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Apart from their killer identity, natural killer (NK) cells have integral roles in shaping the tumor microenvironment. Through immune gene deconvolution, the present study revealed an interplay between NK cells and myeloid-derived suppressor cells (MDSCs) in nonresponders of immune checkpoint therapy. Given that the mechanisms governing the outcome of NK cell-to-myeloid cell interactions remain largely unknown, we sought to investigate the cross-talk between NK cells and suppressive myeloid cells. Upon contact with tumor-experienced NK cells, monocytes and neutrophils displayed increased expression of MDSC-related suppressive factors along with increased capacities to suppress T cells. These changes were accompanied by impaired antigen presentation by monocytes and increased ER stress response by neutrophils. In a cohort of patients with sarcoma and breast cancer, the production of interleukin-6 (IL-6) by tumor-infiltrating NK cells correlated with S100A8/9 and arginase-1 expression by MDSCs. At the same time, NK cell-derived IL-6 was associated with tumors with higher major histocompatibility complex class I expression, which we further validated with b2m-knockout (KO) tumor mice models. Similarly in syngeneic wild-type and IL-6 KO mouse models, we then demonstrated that the accumulation of MDSCs was influenced by the presence of such regulatory NK cells. Inhibition of the IL-6/signal transducer and activator of transcription 3 (STAT3) axis alleviated suppression of T cell responses, resulting in reduced tumor growth and metastatic dissemination. Together, these results characterize a critical NK cell-mediated mechanism that drives the development of MDSCs during tumor immune escape.
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Tolerancia Inmunológica , Interleucina-6 , Células Asesinas Naturales , Células Supresoras de Origen Mieloide , Factor de Transcripción STAT3 , Factor de Transcripción STAT3/metabolismo , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Interleucina-6/metabolismo , Células Supresoras de Origen Mieloide/metabolismo , Células Supresoras de Origen Mieloide/inmunología , Animales , Humanos , Transducción de Señal , Microambiente Tumoral/inmunología , Ratones Noqueados , Línea Celular Tumoral , Femenino , Ratones , Ratones Endogámicos C57BL , Neoplasias/inmunología , Neoplasias/patologíaRESUMEN
Granulosa-cell tumors (GCTs) are the most common type of malignant ovarian sex cord-stromal tumor (SCST). The histopathologic diagnosis of these tumors can be challenging. A recurrent somatic mutation of the forkhead box L2 (FOXL2) gene has been identified in adult GCT. In this retrospective single-center study of 44 SCST, a morphologic review together with analysis of FOXL2 C134W was evaluated in relation to tumor morphology. In addition, TERT promoter mutation testing was performed. Twelve of 36 cases got an altered diagnosis based on morphology alone. The overarching architectural growth pattern in 32/44 (72.7%) tumors was diffuse/solid with several tumors showing markedly heterogeneous architecture. In correlation to FOXL2 C134W mutation status, cytoplasmic color, and nuclear shape, differed between the FOXL2 C134W positive and FOXL2 C134 W negative groups, but these differences were not significant when comparing them separately. Nineteen of 44 cases underwent TERT promoter sequencing with a positive result in 3 cases; 2 adult GCTs and 1 cellular fibroma. Three patients developed a recurrence of which 2 were FOXL2 C134W positive adult GCTs and the third was an unclassified SCST. In conclusion, the morphologic and immunohistochemical diagnosis of different SCSTs is challenging and one cannot reliably identify FOXL2 mutation-positive tumors solely by morphologic features. Therefore, broad use of molecular analysis of the FOXL2 C134W mutation is suggested for SCSTs, and further studies are needed to evaluate the clinical outcome of these tumors as well as the diagnostic and prognostic implications of TERT promoter mutations.
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Tumor de Células de la Granulosa , Neoplasias Ováricas , Tumores de los Cordones Sexuales y Estroma de las Gónadas , Adulto , Femenino , Humanos , Estudios Retrospectivos , Proteína Forkhead Box L2/genética , Tumores de los Cordones Sexuales y Estroma de las Gónadas/diagnóstico , Tumores de los Cordones Sexuales y Estroma de las Gónadas/genética , Tumores de los Cordones Sexuales y Estroma de las Gónadas/patología , Mutación , Tumor de Células de la Granulosa/diagnóstico , Tumor de Células de la Granulosa/genética , Tumor de Células de la Granulosa/patología , Neoplasias Ováricas/patología , Factores de Transcripción Forkhead/genéticaRESUMEN
BACKGROUND: Current risk models in solitary fibrous tumour (SFT) were developed using cohorts with short follow-up and cannot reliably identify low-risk patients. We recently developed a novel risk model (G-score) to account for both early and late recurrences. Here, we aimed to validate the G-score in a large international cohort with long-term follow-up. METHODS: Data were collected from nine sarcoma referral centres worldwide. Recurrence-free interval (RFi) was the primary endpoint. RESULTS: The cohort comprised 318 patients with localised extrameningeal SFTs. Disease recurrence occurred in 96 patients (33%). The estimated 5-year RFi rate was 72%, and the 10-year RFi rate was 52%. G-score precisely predicted recurrence risk with estimated 10-year RFi rate of 84% in low risk, 54% in intermediate risk and 36% in high risk (p < 0.001; C-index 0.691). The mDemicco (p < 0.001; C-index 0.749) and SalasOS (p < 0.001; C-index 0.674) models also predicted RFi but identified low-risk patients less accurate with 10-year RFi rates of 72% and 70%, respectively. CONCLUSIONS: G-score is a highly significant predictor of early and late recurrence in SFT and is superior to other models to predict patients at low risk of relapse. A less intensive follow-up schedule could be considered for patients at low recurrence risk according to G-score.
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Recurrencia Local de Neoplasia , Tumores Fibrosos Solitarios , Humanos , Pronóstico , Recurrencia Local de Neoplasia/patología , Tumores Fibrosos Solitarios/cirugía , Tumores Fibrosos Solitarios/patología , Factores de Riesgo , Estudios de Cohortes , Enfermedad CrónicaRESUMEN
BACKGROUND AND OBJECTIVES: Treatment of high-grade osteosarcoma (OS) relies on a combination of systemic chemotherapy and radical surgical excision of the tumor. Little is known on what happens in case of an irrefutably inadequate (intralesional) margin. We aimed to describe the outcome of patients with high-grade OSs of the trunk and the extremities where planned wide resection resulted in an intralesional margin. METHODS: A retrospective study from the Scandinavian Sarcoma Group registry and the Royal Orthopaedic Hospital databases including data from 53 patients surgically treated between the years 1990 and 2017. RESULTS: Local recurrence was observed in 13/53 patients. All patients with local recurrence where the neoadjuvant chemotherapy response could be retrieved (n = 9) were shown to be poor responders. None of the patients with good response to chemotherapy relapsed. Postoperative radiotherapy was not associated with improved local control of the disease. Re-excision surgery was performed in only seven patients, and two of them had tumor relapse. CONCLUSIONS: Good response to chemotherapy salvages the outcome of surgical excision with a poor margin in patients with high-grade OSs and a watchful waiting strategy may be justified in these cases. Poor responders have a higher recurrence risk and their approach should be individualized.
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Neoplasias Óseas , Osteosarcoma , Neoplasias Óseas/patología , Humanos , Márgenes de Escisión , Recurrencia Local de Neoplasia , Osteosarcoma/patología , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Adenosine is a metabolite that suppresses antitumor immune response of T and NK cells via extracellular binding to the two subtypes of adenosine-2 receptors, A2ARs. While blockade of the A2AARs subtype effectively rescues lymphocyte activity, with four A2AAR antagonists currently in anticancer clinical trials, less is known for the therapeutic potential of the other A2BAR blockade within cancer immunotherapy. Recent studies suggest the formation of A2AAR/A2BAR dimers in tissues that coexpress the two receptor subtypes, where the A2BAR plays a dominant role, suggesting it as a promising target for cancer immunotherapy. METHODS: We report the synthesis and functional evaluation of five potent A2BAR antagonists and a dual A2AAR/A2BAR antagonist. The compounds were designed using previous pharmacological data assisted by modeling studies. Synthesis was developed using multicomponent approaches. Flow cytometry was used to evaluate the phenotype of T and NK cells on A2BAR antagonist treatment. Functional activity of T and NK cells was tested in patient-derived tumor spheroid models. RESULTS: We provide data for six novel small molecules: five A2BAR selective antagonists and a dual A2AAR/A2BAR antagonist. The growth of patient-derived breast cancer spheroids is prevented when treated with A2BAR antagonists. To elucidate if this depends on increased lymphocyte activity, immune cells proliferation, and cytokine production, lymphocyte infiltration was evaluated and compared with the potent A2AAR antagonist AZD-4635. We find that A2BAR antagonists rescue T and NK cell proliferation, IFNγ and perforin production, and increase tumor infiltrating lymphocytes infiltration into tumor spheroids without altering the expression of adhesion molecules. CONCLUSIONS: Our results demonstrate that A2BAR is a promising target in immunotherapy, identifying ISAM-R56A as the most potent candidate for A2BAR blockade. Inhibition of A2BAR signaling restores T cell function and proliferation. Furthermore, A2BAR and dual A2AAR/A2BAR antagonists showed similar or better results than A2AAR antagonist AZD-4635 reinforcing the idea of dominant role of the A2BAR in the regulation of the immune system.
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Neoplasias , Antagonistas de Receptores Purinérgicos P1 , Adenosina/farmacología , Humanos , Linfocitos/metabolismo , Neoplasias/tratamiento farmacológico , Receptor de Adenosina A2B/genética , Receptor de Adenosina A2B/metabolismoRESUMEN
Immune checkpoint inhibitors (ICIs) such as PD1/PD-L1 blockers are an established treatment for many solid cancers. There are currently no approved ICIs for sarcomas, but satisfactory results have been seen in some patients with disseminated disease in certain histological types. Most studies on PD-L1 in sarcoma have used small specimens and there are no clear cutoff values for scoring. We investigated PD-L1 immunoreactivity in high-grade chondrosarcomas (CS), abdominal liposarcoma (LS) and undifferentiated pleomorphic sarcomas (UPS). In total, 230 tumors were stained with SP142 and SP263 assays and evaluated by two clinical pathologists. Immunoreactivity in tumor and immune cells was correlated with clinical outcome. Overall, ≥1% PD-L1 immunoreactivity in tumor cells was found in 11 CS, 26 LS and 59 UPS (SP142 assay) and in 10 CS, 26 LS and 77 UPS (SP263 assay). Most tumors exhibited ≤10% PD-L1 immunoreactivity, but a subset across all three subtypes had >50%. Kaplan-Meier survival analysis showed no significant difference in metastasis-free or overall survival in relation to PD-L1 immunoreactivity in tumor or immune cells for any subtype. As there is a lack of clinical data regarding PD-L1/PD-1 status and therapy response, it is not currently possible to establish clear cutoff values. Patients with high (>50%) PD-L1 immunoreactivity in tumor cells (TC) with the SP263 assay would be a logical group to investigate for potentially beneficial PD1/PD-L1-targeted treatment.
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Antígeno B7-H1 , Neoplasias Óseas , Condrosarcoma , Liposarcoma , Sarcoma , Antígeno B7-H1/biosíntesis , Antígeno B7-H1/inmunología , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/biosíntesis , Biomarcadores de Tumor/inmunología , Neoplasias Óseas/inmunología , Neoplasias Óseas/patología , Condrosarcoma/inmunología , Condrosarcoma/patología , Humanos , Liposarcoma/inmunología , Liposarcoma/patología , Sarcoma/inmunología , Sarcoma/patología , Coloración y EtiquetadoRESUMEN
AIMS: Accurate and reliable diagnosis is essential for lung cancer treatment. The study aim was to investigate interpathologist diagnostic concordance for pulmonary tumours according to WHO diagnostic criteria. METHODS: Fifty-two unselected lung and bronchial biopsies were diagnosed by a thoracic pathologist based on a broad spectrum of immunohistochemical (IHC) stainings, molecular data and clinical/radiological information. Slides stained with H&E, thyroid transcription factor-1 (TTF-1) clone SPT24 and p40 were scanned and provided digitally to 20 pathologists unaware of reference diagnoses. The pathologists independently diagnosed the cases and stated if further diagnostic markers were deemed necessary. RESULTS: In 31 (60%) of the cases, ≥80% of the pathologists agreed with each other and with the reference diagnosis. Lower agreement was seen in non-small cell neuroendocrine tumours and in squamous cell carcinoma with diffuse TTF-1 positivity. Agreement with the reference diagnosis ranged from 26 to 45 (50%-87%) for the individual pathologists. The pathologists requested additional IHC staining in 15-44 (29%-85%) of the 52 cases. In nearly half (17 of 36) of the malignant cases, one or more pathologist advocated for a different final diagnosis than the reference without need of additional IHC markers, potentially leading to different clinical treatment. CONCLUSIONS: Interpathologist diagnostic agreement is moderate for small unselected bronchial and lung biopsies based on a minimal panel of markers. Neuroendocrine morphology is sometimes missed and TTF-1 clone SPT24 should be interpreted with caution. Our results suggest an intensified education need for thoracic pathologists and a more generous use of diagnostic IHC markers.
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Carcinoma de Pulmón de Células no Pequeñas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Biomarcadores de Tumor , Biopsia , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/patología , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologíaRESUMEN
OBJECTIVES: Accurate and reliable diagnostics are crucial as histopathological type influences selection of treatment in lung cancer. The aim of this study was to evaluate real-world accuracy and use of immunohistochemical (IHC) staining in lung cancer diagnostics. MATERIALS AND METHODS: The diagnosis and used IHC stains for small specimens with lung cancer on follow-up resection were retrospectively investigated for a 15-month period at two major sites in Sweden. Additionally, 10 pathologists individually suggested diagnostic IHC staining for 15 scanned bronchial and lung biopsies and cytological specimens. RESULTS: In 16 (4.7%) of 338 lung cancer cases, a discordant diagnosis of potential clinical relevance was seen between a small specimen and the follow-up resection. In half of the cases, there was a different small specimen from the same investigational work-up with a concordant diagnosis. Diagnostic inaccuracy was often related to a squamous marker not included in the IHC panel (also seen for the scanned cases), the case being a neuroendocrine tumor, thyroid transcription factor-1 (TTF-1) expression in squamous cell carcinomas (with clone SPT24), or poor differentiation. IHC was used in about 95% of cases, with a higher number of stains in biopsies and in squamous cell carcinomas and especially neuroendocrine tumors. Pre-surgical transthoracic samples were more often diagnostic than bronchoscopic ones (72-85% vs. 9-53% for prevalent types). CONCLUSIONS: Although a high overall diagnostic accuracy of small specimens was seen, small changes in routine practice (such as consequent inclusion of p40 and TTF-1 clone 8G7G3/1 in the IHC panel for non-small cell cancer with unclear morphology) may lead to improvement, while reducing the number of IHC stains would be preferable from a time and cost perspective.
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Neoplasias Pulmonares , Adulto , Carcinoma de Pulmón de Células no Pequeñas , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Factor Nuclear Tiroideo 1RESUMEN
RNA-binding proteins (RBPs) are important transcriptomic regulators and may be important in tumorigenesis. Here, we sought to investigate the clinical impact of RBPs for patients with Ewing sarcoma (ES). ES transcriptome signatures were characterized from four previously published cohorts and grouped into new training and validation cohorts. A total of three distinct subtypes were identified and compared for differences in patient prognosis and RBP signatures. Next, univariate Cox and Lasso regression models were used to identify hub prognosis-related RBPs and construct a prognostic risk model, and prediction capacity was assessed through time-dependent receiver operating characteristics (ROCs), Kaplan-Meier curves, and nomograms. Across the three RBP subtypes, 29 significant prognostic-associated RBP genes were identified, of which 10 were used to build and validate an RBP-associated prognostic risk model (RPRM) that had a stable predictive value and could be considered valuable for clinical risk-stratification of ES. A comparison with immunohistochemistry validation showed a significant association between overall survival and NSUN7 immunoreactivity, which was an independent favorable prognostic marker. The association of RBP signatures with ES clinical prognosis provides a strong rationale for further investigation into RBPs molecular mechanisms.
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Nuclear insulinlike growth factor 1 receptor (nIGF1R) has been associated with poor overall survival and chemotherapy resistance in various types of cancer; however, the underlying mechanism remains unclear. In the present study, immunoprecipitationcoupled mass spectrometry was performed in an IGF1Roverexpressing SW480OE colorectal cancer cell line to identify the nIGF1R interactome. Network analysis revealed 197 proteins of interest which were involved in several biological pathways, including RNA processing, DNA doublestrand break (DSB) repair and SUMOylation pathways. Nuclear mitotic apparatus protein (NuMA) was identified as one of nIGF1R's colocalizing partners. Proximity ligation assay (PLA) revealed different levels of p53binding protein 1 (53BP1)NuMA colocalization between IGF1Rpositive (R+) and IGF1Rnegative (R) mouse embryonic fibroblasts following exposure to ionizing radiation (IR). 53BP1 was retained by NuMA in the R cells during IRinduced DNA damage. By contrast, the level of NuMA53BP1 was markedly lower in R+ cells compared with R cells. The present data suggested a regulatory role of nIGF1R in 53BP1dependent DSB repair through its interaction with NuMA. Brightfield PLA analysis on a paraffinembedded tissue microarray from patients with colorectal cancer revealed a significant association between increased nuclear colocalizing signals of NuMA53BP1 and a shorter overall survival. These results indicate that nIGF1R plays a role in facilitating 53BP1dependent DDR by regulating the NuMA53BP1 interaction, which in turn might affect the clinical outcome of patients with colorectal cancer.
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Proteínas de Ciclo Celular/metabolismo , Núcleo Celular/metabolismo , Neoplasias Colorrectales/metabolismo , Receptor IGF Tipo 1/metabolismo , Proteína 1 de Unión al Supresor Tumoral P53/metabolismo , Animales , Línea Celular Tumoral , Células Cultivadas , Neoplasias Colorrectales/genética , Roturas del ADN de Doble Cadena , Reparación del ADN , Femenino , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Humanos , Masculino , Espectrometría de Masas , Ratones , Proteómica , Regulación hacia ArribaRESUMEN
BACKGROUND: The genomic and transcriptomic landscape of widely invasive follicular thyroid carcinomas (wiFTCs) and Hürthle cell carcinoma (HCC) are poorly characterized, and subsets of these tumors lack information on genetic driver events. OBJECTIVE: The aim of this study was to bridge this gap. METHODS: We performed whole-genome and RNA sequencing and subsequent bioinformatic analyses of 11 wiFTCs and 2 HCCs with a particularly poor prognosis, and matched normal tissue. RESULTS: All wiFTCs exhibited one or several mutations in established thyroid cancer genes, including TERT (nâ =â 4), NRAS (nâ =â 3), HRAS, KRAS, AKT, PTEN, PIK3CA, MUTYH, TSHR, and MEN1 (nâ =â 1 each). MutSig2CV analysis revealed recurrent somatic mutations in FAM72D (nâ =â 3, in 2 wiFTCs and in a single HCC), TP53 (nâ =â 3, in 2 wiFTCs and a single HCC), and EIF1AX (nâ =â 3), with DGCR8 (nâ =â 2) as borderline significant. The DGCR8 mutations were recurrent p.E518K missense alterations, known to cause familial multinodular goiter via disruption of microRNA (miRNA) processing. Expression analyses showed reduced DGCR8 messenger RNA expression in FTCs in general, and the 2 DGCR8 mutants displayed a distinct miRNA profile compared to DGCR8 wild-types. Copy number analyses revealed recurrent gains on chromosomes 4, 6, and 10, and fusion gene analyses revealed 27 high-quality events. Both HCCs displayed hyperploidy, which was fairly unusual in the FTC cohort. Based on the transcriptome data, tumors amassed in 2 principal clusters. CONCLUSION: We describe the genomic and transcriptomic landscape in wiFTCs and HCCs and identify novel recurrent mutations and copy number alterations with possible driver properties and lay the foundation for future studies.
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Adenocarcinoma Folicular/patología , Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/patología , MicroARNs/metabolismo , Proteínas de Unión al ARN/genética , Neoplasias de la Tiroides/patología , Adenocarcinoma Folicular/genética , Adenocarcinoma Folicular/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Masculino , MicroARNs/genética , Persona de Mediana Edad , Mutación , Pronóstico , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/metabolismo , Secuenciación Completa del GenomaRESUMEN
Chondrosarcomas are the second most common malignant bone tumor. Activating promoter mutations in telomerase reverse transcriptase (TERT) was recently described by us and others as a frequent mutation in high-grade chondrosarcoma. In this study, we investigate the prognostic significance of TERT promoter mutations in 241 chondrosarcomas from 190 patients collected over 24 years (1994-2017). The TERT promoter was sequenced after microdissection of 135 chondrosarcomas from 106 patients in addition to data from our previous cohort. The TERT promoter mutation at -124 C > T was found in 45% of all patients and was significantly associated (p > 0,001) with higher tumor grade, shorter metastasis-free survival, and disease-specific survival. Additionally, TERT promoter-mutated tumors were associated with a more aggressive metastatic pattern. Shorter survival was observed in patients with wild-type primary tumors who developed a mutated metastasis indicative of tumor progression. Primary tumor genetic heterogeneity and altering mutational status between nonsynchronous metastatic lesions suggests that chondrosarcoma is a multiclonal disease progressing through a branching evolution. Conclusion: TERT promoter mutation seems to be a central event in chondrosarcoma progression with association to metastatic disease and disease-related mortality. As an easily analyzed marker, there is future potential to utilize TERT promoter mutation status as a prognostic marker and investigate telomerase-targeted therapy in chondrosarcomas.
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Biomarcadores de Tumor/genética , Neoplasias Óseas/diagnóstico , Condrosarcoma/diagnóstico , Mutación/genética , Regiones Promotoras Genéticas , Telomerasa/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Óseas/genética , Niño , Condrosarcoma/genética , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
Rapidly expanding knowledge of the molecular landscape of cancers has resulted in the implementation of an increasing number of specific therapies targeted at tumors with specific molecular aberrations. In response to this development, new tools for predictive testing for molecular targets need to be implemented in routine health care. To achieve robust future molecular diagnostic pathology, and equal opportunity for patients to qualify for targeted therapy, the national working group for Solid Tumors in the initiative Genomic Medicine Sweden (GMS) aims to implement regional and national platforms for comprehensive genomic tumor profiling and linked analysis pipelines. Novel IT-infrastrucutures and recruitment of bioinformaticians and molecular biologists to hospital labotatories are paramount. The infrastructure will allow wider inclusion into clinical trials and supplement the national cancer registries with molecular ¼real world data« for research and evaluation of implemented cancer therapies and diagnostic procedures.
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Neoplasias , Patología Molecular , Humanos , Terapia Molecular Dirigida , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/terapia , Medicina de Precisión , SueciaRESUMEN
Checkpoint inhibitors are slowly being introduced in the care of specific sarcoma subtypes such as undifferentiated pleomorphic sarcoma, alveolar soft part sarcoma, and angiosarcoma even though formal indication is lacking. Proper biomarkers to unravel potential immune reactivity in the tumor microenvironment are therefore expected to be highly warranted. In this study, intratumoral spatial cross presentation was investigated as a novel concept where immune cell composition in the tumor microenvironment was suggested to act as a proxy for immune surveillance. Double immunohistochemistry revealed a prognostic role of direct spatial interactions between CD11c+ antigen-presenting cells (APCs) and CD8+ cells in contrast to each marker alone in a soft tissue sarcoma (STS) cohort of 177 patients from the Karolinska University Hospital (MFS p = 0.048, OS p = 0.025). The survival benefit was verified in multivariable analysis (MFS p = 0.012, OS p = 0.004). Transcriptomics performed in the TCGA sarcoma cohort confirmed the prognostic value of combining CD11c with CD8 (259 patients, p = 0.005), irrespective of FOXP3 levels and in a CD274 (PD-LI)-rich tumor microenvironment. Altogether, this study presents a histopathological approach to link immune surveillance and patient survival in STS. Notably, spatial cross presentation as a prognostic marker is distinct from therapy response-predictive biomarkers such as immune checkpoint molecules of the PD-L1/PD1 pathway.
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Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive tumors, accounting for around 5% of all soft tissue sarcomas. A better understanding of the pathogenesis of these tumors and the development of effective treatments are needed. In this context, established tumor cell lines can be very informative, as they may be used for in-depth molecular analyses and improvement of treatment strategies. Here, we present the genomic and transcriptomic profiling analysis of a MPNST cell line (BL1391) that was spontaneously established in our laboratory from a primary tumor that had not been exposed to genotoxic treatment. This cell line shows peculiar genetic features, such as a large marker chromosome composed of high-copy number amplifications of regions from chromosomes 1 and 11 with an embedded neocentromere. Moreover, the transcriptome profiling revealed the presence of several fusion transcripts involving the CACHD1, TNMA4, MDM4, and YAP1 genes, all of which map to the amplified regions of the marker. BL1391 could be a useful tool to study genomic amplifications and neocentromere seeding in MPNSTs and to develop new therapeutic strategies.
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Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas de Ciclo Celular/genética , Ciclina D1/genética , Quinasa 4 Dependiente de la Ciclina/genética , Proteínas de la Membrana/genética , Neoplasias de la Vaina del Nervio/genética , Neoplasias de la Vaina del Nervio/patología , Neoplasias del Sistema Nervioso Periférico/genética , Neoplasias del Sistema Nervioso Periférico/patología , Proteínas Proto-Oncogénicas/genética , Factores de Transcripción/genética , Anciano de 80 o más Años , Línea Celular Tumoral , Femenino , Amplificación de Genes/genética , Perfilación de la Expresión Génica , Humanos , Proteínas Señalizadoras YAPRESUMEN
Despite the fact that management of EC is moving towards four TCGA-based molecular classifications, a pronounced variation in immune response among these molecular subtypes limits its clinical use. We aimed to investigate the determinant biomarker of ICI response in endometrial cancer (EC). We characterized transcriptome signatures associated with tumor immune microenvironment in EC. Two immune infiltration signatures were identified from the TCGA database (n = 520). The high- and low-infiltration clusters were compared for differences in patient clinical characteristics, genomic features, and immune cell transcription signatures for ICI prediction. A Lasso Cox regression model was applied to construct a prognostic gene signature. Time-dependent receiver operating characteristic curve, Kaplan-Meier curve, nomogram, and decision curve analyses were used to assess the prediction capacity. The efficacy of potential biomarker was validated by the Karolinska endometrial cancer cohort (n = 260). Immune signature profiling suggested that T follicular helper-like cells (Tfh) may be an important and favorable factor for EC; high Tfh infiltration showed potential for clinical use in the anti-PD-1 treatment. A Tfh Infiltration Risk Model (TIRM) established using eight genes was validated, and it outperformed the Immune Infiltration Risk Model. The TIRM had a stable prognostic value in combination with clinical risk factors and could be considered as a valuable tool in a clinical prediction model. We identified CRABP1 as an individual poor prognostic factor in EC. The Tfh-based classification distinguishes immune characteristics and predicts ICI efficacy. A nomogram based on Tfh-related risk score accurately predicted the prognosis of patients with EC, demonstrating superior performance to TCGA-based classification.
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Neoplasias Endometriales , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Inmunoterapia , Linfocitos Infiltrantes de Tumor/inmunología , Modelos Inmunológicos , Linfocitos T Colaboradores-Inductores/inmunología , Supervivencia sin Enfermedad , Neoplasias Endometriales/inmunología , Neoplasias Endometriales/mortalidad , Neoplasias Endometriales/terapia , Femenino , Humanos , Persona de Mediana Edad , Tasa de SupervivenciaRESUMEN
Background: Cancer immunotherapy has produced significant positive clinical effects in a variety of tumor types. However, pancreatic ductal adenocarcinoma (PDAC) is widely considered to be a "cold" cancer with poor immunogenicity. Our aim is to determine the detailed immune features of PDAC to seek new treatment strategies. Methods: The immune cell abundance of PDAC patients was evaluated with the single-sample gene set enrichment analysis (ssGSEA) using 119 immune gene signatures. Based on these data, patients were classified into different immune subtypes (ISs) according to immune gene signatures. We analyzed their response patterns to immunotherapy in the datasets, then established an immune index to reflect the different degrees of immune infiltration through linear discriminant analysis (LDA). Finally, potential prognostic markers associated with the immune index were identified based on weighted correlation network analysis (WGCNA) that was functionally validated in vitro. Results: Three ISs were identified in PDAC, of which IS3 had the best prognosis across all three cohorts. The different expressions of immune profiles among the three ISs indicated a distinct responsiveness to immunotherapies in PDAC subtypes. By calculating the immune index, we found that the IS3 represented higher immune infiltration, while IS1 represented lower immune infiltration. Among the investigated signatures, we identified ZNF185, FANCG, and CSTF2 as risk factors associated with immune index that could potentially facilitate diagnosis and could be therapeutic target markers in PDAC patients. Conclusions: Our findings identified immunologic subtypes of PDAC with distinct prognostic implications, which allowed us to establish an immune index to represent the immune infiltration in each subtype. These results show the importance of continuing investigation of immunotherapy and will allow clinical workers to personalized treatment more effectively in PDAC patients.
Asunto(s)
Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Adenocarcinoma/inmunología , Adenocarcinoma/patología , Biomarcadores de Tumor/inmunología , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/patología , Línea Celular , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica/inmunología , Humanos , Inmunoterapia/métodos , Pronóstico , Microambiente Tumoral/inmunología , Neoplasias PancreáticasRESUMEN
BACKGROUND: Clear-cell chondrosarcomas (CCCSs) constitute a very rare subtype of chondrosarcoma. CCCS may radiologically mimic chondroblastoma, and given the difference in surgical approach, it is important to distinguish these two entities preoperatively. DESIGN: Using the institutional digital records, we identified histologically verified CCCS between 1996 and 2013, where preoperative fine-needle aspiration (FNA) cytology was available. Clinical characteristics were categorized and described, and FNAs were reviewed by a panel of senior cytopathologists. In addition, corresponding radiological imaging was reviewed by senior radiologists, and a literature review on CCCS and chondroblastoma was conducted. RESULTS: A total of seven CCCS FNAs were identified from six patients. The cytomorphology showed low to intermediate cellular smears of clusters and single round or oval tumor cells. Tumor cells had rounded (sometimes binucleated) nuclei with limited pleomorphism and rich vacuolated cytoplasm. Chondroid background matrix was always found. While CCCS patients had a significantly higher age at diagnosis compared to chondroblastoma, no age cut-off would distinctly separate the two. CONCLUSIONS: CCCS has distinguished cytomorphological features on FNA smears. CCCS should be considered as a possible differential diagnosis in adults (>25 years) with a radiological suspicion of chondroblastoma. Since radiology and patient age cannot conclusively distinguish CCCS from chondroblastoma, FNA may prove an important tool for correct preoperative diagnosis of CCCS.
Asunto(s)
Neoplasias Óseas/diagnóstico , Neoplasias Óseas/patología , Condrosarcoma/diagnóstico , Condrosarcoma/patología , Adolescente , Adulto , Biopsia con Aguja Fina/métodos , Condroblastoma/diagnóstico , Condroblastoma/patología , Citodiagnóstico/métodos , Demografía/métodos , Diagnóstico Diferencial , Femenino , Humanos , MasculinoRESUMEN
Rarely, salivary gland tumors such as mucoepidermoid carcinoma, mammary analogue secretory carcinoma and mucinous carcinoma arise as primary tumors from ectopic or metaplastic salivary gland tissue adjacent to or within the thyroid gland. We report for the first time a case of primary salivary acinic cell carcinoma (AcCC) adjacent to the thyroid gland in a 71-year-old female patient with Crohns disease and a previous history of malignant melanoma. Following the development of a nodule adjacent to the left thyroid lobe, a fine-needle aspiration biopsy was reported as consistent with a follicular lesion of undetermined significance (Bethesda III). A left-sided hemithyroidectomy was performed. A circumscribed lesion measuring 33 mm was noted adjacent to the thyroid and trapping parathyroid, it was composed of solid nests and glands with microcystic and follicular patterns. The tumor was negative for thyroid, parathyroid and paraganglioma markers, but positive for pan-cytokeratins, CK7, CD10, CD117, androgen receptor and HNF-beta. A metastasis of a thyroid-like renal cell carcinoma was suspected but ruled out, and the patient had no evident lesions on extensive radiology of the urogenital, pulmonary and GI tracts. Based on the morphology, a diagnosis of AcCC was suggested, and confirmed with DOG1 and PAS-diastase staining. Molecular analyses pinpointed a constitutional ASXL1 variant of uncertain significance, but no fusion events. The patient had no radiological or clinical evidence of parotid, submandibular or sublingual tumors postoperatively, and the excised lesion was therefore assumed to be a primary tumor. We here detail the morphological and immunophenotypic profile of this previously undescribed perithyroidal tumor.