Perspectives of Young Women With Gynecologic Cancers on Fertility and Fertility Preservation: A Systematic Review.

BACKGROUND: Gynecologic cancers standard treatment often requires the removal of some reproductive organs, making fertility preservation a complex challenge. Despite heightened oncofertility awareness, knowledge about fertility attitudes and decisions of young patients with gynecologic cancer is scarce. The aim of this systematic review was to highlight what is currently known about knowledge, attitudes, and decisions about fertility, fertility preservation, and parenthood among these patients. METHODS: Peer-reviewed journals published in English were searched in PubMed, Web of Science and EMBASE from January 1, 2000 to July 1, 2020. Childbearing, fertility, fertility preservation, pregnancy, and parenthood attitudes/decisions after gynecologic cancer from women's perspective were evaluated. RESULTS: A total of 13 studies comprised the review. Most of the women valued fertility preservation procedures that could be regarded as a means to restore fertility. A unique feature identified was that fertility preservation was seen also as a way to restore gender identity perceived to be lost or threatened during diagnosis and treatment. Fertility counseling was suboptimal, with wide variability among studies reviewed. Comparisons between gynecologic cancers and other cancer types about fertility counseling rates were inconclusive. The potential negative impact of impaired fertility on patients' mental health and quality of life was also documented. CONCLUSIONS: Fertility and parenthood were important matters in patients' lives, with the majority of patients expressing positive attitudes toward future childbearing. Results confirm that the inclusion of patients with gynecologic cancer in research studies focusing on this topic still remains low. Additionally, the provision of fertility counseling and referral by health professionals is still suboptimal.

Decisional Regret in Female Oncofertility Decision Making-An Integrative Narrative Review.

It is well established that fertility is an important issue for young women with cancer at reproductive age, as many have not initiated or completed their parenthood goals when diagnosed. Because cancer treatments may impair fertility, women face fertility decisions that are often complex and surrounded by uncertainty. This may put patients at risk for psychological distress and the experience of regret regarding decisions made at diagnosis, which may be associated with a negative impact on women's QoL. This narrative review addresses current knowledge about decisional regret regarding fertility preservation decisions in adult female cancer patients at reproductive age. Electronic searches were conducted on Pubmed database for articles published in English from 1 January 2000 to 1 July 2021 that assessed decisional regret following fertility decisions in young women diagnosed at childbearing age. Of the 96 articles identified, nine provided information on decisional regret regarding fertility decisions. Studies reported that, overall, decisional regret regarding oncofertility decisions was low. Factors associated with the experience of decisional regret were patients' perceived quality and satisfaction with fertility counseling received, the decision to undergo fertility preservation, desire for children and decisional conflict. Health providers should be aware of the factors that are potentially modifiable and prone to improvement in order to reduce decisional regret. All efforts should be made to improve availability of and access to tailored high quality fertility counseling and fertility preservation. Given the growing evidence that decision aids (DAs) are effective in increasing knowledge and reducing decisional conflict and regret, their use in a routine and timely manner to complement fertility counseling is recommended.

Ibuprofen disrupts a WNK1/GSK3ß/SRPK1 protein complex required for expression of tumor-related splicing variant RAC1B in colorectal cells.

A major risk factor promoting tumor development is chronic inflammation and the use of nonsteroidal anti-inflammatory drugs (NSAID), including ibuprofen, can decrease the risk of developing various types of cancer, including colorectal cancer (CRC). Although the molecular mechanism behind the antitumor properties of NSAIDs has been largely attributed to inhibition of cyclooxygenases (COXs), several studies have shown that the chemopreventive properties of ibuprofen also involve multiple COX-independent effects. One example is its ability to inhibit the alternative splicing event generating RAC1B, which is overexpressed in a specific subset of BRAF-mutated colorectal tumors and sustains cell survival. Here we describe the mechanism by which ibuprofen prevents RAC1B alternative splicing in a BRAF mutant CRC cell line: it leads to decreased translocation of SRPK1 and SRSF1 to the nucleus and is regulated by a WNK1/GSK3ß/SRPK1 protein kinase complex. Surprisingly, we demonstrate that ibuprofen does not inhibit the activity of any of the involved kinases but rather promotes disassembly of this regulatory complex, exposing GSK3ß serine 9 to inhibitory phosphorylation, namely by AKT, which results in nuclear exclusion of SRPK1 and SRSF1 hypophosphorylation. The data shed new light on the biochemical mechanisms behind ibuprofen's action on alternative spliced RAC1B and may support its use in personalized approaches to CRC therapy or chemoprevention regimens.

Alternative Splicing: Expanding the Landscape of Cancer Biomarkers and Therapeutics.

Alternative splicing (AS) is a critical post-transcriptional regulatory mechanism used by more than 95% of transcribed human genes and responsible for structural transcript variation and proteome diversity. In the past decade, genome-wide transcriptome sequencing has revealed that AS is tightly regulated in a tissue- and developmental stage-specific manner, and also frequently dysregulated in multiple human cancer types. It is currently recognized that splicing defects, including genetic alterations in the spliced gene, altered expression of both core components or regulators of the precursor messenger RNA (pre-mRNA) splicing machinery, or both, are major drivers of tumorigenesis. Hence, in this review we provide an overview of our current understanding of splicing alterations in cancer, and emphasize the need to further explore the cancer-specific splicing programs in order to obtain new insights in oncology. Furthermore, we also discuss the recent advances in the identification of dysregulated splicing signatures on a genome-wide scale and their potential use as biomarkers. Finally, we highlight the therapeutic opportunities arising from dysregulated splicing and summarize the current approaches to therapeutically target AS in cancer.

Integration of partners of young women with cancer in oncofertility evidence-based informational resources.

Oncofertility has evolved over the years, with a prodigious amount of research documenting the importance of fertility for young patients with cancer, and the potential impact that fertility impairments due to cancer treatments has on their Quality of Life (QoL). Multiple professional bodies and scientific societies have included fertility as an integral part of clinical management. Clinical guidelines advocate that health professionals have the duty to discuss the risk of infertility and fertility preservation options as early as possible and refer to fertility specialists when appropriate. Collectively, fertility decisions are regarded as difficult for both patients and providers. Since providing fertility-related information is vital for better decision making, researchers and policy makers have concentrated their efforts in developing educational tools to aid decisions and guidelines to optimize the delivery of this information, focusing mainly on patients-providers and largely neglecting the role and influence that partners play in this process. Here, we reflect on the importance of partners in fertility decisions, with a focus on the provision of fertility-related information that is also geared towards partner. We highlight the need to involve partners in fertility discussions, and that their needs should be taken into account in both clinical guidelines and in the development of educational tools, for an optimal decision-making process.

Prognostic Factors and Life Expectancy in Canine Leishmaniosis.

Canine leishmaniosis (CanL) is a chronic and potentially fatal disease. The prognosis of CanL depends on the severity of the clinical signs and clinicopathological abnormalities presented by the dog at the time of diagnosis. This study aims to estimate the survival time of dogs with CanL, determining the prognostic value of different clinical and clinicopathological parameters. Medical records of 99 dogs diagnosed with CanL in five veterinary centers of the Alentejo region (Portugal) were examined retrospectively. The majority of dogs presented hyperproteinemia, moderate normocytic normochromic anemia, normal blood urea and creatinine levels and were classified as stage 1 according to the International Interest Society (IRIS) guidelines at the time of diagnosis. The severity of anemia, presence of concomitant infectious diseases at the time of diagnosis and the anti-Leishmania therapy were correlated with the survival time. The influence of renal dysfunction was evaluated by Receiver Operating Characteristic (ROC) curve and survival analysis. Survival analysis demonstrated that patients classified as IRIS 1 at the time of diagnosis survived more than four years, in contrast with dogs classified as IRIS 2 that survived around two and half years and dogs classified as IRIS 3-4 that survived around one month. IRIS stage deteriorated during the course of CanL in one third of the dogs and was the principal cause of death or euthanasia in a high proportion of animals. In some cases, dogs did not receive anti-Leishmania treatment or abandoned the veterinary follow-ups, which may have considerable repercussions for animal wellbeing and public health. This study reinforces the value of blood urea and creatinine levels as prognostic factors in CanL.

Protocol for the development and acceptability of a fertility-related decision aid for young women with breast cancer in Portugal.

INTRODUCTION: Young patients with breast cancer may face impaired fertility due to cancer treatments, which often leads to complex fertility decisions. To aid fertility decision-making, it is crucial that women have access to high-quality information; however, their fertility information needs are often unmet. Decision aids (DAs) are educational materials to assist with decision-making, by addressing individual values and preferences. In oncofertility, DAs may constitute a valuable resource to help patients obtain information and make better informed decisions. This paper reports on the protocol of the development and transcreation of a fertility-related DA booklet to support young Portuguese patients with breast cancer, originally developed and validated for an Australian audience. METHODS AND ANALYSIS: Recent literature on clinical guidelines will be reviewed. A summary of these guidelines will be created and will inform the first round of DAs revisions. A forward translation process will translate the DA from Australian English to Portuguese. A multidisciplinary Portuguese experts panel will revise and give feedback on the scientific and cultural aspects of the DA content for Portuguese audience. Next, a backward translation process will assess content equivalence between the original and the final adapted version. Finally, Learner Verification (LV) will be used in a qualitative study of young patients with breast cancer and their partners. Two focus groups with 6-10 participants each will be conducted with: (1) recently diagnosed young patients with breast cancer; (2) breast cancer survivors and (3) their partners. Results from the DA acceptability assessment will inform its final version. Data will be analysed using content analysis and constant comparison method to identify key themes/textual units related to LV. ETHICS AND DISSEMINATION: Ethical approval was granted by the Portuguese Institute of Oncology Porto. Results will be disseminated through peer-reviewed journals and presented at scientific meetings for academic and health professionals audiences.

Networks of mRNA Processing and Alternative Splicing Regulation in Health and Disease.

mRNA processing events introduce an intricate layer of complexity into gene expression processes, supporting a tremendous level of diversification of the genome's coding and regulatory potential, particularly in vertebrate species. The recent development of massive parallel sequencing methods and their adaptation to the identification and quantification of different RNA species and the dynamics of mRNA metabolism and processing has generated an unprecedented view over the regulatory networks that are established at this level, which contribute to sustain developmental, tissue specific or disease specific gene expression programs. In this chapter, we provide an overview of the recent evolution of transcriptome profiling methods and the surprising insights that have emerged in recent years regarding distinct mRNA processing events - from the 5' end to the 3' end of the molecule.

Childbearing across borders: Fertility and parenthood attitudes and decisions among breast cancer survivors in USA and Portugal.

OBJECTIVE: To compare fertility and childbearing attitudes and decisions of Portuguese and American female reproductive aged breast cancer survivors. METHODS: This was a cross-sectional study of 102 young breast cancer survivors (59 from Portugal and 43 from USA). Demographic, clinical and reproductive information were collected. Fertility and parenthood attitudes and decisions were assessed through a self-report questionnaire devised specifically for the study. RESULTS: Fertility issues became very important after the diagnosis for most of the women (51%). Few differences existed between USA and Portuguese participants. USA participants were more likely to undergo FP (23% USA vs Portugal 5%, p = 0.01). Portuguese women were more dissatisfied with their physician's explanations about fertility (Portugal: 23% vs USA: 3%; p = 0.01). Overall, women relied on their oncologist for fertility information (70%); only Portuguese women discussed fertility with their family medicine physician (11%). Overall, women showed positive attitudes towards motherhood. Portuguese women were more likely to report their partners placed more value on the family after their illness (Portuguese agree: 55% vs USA agree: 14%; p < 0.001). CONCLUSIONS: Fertility and childbearing after breast cancer are important issues regardless of culture, background or country's heath care system. Overall, few differences across the USA and Portuguese samples were found on fertility and childbearing attitudes and decisions.

Genetics of personalized medicine: cancer and rare diseases.

The 21st annual meeting of the Portuguese Society of Human Genetics (SPGH), organized by Luísa Romão, Ana Sousa and Rosário Pinto Leite, was held in Caparica, Portugal, from the 16th to the 18th of November 2017. Having entered an era in which personalized medicine is emerging as a paradigm for disease diagnosis, treatment and prevention, the program of this meeting intended to include lectures by leading national and international scientists presenting exceptional findings on the genetics of personalized medicine. Various topics were discussed, including cancer genetics, transcriptome dynamics and novel therapeutics for cancers and rare disorders that are designed to specifically target molecular alterations in individual patients. Several panel discussions were held to emphasize (ethical) issues associated with personalized medicine, including genetic cancer counseling.

Signaling Pathways Driving Aberrant Splicing in Cancer Cells.

Aberrant profiles of pre-mRNA splicing are frequently observed in cancer. At the molecular level, an altered profile results from a complex interplay between chromatin modifications, the transcriptional elongation rate of RNA polymerase, and effective binding of the spliceosome to the generated transcripts. Key players in this interplay are regulatory splicing factors (SFs) that bind to gene-specific splice-regulatory sequence elements. Although mutations in genes of some SFs were described, a major driver of aberrant splicing profiles is oncogenic signal transduction pathways. Signaling can affect either the transcriptional expression levels of SFs or the post-translational modification of SF proteins, and both modulate the ratio of nuclear versus cytoplasmic SFs in a given cell. Here, we will review currently known mechanisms by which cancer cell signaling, including the mitogen-activated protein kinases (MAPK), phosphatidylinositol 3 (PI3)-kinase pathway (PI3K) and wingless (Wnt) pathways but also signals from the tumor microenvironment, modulate the activity or subcellular localization of the Ser/Arg rich (SR) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs) families of SFs.

Review of fertility preservation issues for young women with breast cancer.

It is well documented that cancer treatment may temporarily or permanently impair childbearing potential of young women with breast cancer. Given that many patients have not initiated or completed their families when diagnosed, fertility issues are of utmost importance in this clinical population. This review addresses the importance of incorporating fertility issues into the clinical care of young breast cancer patients, focusing on recent knowledge and counselling practices about fertility-related issues and the complexity of fertility-related decisions in this population. Multiple studies report cancer-related infertility may have serious psychological consequences and reduce Quality of Life for some patients. To guide health care providers and patients regarding appropriate, safe, and cost-effective fertility care for women who desire biological children, several professional organizations have developed clinical practice guidelines. However, the extent to which health professionals use these guidelines and provide timely and appropriate fertility-related information to patients is questionable. Fertility should not be neglected by health care providers and a multidisciplinary team is needed to target fertility issues at diagnosis and into survivorship care, providing timely, clear information that includes support, resources, and appropriate referral to fertility specialists. This information will assist in making well-informed decisions about fertility after breast cancer.

Targeting the serrated pathway of colorectal cancer with mutation in BRAF.

A recently acknowledged morphological pathway to colorectal cancer originates from precursor polyps with a serrated appearance due to branching and folding of the colon epithelium. This serrated origin accounts for up to 30% of all colorectal tumors but these are heterogeneous regarding molecular characteristics and patient outcome. Here we review the current knowledge about the classification of this tumor subtype and its association with five key features: mutation status of the BRAF or KRAS genes, the CpG island methylation phenotype, microsatellite instability, immune cell infiltration, and overexpression of GTPase RAC1b. Subsequently, available therapeutic approaches for targeting these molecular characteristics are presented and critically discussed.

Data in support of a functional analysis of splicing mutations in the IDS gene and the use of antisense oligonucleotides to exploit an alternative therapy for MPS II.

This data article contains insights into the methodology used for the analysis of three exonic mutations altering the splicing of the IDS gene: c.241C>T, c.257C>T and c.1122C>T. We have performed splicing assays for the wild-type and mutant minigenes corresponding to these substitutions. In addition, bioinformatic predictions of splicing regulatory sequence elements as well as RNA interference and overexpression experiments were conducted. The interpretation of these data and further extensive experiments into the analysis of these three mutations and also into the methodology applied to correct one of them can be found in "Functional analysis of splicing mutations in the IDS gene and the use of antisense oligonucleotides to exploit an alternative therapy for MPS II" Matos et al. (2015) [1].

Functional analysis of splicing mutations in the IDS gene and the use of antisense oligonucleotides to exploit an alternative therapy for MPS II.

Mucopolysaccharidosis II is a lysosomal storage disorder caused by mutations in the IDS gene, including exonic alterations associated with aberrant splicing. In the present work, cell-based splicing assays were performed to study the effects of two splicing mutations in exon 3 of IDS, i.e., c.241C>T and c.257C>T, whose presence activates a cryptic splice site in exon 3 and one in exon 8, i.e., c.1122C>T that despite being a synonymous mutation is responsible for the creation of a new splice site in exon 8 leading to a transcript shorter than usual. Mutant minigene analysis and overexpression assays revealed that SRSF2 and hnRNP E1 might be involved in the use and repression of the constitutive 3' splice site of exon 3 respectively. For the c.1122C>T the use of antisense therapy to correct the splicing defect was explored, but transfection of patient fibroblasts with antisense morpholino oligonucleotides (n=3) and a locked nucleic acid failed to abolish the abnormal transcript; indeed, it resulted in the appearance of yet another aberrant splicing product. Interestingly, the oligonucleotides transfection in control fibroblasts led to the appearance of the aberrant transcript observed in patients' cells after treatment, which shows that the oligonucleotides are masking an important cis-acting element for 5' splice site regulation of exon 8. These results highlight the importance of functional studies for understanding the pathogenic consequences of mis-splicing and highlight the difficulty in developing antisense therapies involving gene regions under complex splicing regulation.

Posttranscriptional Regulation of Splicing Factor SRSF1 and Its Role in Cancer Cell Biology.

Over the past decade, alternative splicing has been progressively recognized as a major mechanism regulating gene expression patterns in different tissues and disease states through the generation of multiple mRNAs from the same gene transcript. This process requires the joining of selected exons or usage of different pairs of splice sites and is regulated by gene-specific combinations of RNA-binding proteins. One archetypical splicing regulator is SRSF1, for which we review the molecular mechanisms and posttranscriptional modifications involved in its life cycle. These include alternative splicing of SRSF1 itself, regulatory protein phosphorylation events, and the role of nuclear versus cytoplasmic SRSF1 localization. In addition, we resume current knowledge on deregulated SRSF1 expression in tumors and describe SRSF1-regulated alternative transcripts with functional consequences for cancer cell biology at different stages of tumor development.

Quality of life in adolescent and young adult cancer patients: a systematic review of the literature.

INTRODUCTION: Adolescent and young adult (AYA) cancer survivors experience many unique challenges and quality of life (QoL) effects that persist beyond cancer diagnosis and treatment. Due to continuous improvements in technology and cancer treatments resulting in improved survival rates, the identification of late effects, survivorship issues, and QoL is moving to the forefront of cancer research. The goal of this systematic review was to identify key psychosocial factors impacting QoL in AYA oncology populations. METHODS: A systematic review of the literature was conducted using combinations of these phrases or keywords: "adolescent and young adult or AYA" AND "health outcomes OR quality of life OR psychology" AND "neoplasm OR cancer OR oncology". A total of 35 articles were included in this review. Studies were classified into two categories: AYA perceptions and stakeholder perceptions. RESULTS: AYA cancer survivors were more likely to have "worse" or impaired QoL compared with the general population, regardless of other demographic factors. AYAs described both positive and negatives experiences with their medical care, the educational information received, and the supportive care services. Although health care professionals were likely to underestimate or misjudge the health preferences and support needs of AYAs, these perceptions varied across disciplines and levels of experience. CONCLUSION: The literature is lacking in sufficient evidence-based interventions to improve QoL in AYA cancer populations. Further, the tools to adequately measure QoL in this population are also unsatisfactory. The literature, however, consistently shows agreement regarding the unique needs of this population, indicating a trend toward health care standardization within age ranges or life stages. We suggest the need for AYA-specific programs in health care institutions that comprise a multidisciplinary team that addresses all the unique medical and QoL needs of AYAs.