Risk of Second Tumors in Retinoblastoma Survivors after Ionizing Radiation: A Review.

Retinoblastoma (RB) is the most common ocular neoplasm in children, whose development depends on two mutational events that occur in both alleles of the retinoblastoma susceptibility gene (RB1). Regarding the nature of these mutational events, RB can be classified as hereditary if the first event is a germline mutation and the second one is a somatic mutation in retina cells or nonhereditary if both mutational events occur in somatic cells. Although the rate of survival of RB is significantly elevated, the incidence of second malignant neoplasms (SMNs) is a concern, since SMNs are the main cause of death in these patients. Effectively, RB patients present a higher risk of SMN incidence compared to other oncology patients. Furthermore, evidence confirms that hereditary RB survivors are at a higher risk for SMNs than nonhereditary RB survivors. Over the decades, some studies have been performed to better understand this subject, evaluating the risk of the development of SMNs in RB patients. Furthermore, this risk seems to increase with the use of ionizing radiation in some therapeutic approaches commonly used in the treatment of RB. This review aims to clarify the effect of ionizing radiation in RB patients and to understand the association between the risk of SMN incidence in patients that underwent radiation therapy, especially in hereditary RB individuals.

An Overview on Radiation Sensitivity in Hereditary Breast and Ovarian Cancer Syndrome.

Hereditary breast and ovarian cancer (HBOC) syndrome is a condition in which individuals have an increased risk of developing different types of cancer when compared to the general population. BRCA1 repair associated (BRCA1) and BRCA2 repair associated (BRCA2) genes are tumor suppressor genes that play a crucial role in cell, by repairing DNA damage. Mutations in these genes are responsible for 25% of HBOC cases. Individuals with this syndrome are often subjected to diagnostic imaging techniques, as well as therapeutic options, that use ionizing radiation, so it is crucial to understand whether these individuals may present higher radiosensitivity and, therefore, its consequences. Several studies have been carried out to understand if the exposure to different ionizing radiation doses can induce cancer in individuals with HBOC. Some of these studies have shown that individuals with HBOC are hypersensitive to the ionizing radiation and, therefore, have neoplasms resulting from mutations in genes that are important in maintaining genomic stability. When mutated, genes no longer guarantee this stability and promote the induction of carcinogenesis. Oppositely, other studies show that there is no association between exposure to ionizing radiation and an increased risk of developing cancer. Thus, the results are inconsistent, and there is a great need to clarify this relationship. In this review, we present the characteristics of HBOC syndrome and the effects that ionizing radiation can induce in individuals who have it. In addition, we review the studies that have already been carried out on this subject.

The Footprint of Exosomes in the Radiation-Induced Bystander Effects.

Radiation therapy is widely used as the primary treatment option for several cancer types. However, radiation therapy is a nonspecific method and associated with significant challenges such as radioresistance and non-targeted effects. The radiation-induced non-targeted effects on nonirradiated cells nearby are known as bystander effects, while effects far from the ionising radiation-exposed cells are known as abscopal effects. These effects are presented as a consequence of intercellular communications. Therefore, a better understanding of the involved intercellular signals may bring promising new strategies for radiation risk assessment and potential targets for developing novel radiotherapy strategies. Recent studies indicate that radiation-derived extracellular vesicles, particularly exosomes, play a vital role in intercellular communications and may result in radioresistance and non-targeted effects. This review describes exosome biology, intercellular interactions, and response to different environmental stressors and diseases, and focuses on their role as functional mediators in inducing radiation-induced bystander effect (RIBE).

Oxymestane, a cytostatic steroid derivative of exemestane with greater antitumor activity in non-estrogen-dependent cell lines.

A new promising steroid derivative of Exemestane (Exe), the drug used for the treatment of estrogen-dependent breast cancer, was synthesized and evaluated against a set of human cancer cell lines. The new compound (Oxymestane-D1, Oxy) was tested comparatively with Exe against colon (C2BBe1, WiDr), liver (HepG2, HuH-7), lung (A549, H1299) and prostate (LNCaP, PC3) human cancer cell lines. Likewise, its effect on human colon normal cells (CCD-841 CoN) and human normal fibroblast cells (HFF-1) was studied. The cytostatic activity of Oxy was also compared with that of the reference cytostatic drugs used in chemotherapy protocols, namely carboplatin, cisplatin, doxorubicin, epirubicin, etoposide, flutamide, 5-fluorouracil, irinotecan, oxaliplatin and sorafenib. In all cell lines tested, Oxy proved to be more powerful cytostatic than Exe. Additionally, the IC50 at 72 h showed a three-fold activity greater than 5-fluorouracil in the WiDr cell line, twice as high as cisplatin for cell line A549 and five times higher than cisplatin for cell line H1299. Also, Oxy surprisingly revealed to induce DNA damage and inhibit the DNA damage response (DDR) proteins ATM, ATR, CHK1 and CHK2. The results obtained allow concluding that Oxy can be a promising anticancer agent to be used in chemotherapy protocols. Furthermore, its ability to inhibit crucial components of DDR can also be useful for the monotherapy or for combination with chemo and/or radiotherapy of cancer.

Kinetics of radium-223 and its effects on survival, proliferation and DNA damage in lymph-node and bone metastatic prostate cancer cell lines.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) is associated with a very unfavorable prognosis. At this advanced stage of the disease, there are several therapeutic strategies approved in recent times, being one of them Radium-223 dichloride (Radium-223). However, its mechanisms of action and the process that conducts to cell death are not fully understood. Given this, our main goal is to characterize the radiobiological effects induced by Radium-223 and to evaluate its kinetics on metastatic Prostate Cancer (mPCa) cells. MATERIALS AND METHODS: In vitro studies were conducted using two mPCa cell lines, the LNCaP and PC3, the first being derived from lymph node metastasis and the second from bone metastasis. Kinetic studies were conducted to access the capacity of these cell lines to uptake, retain and internalize the Radium-223. For the assessment of radiobiological effects, cells were first exposed to different doses of Radium-223 and the clonogenic assay was done to evaluate cell survival and to determine lethal doses (LD50). Then, the effects were also evaluated in terms of proliferation, oxidative stress, morphological changes and cell damage. RESULTS: Radium-223 is uptaken by mPCa cells and reaches the nucleus, where it is retained over time. Irradiation decreases cell survival and proliferation, with LNCaP cells (LD50 = 1.73mGy) being more radiosensitive than PC3 cells (LD50 = 4.20mGy). Irradiated cells showed morphological changes usually associated with apoptosis and a dose-dependent increase in DNA damage. Moreover, activation of cell cycle checkpoints occurs through ATM/CHK2 pathway, which is involved in cell cycle arrest and cell death. CONCLUSIONS: The cytotoxic and anti-proliferative effects on both cell lines showed that Radium-223 can decrease the aggressiveness of tumor cells by decreasing the cell survival and proliferation and, also, by increasing the DNA damage. The similar results observed in both cell lines indicated that Radium-223 may have the potential to be used as a therapeutic option also for mCRPC patients with lymph node metastasis. The activation of DNA Damage Response pathways allows the possibility to understand the importance of these checkpoints as targets for new combined therapies.

Cold Atmospheric Plasma, a Novel Approach against Bladder Cancer, with Higher Sensitivity for the High-Grade Cell Line.

Antitumor therapies based on Cold Atmospheric Plasma (CAP) are an emerging medical field. In this work, we evaluated CAP effects on bladder cancer. Two bladder cancer cell lines were used, HT-1376 (stage III) and TCCSUP (stage IV). Cell proliferation assays were performed evaluating metabolic activity (MTT assay) and protein content (SRB assay). Cell viability, cell cycle, and mitochondrial membrane potential (Δψm) were assessed using flow cytometry. Reactive oxygen and nitrogen species (RONS) and reduced glutathione (GSH) were evaluated by fluorescence. The assays were carried out with different CAP exposure times. For both cell lines, we obtained a significant reduction in metabolic activity and protein content. There was a decrease in cell viability, as well as a cell cycle arrest in S phase. The Δψm was significantly reduced. There was an increase in superoxide and nitric oxide and a decrease in peroxide contents, while GSH content did not change. These results were dependent on the exposure time, with small differences for both cell lines, but overall, they were more pronounced in the TCCSUP cell line. CAP showed to have a promising antitumor effect on bladder cancer, with higher sensitivity for the high-grade cell line.

Brief Report on Double-Chamber Syringes Patents and Implications for Infusion Therapy Safety and Efficiency.

This review aimed to map the existing patents of double-chamber syringes that can be used for intravenous drug administration and catheter flush. A search was conducted in the Google patents database for records published prior to 28 October 2020, using several search terms related to double-chamber syringes (DCS). Study eligibility and data extraction were performed by two independent reviewers. Of the initial 26,110 patents found, 24 were included in this review. The 24 DCS that were found display two or more independent chambers that allow for the administration of multiple solutions. While some of the DCS have designated one of the chambers as the flushing chamber, most patents only allow for the sequential use of the flushing chamber after intravenous drug administration. Most DCS were developed for drug reconstitution, usually with a freeze-dried drug in one chamber. Some patents were designed for safety purposes, with a parallel post-injection safety sheath chamber for enclosing a sharpened needle tip. None of the DCS found allow for a pre- and post-intravenous drug administration flush. Given the current standards of care in infusion therapy, future devices must allow for the sequential use of the flushing chamber to promote a pre-administration patency assessment and a post-administration device flush.

Usability Assessment of an Innovative Device in Infusion Therapy: A Mix-Method Approach Study.

Background: Flushing a venous access device is an important procedure to maintain their patency and prevent malfunctioning and complications. An innovative double-chamber syringe was developed, allowing for the assessment of catheter patency, drug delivery and final flush. This study aims to assess the usability of this new device, considering three development stages (concept, semi-functional prototype, functional prototype). Methods: An iterative methodology based on a mix-method design (qualitative and quantitative) enabled the assessment of the devices' usability by their primary end-users. A usability questionnaire was developed and applied, along with focus groups and individual interviews to nurses. Results: The usability questionnaire integrated 42 items focused on four dimensions (usefulness; ease of use; ease of learning; satisfaction and intention to use). The initial psychometric findings indicate a good internal consistency and the conceptual relevance of the items. The scores seem to be sensitive to the usability evaluation of the medical devices in different stages of product development (with lower values on functional prototype evaluation), and related to nurses' perceptions about functional and ergonomic characteristics. Conclusions: Quantitative and qualitative data provided a comprehensive overview of the double-chamber syringes' usability from the nurses' point of view, informing us of features that must be addressed.

Development of an innovative double-chamber syringe for intravenous therapeutics and flushing: Nurses' involvement through a human-centred approach.

BACKGROUND: In nursing practice, flushing the catheters pre and post-drug administration is considered an important clinical procedure to prevent complications, and requires the use of several syringes to comply with international standards of care. We envisioned an innovative double-chamber syringe that enables the filling and administration of both solutions. Following current international recommendations, the development of new medical devices should integrate Health Technology Assessment. The Human-centred design is usually used for that assessment purposes, as a method that actively include end-users in the devices development process. METHOD: Application of the Human-Centred Design through the involvement of nurses in the initial stages of the device development in order to accomplish the initial stages of Technology Readiness Level. A multi-method approach was used, including literature/guidelines review, focus groups with end-users and expert panels. RESULTS: The involvement of nurses enabled the definition of user requirements and contexts of use, as well as the evaluation of design solutions and prototypes in order to accomplish with usability and ergonomic features of the medical device. CONCLUSIONS: Significant contributions were made regarding the final design solution of this innovative double-chamber syringe.

Double-chamber syringe versus classic syringes for peripheral intravenous drug administration and catheter flushing: a study protocol for a randomised controlled trial.

BACKGROUND: The prevention of catheter-related complications is nowadays an important topic of research. Flushing catheters is considered an important clinical procedure in preventing malfunction and several complications such as phlebitis or infection. Considering the latest guidelines of the Infusion Nurses Society, the flushing should be carried out both pre- and post-drug administration, requiring different syringes (with associated overall increased times of preparation/administration of intravenous medication by nurses, and also increasing the need for manipulation of the venous catheter). METHODS/DESIGN: A multi-centre, two-arm randomised controlled trial with partially blinded outcome assessment of 146 adult patients. After eligibility analysis and informed consent, participants will receive usual intravenous administration drugs with flushing procedures, with a double-chamber syringe (arm A) or with classic syringes (arm B). The outcomes assessment will be performed on a daily basis by an unblinded ward team, with the same procedures in both groups. Some main outcomes, such as phlebitis and infiltration, will also be evaluated by nurses from a blinded research team and registered once a day. DISCUSSION: The study outlined in this protocol will provide valuable insight regarding the effectiveness and safety of this new medical device. The development of this medical device (dual-chamber syringe, for drug and flush solution) seems to be an important step to facilitate nurses' adoption of good clinical practices in intravenous procedures, reducing catheter manipulations. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04046770. Registered 13 August 2019.

Flushing em cateteres venosos periféricos: um protocolo de scoping review / Peripheral intravenous catheter flushing: a scoping review protocol / Lavado en catéteres venosos periféricos: un protocolo de revisión exploratoria

Contexto: O flushing dos cateteres venosos periféricos (CVPs), aquando da administração intravenosa, encontra-se descrito como um procedimento preventivo das complicações associadas aos CVPs. Contudo, esta prática não se escontra convenientemente operacionalizada nas diretrizes internacionais em termos do volume da solução de flushing, frequência e técnica. Objetivos: Mapear as evidências no âmbito do flushing dos CVPs. Método de revisão: Foi definido o protocolo de scoping review, baseado na metodologia proposta pelo Joanna Briggs Institute, considerando os critérios definidos e a adequação às bases/repositórios propostos. Apresentação e interpretação dos resultados: O mapeamento das evidências permitirá identificar os volumes, frequências e técnicas utilizadas na prática de flushing. Conclusão: Prevê-se que esta revisão constitua um ponto de partida para a análise e sistematização dos estudos relativos às práticas de flushing dos CVPs, contribuindo não apenas para a otimização desta prática clínica, mas também para a investigação científica nesta temática.

Context: Flushing of peripheral venous catheters (PVC) during intravenous administration is described as a preventive procedure for PVC-related complications. However, this practice is not adequately covered by international guidelines in terms of flushing volume, frequency and technique. Objectives: To map the existing evidence within the scope of PVC flushing. Review method: The scoping review protocol, based on the methodology proposed by Joanna Briggs Institute, was defined in order to answer the established questions, considering the criteria defined and the adequacy to the type of databases/repository to be used. Presentation and interpretation of the results: The mapping of the evidences will allow to identify the typology of studies, the characteristics of PVCs and other information inherent to flushing practice, such as volume, frequency and technique. Conclusion: It is expected that this review will be a starting point for the analysis and systematization of PVC flushing studies, allowing the identification of gaps and contributing to the optimization of this clinical practice, as well as to scientific research in this thematic scope.

Contexto: El lavado de los catéteres venosos periféricos (CVP), durante la administración intravenosa, se describe como un procedimiento preventivo para las complicaciones asociadas con los CVP. Sin embargo, esta práctica no se encuentra convenientemente operacionalizada en las directrices internacionales, en lo que se refiere al volumen de la solución del lavado, la frecuencia y la técnica. Objetivos: Mapear las evidencias en el ámbito del lavado de los CVP. Método de revisión: Se definió el protocolo de revisión exploratoria, basado en la metodología propuesta por el Joanna Briggs Institute, considerando los criterios definidos y la adecuación con las bases/repositorios propuestos. Presentación e interpretación de los resultados: El mapeado de las evidencias permitirá identificar los volúmenes, las frecuencias y las técnicas utilizadas en la práctica del lavado. Conclusión: Se espera que esta revisión sea un punto de partida para el análisis y la sistematización de los estudios sobre las prácticas del lavado de los CVP, lo que contribuye no solo a la optimización de esta práctica clínica, sino también a la investigación científica sobre este tema.

Study Protocol for Two-Steps Parallel Randomized Controlled Trial: Pre-Clinical Usability Tests for a New Double-Chamber Syringe.

A new double-chamber syringe (DUO Syringe) was developed for intravenous drug administration and catheter flushing. This study presents a protocol for pre-clinical usability tests to validate the golden prototype of this new device, performed in a high-fidelity simulation lab by nurses. A two-steps parallel randomized controlled trial with two arms was designed (with standard syringes currently used in clinical practice and with the DUO Syringe). After randomization, eligible and consented participants will be requested to perform, individually, intravenous drug administration and flushing, following the arm that has been allocated. The procedure will be video-recorded for posterior analyses. After the completion of the tasks, nurses will be asked to answer a demographic survey, as well as an interview about their qualitative assessment of the device. A final focus group with all participants will also be conducted. Primary outcomes will concern the DUO Syringe's effectiveness, efficiency, and safety, while secondary outcomes will focus on nurses' satisfaction and intention of use. The pre-clinical protocol was defined according to the legal requirements and ISO norms and was reviewed and approved by the Ethics Committee of the Health Sciences Research Unit: Nursing of the Nursing School of Coimbra.

Impact of an Innovative Securement Dressing and Tourniquet in Peripheral Intravenous Catheter-Related Complications and Contamination: An Interventional Study.

Reusable tourniquets and conventional securement dressings are considered risk factors for the occurrence of reported complications and catheter-related bloodstream infections. This study's purpose is to assess the impact of single-use disposable tourniquets and advanced occlusive polyurethane dressings with reinforced cloth borders on peripheral intravenous catheter (PIVC)-related complications and contamination. A pre- and post-interventional prospective observational study was conducted in a cardiology ward of a tertiary hospital between April 2018 and February 2019. Overall, demographic and clinical data from 156 patients and PIVC-related outcomes were collected (n = 296) as well as PIVC tips for microbiological analysis (n = 90). In the pre-intervention phase (n = 118), complication rates of 62.1% were reported, while 44.1% of the PIVCs were contaminated (n = 34). In the post-intervention phase (n = 178), complication rates decreased to 57.3%, while contamination rates significantly decreased to 17.9% (p = 0.014; n = 56). Through a logistic regression, it was found that the use of innovative technologies reduces the chance of PIVC contamination by 79% (odds ratio (OR): 0.21; 95% confidence interval (CI): 0.05-0.98; p = 0.046). Meanwhile, PIVC-related complications and fluid therapy emerged as predictors for PIVC contamination. Findings suggest that the adoption of these innovative devices in nurses' practice contributes to the significant reduction of PIVC contamination.

Ascorbic Acid Chemosensitizes Colorectal Cancer Cells and Synergistically Inhibits Tumor Growth.

Colorectal cancer (CRC) is continuously classified as one of the most incidental and mortal types of cancer worldwide. The positive outcomes of the conventional chemotherapy are frequently associated with high toxicity, which often leads to the suspension of the treatment. Growing evidences consider the use of pharmacological concentrations of ascorbic acid (AA), better known as vitamin C, in the treatment of cancer. The use of AA in a clinical context is essentially related to the adoption of new therapeutic strategies based on combination regimens, where AA plays a chemosensitizing role. The reduced sensitivity of some tumors to chemotherapy and the highly associated adverse effects continue to be some of the major obstacles in the effective treatment of CRC. So, this paper aimed to study the potential of a new therapeutic approach against this neoplasia with diminished side effects for the patient. This approach was based on the study of the combination of high concentrations of AA with reduced concentrations of drugs conventionally used in CRC patients and eligible for first and second line chemotherapeutic regimens, namely 5-fluorouracilo (5-FU), oxaliplatin (Oxa) or irinotecan (Iri). The evaluation of the potential synergy between the compounds was first assessed in vitro in three CRC cell lines with different genetic background and later in vivo using one xenograft animal model of CRC. AA and 5-FU act synergistically in vitro just for longer incubation times, however, in vivo showed no benefit compared to 5-FU alone. In contrast to the lack of synergy seen in in vitro studies with the combination of AA with irinotecan, the animal model revealed the therapeutic potential of this combination. AA also potentiated the effect of Oxa, since a synergistic effect was demonstrated, in almost all conditions and in the three cell lines. Moreover, this combined therapy (CT) caused a stagnation of the tumor growth rate, being the most promising tested combination. Pharmacological concentrations of AA increased the efficacy of Iri and Oxa against CRC, with promising results in cell lines with more aggressive phenotypes, namely, tumors with mutant or null P53 expression and tumors resistant to chemotherapy.