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During the SARS-CoV-2 pandemic, novel and traditional vaccine strategies have been deployed globally. We investigated whether antibodies stimulated by mRNA vaccination (BNT162b2), including third-dose boosting, differ from those generated by infection or adenoviral (ChAdOx1-S and Gam-COVID-Vac) or inactivated viral (BBIBP-CorV) vaccines. We analyzed human lymph nodes after infection or mRNA vaccination for correlates of serological differences. Antibody breadth against viral variants is lower after infection compared with all vaccines evaluated but improves over several months. Viral variant infection elicits variant-specific antibodies, but prior mRNA vaccination imprints serological responses toward Wuhan-Hu-1 rather than variant antigens. In contrast to disrupted germinal centers (GCs) in lymph nodes during infection, mRNA vaccination stimulates robust GCs containing vaccine mRNA and spike antigen up to 8 weeks postvaccination in some cases. SARS-CoV-2 antibody specificity, breadth, and maturation are affected by imprinting from exposure history and distinct histological and antigenic contexts in infection compared with vaccination.
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Anticuerpos Antivirales , Vacuna BNT162 , COVID-19 , Centro Germinal , Antígenos Virales , COVID-19/prevención & control , Humanos , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus , VacunaciónRESUMEN
Hypoxia is a critical factor for restricting photodynamic therapy (PDT) of tumor, and it becomes increasingly severe with increasing tissue depth. Thus, the relief of deep tumor hypoxia is extremely important to improve the PDT efficacy. Herein, tumor microenvironment (TME)-responsive size-switchable hyaluronic acid-hybridized Ru nanoaggregates (HA@Ru NAs) were developed via screening reaction temperature to alleviate deep tumor hypoxia for improving the tumor-specific PDT by the artful integration multiple bioactivated chemical reactions inâ situ and receptor-mediated targeting (RMT). In this nanosystem, Ru NPs not only enabled HA@Ru NAs to have near infrared (NIR)-mediated photothermal/photodynamic functions, but also could catalyze endogenous H2O2 to produce O2 inâ situ. More importantly, hyaluronidase (HAase) overexpressed in the TME could trigger disassembly of HA@Ru NAs via the hydrolysis of HA, offering the smart size switch capability from 60 to 15â nm for enhancing tumor penetration. Moreover, the RMT characteristics of HA ensured that HA@Ru NAs could specially enter CD44-overexpressed tumor cells, enhancing tumor-specific precision of phototherapy. Taken together these distinguishing characteristics, smart HA@Ru NAs successfully realized the relief of deep tumor hypoxia to improve the tumor-specific PDT.
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SUMMARY: We reviewed the clinicopathologic findings of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-exposed placentas at our institution. We identified patients diagnosed with SARS-CoV-2 during pregnancy (March-October 2020). Clinical data included gestational age at diagnosis and delivery and maternal symptoms. Hematoxylin and eosin slides were reviewed for maternal vascular malperfusion, fetal vascular malperfusion, chronic villitis, amniotic fluid infection, intervillous thrombi, fibrin deposition, and infarction. Immunohistochemistry (IHC) for coronavirus spike protein and RNA in situ hybridization (ISH) for SARS-CoV-2 was performed on a subset of blocks. A review of placentas from age-matched patients received March-October 2019 was conducted as a comparison cohort. A total of 151 patients were identified. Placentas in the 2 groups were similar in weight for gestational age and had similar rates of maternal vascular malperfusion, fetal vascular malperfusion, amniotic fluid infection, intervillous thrombi, fibrin deposition, and infarction. Chronic villitis was the only significantly different pathologic finding between cases and controls (29% of cases showed chronic villitis vs. 8% of controls, P <0.001). Overall, 146/151 (96.7%) cases were negative for IHC and 129/133 (97%) cases were negative for RNA ISH. There were 4 cases that stained positively for IHC/ISH, 2 of which showed massive perivillous fibrin deposition, inflammation, and decidual arteriopathy. Coronavirus disease 2019 (COVID-19)-positive patients were more likely to self-identify as Hispanic and more likely to have public health insurance. Our data suggests SARS-CoV-2 exposed placentas that stain positively for SARS-CoV-2 show abnormal fibrin deposition, inflammatory changes, and decidual arteriopathy. The group of patients with clinical COVID-19 are more likely to show chronic villitis. IHC and ISH evidence of viral infection is rare.
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COVID-19 , Placenta , Embarazo , Humanos , Femenino , Placenta/patología , COVID-19/patología , SARS-CoV-2 , ARN , Infarto/patología , FibrinaRESUMEN
As a critical tumor suppressor, PTEN has gained much attention in cancer research. Emerging evidence suggests an association between PTEN status and clinical outcome in certain tumors, and may be predictive of response to several therapies. However, the significance of PTEN deficiency in tubo-ovarian high-grade serous carcinomas (HGSCs) is still poorly understood. We evaluated PTEN expression in HGSCs and determined its clinical relevance. A cohort of 76 HGSC specimens was profiled using tissue microarray. Immunohistochemistry (IHC) of PTEN, ER, PR, AR, CD8, FOXP3, and PD-L1 was performed. Targeted gene panel testing by massively parallel sequencing was performed in 51 cases. PTEN deficiency (complete or subclonal loss) detected by IHC was identified in 13 of the 62 HGSCs (21%) and was significantly correlated with reduced expression of ER and worse first progression-free survival (P < .05) but not with PD-L1 expression, the density of intratumoral T lymphocytes, or overall survival. In our cohort, tumor progression within 1 year of PARP inhibitor therapy was found more frequently in PTEN-deficient cases than in PTEN-intact cases (100% vs 52%). Molecular profiling showed that intragenic mutation or deletion was not the predominant mechanism for PTEN inactivation in HGSCs. In addition, CCNE1 amplification was found to be mutually exclusive with PTEN deficiency at both protein and DNA levels. An analysis of the genomic data from 1702 HGSC samples deposited with The Cancer Genome Atlas database obtained from cBioPortal confirmed the low rate of detection of PTEN gene alterations and the mutually exclusive nature of PTEN loss and CCNE1 amplification in HGSCs. These findings indicate that PTEN deficiency defines a distinct clinically significant subgroup of HGSCs with a tendency for ER negativity, wild-type CCNE1 status, inferior clinical outcomes, and potential drug resistance. These tumors may benefit from PI3K pathway inhibitors in combination with other ovarian cancer regimens, which deserves further investigation.
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Carcinoma , Cistadenocarcinoma Seroso , Neoplasias Ováricas , Femenino , Humanos , Supervivencia sin Progresión , Antígeno B7-H1/genética , Fosfatidilinositol 3-Quinasas , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Cistadenocarcinoma Seroso/patología , Proteínas Oncogénicas/genética , Ciclina E/genética , Fosfohidrolasa PTEN/genéticaRESUMEN
Adult granulosa cell tumors (AGCTs) are a molecularly distinct group of malignant ovarian sex cord-stromal tumors (SCSTs) characterized by a nearly ubiquitous c.402C>G/p.C134W mutation in FOXL2 (hereafter referred to as "C134W"). In some cases, AGCT exhibits marked morphologic overlap with other SCSTs and has an identical immunophenotype, and molecular testing may be necessary to help confirm the diagnosis. However, molecular testing is time consuming, relatively expensive, and unavailable in many pathology laboratories. We describe the development and validation of an in situ hybridization (ISH) custom BaseScope assay for the detection of the FOXL2 C134W mutation. We evaluated 106 ovarian SCSTs, including 78 AGCTs, 9 juvenile granulosa cell tumors, 18 fibromas (cellular and conventional), and 1 SCST, not otherwise specified, as well as 53 epithelial ovarian tumors (42 endometrioid carcinomas and 11 carcinosarcomas) and 1 STK11 adnexal tumor for the presence or absence of FOXL2 wild-type and FOXL2 C134W RNA expression via BaseScope-ISH. Fifty-one tumors had previously undergone DNA sequencing of the FOXL2 gene. Across the entire cohort, the FOXL2 C134W probe staining was positive in 77 of 78 (98.7%) AGCTs. Two of 81 (2.5%) non-AGCTs also showed positive staining, both of which were epithelial ovarian tumors. The assay worked in tissue from blocks >20 years old. There was 100% concordance between the FOXL2 sequencing and BaseScope-ISH results. Overall, assessment of FOXL2 mutation status by custom BaseScope-ISH demonstrated 98.7% sensitivity and 97.5% specificity for the diagnosis of AGCT. BaseScope-ISH for FOXL2 C134W represents a reasonable alternative to sequencing, is quicker and less expensive, and is more easily incorporated than molecular testing into many pathology laboratories. It also has the advantage of requiring less tissue, and the neoplastic cells can be directly visualized on stained sections.
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Tumor de Células de la Granulosa , Neoplasias Ováricas , Femenino , Adulto , Humanos , Adulto Joven , Tumor de Células de la Granulosa/diagnóstico , Tumor de Células de la Granulosa/genética , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Proteína Forkhead Box L2/genética , Mutación , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Hibridación in SituRESUMEN
Mucoepidermoid carcinoma (MEC) is exceedingly rare in the breast, with <45 cases reported in the literature. Although estrogen receptor/progesterone receptor/human epidermal growth factor 2 triple-negative, MEC is characterized as a special subtype of breast carcinoma with significantly better prognosis than conventional basal-type tumors. Cutaneous hidradenoma (HA) is considered a benign adnexal neoplasm showing histomorphologic overlap with MEC. Rare cases of HA have also been reported in the breast, but these are relatively uncharacterized. In this study, we examined the clinicopathologic, immunohistochemical (IHC), and genetic features of 8 breast HAs, in comparison to 3 mammary MECs. All cases were positive for MAML2 break-apart fluorescence in situ hybridization. Eight cases demonstrated a CRTC1::MAML2 fusion, and one MEC harbored a CRTC3::MAML2 fusion; the latter is a novel finding in the breast. Mutational burden was very low, with only one HA exhibiting a MAP3K1 pathogenic alteration. By IHC, both MEC and HA demonstrated cell type-dependent expression of high- and low-molecular-weight keratins and p63, as well as negative to low-positive estrogen receptor and androgen receptor. Smooth muscle myosin and calponin highlighted an in situ component in the 3 cases of MEC; expression of these myoepithelial markers was negative in HAs. Additional distinguishing characteristics included the growth pattern and tumor architecture, the presence of glandular/luminal cells in HA, and overall higher IHC expression of SOX10, S100 protein, MUC4, and mammaglobin in MEC. Morphologic findings were also compared to a series of 27 cutaneous nonmammary HAs. Mucinous and glandular/luminal cells were identified in significantly more mammary HAs than nonmammary lesions. The findings provide insight into the pathogenesis of MAML2-rearranged neoplasms of the breast, underscore the overlapping genetic features of MEC and HA, and highlight similarities to their extramammary counterparts.
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Adenoid cystic carcinoma (AdCC) is a rare triple-negative breast cancer analogous to its extramammary counterparts. Diagnosis of the more aggressive solid-basaloid variant of AdCC (SB-AdCC) can be challenging due to poorly defined histopathologic and molecular features. We characterized 22 invasive and in situ basaloid carcinomas by morphology, immunohistochemistry, genetics, and MYB status using multiple platforms and assessed clinical behavior and neoadjuvant chemotherapy responses. After consensus review, 16/22 cases were classified as SB-AdCC. All SB-AdCC had predominantly solid growth and at least focal myxohyaline stroma and were immune-poor. Eosinophilic squamoid cells (69%, 11/16) and basement membrane-like secretions (69%, 11/16) were common, and intercalated ducts (31%, 5/16) were less frequent. SB-AdCC typically expressed SOX10 (100%, 16/16) and luminal markers (100%, 16/16 CK7; 88%, 14/16 CD117; 93%, 13/14 CAM5.2). SMA (40%, 6/15) expression was less common, and SMM (27%, 3/11), GATA3 (20%, 3/15), and p63 (25%, 4/16) were mostly negative. MYB protein and/or MYB RNA overexpression was universal in evaluable cases (13/13), with RNA in situ hybridization (10/10) more reliable than immunohistochemistry (10/11, plus 4 excisions inconclusive). Fluorescence in situ hybridization and/or next-generation sequencing identified MYB rearrangements (20%, 3/15) and amplifications/copy gains (60%, 9/15) but no MYB::NFIB fusions. SB-AdCC often had aberrations in Notch pathway (60%, including 40% NOTCH1 and 20% NOTCH2) and/or chromatin modifier (60%, including 33% CREBBP) genes, with relatively infrequent TP53 mutations (27%). Unclassified invasive basaloid carcinomas lacking described histologic features of SB-AdCC (n = 4) and basaloid ductal carcinoma in situ (n = 2) showed similar immunoprofiles and genetics as SB-AdCC, including Notch aberrations and MYB overexpression with MYB rearrangements/amplifications. Overall, nodal (22%) and distant (33%) metastases were common, and 23% of patients died of disease (mean follow-up, 35 months; n = 22). Responses were poor in all 7 neoadjuvant chemotherapy-treated patients, without any achieving pathologic complete response. The data highlight the histopathologic spectrum of basaloid carcinomas including SB-AdCC and reveal shared genetics and MYB activation, which can be diagnostically useful. Aggressive behavior and poor treatment responses emphasize a need for additional treatment approaches.
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Carcinoma Adenoide Quístico , Humanos , Carcinoma Adenoide Quístico/genética , Carcinoma Adenoide Quístico/patología , Hibridación Fluorescente in Situ , Mutación , ARN , CromatinaRESUMEN
AIMS: Rhabdomyosarcomas currently are classified into one of four subtypes (alveolar, embryonal, spindle cell/sclerosing, or pleomorphic) according to their morphological, immunohistochemical, and molecular genetic features. The alveolar subtype is characterised by a recurrent translocation involving PAX3 or PAX7 and FOXO1; identification of this translocation is important for appropriate classification and prognostication. In this study, we aimed to explore the diagnostic utility of FOXO1 immunohistochemistry for rhabdomyosarcoma classification. METHODS/RESULTS: A monoclonal antibody targeting a FOXO1 epitope retained in the fusion oncoprotein was used to study 105 rhabdomyosarcomas. FOXO1 was positive for expression by immunohistochemistry in all 25 alveolar rhabdomyosarcomas, with 84% showing diffuse expression in greater than 90% of neoplastic cells; the remainder of alveolar rhabdomyosarcomas displayed at least moderate staining in a minimum of 60% of lesional cells. Apart from three spindle cell rhabdomyosarcomas showing heterogeneous nuclear immunoreactivity in 40-80% of tumour cells, the 80 cases of embryonal, pleomorphic, and spindle cell/sclerosing rhabdomyosarcoma were negative for FOXO1 expression (96.3% specific) when using a threshold of nuclear staining in 20% of neoplastic cells to determine positivity. Variable cytoplasmic staining was present in a fraction of all rhabdomyosarcoma subtypes. Nonneoplastic lymphocytes, endothelial cells, and Schwann cells also showed variably intense nuclear anti-FOXO1 immunoreactivity. CONCLUSION: Taken together, our findings suggest that FOXO1 immunohistochemistry is a highly sensitive and relatively specific surrogate marker of the PAX3/7::FOXO1 fusion oncoprotein in rhabdomyosarcoma. Cytoplasmic immunoreactivity, expression in nonneoplastic tissues, and limited nuclear staining of nonalveolar rhabdomyosarcomas represent potential pitfalls in interpretation.
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Rabdomiosarcoma Alveolar , Rabdomiosarcoma , Niño , Humanos , Adulto , Rabdomiosarcoma Alveolar/patología , Inmunohistoquímica , Células Endoteliales/metabolismo , Rabdomiosarcoma/patología , Proteínas Oncogénicas , Proteínas de Fusión Oncogénica/genéticaRESUMEN
BACKGROUND: Viral infection is an oncogenic factor in many hematolymphoid malignancies. We sought to determine the diagnostic yield of aligning off-target reads incidentally obtained during targeted hematolymphoid next-generation sequencing to a large database of viral genomes to screen for viral sequences within tumor specimens. METHODS: Alignment of off-target reads to viral genomes was performed using magicBLAST. Localization of Merkel cell polyomavirus (MCPyV) RNA was confirmed by RNAScope in situ hybridization. Integration analysis was performed using Virus-Clip. RESULTS: Four cases of post-cardiac-transplant folliculotropic mycosis fungoides (fMF) and one case of peripheral T-cell lymphoma (PTCL) were positive in off-target reads for MCPyV DNA. Two of the four cases of posttransplant fMF and the case of PTCL showed localization of MCPyV RNA to malignant lymphocytes, whereas the remaining two cases of posttransplant fMF showed MCPyV RNA in keratinocytes. CONCLUSIONS: Our findings raise the question of whether MCPyV may play a role in rare cases of T-lymphoproliferative disorders, particularly in the skin and in the heavily immunosuppressed posttransplant setting.
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Carcinoma de Células de Merkel , Poliomavirus de Células de Merkel , Micosis Fungoide , Infecciones por Polyomavirus , Poliomavirus , Neoplasias Cutáneas , Infecciones Tumorales por Virus , Humanos , Poliomavirus de Células de Merkel/genética , Carcinoma de Células de Merkel/patología , Neoplasias Cutáneas/patología , Infecciones por Polyomavirus/complicaciones , Infecciones por Polyomavirus/patología , ADN Viral/análisis , Hibridación in Situ , Infecciones Tumorales por Virus/patología , Poliomavirus/genéticaRESUMEN
Lower limb exoskeleton robots have shown significant research value due to their capabilities of providing assistance to wearers and improving physical motion functions. As a type of robotic technology, wearable robots are directly in contact with the wearer's limbs during operation, necessitating a high level of human-robot collaboration to ensure safety and efficacy. Furthermore, gait prediction for the wearer, which helps to compensate for sensor delays and provide references for controller design, is crucial for improving the the human-robot collaboration capability. For gait prediction, the plantar force intrinsically reflects crucial gait patterns regardless of individual differences. To be exact, the plantar force encompasses a doubled three-axis force, which varies over time concerning the two feet, which also reflects the gait patterns indistinctly. In this paper, we developed a transformer-based neural network (TFSformer) comprising convolution and variational mode decomposition (VMD) to predict bilateral hip and knee joint angles utilizing the plantar pressure. Given the distinct information contained in the temporal and the force-space dimensions of plantar pressure, the encoder uses 1D convolution to obtain the integrated features in the two dimensions. As for the decoder, it utilizes a multi-channel attention mechanism to simultaneously focus on both dimensions and a deep multi-channel attention structure to reduce the computational and memory consumption. Furthermore, VMD is applied to networks to better distinguish the trends and changes in data. The model is trained and tested on a self-constructed dataset that consists of data from 35 volunteers. The experimental results show that FTSformer reduces the mean absolute error (MAE) up to 10.83%, 15.04% and 8.05% and the mean squared error (MSE) by 20.40%, 29.90% and 12.60% compared to the CNN model, the transformer model and the CNN transformer model, respectively.
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Dispositivo Exoesqueleto , Robótica , Humanos , Marcha , Extremidad Inferior , Redes Neurales de la ComputaciónRESUMEN
We describe 3 patients in California, USA, with trichodysplasia spinulosa polyomavirus (TSPyV) infection of endothelium after steroid administration. We detected TSPyV RNA in tissue specimens by in situ hybridization, which revealed localization to endothelial cells. These cases suggest that diseases associated with endothelial inflammation could be associated with TSPyV infection.
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Infecciones por Polyomavirus , Poliomavirus , California/epidemiología , Células Endoteliales , Endotelio , Humanos , Poliomavirus/genética , Infecciones por Polyomavirus/epidemiologíaRESUMEN
BACKGROUND: Circulating tumor cells (CTCs) shed into blood provide prognostic and/or predictive information. Previously, the authors established an assay to detect carcinoma cells from pleural fluid, termed effusion tumor cells (ETCs), by employing an immunofluorescence-based CTC-identification platform (RareCyte) on air-dried unstained ThinPrep (TP) slides. To facilitate clinical integration, they evaluated different slide processing and storage conditions, hypothesizing that alternative comparable conditions for ETC detection exist. METHODS: The authors enumerated ETCs on RareCyte, using morphology and mean fluorescence intensity (MFI) cutoffs of >100 arbitrary units (a.u.) for epithelial cellular adhesion molecule (EpCAM) and <100 a.u. for CD45. They analyzed malignant pleural fluid from three patients under seven processing and/or staining conditions, three patients after short-term storage under three conditions, and seven samples following long-term storage at -80°C. MFI values of 4',6-diamidino-2-phenylindol, cytokeratin, CD45, and EpCAM were compared. RESULTS: ETCs were detected in all conditions. Among the different processing conditions tested, the ethanol-fixed, unstained TP was most similar to the previously established air-dried, unstained TP protocol. All smears and Pap-stained TPs had significantly different marker MFIs from the established condition. After short-term storage, the established condition showed comparable results, but ethanol-fixed and Pap-stained slides showed significant differences. ETCs were detectable after long-term storage at -80°C in comparable numbers to freshly prepared slides, but most marker MFIs were significantly different. CONCLUSIONS: It is possible to detect ETCs under different processing and storage conditions, lending promise to the application of this method in broader settings. Because of decreased immunofluorescence-signature distinctions between cells, morphology may need to play a larger role.
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Molécula de Adhesión Celular Epitelial , Células Neoplásicas Circulantes , Derrame Pleural Maligno , Humanos , Células Neoplásicas Circulantes/patología , Células Neoplásicas Circulantes/metabolismo , Derrame Pleural Maligno/patología , Derrame Pleural Maligno/diagnóstico , Molécula de Adhesión Celular Epitelial/metabolismo , Manejo de Especímenes/métodos , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/análisis , Antígenos Comunes de Leucocito/metabolismo , Antígenos Comunes de Leucocito/análisis , Técnica del Anticuerpo Fluorescente/métodosRESUMEN
The tumor immunosuppressive microenvironment (TIME) and uncontrollable release of antigens can lower the efficacy of nanovaccine-based immunotherapy (NBI). Therefore, it is necessary to develop a new strategy for TIME reshaping and controllable release of antigens to improve the NBI efficacy. Herein, an acidity-responsive Schiff base-conjugated polyphenol-coordinated nanovaccine was constructed for the first time to realize bidirectional TIME reshaping and controllable release of antigens for activating T cells. In particular, an acidity-responsive tannic acid-ovalbumin (TA-OVA) nanoconjugate was prepared via a Schiff base reaction. FeIII was coordinated with TA-OVA to produce a FeIII-TA-OVA nanosystem, and 1-methyltryptophan (1-MT) as an indoleamine 2,3-dioxygenase inhibitor was loaded to form a polyphenol-coordinated nanovaccine. The coordination between FeIII and TA could cause photothermal ablation of primary tumors, and the acidity-triggered Schiff base dissociation of TA-OVA could controllably release OVA to realize lysosome escape, initiating the body's immune response. More importantly, oxidative stress generated by a tumor-specific Fenton reaction of Fe ions could promote the polarization of tumor-associated macrophages from the M2 to M1 phenotype, resulting in the upregulation of cytotoxic T cells and helper T cells. Meanwhile, 1-MT could downregulate immunosuppressive regulatory T cells. Overall, such skillful combination of bidirectional TIME reshaping and controllable antigen release into one coordination nanosystem could effectively enhance the NBI efficacy of tumors.
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Inmunoterapia , Ovalbúmina , Polifenoles , Bases de Schiff , Taninos , Microambiente Tumoral , Animales , Microambiente Tumoral/efectos de los fármacos , Ovalbúmina/inmunología , Ovalbúmina/química , Ovalbúmina/administración & dosificación , Polifenoles/química , Polifenoles/farmacología , Ratones , Taninos/química , Taninos/farmacología , Bases de Schiff/química , Concentración de Iones de Hidrógeno , Vacunas contra el Cáncer/química , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/administración & dosificación , Triptófano/química , Triptófano/análogos & derivados , Nanoconjugados/química , Ratones Endogámicos C57BL , Nanopartículas/química , Línea Celular Tumoral , Compuestos Férricos/química , NanovacunasRESUMEN
PURPOSE: Risk prediction with genomic and transcriptomic data has the potential to improve patient outcomes by enabling clinicians to identify patients requiring adjuvant treatment approaches, while sparing low-risk patients from unnecessary interventions. Endometrioid endometrial carcinoma (EEC) is the most common cancer in women in developed countries, and rates of endometrial cancer are increasing. EXPERIMENTAL DESIGN: We collected a 105-patient case-control cohort of stage I EEC comprising 45 patients who experienced recurrence less than 6 years after excision, and 60 Fédération Internationale de Gynécologie et d'Obstétrique grade-matched controls without recurrence. We first utilized two RNA-based, previously validated machine learning approaches, namely, EcoTyper and Complexity Index in Sarcoma (CINSARC). We developed Endometrioid Endometrial RNA Index (EERI), which uses RNA expression data from 46 genes to generate a personalized risk score for each patient. EERI was trained on our 105-patient cohort and tested on a publicly available cohort of 263 patients with stage I EEC. RESULTS: EERI was able to predict recurrences with 94% accuracy in the training set and 81% accuracy in the test set. In the test set, patients assigned as EERI high-risk were significantly more likely to experience recurrence (30%) than the EERI low-risk group (1%) with a hazard ratio of 9.9 (95% CI, 4.1-23.8; P < 0.001). CONCLUSIONS: Tumors with high-risk genetic features may require additional treatment or closer monitoring and are not readily identified using traditional clinicopathologic and molecular features. EERI performs with high sensitivity and modest specificity, which may benefit from further optimization and validation in larger independent cohorts.
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Carcinoma Endometrioide , Neoplasias Endometriales , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Humanos , Femenino , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Persona de Mediana Edad , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patología , Anciano , Estudios de Casos y Controles , Pronóstico , Biomarcadores de Tumor/genética , Adulto , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Aprendizaje AutomáticoRESUMEN
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.
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Biomarcadores de Tumor , Neoplasias Endometriales , Clasificación del Tumor , Humanos , Femenino , Neoplasias Endometriales/patología , Neoplasias Endometriales/clasificación , Neoplasias Endometriales/mortalidad , Neoplasias Endometriales/genética , Anciano , Persona de Mediana Edad , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Anciano de 80 o más Años , Inmunohistoquímica , Supervivencia sin Progresión , Carcinosarcoma/patología , Carcinosarcoma/mortalidad , Carcinosarcoma/clasificación , Carcinosarcoma/genética , Adulto , Valor Predictivo de las Pruebas , Diferenciación Celular , Carcinoma Endometrioide/patología , Carcinoma Endometrioide/clasificación , Carcinoma Endometrioide/mortalidad , Carcinoma Endometrioide/genética , Mutación , Estudios Retrospectivos , Factores de TiempoRESUMEN
Natural biopolymers can be controllably in situ synthesized in organisms and play important roles in biological activities. Inspired by this, the manipulation of in situ biosynthesis of functional polymers in vivo will be an important way to obtain materials for meeting biological requirements. Herein, in situ biosynthesis of functional conjugated polymer at the tumor site was achieved via the utilization of specific tumor microenvironment (TME) characteristics for the first time. Specially, a water-soluble aniline dimer derivative (N-(3-sulfopropyl) p-aminodiphenylamine, SPA) was artfully in situ polymerized into polySPA (PSPA) nanoparticles at the tumor site, which was activated via the catalysis of hydrogen peroxide (H2O2) overexpressed in TME to produce hydroxyl radical (â¢OH) by coinjected horseradish peroxidase (HRP). Benefiting from outstanding near-infrared (NIR)-II absorption of PSPA, the in situ polymerization process can be validly monitored by photoacoustic (PA) signal at the NIR-II region. Meanwhile, in situ polymerization would induce the size of polymeric materials from small to large, improving the distribution and retention of PSPA at the tumor site. On the combination of NIR-II absorption of PSPA and the size variation induced by polymerization, such polymerization can be applied for tumor-specific NIR-II light mediated PA image and photothermal inhibition of tumors, enhancing the precision and efficacy of tumor phototheranostics. Therefore, the present work opens the way to manipulate TME-activated in situ biosynthesis of functional conjugated polymer at the tumor site for overcoming formidable challenges in tumor theranostics.
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Nanopartículas , Neoplasias , Técnicas Fotoacústicas , Humanos , Polimerizacion , Peróxido de Hidrógeno , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , Polímeros , Compuestos de Anilina , Línea Celular Tumoral , Nanomedicina Teranóstica/métodos , Fototerapia/métodos , Técnicas Fotoacústicas/métodos , Microambiente TumoralRESUMEN
OBJECTIVES: By comparing the prognostic performance of 18F-FDG PET/CT-based radiomics combining dose features [Includes Dosiomics feature and the dose volume histogram (DVH) features] with that of conventional radiomics in head and neck cancer (HNC), multidimensional prognostic models were constructed to investigate the overall survival (OS) in HNC. MATERIALS AND METHODS: A total of 220 cases from four centres based on the Cancer Imaging Archive public dataset were used in this study, 2260 radiomics features and 1116 dosiomics features and 8 DVH features were extracted for each case, and classified into seven different models of PET, CT, Dose, PET+CT, PET+Dose, CT+Dose and PET+CT+Dose. Features were selected by univariate Cox and Spearman correlation coefficients, and the selected features were brought into the least absolute shrinkage and selection operator (LASSO)-Cox model. A nomogram was constructed to visually analyse the prognostic impact of the incorporated dose features. C-index and Kaplan-Meier curves (log-rank analysis) were used to evaluate and compare these models. RESULTS: The cases from the four centres were divided into three different training and validation sets according to the hospitals. The PET+CT+Dose model had C-indexes of 0.873 (95% CI 0.812-0.934), 0.759 (95% CI 0.663-0.855) and 0.835 (95% CI 0.745-0.925) in the validation set respectively, outperforming the rest models overall. The PET+CT+Dose model did well in classifying patients into high- and low-risk groups under all three different sets of experiments (p < 0.05). CONCLUSION: Multidimensional model of radiomics features combining dosiomics features and DVH features showed high prognostic performance for predicting OS in patients with HNC.
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BACKGROUND: Epithelial cell adhesion molecule (EpCAM) is frequently used to distinguish carcinoma from background mesothelial cells during cytologic examination of body cavity fluids. Previously, the authors identified one malignant mesothelioma case with strong and diffuse membranous EpCAM staining, making it indistinguishable from carcinoma. METHODS: In this study, the authors evaluated all available effusion specimens from patients with malignant mesothelioma, including the above-mentioned index case, obtained at Stanford Health Care, from 2011 to 2021 (N = 17) as well as control cases (N = 5). Analyses included an immunohistochemistry (IHC) assay for EpCAM and claudin-4, a multiplexed immunofluorescent (IF) assay for EpCAM, and an RNA in situ hybridization assay targeting EpCAM. RESULTS: The authors detected EpCAM positivity of variable intensity and percentage in four malignant mesothelioma cases (23.5%; although only two showed positivity for the epithelial-specific IHC marker MOC31 in ≥40% of cells) and claudin-4 negativity in all cases, with two cases displaying focal and weak claudin-4 staining in <1% of cells. Multiplexed IF staining on the cases with EpCAM IHC positivity showed strong, membranous EpCAM staining in one of four cases. RNA in situ hybridization also was used to assess the correlation between EpCAM positivity by IHC/IF and RNA expression levels. Strong EpCAM RNA expression was detected in the three malignant mesothelioma cases. CONCLUSIONS: The current findings revealed that a subset of epithelioid malignant mesothelioma cases mimic or exhibit the immunophenotypic features of carcinoma when evaluating for EpCAM only. Additional biomarker testing, such as claudin-4, may help avoid this potential pitfall to yield accurate diagnoses.
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Carcinoma , Mesotelioma Maligno , Mesotelioma , Humanos , Mesotelioma Maligno/diagnóstico , Molécula de Adhesión Celular Epitelial/metabolismo , Mesotelioma/patología , Claudina-4 , Biomarcadores , Carcinoma/diagnóstico , Biomarcadores de Tumor/metabolismo , Diagnóstico DiferencialRESUMEN
Spindle cell lesions of the breast elicit a specific, relatively limited differential diagnosis, and accurate classification often requires careful morphologic evaluation and immunohistochemical workup. Low-grade fibromyxoid sarcoma (LGFMS) is a rare malignant fibroblastic tumor with deceptively bland spindle cell morphology. Involvement of the breast is exceedingly rare. We examined the clinicopathologic and molecular characteristics of three cases of breast/axillary LGFMS. In addition, we interrogated the immunohistochemical expression of MUC4, a commonly used marker of LGFMS, in other breast spindle cell lesions. LGFMS presented in women at 23, 33, and 59 years of age. Tumor size ranged from 0.9 to 4.7 cm. Microscopically, they were circumscribed nodular masses composed of bland spindle cells with fibromyxoid stroma. Immunohistochemically, tumors were diffusely positive for MUC4 and negative for keratin, CD34, S100 protein, and nuclear beta-catenin. Fluorescence in-situ hybridization demonstrated FUS (n = 2) or EWSR1 (n = 1) rearrangements. Next-generation sequencing identified FUS::CREB3L2 and EWSR1::CREB3L1 fusions. MUC4 immunohistochemistry performed on 162 additional breast lesions demonstrated only weak and limited expression in a subset of cases of fibromatosis (10/20, ≤30% staining), scar (5/9, ≤10%), metaplastic carcinoma (4/23, ≤5%), and phyllodes tumor (3/74, ≤10%). MUC4 was entirely negative in cases of pseudoangiomatous stromal hyperplasia (n = 9), myofibroblastoma (n = 6), periductal stromal tumor (n = 3), and cellular/juvenile fibroadenoma (n = 21). LGFMS can rarely occur in the breast and should be considered in the differential diagnosis of breast spindle cell lesions. Strong and diffuse MUC4 expression is highly specific in this histologic context. Detection of an FUS or EWSR1 rearrangement can confirm the diagnosis.
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Fibroma , Fibrosarcoma , Neoplasias de los Tejidos Blandos , Humanos , Femenino , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Fibrosarcoma/genética , Inmunohistoquímica , Diagnóstico Diferencial , Proteínas S100 , Fibroma/genética , Neoplasias de los Tejidos Blandos/patologíaRESUMEN
Global warming can have positive or negative impacts on society depending on sectors and changes in climate impact drivers, resulting in opportunities or risks. The same holds true for social-economic changes. However, past research has mostly focused on assessing risks, leaving potential opportunities under-addressed. Here, we simulated the impact of climate change and socioeconomic development on livestock snow disasters over the Qinghai-Tibetan Plateau during 1986-2100, by integrating the drivers of climate and socioeconomic changes via an event-based disaster risk assessment model. Model results show climate change and socioeconomic development contributes about equally to reducing livestock loss in snow disasters by 4% yr-1 up to 2100 under representative concentration pathway 8.5 and shared-socioeconomic pathway 5. The marginal benefit from climate change was projected to be a 43.2% reduction in annual average loss per degree kelvin warming, and that from socioeconomic development was a 12.4% reduction per 100% increase in gross domestic production. In a 2 °C warmer world, the annual average loss could be 91% smaller compared with the baseline period (1986-2005). Limiting global warming to 1.5 °C instead of 2 °C would reduce the benefit by 5%, requiring a 135% increase in the marginal benefits of prevention capacity to offset the reduction.