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Despite advancements in treating cutaneous melanoma, patients with acral and mucosal (A/M) melanomas still have limited therapeutic options and poor prognoses. We analyzed 156 melanomas (101 cutaneous, 28 acral, and 27 mucosal) using the Foundation One cancer-gene specific clinical testing platform and identified new, potentially targetable genomic alterations (GAs) in specific anatomic sites of A/M melanomas. Using novel pre-clinical models of A/M melanoma, we demonstrate that several GAs and corresponding oncogenic pathways associated with cutaneous melanomas are similarly targetable in A/M melanomas. Other alterations, including MYC and CRKL amplifications, were unique to A/M melanomas and susceptible to indirect targeting using the BRD4 inhibitor JQ1 or Src/ABL inhibitor dasatinib, respectively. We further identified new, actionable A/M-specific alterations, including an inactivating NF2 fusion in a mucosal melanoma responsive to dasatinib in vivo. Our study highlights new molecular differences between cutaneous and A/M melanomas, and across different anatomic sites within A/M, which may change clinical testing and treatment paradigms for these rare melanomas.
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Introduction: Primary pulmonary vein stenosis (PVS) is a rare congenital heart disease that proves to be a clinical challenge due to the rapidly progressive disease course and high rates of treatment complications. PVS intervention is frequently faced with in-stent restenosis and persistent disease progression despite initial venous recanalization with balloon angioplasty or stenting. Alterations in wall shear stress (WSS) have been previously associated with neointimal hyperplasia and venous stenosis underlying PVS progression. Thus, the development of patient-specific three-dimensional (3D) in vitro models is needed to further investigate the biomechanical outcomes of endovascular and surgical interventions. Methods: In this study, deidentified computed tomography images from three patients were segmented to generate perfusable phantom models of pulmonary veins before and after catheterization. These 3D reconstructions were 3D printed using a clear resin ink and used in a benchtop experimental setup. Computational fluid dynamic (CFD) analysis was performed on models in silico utilizing Doppler echocardiography data to represent the in vivo flow conditions at the inlets. Particle image velocimetry was conducted using the benchtop perfusion setup to analyze WSS and velocity profiles and the results were compared with those predicted by the CFD model. Results: Our findings indicated areas of undesirable alterations in WSS before and after catheterization, in comparison with the published baseline levels in the healthy in vivo tissues that may lead to regional disease progression. Discussion: The established patient-specific 3D in vitro models and the developed in vitro-in silico platform demonstrate great promise to refine interventional approaches and mitigate complications in treating patients with primary PVS.
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BACKGROUND: Accurate classification of breast cancer molecular subtypes is crucial in determining treatment strategies and predicting clinical outcomes. This classification largely depends on the assessment of human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), and progesterone receptor (PR) status. However, variability in interpretation among pathologists pose challenges to the accuracy of this classification. This study evaluates the role of artificial intelligence (AI) in enhancing the consistency of these evaluations. METHODS: AI-powered HER2 and ER/PR analyzers, consisting of cell and tissue models, were developed using 1,259 HER2, 744 ER, and 466 PR-stained immunohistochemistry (IHC) whole-slide images of breast cancer. External validation cohort comprising HER2, ER, and PR IHCs of 201 breast cancer cases were analyzed with these AI-powered analyzers. Three board-certified pathologists independently assessed these cases without AI annotation. Then, cases with differing interpretations between pathologists and the AI analyzer were revisited with AI assistance, focusing on evaluating the influence of AI assistance on the concordance among pathologists during the revised evaluation compared to the initial assessment. RESULTS: Reevaluation was required in 61 (30.3%), 42 (20.9%), and 80 (39.8%) of HER2, in 15 (7.5%), 17 (8.5%), and 11 (5.5%) of ER, and in 26 (12.9%), 24 (11.9%), and 28 (13.9%) of PR evaluations by the pathologists, respectively. Compared to initial interpretations, the assistance of AI led to a notable increase in the agreement among three pathologists on the status of HER2 (from 49.3 to 74.1%, p < 0.001), ER (from 93.0 to 96.5%, p = 0.096), and PR (from 84.6 to 91.5%, p = 0.006). This improvement was especially evident in cases of HER2 2+ and 1+, where the concordance significantly increased from 46.2 to 68.4% and from 26.5 to 70.7%, respectively. Consequently, a refinement in the classification of breast cancer molecular subtypes (from 58.2 to 78.6%, p < 0.001) was achieved with AI assistance. CONCLUSIONS: This study underscores the significant role of AI analyzers in improving pathologists' concordance in the classification of breast cancer molecular subtypes.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/metabolismo , Receptores de Estrogênio/metabolismo , Biomarcadores Tumorais/metabolismo , Inteligência Artificial , Variações Dependentes do Observador , Receptores de Progesterona/metabolismo , Receptor ErbB-2/metabolismoRESUMO
BACKGROUND: The inflamed immune phenotype (IIP), defined by enrichment of tumor-infiltrating lymphocytes (TILs) within intratumoral areas, is a promising tumor-agnostic biomarker of response to immune checkpoint inhibitor (ICI) therapy. However, it is challenging to define the IIP in an objective and reproducible manner during manual histopathologic examination. Here, we investigate artificial intelligence (AI)-based immune phenotypes capable of predicting ICI clinical outcomes in multiple solid tumor types. METHODS: Lunit SCOPE IO is a deep learning model which determines the immune phenotype of the tumor microenvironment based on TIL analysis. We evaluated the correlation between the IIP and ICI treatment outcomes in terms of objective response rates (ORR), progression-free survival (PFS), and overall survival (OS) in a cohort of 1,806 ICI-treated patients representing over 27 solid tumor types retrospectively collected from multiple institutions. RESULTS: We observed an overall IIP prevalence of 35.2% and significantly more favorable ORRs (26.3% vs 15.8%), PFS (median 5.3 vs 3.1 months, HR 0.68, 95% CI 0.61 to 0.76), and OS (median 25.3 vs 13.6 months, HR 0.66, 95% CI 0.57 to 0.75) after ICI therapy in IIP compared with non-IIP patients, respectively (p<0.001 for all comparisons). On subgroup analysis, the IIP was generally prognostic of favorable PFS across major patient subgroups, with the exception of the microsatellite unstable/mismatch repair deficient subgroup. CONCLUSION: The AI-based IIP may represent a practical, affordable, clinically actionable, and tumor-agnostic biomarker prognostic of ICI therapy response across diverse tumor types.
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Inteligência Artificial , Neoplasias Encefálicas , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Estudos Retrospectivos , Biomarcadores Tumorais , Fenótipo , Microambiente TumoralRESUMO
A synthetic method for the reductive transformation of nitroarenes into ortho-aminated and -annulated products is reported. The method operates via the exhaustive deoxygenation of nitroarenes by an organophosphorus catalyst and a mild terminal reductant to access aryl nitrenes, which after ring expansion, are trapped by amine nucleophiles to give dearomatized 2-amino-3H-azepines. Treatment of these ring-expanded intermediates with acyl electrophiles triggers 6π electrocyclization to extrude the nitrogen atom and restore aromaticity of the phenyl ring, which delivers via C-H functionalization 2-aminoanilide and benzimidazole products.
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Aminas , Nitrogênio , Aminação , CatáliseRESUMO
BACKGROUND: Cyclin pathway gene alterations are frequent in urothelial tumors and may co-exist with other important aberrations, leading to therapeutic opportunities. We characterized the landscape of cyclin gene alterations in urothelial and non-urothelial urinary tract (UT) malignancies. PATIENTS AND METHODS: Overall, 6842 urothelial and 897 non-urothelial UT cancers were analyzed (hybrid-capture-based comprehensive genomic profile (Foundation Medicine)). Alteration frequency in cyclin-sensitizing and -resistance genes, and co-occurrence with fibroblast growth factor receptor (FGFR) gene abnormalities were evaluated. RESULTS: Cyclin-activating gene alterations were detected in 47.3% of urothelial and 37.9% of non-urothelial UT cancers. Frequency varied by histology and tumor site. CDKN2A and CDKN2B loss were the most frequent alterations in urothelial tumors (present in 38.5% and 30.4% of patients, respectively). Both genes were less frequently altered in adenocarcinomas (15.2% and 8.9%), but commonly altered in squamous cell carcinomas (74.4% and 39%). Tumors of neuroendocrine origin were relatively silent in activating cyclin alterations, but frequently displayed Rb1 alterations (86% and 83.7% of neuroendocrines and small cell carcinomas). Urachal tumors (nâ =â 79) presented a distinct landscape of cyclin alterations relative to other UT cancers, with less frequent alterations overall. FGF/FGFR genes were altered in 34.9% of urothelial (22.1% in FGFR3), and 19.4% of non-urothelial urinary tract tumors (6.8% FGFR3). Cyclin-activating alterations frequently co-occurred with FGF/FGFR alterations but were in general mutually exclusively with cyclin resistance alterations (RB1/CCNE1). CONCLUSIONS: Cyclin pathway activating alterations are common in urinary tract tumors, but frequency varies with histology and tumors sites. Co-occurrence of cyclin and FGFR pathway alterations may inform therapeutic opportunities.
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Neoplasias da Bexiga Urinária , Neoplasias Urológicas , Humanos , Pontos de Checagem do Ciclo Celular , Ciclinas , Neoplasias da Bexiga Urinária/genética , Neoplasias Urológicas/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismoRESUMO
Introduction: Basic Life Support is a level of medical care Applied to victims of life-threatening illnesses and injuries before professional help is provided. This study aimed to assess the knowledge, attitude, and practice toward Basic Life support in Graduating class of health science and medical students at Dilla university referral hospital. Method: ology: A cross-sectional study was conducted on graduating class students of Dilla University, college of medicine and health science from September 10/2021 to December 13/2021. A total of 167 participants were selected by a systematic random sampling technique. A bi-variable and multi-variable logistic regression analysis were carried out. Result: Among the study participants, 95 (56.9%) and 86(51.5%) have good knowledge and good practice towards basic life support respectively. Being trained for basic life support and advanced life support, exposure with the person in need of basic life support were found more knowledgeable with odd ratio of [AOR = 13.8, 95% CI (6.3-30.1)], [AOR = 27.7, 95% CI (6.4-119)] and [AOR = 15.7, 95% CI (6.6-37.5)]. Learning anesthesia increases knowledge about basic life support nearly two times [AOR = 1.8, 95% CI (o.4-9.5)] when compared to medicine. Conclusion: The findings of this study suggest that nearly half of health science students in our hospital lack adequate knowledge and skills in BLS. Training on basic life support and advanced life support, learning in anesthesia and medicine departments, and exposure to the person in need of basic life support were significantly associated with high knowledge. To increase knowledge of BLS standardized Training and assessments are recommended.
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This case signifies the importance of obtaining tumor comprehensive genomic profiling (CGP) as it has utility in cancer type classification and helping in diagnosing recurrence/metastasis or separately occurring primary tumors. CGP can also help guiding treatment as in this case separately occurring Inflammatory Myofibroblastic Tumor had ALK fusion and responded to crizotinib. As treatment progresses, new biopsies should be obtained and CGP used to evaluate for appearance of any new genomic alterations, in order to guide further therapy.
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Quinase do Linfoma Anaplásico/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Adenocarcinoma de Pulmão/genética , Crizotinibe/uso terapêutico , GenômicaRESUMO
Somatic hotspot mutations and structural amplifications and fusions that affect fibroblast growth factor receptor 2 (encoded by FGFR2) occur in multiple types of cancer1. However, clinical responses to FGFR inhibitors have remained variable1-9, emphasizing the need to better understand which FGFR2 alterations are oncogenic and therapeutically targetable. Here we apply transposon-based screening10,11 and tumour modelling in mice12,13, and find that the truncation of exon 18 (E18) of Fgfr2 is a potent driver mutation. Human oncogenomic datasets revealed a diverse set of FGFR2 alterations, including rearrangements, E1-E17 partial amplifications, and E18 nonsense and frameshift mutations, each causing the transcription of E18-truncated FGFR2 (FGFR2ΔE18). Functional in vitro and in vivo examination of a compendium of FGFR2ΔE18 and full-length variants pinpointed FGFR2-E18 truncation as single-driver alteration in cancer. By contrast, the oncogenic competence of FGFR2 full-length amplifications depended on a distinct landscape of cooperating driver genes. This suggests that genomic alterations that generate stable FGFR2ΔE18 variants are actionable therapeutic targets, which we confirmed in preclinical mouse and human tumour models, and in a clinical trial. We propose that cancers containing any FGFR2 variant with a truncated E18 should be considered for FGFR-targeted therapies.
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Éxons , Deleção de Genes , Terapia de Alvo Molecular , Neoplasias , Oncogenes , Inibidores de Proteínas Quinases , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos , Animais , Éxons/genética , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Oncogenes/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismoRESUMO
BACKGROUND: Spinal anesthesia with bupivacaine has side effects such as hypotension, respiratory depression, vomiting, and shivering. The side effects are dose-dependent, therefore different approaches have been attempted to avoid spinal-induced complications including lowering the dose of local anesthetic and mixing it with additives like Neuraxial opioids. OBJECTIVE: To compare the Hemodynamic and analgesic effects of intrathecal fentanyl as an adjuvant with low and conventional doses of bupivacaine in patients undergoing elective cesarean section under spinal anesthesia. METHODOLOGY: An institutional-based prospective cohort study was conducted on 90 patients. Data was collected with chart review, intraoperative observation, and postoperatively patient interview. Data was entered into EPI INFO and transport to SPSS version 23 for analysis of variables using one-way ANOVA, Kruskal Wallis H rank test, and chi-square. RESULT: Hypotension but not bradycardia, was significantly frequent in a conventional dose of bupivacaine alone (CB) group and a conventional dose of bupivacaine with fentanyl (CBF) groups than that of the lower dose of bupivacaine with fentanyl (LBF) groups. Duration of analgesia was significantly longer in LBF (248± 35.6 minutes) and in CBF groups (260.3±40.3 minutes) than in CB group (167.10 ± 31.45 minutes). Time for the first analgesic request was significantly later in LBF (304±47.8 minutes) and CBF (294.6±99.5 minutes) groups than that in CB group (177±25.88 minutes). CONCLUSION: The Lower dose of bupivacaine is associated with less risk of hypotension and faster recovery. Adding fentanyl with the lower dose of bupivacaine in spinal anesthesia for cesarean section could provide comparable anesthesia with the lower risk of hypotension and longer postoperative analgesia.
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Anestesia Obstétrica , Raquianestesia , Hipotensão , Anestesia Obstétrica/efeitos adversos , Raquianestesia/efeitos adversos , Anestésicos Locais , Bupivacaína , Cesárea/efeitos adversos , Método Duplo-Cego , Feminino , Fentanila , Hemodinâmica , Humanos , Hipotensão/induzido quimicamente , Injeções Espinhais , Gravidez , Estudos ProspectivosRESUMO
There are more than 70 distinct sarcomas, and this diversity complicates the development of precision-based therapeutics for these cancers. Prospective comprehensive genomic profiling could overcome this challenge by providing insight into sarcomas' molecular drivers. Through targeted panel sequencing of 7494 sarcomas representing 44 histologies, we identify highly recurrent and type-specific alterations that aid in diagnosis and treatment decisions. Sequencing could lead to refinement or reassignment of 10.5% of diagnoses. Nearly one-third of patients (31.7%) harbor potentially actionable alterations, including a significant proportion (2.6%) with kinase gene rearrangements; 3.9% have a tumor mutational burden ≥10 mut/Mb. We describe low frequencies of microsatellite instability (<0.3%) and a high degree of genome-wide loss of heterozygosity (15%) across sarcomas, which are not readily explained by homologous recombination deficiency (observed in 2.5% of cases). In a clinically annotated subset of 118 patients, we validate actionable genetic events as therapeutic targets. Collectively, our findings reveal the genetic landscape of human sarcomas, which may inform future development of therapeutics and improve clinical outcomes for patients with these rare cancers.
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Neoplasias Ósseas , Osteossarcoma , Sarcoma , Biomarcadores Tumorais/genética , Neoplasias Ósseas/genética , Genômica , Humanos , Mutação , Estudos Prospectivos , Sarcoma/diagnóstico , Sarcoma/genética , Sarcoma/terapiaRESUMO
PURPOSE: Colorectal carcinomas (CRCs) with microsatellite-instability (MSI) are enriched for oncogenic kinase fusions (KFs), including NTRK1, RET, and BRAF, but the mechanism underlying this finding is unclear. METHODS: The genomic profiles of 32,218 advanced CRC tumor specimens were analyzed to assess the fusion breakpoints of oncogenic alterations including KFs in microsatellite-stable and microsatellite-unstable CRC. Genomic contexts of such alterations were analyzed to obtain mechanistic insights. RESULTS: Genomic analysis demonstrated that oncogenic fusion breakpoints in MSI tumors do not preferentially involve repetitive or low-complexity sequences. Instead, their junction regions showed pronounced guanine and cytosine bias and elevated mutation frequency at G:C contexts. Elevated mutation frequency at G:C bases in relevant introns predicted prevalence of associated oncogenic fusions in MSI CRCs. CRCs harboring mismatch repair signatures had enrichment of butyrate-producing microbial species, reported to be associated with induction of 8-oxoguanine lesions in the intestine. CONCLUSION: Detailed analysis of breakpoints in MSI-associated KFs support a model in which inefficient repair and/or processing of microbiome-induced clustered 8-oxoguanine damage in MSI CRC contributes to the increased incidence of specific oncogenic fusions.
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Neoplasias Colorretais , Carcinogênese/genética , Neoplasias Colorretais/genética , Fusão Gênica , Guanina , Humanos , Instabilidade de Microssatélites , Repetições de Microssatélites , MutaçãoRESUMO
Molecularly targeted cancer therapy has improved outcomes for patients with cancer with targetable oncoproteins, such as mutant EGFR in lung cancer. Yet, the long-term survival of these patients remains limited, because treatment responses are typically incomplete. One potential explanation for the lack of complete and durable responses is that oncogene-driven cancers with activating mutations of EGFR often harbor additional co-occurring genetic alterations. This hypothesis remains untested for most genetic alterations that co-occur with mutant EGFR. Here, we report the functional impact of inactivating genetic alterations of the mRNA splicing factor RNA-binding motif 10 (RBM10) that co-occur with mutant EGFR. RBM10 deficiency decreased EGFR inhibitor efficacy in patient-derived EGFR-mutant tumor models. RBM10 modulated mRNA alternative splicing of the mitochondrial apoptotic regulator Bcl-x to regulate tumor cell apoptosis during treatment. Genetic inactivation of RBM10 diminished EGFR inhibitor-mediated apoptosis by decreasing the ratio of (proapoptotic) Bcl-xS to (antiapoptotic) Bcl-xL isoforms of Bcl-x. RBM10 deficiency was a biomarker of poor response to EGFR inhibitor treatment in clinical samples. Coinhibition of Bcl-xL and mutant EGFR overcame the resistance induced by RBM10 deficiency. This study sheds light on the role of co-occurring genetic alterations and on the effect of splicing factor deficiency on the modulation of sensitivity to targeted kinase inhibitor cancer therapy.
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Fator X , Neoplasias Pulmonares , Apoptose/genética , Linhagem Celular Tumoral , Receptores ErbB/genética , Fator X/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Fatores de Processamento de RNA , RNA Mensageiro/genética , Motivos de Ligação ao RNA , Proteínas de Ligação a RNA/metabolismoRESUMO
Intermolecular cross-coupling of terminal olefins with secondary amines to form complex tertiary amines-a common motif in pharmaceuticals-remains a major challenge in chemical synthesis. Basic amine nucleophiles in nondirected, electrophilic metal-catalyzed aminations tend to bind to and thereby inhibit metal catalysts. We reasoned that an autoregulatory mechanism coupling the release of amine nucleophiles with catalyst turnover could enable functionalization without inhibiting metal-mediated heterolytic carbon-hydrogen cleavage. Here, we report a palladium(II)-catalyzed allylic carbon-hydrogen amination cross-coupling using this strategy, featuring 48 cyclic and acyclic secondary amines (10 pharmaceutically relevant cores) and 34 terminal olefins (bearing electrophilic functionality) to furnish 81 tertiary allylic amines, including 12 drug compounds and 10 complex drug derivatives, with excellent regio- and stereoselectivity (>20:1 linear:branched, >20:1 E:Z).
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Alcenos , Paládio , Alcenos/química , Aminação , Aminas/química , Carbono , Catálise , Hidrogênio/química , Paládio/químicaRESUMO
Black people have a higher incidence of colorectal cancer and worse survival rates when compared with white people. Comprehensive genomic profiling was performed in 46,140 colorectal adenocarcinoma cases. Ancestry-informative markers identified 5,301 patients of African descent (AFR) and 33,770 patients of European descent (EUR). AFR were younger, had fewer microsatellite instability-high (MSI-H) tumors, and had significantly more frequent alterations in KRAS, APC, and PIK3CA. AFR had increased frequency of KRAS mutations, specifically KRASG12D and KRASG13. There were no differences in rates of actionable kinase driver alterations (HER2, MET, NTRK, ALK, ROS1, and RET). In patients with young-onset colorectal cancer (<50 years), AFR and EUR had a similar frequency of MSI-H and tumor mutational burden-high (TMB-H) tumors, and strikingly different trends in APC mutations by age, as well as differences in MAPK pathway alterations. These findings inform treatment decisions, impact prognosis, and underscore the need for model systems representative of the diverse U.S. population. SIGNIFICANCE: KRAS (particularly KRASG12D/G13), APC, and PIK3CA were more frequently altered in AFR who had a lower frequency of MSI-H tumors. There were no differences in actionable kinase driver alterations. In young-onset colorectal cancer, both ancestries had a similar frequency of MSI-H/TMB-H tumors, but strikingly different trends in APC. See related commentary by Eng and Holowatyj, p. 1187. This article is highlighted in the In This Issue feature, p. 1171.
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Neoplasias Colorretais , Proteínas Tirosina Quinases , Classe I de Fosfatidilinositol 3-Quinases/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Genômica , Humanos , Instabilidade de Microssatélites , Mutação , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
Emerging evidence suggests a correlation between the tumor mutational burden (TMB) and the response to programmed cell death-1 protein (PD-1) monotherapy across multiple cancer types. In skin cancers, as high TMB is mostly because of ultraviolet (UV) exposure, we hypothesized a correlation between the primary melanoma cutaneous location according to sun exposure and response to anti-PD-1 monotherapy. METHODS: The aim of this study was to analyze, in advanced melanoma, the relationship between TMB, locations according to sun exposure, and response to PD-1 inhibitors. We conducted a prospective multicentric analysis, by sequencing the most recent metastatic sample before PD-1 inhibitors using FoundationOne assay. RESULTS: One hundred two patients were included, with TMB available for 94 cases. In univariate and multivariate linear regression, TMB was significantly associated with sun-exposed areas of the primary melanoma location and with age (coefficients of the association with log-TMB: non-UV location, -1.05; chronic sun-exposed area, 1.12; P value for the location, < 10-5; age, 0.021 per year, P value for age, .002). Molecular UV signature present on the metastatic site was associated with higher TMB (P = .003). Melanomas bearing a high TMB had a higher probability of response to PD-1 inhibitors compared with melanomas with a low TMB, with a dose-dependent effect following an exponential curve and a negative odds ratio of 0.40 (95% CI, 0.20 to 0.72, P = .004) between log-TMB and 6-month progression. CONCLUSION: Cumulative sun exposure related to skin location and molecular UV signature present on the metastatic site appear to be relevant biomarkers directly linked to TMB. Because TMB is not yet available to all for routine clinical use, the location of the primary melanoma in a sun-exposed area may play an important role in clinical decisions regarding therapeutic choice.
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Antígeno B7-H1 , Melanoma , Antígeno B7-H1/genética , Biomarcadores Tumorais , Pré-Escolar , Humanos , Recém-Nascido , Melanoma/tratamento farmacológico , Mutação , Estudos ProspectivosRESUMO
PURPOSE: Combined hepatocellular cholangiocarcinoma (cHCC-CCA) is a rare, aggressive primary liver carcinoma, with morphologic features of both hepatocellular carcinomas (HCC) and liver cholangiocarcinomas (CCA). METHODS: The genomic profiles of 4,975 CCA, 1,470 HCC, and 73 cHCC-CCA cases arising from comprehensive genomic profiling in the course of clinical care were reviewed for genomic alterations (GA), tumor mutational burden, microsatellite instability status, genomic loss of heterozygosity, chromosomal aneuploidy, genomic ancestry, and hepatitis B virus status. RESULTS: In cHCC-CCA, GA were most common in TP53 (65.8%), TERT (49.3%), and PTEN (9.6%), and 24.6% cHCC-CCA harbored potentially targetable GA. Other GA were predominantly associated with either HCC or CCA, including, but not limited to, TERT, FGFR2, IDH1, and presence of hepatitis B virus. On the basis of these features, a machine learning (ML) model was trained to classify a cHCC-CCA case as CCA-like or HCC-like. Of cHCC-CCA cases, 16% (12/73) were ML-classified as CCA-like and 58% (42/73) cHCC-CCA were ML-classified as HCC-like. The ML model classified more than 70% of cHCC-CCA as CCA-like or HCC-like on the basis of genomic profiles, without additional clinico-pathologic input. CONCLUSION: These findings demonstrate the use of ML for classification as based on a targeted exome panel used during routine clinical care. Classification of cHCC-CCA by genomic features alone creates insights into the biology of the disease and warrants further investigation for relevance to clinical care.
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Neoplasias dos Ductos Biliares/genética , Carcinoma Hepatocelular/genética , Colangiocarcinoma/genética , Neoplasias Hepáticas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/patologia , Carcinoma Hepatocelular/patologia , Colangiocarcinoma/patologia , Feminino , Genômica , Humanos , Fígado/patologia , Neoplasias Hepáticas/patologia , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: The body of evidence showed that there is a strong correlation between acute myocardial Injury and COVID-19 infection. However, the link between acute myocardial infection and COVID-19, the prevalence, reliability of diagnostic modalities, independent predictors, and clinical outcomes are still uncertain and a topic of debate. The current study was designed to determine the prevalence, determinants, and outcomes of acute myocardial injury based on a systematic review and meta-analysis the global published peer-reviewed works of literature. METHODS: A comprehensive search was conducted in PubMed/Medline; Science direct, CINHAL, and LILACS from December 2019 to May 2021. All observational studies reporting the prevalence of AMI were included while case reports and reviews were excluded. The data were extracted with two independent authors in a customized format. The methodological quality of included studies was evaluated using the Newcastle-Ottawa appraisal tool. RESULTS: A total of 397 articles were identified from different databases. Thirty-seven Articles with 21, 204 participants were included while seven studies were excluded. The meta-analysis revealed that the pooled prevalence of myocardial injury during the COVID-19 pandemic was 22.33 % (95 % CI: 17.86 to 26.81, 37). CONCLUSION: Our meta-analysis showed that mortality among patients with an acute myocardial injury during COVID-19 was more than four times more likely as compared to those without AMI. This necessitates a mitigating strategy to prevent and manage before its clinical outcomes getting worse.
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Aim: To assess concordance between HER2 status measured by traditional methods and ERBB2 amplification measured by next-generation sequencing and its association with first-line trastuzumab clinical benefit in patients with advanced esophagogastric cancer. Methods: Retrospective analysis of HER2/ERBB2 concordance using a deidentified USA-based clinicogenomic database. Clinical outcomes were assessed for patients with HER2+ advanced esophagogastric cancer who received first-line trastuzumab. Results: Overall HER2/ERBB2 concordance was 87.5%. Among patients who received first-line trastuzumab, concordant HER2/ERBB2 was associated with longer time to treatment discontinuation (adjusted hazard ratio [aHR]: 0.63; 95% CI: 0.43-0.90) and overall survival (aHR: 0.51; 95% CI: 0.33-0.79). ERBB2 copy number ≥25 (median) was associated with longer time to treatment discontinuation (aHR: 0.56; 95% CI: 0.35-0.88) and overall survival (aHR: 0.52; 95% CI: 0.30-0.91). Conclusion: HER2/ERBB2 concordance and higher ERBB2 copy number predicted clinical benefit from trastuzumab.
Lay abstract Trastuzumab is a drug that has been shown to prolong survival in some patients with advanced esophagogastric cancer whose tumor expresses a protein biomarker called HER2. There are different methods for assessing whether a patient's tumor expresses HER2, including but not limited to traditional methods such as immunohistochemistry and in situ hybridization and novel methods such as next-generation sequencing, which detects alterations in the gene (ERBB2) that encodes the HER2 protein. In our study, we assessed concordance between HER2 status (HER2-positive or HER2-negative) measured by traditional methods and ERBB2 amplification measured by next-generation sequencing, to determine whether there was an association between concordance and clinical benefit in patients with advanced esophagogastric cancer treated with trastuzumab. Our results suggest that, when HER2 positivity is detected through traditional methods, both ERBB2 concordance (i.e., agreement that a patient's tumor had the biomarker) and a higher ERBB2 copy number (the amount of the ERBB2 gene expressed by the tumor) were associated with longer time to treatment discontinuation and overall survival in patients with advanced esophagogastric cancer treated with first-line trastuzumab.