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PURPOSE: Intestinal-type adenocarcinoma (ITAC) is a rare sinonasal malignancy. Curative treatment requires multidisciplinary approach, with surgical options consist of the endonasal endoscopic approach (EEA) and external surgery (EXTS). Here, we provide the post-operative and survival results from a single-center long-term follow-up. METHODS: We report long-term follow-up of 92 ITAC cases treated between 1998 and 2018, treated with EEA (n = 40) or EXTS (n = 52). Survival estimates, post-operative complications and duration of hospitalization were compared between surgical modalities. RESULTS: Baseline characteristics were similar. A higher number of T4b tumors (16%), and subsequently more tumoral invasion (39%), was present in patients undergoing EXTS compared to EEA (3% and 18%, respectively). No difference in Barnes histology subtypes was noticed. Patients undergoing EEA had a shorter post-operative hospitalization stay versus EXTS (4 versus 7 days). Use of EEA was associated to improved disease-specific survival (DSS; 11.4 versus 4.4 years; HREEA = 0.53), especially for patients with T3-4a tumors (11.4 versus 3.0 years; HREEA = 0.41). Patients with T3-4 stage, tumoral invasion, positive surgical margins, mucinous or mixed histology, and prolonged post-operative hospital stay showed poor local relapse-free, disease-free, overall, and DSS. CONCLUSIONS: Long-term follow-up in locally advanced ITAC demonstrates that resection by EEA is correlated with improved DSS compared to EXTS, especially for T3-4 tumors. No significant differences between both treatment modalities was observed regarding per- and post-operative complications, although hospitalization in patients undergoing EEA was shorter than for patients treated with EXTS. These results confirm that EEA should remain the preferred surgical procedure in operable cases of sinonasal ITAC.
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Adenocarcinoma , Neoplasias de los Senos Paranasales , Humanos , Masculino , Femenino , Neoplasias de los Senos Paranasales/cirugía , Neoplasias de los Senos Paranasales/patología , Neoplasias de los Senos Paranasales/mortalidad , Adenocarcinoma/cirugía , Adenocarcinoma/patología , Adenocarcinoma/mortalidad , Persona de Mediana Edad , Anciano , Estudios de Seguimiento , Complicaciones Posoperatorias/epidemiología , Estudios Retrospectivos , Tiempo de Internación/estadística & datos numéricos , Adulto , Endoscopía/métodos , Tasa de Supervivencia , Estadificación de NeoplasiasRESUMEN
Myxoid pleomorphic liposarcoma is a recently defined subtype of liposarcoma, which preferentially involves the mediastinum of young patients and shows mixed histological features of conventional myxoid liposarcoma and pleomorphic liposarcoma. While myxoid pleomorphic liposarcoma is known to lack the EWSR1/FUS-DDIT3 fusions characteristic of the former, additional genetic data are limited. To further understand this tumor type, we extensively examined a series of myxoid pleomorphic liposarcomas by fluorescence in situ hybridization (FISH), shallow whole genome sequencing (sWGS) and genome-wide DNA methylation profiling. The 12 tumors occurred in 6 females and 6 males, ranging from 17 to 58 years of age (mean 33 years, median 35 years), and were located in the mediastinum (n = 5), back, neck, cheek and leg, including thigh. Histologically, all cases consisted of relatively, bland, abundantly myxoid areas with a prominent capillary vasculature, admixed with much more cellular and less myxoid foci containing markedly pleomorphic spindled cells, numerous pleomorphic lipoblasts and elevated mitotic activity. Using sWGS, myxoid pleomorphic liposarcomas were found to have complex chromosomal alterations, including recurrent large chromosomal gains involving chromosomes 1, 6-8, 18-21 and losses involving chromosomes 13, 16 and 17. Losses in chromosome 13, in particular loss in 13q14 (including RB1, RCTB2, DLEU1, and ITM2B genes), were observed in 4 out of 8 cases analyzed. Additional FISH analyses confirmed the presence of a monoallelic RB1 deletion in 8/12 cases. Moreover, nuclear Rb expression was deficient in all studied cases. None showed DDIT3 gene rearrangement or MDM2 gene amplification. Using genome-wide DNA methylation profiling, myxoid pleomorphic liposarcomas and conventional pleomorphic liposarcomas formed a common methylation cluster, which segregated from conventional myxoid liposarcomas. While the morphologic, genetic and epigenetic characteristics of myxoid pleomorphic liposarcoma suggest a link with conventional pleomorphic liposarcoma, its distinctive clinical features support continued separate classification for the time being.
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ADN de Neoplasias/genética , Neoplasias de Cabeza y Cuello/clasificación , Liposarcoma Mixoide/clasificación , Liposarcoma/clasificación , Neoplasias del Mediastino/clasificación , Proteínas de Neoplasias/genética , Neoplasias de los Tejidos Blandos/clasificación , Adolescente , Adulto , Metilación de ADN , Epigenómica , Femenino , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Liposarcoma/genética , Liposarcoma/metabolismo , Liposarcoma/patología , Liposarcoma Mixoide/genética , Liposarcoma Mixoide/metabolismo , Liposarcoma Mixoide/patología , Masculino , Neoplasias del Mediastino/genética , Neoplasias del Mediastino/metabolismo , Neoplasias del Mediastino/patología , Persona de Mediana Edad , Biología Molecular , Proteínas de Neoplasias/metabolismo , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/metabolismo , Neoplasias de los Tejidos Blandos/patología , Secuenciación Completa del Genoma , Adulto JovenRESUMEN
BACKGROUND & AIMS: Patients with inflammatory bowel diseases (IBD) have increased risks of dysplasia and colitis-associated cancer (CAC). We evaluated the risk of development of high-grade dysplasia (HGD) or CAC after diagnosis of dysplasia using data from a national cohort of patients with IBD. METHODS: We performed a multicenter retrospective analysis of data collected from 7 tertiary referral regional or academic centers in Belgium. In searches of IBD pathology databases, we identified 813 lesions (616 low-grade dysplasias [LGDs], 64 high-grade dysplasias [HGDs], and 133 CACs) in 410 patients with IBD: 299 had dysplasia (73%) and 111 had CAC (27%). The primary aim was to determine the risk of more-advanced lesions after diagnosis of LGD or HGD. RESULTS: Of the 287 patients with LGD, 21 (7%) developed more-advanced lesions (HGD or CAC) after a median time period of 86 months (interquartile range, 34-214). Of the 28 patients with HGD, 4 (14%) developed CAC after a median time period of 180 months (interquartile range, 23-444). The overall cumulative incidence of CAC at 10 years after an initial diagnosis of HGD was 24.3% and after an initial diagnosis of LGD was 8.5% (P < .05). Metachronous lesions, non-polypoid lesions, and colonic stricture were associated with risk of occurrence of more-advanced lesions after LGD (P < .05). Of the 630 dysplastic lesions identified during endoscopy, 545 (86%) were removed during the same procedure or during a follow-up endoscopy or by surgery. Of 111 patients with CAC, 95 (86%) did not have prior detection of dysplasia and 64 of these 95 patients (67%) developed CAC outside of the screening or surveillance period recommended by the European Crohn's and Colitis Organisation. CONCLUSIONS: In an analysis of pathology data from 7 medical centers in Belgium, we found a low rate of detection of more-advanced lesions following detection of LGD or HGD-taking into account that most of the lesions were removed. Main risk factors for development of more-advanced lesions after LGD were metachronous lesions, non-polypoid lesions, and colon strictures.
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Neoplasias Colorrectales , Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Colonoscopía , Humanos , Hiperplasia , Enfermedades Inflamatorias del Intestino/complicaciones , Estudios RetrospectivosAsunto(s)
Lipoblastoma , Humanos , Osteogénesis , Factor 1 de Elongación Peptídica , Proteínas de Unión al ADNRESUMEN
BACKGROUND: Non-V600E BRAF mutated colorectal cancer (CRC) is a rare disease entity with specific clinical features. These tumors are less likely to have microsatellite instability than CRC with a V600E BRAF mutation and often harbor a KRAS or NRAS mutation. Notably, median overall survival is longer than in wild-type BRAF CRC. Little is known about treatment possibilities in these patients. CASE PRESENTATION: We present the case of a 59 year old patient with a rare mutation in BRAF codon 594, who progressed rapidly on all classical therapies but experienced a clear and long lasting response on treatment with Regorafenib. CONCLUSION: Little is known about therapies that can be effective in the rare non-V600E BRAF mutated CRCs. We present a patient who had a definite response to treatment with Regorafenib. There are no predictive markers that define a subset of CRC patients who benefit most from Regorafenib. The specific features of this non-V600E BRAF mutated CRC may be relevant in the exploration of predictive biomarkers for the efficacy of Regorafenib.
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Adenocarcinoma del Pulmón/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Mutación , Compuestos de Fenilurea/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/genética , Piridinas/uso terapéutico , Adenocarcinoma del Pulmón/secundario , Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/uso terapéutico , Biomarcadores de Tumor/genética , Antígeno Carcinoembrionario/sangre , Cetuximab/uso terapéutico , Neoplasias del Colon/patología , Neoplasias del Colon/radioterapia , Neoplasias del Colon/cirugía , Exones/genética , Fluorouracilo/uso terapéutico , Estudios de Seguimiento , Humanos , Leucovorina/uso terapéutico , Neoplasias Pulmonares/secundario , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/uso terapéutico , Compuestos de Fenilurea/administración & dosificación , Piridinas/administración & dosificación , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
AIMS: A great deal of research is being conducted into PD-L1 immunohistochemistry (IHC) and tumour-infiltrating lymphocytes (TILs) as predictive or prognostic biomarkers for immunotherapy, although several practical issues exist concerning their assessment. The aim of this research was therefore to assess the importance of choice of materials and methods in PD-L1 and TILs scoring in oropharyngeal squamous cell carcinoma (OSCC). METHODS AND RESULTS: IHC for PD-L1 (SP142 and 22C3 clone) and TILs subtyping was performed on formalin-fixed paraffin-embedded tissue slides (biopsy, resection and/or lymph nodes specimens) of 99 patients with OSCC. A comparative analysis of PD-L1 and TILs scoring was made between different types of tissue specimens, between different PD-L1 clones, between TILs and different subsets of TILs and between the quantitative and semiquantitative assessments. PD-L1 scoring resulted in fair to moderate agreement for 22C3 and SP142 between various tissue specimens, with higher agreement at higher cut-off values, and in moderate agreement for 22C3 versus SP142. Evaluation by four independent observers proved substantial inter-rater agreement for both clones with high consistency in their ratings. Moderate agreement was observed for TILs and TILs subsets for the comparison between biopsy and resection. Lastly, strong correlations were found between quantitative and semiquantitative assessment for all PD-L1 and TILs scores. CONCLUSIONS: Our results highlight the challenges associated with the evaluation of PD-L1 and TILs in OSCC. Further research is warranted to evaluate the use of these biomarkers in order to allow implementation of PD-L1 and TILs infiltrate as biomarkers in daily clinical practice.
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Antígeno B7-H1/análisis , Biomarcadores de Tumor/análisis , Inmunohistoquímica/métodos , Linfocitos Infiltrantes de Tumor/patología , Neoplasias Orofaríngeas/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Variaciones Dependientes del ObservadorRESUMEN
OBJECTIVE: Over the last decade, efforts have been made to get a better understanding of the tumor microenvironment and the role of the immune system in it. New insights into the CD27/CD70 signaling pathway point towards a role in tumor immunology, making CD70 an attractive target for immunotherapy. Here, we evaluate CD70 expression in squamous cell carcinoma of the head and neck (SCCHN). METHODS: CD70 immunohistochemistry was retrospectively performed on 95 tumor samples. Tumoral CD70 expression was scored and correlated with clinicopathological variables and overall survival (OS). RESULTS: CD70 expression in tumor cells was observed in 66 samples (69%) and was strongly associated with tumor differentiation grade (p < 0.001). CD70 expression was also observed in tumor-associated fibroblasts and endothelial cells. Additionally, the density of tumor-infiltrating lymphocytes correlated with OS (p = 0.042). CONCLUSION: This study describes the tumoral expression of CD70 in SCCHN. Results highlight the role of CD70 in tumor biology and identify CD70 as a novel therapeutic target. Further research is warranted.
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Ligando CD27/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Neoplasias de Cabeza y Cuello/diagnóstico , Transducción de Señal , Adolescente , Adulto , Anciano , Carcinoma de Células Escamosas/metabolismo , Femenino , Neoplasias de Cabeza y Cuello/metabolismo , Humanos , Inmunohistoquímica , Linfocitos Infiltrantes de Tumor/patología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello , Adulto JovenRESUMEN
PURPOSE: Recent studies have reported that margins alone do not predict survival in patients with a positive chemotherapy response. The aim of this retrospective study is to analyze the surgical and oncological outcomes of patients who underwent chemotherapy and liver resection for colorectal liver metastases (CRLM) with lesions detached from the main hepatic veins, comparing the vein-preserving (VP) approach with traditional surgery. METHODS: Fourteen patients undergoing VP surgery from January 2006 to January 2013 were matched in a 1:2 ratio with a control group (CG) of 28 patients undergoing traditional resection. RESULTS: The median follow-up was 43 months. The radiological response was classified as 'partial response' in eight VP patients and 11 controls (57 vs. 39 %, p = 0.249) and as 'stable disease' in three VP patients and 9 controls (21 vs. 32 %, p = 0.465). Ten VP (71.4 %) and twenty CG patients (71.4 %) experienced tumor relapse (p = 0.99). No venous edge recurrences were recorded in the VP group, whereas 1/13 (7.7 %) was observed in the control group (p = 0.99). The pathological response rate was 64 vs. 39 % (p = 0.037) in VP and CG patients, respectively. The 5-year recurrence-free survival rate was 24 % for VP patients and 25 % for CG patients (p = 0.431). CONCLUSION: In patients with a positive CT response, CRLM can be detached from the hepatic veins, as the oncological outcome is similar to that of a larger resection. The VP approach offers the possibility to enlarge the surgical indications, thus optimizing future surgical treatment chances.
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Neoplasias Colorrectales/patología , Hepatectomía , Venas Hepáticas , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/cirugía , Recurrencia Local de Neoplasia/epidemiología , Anciano , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/terapia , Femenino , Humanos , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Myxoid pleomorphic liposarcoma (MPL) is an extremely rare adipocytic tumor, recently recognized as a distinct entity in the 5th edition of the World Health Organization (WHO) Classification of Soft Tissue and Bone Tumors. Predominantly found in the mediastinum of young women, MPLs exhibit a combination of histological features characteristic of myxoid liposarcoma and pleomorphic (lipo)sarcoma. Their unique molecular features distinguish MPLs from other liposarcomas. Unlike myxoid liposarcomas and well-differentiated/dedifferentiated liposarcomas, MPLs lack specific FUS/EWSR1::DDIT3 gene fusions and MDM2/CDK4 gene amplifications, respectively. MPLs are associated with complex karyotypes, further highlighting their distinct genetic profile. They demonstrate aggressive growth patterns, high recurrence rates, and a high tendency to metastasize. These factors contribute to a poor prognosis, with a median survival of approximately 22.6 months. The aim of this review article is to provide a comprehensive summary of previously documented case reports and studies related to MPLs. By shedding light on the intricate details of MPLs, researchers and clinicians can gain valuable insights that may pave the way for improvements in diagnosis, treatment, and patient outcomes in the future.
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Liposarcoma Mixoide , Humanos , Liposarcoma Mixoide/genética , Liposarcoma Mixoide/patología , Liposarcoma/genética , Liposarcoma/patología , Femenino , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/patologíaRESUMEN
Paired-like homeobox 2B (PHOX2B) is a gene essential in the development of the autonomic nervous system. PHOX2B mutations are associated with neurocristopathies-Hirschsprung disease (HSCR) and congenital central hypoventilation syndrome (CCHS)-and peripheral neuroblastic tumours. PHOXB2 plays an important role in the diagnostics of these conditions.Genotyping of a PHOX2B pathogenic variant is required to establish a diagnosis of CCHS. In HSCR patients, PHOX2B immunohistochemical staining has proven to be a valuable tool in identifying this disease. Furthermore, PHOXB2 is a predisposition gene for neuroblastoma, in which PHOX2B immunohistochemical staining can be used as a highly sensitive and specific diagnostic marker. The utility of PHOX2B immunohistochemistry in pheochromocytoma and paraganglioma has also been studied but yields conflicting results.In this review, an overview is given of PHOX2B, its associated diseases and the usefulness of PHOX2B immunohistochemistry as a diagnostic tool.
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Proteínas de Homeodominio , Hipoventilación , Inmunohistoquímica , Neuroblastoma , Factores de Transcripción , Humanos , Proteínas de Homeodominio/genética , Factores de Transcripción/genética , Hipoventilación/congénito , Hipoventilación/diagnóstico , Hipoventilación/genética , Neuroblastoma/diagnóstico , Neuroblastoma/genética , Neuroblastoma/patología , Apnea Central del Sueño/diagnóstico , Apnea Central del Sueño/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Enfermedad de Hirschsprung/diagnóstico , Enfermedad de Hirschsprung/genética , Enfermedad de Hirschsprung/patología , Mutación , Neoplasias de las Glándulas Suprarrenales/genética , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Neoplasias de las Glándulas Suprarrenales/patología , Predisposición Genética a la EnfermedadRESUMEN
Non-small cell lung cancer (NSCLC) is known for high relapse rates despite resection in early stages. Here, we present the results of a phase I clinical trial in which a dendritic cell (DC) vaccine targeting patient-individual neoantigens is evaluated in patients with resected NSCLC. Vaccine manufacturing is feasible in six of 10 enrolled patients. Toxicity is limited to grade 1-2 adverse events. Systemic T cell responses are observed in five out of six vaccinated patients, with T cell responses remaining detectable up to 19 months post vaccination. Single-cell analysis indicates that the responsive T cell population is polyclonal and exhibits the near-entire spectrum of T cell differentiation states, including a naive-like state, but excluding exhausted cell states. Three of six vaccinated patients experience disease recurrence during the follow-up period of 2 years. Collectively, these data support the feasibility, safety, and immunogenicity of this treatment in resected NSCLC.
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Antígenos de Neoplasias , Vacunas contra el Cáncer , Carcinoma de Pulmón de Células no Pequeñas , Diferenciación Celular , Células Dendríticas , Neoplasias Pulmonares , Linfocitos T , Vacunación , Humanos , Células Dendríticas/inmunología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Vacunas contra el Cáncer/inmunología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Masculino , Femenino , Persona de Mediana Edad , Antígenos de Neoplasias/inmunología , Diferenciación Celular/inmunología , Anciano , Linfocitos T/inmunologíaRESUMEN
Inflammatory myofibroblastic tumor (IMT) of the biliary tract is rare, and often difficult to diagnose or to distinguish from other tumors due to its atypical clinical presentation and nonspecific radiological features. Histologically, IMTs are (myo)fibroblastic neoplasms with a prominent inflammatory infiltrate. They are characterized by receptor tyrosine kinase gene rearrangements, most often involving an anaplastic lymphoma kinase (ALK) translocation. The final diagnosis of IMT depends on histopathology and immunohistochemical examination. In this manuscript, we provide a clinical and morphomolecular overview of IMT and the difficulties that may arise in using immunohistochemical and molecular techniques in diagnosing IMT.
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Since the introduction of new molecular techniques, the diagnostic landscape of soft tissue and bone tumors has expanded greatly over the past few years. The use of new molecular techniques has led to the identification of new genetic alterations and, therefore, to a better understanding of tumorigenesis, tumor detection and classification. Furthermore, methylation profiling has emerged as a classification tool for soft tissue and bone tumors. Molecular pathology also plays an important role in the determination of patient prognosis and in the identification of targets that can be used for targeted therapy. As a result, molecular pathology has gained a more prominent role in the daily practice of the surgical pathologist. This review delves into various molecular techniques applied in the surgical pathology of soft tissue and bone tumors. It highlights their applications through the analysis of five specific cases.
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Neoplasias Óseas , Neoplasias de los Tejidos Blandos , Humanos , Neoplasias de los Tejidos Blandos/diagnóstico , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/patología , Mutación , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/genética , Pronóstico , Patología MolecularRESUMEN
We report an exceptional case of an undifferentiated round and spindle cell sarcoma, occurring in the periprostatic region of a 54-year-old male, with a 'high-grade endometrial stromal sarcoma-like' (HG-ESS) morphology and harboring a ZC3H7B::BCOR gene fusion identified by RNA-based next-generation sequencing. In this report, we describe the striking overlap of morphologic, immunohistochemical and molecular features of this current case and previously reported similar cases with ZC3H7B::BCOR fusion-positive HG-ESS, and discuss the differential diagnosis and possible pathogenesis of this unusual entity.
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Neoplasias Endometriales , Sarcoma Estromático Endometrial , Sarcoma , Femenino , Masculino , Humanos , Persona de Mediana Edad , Neoplasias Endometriales/patología , Sarcoma Estromático Endometrial/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Sarcoma/diagnóstico , Sarcoma/genéticaRESUMEN
AIMS: PRRX1-rearranged mesenchymal tumours are a recently identified and rare subgroup of soft tissue neoplasms with distinct morphological features and genetic alterations. This study aims to further investigate the immunohistochemical profile and underlying genetic alterations in these tumours in order to get more insight on their underlying biology and the unique profile of these tumours. METHODS: Two new molecular confirmed cases of PRRX1-rearranged mesenchymal tumours were thoroughly studied with immunohistochemical stainings (RB1, CD34, ALK and pan-TRK), fluorescence in situ hybridisation (FISH) RB1/13q12 and RNA-based next-generation sequencing. RESULTS: Both cases exhibited typical morphological and molecular features, confirming the diagnosis of PRRX1-rearranged mesenchymal tumours. Immunohistochemistry revealed RB1 loss in both cases, which was subsequently confirmed through FISH analysis. Additionally, one case showed focal positivity for CD34, ALK and pan-TRK on immunohistochemistry. CONCLUSIONS: We identified loss of RB1 in two cases of PRRX1-rearranged mesenchymal tumours. This could suggest a potential association with RB1-deficient soft tissue tumours, although further research is necessary. Furthermore, the finding of focal positivity for CD34, ALK and pan-TRK on immunohistochemistry enriches the immunohistochemical profile of these tumours.
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Hydroxylase inhibitors stabilize hypoxia-inducible factor-1 (HIF-1), which has barrier-protective activity in the gut. Because the inflammatory cytokine TNF-α contributes to inflammatory bowel disease in part by compromising intestinal epithelial barrier integrity, hydroxylase inhibition may have beneficial effects in TNF-α-induced intestinal epithelial damage. The hydroxylase inhibitor dimethyloxalylglycin (DMOG) was tested in a murine model of TNF-α-driven chronic terminal ileitis. DMOG-treated mice experienced clinical benefit and showed clear attenuation of chronic intestinal inflammation compared with that of vehicle-treated littermates. Additional in vivo and in vitro experiments revealed that DMOG rapidly restored terminal ileal barrier function, at least in part through prevention of TNF-α-induced intestinal epithelial cell apoptosis. Subsequent transcriptional studies indicated that DMOG repressed Fas-associated death domain protein (FADD), a critical adaptor molecule in TNFR-1-mediated apoptosis, in an HIF-1α-dependent manner. Loss of this FADD repression by HIF-1α-targeting small interfering RNA significantly diminished the antiapoptotic action of DMOG. Additional molecular studies led to the discovery of a previously unappreciated HIF-1 binding site in the FADD promoter, which controls repression of FADD during hypoxia. As such, the results reported in this study allowed the identification of an innate mechanism that protects intestinal epithelial cells during (inflammatory) hypoxia, by direct modulation of death receptor signaling. Hydroxylase inhibition could represent a promising alternative treatment strategy for hypoxic inflammatory diseases, including inflammatory bowel disease.
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Inhibidores Enzimáticos/farmacología , Proteína de Dominio de Muerte Asociada a Fas/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Mucosa Intestinal/metabolismo , Oxigenasas de Función Mixta/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/metabolismo , Aminoácidos Dicarboxílicos/farmacología , Animales , Western Blotting , Hipoxia de la Célula/genética , Hipoxia de la Célula/inmunología , Inmunoprecipitación de Cromatina , Ensayo de Inmunoadsorción Enzimática , Proteína de Dominio de Muerte Asociada a Fas/genética , Regulación de la Expresión Génica/genética , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Ileítis/genética , Ileítis/metabolismo , Inmunidad Mucosa/genética , Inmunidad Mucosa/inmunología , Inmunohistoquímica , Mucosa Intestinal/patología , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Regiones Promotoras Genéticas/genética , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
BACKGROUND: Composition changes of extracellular matrix (ECM) can lead to functional disorders of the upper airways (UA). The aim of this study was to systematically measure both the association patterns and the correlation degree between tissue composition parameters in UA inflammatory diseases. METHODOLOGY: Nasal samples were obtained from patients with chronic rhinosinusitis with (CRS+NP), without nasal polyps (CRS), with post-operative adhesions (S) and normal nasal mucosa (NM). A reproducible semi-quantitative method, which takes epithelial and lamina propria damages into account was applied for haematoxylin and eosin, alpha-smooth muscle actin, reticulin, elastin, laminin and collagen type IV stainings. RESULTS: The most severe cases of epithelial shedding have been found in a significant higher amount in CRS+NP when compared with NM. The most severe cases of inflammatory reaction were mainly found in CRS+NP. CRS+NP had significantly more severe cases of oedema than NM. Excluding elastin, networks in other ECM proteins were found modified in fibrotic fields but to a lesser extend in oedematous regions in all conditions. CONCLUSION: Although non specific, oedema in the lamina propria is a key-feature of CRS+NP, while fibrosis, massively present in CRS and S, affects profoundly the distribution of ECM proteins in these areas.
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Pólipos Nasales/metabolismo , Rinitis/metabolismo , Sinusitis/metabolismo , Actinas/metabolismo , Adolescente , Adulto , Enfermedad Crónica , Colágeno Tipo IV/metabolismo , Tejido Conectivo/metabolismo , Edema/metabolismo , Elastina/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Femenino , Fibrosis , Humanos , Inmunohistoquímica , Laminina/metabolismo , Masculino , Persona de Mediana Edad , Mucosa Nasal/metabolismo , Reticulina/metabolismo , Adulto JovenRESUMEN
The evaluation of tumor-infiltrating lymphocytes (TILs) has received global attention as a promising prognostic cancer biomarker that can aid in clinical decision making. Proof of their significance was first shown in breast cancer, where TILs are now recommended in the classification of breast tumors. Emerging evidence indicates that the significance of TILs extends to other cancer types, including head and neck cancer. In the era of immunotherapy as a treatment choice for head and neck cancer, assessment of TILs and immune checkpoints is of high clinical relevance. The availability of the standardized method from the International Immuno-oncology Biomarker Working Group (IIBWG) is an important cornerstone toward standardized assessment. The aim of the current article is to summarize the accumulated evidence and to establish a clear premise for future research toward the implementation of TILs in the personalized management of head and neck squamous cell carcinoma patients.
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BACKGROUND: The clinical significance of tumor-infiltrating lymphocytes (TILs) and programmed cell death-ligand 1 (PD-L1) expression has been thoroughly researched in squamous cell carcinoma of the head and neck (SCCHN). To address the impact of intra- and intertumoral heterogeneity in these biomarkers, we explored the concordance of PD-L1 combined positive score (CPS) and stromal TILs in different paired tissue sample types, while evaluating their internal relationship and prognostic impact. METHODS: A total of 165 tissue blocks from 80 SCCHN patients were reviewed for TILs and PD-L1 CPS. Concordance between paired tissue samples was evaluated, and their association with several clinicopathological variables, overall survival (OS), and disease-free survival (DFS) was determined. RESULTS: Biopsies and paired resection material were severely discordant in 39% and 34% of samples for CPS and TIL count, respectively, of which CPS was underscored in 27% of biopsies. In paired primary tumor-metastatic lesions, the disagreement was lower for CPS (19%) but not for TIL count (44%). PD-L1 CPS was correlated with prolonged OS when calculated from tissue acquirement, while extended OS and DFS were observed for high TIL density. CONCLUSION: Intertumoral and, especially, intratumoral heterogeneity were confounding factors when determining PD-L1 CPS and TIL count on paired tissue samples, indicating the increasing necessity of assessing both biomarkers on representative tissue material. Although TILs hold valuable prognostic information in SCCHN, the robustness of PD-L1 as a biomarker in SCCHN remains ambiguous.