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Abstract Background Validated prognostic biomarkers for anti-angiogenic therapy using the anti-VEGF antibody Bevacizumab in ovarian cancer (OC) patients are still an unmet clinical need. The EGFR can contribute to cancer-associated biological mechanisms in OC cells including angiogenesis, but its targeting gave disappointing results with less than 10% of OC patients treated with anti-EGFR compounds showing a positive response, likely due to a non adequate selection and stratification of EGFR-expressing OC patients. Methods EGFR membrane expression was evaluated by immunohistochemistry in a cohort of 310 OC patients from the MITO-16A/MANGO-OV2A trial, designed to identify prognostic biomarkers of survival in patients treated with first line standard chemotherapy plus bevacizumab. Statistical analyses assessed the association between EGFR and clinical prognostic factors and survival outcomes. A single sample Gene Set Enrichment-like and Ingenuity Pathway Analyses were applied to the gene expression profile of 195 OC samples from the same cohort. In an OC in vitro model, biological experiments were performed to assess specific EGFR activation. Results Based on EGFR-membrane expression, three OC subgroups of patients were identified being the subgroup with strong and homogeneous EGFR membrane localization, indicative of possible EGFR out/in signalling activation, an independent negative prognostic factor for overall survival of patients treated with an anti-angiogenic agent. This OC subgroup resulted statistically enriched of tumors of histotypes different than high grade serous lacking angiogenic molecular characteristics. At molecular level, among the EGFR-related molecular traits identified to be activated only in this patients’ subgroup the crosstalk between EGFR with other RTKs also emerged. In vitro, we also showed a functional cross-talk between EGFR and AXL RTK; upon AXL silencing, the cells resulted more sensitive to EGFR targeting with erlotinib. Conclusions Strong and homogeneous cell membrane localization of EGFR, associated with specific transcriptional traits, can be considered a prognostic biomarker in OC patients and could be useful for a better OC patients’ stratification and the identification of alternative therapeutic target/s in a personalized therapeutic approach.

Em 31 biópsias de pacientes portadores de câncer de mama foram realizados diagnóstico histopatológico e avaliação do status hormonal. A técnica histoquímica usada para o estudo de receptores de estrogênio e progesterona (ER e PgR) em cortes criostáticos é simples e de fluorescência alternativa. Cortes adjacentes foram corados por hematoxilina-eosina (HE) e laranja de acrídina (AO) para diagnóstico e identificação da população celular maligna. Achados preliminares mostram: 1) dos tumores estudados, 38,7% foram positivos, 12,9% duvidosos e 48,4% negativos. 2) Maior freqüência de ER e PgR foi encontrada nas pacientes pós-menopáusicas. 3) O carcinoma lobular infiltrante apresentou elevada positividade para ER e PgR. 4) Valores baixos de ER e PgR foram encontrados em tumores com infiltrado linfocitário intenso. 5) A população heterogênea que forma os tumores malignos de mama está constituída por células ER e PgR positivas e negativas em diversas proporções. Os autores também relatam observações sobre a presença de receptores nucleares e dados morfológicos.

Numerosos marcadores biológicos associados a tumor e detectados imunologicamente têm grande aplicabilidade no diagnóstico e monitorização do câncer. Os mais utilizados para a mama são os receptores esteróides e os antígenos de superfície relacionados com as células tumorais. Para que a avaliação hormonal seja mais apurada, sugere-se analisar os receptores de estrogénio e progesterona (ER e PgR). Já para a análise da eficácia terapêutica, sugere-se a monitorização com o antígeno carcinoembriônico (CEA).

Conforme demonstrado, os tumores malignos não são entidades uniformes, constituídas por células com características idênticas. Utilizando método histoquímico direto por conjugado hormonal fluorescente, mostra-se que os carcinomas mamários são compostos por população heterogênea, de células receptor-positivas e receptor-negativas em diversas proporções. Nossos resultados comprovam que poucos tumores malignos de mama podem ser considerados como totalmente hormônio-dependentes. Isto explicaria por que em alguns tumores ER+e PgR+, obtêm-se apenas respostas parciais ou curtas remissões pela hormonioterapia. As dificuldades inerentes à racionalização do tratamento são analisadas.

Foi realizado um estudo por microscopia de fluorescência de biópsias de pacientes portadores de neoplasia maligna de mama, utilizando-se como técnica de coloração o método da laranja de acridina em cortes criostáticos. Os dados apresentados neste trabalho demonstram que as células malignas são identificadas facilmente e de modo rápido e portanto, este método pode ser de grande utilidade para o especialista experiente em morfologia celular. Por outro lado, o estudo da coloração e da fluorescência da estrutura celular pode dar melhor indicação das modificações sofridas pelos ácidos nucleicos nas células tumorais. Conclui-se, que este método é muito importante para caracterizar a percentagem de células cancerosas que podem também apresentar fluorescência devido à presença de marcadores biológicos específicos do câncer.

Realizou-se uma análise de receptores de estrogênio (ER) e progesterona (PgR) em lesões benignas de mama, mediante técnica cito química de fluorescência. os resultados em fibroadenoma e mastopatia fibrocística foram similares entre si, apresentando capacidade variável de ligação estrogênica e progesterônica citoplasmática. A correlação ciclo menstrual/níveis de receptores foi determinada com conhecimento do dia exato de início do último ciclo e sua regularidade. Nossos resultados sugerem que a mensuração na fase folicular inicial, mais que nas outras, previne a ocorrência de níveis falso-negativos de ER e PgR. Outrossim, o uso prévio de contraceptivos orais apresentou-se associado a valores decrescentes de ER e PgR.

Background and purpose: Radiomics features derived from medical images have the potential to act as imaging biomarkers to improve diagnosis and predict treatment response in oncology. However, the complex relationships between radiomics features and the biological characteristics of tumours are yet to be fully determined. In this study, we developed a preclinical cone beam computed tomography (CBCT) radiomics workflow with the aim to use in vivo models to further develop radiomics signatures. Materials and methods: CBCT scans of a mouse phantom were acquired using onboard imaging from a small animal radiotherapy research platform (SARRP, Xstrahl). The repeatability and reproducibility of radiomics outputs were compared across different imaging protocols, segmentation sizes, pre-processing parameters and materials. Robust features were identified and used to compare scans of two xenograft mouse tumour models (A549 and H460). Results: Changes to the radiomics workflow significantly impact feature robustness. Preclinical CBCT radiomics analysis is feasible with 119 stable features identified from scans imaged at 60 kV, 25 bin width and 0.26 mm slice thickness. Large variation in segmentation volumes reduced the number of reliable radiomics features for analysis. Standardization in imaging and analysis parameters is essential in preclinical radiomics analysis to improve accuracy of outputs, leading to more consistent and reproducible findings. Conclusions: We present the first optimised workflow for preclinical CBCT radiomics to identify imaging biomarkers. Preclinical radiomics has the potential to maximise the quantity of data captured in in vivo experiments and could provide key information supporting the wider application of radiomics.

Abstract Purpose The recent implementation of MR-Linacs has highlighted theranostic opportunities of contrast agents in both imaging and radiotherapy. There is a lack of data exploring the potential of superparamagnetic iron oxide nanoparticles (SPIONs) as radiosensitisers. Through preclinical 225 kVp exposures, this study aimed to characterise the uptake and radiobiological effects of SPIONs in tumour cell models in vitro and to provide proof-of-principle application in a xenograft tumour model. Methods SPIONs were also characterised to determine their hydrodynamic radius using dynamic light scattering and uptake was measured using ICP-MS in 6 cancer cell lines; H460, MiaPaCa2, DU145, MCF7, U87 and HEPG2. The impact of SPIONs on radiobiological response was determined by measuring DNA damage using 53BP1 immunofluorescence and cell survival. Sensitisation Enhancement Ratios (SERs) were compared with the predicted Dose Enhancement Ratios (DEFs) based on physical absorption estimations. In vivo efficacy was demonstrated using a subcutaneous H460 xenograft tumour model in SCID mice by following intra-tumoural injection of SPIONs. Results The hydrodynamic radius was found to be between 110 and 130 nm, with evidence of being monodisperse in nature. SPIONs significantly increased DNA damage in all cell lines with the exception of U87 cells at a dose of 1 Gy, 1 h post-irradiation. Levels of DNA damage correlated with the cell survival, in which all cell lines except U87 cells showed an increased sensitivity (P

Abstract Background Chemotherapy-induced neutropenia (CIN) has been demonstrated to be a prognostic factor in several cancer conditions. We previously found a significant prognostic value of CIN on overall survival (OS), in a pooled dataset of patients with advanced non-small-cell lung cancer (NSCLC) receiving first line chemotherapy from 1996 to 2001. However, the prognostic role of CIN in NSCLC is still debated. Methods We performed a post hoc analysis pooling data prospectively collected in six randomized phase 3 trials in NSCLC conducted from 2002 to 2016. Patients who never started chemotherapy and those for whom toxicity data were missing were excluded. Neutropenia was categorized on the basis of worst grade during chemotherapy: absent (grade 0), mild (grade 1–2), or severe (grade 3–4). The primary endpoint was OS. Multivariable Cox model was applied for statistical analyses. In the primary analysis, a minimum time (landmark) at 180 days from randomization was applied in order to minimize the time-dependent bias. Results Overall, 1529 patients, who received chemotherapy, were eligible; 572 of them (who received 6 cycles of treatment) represented the landmark population. Severe CIN was reported in 143 (25.0%) patients and mild CIN in 135 (23.6%). At multivariable OS analysis, CIN was significantly predictive of prognosis although its prognostic value was entirely driven by severe CIN (hazard ratio [HR] of death 0.71; 95%CI: 0.53–0.95) while it was not evident with mild CIN (HR 1.21; 95%CI: 0.92–1.58). Consistent results were observed in the out-of-landmark group (including 957 patients), where both severe and mild CIN were significantly associated with a reduced risk of death. Conclusion The pooled analysis of six large trials of NSCLC treatment shows that CIN occurrence is significantly associated with a longer overall survival, particularly in patients developing severe CIN, confirming our previous findings.

La terapia de células T con receptores de antígeno quimérico (CAR-T, en inglés) es una de las más avanzadas formas de inmunoterapia. Se basa en la modificación genética de linfocitos T por medio de un retrovirus que funciona como vector. El material genético insertado es traducido en un receptor de membrana quimérico dirigido específicamente en contra de una proteína tumoral. Estos linfocitos proliferan y generan una respuesta inflamatoria hacia las células tumorales, alcanzado incluso, en muchos casos una, respuesta curativa. Esta nueva modalidad ha demostrado resultados prometedores en el tratamiento de malignidades refractarias a quimioterapias citotóxicas convencionales, especialmente en leucemia linfoide aguda y algunos subtipos de linfomas no Hodgkin. Actualmente existen tres formas de CAR-T aprobadas por la Food and Drug Administration. Esta revisión de la literatura sintetiza los principios de la ingeniería genética de las células CAR-T, su mecanismo de acción, aplicaciones clínicas y los efectos adversos más representativos.

Abstract Background Although it is known that portomesenteric venous thrombosis (PMVT) is associated with total colectomy and proctocolectomy in young patients with inflammatory bowel disease, little is known about incidence and risk factors of PMVT among the elderly population undergoing colorectal surgery for cancer. Methods Data of elderly patients (> 70 years) undergoing surgery for colorectal cancer were retrospectively registered. The occurrence of PMVT was correlated with the patients’ characteristics and operative variables. Data collected included age, sex, obesity, ASA score, tumor degree, type of surgical resection, surgical approach (laparoscopic or open), and duration of surgery (from skin incision to the application of dressings). Results A total of 137 patients > 70 years who underwent surgery for colorectal cancer and developed an acute intraabdominal process with suggestive symptoms, needing a CT scan, were included. Three of these patients (2.1%) had portomesenteric venous thrombosis during the study period, which was proved with CT scan. There were no significant patients’ characteristics or operative variables between patients with or without the occurrence of PMVT after surgery. Of interest, only operative time was significantly higher in patients with PMVT after surgery (256 ± 40 vs 140 ± 41, p

Biologically based treatment planning is a broad term used to cover any instance in radiotherapy treatment planning where some form of biological input has been used. This is wide ranging, and the simpler forms (e.g., fractionation modification/optimization) have been in use for many years. However, there is a reluctance to use more sophisticated methods that incorporate biological models either for plan evaluation purposes or for driving plan optimizations. This is due to limited data available regarding the uncertainties in these model parameters and what impact these have clinically. This work aims to address some of these issues and to explore the role that uncertainties in individual model parameters have on the overall tissue control probability (TCP)/normal tissue control probability (NTCP) calculated, those parameters that have the largest influence and situations where extra care must be taken. In order to achieve this, a software tool was developed, which can import individual clinical DVH's for analysis using a range of different TCP/NTCP models. On inputting individual model parameters, an uncertainty can be applied. Using a normally distributed random number generator, distributions of parameters can be generated, from which TCP/NTCP values can be calculated for each parameter set for the DVH in question. These represent the spread in TCP/NTCP parameters that would be observed for a simulated population of patients all being treated with that particular dose distribution. A selection of clinical DVHs was assessed using published parameters and their associated uncertainties. A range of studies was carried out to determine the impact of individual parameter uncertainties including reduction of uncertainties and assessment of what impact fractionation and dose have on these probabilities.

Abstract Background Preclinical radiation biology has become increasingly sophisticated due to the implementation of advanced small animal image guided radiation platforms into laboratory investigation. These small animal radiotherapy devices enable state-of-the-art image guided therapy (IGRT) research to be performed by combining high-resolution cone beam computed tomography (CBCT) imaging with an isocentric irradiation system. Such platforms are capable of replicating modern clinical systems similar to those that integrate a linear accelerator with on-board CBCT image guidance. Methods In this study, we present a dosimetric evaluation of the small animal radiotherapy research platform (SARRP, Xstrahl Inc.) focusing on small field dosimetry. Physical dosimetry was assessed using ion chamber for calibration and radiochromic film, investigating the impact of beam focus size on the dose rate output as well as beam characteristics (beam shape and penumbra). Two film analysis tools) have been used to assess the dose output using the 0.5 mm diameter aperture. Results Good agreement (between 1.7–3%) was found between the measured physical doses and the data provided by Xstrahl for all apertures used. Furthermore, all small field dosimetry data are in good agreement for both film reading methods and with our Monte Carlo simulations for both focal spot sizes. Furthermore, the small focal spot has been shown to produce a more homogenous beam with more stable penumbra over time. Conclusions FilmQA Pro is a suitable tool for small field dosimetry, with a sufficiently small sampling area (0.1 mm) to ensure an accurate measurement. The electron beam focus should be chosen with care as this can potentially impact on beam stability and reproducibility.

More than 40% of cases of all lung cancers are diagnosed in patients over the age of 70 years. Elderly patients have more comorbidities and tend to be less tolerant to toxic medical treatments than their younger counterparts. Thus, clinical data obtained in a younger population cannot be automatically extrapolated to the great majority of nonselected elderly patients with non-small cell lung cancer (NSCLC). The bulk of prospective clinical data regarding chemotherapy and molecularly targeted therapy for elderly NSCLC patients come from studies in advanced disease. In elderly advanced NSCLC patients, single-agent chemotherapy with third-generation agents (vinorelbine, gemcitabine, taxanes) is to be considered the routine standard of care for unselected patients, based on phase II and III trials specifically designed for this special population. Cisplatin-based chemotherapy with cisplatin at attenuated doses has been demonstrated to be an active and feasible option in phase II trials. Among targeted therapies, the epidermal growth factor receptor tyrosine kinase inhibitors, erlotinib and gefitinib, have relevant phase II prospective data showing activity and good tolerability as first-line treatment in this population. Concerning the antivascular endothelial growth factor monoclonal antibody, bevacizumab, combined with chemotherapy, particular care must be taken for elderly patients because of the higher incidence of cardiovascular comorbidities. The lack of data on octogenarians suggest that clinicians should exercise caution when applying the existing data on chemotherapy and targeted therapies for patients aged 70-79 years to those aged >80 years. Further specifically designed clinical trials are needed to optimize medical treatment of NSCLC in elderly patients.

Improving outcomes for early-stage non-small cell lung cancer (NSCLC) is a major research area considering that a significant percentage of such patients develop recurrent disease within 5 years of complete lung resection. Adjuvant chemotherapy prolongs survival, with an absolute improvement in 5-year overall survival of about 5% with drawbacks such as treatment toxicity. Approximately, one third of patients with newly diagnosed NSCLC have locally advanced disease not amenable for surgical resection - in this setting of patients concurrent chemoradiation is the standard of therapy. However, the treatment of locally advanced NSCLC is still controversial and clinical outcomes are disappointing, and so new approaches are required to improve the clinical benefit in this setting of patients. Vascular endothelial growth factor (VEGF) is a key angiogenic factor implicated in tumor blood vessels formation and permeability, and tumor VEGF overexpression in patients with early stage lung cancer has been associated with worse relapse free and overall survival. Several agents have been developed that inhibit VEGF or its receptor signalling system. Bevacizumab is the first recombinant humanized monoclonal antibody binding VEGF to demonstrate clinical benefit or rather a survival prolongation in combination with chemotherapy in the treatment of non-squamous advanced NSCLC patients. These positive results led to a large number of clinical trials to evaluate bevacizumab in combination with other targeted agents in advanced disease, and to define the role of this agent in early stage NSCLC such as the impact of bevacizumab integration in chemoradiotherapy strategy for locally advanced disease.