Molecular classification of metastatic and recurrent endometrial endometrioid carcinoma: prognostic relevance among low- and high-stage tumours.

AIMS: Molecular classification according to The Cancer Genome Atlas (TCGA) improves endometrial endometrioid carcinoma (EEC) prognostication and has specific treatment implications; however, original data were skewed towards low-grade and low-stage tumours. Herein, we molecularly classify EECs metastatic at the time of diagnosis or with subsequently documented recurrent/metastatic disease to examine correlation with clinical outcomes. METHODS: TCGA categories include POLE-mutated, microsatellite instability (MSI), p53 abnormal (p53 abnl) and no specific molecular profile (NSMP). POLE targeted sequencing at exons 9, 11, 13 and 14 and immunohistochemistry (IHC) for PMS2, MSH6 and p53 were performed to establish molecular classification. RESULTS: The distribution in our cohort of 141 EECs was similar to that generally reported in EEC, with nine POLE-mutated (6%), 45 MSI (32%), 16 p53 abnl (11%) and 71 NSMP (50%), with similar distributions between low- and high-stage cohorts. We demonstrate that when stratified by molecular subtype, disease-specific survival from the time of high-stage (stages III-IV) presentation or time of recurrence in low-stage (stages I-II) disease among metastatic and/or recurrent EEC is strongly associated with TCGA classification (high-stage P = 0.02, low-stage P = 0.017). Discordant molecular classification between primary and metastatic/recurrent tumours occurred in four of 105 (3.8%) patients, two related to PMS2/MSH6 IHC and two related to p53 IHC. CONCLUSIONS: We demonstrate that molecular classification is prognostically relevant not only at the time of diagnosis, but also at the time of recurrence and in the metastatic setting. Rare subclonal alterations occur and suggest a role for confirming TCGA classification in recurrent/metastatic tumours.

General Applicability of Existing College of American Pathologists Accreditation Requirements to Clinical Implementation of Machine Learning-Based Methods in Molecular Oncology Testing.

CONTEXT.­: The College of American Pathologists (CAP) accreditation requirements for clinical laboratory testing help ensure laboratories implement and maintain systems and processes that are associated with quality. Machine learning (ML)-based models share some features of conventional laboratory testing methods. Accreditation requirements that specifically address clinical laboratories' use of ML remain in the early stages of development. OBJECTIVE.­: To identify relevant CAP accreditation requirements that may be applied to the clinical adoption of ML-based molecular oncology assays, and to provide examples of current and emerging ML applications in molecular oncology testing. DESIGN.­: CAP accreditation checklists related to molecular pathology and general laboratory practices (Molecular Pathology, All Common and Laboratory General) were reviewed. Examples of checklist requirements that are generally applicable to validation, revalidation, quality management, infrastructure, and analytical procedures of ML-based molecular oncology assays were summarized. Instances of ML use in molecular oncology testing were assessed from literature review. RESULTS.­: Components of the general CAP accreditation framework that exist for traditional molecular oncology assay validation and maintenance are also relevant for implementing ML-based tests in a clinical laboratory. Current and emerging applications of ML in molecular oncology testing include DNA methylation profiling for central nervous system tumor classification, variant calling, microsatellite instability testing, mutational signature analysis, and variant prediction from histopathology images. CONCLUSIONS.­: Currently, much of the ML activity in molecular oncology is within early clinical implementation. Despite specific considerations that apply to the adoption of ML-based methods, existing CAP requirements can serve as general guidelines for the clinical implementation of ML-based assays in molecular oncology testing.

Targeted mutational profiling of Epstein Barr virus-positive mucocutaneous ulcer: Implications for differential diagnosis with EBV-positive diffuse large B-cell lymphoma.

Epstein Barr Virus-positive mucocutaneous ulcer (EBVMCU) can be difficult to distinguish from EBV-positive diffuse large B cell lymphoma (DLBCL). We used targeted next-generation sequencing (NGS) to explore genetic alterations in EBVMCU to aid in this diagnostic challenge. Ten cases of EBVMCU were evaluated by a targeted NGS panel of 164 genes. Targeted NGS identified 18 variants in 15 genes in eight cases of EBVMCU. Loss of function TET2 variants were most frequently identified (3 of 10 cases, 30 %). One TET2 variant occurred at low variant allele frequency (VAF) of 3 %, which may be suggestive of clonal hematopoiesis of indeterminate potential. One case harbored a loss of function DNMT3A variant at low VAF. Two cases demonstrated missense variants in the IRF8 gene. Both variants occurred at a VAF close to 50 % and with an estimated high burden of disease (75 %). Two cases of mucosal gastrointestinal involvement had no reportable variants. Mutational profiling of EBVMCU identified TET2 loss of function variants at an elevated frequency in our cohort; however, the findings are not specific and its clinical significance cannot be completely elucidated. Further studies are needed to confirm the findings in an independent and larger cohort of EBVMCU, to determine the cell of origin of the variants, and to further assess their significance in the pathogenesis of this disorder.

A conserved motif in the immune-subdominant RAP-1 related antigen of Babesia bovis contains a B-cell epitope recognized by antibodies from protected cattle.

Introduction: Babesia bovis, a tick-borne apicomplexan parasite causing bovine babesiosis, remains a significant threat worldwide, and improved and practical vaccines are needed. Previous studies defined the members of the rhoptry associated protein-1 (RAP-1), and the neutralization-sensitive rhoptry associated protein-1 related antigen (RRA) superfamily in B. bovis, as strong candidates for the development of subunit vaccines. Both RAP-1 and RRA share conservation of a group of 4 cysteines and amino acids motifs at the amino terminal end (NT) of these proteins. Methods and results: Sequence comparisons among the RRA sequences of several B. bovis strains and other Babesia spp parasites indicate a high level of conservation of a 15-amino acid (15-mer) motif located at the NT of the protein. BlastP searches indicate that the 15-mer motif is also present in adenylate cyclase, dynein, and other ATP binding proteins. AlphaFold2 structure predictions suggest partial exposure of the 15-mer on the surface of RRA of three distinct Babesia species. Antibodies in protected cattle recognize a synthetic peptide representing the 15-mer motif sequence in iELISA, and rabbit antibodies against the 15-mer react with the surface of free merozoites in immunofluorescence. Discussion and conclusion: The presence of the 15-mer-like regions in dynein and ATP-binding proteins provides a rationale for investigating possible functional roles for RRA. The demonstrated presence of a surface exposed B-cell epitope in the 15-mer motif of the B. bovis RRA, which is recognized by sera from protected bovines, supports its inclusion in future subunit epitope-based vaccines against B. bovis.

Molecular Classification Outperforms Histologic Classification in Prognostication of High-grade Endometrial Carcinomas With Undifferentiated and Sarcomatous Components.

Since the establishment of 4 molecular subgroups of endometrial carcinoma (EC), there has been significant interest in understanding molecular classification in the context of histologic features and diagnoses. ECs with undifferentiated, spindle, and/or sarcomatous components represent a diagnostically challenging subset of tumors with overlapping clinical and histologic features. We examined the clinicopathologic, morphologic, immunohistochemical, and molecular features of these tumors identified in our institutions' pathology databases using immunohistochemistry and targeted sequencing. Disease-specific survival (DSS) and progression-free survival (PFS) were analyzed using Kaplan-Meier curves and log-rank tests. One hundred sixty-two ECs were included: carcinosarcomas (UCS; n=96), dedifferentiated/undifferentiated EC (DDEC/UDEC; n=49), and grade 3 endometrioid EC with spindled growth (GR3spEEC) (n=17). All molecular subgroups were represented in all histologic subtypes and included 12 (7%) POLE -mutated ( POLE mut), 43 (27%) mismatch repair-deficient (MMRd), 77 (48%) p53-abnormal (p53abn), and 30 (19%) no specific molecular profile (NSMP) tumors. However, the molecular classification (irrespective of histologic diagnosis) was a significant predictor for both DSS ( P =0.008) and P≤0.0001). POLE mut EC showed an excellent prognosis with no recurrences or deaths from the disease. MMRd tumors also showed better outcomes relative to NSMP and p53abn tumors. In conclusion, molecular classification provides better prognostic information than histologic diagnosis for high-grade EC with undifferentiated and sarcomatous components. Our study strongly supports routine molecular classification of these tumors, with emphasis on molecular group, rather than histologic subtyping, in providing prognostication.

Identifying major histocompatibility complex class II-DR molecules in bovine and swine peripheral blood monocyte-derived macrophages using mAb-L243.

Major histocompatibility complex class II (MHC-II) molecules are involved in immune responses against pathogens and vaccine candidates' immunogenicity. Immunopeptidomics for identifying cancer and infection-related antigens and epitopes have benefited from advances in immunopurification methods and mass spectrometry analysis. The mouse anti-MHC-II-DR monoclonal antibody L243 (mAb-L243) has been effective in recognising MHC-II-DR in both human and non-human primates. It has also been shown to cross-react with other animal species, although it has not been tested in livestock. This study used mAb-L243 to identify Staphylococcus aureus and Salmonella enterica serovar Typhimurium peptides binding to cattle and swine macrophage MHC-II-DR molecules using flow cytometry, mass spectrometry and two immunopurification techniques. Antibody cross-reactivity led to identifying expressed MHC-II-DR molecules, together with 10 Staphylococcus aureus peptides in cattle and 13 S. enterica serovar Typhimurium peptides in swine. Such data demonstrates that MHC-II-DR expression and immunocapture approaches using L243 mAb represents a viable strategy for flow cytometry and immunopeptidomics analysis of bovine and swine antigen-presenting cells.

Update on olfactory neuroblastoma.

Olfactory neuroblastomas are uncommon malignancies that arise from olfactory receptor cells located high in the nasal cavity. Accurate diagnosis plays a crucial role in determining clinical results and guiding treatment decisions. Diagnosis can be a major challenge for pathologists, especially when dealing with tumours with poor differentiation. The discovery of several molecular and immunohistochemical markers would help to overcome classification difficulties. Due to the paucity of large-scale studies, standardisation of diagnosis, treatment and prediction of outcome remains a challenge. Surgical resection by endoscopic techniques with the addition of postoperative irradiation is the treatment of choice. In addition, it is advisable to consider elective neck irradiation to minimise the risk of nodal recurrence. Molecular characterisation will help not only to make more accurate diagnoses but also to identify specific molecular targets that can be used to develop personalised treatment options tailored to each patient. The present review aims to summarise the current state of knowledge on histopathological diagnosis, the molecular biology and management of this disease.

Diagnostic impact of RNA-based next-generation sequencing fusion panel for solid tumors: A single-institution experience.

OBJECTIVES: Gene rearrangements frequently act as oncogenic driver mutations and determine the onset and progression of cancer. RNA-based next-generation sequencing (NGS) is being used with increasing frequency for solid tumors. The purpose of our study is to investigate the feasibility and utility of an RNA-based NGS fusion panel for solid tumors. METHODS: We conducted a retrospective, single-institution review of fusion panels requested between May 2022 and March 2023. Demographic, clinical, pathologic, and molecular findings of the patients were reviewed. The utility of the RNA-based NGS fusion panel for the pathologic diagnosis of solid tumors was assessed. RESULTS: Our study included 345 cases, and a fusion event was identified in 24.3% (78/321) of cases. Among the 110 cases submitted for diagnostic purposes, a fusion event was detected in 42.7% (47/110) of cases. The results led to refinement or clarification of the initial diagnosis in 31.9% (15/47) of cases and agreement or support for the initial diagnosis in 59.6% (28/47) of cases. Furthermore, our study indicated that the overall cellularity (tumor and normal tissue) of the tested specimen influences the success of the testing process. CONCLUSIONS: In summary, this study demonstrated the feasibility and utility of an RNA-based NGS fusion panel for a wide variety of solid tumors in the appropriate clinicopathologic context. These findings warrant further validation in larger studies involving multiple institutional patient cohorts.

Estabilidad dimensional de hidrocoloides irreversibles de vaciado convencional y de vaciado de tiempo extendido disponibles en el mercado uruguayo

Objetivo. Comparar la estabilidad dimensional de un hidrocoloide irreversible de vaciado convencional con hidrocoloides irreversibles de vaciado extendido. Metodología. Fueron evaluados cuatro productos con indicación de vaciado extendido: Jeltrate Plus (Denstply Sirona), Hydrogum 5 (Zhermack SpA), Algimax (Major), Kromopan (Lascod) y un producto de vaciado convencional (Tropicalgin; Zhermack SpA). Con cada producto se realizaron 10 impresiones y se vaciaron en yeso tipo III en cinco tiempos de almacenamiento diferentes (0, 24, 96, 120 y 168 horas). Un escáner para modelos tridimensionales se utilizó para digitalizar los modelos de yeso y realizar las mediciones correspondientes: sumatoria de las longitudes, variabilidad dimensional, porcentaje de variabilidad. Resultados. Las cinco marcas comerciales presentaron una sumatoria de longitudes mayor al grupo control (p<0,033). A las 0, 24 y 96h Tropicalgin e Hydrogum 5 presentaron significativamente menor variación dimensional en comparación con el modelo maestro (p<0,001). Los porcentajes de variabilidad oscilaron entre un 0.24 a 0.91%. Conclusiones. La estabilidad dimensional depende del producto utilizado. Almacenado correctamente, el hidrocoloide irreversible de vaciado convencional parece no sufrir alteraciones significativas hasta 96h, mientras que en el caso de Hydrogum 5 parece mantener su estabilidad dimensional hasta 168h.

Objetivo. Comparar a estabilidade dimensional de um hidrocolóide irreversível de vazamento convencional com hidrocolóides irreversíveis de vazamento prolongado. Metodologia. Foram avaliados quatro produtos com indicação de vazamento estendido: Jeltrate Plus (Denstply Sirona), Hydrogum 5 (Zhermack SpA), Algimax (Major), Kromopan (Lascod) e um produto de vaziamento convencional (Tropicalgin; Zhermack SpA). Para cada produto foram feitas 10 impressões e vazadas em gesso tipo III em cinco tempos de armazenamento diferentes (0, 24, 96, 120 e 168 horas). Um scanner de modelos tridimensionais foi utilizado para digitalizar os modelos de gesso e fazer as medições correspondentes: soma dos comprimentos, variabilidade dimensional, percentagem de variabilidade. Resultados. As cinco marcas comerciais apresentaram somatório de comprimentos maior que o grupo controle (p<0,033). Nos tempos 0, 24 e 96h Tropicalgin e Hydrogum 5 apresentaram variação dimensional significativamente menor em comparação ao modelo Mestre (p<0,001). Os percentuais de variabilidade variaram de 0,24 a 0,91%. Conclusões. A estabilidade dimensional depende do produto utilizado. Armazenado corretamente, o hidrocolóide irreversível de vaziamento convencional convencionalmente parece não sofrer alterações significativas até 96h, enquanto no caso do Hydrogum 5 parece manter sua estabilidade dimensional até 168h.

Aim . Compare the dimensional stability of a conventional pouring irreversible hydrocolloid with extended pouring irreversible hydrocolloids. Methodology. Four products with extended emptying indication were evaluated: Jeltrate Plus (Denstply Sirona), Hydrogum 5 (Zhermack SpA), Algimax (Major), Kromopan (Lascod) and a conventional emptying product (Tropicalgin; Zhermack SpA). For each product, 10 impressions were made and cast in type III plaster at five different storage times (0, 24, 96, 120 and 168 hours). A three-dimensional model scanner was used to digitize the plaster models and make the corresponding measurements: sum of lengths, dimensional variability, percentage of variability. Results . The five commercial brands presented a greater sum of lengths than the control group (p<0,033). At 0, 24 and 96h Tropicalgin and Hydrogum 5 presented significantly less dimensional variation compared to the master model (p<0,001). The variability percentages ranged from 0.24 to 0.91%. Conclusions. Dimensional stability depends on the product used. Stored correctly, the conventionally cast irreversible hydrocolloid appears not to undergo significant alterations up to 96h, while in the case of Hydrogum 5 it appears to maintain its dimensional stability up to 168h.

In vitro characterization of a novel resin-based restorative material containing alkaline fillers

Abstract Objective: In this study, a comparative evaluation of the physicochemical properties of Cention N and other direct restorative materials was performed. Three restorative materials—a resin-modified glass ionomer (Fuji II LC), an alkasite-based resinous material (Cention N), and a resin composite (Tetric N Ceram)—were characterized in terms of degree of conversion, Knoop hardness number (KHN) ratio, flexural strength, elastic modulus, water sorption, water solubility, microshear bond strength to dentin, immediate microleakage, and radiopacity. Methodology: The microshear bond strength to dentin and microleakage of Cention N were evaluated with and without the application of an adhesive system (Tetric N Bond Universal). A one-way ANOVA test was used to analyze the data in terms of degree of conversion, KHN ratio, water sorption, water solubility, microshear bond strength to dentin, and radiopacity. A two-way ANOVA test (carried out considering the material type and ethanol aging as factors) was used to analyze the data in terms of flexural strength and elastic modulus. The Kruskal-Wallis test was used to statistically analyze the data on microleakage. A significance level of α=0.05 was used for all tests. Results: Fuji II LC was found to have the highest degree of conversion, water sorption, and microleakage, as well as the lowest flexural strength. Cention N had the highest solubility; when used with an adhesive system, it achieved bond strength and microleakage similar to those of the Tetric N Ceram composite. Tetric N Ceram had the highest degree of conversion, KHN ratio, and radiopacity. Conclusion: The properties of Cention N validate its efficacy as an alternative direct restorative material when used in conjunction with an adhesive system.

Development of Lead-Free Radiation Shielding Material Utilizing Barium Sulfate and Magnesium Oxide as Fillers in Addition Cure Liquid Silicone Rubber.

The radiological protection has the purpose of safeguarding the physical well-being of the user, preventing exposure to detrimental levels of ionizing radiation. This study introduces a novel, cost-effective category of lead-free elastomeric material designed for radiation shielding. The filler compounds utilized are notably lighter than conventional lead-based materials, enhancing user ergonomics during application. They comprise of a blend of barium sulfate combined or not with magnesium oxide with addition-cure liquid silicone rubber. To ensure the effectiveness of the radiation shielding, X-ray transmission measurements were performed for the different thicknesses of the materials and the results compared with Monte Carlo simulations. Additionally, the physical properties of the new materials, such as density, homogeneity, tensile strength, viscosity, and wettability, were also evaluated. The findings indicate that both materials fulfill the requirement for application in radiation protection garments.

Pharyngeal Reconstruction Methods to Reduce the Risk of Pharyngocutaneous Fistula After Primary Total Laryngectomy: A Scoping Review.

INTRODUCTION: The most common early postoperative complication after total laryngectomy (TL) is pharyngocutaneous fistula (PCF). Rates of PCF are higher in patients who undergo salvage TL compared with primary TL. Published meta-analyses include heterogeneous studies making the conclusions difficult to interpret. The objectives of this scoping review were to explore the reconstructive techniques potentially available for primary TL and to clarify which could be the best technique for each clinical scenario. METHODS: A list of available reconstructive techniques for primary TL was built and the potential comparisons between techniques were identified. A PubMed literature search was performed from inception to August 2022. Only case-control, comparative cohort, or randomized controlled trial (RCT) studies were included. RESULTS: A meta-analysis of seven original studies showed a PCF risk difference (RD) of 14% (95% CI 8-20%) favoring stapler closure over manual suture. In a meta-analysis of 12 studies, we could not find statistically significant differences in PCF risk between primary vertical suture and T-shaped suture. Evidence for other pharyngeal closure alternatives is scarce. CONCLUSION: We could not identify differences in the rate of PCF between continuous and T-shape suture configuration. Stapler closure seems to be followed by a lower rate of PCF than manual suture in those patients that are good candidates for this technique.

Captadores de niebla y recolección de agua en un ecosistema de páramo colombiano

Los captadores de niebla son usados para interceptar agua contenida en la niebla y abastecer de agua a comunidades que habitan en lugares donde este recurso escasea. Se evaluó el uso de captadores de niebla para la captación de agua en un área ubicada en el páramo Pan de Azúcar, Duitama-Boyacá. Se instalaron 60 captadores de niebla, 24 de ellos, con dispositivos para medir los volúmenes de agua interceptados. Los volúmenes de agua captados, se midieron en periodos de 24 horas, por 26 días, durante un año y se usó el modelo geométrico para diferenciar el agua proveniente de la niebla. La precipitación registrada fue mayor a la reportada en la literatura. La precipitación mensual osciló entre 51 y 1198 mm y la temperatura media mensual entre los 6 y 8 °C. Los volúmenes de agua promedio colectados por los 24 captadores de niebla estuvieron entre los 0,02 Lm-2dia-1 hasta los 4,4Lm-2dia-1. Los aportes de agua provenientes de la niebla oscilaron entre los 0,02 y 1,77 mmdía-1. La dirección del viento no afectó la captación de agua y aún se presenta incertidumbre al separar el aporte real de agua proveniente de la niebla a partir de la lluvia orográfica, lo cual, sigue siendo un desafío en los ecosistemas de páramo, por lo que se debe ampliar la investigación, para mejorar los diseños y las eficiencias de los captadores de niebla.

Fog collectors are used to intercept water contained in fog and supply water to communities that live in places where this resource is scarce. We evaluated the use of mist collectors to collect water in an area located in the Pan de Azúcar paramo, Duitama-Boyacá. We installed 60 mist collectors, 24 of them with devices to measure the volumes of water intercepted. The volumes of water captured were measured in periods of 24 hours for 26 days during one year and we used the geometric model to differentiate the water from the fog. The recorded precipitation was higher than that reported in the literature. Monthly rainfall ranged between 51 and 1198mm and mean monthly temperature ranged between 6 and 8°C. The average volumes of water collected by the fog collectors were below 0.5Lm-2day-1 with a maximum of 4.4Lm-2day-1. The contributions of water from the mist ranged between 0.02 and 1.77 mmday-1. The direction of the wind did not affect the capture of water and there is still uncertainty when separating the real contribution of water from the fog from the orographic rain, which continues to be a challenge in the paramo ecosystems, for which it is necessary to expand research, to improve the designs and efficiencies of fog collectors.

Renal Amyloidosis (AL Kappa Type) With an Uncommon Presentation: A Case Report.

Amyloidosis is a disease associated with deposits of amyloid fibrils that aggregate in various tissues leading to progressive organ failure and often multi-systemic involvement. It may be classified as localized or systemic, acquired or hereditary. Renal presentation is variable but can include nephrotic syndrome, acute renal failure, tubular dysfunction, or just varying degrees of proteinuria. Although most cases of renal amyloidosis are due to acquired causes, in rare instances, the cause can be gene mutations leading to hereditary amyloidosis. We present the case of a 77-year-old Caucasian man diagnosed with renal biopsy-proven AL (kappa) type amyloidosis with isolated renal involvement who had a significant family history of renal biopsy-proven amyloidosis.

Deterministic evolution and stringent selection during preneoplasia.

The earliest events during human tumour initiation, although poorly characterized, may hold clues to malignancy detection and prevention1. Here we model occult preneoplasia by biallelic inactivation of TP53, a common early event in gastric cancer, in human gastric organoids. Causal relationships between this initiating genetic lesion and resulting phenotypes were established using experimental evolution in multiple clonally derived cultures over 2 years. TP53 loss elicited progressive aneuploidy, including copy number alterations and structural variants prevalent in gastric cancers, with evident preferred orders. Longitudinal single-cell sequencing of TP53-deficient gastric organoids similarly indicates progression towards malignant transcriptional programmes. Moreover, high-throughput lineage tracing with expressed cellular barcodes demonstrates reproducible dynamics whereby initially rare subclones with shared transcriptional programmes repeatedly attain clonal dominance. This powerful platform for experimental evolution exposes stringent selection, clonal interference and a marked degree of phenotypic convergence in premalignant epithelial organoids. These data imply predictability in the earliest stages of tumorigenesis and show evolutionary constraints and barriers to malignant transformation, with implications for earlier detection and interception of aggressive, genome-instable tumours.

Antibacterial activity and physicochemical properties of a sealer containing copaiba oil.

This study aimed to evaluate the antimicrobial activity and physicochemical properties of a novel dual-cure endodontic sealer containing copaiba oil. The copaiba oil was obtained and characterized by gas chromatography (GC), and the minimum inhibitory concentration (MIC) was performed. The experimental sealers were formulated with copaiba oil concentrations of 0, 0.5, 1, and 2%, and the RealSeal™ (Sybron endo, Orange, USA) and AH Plus (Dentsply De Trey Gmbh, Konstanz, Germany) were used as the commercial references. The antimicrobial activity of the sealers was evaluated by the direct contact test for 1h and 24h. To evaluate the physicochemical properties of the sealers, the degree of conversion, setting time, film thickness, dimensional stability, and radiopacity tests were performed. The data were statistically analyzed by one-way ANOVA and Tukey's test (α = 0.05). Concerning the results, the sealers containing copaiba oil showed antimicrobial activity without harming the physicochemical properties.

Patterns of mosaicism for sequence and copy-number variants discovered through clinical deep sequencing of disease-related genes in one million individuals.

DNA variants that arise after conception can show mosaicism, varying in presence and extent among tissues. Mosaic variants have been reported in Mendelian diseases, but further investigation is necessary to broadly understand their incidence, transmission, and clinical impact. A mosaic pathogenic variant in a disease-related gene may cause an atypical phenotype in terms of severity, clinical features, or timing of disease onset. Using high-depth sequencing, we studied results from one million unrelated individuals referred for genetic testing for almost 1,900 disease-related genes. We observed 5,939 mosaic sequence or intragenic copy number variants distributed across 509 genes in nearly 5,700 individuals, constituting approximately 2% of molecular diagnoses in the cohort. Cancer-related genes had the most mosaic variants and showed age-specific enrichment, in part reflecting clonal hematopoiesis in older individuals. We also observed many mosaic variants in genes related to early-onset conditions. Additional mosaic variants were observed in genes analyzed for reproductive carrier screening or associated with dominant disorders with low penetrance, posing challenges for interpreting their clinical significance. When we controlled for the potential involvement of clonal hematopoiesis, most mosaic variants were enriched in younger individuals and were present at higher levels than in older individuals. Furthermore, individuals with mosaicism showed later disease onset or milder phenotypes than individuals with non-mosaic variants in the same genes. Collectively, the large compendium of variants, disease correlations, and age-specific results identified in this study expand our understanding of the implications of mosaic DNA variation for diagnosis and genetic counseling.

Endovascular Closure of an Acquired Vascular Fistula, an Uncommon Complication of a Tunneled Hemodialysis Catheter: A Case Report.

PURPOSE: The objective of this case is to report an endovascular occlusion of an acquired vascular fistula using an Amplatzer Vascular Plug II. Also, it is to review the available literature on risk factors, pathophysiology, and related management strategies about complications of the tunneled central venous catheter (TCVC). CASE REPORT: The case was a 40-year-old man with a chronic kidney disease (CKD) on dialysis and with a history of several previous TCVC placements, along with recurrent infections. The last TCVC developed a fistula between the superior vena cava and the right pulmonary artery, shown by computed tomography (CT). We decided to remove a long-term TCVC and occluded the fistula applying an endovascular embolic device, an Amplatzer Vascular Plug II, subsequently. The patient was given parenteral treatment during 10 days of hospitalization. Over 9 months of follow-up, the device was appropriately positioned and did not obstruct the vascular flow. CONCLUSION: Tunneled central venous catheters are frequently used for hemodialysis in patients in the last stage of CKD who do not have an arteriovenous fistula. Occasionally, delayed complications such as adherence or catheter migration occur. This case illustrates an endovascular treatment with excellent results and low risk of morbidity and mortality. CLINICAL IMPACT: The purpose of this work is to present an endovascular occlusion by means of an Amplatzer® Vascular Plug II in a residual fistula. The endovascular way is decided in situations, for instance, once the cardiothoracic surgeons argue that the patient is not in general conditions to tolerate surgery, the surgical procedure would be complex, or, in a surgical approach with a difficult-to-resolve hemorrhage. We explain the technique and the materials we used for an excellent result and a low risk of complications. This case is intended to serve as an aid in the treatment of similar events.