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BACKGROUND: The epidemiology and management of thyroid cancer has changed radically in the recent past, with rising international incidence of early-stage papillary thyroid cancer (PTC) in particular. In this paper, we review the epidemiology of thyroid cancer in Ireland. METHODS: A retrospective cohort study of National Cancer Registry of Ireland data, 1994-2019. RESULTS: Records from 4158 patients were analysed. 73 % (n = 3040) were female. The average age was 50.4 years. Patient sex did not change over time (p = 0.662), while age decreased significantly (p < 0.0001). The most common diagnoses were PTC (n = 2,905, 70 %) and follicular thyroid carcinoma (n = 549, 13 %). Incidence rose over threefold (1.8-6.2 cases/100000 person-years). The incidence of T1 PTC rose over twelvefold (0.169-2.1 cases/100000 person-years), while the incidence of stage III and IV disease did not change significantly. Five-year disease-specific survival (DSS) was 85 % and varied significantly by diagnosis - 97 % for PTC versus 5 % for anaplastic thyroid carcinoma. Survival did not change significantly over time. Male sex was a risk factor for more advanced disease (p < 0.0001) but did not independently predict overall survival except in PTC (HR 1.6, p = 0.03). The use of radioactive iodine declined markedly from 49 % to 12.5 %. RAI improved DSS for PTC patients aged over 55 years (p = 0.02) without a notable effect on survival for those under 55 years (p = 0.99). CONCLUSION: The epidemiology and management of thyroid cancer in Ireland has changed dramatically in a manner reflective of international trends.
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Breast cancer remains a significant global health challenge. In Australia, the adoption of publicly-funded multigene panel testing for eligible cancer patients has increased accessibility to personalised care, yet has also highlighted the increasing prevalence of variants of uncertain significance (VUS), complicating clinical decision-making. This project aimed to explore the spectrum and actionability of breast cancer VUS in Australian familial cancer centers (FCCs). Leveraging data from 11 FCCs participating in the Inherited Cancer Connect database, we retrieved VUS results from 1472 patients. Through ClinVar crosschecks and application of gene-specific ACMG/AMP guidelines, we showed the potential for reclassification of 4% of unique VUS as pathogenic or likely pathogenic, and 80% as benign or likely benign. Surveys conducted with FCCs and diagnostic laboratories described current practices and challenges in variant reclassifications, highlighting resource constraints preventing periodic VUS review and notifications from the laboratories to the FCCs. Our study suggests there are benefits to routine VUS review and reclassification, particularly in publicly-funded healthcare systems. Future research should focus on assessing the clinical impact and cost-effectiveness of implementing routine variant review practices, alongside efforts to enhance communication between FCCs and laboratories.
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The ENIGMA research consortium develops and applies methods to determine clinical significance of variants in hereditary breast and ovarian cancer genes. An ENIGMA BRCA1/2 classification sub-group, formed in 2015 as a ClinGen external expert panel, evolved into a ClinGen internal Variant Curation Expert Panel (VCEP) to align with Food and Drug Administration recognized processes for ClinVar contributions. The VCEP reviewed American College of Medical Genetics and Genomics/Association of Molecular Pathology (ACMG/AMP) classification criteria for relevance to interpreting BRCA1 and BRCA2 variants. Statistical methods were used to calibrate evidence strength for different data types. Pilot specifications were tested on 40 variants and documentation revised for clarity and ease of use. The original criterion descriptions for 13 evidence codes were considered non-applicable or overlapping with other criteria. Scenario of use was extended or re-purposed for eight codes. Extensive analysis and/or data review informed specification descriptions and weights for all codes. Specifications were applied to pilot variants with pre-existing ClinVar classification as follows: 13 uncertain significance or conflicting, 14 pathogenic and/or likely pathogenic, and 13 benign and/or likely benign. Review resolved classification for 11/13 uncertain significance or conflicting variants and retained or improved confidence in classification for the remaining variants. Alignment of pre-existing ENIGMA research classification processes with ACMG/AMP classification guidelines highlighted several gaps in the research processes and the baseline ACMG/AMP criteria. Calibration of evidence strength was key to justify utility and strength of different data types for gene-specific application. The gene-specific criteria demonstrated value for improving ACMG/AMP-aligned classification of BRCA1 and BRCA2 variants.
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Proteína BRCA1 , Proteína BRCA2 , Variação Genética , Humanos , Proteína BRCA2/genética , Proteína BRCA1/genética , Feminino , Neoplasias da Mama/genética , Genômica/métodos , Bases de Dados Genéticas , Neoplasias Ovarianas/genética , Predisposição Genética para Doença , Testes Genéticos/métodosRESUMO
PURPOSE: Despite increasing evidence of benefit supporting complex genomic sequencing (CGS) in personalizing cancer therapy, its widespread uptake remains limited. METHODS: This mixed-methods, prospective cross-institutional demonstration study was designed to evaluate implementation of CGS in the care of patients with advanced cancer. DNA sequencing was undertaken on formalin-fixed paraffin-embedded tumor and matched blood was completed with the Peter MacCallum Cancer Centre Comprehensive Cancer Panel; 391 genes via central laboratory. Oncologists performed consent and result delivery. Patients completed pre- and post-test surveys, including validated and study-specific questions and, if eligible, semistructured interviews. Qualitative interviews were undertaken with study clinicians to evaluate processes. RESULTS: One hundred ninety-nine (63%) had ≥1 finding with the potential to affect management, including 172 (55%) whose finding could affect their treatment options, 25 (8%) whose test led to the resolution of diagnostic ambiguity, and 49 (16%) with a pathogenic germline variant. In 6-month follow-up, 50 (16%) participants had their subsequent therapy changed on the basis of their CGS results. Two hundred ninety-three (88% of adult patients) completed surveys at three time points. At consent, patients cited multifaceted value in testing, showed good understanding of basic concepts, but most (69%) overestimated the likelihood of result-led change. Post-test patients remained consistently satisfied with accessing CGS. 21% struggled with understanding results but there were low levels of decisional regret after participation (89% had nil/mild regret). Clinicians cited collaboration and communication as critical to delivery. CONCLUSION: Patients undergoing CGS are generally satisfied and place value on its use beyond potential therapeutic benefit. Our results suggest that to improve test utility and delivery of CGS with value to patients and investing institutions, focus must be placed on addressing the additional barriers to its wider implications including efforts to improve process efficiencies, clinician genomic literacy, and decision-making support.
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Neoplasias , Preferência do Paciente , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto , Idoso , Neoplasias/genética , Neoplasias/terapia , Genômica , Medicina de Precisão/métodos , Idoso de 80 Anos ou mais , Adulto Jovem , Análise de Sequência de DNA/métodosRESUMO
INTRODUCTION: Established personal and familial risk factors contribute collectively to a woman's risk of breast or ovarian cancer. Existing clinical services offer genetic testing for pathogenic variants in high-risk genes to investigate these risks but recent information on the role of common genomic variants, in the form of a Polygenic Risk Score (PRS), has provided the potential to further personalise breast and ovarian cancer risk assessment. Data from cohort studies support the potential of an integrated risk assessment to improve targeted risk management but experience of this approach in clinical practice is limited. METHODS AND ANALYSIS: The polygenic risk modification trial is an Australian multicentre prospective randomised controlled trial of integrated risk assessment including personal and family risk factors with inclusion of breast and ovarian PRS vs standard care. The study will enrol women, unaffected by cancer, undergoing predictive testing at a familial cancer clinic for a pathogenic variant in a known breast cancer (BC) or ovarian cancer (OC) predisposition gene (BRCA1, BRCA2, PALB2, CHEK2, ATM, RAD51C, RAD51D). Array-based genotyping will be used to generate breast cancer (313 SNP) and ovarian cancer (36 SNP) PRS. A suite of materials has been developed for the trial including an online portal for patient consent and questionnaires, and a clinician education programme to train healthcare providers in the use of integrated risk assessment. Long-term follow-up will evaluate differences in the assessed risk and management advice, patient risk management intentions and adherence, patient-reported experience and outcomes, and the health service implications of personalised risk assessment. ETHICS AND DISSEMINATION: This study has been approved by the Human Research Ethics Committee of Peter MacCallum Cancer Centre and at all participating centres. Study findings will be disseminated via peer-reviewed publications and conference presentations, and directly to participants. TRIAL REGISTRATION NUMBER: ACTRN12621000009819.
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Neoplasias da Mama , Predisposição Genética para Doença , Testes Genéticos , Humanos , Feminino , Neoplasias da Mama/genética , Neoplasias da Mama/prevenção & controle , Medição de Risco/métodos , Testes Genéticos/métodos , Estudos Prospectivos , Austrália , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/prevenção & controle , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Herança Multifatorial , Fatores de Risco , Adulto , Polimorfismo de Nucleotídeo ÚnicoRESUMO
The duplication-triplication/inverted-duplication (DUP-TRP/INV-DUP) structure is a complex genomic rearrangement (CGR). Although it has been identified as an important pathogenic DNA mutation signature in genomic disorders and cancer genomes, its architecture remains unresolved. Here, we studied the genomic architecture of DUP-TRP/INV-DUP by investigating the DNA of 24 patients identified by array comparative genomic hybridization (aCGH) on whom we found evidence for the existence of 4 out of 4 predicted structural variant (SV) haplotypes. Using a combination of short-read genome sequencing (GS), long-read GS, optical genome mapping, and single-cell DNA template strand sequencing (strand-seq), the haplotype structure was resolved in 18 samples. The point of template switching in 4 samples was shown to be a segment of â¼2.2-5.5 kb of 100% nucleotide similarity within inverted repeat pairs. These data provide experimental evidence that inverted low-copy repeats act as recombinant substrates. This type of CGR can result in multiple conformers generating diverse SV haplotypes in susceptible dosage-sensitive loci.
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Haplótipos , Humanos , Haplótipos/genética , Hibridização Genômica Comparativa , Variação Estrutural do Genoma/genética , Genoma Humano/genética , Duplicação Gênica/genéticaRESUMO
The clinical application of Pharmacogenomics (PGx) has improved patient safety. However, comprehensive PGx testing has not been widely adopted in clinical practice, and significant opportunities exist to further optimize PGx in cancer care. This systematic review and meta-analysis aim to evaluate the safety outcomes of reported PGx-guided strategies (Analysis 1) and identify well-studied emerging pharmacogenomic variants that predict severe toxicity and symptom burden (Analysis 2) in patients with cancer. We searched MEDLINE, EMBASE, CENTRAL, clinicaltrials.gov, and International Clinical Trials Registry Platform from inception to January 2023 for clinical trials or comparative studies evaluating PGx strategies or unconfirmed pharmacogenomic variants. The primary outcomes were severe adverse events (SAE; ≥ grade 3) or symptom burden with pain and vomiting as defined by trial protocols and assessed by trial investigators. We calculated pooled overall relative risk (RR) and 95% confidence interval (95%CI) using random effects models. PROSPERO, registration number CRD42023421277. Of 6811 records screened, six studies were included for Analysis 1, 55 studies for Analysis 2. Meta-analysis 1 (five trials, 1892 participants) showed a lower absolute incidence of SAEs with PGx-guided strategies compared to usual therapy, 16.1% versus 34.0% (RR = 0.72, 95%CI 0.57-0.91, p = 0.006, I2 = 34%). Meta-analyses 2 identified nine medicine(class)-variant pairs of interest across the TYMS, ABCB1, UGT1A1, HLA-DRB1, and OPRM1 genes. Application of PGx significantly reduced rates of SAEs in patients with cancer. Emergent medicine-variant pairs herald further research into the expansion and optimization of PGx to improve systemic anti-cancer and supportive care medicine safety and efficacy.
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Neoplasias , Farmacogenética , Adulto , Humanos , Antineoplásicos/efeitos adversos , Antineoplásicos/administração & dosagem , Mutação em Linhagem Germinativa , Neoplasias/tratamento farmacológico , Neoplasias/genética , Testes Farmacogenômicos , Variantes Farmacogenômicos , Carga de SintomasRESUMO
INTRODUCTION: The epidemiology and management of oral cavity cancer have changed considerably in recent decades. This study examines epidemiological and management trends in oral cavity squamous cell carcinoma (OCSCC). METHODS: A retrospective cohort study of data from the National Cancer Registry of Ireland between 1994 and 2014. RESULTS: A total of 2725 patients were identified. The most common subsites were the tongue (34 %, n = 1025), lip (19 %, n = 575), floor of mouth (FOM) (18 %, n = 550), and retromolar trigone (RMT) (6 %, n = 189). The incidence of OCSCC remained largely unchanged (3.14 cases/100000/year) during the study period. 5-year disease-specific survival (DSS) was 58.6 % overall, varying between subsites (lip 85 %, RMT 62.9 %, tongue 54.7 %, and FOM 47.3 %). DSS improved over the study period (p = 0.03), in particular for tongue primaries (p = 0.007). Primary surgery significantly improved DSS versus radiotherapy (HR 0.28, p < 0.0001). Survival of T4 disease managed surgically was superior to that of T1 disease managed with radiotherapy. In node positive patients, chemotherapy improved overall survival (HR 0.8 p = 0.038) but not DSS (HR 0.87 p = 0.215). CONCLUSION: Primary surgery remains the standard of care in the management of OCSCC. Prognosis has improved in line with an increase in the use of primary surgery in the same time frame, though the incidence remains unchanged.
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Carcinoma de Células Escamosas , Neoplasias Bucais , Humanos , Masculino , Irlanda/epidemiologia , Feminino , Estudos Retrospectivos , Neoplasias Bucais/terapia , Neoplasias Bucais/epidemiologia , Neoplasias Bucais/mortalidade , Pessoa de Meia-Idade , Idoso , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/mortalidade , Incidência , Sistema de Registros , Taxa de Sobrevida , Adulto , Estadiamento de Neoplasias , Idoso de 80 Anos ou mais , Estudos de CoortesRESUMO
PURPOSE: Establishing accurate age-related penetrance figures for the broad range of cancer types that occur in individuals harboring a pathogenic germline variant in the TP53 gene is essential to determine the most effective clinical management strategies. These figures also permit optimal use of cosegregation data for classification of TP53 variants of unknown significance. Penetrance estimation can easily be affected by bias from ascertainment criteria, an issue not commonly addressed by previous studies. MATERIALS AND METHODS: We performed a maximum likelihood penetrance estimation using full pedigree data from a multicenter study of 146 TP53-positive families, incorporating adjustment for the effect of ascertainment and population-specific background cancer risks. The analysis included pedigrees from Australia, Spain, and United States, with phenotypic information for 4,028 individuals. RESULTS: Core Li-Fraumeni syndrome (LFS) cancers (breast cancer, adrenocortical carcinoma, brain cancer, osteosarcoma, and soft tissue sarcoma) had the highest hazard ratios of all cancers analyzed in this study. The analysis also detected a significantly increased lifetime risk for a range of cancers not previously formally associated with TP53 pathogenic variant status, including colorectal, gastric, lung, pancreatic, and ovarian cancers. The cumulative risk of any cancer type by age 50 years was 92.4% (95% CI, 82.2 to 98.3) for females and 59.7% (95% CI, 39.9 to 81.3) for males. Females had a 63.3% (95% CI, 35.6 to 90.1) cumulative risk of developing breast cancer by age 50 years. CONCLUSION: The results from maximum likelihood analysis confirm the known high lifetime risk for the core LFS-associated cancer types providing new risk estimates and indicate significantly increased lifetime risks for several additional cancer types. Accurate cancer risk estimates will help refine clinical recommendations for TP53 pathogenic variant carriers and improve TP53 variant classification.
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Neoplasias da Mama , Síndrome de Li-Fraumeni , Masculino , Feminino , Humanos , Estados Unidos , Pessoa de Meia-Idade , Síndrome de Li-Fraumeni/diagnóstico , Síndrome de Li-Fraumeni/genética , Genes p53/genética , Linhagem , Proteína Supressora de Tumor p53/genética , Predisposição Genética para Doença/genética , Neoplasias da Mama/genética , Fatores de RiscoRESUMO
Since first publication of the American College of Medical Genetics and Genomics/Association for Medical Pathology (ACMG/AMP) variant classification guidelines, additional recommendations for application of certain criteria have been released (https://clinicalgenome.org/docs/), to improve their application in the diagnostic setting. However, none have addressed use of the PS4 and PP4 criteria, capturing patient presentation as evidence towards pathogenicity. Application of PS4 can be done through traditional case-control studies, or "proband counting" within or across clinical testing cohorts. Review of the existing PS4 and PP4 specifications for Hereditary Cancer Gene Variant Curation Expert Panels revealed substantial differences in the approach to defining specifications. Using BRCA1, BRCA2 and TP53 as exemplar genes, we calibrated different methods proposed for applying the "PS4 proband counting" criterion. For each approach, we considered limitations, non-independence with other ACMG/AMP criteria, broader applicability, and variability in results for different datasets. Our findings highlight inherent overlap of proband-counting methods with ACMG/AMP frequency codes, and the importance of calibration to derive dataset-specific code weights that can account for potential between-dataset differences in ascertainment and other factors. Our work emphasizes the advantages and generalizability of logistic regression analysis over simple proband-counting approaches to empirically determine the relative predictive capacity and weight of various personal clinical features in the context of multigene panel testing, for improved variant interpretation. We also provide a general protocol, including instructions for data formatting and a web-server for analysis of personal history parameters, to facilitate dataset-specific calibration analyses required to use such data for germline variant classification.
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Variação Genética , Neoplasias , Humanos , Variação Genética/genética , Testes Genéticos/métodos , Genoma Humano , Fenótipo , Genes Neoplásicos , Neoplasias/genéticaRESUMO
BACKGROUND: Multiple causes of death are increasingly reported, particularly in older populations. Rates of multiple causes of young sudden death have not been quantified. METHOD: The End Unexplained Cardiac Death (EndUCD) registry was utilised to identify cases of young sudden death (aged 1-50 years) referred for forensic assessment from April 2019 to April 2022. Causes of death were coded according to whether one or more underlying causes of death were identified. Patients were compared according to the number of causes of death, with significant predictors assessed using logistic regression analysis. RESULTS: 1,085 cases of sudden death were identified. 263 (24.2%) cases had more than one competing cause of their sudden death. The most common multi-causal associations identified were dual non-cardiac causes of the sudden death (n=68), cardiomyopathy with non-cardiac event (n=64) and coronary artery disease with non-cardiac cause (n=63). Multi-causal death was more common in those undergoing comprehensive autopsy examination (95.8% vs 77.6%, p<0.0001), and in the setting of higher body mass index (median 31.3 kg/m2 vs 29.9 kg/m2, p=0.01), older age (44.3 years vs 41.4 years, p<0.0001), non-ventricular cardiac arrest rhythm (93.2% vs 87.3%, p=0.009), and smoking (22.8% vs 14.2%, p=0.001). The strongest predictor of multiple pathologies was comprehensive autopsy examination compared with external inspection, full-body post-mortem computed tomography and review of ancillary documentation and investigations (odds ratio 6.49, 95% confidence interval 3.47-12.14). CONCLUSIONS: One-quarter of young sudden deaths have more than one underlying cause, highlighting the value of comprehensive investigations including autopsy. Awareness of the complexity of young sudden death is important, along with multidisciplinary involvement to ensure all contributors to death are identified.
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Doença da Artéria Coronariana , Morte Súbita Cardíaca , Pessoa de Meia-Idade , Humanos , Idoso , Causas de Morte , Prevalência , Morte Súbita Cardíaca/epidemiologia , Morte Súbita Cardíaca/etiologia , Causalidade , Doença da Artéria Coronariana/complicaçõesRESUMO
BACKGROUND: Genetic counselling aims to identify, and address, patient needs while facilitating informed decision-making about genetic testing and promoting empowerment and adaptation to genetic information. Increasing demand for cancer genetic testing and genetic counsellor workforce capacity limitations may impact the quality of genetic counselling provided. The use of a validated genetic-specific screening tool, the Genetic Psychosocial Risk Instrument (GPRI), may facilitate patient-centred genetic counselling. The aim of this study is to assess the effectiveness and implementation of using the GPRI in improving patient outcomes after genetic counselling and testing for an inherited cancer predisposition. METHODS: The PersOnalising gEneTIc Counselling (POETIC) trial is a hybrid type 2 effectiveness-implementation trial using a randomised control trial to assess the effectiveness of the GPRI in improving patient empowerment (primary outcome), while also assessing implementation from the perspective of clinicians and the healthcare service. Patients referred for a cancer risk assessment to the conjoint clinical genetics service of two metropolitan hospitals in Victoria, Australia, who meet the eligibility criteria and consent to POETIC will be randomised to the usual care or intervention group. Those in the intervention group will complete the GPRI prior to their appointment with the screening results available for the clinicians' use during the appointment. Appointment audio recordings, clinician-reported information about the appointment, patient-reported outcome measures, and clinical data will be used to examine the effectiveness of using the GPRI. Appointment audio recordings, health economic information, and structured interviews will be used to examine the implementation of the GPRI. DISCUSSION: The POETIC trial takes a pragmatic approach by deploying the GPRI as an intervention in the routine clinical practice of a cancer-specific clinical genetics service that is staffed by a multidisciplinary team of genetics and oncology clinicians. Therefore, the effectiveness and implementation evidence generated from this real-world health service setting aims to optimise the relevance of the outcomes of this trial to the practice of genetic counselling while enhancing the operationalisation of the screening tool in routine practice. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry registration number 12621001582842p. Date of registration: 19th November 2021.
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Aconselhamento Genético , Neoplasias , Humanos , Participação do Paciente , Detecção Precoce de Câncer/métodos , Aconselhamento/métodos , Vitória , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/terapia , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Burkholderia cenocepacia is an opportunistic pathogen that is primarily associated with severe respiratory infections in people with cystic fibrosis. These bacteria have significant intrinsic resistance to antimicrobial therapy, and there is a need for more effective treatments. Bacterial zinc uptake and homeostasis systems are attractive targets for new drugs, yet our understanding of how bacteria acquire and utilise zinc remains incomplete. Here we have used RNA-sequencing and differential gene expression analysis to investigate how B. cenocepacia H111 is able to survive in zinc poor environments, such as those expected to be encountered within the host. The data shows that 201 genes are significantly differentially expressed when zinc supply is severely limited. Included in the 85 upregulated genes, are genes encoding a putative ZnuABC high affinity zinc importer, two TonB-dependent outer membrane receptors that may facilitate zinc uptake across the outer cell membrane, and a COG0523 family zinc metallochaperone. Amongst the 116 downregulated genes, are several zinc-dependent enzymes suggesting a mechanism of zinc sparring to reduce the cells demand for zinc when bioavailability is low.
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Infecções por Burkholderia , Burkholderia cenocepacia , Humanos , Burkholderia cenocepacia/genética , Zinco/metabolismo , Regulação Bacteriana da Expressão Gênica , Infecções por Burkholderia/genéticaRESUMO
Deleterious germ line variants in DDX41 are a common cause of genetic predisposition to hematologic malignancies, particularly myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). Targeted next-generation sequencing was performed in a large cohort of sequentially recruited patients with myeloid malignancy, covering DDX41 as well as 30 other genes frequently mutated in myeloid malignancy. Whole genome transcriptome sequencing data was analyzed on a separate cohort of patients with a range of hematologic malignancies to investigate the spectrum of cancer predisposition. Altogether, 5737 patients with myeloid malignancies were studied, with 152 different DDX41 variants detected. Multiple novel variants were detected, including synonymous variants affecting splicing as demonstrated by RNA-sequencing. The presence of a somatic DDX41 variant was highly associated with DDX41 germ line variants in patients with MDS and AML, and we developed a statistical approach to incorporate the co-occurrence of a somatic DDX41 variant into germ line variant classification at a very strong level (as per the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines). Using this approach, the MDS cohort contained 108 of 2865 (3.8%) patients with germ line likely pathogenic/pathogenic (LP/P) variants, and the AML cohort 106 of 2157 (4.9%). DDX41 LP/P variants were markedly enriched in patients with AML and MDS compared with those in patients with myeloproliferative neoplasms, B-cell neoplasm, and T- or B-cell acute lymphoblastic leukemia. In summary, we have developed a framework to enhance DDX41 variant curation as well as highlighted the importance of assessment of all types of genomic variants (including synonymous and multiexon deletions) to fully detect the landscape of possible clinically relevant DDX41 variants.
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Neoplasias Hematológicas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Transtornos Mieloproliferativos , Humanos , RNA Helicases DEAD-box/genética , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Transtornos Mieloproliferativos/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , GenômicaRESUMO
BACKGROUND: Tracheobronchomalacia (TBM) and airway stenosis are recognized etiologies of airway obstruction among children. Their management is often challenging, requiring multiple interventions and prolonged respiratory support with associated long-term morbidity. Metallic or silicone stents have been used with mixed success and high complication rates. More recently biodegradable Ella stents (BES) provided an attractive interventional option. OBJECTIVES: We report our experience in the treatment of TBM and vascular airway compression using BES. We deliberately downsized them to minimize intraluminal granulation tissue formation. MATERIALS AND METHODS: Retrospective study over an 8-year period between November 2012 and December 2020 of pediatric patients with severe airway obstruction requiring airway stenting for extubation failure, malacic death spells, recurrent chest infections, or lung collapse. RESULTS: Thirty-three patients (5 tracheal and 28 bronchial diseases) required 55 BES during the study period. The smallest patient weighed 1.8 kg. Median age of patient at first stent implantation was 13.1 months (IQR 4.9-58.3). The majority of the bronchial stents were in the left main bronchus (93%), of which 57% for vascular compression. Repeat stents were used in 19 patients (57.7%), with a range of two to four times. We did not experience erosion, infection, or obstructive granuloma needing removal by forceps or lasering. Three stent grid occluded with secretions needing bronchoscopic lavage. Stent migration occurred in three patients. CONCLUSIONS: BES holds promise as a treatment option with low rate of adverse effects for a specific subset of pediatric patients with airway malacia or vascular compression. Further studies are warranted.
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Obstrução das Vias Respiratórias , Traqueobroncomalácia , Criança , Humanos , Lactente , Pré-Escolar , Estudos Retrospectivos , Resultado do Tratamento , Obstrução das Vias Respiratórias/etiologia , Obstrução das Vias Respiratórias/cirurgia , Traqueobroncomalácia/complicações , Traqueobroncomalácia/cirurgia , Stents/efeitos adversos , Broncoscopia/efeitos adversosRESUMO
BACKGROUND: Many families and individuals do not meet criteria for a known hereditary cancer syndrome but display unusual clusters of cancers. These families may carry pathogenic variants in cancer predisposition genes and be at higher risk for developing cancer. METHODS: This multi-centre prospective study recruited 195 cancer-affected participants suspected to have a hereditary cancer syndrome for whom previous clinical targeted genetic testing was either not informative or not available. To identify pathogenic disease-causing variants explaining participant presentation, germline whole-genome sequencing (WGS) and a comprehensive cancer virtual gene panel analysis were undertaken. RESULTS: Pathogenic variants consistent with the presenting cancer(s) were identified in 5.1% (10/195) of participants and pathogenic variants considered secondary findings with potential risk management implications were identified in another 9.7% (19/195) of participants. Health economic analysis estimated the marginal cost per case with an actionable variant was significantly lower for upfront WGS with virtual panel ($8744AUD) compared to standard testing followed by WGS ($24,894AUD). Financial analysis suggests that national adoption of diagnostic WGS testing would require a ninefold increase in government annual expenditure compared to conventional testing. CONCLUSIONS: These findings make a case for replacing conventional testing with WGS to deliver clinically important benefits for cancer patients and families. The uptake of such an approach will depend on the perspectives of different payers on affordability.
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Síndromes Neoplásicas Hereditárias , Humanos , Estudos Prospectivos , Oncogenes , Testes Genéticos , Células GerminativasRESUMO
The gene-disease relationship for CHEK2 remains listed as 'Li-Fraumeni syndrome 2' in public resources such as OMIM and MONDO, despite published evidence to the contrary, causing frustration among Li-Fraumeni syndrome (LFS) clinical experts. Here, we compared personal cancer characteristics of 2095 CHEK2 and 248 TP53 pathogenic variant carriers undergoing multigene panel testing at Ambry Genetics against 15 135 individuals with no known pathogenic variant. Our results from a within-cohort logistic regression approach highlight obvious differences between clinical presentation of TP53 and CHEK2 pathogenic variant carriers, with no evidence of CHEK2 being associated with any of the TP53-related core LFS cancers. These findings emphasise the need to replace 'Li-Fraumeni syndrome 2' as the CHEK2-associated disease name, thereby limiting potential confusion.
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Síndrome de Li-Fraumeni , Humanos , Síndrome de Li-Fraumeni/epidemiologia , Síndrome de Li-Fraumeni/genética , Proteína Supressora de Tumor p53/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Quinase do Ponto de Checagem 2/genéticaRESUMO
BACKGROUND: Oesophageal cancer is the eighth most common malignancy worldwide and is associated with a poor prognosis. Oesophagectomy remains the best prospect for a cure if diagnosed in the early disease stages. However, the procedure is associated with significant morbidity and mortality and is undertaken only after careful consideration. Appropriate patient selection, counselling and resource allocation is essential. Numerous risk models have been devised to guide surgeons in making these decisions. AIM: To evaluate which multivariate risk models, using intraoperative information with or without preoperative information, best predict perioperative oesophagectomy outcomes. METHODS: A systematic review of the MEDLINE, EMBASE and Cochrane databases was undertaken from 2000-2020. The search terms used were [(Oesophagectomy) AND (Model OR Predict OR Risk OR score) AND (Mortality OR morbidity OR complications OR outcomes OR anastomotic leak OR length of stay)]. Articles were included if they assessed multivariate based tools incorporating preoperative and intraoperative variables to forecast patient outcomes after oesophagectomy. Articles were excluded if they only required preoperative or any post-operative data. Studies appraising univariate risk predictors such as preoperative sarcopenia, cardiopulmonary fitness and American Society of Anesthesiologists score were also excluded. The review was conducted following the preferred reporting items for systematic reviews and meta-analyses model. All captured risk models were appraised for clinical credibility, methodological quality, performance, validation and clinical effectiveness. RESULTS: Twenty published studies were identified which examined eleven multivariate risk models. Eight of these combined preoperative and intraoperative data and the remaining three used only intraoperative values. Only two risk models were identified as promising in predicting mortality, namely the Portsmouth physiological and operative severity score for the enumeration of mortality and morbidity (POSSUM) and POSSUM scores. A further two studies, the intraoperative factors and Esophagectomy surgical Apgar score based nomograms, adequately forecasted major morbidity. The latter two models are yet to have external validation and none have been tested for clinical effectiveness. CONCLUSION: Despite the presence of some promising models in forecasting perioperative oesophagectomy outcomes, there is more research required to externally validate these models and demonstrate clinical benefit with the adoption of these models guiding postoperative care and allocating resources.