Distinct members of the Caenorhabditis elegans CeMbio reference microbiota exert cryptic virulence that is masked by host defense.

Microbiotas are complex microbial communities that colonize specific niches in the host and provide essential organismal functions that are important in health and disease. Understanding the ability of each distinct community member to promote or impair host health, alone or in the context of the community, is imperative for understanding how differences in community structure affect host health and vice versa. Recently, a reference 12-member microbiota for the model organism Caenorhabditis elegans, known as CeMbio, was defined. Here, we show the differential ability of each CeMbio bacterial species to activate innate immunity through the conserved PMK-1/p38 MAPK, ACh-WNT, and HLH-30/TFEB pathways. Although distinct CeMbio members differed in their ability to activate the PMK-1/p38 pathway, the ability to do so did not correlate with bacterial-induced lifespan reduction in wild-type or immunodeficient animals. In contrast, most species activated HLH-30/TFEB and showed virulence toward hlh-30-deficient animals. These results suggest that the microbiota of C. elegans is rife with bacteria that can shorten the host's lifespan if host defense is compromised and that HLH-30/TFEB is a fundamental and key host protective factor.

Differentially expressed microRNAs in aneuploid preimplantation blastocysts: a systematic review.

Introduction: MicroRNAs are small noncoding genes with gene expression regulatory function. Their emergence as potential diagnostic biomarker for many diseases has gained a specific interest among researchers. Observations of changes in miRNA levels correlating with aneuploidy in early embryos raise the prospective of employing miRNA as biomarkers to assess the embryo quality. Method: To identify and gather the miRNAs with potential link to chromosomal abnormalities in embryos from previous research, we conducted a systematic search using four databases, including Embase, Medline, Web of Science, and Cochrane databases in accordance with PRISMA guidelines. Results: Out of 200 identified records, only seven met the inclusion criteria. Seven miRNAs: miR-19b, miR-517c, miR-518e, miR-522, miR-92a, and miR-106a exhibited persistent downregulation in aneuploid blastocysts in the included studies. These miRNAs are members of important miRNA clusters, associated with abnormal expression in studies on reproductive failure. Pathway analysis revealed their involvement in regulating gene transcription, as well as cell cycle progression and apoptosis. Discussion: The changes detected in the miRNA expression in aneuploid embryos across different studies support the aneuploidy and miRNA relationship and prospect miRNA as a valuable tool for the assessment of embryo quality. Collectively, these observations highlight the role of miRNAs in embryonic development, and their involvement in genetic abnormalities that occur in embryos, such as aneuploidy, indicating their potential implementation to improve the embryo selection and reproductive outcomes.

Distinct members of the C. elegans CeMbio reference microbiota exert cryptic virulence and infection protection.

Microbiotas are complex microbial communities that colonize specific niches in the host and provide essential organismal functions that are important in health and disease. A key aspect is the ability of each distinct community member to promote or impair host health, alone or in the context of the community, in hosts with varied levels of immune competence. Understanding such interactions is limited by the complexity and experimental accessibility of current systems and models. Recently, a reference twelve-member microbiota for the model organism C. elegans, known as CeMbio, was defined to aid the dissection of conserved host-microbiota interactions. Understanding the physiological impact of the CeMbio bacteria on C. elegans is in its infancy. Here, we show the differential ability of each CeMbio bacterial species to activate innate immunity through the conserved PMK-1/p38 MAPK, ACh/WNT, and HLH-30/TFEB pathways. Using immunodeficient animals, we uncovered several examples of bacterial 'cryptic' virulence, or virulence that was masked by the host defense response. The ability to activate the PMK-1/p38 pathway did not correlate with bacterial virulence in wild type or immunodeficient animals. In contrast, ten out of twelve species activated HLH-30/TFEB, and most showed virulence towards hlh-30-deficient animals. In addition, we identified Pseudomonas lurida as a pathogen in wild type animals, and Acinetobacter guillouiae as avirulent despite activating all three pathways. Moreover, short pre-exposure to A. guillouiae promoted host survival of infection with P. lurida, which was dependent on PMK-1/p38 MAPK and HLH-30/TFEB. These results suggest that the microbiota of C. elegans is rife with "opportunistic" pathogens, and that HLH-30/TFEB is a fundamental and key host protective factor. Furthermore, they support the idea that bacteria like A. guillouiae evolved the ability to induce host innate immunity to improve host fitness when confronted with pathogens, providing new insights into how colonization order impacts host health.

Integrating imaging-based classification and transcriptomics for quality assessment of human oocytes according to their reproductive efficiency.

PURPOSE: Utilising non-invasive imaging parameters to assess human oocyte fertilisation, development and implantation; and their influence on transcriptomic profiles. METHODS: A ranking tool was designed using imaging data from 957 metaphase II stage oocytes retrieved from 102 patients undergoing ART. Hoffman modulation contrast microscopy was conducted with an Olympus IX53 microscope. Images were acquired prior to ICSI and processed using ImageJ for optical density and grey-level co-occurrence matrices texture analysis. Single-cell RNA sequencing of twenty-three mature oocytes classified according to their competence was performed. RESULT(S): Overall fertilisation, blastulation and implantation rates were 73.0%, 62.6% and 50.8%, respectively. Three different algorithms were produced using binary logistic regression methods based on "optimal" quartiles, resulting in an accuracy of prediction of 76.6%, 67% and 80.7% for fertilisation, blastulation and implantation. Optical density, gradient, inverse difference moment (homogeneity) and entropy (structural complexity) were the parameters with highest predictive properties. The ranking tool showed high sensitivity (68.9-90.8%) but with limited specificity (26.5-62.5%) for outcome prediction. Furthermore, five differentially expressed genes were identified when comparing "good" versus "poor" competent oocytes. CONCLUSION(S): Imaging properties can be used as a tool to assess differences in the ooplasm and predict laboratory and clinical outcomes. Transcriptomic analysis suggested that oocytes with lower competence may have compromised cell cycle either by non-reparable DNA damage or insufficient ooplasmic maturation. Further development of algorithms based on image parameters is encouraged, with an increased balanced cohort and validated prospectively in multicentric studies.

Systematic review of mRNA expression in human oocytes: understanding the molecular mechanisms underlying oocyte competence.

The biggest cell in the human body, the oocyte, encloses almost the complete machinery to start life. Despite all the research performed to date, defining oocyte quality is still a major goal of reproductive science. It is the consensus that mature oocytes are transcriptionally silent although, during their growth, the cell goes through stages of active transcription and translation, which will endow the oocyte with the competence to undergo nuclear maturation, and the oocyte and embryo to initiate timely translation before the embryonic genome is fully activated (cytoplasmic maturation). A systematic search was conducted across three electronic databases and the literature was critically appraised using the KMET score system. The aim was to identify quantitative differences in transcriptome of human oocytes that may link to patient demographics that could affect oocyte competence. Data was analysed following the principles of thematic analysis. Differences in the transcriptome were identified with respect to age or pathological conditions and affected chromosome mis segregation, perturbations of the nuclear envelope, premature maturation, and alterations in metabolic pathways-amongst others-in human oocytes.

C. elegans orphan nuclear receptor NHR-42 represses innate immunity and promotes lipid loss downstream of HLH-30/TFEB.

In recent years, transcription factors of the Microphthalmia-TFE (MiT) family, including TFEB and TFE3 in mammals and HLH-30 in Caenorhabditis elegans, have emerged as important regulators of innate immunity and inflammation in invertebrates and vertebrates. Despite great strides in knowledge, the mechanisms that mediate downstream actions of MiT transcription factors in the context of innate host defense remain poorly understood. Here, we report that HLH-30, which promotes lipid droplet mobilization and host defense, induces the expression of orphan nuclear receptor NHR-42 during infection with Staphylococcus aureus. Remarkably, NHR-42 loss of function promoted host infection resistance, genetically defining NHR-42 as an HLH-30-controlled negative regulator of innate immunity. During infection, NHR-42 was required for lipid droplet loss, suggesting that it is an important effector of HLH-30 in lipid immunometabolism. Moreover, transcriptional profiling of nhr-42 mutants revealed wholesale activation of an antimicrobial signature, of which abf-2, cnc-2, and lec-11 were important for the enhanced survival of infection of nhr-42 mutants. These results advance our knowledge of the mechanisms by which MiT transcription factors promote host defense, and by analogy suggest that TFEB and TFE3 may similarly promote host defense via NHR-42-homologous nuclear receptors in mammals.

Challenging Endocrine Sensitivity of Hormone Receptor-Positive/HER2-Negative Advanced Breast Cancer with the Combination of Eribulin and Endocrine Therapy: The REVERT Study.

BACKGROUND: Luminal advanced breast cancer (ABC) patients eventually progress on endocrine therapy. REVERT aimed to explore whether eribulin could restore endocrine sensitivity in a randomized, non-comparative phase II trial. METHODS: Aromatase inhibitor (AI)-resistant patients with luminal ABC were randomized 1:1 to receive eribulin +/- AI. Patients were stratified by prior cyclin-dependent kinases 4/6 inhibitor (CDK4/6i) treatment. The primary endpoint was an investigator-assessed overall response rate (ORR) according to RECIST version 1.1 in the eribulin + AI arm. An interim analysis was planned with 11 evaluable patients according to a two-stage Simon design. RESULTS: Twenty-two patients were enrolled (15 eribulin + AI arm; 7 eribulin arm). The trial was terminated early in March 2021, with eight (36.4%) patients still on treatment. ORR was 26.7% in the eribulin + AI arm (95% CI, 7.8-55.1%; p = 0.0541). In the eribulin arm, two (28.6%) patients had an objective response (95% CI, 3.7-71.0%). The difference between the study arms was not significant (p = 0.918). The addition of AI to eribulin also failed to show improvement in other efficacy endpoints. A significant interaction between the treatment arm and previous CDK4/6i treatment was observed for ORR (p = 0.018) and progression-free survival (p = 0.084). Overall, the toxicity profile was consistent with the known safety profile of eribulin. No treatment-related deaths were reported. CONCLUSION: Eribulin + AI does not seem to improve outcomes compared with eribulin monotherapy in patients with AI-resistant luminal ABC. This chemo-endocrine approach deserves further investigation after progression to CDK4/6i-based therapy.

SOLTI-1904 ACROPOLI TRIAL: efficacy of spartalizumab monotherapy across tumor-types expressing high levels of PD1 mRNA.

Improved selection of cancer patients who are most likely to respond to immune checkpoint inhibitors remains an unmet clinical need. Recently, a positive correlation between levels of PD1 mRNA and clinical outcome in response to PD1 blockade across diverse tumor histologies has been confirmed in several datasets. ACROPOLI is a parallel cohort, non-randomized, phase II study that aims to evaluate the efficacy of the anti-PD1 immune checkpoint inhibitor spartalizumab as monotherapy in metastatic patients with solid tumors that express high levels of PD1 (cohort 1; n = 111). An additional cohort of 30 patients with tumors expressing low levels of PD1, where PD1/PD-L1 antibodies in monotherapy are standard treatment, will also be included (cohort 2). Primary end point is overall response rate in cohort 1. Trial registration number: NCT04802876 (ClinicalTrials.gov).

A Comparative Analysis of Outcomes Between Two Different Intramuscular Progesterone Preparations in Women Undergoing Frozen Embryo Transfer Cycles.

Background: The purpose of the current study was to assess if luteal support with intramuscular (IM) 17 alpha-hydroxyprogesterone caproate (17-OHPC) (Lentogest, IBSA, Italy) improves the pregnancy outcome in comparison to natural intramuscular progesterone (Prontogest, AMSA, Italy) when administered to recipients in a frozen embryo transfer cycle. Methods: A retrospective comparative study was performed to evaluate outcomes between two different intramuscular regimens used for luteal support in frozen embryo transfer cycles in patients underwent autologous in vitro fertilization (IVF) cycles (896 IVF cycles) and intracytoplasmic sperm injection (ICSI) who had a blastocyst transfer from February 2014 to March 2017 at the Centre for Reproductive and Genetic Health (CRGH) in London. Results: The live birth rates were significantly lower for the IM natural progesterone group when compared to 17-OHPC group (41.8% vs. 50.9%, adjusted OR of 0.63 (0.31-0.91)). The miscarriage rates were significantly lower in the 17-OHPC group compared to the IM natural progesterone group (14.5% vs. 19.2%, OR of 1.5, 95% CI of 1.13-2.11). The gestational age at birth and birth weight were similar in both groups (p=0.297 and p=0.966, respectively). Conclusion: It is known that both intramuscular and vaginal progesterone preparations are the standard of care for luteal phase support in women having frozen embryo transfer cycles. However, there is no clear scientific consensus regarding the optimal luteal support. In this study, it was revealed that live birth rates are significantly higher in women who received artificial progesterone compared to women who received natural progesterone in frozen embryo transfer cycles.

Oncolytic viruses: A new immunotherapeutic approach for breast cancer treatment?

Immunotherapy has revolutionized the oncology field during the last years, mainly with the introduction of immune checkpoint inhibitors in the clinical routine. Despite the recent approval of these drugs for the treatment of triple-negative breast cancer, most breast cancer patients cannot benefit from immunotherapy as most tumors are not considered immunoreactive. Therefore, new strategies must be developed to bring immunotherapy closer to breast cancer patients. The introduction of oncolytic viruses in the immuno-oncology field has shown promising results in cancer treatment, including breast cancer. However, a better understanding of their mechanisms of action, increase evidence of safety and efficacy, and the implications of its use as a systemic therapy must be examined in more depth. This review provides a summary of oncolytic virotherapy in the context of breast cancer, both in the pre-clinical and clinical setting.

Next Generation Sequencing Detects Premeiotic Errors in Human Oocytes.

Autosomal aneuploidy is the leading cause of embryonic and foetal death in humans. This arises mainly from errors in meiosis I or II of oogenesis. A largely ignored source of error stems from germinal mosaicism, which leads to premeiotic aneuploidy. Molecular cytogenetic studies employing metaphase fluorescence in situ hybridization and comparative genomic hybridisation suggest that premeiotic aneuploidy may affect 10-20% of oocytes overall. Such studies have been criticised on technical grounds. We report here an independent study carried out on unmanipulated oocytes that have been analysed using next generation sequencing (NGS). This study confirms that the incidence of premeiotic aneuploidy in an unselected series of oocytes exceeds 10%. A total of 140 oocytes donated by 42 women gave conclusive results; of these, 124 (88.5%) were euploid. Sixteen out of 140 (11.4%) provided evidence of premeiotic aneuploidy. Of the 140, 112 oocytes were immature (germinal vesicle or metaphase I), of which 10 were aneuploid (8.93%); the remaining 28 were intact metaphase II - first polar body complexes, and six of these were aneuploid (21.4%). Of the 16 aneuploid cells, half contained simple errors (one or two abnormal chromosomes) and half contained complex errors. We conclude that germinal mosaicism leading to premeiotic aneuploidy is a consistent finding affecting at least 10% of unselected oocytes from women undergoing egg collection for a variety of reasons. The importance of premeiotic aneuploidy lies in the fact that, for individual oocytes, it greatly increases the risk of an aneuploid mature oocyte irrespective of maternal age. As such, this may account for some cases of aneuploid conceptions in very young women.

Sociodemographic characteristics, comorbidity, and baseline functional status of older patients treated in emergency departments during the COVID-19 pandemic and associations with mortality: an analysis based on the EDENCOVID cohort. / Sociodemografía, comorbilidad y situación funcional basal de los pacientes mayores atendidos en urgencias durante la pandemia de COVID y su relación con la mortalidad: análisis a partir de la cohorte EDEN-Covid.

OBJECTIVES: To describe the sociodemographic characteristics, comorbidity, and baseline functional status of patients aged 65 or older who came to hospital emergency departments (EDs) during the first wave of the COVID-19 pandemic, and to compare them with the findings for an earlier period to analyze factors of the index episode that were related to mortality. MATERIAL AND METHODS: We studied data from the EDEN-COVID cohort (Emergency Department and Elder Needs During COVID-19) of patients aged 65 years or older treated in 40 Spanish EDs on 7 consecutive days. Nine sociodemographic variables, 18 comorbidities, and 7 function variables were registered and compared with the findings for the EDEN cohort of patients included with the same criteria and treated a year earlier in the same EDs. In-hospital mortality was calculated in the 2 cohorts and a multivariable logistic regression model was used to explore associated factors. RESULTS: The EDEN-COVID cohort included 6806 patients with a median age of 78 years; 49% were women. The pandemic cohort had a higher proportion of men, patients covered by the national health care system, patients brought from residential facilities, and patients who arrived in an ambulance equipped for advanced life support. Pandemic-cohort patients more often had diabetes mellitus, chronic kidney disease, and dementia; they less often had connective tissue and thromboembolic diseases. The Barthel and Charlson indices were worse in this period, and cognitive decline was more common. Fewer patients had a history of depression or falls. Eight hundred ninety these patients (13.1%) died, 122 of them in the ED (1.8%); these percentages were lower in the earlier EDEN cohort, at 3.1% and 0.5%, respectively. Independent sociodemographic factors associated with higher mortality were transport by ambulance, older age, male sex, and living in a residential facility. Mortalityassociated comorbidities were neoplasms, chronic kidney disease, and heart failure. The only function variable associated with mortality was the inability to walk independently. A history of falls in the past 6 months was a protective factor. CONCLUSION: The sociodemographic characteristics, comorbidity, and functional status of patients aged 65 years or older who were treated in hospital EDs during the pandemic differed in many ways from those usually seen in this older-age population. Mortality was higher than in the prepandemic period. Certain sociodemographic, comorbidity, and function variables were associated with in-hospital mortality.

OBJETIVO: Investigar sociodemografía, comorbilidad y situación funcional de los pacientes de 65 o más años de edad que consultaron a los servicios de urgencias hospitalarios (SUH) durante la primera oleada epidémica de COVID, compararlas con un periodo previo y ver su relación. METODO: Se utilizaron los datos obtenidos de la cohorte EDEN-Covid (Emergency Department and Elder Needs during COVID) en la que participaron 40 SUH españoles que incluyeron todos los pacientes de $ 65 años atendidos durante 7 días consecutivos. Se analizaron 9 características sociodemográficas, 18 comorbilidades y 7 variables de funcionalidad, que se compararon con las de la cohorte EDEN (Emergency Department and Elder Needs), que contiene pacientes con el mismo criterio de inclusión etario reclutados por los mismos SUH un año antes. Se recogió la mortalidad intrahospitalaria y se investigaron los factores asociados mediante regresión logística multivariable. RESULTADOS: La cohorte EDEN-Covid incluyó 6.806 pacientes (mediana edad: 78 años; 49% mujeres). Hubo más varones, con cobertura sanitaria pública, procedentes de residencia y que llegaron con ambulancia medicalizada que durante el periodo prepandemia. Presentaron más frecuentemente diabetes mellitus, enfermedad renal crónica, enfermedad cerebrovascular y demencia y menos conectivopatías y enfermedad tromboembólica, peores índices de Barthel y Charlson, más deterioro cognitivo y menos antecedentes de depresión o caídas previas. Fallecieron durante el episodio 890 pacientes (13,1%), 122 de ellos en urgencias (1,8%), porcentajes superiores al periodo prepandemia (3,1% y 0,5%, respectivamente). Se asociaron de forma independiente a mayor mortalidad durante el periodo COVID la llegada en ambulancia, mayor edad, ser varón y vivir en residencia como variables sociodemográficas, y neoplasia, enfermedad renal crónica e insuficiencia cardiaca como comorbilidades. La única variable funcional asociada a mortalidad fue no deambular respecto a ser autónomo, y la existencia de caídas los 6 meses previos resultó un factor protector. CONCLUSIONES: La sociodemografía, comorbilidad y funcionalidad de los pacientes de 65 o más años que consultaron en los SUH españoles durante la primera ola pandémica difirieron en muchos aspectos de lo habitualmente observado en esta población. La mortalidad fue mayor a la del periodo prepandémico. Algunos aspectos sociodemográficos, de comorbilidad y funcionales se relacionaron con la mortalidad intrahospitalaria.

Paternal age over 50 years decreases assisted reproductive technology (ART) success: A single UK center retrospective analysis.

INTRODUCTION: To study whether paternal age exerts an effect, independent of maternal age, on the outcomes of fresh in vitro fertilization/ intracytoplasmic sperm injection (IVF/ICSI) cycles. Semen quality deteriorates with increasing paternal age; however, there is conflicting evidence for any impact paternal age may have on the outcome of IVF/ICSI. Several retrospective and prospective cohort studies have shown that paternal age increases the miscarriage rate and reduces the live birth rate. Some studies have shown no effect of paternal age on live birth rate or miscarriage rate. Studies involving donor oocytes have tended to show no independent effect of paternal age on assisted reproductive technology (ART) outcomes. The age at which paternal age may exert a significant deleterious effect on outcome is not known and there is no limit to paternal age in IVF/ICSI treatment. MATERIAL AND METHODS: A single-center retrospective cohort study was carried out at the Centre for Reproductive and Genetic Health, London, UK. Included in the analysis were all couples with primary or secondary infertility undergoing IVF/ICSI cycles in which the male partner produced a fresh semen sample and the cycle proceeded to fresh embryo transfer. All cycles of IVF/ICSI that used donor oocytes-donor sperm, frozen sperm, cycles leading to embryo storage and cycles including preimplantation genetic testing (PGT-A/PGT-M)-were excluded from analysis. The primary outcome was live birth rate and secondary outcomes were clinical pregnancy rate and miscarriage rate. Multivariate logistic regression analysis with live birth as a dependent variable and maternal and paternal age class as independent variables was performed. RESULTS: During the study period there were 4833 cycles, involving 4271 men, eligible for analysis; 1974/4833 (40.8%, 95% confiene intervals [CI] 39.5-42.2%) cycles resulted in a live birth. A significantly lower proportion of men over 51 years met World Health Organization semen analysis criteria (56/133, [42.1%, 95% CI 34.1-50.6]) compared with men under 51 years of age (2530/4138 [61.1%, 95% CI 60.0-62.6]) (p = 0.001). Both maternal and paternal age were retained in the multivariate model and for all maternal age subgroups the probability of live birth decreased with paternal age over 50 years (odds ratio [OR] 0.674, 95% CI 0.482-0.943) (p = 0.021). Paternal age over 50 years was not an independent predictor of miscarriage (OR 0.678, 95% CI 0.369-1.250) (p = 0.214). CONCLUSIONS: Paternal age over 50 significantly affects the chance of achieving a live birth following ART. Paternal age does not independently affect the risk of miscarriage following ART. There should be a public health message for men not to delay fatherhood.

Outcomes of COVID-19 in Patients With Cancer: A Closer Look at Pre-Emptive Routine Screening Strategies.

PURPOSE: The benefit of routine pre-emptive screening for severe acute respiratory syndrome coronavirus 2 infections in patients with cancer before cancer-directed therapies is unclear. Herein, we characterize the outcomes of a cohort of patients with cancer who were diagnosed with COVID-19 by routine screening (RS) in comparison with those diagnosed on the basis of clinical suspicion or exposure history (nonroutine screening [NRS]). METHODS: A multisite prospective observational study was conducted at three major and five satellite campuses of the Mayo Clinic Cancer Center between March 18 and July 31, 2020. The primary outcome was COVID-19-related hospital admission. Secondary outcomes included intensive care unit admissions and all-cause mortality. RESULTS: Five thousand four hundred fifty-two patients underwent RS in the outpatient setting only, and 44 (0.81%) were diagnosed with COVID-19. RS detected 19 additional patients from the scheduled inpatient admissions for surgical or interventional procedures or inpatient chemotherapy. One hundred sixty-one patients were diagnosed with COVID-19 on the basis of NRS. COVID-19-related hospitalization rate (17.5% v 26.7%; P = .14), intensive care unit admission (1.6% v 5.6%; P = .19), and mortality (4.8% v 3.7%; P = .72) were not significantly different between the RS and NRS groups. In the multivariable analysis, age ≥ 60 years (odds ratio, 4.4; P = .023) and an absolute lymphocyte count ≤ 1.4 × 109/L (odds ratio, 9.2; P = .002) were independent predictors of COVID-19-related hospital admission. CONCLUSION: The COVID-19 positivity rate was low on the basis of RS. Comparing the hospital admission and mortality outcomes with the NRS cohort, there were no significant differences. The value of routine pre-emptive screening of asymptomatic patients with cancer for COVID-19 remains low.

Chromosomal Analysis of Cumulus Cells as a Future Predictor for Oocyte Aneuploidy: A Case Report.

BACKGROUND: Within the ovary, the optimal growth of the follicle, oocyte maturation and ovulation are highly conditioned by the two-way cross talk and interactions between the oocyte and the immediate somatic cells, known as cumulus cells (CCs). This biological communication between cell lines triggered the interest in the study of CCs as a biomarker of oocyte competence. CASE PRESENTATION: The findings of a 45,X mosaic pattern on CCs from a female patient with unremarkable medical history are reported in this study. The patient came to the Centre for Reproductive and Genetic Health, London on 14th August 2019 for her first visit and the follow up procedures were done for her to determine underlying genetic status. For this purpose, four sources of DNA including CCs, blood lymphocytes, buccal cells and immature oocytes were analyzed in the present report. CONCLUSION: In the present case study, the hypothesis of the female patient being mosaic 45,X was confirmed although the degree of mosaicism and whether this was affecting the germinal line could not be determined. In the event of the discovery of a cell line with an apparently abnormal genetic makeup, genetic counselling is important in order to understand the implications from somatic to germinal cells for patients exploring fertility journeys.

Novel Therapies in the Treatment of Hodgkin Lymphoma.

OPINION STATEMENT: Patients with Hodgkin lymphoma (HL) can achieve excellent response and survival rates following frontline combination chemo- and radiation therapy. However, about 10-15% of patients will experience disease relapse which is associated with poor outcomes. Recent breakthroughs in understanding the mechanisms of oncogenicity and interactions within the tumor microenvironment have resulted in development of novel drugs for treatment of patients with HL. Utilizing this information, treatment of newly diagnosed and relapsed HL has become a rapidly evolving field with multiple clinical trials evaluating novel treatment approaches incorporating targeted immunotherapy. In the frontline setting, the use of novel drugs may allow for de-escalation of therapy to avoid long-term complications associated with bleomycin and consolidation radiation therapy. Patients with early-stage, non-bulky disease are candidates for omitting radiation therapy using treatment combinations that include upfront use of brentuximab vedotin or nivolumab. In patients with advanced disease, the addition of brentuximab vedotin to a chemotherapy backbone is currently the standard of care in our practice, particularly in patients with a contraindication for receiving bleomycin. Future investigations in patients with advanced-stage HL will focus on establishing a new standard of care by comparing brentuximab vedotin and nivolumab in combination with chemotherapy (BV-AVD vs. N-AVD) and decreasing the risk of relapse by exploring consolidation therapy in patients with high-risk disease. In patients who have relapsed or are refractory to first-line therapy, salvage treatment has incorporated brentuximab vedotin or PD-1 checkpoint inhibitors to improve response rates of cytotoxic chemotherapy thereby improving the probability of a successful stem cell transplant. Post-transplant consolidation with brentuximab is currently standard of care in patients with high-risk disease. Patients who relapse following autologous stem cell transplant now have an expanded armamentarium of chemo- and immunotherapy options. However, the challenge is to determine the sequence of therapy after prior brentuximab or checkpoint inhibitor exposure.

Is oocyte maturity influenced by ovulation trigger type in oocyte donation cycles?

The aim of this study was to compare clinical and laboratory outcomes between GnRHa, dual and HCG triggers in altruistic oocyte donation cycles. Normal or high responders were given either gonadotropin releasing hormone agonist (GnRHa) or a dual trigger of GnRHa and a low dose of human chorionic gonadotropin (HCG). Low responders were given HCG trigger. In 333 cycles, 232 (69.7%) received GnRHa trigger, 59 (17.7%) received dual trigger and 42 (12.6%) had HCG trigger. The total number of mature oocytes retrieved and cryopreserved were significantly higher in the GnRHa and dual trigger groups, compared to the HCG group (p < 0.001). However, the ovarian hyperstimulation syndrome (OHSS) rate was significantly higher in the dual trigger group (n = 5 (8.5%)), compared to the GnRH agonist (n = 1 (0.4%)) and HCG groups (n = 0 (0%)) (p = 0.001). GnRHa trigger maximises mature oocyte yields in oocyte donors suspected of normal and high response but offers a significant reduction in OHSS risk compared to dual trigger. As such, dual trigger should not be used in oocyte donation. HCG trigger can also be used with a very low risk of OHSS at low risk of OHSS in carefully selected donors where GnRHa is unlikely to be effective.

Palbociclib and Trastuzumab in HER2-Positive Advanced Breast Cancer: Results from the Phase II SOLTI-1303 PATRICIA Trial.

PURPOSE: To assess palbociclib in combination with trastuzumab with or without endocrine therapy in patients with HER2-positive advanced breast cancer. PATIENTS AND METHODS: PATRICIA is a prospective, open-label, multicenter phase II trial. Patients had received 2-4 prior lines of anti-HER2-based regimens. Treatment consisted of palbociclib 200 mg daily for 2 weeks and 1 week off plus trastuzumab. The study was based on a Simon two-stage design comprising three cohorts: estrogen receptor (ER)-negative (cohort A), ER-positive (cohort B1), and ER-positive with letrozole (cohort B2). ER-positive patients were randomized to cohorts B1 or B2. Primary endpoint was progression-free survival rate at 6 months (PFS6). Secondary objectives included safety and evaluation of the PAM50 intrinsic subtypes. RESULTS: Seventy-one patients were recruited (n = 15 in cohort A and 28 in each cohort B). The PFS6 rate in cohorts A, B1, and B2 was 33.3% (5/15), 42.8% (12/28), and 46.4% (13/28), respectively. Regarding safety, grade 1-2 and 3-4 toxicities occurred in 97.7% and 84.4% of patients, respectively. The most common grade 3-4 toxicities were neutropenia (66.4%) and thrombocytopenia (11.3%). Regarding PAM50, 59 (83.1%) tumors were profiled. Luminal disease defined by PAM50 was found independently associated with longer PFS compared with non-luminal disease (10.6 vs. 4.2 months median PFS; adjusted hazard ratio = 0.40; P = 0.003). CONCLUSIONS: Palbociclib in combination with trastuzumab is safe and exhibits promising survival outcomes in trastuzumab pretreated ER-positive/HER2-positive advanced breast cancer with a PAM50 Luminal A or B subtype. The enrollment was stopped prematurely, and a new randomized cohort was opened in this population.

SOLTI-1503 PROMETEO TRIAL: combination of talimogene laherparepvec with atezolizumab in early breast cancer.

New treatment strategies such as immune checkpoint inhibitors and oncolytic viruses are opening new possibilities in cancer therapy. Preliminary results in melanoma and other tumors showed that the combination of talimogene laherparepvec with an anti-PD-1/PD-L1 or anti-CTLA4 has greater efficacy than either therapy alone, without additional safety concerns beyond those expected for each agent. The presence of residual cancer after neoadjuvant chemotherapy in early breast cancer patients is an unmet medical need. SOLTI-1503 PROMETEO is a window of opportunity trial, which evaluates the combination of talimogene laherparepvec in combination with atezolizumab in women with operable HER2-negative breast cancer who present residual disease after neoadjuvant chemotherapy. The primary end point is the rate of residual cancer burden 0/1. Clinical Trial Registration: NCT03802604.