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\"Jennifer Scott is the powerhouse behind the internationally best-selling series of Madame Chic books about how to live with the grace and elegance of a Frenchwoman. In Connoisseur Kids, her departure from the Madame Chic publishing, she presents the do's and don'ts of raising responsible, civilized, well-behaved children who are a pleasure to be around. In 5 chapters detailing the basics of manners, hygiene, being neat, and physical and emotional health, children ages 4 to 7 will be equipped to be good citizens of the world through rhymes and songs, hands-on activities, and lovely illustrations. Authoritatively curated by a mother of 3 recognized for her social graces, the content includes must-know guidance for everyday life (please and thank yous, table manners, listening), social protocols (thank-you cards, listening), as well as tidy habits for their rooms, possessions, and tiny bodies. Packaged in a gifty, full-color hardcover, and featuring an engaging introduction on the importance of creating a harmonious family life, this is irresistibly chic and charming reference at its gifty best\"-- Provided by publisher.

Maintenance monotherapy with the PARP inhibitor olaparib significantly prolonged progression-free survival (PFS) versus placebo in patients with platinum-sensitive recurrent serous ovarian cancer. We aimed to explore the hypothesis that olaparib is most likely to benefit patients with a BRCA mutation. We present data from the second interim analysis of overall survival and a retrospective, preplanned analysis of data by BRCA mutation status from our randomised, double-blind, phase 2 study that assessed maintenance treatment with olaparib 400 mg twice daily (capsules) versus placebo in patients with platinum-sensitive recurrent serous ovarian cancer who had received two or more platinum-based regimens and who had a partial or complete response to their most recent platinum-based regimen. Randomisation was by an interactive voice response system, stratified by time to progression on penultimate platinum-based regimen, response to the most recent platinum-based regimen before randomisation, and ethnic descent. The primary endpoint was PFS, analysed for the overall population and by BRCA status. This study is registered with ClinicalTrials.gov, number NCT00753545. Between Aug 28, 2008, and Feb 9, 2010, 136 patients were assigned to olaparib and 129 to placebo. BRCA status was known for 131 (96%) patients in the olaparib group versus 123 (95%) in the placebo group, of whom 74 (56%) versus 62 (50%) had a deleterious or suspected deleterious germline or tumour BRCA mutation. Of patients with a BRCA mutation, median PFS was significantly longer in the olaparib group than in the placebo group (11·2 months [95% CI 8·3–not calculable] vs 4·3 months [3·0–5·4]; HR 0·18 [0·10–0·31]; p<0·0001); similar findings were noted for patients with wild-type BRCA, although the difference between groups was lower (7·4 months [5·5–10·3] vs 5·5 months [3·7–5·6]; HR 0·54 [0·34–0·85]; p=0·0075). At the second interim analysis of overall survival (58% maturity), overall survival did not significantly differ between the groups (HR 0·88 [95% CI 0·64–1·21]; p=0·44); similar findings were noted for patients with mutated BRCA (HR 0·73 [0·45–1·17]; p=0·19) and wild-type BRCA (HR 0·99 [0·63–1·55]; p=0·96). The most common grade 3 or worse adverse events in the olaparib group were fatigue (in ten [7%] patients in the olaparib group vs four [3%] in the placebo group) and anaemia (seven [5%] vs one [<1%]). Serious adverse events were reported in 25 (18%) patients who received olaparib and 11 (9%) who received placebo. Tolerability was similar in patients with mutated BRCA and the overall population. These results support the hypothesis that patients with platinum-sensitive recurrent serous ovarian cancer with a BRCA mutation have the greatest likelihood of benefiting from olaparib treatment. AstraZeneca.

Epigenetic alterations, including aberrant DNA methylation, are now recognized as bone fide hallmarks of cancer, which can contribute to cancer initiation, progression, therapy responses and therapy resistance. Methylation of gene promoters can have a range of impacts on cancer risk, clinical stratification and therapeutic outcomes. We provide several important examples of genes, which can be silenced or activated by promoter methylation and highlight their clinical implications. These include the mismatch DNA repair genes MLH1 and MSH2, homologous recombination DNA repair genes BRCA1 and RAD51C, the TERT oncogene and genes within the P15/P16/RB1/E2F tumour suppressor axis. We also discuss how these methylation changes might occur in the first place – whether in the context of the CpG island methylator phenotype or constitutional DNA methylation. The choice of assay used to measure methylation can have a significant impact on interpretation of methylation states, and some examples where this can influence clinical decision-making are presented. Aberrant DNA methylation patterns in circulating tumour DNA (ctDNA) are also showing great promise in the context of non-invasive cancer detection and monitoring using liquid biopsies; however, caution must be taken in interpreting these results in cases where constitutional methylation may be present. Thus, this review aims to provide researchers and clinicians with a comprehensive summary of this broad, but important subject, illustrating the potentials and pitfalls of assessing aberrant DNA methylation in cancer. Plain language summary Silencing genes role in initiation of cancer and clinical impacts Genes can be silenced by molecular tags being placed on them. This is a normal process that controls when and where genes are available to be used. In some cases this silencing can be incorrectly applied to genes involved in preventing cancer, causing cancer initiation and progression. This review discusses the role of one of these tagging processes, DNA methylation and its role in initiation of cancer and implications for treatment.

Female gametes are stored in the ovary in structures called primordial follicles, the supply of which is non-renewable. It is well established that DNA-damaging cancer treatments can deplete the ovarian reserve of primordial follicles, causing premature ovarian failure and infertility. The precise mechanisms underlying this chemotherapy-driven follicle loss are unclear, and this has limited the development of targeted ovarian-protective agents. To address this fundamental knowledge gap, we used gene deletion mouse models to examine the role of the DNA damage-induced pro-apoptotic protein, PUMA, and its transcriptional activator TAp63, in primordial follicle depletion caused by treatment with cyclophosphamide or cisplatin. Cyclophosphamide caused almost complete destruction of the primordial follicle pool in adult wild-type (WT) mice, and a significant destructive effect was also observed for cisplatin. In striking contrast, Puma −/− mice retained 100% of their primordial follicles following either genotoxic treatment. Furthermore, elimination of PUMA alone completely preserved fertility in cyclophosphamide-treated mice, indicating that oocytes rescued from DNA damage-induced death can repair themselves sufficiently to support reproductive function and offspring health. Primordial follicles were also protected in TAp63 −/− mice following cisplatin treatment, but not cyclophosphamide, suggesting mechanistic differences in the induction of apoptosis and depletion of the ovarian reserve in response to these different chemotherapies. These studies identify PUMA as a crucial effector of apoptosis responsible for depletion of primordial follicles following exposure to cyclophosphamide or cisplatin, and this indicates that inhibition of PUMA may be an effective ovarian-protective strategy during cancer treatment in women.

Ovarian cancer, in particularly high-grade serous ovarian cancer (HGSOC) and ovarian carcinosarcoma (OCS), are highly aggressive and deadly female cancers with limited treatment options. These tumors are generally unresponsive to immune check-point inhibitor (ICI) therapy and are referred to as immunologically “cold” tumors. Cell-based therapy, in particular, adoptive T-cell therapy, is an alternative immunotherapy option that has shown great potential, especially chimeric antigen receptor T cell (CAR-T) therapy in the treatment of hematologic malignancies. However, the efficacy of CAR-T therapy in solid tumors has been modest. This review explores the potential of another cell-based therapy, T-cell receptor therapy (TCR-T) as an alternate treatment option for immunological “cold” OC and OCS tumors.

Can combining oncogenic kinase inhibitors with direct activators of the apoptosis machinery, such as the BH3 mimetic ABT-737, produce durable clinical responses in patients with cancer? Therapeutic targeting of tumours on the basis of molecular analysis is a new paradigm for cancer treatment but has yet to fulfil expectations. For many solid tumours, targeted therapeutics, such as inhibitors of oncogenic kinase pathways, elicit predominantly disease-stabilizing, cytostatic responses, rather than tumour regression. Combining oncogenic kinase inhibitors with direct activators of the apoptosis machinery, such as the BH3 mimetic ABT-737, may unlock potent anti-tumour potential to produce durable clinical responses with less collateral damage.

Uterine malignancies represent a broad and heterogeneous group of neoplasms, which collectively account for the majority of gynaecological malignancies in developed countries. For a significant proportion of these, mortality rates and clinical outcomes are of major concern, owing to complex molecular profiles and aggressive phenotypes that are largely refractory to conventional therapeutic approaches. Recent advancements in precision medicine and the development of targeted therapies have been transformative for several common cancer types; however, the same benefits are yet to be realised for many uterine cancers. This review comprehensively details the diverse molecular features characterising the various subtypes of uterine malignancies. Furthermore, we have examined the therapeutic approaches actively investigated to target these unique molecular features, identifying pathways and treatments that offer the greatest potential patient benefit. Among increasingly personalised strategies, particular promise is shown by HER2-targeted therapies for HER2-positive malignancies (e.g. trastuzumab deruxtecan). Additionally, targeting TP53 wild-type tumours with selinexor, as well as addressing AKT and DNA repair pathways in both uterine carcinomas and sarcomas (i.e. AKT inhibitor and poly(ADP-ribose) polymerase inhibitor combinations), represents key advancements. Furthermore, anti-angiogenic and immune checkpoint inhibitor combinations hold significant promise for future therapeutic strategies. Plain language summary Investigating the potential of matching drugs to specific molecular changes in uterine cancers Uterine malignancies represent a common and complex group of cancers affecting many individuals. Unfortunately, a significant proportion of these are very aggressive and challenging to treat with standard methods. Recent progress in matching treatments based on DNA and molecular changes in individual malignancies have been transformative for several common cancer types, however the same benefits are yet to be shown for many uterine malignancies. In this review, we explore new treatments that are currently being studied to specifically target these genetic and molecular features, highlighting the personalised approaches that show the most promise for patients.

Most cases of cervical cancer are still caused by persistent infection with high-risk human papillomavirus (HPV) variants, which also drives the development of ~30% of vulvar and ~76% of vaginal malignancies. Implementation of HPV vaccination has significantly decreased the incidence of high-grade pre-cancerous cervical, vulvar and vaginal lesions. However, cervical, vulvar and vaginal cancers can still develop (with or without HPV integration) and treatment options are limited compared to more common cancers. As with many other cancer types, molecular studies should identify targeted agents that could be added to treatment regimens to improve response rates and survival. Combination regimens involving chemoradiotherapy, anti-angiogenics and immune checkpoint inhibitors should be considered in the first instance. Then, depending on the molecular profile of a particular tumour, more targeted therapies should be considered. In particular, HER2-targeted therapies are likely to be a viable treatment option for many individuals, including those with cervical adenocarcinoma of gastric-type and vulvar Paget’s disease. In cervical cancer, TGFβ, PI3K, ATR and PARP inhibitors have shown some benefit and warrant further investigation. In vulvar cancer, combination therapies involving EGFR inhibitors require ongoing evaluation. In vaginal cancer, combination therapies targeting the PI3K and MAPK pathways should be investigated for squamous cell carcinoma and melanoma, respectively. Finally, with the rapid expansion of antibody-drug conjugates in recent years, this is an especially exciting area of investigation. For cervical, vulvar and vaginal cancers specifically, trastuzumab deruxtecan and tisotumab vedotin could be important therapeutic options in the right context. In this review, we describe the molecular features of different cervical, vulvar and vaginal cancer types, current genomically-matched therapies being investigated and discuss treatment strategies with future potential. Plain language summary Investigating the potential of matching drugs to specific changes in the DNA in cervical, vulvar and vaginal cancers Most cases of cervical cancer are still caused by persistent infection with high-risk human papilloma virus (HPV) variants, which also drives the development of ~30% of vulvar and ~76% of vaginal malignancies. HPV vaccination has been an important preventative mechanism for these types of malignancies, however, they can still arise (with or without HPV infection). Treatment options for cervical, vulvar and vaginal cancers are still limited compared to more common cancers. Investigating changes in the DNA in a particular tumour may indicate therapeutic options involving targeted agents (specific for the DNA alterations). Clinical trials have been developed to test responses to some of these targeted agents in tumours carrying the relevant DNA alterations. Results from these trials indicate that drugs targeting specific molecules, such as HER2, TGFβ, PI3K, ATR and PARP, may be effective against cervical, vulvar or vaginal tumours harbouring relevant DNA alterations. In this review, we describe the most frequent DNA changes observed in the different subtypes of cervical, vulvar and vaginal cancers and discuss different therapies currently being investigated to target these changes, with consideration of what might be possible in the future.

Epithelial ovarian cancer (OC) comprises molecularly distinct disease types, with high-grade serous ovarian cancer (HGSOC) accounting for ~75% of OC diagnoses; ovarian clear cell carcinoma (OCCC) and endometrioid ovarian carcinoma (EnOC) at ~10% each; mucinous ovarian carcinoma (MOC) and low-grade serous ovarian carcinoma (LGSOC) at ⩽5% each; and ovarian carcinosarcoma (OCS), the rarest type of OC at 1%–4% of OC diagnoses. LGSOC has the best prognosis, followed by EnOC, MOC and OCCC, with HGSOC then OCS being the most aggressive. For all types of OC, diagnosis at the advanced-stage results in dramatically reduced survival. Initial treatment consists of debulking surgery and platinum-based chemotherapy, usually in combination with a taxane; however, response rates vary depending on the OC type. Treatments specific to the OC type may improve treatment outcomes. For HGSOC, poly(ADP-ribose) polymerase inhibitor (PARPi) therapy has improved survival for women with DNA homologous recombination repair (HRR) defects; however, acquired resistance remains an issue and more effective treatments are needed. Next-generation sequencing of distinct types of OC has revealed the complexity of genetic variants and larger-scale genomic and epigenomic alterations harboured, including proven and putative biomarkers of drug response. A predominance of distinct gene classes is altered in specific OC types: HRR genes (e.g. BRCA1 and BRCA2) in HGSOC; ARID1A and PIK3CA in OCCC; PIK3CA and KRAS in EnOC; CDKN2A and KRAS in MOC and MAPK pathway genes (e.g. BRAF and KRAS) in LGSOC. Generating evidence for effective drug combination therapies targeting relevant aberrations in each OC type is urgently needed. The effects of long-term drug treatment on OC genomes, acquired drug-resistance and OC relapse require clarification, especially in women with HGSOC with acquired resistance to PARPi. This article provides an overview of the main types of OC and their genomic profiles. It highlights recent encouraging clinical trials, with an emphasis on the future of genomically-targeted combination therapies, for both first-line and subsequent treatment of OC. We focus on PARPi combinations for HGSOC, MAPK pathway inhibitors for LGSOC, cell cycle checkpoint inhibitors for OC with CCNE1 amplification, the potential of immune checkpoint inhibitors in OCCC and encouraging, as yet preliminary, responses for antibody-drug conjugate-based therapy. Thus, OC type-specific genomic susceptibilities provide direction for personalised therapy in OC. Plain language summary Investigating the potential of matching drugs to specific changes in the DNA in ovarian cancers Ovarian cancer (OC) can be divided into distinct disease types based on the cell type from which the cancer originated, with high-grade serous ovarian cancer being the most prevalent OC type. Each type of OC can be further classified by changes in the DNA which affect specific genes. Treatment options are increasing as a result of the number of drugs in clinical trials shown to have efficacy in matching these DNA changes. Changes in the DNA may affect cancer cell growth and survival, DNA repair, or interaction of the cancer cells with the immune system. Finding effective drug combinations to target these changes is essential, to most effectively treat patients. In addition, understanding how long-term drug treatment may lead to drug resistance and OC relapse is crucial. In this review, we describe the most frequent DNA or protein changes observed in the different types of OC and discuss different therapies currently being investigated to target these changes. We focus on PARP inhibitors, MAPK pathway inhibitors, cell cycle checkpoint inhibitors, immune checkpoint inhibitors, and antibody-drug conjugate (ADC)-based therapies for specific OC types depending on genomic susceptibilities.

Improvement in the ability to target underlying drivers and vulnerabilities of high-grade serous ovarian cancer (HG-SOC) requires the development of molecularly annotated pre-clinical models reflective of clinical responses. We generated patient-derived xenografts (PDXs) from consecutive, chemotherapy-naïve, human HG-SOC by transplanting fresh human HG-SOC fragments into subcutaneous and intra-ovarian bursal sites of NOD/SCID IL2Rγnull recipient mice, completed molecular annotation and assessed platinum sensitivity. The success rate of xenografting was 83%. Of ten HG-SOC PDXs, all contained mutations in TP53, two were mutated for BRCA1, three for BRCA2, and in two, BRCA1 was methylated. In vivo cisplatin response, determined as platinum sensitive (progression-free interval ≥100 d, n = 4), resistant (progression-free interval <100 d, n = 3) or refractory (n = 3), was largely consistent with patient outcome. Three of four platinum sensitive HG-SOC PDXs contained DNA repair gene mutations, and the fourth was methylated for BRCA1. In contrast, all three platinum refractory PDXs overexpressed dominant oncogenes (CCNE1, LIN28B and/or BCL2). Because PDX platinum response reflected clinical outcome, these annotated PDXs will provide a unique model system for preclinical testing of novel therapies for HG-SOC. •High-grade serous ovarian cancer patient-derived xenografts from fragments (83% success).•In vivo platinum response (sensitive ≥ 100 d) consistent with patient outcome.•Three of four platinum-sensitive PDX contained mutations in BRCA1 or BRCA2.•All three platinum refractory PDX overexpressed dominant oncogenes.•These annotated PDX will enhance preclinical testing of novel therapies.