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Purpose: Breast density is associated with the risk of developing cancer and can be automatically estimated using deep learning models from digital mammograms. Our aim is to evaluate the capacity and reliability of such models to predict density from low-dose mammograms taken to enable risk estimates for younger women. Approach: We trained deep learning models on standard-dose and simulated low-dose mammograms. The models were then tested on a mammography dataset with paired standard- and low-dose images. The effect of different factors (including age, density, and dose ratio) on the differences between predictions on standard and low doses is analyzed. Methods to improve performance are assessed, and factors that reduce the model quality are demonstrated. Results: We showed that, although many factors have no significant effect on the quality of low-dose density prediction, both density and breast area have an impact. The correlation between density predictions on low- and standard-dose images of breasts with the largest breast area is 0.985 (0.949 to 0.995), whereas that with the smallest is 0.882 (0.697 to 0.961). We also demonstrated that averaging across craniocaudal-mediolateral oblique (CC-MLO) images and across repeatedly trained models can improve predictive performance. Conclusions: Low-dose mammography can be used to produce density and risk estimates that are comparable to standard-dose images. Averaging across CC-MLO and model predictions should improve this performance. The model quality is reduced when making predictions on denser and smaller breasts.
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Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time. Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender. Findings: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers. Interpretation: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. Funding: We acknowledge funding from the Norwegian Cancer Society, contract 194751-2017.
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OBJECTIVE: To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. METHODS: CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. RESULTS: In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. CONCLUSIONS: Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so.
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Ovarian cancer (OC) is the least survivable gynecological malignancy and presents late. Five-year survival for OC is around 45% increasing the need for innovative treatments. Checkpoint inhibitors have shown significant clinical efficacy in mismatch repair deficient (MMRd) cancers and could be a powerful treatment in OC. However, their application in OC is limited due to the lack of data on the prevalence of MMRd. The aim of our study was to conduct a systematic review of the literature and meta-analysis to provide an accurate estimate of the prevalence of MMRd in OC. We followed PRISMA guidelines throughout. Studies were identified by electronic searches of Medline, Embase, Cochrane CENTRAL and Web of Science followed by citation searching. Studies not written in English were excluded. All studies were reviewed by at least two independent reviewers. Proportions of test positivity were calculated by random and fixed-effects meta-analysis models. I2 score was used to assess heterogeneity across studies. In total 54 studies were included with 17 532 analyzed for MMRd. The overall proportions of MMRd by immunohistochemistry and microsatellite instability analysis were 6.7% and 10.4%, respectively. MMRd was reported in all histotypes of epithelial OC but was most common in endometrioid OC. We estimate that on average 46.7% (95% CI: 28.8-65.4) of ovarian carcinomas showing MMRd by IHC had a germline path_MMR variant identified. OC in those with Lynch syndrome seems to present at an earlier age and stage. Studies however were generally of low quality and there was a high degree of heterogeneity. A significant minority (up to 16%) of OC displays MMRd and, therefore, could be amenable to checkpoint inhibition therapy. However, the current literature base is of limited quality and therefore high-quality prospective studies exploring MMRd in OC with the use of multimodal testing are required. In addition, trials researching efficacy of checkpoint inhibition in MMRd OC are needed.
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Síndromes Neoplásicas Hereditárias , Neoplasias Ovarianas , Neoplasias Encefálicas , Carcinoma Epitelial do Ovário , Neoplasias Colorretais , Reparo de Erro de Pareamento de DNA/genética , Feminino , Humanos , Instabilidade de Microssatélites , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Prevalência , Estudos ProspectivosRESUMO
BACKGROUND: Bilateral vestibular schwannomas (VS) are pathognomonic of neurofibromatosis type 2 (NF2), but the diagnostic criteria also include unilateral VS (UVS) in combination with multiple meningiomas (MM) and other schwannomas, as well as MM without VS. OBJECTIVE: To investigate the diagnostic value of these criteria and establish the presence of other genetic conditions in patients presenting in this manner. METHODS: The Manchester International NF2 database was accessed to obtain information on patients presenting with a UVS and MM or ≥2 nonintradermal schwannomas (NIDS). We gathered data on patients diagnosed with NF2 due to MM without VS and on patients presenting with MM without meeting NF2 criteria. Analysis was performed for pathogenic variants (PVs) in NF2, SMARCE1, SMARCB1, and LZTR1. RESULTS: A total of 31 of 131 patients presenting with a UVS and MM had a nonrefuted diagnosis of NF2 after molecular studies, in comparison with 85 of 96 patients presenting with UVS and ≥2 NIDS (P ≤ .00001). Fifty percent of patients presenting with a UVS and ≥2 NIDS with NF2 developed bilateral VS, compared with only 26% of those who presented with a UVS and MM (P = .0046). In total, 11 of 152 patients presenting with MM without fulfilling NF2 criteria were found to have a PV in SMARCE1, and 7 of 152 were confirmed to have mosaic NF2. CONCLUSION: Patients presenting with UVS and MM are significantly more likely to have a nonrefuted diagnosis of NF2 than patients presenting with UVS and ≥2 NIDS, but significantly less likely to develop bilateral VS. Seven percent of those presenting with MM without meeting NF2 criteria had PV in SMARCE1, and 5% had mosaic NF2.
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Neoplasias Meníngeas , Meningioma , Neurilemoma , Neurofibromatose 2 , Proteínas Cromossômicas não Histona , Proteínas de Ligação a DNA , Humanos , Neoplasias Meníngeas/diagnóstico , Neoplasias Meníngeas/genética , Meningioma/diagnóstico , Meningioma/genética , Neurilemoma/diagnóstico , Neurilemoma/genética , Neurilemoma/patologia , Neurofibromatose 2/diagnóstico , Neurofibromatose 2/genética , Neurofibromatose 2/patologia , Síndrome , Fatores de Transcrição/genéticaRESUMO
Epidemiology is the study of the distribution and determinants of health-related states or events in specified populations, and the application of this study to the control of health problems [...].
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OBJECTIVE: To review the outcomes of cochlear implants (CI) in patients with neurofibromatosis type 2 (NF2) in a large cohort, and identify factors associated with poor hearing benefit. STUDY DESIGN: Fifteen-year retrospective national observational case series. SETTING: United Kingdom regional NF2 multidisciplinary teams. PATIENTS: Consecutive patients with NF2 receiving a CI. INTERVENTIONS: CI for hearing rehabilitation. MAIN OUTCOME MEASURES: 1) Audiometric performance at 9 to 12âmonths after implantation using City University of New York (CUNY) sentence recognition score, and Bamford- Kowal-Bench (BKB) word recognition score in quiet (BKBq), and in noise (BKBn). 2) CI use at most recent review. RESULTS: Sixty four consecutive patients, median age 43âyears, were included. Nine to 12âmonths mean audiometric scores were: CUNY 60.9%, BKBq 45.8%, BKBn 41.6%. There was no difference in audiometric outcomes between VS treatment modalities. At most recent review (median 3.6âyears from implantation), 84.9% with device in situ/available data were full or part-time users. Between 9 and 12âmonths and most recent review there was an interval reduction in mean audiometric scores: CUNY -12.9%, BKBq -3.3%, BKBn -4.9%. Larger tumor size and shorter duration of profound hearing loss were the only variables associated with poorer audiometric scores. Tumor growth at the time of surgery was the only variable associated with CI non-use. Individual patient response was highly variable. CONCLUSIONS: CI can provide significant and sustained auditory benefits to patients with NF2 independent of tumor treatment modality, with the majority of those implanted becoming at least part-time users. Larger datasets are required to reliably assess the role of independent variables.
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Implante Coclear , Implantes Cocleares , Neurofibromatose 2 , Neuroma Acústico , Percepção da Fala , Adulto , Humanos , Neurofibromatose 2/complicações , Neurofibromatose 2/cirurgia , Neuroma Acústico/complicações , Neuroma Acústico/cirurgia , Estudos Retrospectivos , Percepção da Fala/fisiologia , Resultado do Tratamento , Reino UnidoRESUMO
BACKGROUND: Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. OBJECTIVE: To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. METHODS: Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. RESULTS: Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. CONCLUSION: Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.
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The authors present the case of a 24-year-old female with neurofibromatosis type 2. Growth of the left vestibular schwannoma and progressive hearing loss prompted the decision to proceed to translabyrinthine resection with cochlear nerve preservation and cochlear implant insertion. Complete resection with preservation of the facial and cochlear nerves was achieved. The patient had grade 1 facial function and was discharged on postoperative day 4 following suturing of a minor CSF leak. This case highlights the feasibility of cochlear nerve preservation and cochlear implant insertion in appropriately selected patients, offering a combination of effective tumor control and hearing rehabilitation. The video can be found here: https://stream.cadmore.media/r10.3171/2021.7.FOCVID21122.
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Meningiomas are the most common primary brain tumor and their incidence and prevalence is increasing. This review summarizes current evidence regarding the embryogenesis of the human meninges in the context of meningioma pathogenesis and anatomical distribution. Though not mutually exclusive, chromosomal instability and pathogenic variants affecting the long arm of chromosome 22 (22q) result in meningiomas in neural-crest cell-derived meninges, while variants affecting Hedgehog signaling, PI3K signaling, TRAF7, KLF4, and POLR2A result in meningiomas in the mesodermal-derived meninges of the midline and paramedian anterior, central, and ventral posterior skull base. Current evidence regarding the common pathways for genetic pathogenesis and the anatomical distribution of meningiomas is presented alongside existing understanding of the embryological origins for the meninges prior to proposing next steps for this work.
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Proteínas Hedgehog/genética , Fatores de Transcrição Kruppel-Like/genética , Neoplasias Meníngeas/genética , Meningioma/genética , Genótipo , Humanos , Fator 4 Semelhante a Kruppel , Neoplasias Meníngeas/patologia , Meningioma/patologia , Mutação/genética , Fenótipo , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/genéticaRESUMO
Vestibular schwannomas are tumors arising from the vestibulocochlear nerve at the cerebellopontine angle. Their proximity to eloquent brainstem structures means that the pathology itself and the treatment thereof can be associated with significant morbidity. The vast majority of these tumors are sporadic, with the remainder arising as a result of the genetic syndrome Neurofibromatosis Type 2 or, more rarely, LZTR1-related schwannomatosis. The natural history of these tumors is extremely variable, with some tumors not displaying any evidence of growth, others demonstrating early, persistent growth and a small number growing following an extended period of indolence. Emerging evidence now suggests that far from representing Schwann cell proliferation only, the tumor microenvironment is complex, with inflammation proposed to play a key role in their growth. In this review, we provide an overview of this new evidence, including the role played by immune cell infiltration, the underlying molecular pathways involved, and biomarkers for detecting this inflammation in vivo. Given the limitations of current treatments, there is a pressing need for novel therapies to aid in the management of this condition, and we conclude by proposing areas for future research that could lead to the development of therapies targeted toward inflammation in vestibular schwannoma.
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Panels of single nucleotide polymorphisms (SNPs) stratify risk for breast cancer in women from the general population, but studies are needed assess their use in a fully comprehensive model including classical risk factors, mammographic density and more than 100 SNPs associated with breast cancer. A case-control study was designed (1,668 controls, 405 cases) in women aged 47-73 years attending routine screening in Manchester UK, and enrolled in a wider study to assess methods for risk assessment. Risk from classical questionnaire risk factors was assessed using the Tyrer-Cuzick model; mean percentage visual mammographic density was scored by two independent readers. DNA extracted from saliva was genotyped at selected SNPs using the OncoArray. A predefined polygenic risk score based on 143 SNPs was calculated (SNP143). The odds ratio (OR, and 95% confidence interval, CI) per interquartile range (IQ-OR) of SNP143 was estimated unadjusted and adjusted for Tyrer-Cuzick and breast density. Secondary analysis assessed risk by oestrogen receptor (ER) status. The primary polygenic risk score was well calibrated (O/E OR 1.10, 95% CI 0.86-1.34) and accuracy was retained after adjustment for Tyrer-Cuzick risk and mammographic density (IQ-OR unadjusted 2.12, 95% CI% 1.75-2.42; adjusted 2.06, 95% CI 1.75-2.42). SNP143 was a risk factor for ER+ and ER- breast cancer (adjusted IQ-OR, ER+ 2.11, 95% CI 1.78-2.51; ER- 1.81, 95% CI 1.16-2.84). In conclusion, polygenic risk scores based on a large number of SNPs improve risk stratification in combination with classical risk factors and mammographic density, and SNP143 was similarly predictive for ER-positive and ER-negative disease.
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Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Idoso , Densidade da Mama , Neoplasias da Mama/diagnóstico por imagem , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Mamografia , Pessoa de Meia-Idade , Sobrepeso/genética , Sobrepeso/patologia , Polimorfismo de Nucleotídeo Único , RiscoRESUMO
Observational studies suggest that higher birth weight (BW) is associated with increased risk of breast cancer in adult life. We conducted a two-sample Mendelian randomisation (MR) study to assess whether this association is causal. Sixty independent single nucleotide polymorphisms (SNPs) known to be associated at P < 5 × 10-8 with BW were used to construct (1) a 41-SNP instrumental variable (IV) for univariable MR after removing SNPs with pleiotropic associations with other breast cancer risk factors and (2) a 49-SNP IV for multivariable MR after filtering SNPs for data availability. BW predicted by the 41-SNP IV was not associated with overall breast cancer risk in inverse-variance weighted (IVW) univariable MR analysis of genetic association data from 122,977 breast cancer cases and 105,974 controls (odds ratio = 0.86 per 500 g higher BW; 95% confidence interval 0.73-1.01). Sensitivity analyses using four alternative methods and three alternative IVs, including an IV with 59 of the 60 BW-associated SNPs, yielded similar results. Multivariable MR adjusting for the effects of the 49-SNP IV on birth length, adult height, adult body mass index, age at menarche, and age at menopause using IVW and MR-Egger methods provided estimates consistent with univariable analyses. Results were also similar when all analyses were repeated after restricting to estrogen receptor-positive or -negative breast cancer cases. Point estimates of the odds ratios from most analyses performed indicated an inverse relationship between genetically-predicted BW and breast cancer, but we are unable to rule out an association between the non-genetically-determined component of BW and breast cancer. Thus, genetically-predicted higher BW was not associated with an increased risk of breast cancer in adult life in our MR study.
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Peso ao Nascer , Neoplasias da Mama/epidemiologia , Peso ao Nascer/genética , Feminino , Humanos , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Medição de RiscoRESUMO
Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.
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Predisposição Genética para Doença/genética , Variação Genética/genética , Neoplasias Primárias Múltiplas/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Feminino , Testes Genéticos/métodos , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Pessoa de Meia-Idade , FenótipoRESUMO
OBJECTIVE: Onset of symptoms in severe sporadic neurofibromatosis type 2 (NF2) is typically within childhood; however, there is poor awareness of presenting features in young children, potentially resulting in delayed diagnosis and poorer outcome. We have reviewed presentation of sporadic paediatric NF2 to raise awareness of early features, highlighting those requiring further investigation. DESIGN: Patients diagnosed with NF2 at age ≤16 and seen between 2012 and 2015 were notified via the British Paediatric Neurology Surveillance Unit or identified through the English NF2 service. RESULTS: Epidemiological data estimate that 1 in 110 611 births are affected with childhood-onset NF2. Notes of 32 patients with sporadic NF2 were reviewed. Of those presenting under the age of 5, 89% (17/19) had ocular, 74% (14/19) dermatological and 58% (11/19) neurological signs; in 84% (16/19) features were multisystemic. Sixty-six per cent (21/32) had ≥1 atypical feature, including cerebellar hypoplasia in three cases (9%) and focal cortical dysplasia in five out of seven seizure-related presentations. Five cases presented with a sometimes transient or intermittent cranial nerve mononeuropathy. The mean delay to diagnosis was 3.16 years; in eight cases (25%) this exceeded 6 years. Most significant delay occurred in mononeuropathy, ophthalmological and/or seizure presentations, with a mean delay of 3, 4.5 and 6 years, respectively. Eighty-four per cent (27/32) of cases needed intervention in childhood. CONCLUSIONS: All non-vestibular schwannoma NF2 presentations in childhood had significant diagnostic delay. We emphasise the importance of detailed assessment of skin and eyes in unusual presentations and propose an aide to prompt timely referral to specialist services.
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Neurofibromatose 2/diagnóstico , Adolescente , Fatores Etários , Criança , Pré-Escolar , Diagnóstico Tardio , Inglaterra/epidemiologia , Oftalmopatias/epidemiologia , Oftalmopatias/etiologia , Feminino , Genes da Neurofibromatose 2 , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Doenças do Sistema Nervoso/epidemiologia , Doenças do Sistema Nervoso/etiologia , Neurofibromatose 2/complicações , Neurofibromatose 2/epidemiologia , Neurofibromatose 2/genética , Vigilância da População , Dermatopatias/epidemiologia , Dermatopatias/etiologiaRESUMO
BACKGROUND: Germline mutations in the BRCA1 and BRCA2 genes have significant clinical implications for both risk-reducing and early surveillance management. The third and most recent revision of the Manchester scoring system (MSS3) used to distinguish patients indicated for germline BRCA1/2 testing included further adjustments for triple negative breast cancer, high-grade serous ovarian cancer and human epidermal growth factor 2 (HER2) receptor status. This study aims to evaluate the relative effectiveness of MSS3 in a Southeast Asian population. METHODS: All patients in our centre were tested using next-generation sequencing (NGS) panels that included full gene sequencing as well as coverage for large deletions/duplications in BRCA1/2. We calculated MSS1-3 scores for index patients between 2014 and 2017 who had undergone BRCA1/2 genetic testing and recorded their genetic test results. MSS1-3 outcomes were compared using receiver operating characteristic analysis, while associations with predictors were investigated using Fisher's exact test and logistics regression. Calculations were performed using Medcalc17. RESULTS: Of the 330 included patients, 47 (14.2%) were found to have a germline mutation in BRCA1 or BRCA2. A positive HER2 receptor was associated with a lower likelihood of a BRCA1/2mutation (OR=0.125, 95% CI 0.016 to 0.955; P=0.007), while high-grade serous ovarian cancer was conversely associated with an increased likelihood of a BRCA1/2 mutation (OR=5.128, 95% CI 1.431 to 18.370; P=0.012). At the 10% threshold, 43.0% (142/330) of patients were indicated for testing under MSS3, compared with 35.8% (118/330) for MSS1% and 36.4% (120/330) for MSS2. At the 10% threshold, MSS3 sensitivity was 91.5% and specificity 65.0%, significantly better than the previous MSS1 (P=0.037) and MSS2 (P=0.032) models. CONCLUSION: Our results indicate that the updated MSS3 outperforms previous iterations and relative to the Manchester population, is just as effective in identifying patients with BRCA1/2 mutations in a Southeast Asian population.
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Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/diagnóstico , Neoplasias Ovarianas/diagnóstico , Adulto , Idoso , Sudeste Asiático/epidemiologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Testes Genéticos , Mutação em Linhagem Germinativa/genética , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Valor Preditivo dos TestesRESUMO
BACKGROUND: We have previously reported a high incidence of colorectal cancer (CRC) in carriers of pathogenic MLH1 variants (path_MLH1) despite follow-up with colonoscopy including polypectomy. METHODS: The cohort included Finnish carriers enrolled in 3-yearly colonoscopy (n = 505; 4625 observation years) and carriers from other countries enrolled in colonoscopy 2-yearly or more frequently (n = 439; 3299 observation years). We examined whether the longer interval between colonoscopies in Finland could explain the high incidence of CRC and whether disease expression correlated with differences in population CRC incidence. RESULTS: Cumulative CRC incidences in carriers of path_MLH1 at 70-years of age were 41% for males and 36% for females in the Finnish series and 58% and 55% in the non-Finnish series, respectively (p > 0.05). Mean time from last colonoscopy to CRC was 32.7 months in the Finnish compared to 31.0 months in the non-Finnish (p > 0.05) and was therefore unaffected by the recommended colonoscopy interval. Differences in population incidence of CRC could not explain the lower point estimates for CRC in the Finnish series. Ten-year overall survival after CRC was similar for the Finnish and non-Finnish series (88% and 91%, respectively; p > 0.05). CONCLUSIONS: The hypothesis that the high incidence of CRC in path_MLH1 carriers was caused by a higher incidence in the Finnish series was not valid. We discuss whether the results were influenced by methodological shortcomings in our study or whether the assumption that a shorter interval between colonoscopies leads to a lower CRC incidence may be wrong. This second possibility is intriguing, because it suggests the dogma that CRC in path_MLH1 carriers develops from polyps that can be detected at colonoscopy and removed to prevent CRC may be erroneous. In view of the excellent 10-year overall survival in the Finnish and non-Finnish series we remain strong advocates of current surveillance practices for those with LS pending studies that will inform new recommendations on the best surveillance interval.
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OBJECTIVE: To describe the experience of auditory brainstem implantation (ABI) in patients with Neurofibromatosis type 2 (NF2). STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral centre. PATIENTS: Implanted with a Cochlear ABI22 or ABI24M between 1994 and 2009 because of NF2 disease. INTERVENTION(S): Rehabilitative. MAIN OUTCOME MEASURE(S): Surgical complication rate; audiological outcomes. RESULTS: There were 50 primary ABI insertions in 49 patients, including 16 inserted at the time of first side tumor removal as a sleeper, and two revision repositionings which failed to improve outcome. Postoperatively three patients had cerebrospinal fluid leaks which did not require reoperation, one patient had meningitis, and eleven patients suffered either temporary or permanent lower cranial nerve dysfunction. Twenty-nine patients became full time users; a further 12 patients became non-users. Three patients died while their device was inactive. Five patients retain serviceable contralateral hearing. Audiological open set testing of users showed means of: environmental sounds discrimination 51%; phoneme discrimination: with ABI alone 22%/lip reading (LR) 45%/ABI with LR 65%; sentence testing: with ABI alone 13%/LR 19%/ABI with LR 54%. CONCLUSIONS: The majority of patients with NF2 implanted with an ABI find the device a useful aid to communication in conjunction with LR and in recognizing common environmental sounds. A small proportion gain open set discrimination. Almost a third of patients may end up as non-users. There is probably an increased risk of postoperative lower cranial nerve dysfunction so careful preoperative assessment is advised.
Assuntos
Implante Auditivo de Tronco Encefálico , Surdez/cirurgia , Neurofibromatose 2/complicações , Neuroma Acústico/complicações , Adulto , Implantes Auditivos de Tronco Encefálico , Percepção Auditiva , Surdez/etiologia , Feminino , Humanos , Masculino , Neurofibromatose 2/cirurgia , Neuroma Acústico/cirurgia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Neurofibromatosis type 2 (NF2; MIM # 101000) is an autosomal dominant disorder characterized by the development of vestibular schwannomas (VSs); schwannomas of other cranial, spinal, and cutaneous nerves; cranial and spinal meningiomas or other central nervous system tumors (eg, ependymomas and astrocytomas) or both. Additional features include eye (eg, early onset cataracts, optic nerve sheath meningiomas, retinal or pigment epithelial hamartomas or both, and epithelial retinal membranes) and skin abnormalities (eg, flat dermal [NF2 plaques] or spherical subcutaneous nodular schwannomas or both, and few, atypical café-au-lait spots). Clinically, children with NF2 fall into 2 main groups: (1) congenital NF2 with bilateral VSs detected as early as the first days to months of life, which can be stable or asymptomatic for 1-2 decades and suddenly progress; and (2) severe prepubertal (Wishart type) NF2 with multiple (and rapidly progressive) central nervous system tumors other-than-VS, which usually presents first, years before VSs, both associated with more marked skin and eye involvement (vs the classical mild adult [Gardner type] NF2, with bilateral VSs presenting in young adulthood, sometimes as the only disease feature). Individuals manifesting unilateral VS associated with ipsilateral meningiomas or multiple schwannomas localized to a part of the peripheral nervous system have mosaic or segmental NF2; individuals developing multiple nonVS, nonintradermal cranial, spinal, and peripheral schwannomas (histologically proven) have schwannomatosis (SWNTS). NF2 is caused by mutations in the NF2 gene at chromosome 22q12.1, which encodes for a protein called merlin or schwannomin, most similar to the exrin-readixin-moesin proteins; mosaic or segmental NF2 is because of mosaic phenomena for the NF2 gene, whereas SWNTS is caused by germline and possibly mosaic mutations either in the SMARCB1 gene (SWNTS1; MIM # 162091) or the LZTR1 gene (SWNTS2; MIM # 615670), both falling within the 22q region. Data driven from in vitro and animal studies on the merlin pathway allowed biologically targeted treatment strategies (employing Lapatinib, Erlotinib, Everolimus, Picropodophyllin, OSU.03012, Imatinib, Sorafenib, and Bevacizumab) aimed at multiple tumor shrinkage or regression or both and tumor arrest of progression with functional improvement.