges and promises for the future.

Identification of Novel Molecular and Clinical Biomarkers of Survival in Glioblastoma Multiforme Patients: A Study Based on The Cancer Genome Atlas Data.

Glioblastoma multiforme (GBM) is the most prevalent type of brain tumour; although advancements in treatment have been made, the median survival time for GBM patients has persisted at 15 months. This study is aimed at investigating the genetic alterations and clinical features of GBM patients to find predictors of survival. GBM patients' methylation and gene expression data along with clinical information from TCGA were retrieved. The most overrepresented pathways were identified independently for each omics dataset. From the genes found in at least 30% of these pathways, one gene that was identified in both sets was further examined using the Kaplan-Meier method for survival analysis. Additionally, three groups of patients who started radio and chemotherapy at different times were identified, and the influence of these variations in treatment modality on patient survival was evaluated. Four pathways that seemed to negatively impact survival and two with the opposite effect were identified. The methylation status of PRKCB was highlighted as a potential novel biomarker for patient survival. The study also found that treatment with chemotherapy prior to radiotherapy can have a significant impact on patient survival, which could lead to improvements in clinical management and therapeutic approaches for GBM patients.

Hemangiopericytoma/Solitary Fibrous Tumor of the Parietal Bone: A Case Report.

Hemangiopericytoma/solitary fibrous tumor (HPC/STF) is a rare tumor arising from Zimmerman's pericytes and it is characterized by an aggressive malignancy, with a high tendency for local and distant recurrence. The authors report the case of a middle-aged woman with HPC/SFT of the right parietal bone, which is an extremely rare primary location of involvement. The patient presented with a painful deformity of insidious growth at the right parietal region. Assessment with cranial computed tomography scan and magnetic resonance imaging revealed an expansive lesion at the right parietal bone, with exocranial extension and 27 mm of maximal diameter. Craniotomy with gross tumor removal, duraplasty, and cranioplasty was performed, and the diagnosis of HPC/SFT, WHO grade III, was established by pathological and immunohistochemical analysis. The patient was then evaluated for adjuvant radiation therapy and received a dose of 60 Gy (2 Gy/fraction) with 3D conformal radiotherapy to the surgical bed. The adjuvant treatment was uneventful and, after 8 months of follow-up, there was no suspected local or distant recurrence. The rarity of this diagnosis, its aggressive behavior, and the lack of published data posed several challenges for the treatment management.

Adjuvant radiotherapy in the treatment of dedifferentiated liposarcoma of the spermatic cord: a rare entity.

Dedifferentiated liposarcoma (DDL) of the spermatic cord is a very rare entity in which management is remarkably controversial due to scarce literature. Although the actual standard of care is surgery via radical inguinal orchiectomy, adjuvant therapies like radiotherapy have demonstrated improved local control, particularly in cases with higher risk for local recurrence and worse prognosis. The role of adjuvant chemotherapy remains questionable in this subset of patients. On literature review, the most important prognostic factors for survival outcomes were surgical margin status, histological grade and the presence of metastases prior to the initial surgery. In this report, we discuss the case of a 59-year-old man with DDL of the spermatic cord that was treated with surgery followed by adjuvant radiotherapy. We also provide a comprehensive literature review about the management of this entity.

Neoadjuvant radiotherapy in the approach of locally advanced breast cancer.

BACKGROUND: Approximately 4% of European patients are diagnosed with locally advanced breast cancer (LABC), a clinical condition commonly associated with poorer prognosis. Systemic therapy is the recommended initial treatment and when inoperability criteria prevails, radiotherapy (RT) should be used for tumour downstaging. This study intends to evaluate the impact of neoadjuvant radiotherapy (NART) in the treatment of inoperable LABC. METHODS: A retrospective study of female patients, submitted to the NART between January 2014 and December 2018 at our institution. The evaluation of pathological response (pR) was made based on Pinder criteria. Primary endpoint: pR. Secondary endpoints: overall survival (OS) and progression-free survival (PFS). OS and PFS were calculated using the Kaplan-Meier method. Differences between groups were compared using Student's t-test, ANOVA (Analysis of variance) and χ2 test. The statistical analyses were performed using Stata (V.13). RESULTS: A total of 76 patients were included, 18% with breast complete response. The 5 years OS was 54% and PFS was 61%. Subgroup analysis showed that pR >90% is correlated with a better OS (p=0.004). Basal-like intrinsic subtype is correlated with worse OS and PFS (p<0.05). No relation was found between response and age, intrinsic subtype, treatment performed and clinical T stage. CONCLUSION: Our study confirms that NART is an effective downsizing treatment in inoperable LABC, allowing for a surgical resection regardless of the systemic treatment performed. Response to NART is independent of the intrinsic subtype and pR >90% is correlated with a better OS. Prospective studies to explore predictive response biomarkers are necessary in order to improve patient selection and optimisation of the treatment.

[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.

Efeito do sistema de manejo sobre o comportamento em pastejo, desempenho ponderal e infestação parasitária em ovinos Suffolk / Effect of a management system on grazing behaviour, ponderal growth and parasitic infestation of Suffolk ewes

Foi estudado o comportamento em pastejo, o desempenho ponderal e o nível de infestação parasitária em ovelhas da raça Suffolk, no período de 1994 a 1995, em Nova Odessa, SP. Comparou-se dois sistemas de manejo: pastejo restrito, onde os animais foram soltos às 9:50h e presos às 17:30h e pastejo em período integral, no qual os animais não eram recolhidos, tendo a disposição abrigo para passarem a noite. Foram utilizadas 34 fêmeas adultas no verão (17 em pastejo livre e 17 em pastejo restrito) e 42 fêmeas adultas no inverno (21 em pastejo livre e 21 em pastejo restrito). Trabalhou-se ainda com 12 animais traçadores em cada estação do ano, sendo metade em cada sistema de manejo visando a contagem de nematódeos no trato digestivo dos animais. Durante 3 dias consecutivos nos meses de janeiro/fevereiro (verão) e julho/agosto (inverno) estudou-se, através da observação dos animais, a cada 30 minutos entre as 7:00 e 17:30h, o hábito de pastejo (pastando ou não; na sombra ou no sol). Acompanhou-se o nível de infestação parasitária dos animais em cada sistema, pela contagem do OPG do rebanho e dos traçadores e nematódeos recuperados nos traçadores. Concluiu-se que a restrição do horário de pastejo isoladamente não propiciou um controle efetivo da infestação parasitária nos animais mostrando. A restrição do tempo de pastejo é compensada pela maior atividade dos animais nas horas mais quentes do dia, todavia este comportamento afetou o desempenho, resultando em menor ganho de peso. A maior disponibilidade de forragem, em relação ao consumo estimado, pode explicar a similaridade entre os tempos de pastejo verificados nos dois sistemas de manejo, tanto no verão como no inverno

Efeito do sistema de manejo sobre o comportamento em pastejo, desempenho ponderal e infestação parasitária em ovinos Suffolk

Grazing behaviour, ponderal growth and level of parasitic infestation were studied in Suffolk breed sheep, from 1994 to 1995, in Nova Odessa, São Paulo. Two management systems were compared: restricted grazing, where the animals were released to the pastures at 9:50 a.m. and confined at 5:30 p.m., and 24 hour grazing, where the animals were maintained all the time in the paddocks, but with access to shelters. Thirty-four adult ewes were used in the summer period (17 under restricted grazing and 17 full-time grazing), and 42 ewes in the winter period (21 with restricted grazing and 21 full-time grazing). Also, for both seasons, 12 tracer animals, six in each grazing system, were used to obtain worm counts from their digestive tracts. For three consecutive days, grazing behaviour, that is, whether grazing or not, was observed in January/February (summer) and July/August (winter) at 30 minute intervals from 7:00 a.m. to 5:30 p.m., also whether the animals stayed in the sun or shade, irrespective of whether they were grazing or not. The level of parasitic infestation was evaluated under each system by eggs per gram countings (EPG) of the herd and the tracer animals, as well as by larvae count. It was concluded that restriction of grazing time by itself does not provide any effective control of parasitic infestation in sheep, however a better control was obtained in the summer period. Restricted grazing time was compensated by the greater activity of the animals during the hotter hours of the day, however, this behaviour affected the animal performance, resulting in lower weight gains. Greater forage availability in relation to estimated consumption may explain the similarity between the grazing times observed in both management systems, either in the summer or in the winter.

Foi estudado o comportamento em pastejo, o desempenho ponderal e o nível de infestação parasitária em ovelhas da raça Suffolk, no período de 1994 a 1995, em Nova Odessa, SP. Comparou-se dois sistemas de manejo: pastejo restrito, onde os animais foram soltos às 9:50h e presos às 17:30h e pastejo em período integral, no qual os animais não eram recolhidos, tendo a disposição abrigo para passarem a noite. Foram utilizadas 34 fêmeas adultas no verão (17 em pastejo livre e 17 em pastejo restrito) e 42 fêmeas adultas no inverno (21 em pastejo livre e 21 em pastejo restrito). Trabalhou-se ainda com 12 animais traçadores em cada estação do ano, sendo metade em cada sistema de manejo visando a contagem de nematódeos no trato digestivo dos animais. Durante 3 dias consecutivos nos meses de janeiro/fevereiro (verão) e julho/agosto (inverno) estudou-se, através da observação dos animais, a cada 30 minutos entre as 7:00 e 17:30h, o hábito de pastejo (pastando ou não; na sombra ou no sol). Acompanhou-se o nível de infestação parasitária dos animais em cada sistema, pela contagem do OPG do rebanho e dos traçadores e nematódeos recuperados nos traçadores. Concluiu-se que a restrição do horário de pastejo isoladamente não propiciou um controle efetivo da infestação parasitária nos animais mostrando. A restrição do tempo de pastejo é compensada pela maior atividade dos animais nas horas mais quentes do dia, todavia este comportamento afetou o desempenho, resultando em menor ganho de peso. A maior disponibilidade de forragem, em relação ao consumo estimado, pode explicar a similaridade entre os tempos de pastejo verificados nos dois sistemas de manejo, tanto no verão como no inverno.