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Human Reproduction Update Dec 2021Human male infertility has a notable genetic component, including well-established diagnoses such as Klinefelter syndrome, Y-chromosome microdeletions and monogenic...
BACKGROUND
Human male infertility has a notable genetic component, including well-established diagnoses such as Klinefelter syndrome, Y-chromosome microdeletions and monogenic causes. Approximately 4% of all infertile men are now diagnosed with a genetic cause, but a majority (60-70%) remain without a clear diagnosis and are classified as unexplained. This is likely in large part due to a delay in the field adopting next-generation sequencing (NGS) technologies, and the absence of clear statements from field leaders as to what constitutes a validated cause of human male infertility (the current paper aims to address this). Fortunately, there has been a significant increase in the number of male infertility NGS studies. These have revealed a considerable number of novel gene-disease relationships (GDRs), which each require stringent assessment to validate the strength of genotype-phenotype associations. To definitively assess which of these GDRs are clinically relevant, the International Male Infertility Genomics Consortium (IMIGC) has identified the need for a systematic review and a comprehensive overview of known male infertility genes and an assessment of the evidence for reported GDRs.
OBJECTIVE AND RATIONALE
In 2019, the first standardised clinical validity assessment of monogenic causes of male infertility was published. Here, we provide a comprehensive update of the subsequent 1.5 years, employing the joint expertise of the IMIGC to systematically evaluate all available evidence (as of 1 July 2020) for monogenic causes of isolated or syndromic male infertility, endocrine disorders or reproductive system abnormalities affecting the male sex organs. In addition, we systematically assessed the evidence for all previously reported possible monogenic causes of male infertility, using a framework designed for a more appropriate clinical interpretation of disease genes.
SEARCH METHODS
We performed a literature search according to the PRISMA guidelines up until 1 July 2020 for publications in English, using search terms related to 'male infertility' in combination with the word 'genetics' in PubMed. Next, the quality and the extent of all evidence supporting selected genes were assessed using an established and standardised scoring method. We assessed the experimental quality, patient phenotype assessment and functional evidence based on gene expression, mutant in-vitro cell and in-vivo animal model phenotypes. A final score was used to determine the clinical validity of each GDR, across the following five categories: no evidence, limited, moderate, strong or definitive. Variants were also reclassified according to the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines and were recorded in spreadsheets for each GDR, which are available at imigc.org.
OUTCOMES
The primary outcome of this review was an overview of all known GDRs for monogenic causes of human male infertility and their clinical validity. We identified a total of 120 genes that were moderately, strongly or definitively linked to 104 infertility phenotypes.
WIDER IMPLICATIONS
Our systematic review curates all currently available evidence to reveal the strength of GDRs in male infertility. The existing guidelines for genetic testing in male infertility cases are based on studies published 25 years ago, and an update is far overdue. The identification of 104 high-probability 'human male infertility genes' is a 33% increase from the number identified in 2019. The insights generated in the current review will provide the impetus for an update of existing guidelines, will inform novel evidence-based genetic testing strategies used in clinics, and will identify gaps in our knowledge of male infertility genetics. We discuss the relevant international guidelines regarding research related to gene discovery and provide specific recommendations to the field of male infertility. Based on our findings, the IMIGC consortium recommend several updates to the genetic testing standards currently employed in the field of human male infertility, most important being the adoption of exome sequencing, or at least sequencing of the genes validated in this study, and expanding the patient groups for which genetic testing is recommended.
Topics: Animals; Chromosome Deletion; Genetic Testing; Genomics; High-Throughput Nucleotide Sequencing; Humans; Infertility, Male; Male
PubMed: 34498060
DOI: 10.1093/humupd/dmab030 -
Cancer Treatment Reviews Sep 2023Since their first introduction in clinical practice, immune checkpoint inhibitors showed limited benefit in patients with NSCLC harboring EGFR mutations. With the... (Review)
Review
BACKGROUND
Since their first introduction in clinical practice, immune checkpoint inhibitors showed limited benefit in patients with NSCLC harboring EGFR mutations. With the rationale of increasing immune activation, combinatorial ICI strategies have been evaluated also in this subgroup of patients.
METHODS
We performed a systematic review on efficacy of ICI-based strategies in EGFR-mutant NSCLC according to most updated evidence.
RESULTS
Overall, ICI monotherapy and ICI plus chemotherapy confirm to be ineffective in EGFR-mutant NSCLC, whereas the combination of ICI with antiangiogenic and chemotherapy showed promising results. Limited data are available with alternative ICI combination strategies, driven by strong biological rationale of modulating the tumor immune microenvironment.
CONCLUSIONS
To date, the available evidence do not support the use of ICI in patients with NSCLC harboring EGFR mutations. Clinical trials are ongoing to define which is the best timing and exploring novel combinations with ICI in this specific disease.
PubMed: 37481836
DOI: 10.1016/j.ctrv.2023.102602 -
Journal of Neuro-oncology Aug 2023To synthesize the evidence on the impact on progression-free survival (PFS) and overall survival (OS) of supramaximal resection (SMR) over gross total resection (GTR) in... (Meta-Analysis)
Meta-Analysis Review
Supramaximal versus gross total resection in Glioblastoma, IDH wild-type and Astrocytoma, IDH-mutant, grade 4, effect on overall and progression free survival: systematic review and meta-analysis.
PURPOSE
To synthesize the evidence on the impact on progression-free survival (PFS) and overall survival (OS) of supramaximal resection (SMR) over gross total resection (GTR) in Glioblastoma, IDH wild-type and Astrocytoma, IDH-mutant, grade 4 (Glioblastoma).
METHODS
The PubMed, Scopus, Web of Science, Ovid and Cochrane databases were systematically searched (up to November 30, 2022). Studies reporting OS and PFS on adult humans with a suspected Glioblastoma, treated either with a SMR or GTR were included. Hazard ratios were estimated for each study and treatment effects were calculated through DerSimonian and Laird random effects models.
RESULTS
The literature search yielded 14 studies published between 2013 and 2022, enrolling a total of 6779 patients. Analysis of the included studies reveals significantly better clinical outcomes favoring SMR over GTR in terms of PFS (HR 0.67; p = 0.0007), and OS (HR 0.7; p = 0.0001).
CONCLUSION
Glioblastoma, IDH wild-type and Astrocytoma, IDH-mutant, grade 4, are aggressive tumors with a very short long-term OS. SMR is an effective therapeutic approach contributing to increased PFS and OS in patients with this catastrophic disease.
Topics: Adult; Humans; Astrocytoma; Brain Neoplasms; Disease-Free Survival; Glioblastoma; Progression-Free Survival; Retrospective Studies
PubMed: 37561356
DOI: 10.1007/s11060-023-04409-0 -
BMC Pulmonary Medicine Jun 2023For patients with advanced non-small-cell lung cancer (NSCLC) with EGFR mutations, the suggested course of action is epidermal growth factor receptor-tyrosine kinase... (Meta-Analysis)
Meta-Analysis
Efficacy and safety of EGFR-TKIs in combination with angiogenesis inhibitors as first-line therapy for advanced EGFR-mutant non-small-cell lung cancer: a systematic review and meta-analysis.
BACKGROUND
For patients with advanced non-small-cell lung cancer (NSCLC) with EGFR mutations, the suggested course of action is epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Even with a high disease control rate, a majority of patients develop acquired EGFR-TKIs resistance and eventually advance. To increase the benefits of treatment, clinical trials are increasingly exploring the value of EGFR-TKIs combined with angiogenesis inhibitors as a first-line treatment in advanced NSCLC carrying EGFR mutations.
METHOD
Using PubMed, EMBASE and Cochrane Library, to locate published full-text articles in print or online, a thorough literature search was done from the database's inception to February 2021. Additionally, oral presentation RCTs from ESMO and ASCO were obtained. We sifted out RCTs that used EGFR-TKIs along with angiogenesis inhibitors as first-line therapy for advanced EGFR-mutant NSCLC. ORR, AEs, OS, and PFS were the endpoints. Review Manager version 5.4.1 was used for data analysis.
RESULTS
One thousand eight hundred twenty-one patients were involved in 9 RCTs. According to the results, combining EGFR-TKIs with angiogenesis inhibitors therapy prolonged PFS of advanced EGFR-mutation NSCLC patients on the whole [HR:0.65 (95%CI: 0.59~0.73, P<0.00001)]. No significant statistical difference was identified between the combination group and single drug group in OS(P=0.20) and ORR (P=0.11). There are more adverse effects when EGFR-TKIs are used in combination with angiogenesis inhibitors than when used alone.
CONCLUSION
The combination of EGFR-TKIs and angiogenesis inhibitors prolonged PFS in patients with EGFR-mutant advanced NSCLC, but the OS and ORR benefit was not significant, and the risk of adverse events was higher, more pronounced with hypertension and proteinuria; PFS in subgroups suggested that the combination was associated with better PFS in the smoking, liver metastasis, and no brain metastasis groups, and the included studies suggested that the smoking group , liver metastasis group, and brain metastasis group may have a potential OS benefit.
Topics: Humans; Angiogenesis Inhibitors; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Liver Neoplasms; ErbB Receptors
PubMed: 37316870
DOI: 10.1186/s12890-023-02472-x -
Journal of Neurosurgery. Pediatrics Sep 2022DICER1-mutant malignant brain neoplasms are very rare tumors, and published data have relied on case reports or small case series. In this review, the authors aimed to... (Review)
Review
OBJECTIVE
DICER1-mutant malignant brain neoplasms are very rare tumors, and published data have relied on case reports or small case series. In this review, the authors aimed to systematically summarize the types and distribution patterns of DICER1 mutations, clinicopathological characteristics, and prognostic outcomes of these tumors.
METHODS
The authors searched PubMed and Web of Science for relevant studies. They included studies if they provided individual patient data of primary malignant brain tumors carrying DICER1 mutations.
RESULTS
The authors found 16 studies consisting of 9 embryonal tumors with multilayered rosettes (ETMRs), 30 pineoblastomas, 52 primary intracranial sarcomas, and 27 pituitary blastomas. Pineoblastoma, ETMR, and pituitary blastoma were more likely to carry DICER1 germline mutations, while only a small subset of primary intracranial sarcomas harbored these mutations (p < 0.001). Nearly 80% of tumors with germline mutations also had another somatic mutation in DICER1. ETMR and primary intracranial sarcoma were associated with an increased risk for tumor progression and relapse compared with pituitary blastoma and pineoblastoma (p = 0.0025), but overall survival (OS) was not significantly different. Gross-total resection (GTR) and radiotherapy administration were associated with prolonged OS.
CONCLUSIONS
ETMR, pineoblastoma, primary intracranial sarcoma, and pituitary blastoma should be considered rare phenotypes of the DICER1 syndrome, and families should be counseled and screened for associated tumors. ETMR and primary intracranial sarcoma had a higher risk of relapse. GTR and radiotherapy appeared to improve the OS of patients with DICER1-mutant malignant intracranial tumors.
PubMed: 35901678
DOI: 10.3171/2022.6.PEDS22119 -
Cancer Imaging : the Official... Nov 2022Advances in molecular diagnostics accomplished the discovery of two malignant glioma entities harboring alterations in the H3 histone: diffuse midline glioma, H3... (Review)
Review
BACKGROUND
Advances in molecular diagnostics accomplished the discovery of two malignant glioma entities harboring alterations in the H3 histone: diffuse midline glioma, H3 K27-altered and diffuse hemispheric glioma, H3 G34-mutant. Radiogenomics research, which aims to correlate tumor imaging features with genotypes, has not comprehensively examined histone-altered gliomas (HAG). The aim of this research was to synthesize the current published data on imaging features associated with HAG.
METHODS
A systematic search was performed in March 2022 using PubMed and the Cochrane Library, identifying studies on the imaging features associated with H3 K27-altered and/or H3 G34-mutant gliomas.
RESULTS
Forty-seven studies fulfilled the inclusion criteria, the majority on H3 K27-altered gliomas. Just under half (21/47) were case reports or short series, the remainder being diagnostic accuracy studies. Despite heterogeneous methodology, some themes emerged. In particular, enhancement of H3 K27M-altered gliomas is variable and can be less than expected given their highly malignant behavior. Low apparent diffusion coefficient values have been suggested as a biomarker of H3 K27-alteration, but high values do not exclude this genotype. Promising correlations between high relative cerebral blood volume values and H3 K27-alteration require further validation. Limited data on H3 G34-mutant gliomas suggest some morphologic overlap with 1p/19q-codeleted oligodendrogliomas.
CONCLUSIONS
The existing data are limited, especially for H3 G34-mutant gliomas and artificial intelligence techniques. Current evidence indicates that imaging-based predictions of HAG are insufficient to replace histological assessment. In particular, H3 K27-altered gliomas should be considered when occurring in typical midline locations irrespective of enhancement characteristics.
Topics: Humans; Artificial Intelligence; Brain Neoplasms; Glioma; Histones; Mutation
PubMed: 36397143
DOI: 10.1186/s40644-022-00500-3 -
Schizophrenia Bulletin Jan 2024Consistent with postmortem findings in patients, most animal models for schizophrenia (SCZ) present abnormal levels of parvalbumin (PV), a marker of fast-spiking... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Consistent with postmortem findings in patients, most animal models for schizophrenia (SCZ) present abnormal levels of parvalbumin (PV), a marker of fast-spiking GABAergic interneurons, in the prefrontal cortex (PFC) and hippocampus (HIP). However, there are discrepancies in the literature. PV reductions lead to a functional loss of PV interneurons, which is proposed to underly SCZ symptoms. Given its complex etiology, different categories of animal models have been developed to study SCZ, which may distinctly impact PV levels in rodent brain areas.
STUDY DESIGN
We performed a quantitative meta-analysis on PV-positive cell number/density and expression levels in the PFC and HIP of animal models for SCZ based on pharmacological, neurodevelopmental, and genetic manipulations.
RESULTS
Our results confirmed that PV levels are significantly reduced in the PFC and HIP regardless of the animal model. By categorizing into subgroups, we found that all pharmacological models based on NMDA receptor antagonism decreased PV-positive cell number/density or PV expression levels in both brain areas examined. In neurodevelopmental models, abnormal PV levels were confirmed in both brain areas in maternal immune activation models and HIP of the methylazoxymethanol acetate model. In genetic models, negative effects were found in neuregulin 1 and ERBB4 mutant mice in both brain regions and the PFC of dysbindin mutant mice. Regarding sex differences, male rodents exhibited PV reductions in both brain regions only in pharmacological models, while few studies have been conducted in females.
CONCLUSION
Overall, our findings support deficits in prefrontal and hippocampal PV interneurons in animal models for SCZ.
Topics: Humans; Mice; Male; Female; Animals; Schizophrenia; Parvalbumins; Disease Models, Animal; Interneurons; Prefrontal Cortex; Hippocampus
PubMed: 37584417
DOI: 10.1093/schbul/sbad123 -
Journal of Neuroimaging : Official... Jan 2022Diffuse hemispheric gliomas, H3 G34-mutant (DHGs-G34m), are newly recognized malignant brain tumors characterized by histone gene mutations. However, the neuroradiologic... (Review)
Review
BACKGROUND AND PURPOSE
Diffuse hemispheric gliomas, H3 G34-mutant (DHGs-G34m), are newly recognized malignant brain tumors characterized by histone gene mutations. However, the neuroradiologic characteristics of these tumors require elucidation. We reviewed the demographic, clinical, and neuroradiological features of DHGs-G34m.
METHODS
Data were extracted using a database search in MEDLINE, SCOPUS, and Google Scholar in June 2021. Studies assessing pathologically proven DHGs-G34m with each patient's information and neuroradiological findings were included. After screening and reviewing 332 abstracts, 12 articles including 56 cases met the criteria. We also added the findings for three patients evaluated in our hospital. Two board-certified radiologists reviewed all demographic, clinical, and neuroradiological findings of each study. One board-certified pathologist reviewed all pathological data of each study. Kaplan-Meier analyses with log-rank tests were performed to compare the survival between patients with different tumor margin characteristics (well-delineated and ill-defined).
RESULTS
The median patient age at diagnosis was 19 years (range, 6-66 years), and 31/59 patients (52.5%) were men. Supratentorial tumors were observed in all patients (59/59, 100%). Frequent contact with leptomeninges (92.3%) and ependymal regions (87.5%) was observed. The 1- and 2-year survival rates after initial surgery were 66.7% and 40.0%, respectively. DHGs-G34m with ill-defined and well-delineated margins showed significant differences in survival (p = .04).
CONCLUSIONS
DHGs-G34m occur most often in the supratentorial regions of adolescents. Prognosis varies among patients. Evaluation of tumor margins may provide prognostic value.
Topics: Adolescent; Brain Neoplasms; Glioma; Histones; Humans; Male; Mutation; Neuroimaging
PubMed: 34632671
DOI: 10.1111/jon.12939 -
Cancer Treatment Reviews Nov 2022The objective of this study was to estimate the relative efficacy and safety of targeted therapies for the treatment of metastatic melanoma using a network meta-analysis... (Meta-Analysis)
Meta-Analysis Review
Comparative efficacy and safety of targeted therapies for BRAF-mutant unresectable or metastatic melanoma: Results from a systematic literature review and a network meta-analysis.
BACKGROUND
The objective of this study was to estimate the relative efficacy and safety of targeted therapies for the treatment of metastatic melanoma using a network meta-analysis (NMA).
METHODS
A systematic literature review (SLR) identified studies in Medline, Embase and Cochrane published until November 2020. Screening used prespecified eligibility criteria. Following a transitivity assessment across included studies, Bayesian NMA was conducted.
RESULTS
A total of 43 publications reporting 15 targeted therapy trials and 42 reporting 18 immunotherapy trials were retained from the SLR and considered for the NMA. Due to substantial between-study heterogeneity with immunotherapy trials, the analysis considered a network restricted to targeted therapies. Among combination therapies, encorafenib + binimetinib was superior to dabrafenib + trametinib for overall response rate (OR = 1.86; 95 % credible interval [CrI] 1.10, 3.17), superior to vemurafenib + cobimetinib with fewer serious adverse events (SAEs) (OR = 0.51; 95 % CrI 0.29, 0.91) and fewer discontinuations due to AEs (OR = 0.45; 95 % CrI 0.21, 0.96), and superior to atezolizumab + vemurafenib + cobimetinib with fewer SAEs (OR = 0.41; 95 % CrI 0.21, 0.82). Atezolizumab + vemurafenib + cobimetinib and encorafenib + binimetinib were generally comparable for efficacy endpoints. Among double combination therapies, encorafenib + binimetinib showed high probabilities of being better for all efficacy and safety endpoints.
CONCLUSIONS
This NMA confirms that combination therapies are more efficacious than monotherapies. Encorafenib + binimetinib has a favourable efficacy profile compared to other double combination therapies and a favourable safety profile compared to both double and triple combination therapies.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bayes Theorem; Benzimidazoles; Carbamates; Humans; Melanoma; Mutation; Neoplasms, Second Primary; Network Meta-Analysis; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Sulfonamides; Vemurafenib
PubMed: 36099854
DOI: 10.1016/j.ctrv.2022.102463 -
Clinical and Experimental Medicine Nov 2023Anti-human epidermal growth factor receptor-2 (anti-HER2) therapy has shown excellent efficacy in patients with HER2 overexpression and amplification. Although HER2... (Meta-Analysis)
Meta-Analysis Review
Anti-human epidermal growth factor receptor-2 (anti-HER2) therapy has shown excellent efficacy in patients with HER2 overexpression and amplification. Although HER2 mutations are rarely expressed in several cancers, when they occur, they can activate the HER2 signaling pathway. In recent years, studies have shown that anti-HER2 drugs have promising efficacy in patients with HER2 mutations. Based on keywords, we searched databases, such as PubMed, Embase, and Cochrane Library, and the main conference abstracts. We extracted data on objective response rate (ORR), clinical benefit rate (CBR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) from studies on the efficacy of anti-HER2 therapies in patients with HER2-mutated cancers, and analyzed grade 3 or higher adverse events (AEs). We included 19 single-arm clinical studies and 3 randomized controlled trials (RCTs), containing a total of 1017 patients with HER2 mutations, involving seven drugs and nine cancers, and 18 studies enrolled a high proportion of heavily pretreated patients who had received multiple lines of therapy. Our results showed pooled ORR and CBR of 25.0% (range, 3.8-72.7%; 95% CI, 18-32%) and 36.0% (range, 8.3-63.0%; 95% CI, 31-42%) for anti-HER2 therapy in HER2-mutated cancers. The pooled median PFS, OS, DOR were 4.89 (95% CI, 4.16-5.62), 12.78 (95% CI, 10.24-15.32), and 8.12 (95% CI, 6.48-9.75) months, respectively. In a subgroup analysis, we analyzed the ORR for different cancers, showing 27.0, 25.0, 23.0, and 16.0% for breast, lung, cervical, and biliary tract cancers, respectively. ORR analyses were performed for different drugs as monotherapy or in combination, showing 60.0% for trastuzumab deruxtecan (T-DXd), 31.0% for pyrotinib, 26.0% for neratinib combined with trastuzumab, 25.0% for neratinib combined with fulvestrant, 19.0% for trastuzumab combined with pertuzumab, and 16.0% for neratinib. In addition, we found that diarrhoea, neutropenia, and thrombocytopenia were the most common grade ≥ 3 AEs associated with anti-HER2 therapeutic agents. In this meta-analysis of heavily pretreated patients with HER2 mutations, anti-HER2 therapies, DS-8201 and trastuzumab emtansine, showed promising efficacy and activity. Anti-HER2 therapies showed different efficacies in different or the same cancer settings and all had a tolerable safety profile.
Topics: Humans; Female; Trastuzumab; Receptor, ErbB-2; Ado-Trastuzumab Emtansine; Neoplasms; Breast Neoplasms; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37120775
DOI: 10.1007/s10238-023-01072-7