Analysis of MicroRNA-371-373 supports that a subset of spermatocytic tumors demonstrates biologic features similar to those of GCNIS-derived germ cell tumors.

Spermatocytic tumors are rare testicular tumors occurring predominantly in older men. Most show a classical tripartite morphology (different from seminoma) and are benign. However, well-documented cases of malignant spermatocytic tumors exist. Our previous work showed that a subset of spermatocytic tumors exhibiting TP53 mutations, DNA methylation profiles closer to seminomas, and/or gains in chromosome 12p exhibited aggressive characteristics, including sarcomatoid transformation and metastatic dissemination. The microRNA-371-373 cluster is a promising biomarker which is upregulated in non-teratoma germ cell tumors with malignant behavior. In this work we analyze microRNAs-371-373 b y quantitative real-time polymerase chain reaction in 18 spermatocytic tumors representative of the whole clinical spectrum, including 6 with aggressive features (sarcomatoid transformation, metastases, or gains in chromosome 12p). The levels of microRNAs-371-373 were significantly higher in non-teratoma germ cell tumors compared to spermatocytic tumors, overall (p < 0.0001). Importantly, levels of microRNA-371-373 were higher in spermatocytic tumors with aggressive features compared to non-aggressive neoplasms. The highest levels were observed in one tumor showing isochromosome 12p. These results further support our previous findings that a subset of spermatocytic tumors are intermediate between so-called type II and type III germ cell tumors and that embryonic microRNAs play a role in aggressive behavior in spermatocytic tumors. Accordingly, this subset of tumors may behave aggressively and require close follow up. In the future, this opens an opportunity for microRNA testing in serum of spermatocytic tumor patients for risk stratification purposes.

EHMT2/G9a and EZH2: Epimarkers in testicular germ cell tumors.

BACKGROUND: Testicular germ cell tumors remain the most frequent solid malignancies in young males. Despite excellent prognosis, the fact that only 60% of patients at diagnosis have elevated serum tumor markers (dependent on stage and histology) and the poor quality of life of patients who develop resistance to chemotherapy cannot be neglected. Consequently, it is mandatory to bring out novel biomarkers. OBJECTIVES: The main goal was to evaluate EZH2 and EHMT2/G9a immunoexpression in a well-characterized patients' cohort of primary and metastatic testicular germ cell tumors, seeking associations with clinicopathological features and discovering differential immunoexpression patterns among specific subtypes. MATERIALS AND METHODS: First, an in silico analysis of the Cancer Genome Atlas database was performed regarding EZH2 and EHMT2/G9a. Then, immunohistochemistry for EZH2 and EHMT2/G9a was carried out in a cohort of testicular germ cell tumor patients, comprising 155 chemo-naïve primary tumors and 11 chemo-treated metastases. Immunoexpression was evaluated using a digital pathology analysis software. RESULTS: Higher EZH2 and EHMT2/G9a expression levels were found in non-seminoma in the in silico analysis, particularly in embryonal carcinoma. Through digital pathology analysis, non-seminomas showed significantly higher EZH2 and EHMT2/G9a immunoexpression, with embryonal carcinoma showing higher expression. Moreover, mixed tumors with 50% or more of embryonal carcinoma component revealed the highest nuclei positivity for both biomarkers. Cisplatin-exposed metastases demonstrated a higher EZH2-positive nuclei and H-score, as well as higher EHMT2/G9a-positive nuclei. DISCUSSION AND CONCLUSION: Overall, our data suggest that EZH2 and EHMT2/G9a might be associated with greater aggressiveness and, eventually, involved in the metastatic setting, paving the way for testing targeted therapies.

MicroRNAs for detecting occult genitourinary cancer.

PURPOSE OF REVIEW: Genitourinary (GU) malignancies are a real burden in global health worldwide. Each model has its own clinical challenges, and the early screening and/or detection of occult cancer in follow-up is transversal to all of them. MicroRNAs (miRNAs) have been proposed as minimally invasive liquid biopsy cancer biomarkers, due to their stability and low degradation. RECENT FINDINGS: The different GU tumor models are in different stages concerning miRNAs as biomarkers for cancer detection. Testicular germ cell tumors (TGCTs) already have a specific defined target, miR-371a-3p, that has shown high sensitivity and specificity in different clinical settings, and is now in final stages of preanalytical testing before entering the clinic. The other GU malignancies are in a different stage, with many liquid biopsy studies (both in urine and plasma/serum) being currently performed, but there is not an agreeable miRNA or set of miRNAs that is ready to follow the footsteps of miR-371a-3p in TGCTs. SUMMARY: Further studies with proper molecular characterization of miRNA profiles of GU malignancies and standardization of sampling, biobanking and formal analysis may aid in the advance and choosing of specific target sets to be used for occult cancer detection.

Epigenetic regulation of TP53 is involved in prostate cancer radioresistance and DNA damage response signaling.

External beam radiotherapy (RT) is a leading first-line therapy for prostate cancer (PCa), and, in recent years, significant advances have been accomplished. However, RT resistance can arise and result in long-term recurrence or disease progression in the worst-case scenario. Thus, making crucial the discovery of new targets for PCa radiosensitization. Herein, we generated a radioresistant PCa cell line, and found p53 to be highly expressed in radioresistant PCa cells, as well as in PCa patients with recurrent/disease progression submitted to RT. Mechanism dissection revealed that RT could promote p53 expression via epigenetic modulation. Specifically, a decrease of H3K27me3 occupancy at TP53 gene promoter, due to increased KDM6B activity, was observed in radioresistant PCa cells. Furthermore, p53 is essential for efficient DNA damage signaling response and cell recovery upon stress induction by prolonged fractionated irradiation. Remarkably, KDM6B inhibition by GSK-J4 significantly decreased p53 expression, consequently attenuating the radioresistant phenotype of PCa cells and hampering in vivo 3D tumor formation. Overall, this work contributes to improve the understanding of p53 as a mediator of signaling transduction in DNA damage repair, as well as the impact of epigenetic targeting for PCa radiosensitization.

Is dyslipidemia a risk factor for trastuzumab-induced cardiotoxicity in breast cancer patients? A systematic review and meta-analysis.

INTRODUCTION: Breast cancer patients undergoing trastuzumab therapy have greater risk of cardiovascular disease. Risk factors for this effect have been proposed. However, the role of dyslipidemia is not completely understood. This systematic review aimed to explore the role of dyslipidemia in trastuzumab-induced cardiotoxicity. METHODS: The investigators searched MEDLINE, Scopus, and Web of Science up to October 25, 2020. A random-effects model was used to determine pooled estimates of the results. The primary endpoint was trastuzumab-induced cardiotoxicity in patients with and without dyslipidemia. RESULTS: A total of 39 studies were selected for inclusion in our systematic review assessing 21079 patients. One study demonstrated a statistically significant association between dyslipidemia and cardiotoxicity (OR=2.28, 95% CI 1.22-4.26, p=0.01). In all other studies, no such association was observed. Twenty-one studies including 6135 patients were eligible for meta-analysis. In this meta-analysis of unadjusted data, dyslipidemia was significantly associated with cardiotoxicity (OR=1.25, 95% CI 1.01-1.53, p=0.04, I2=0%), however, a subgroup analysis of studies reporting adjusted measures did not demonstrate a significant association (OR=0.89, 95% CI 0.73-1.10, p=0.28, I2=0%). CONCLUSION: This systematic review and meta-analysis did not demonstrate a significant association between dyslipidemia alone and the development of cardiotoxicity. In the absence of other relevant cardiovascular risk factors, review of lipid profile may not be obligatory, and management of patients could be performed without referral for cardio-oncology assessment. Further investigation of risk factors for trastuzumab-induced cardiotoxicity is required to confirm these results.

Cardiovascular toxicity in breast cancer patients - contributors and role of cardioprotective drugs.

Breast cancer (BC) patients treated with anthracyclines and/or anti-HER2-targeted therapies (AHT) are highly associated with cardiovascular toxicity (CVT). Our objective was to evaluate the risk of CVT secondary to cancer treatment and the role of cardioprotective-drugs (CPD) in BC patients. We collected a retrospective cohort of females with BC treated with chemotherapy and/or AHT from 2017 to 2019. CVT was defined as LVEF<50% or decline ≥10% during follow-up. As CPD, we considered renin-angiotensin-aldosterone-system inhibitors and beta-blockers. A subgroup analysis of the AHT patients was also performed. A total of 203 women were enrolled. The majority had high or very-high CVT risk score and normal cardiac function at presentation. As for CPD, 35.5% were medicated pre-chemotherapy. All patients were submitted to chemotherapy; AHT were applied to 41.7%. During a 16 months follow-up, 8.5% developed CVT. There was a significant decrease of GLS and LVEF at 12-months (decrease of 1.1% and 2.2%, p<0.001). AHT and combined therapy were significantly associated with CVT. In the AHT sub-group analysis (n=85), 15.7% developed CVT. Patients previously medicated with CPD had a significative lower incidence of CVT (2.9% vs 25.0%, p=0.006). Patients already on CPD presented a higher LVEF at 6-months follow-up (62.5% vs 59.2%, p=0.017). Patients submitted to AHT and anthracycline therapy had higher risk of developing CVT. In the AHT sub-group, pre-treatment with CPD was significantly associated with a lower prevalence of CVT. These results highlight the importance of cardio-oncology evaluation and strengthen the value of primary prevention.

A stroll through the present and future of testicular germ cell tumour biomarkers.

INTRODUCTION: Testicular germ cell tumors (TGCT) are the most commonly diagnosed cancers among young men. Although these tumors usually have a good prognosis and are highly treatable, clinicians and pathologists still face specific dilemmas inherent to this tumor model, which is highly due to its developmental origin. AREAS COVERED: A wide-ranging review of the currently available and future prospects in the field of TGCT biomarkers is presented. EXPERT OPINION: The field of TGCT biomarkers has been widely studied in the last decade. Although these patients usually present with good prognosis, there are still specific clinical questions where novel biomarkers are needed to complement the ones already used in the clinic. These questions include the follow-up method of clinical stage-I patients, detection of minimal residual disease, proper identification of teratoma, and suitable selection of patients to chemotherapy, according to their inherent resistance.

The Effect of Ice on Shoulder Proprioception in Badminton Athletes.

This study aims to analyze the influence of the application of cryotherapy on shoulder proprioception in badminton athletes. Thirty federated badminton athletes were included in this study, all of whom belonged to three of the teams currently competing in national competitions (Portugal). Their mean ages were 21.00 ± 5.60 years, and their experience in the modality was 8.40 ± 6.93 years. They practiced in an average of 2.93 ± 1.26 training sessions per week. All of them used their right hand to hold the racket. Each participant's dominant shoulder joint position and force senses were evaluated for four consecutive time points through the isokinetic dynamometer Biodex System 3. The experimental procedure consisted of applying ice for 15 min and the control procedure consisted of no therapeutic intervention. The proprioception outcomes were expressed using the absolute error, relative error, and variable error. All statistical analysis was performed using PASW Statistics 18 software (IBM-SPSS Statistics). There were no statistically significant changes in the joint position and force senses after the intervention, as well as during the subsequent 30 min. We conclude that, after this cryotherapy technique, there is no increased risk of injury associated with a proprioception deficit that prevents athletes from immediately returning to badminton practice.

The Role of Cyclin-Dependent Kinase 4/6 Inhibitors Treatment in Oligometastatic Breast Cancer: A Case Report on a Possible Curative Intent Strategy.

A small but important subset of patients with metastatic breast cancer has an oligometastatic disease. Some of these patients are highly responsive to systemic therapy and have the potential to achieve complete remission with treatment. However, it remains to be clarified the best locoregional and systemic treatment strategy for such patients and what features can determine whose patients are the best candidates. We also don't know what will be the role of cyclin-dependent kinase 4/6 inhibitors in those cases. We report the case of a 41-year-old woman with HR-positive/HER2-negative oligometastatic breast cancer who, after an excellent response to systemic treatment with palbociclib, anastrozole, and goserelin, underwent breast surgery and liver metastasectomy. After completing three years of systemic treatment, the CDK inhibitor was discontinued, maintaining the hormone therapy. The patient remained under regular follow-up with no evidence of disease after eight months.

Evaluation of Current Antiemetic Therapy Response in Patients Undergoing MEC or HEC Regimens in Portugal.

Chemotherapy-induced nausea and vomiting (CINV) negatively impact cancer patients' quality of life and treatment outcomes. This study evaluated the achievement of complete response to CINV prophylaxis during the first five days after chemotherapy in adult outpatient cancer clinics with solid malignant tumours receiving Moderate or Highly Emetogenic Chemotherapy (MEC or HEC) in Portugal. During the study, patients completed three evaluations, and nausea severity and CINV impact on patients' daily life was assessed. A complete response (no emetic episodes, no use of rescue antiemetic medication, and no more than mild nausea) was observed in 72% of the cycles (N = 161) throughout the five days after chemotherapy. Amongst the patient population, 25% classified their CINV episodes as severe. Though more than half of the patients achieved a complete response, suggesting that a therapeutic effort is being made to minimise this side effect, the overall scenario is barely optimistic. Significantly, new CINV-control measures in MEC/HEC patients should be adopted, specifically avoiding the single use of dexamethasone and 5-HT3 and raising awareness of using NK1-RAs. Thus, it is critical to improve CINV prophylactic treatment and implement practical international antiemetic guidelines in Portuguese clinical practice, envisaging the improvement of supportive care for cancer patients.

Patient-Centered Discussions About Disease Progression, Symptom, and Treatment Burden in Chronic Obstructive Pulmonary Disease Could Facilitate the Integration of End-of-Life Discussions in the Disease Trajectory: Patient, Clinician, and Literature Perspectives: A Multimethod Approach.

Background: Patients with chronic obstructive pulmonary disease (COPD) seldom discuss preferences for future care/treatments with clinicians. The lack of discussions prevents the delivery of care grounded on patient preferences. Instead, treatments become increasingly burdensome as disease progresses and patients approach the end of life. Objective: Identify current and best practice in initiating and conducting conversations about future and palliative care, by integrating data from multiple sources. Design: Multiphasic study where the findings of a systematic literature review and qualitative interviews were combined and synthesized using a triangulation protocol. Setting/Participants: Thirty-three patients with COPD and 14 clinicians from multiple backgrounds were recruited in the United Kingdom. Results: Clinicians' and patients' poor understanding about palliative care and COPD, difficulties in timing and initiating discussions, and service rationing were the main factors for late discussions. Divergent perspectives between patients and clinicians about palliative care discussions often prevented their start. Instead, early and gradual patient-centered discussions on treatment choices, symptom, and treatment burden were recommended by patients, clinicians, and the literature. Earlier patient-centered discussions may reduce their emotional impact and enable patients to participate fully, while enabling clinicians to provide timely and accurate information on illness progression and appropriate self-management techniques. Conclusion: Current approaches toward palliative care discussions in COPD do not guarantee that patients' preferences are met. Early and gradual patient-centered discussions may enable patients to fully express their care preferences as they evolve over time, while minimizing the impact of symptom and treatment burden.

Targeting histone deacetylases in testicular germ cell tumours: an encouraging treatment approach for the future†.

Epidrugs, specifically histone deacetylase inhibitors (HDACi), have been increasingly used in preclinical studies for the treatment of testicular germ cell tumours (TGCTs). SINHCAF was recently described as a potential oncogene in TGCTs located on chromosome 12p, the hallmark of type II (malignant) TGCTs. The findings contribute to the field by further supporting the efficacy of HDACi in the treatment of TGCTs, promoting the design of more preclinical studies and providing the motivation for future implementation of clinical studies with these compounds. © 2022 The Pathological Society of Great Britain and Ireland.

MiRNA biomarkers in cancers of the male reproductive system: Are we approaching clinical application?

BACKGROUND: Specific cancer types face specific clinical management challenges. Owing to their stability, robustness and fast, easy and cost-effective detection, microRNAs (miRNAs) are attractive candidate biomarkers to the clinic. OBJECTIVES: Based on a comprehensive review of the relevant literature in the field, we explore the potential of miRNAs as biomarkers to answer relevant clinical dilemmas inherent to cancers of the male reproductive tract (prostate [PCa], testis [TGCTs] and penis [PeCa]) and identify some of the challenges/limitations hampering their widely application. RESULTS AND DISCUSSION: We conclude that the use of miRNAs as biomarkers is at different stages for these distinct cancer types. While for TGCTs, miRNA-371a-3p is universally accepted to fill in important clinicals gaps and is moving fast towards clinical implementation, for PCa almost no overlap of miRNAs exists between studies, denoting the absence of a consistent miRNA biomarker, and for PeCa the field of miRNAs has just recently started, with only a few studies attempting to explore their clinical usefulness. CONCLUSION: Technological advances influencing miRNA detection and quantification will be instrumental to continue to move forward with implementation of miRNAs in the clinic as biomarkers for non-invasive diagnosis, risk stratification, treatment monitoring and follow-up.

Magnetic-Based Human Tissue 3D Cell Culture: A Systematic Review.

Cell-based assays, conducted on monolayer (2D) cultured cells, are an unquestionably valuable tool for biomedical research. However, three-dimensional (3D) cell culture models have gained relevance over the last few years due to the advantages of better mimicking the microenvironment and tissue microarchitecture in vivo. Recent magnetic-based 3D (m3D) cell culture systems can be used for this purpose. These systems are based on exposing magnetized cells to magnetic fields by levitation, bioprinting, or ring formation to promote cell aggregation into 3D structures. However, the successful development of these structures is dependent on several methodological characteristics and can be applied to mimic different human tissues. Thus, a systematic review was performed using Medline (via Pubmed), Scopus, and Web of Science (until February 2022) databases to aggregate studies using m3D culture in which human tissues were mimicked. The search generated 3784 records, of which 25 met the inclusion criteria. The usability of these m3D systems for the development of homotypic or heterotypic spheroids with or without scaffolds was explored in these studies. We also explore methodological differences specifically related to the magnetic method. Generally, the development of m3D cultures has been increasing, with bioprinting and levitation systems being the most used to generate homotypic or heterotypic cultures, mainly to mimic the physiology of human tissues, but also to perform therapeutic screening. This systematic review showed that there are areas of research where the application of this method remains barely explored, such as cancer research.

The use and impact of game-based learning on the learning experience and knowledge retention of nursing undergraduate students: A systematic literature review.

BACKGROUND: Active engagement of nursing students has deteriorated overtime, especially during the global pandemic. Therefore, there has been a widespread search for learning methods that incorporate digital technologies and active student participation in recent years. Game-based learning may be an option, as it uses game-design elements to enhance academic performance and learning. Its use in nursing education is, however, limited. OBJECTIVES: The literature review aimed to explore student experience and learning when using game-based learning and to understand its uses in the nursing curriculum. DESIGN: Systematic literature review using the Preferred Reporting Items for Systematic Reviews and Meta-analysis. DATA SOURCES: ESBCO Discovery Service was used to search healthcare, science and education-related databases. REVIEW METHODS: A comprehensive search of English language primary research published between 2017 and 2022 on the use of game-based learning in nursing undergraduate education was conducted. Data was analysed using thematic analysis. RESULTS: Seventeen papers from 4 different countries were included. The studies explored interventions and subjects of increased teaching complexity that required increased levels of knowledge retention and critical thinking, such as nursing theory and complex clinical skills. Three themes emerged from the literature, including: approaches to game-based learning; student experience and engagement; impact of game-based learning on student learning and knowledge retention. Studies used a wide range of learning methods, such as quizzes, escape rooms and serious games. These methods were in general well-accepted by students, who endorsed its widespread use in the nursing curriculum. Most studies reported an increase in student experience and learning when using game-based learning, although time-limited games can often increase anxiety on students. CONCLUSIONS: Game-based learning is an important alternative to traditional teaching methods. However, the recurrent use of game elements and its limited long-term effects may pose a limitation to its widespread use in nursing undergraduate education.

Effectiveness of Therapeutic Exercise in Musculoskeletal Risk Factors Related to Swimmer's Shoulder.

BACKGROUND: Therapeutic exercise seems to minimize musculoskeletal risk factors related to swimmer's shoulder. However, there is an absence of a qualitative evaluation of these programs and a great variability regarding the characteristics of exercises. The objective of this review was to identify, evaluate, and compare exercise programs used to minimize musculoskeletal risk factors related to swimmer's shoulder. METHODS: PubMed, CochraneLibrary, ScienceDirect, and Medscape were searched during January 2022. The research was limited to meta-analyses, systematic reviews, and RCTs written in English, Spanish, and Portuguese without publication time. The researched papers had swimmers as the population, compared an exercise program with another program or without intervention, and had as outcomes musculoskeletal risk factor variables. RESULTS: Eleven articles were considered for analysis. There were three positive effects of strength programs on shoulder rotators' strength and endurance, two positive effects of strength and stretching programs on shoulder posture, and one positive effect of a stretching program on shoulder ROM and a plyometric program on proprioception. CONCLUSIONS: There is high heterogeneity and little methodological quality evidence about the theme. However, strength programs with five or fewer OKC exercises performed out of the water seems to lead to better results in the swimmer's shoulder prevention.

DNA Methylation Biomarkers for Prediction of Response to Platinum-Based Chemotherapy: Where Do We Stand?

Platinum-based chemotherapy is routinely used for the treatment of several cancers. Despite all the advances made in cancer research regarding this therapy and its mechanisms of action, tumor resistance remains a major concern, limiting its effectiveness. DNA methylation-based biomarkers may assist in the selection of patients that may benefit (or not) from this type of treatment and provide new targets to circumvent platinum chemoresistance, namely, through demethylating agents. We performed a systematic search of studies on biomarkers that might be predictive of platinum-based chemotherapy resistance, including in vitro and in vivo pre-clinical models and clinical studies using patient samples. DNA methylation biomarkers predictive of response to platinum remain mostly unexplored but seem promising in assisting clinicians in the generation of more personalized follow-up and treatment strategies. Improved methodologies for their detection and quantification, including non-invasively in liquid biopsies, are additional attractive features that can bring these biomarkers into clinical practice, fostering precision medicine.

Perceptions of people with motor neurone disease, families and HSCPs: a literature review.

Motor neurone disease or amyotrophic lateral sclerosis is a rapidly progressive terminal neurodegenerative condition caused by degeneration of the upper and lower motor neurones in the central nervous system of the brain. The effects of motor neurone disease are multifaceted, leading to many adjustments in everyday life. This literature review asked what the experiences of people living with motor neurone disease was before and during the COVID-19 pandemic and during the COVID-19 pandemic, especially in terms of their condition and the support they received from health and social care services. A key theme identified was lack of knowledge among professionals when they cared for people living with motor neurone disease and their families. This lack of knowledge often resulted in delayed diagnosis and poor standards of care. COVID-19 impacted on the care of people living with motor neurone disease and their families, and there is a paucity of evidence on how services were perceived by these groups during the COVID-19 pandemic. The experiences of people living with motor neurone disease and their families are currently missing in the literature. In conclusion, further studies are required to include care of people living with motor neurone disease and their families.

Clinician Perspectives on How to Hold Earlier Discussions About Palliative and End-of-Life Care With Chronic Obstructive Pulmonary Disease Patients: A Qualitative Study.

Chronic obstructive pulmonary disease is associated with progressive symptoms and increased treatment burden, especially at the end of life. However, most patients do not receive palliative care until late in their lives or discuss their end-of-life preferences with clinicians. This study explored clinicians' perspectives on the timing and nature of palliative care discussions. Qualitative interviews were conducted with 7 physicians and 7 nurses working in primary and secondary care settings. Data were analyzed using a thematic analysis. Participants advocated for early, gradual, and informed palliative and future care discussions, because these discussions were thought to be less traumatic and better accepted by patients. Despite this, patient- and clinician-related barriers severely affected clinicians' ability to start discussions at earlier stages. Participants felt many patients were not ready for these discussions and feared damaging hope if the subject was broached. Therefore, clinicians delayed discussions until patients approached the end of life. Stand-alone conversations about and near the end of life were described as current practice; however, clinicians believed these discussions reduced patients' hope and were potentially upsetting. Instead, individualized early, regular, and gradual discussions about immediate and long-term care plans were thought to be less negative and be better accepted.