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BACKGROUND & AIMS: Patients with early-onset colorectal cancer (eoCRC) are managed according to guidelines that are not age-specific. A multidisciplinary international group (DIRECt), composed of 69 experts, was convened to develop the first evidence-based consensus recommendations for eoCRC. METHODS: After reviewing the published literature, a Delphi methodology was used to draft and respond to clinically relevant questions. Each statement underwent 3 rounds of voting and reached a consensus level of agreement of ≥80%. RESULTS: The DIRECt group produced 31 statements in 7 areas of interest: diagnosis, risk factors, genetics, pathology-oncology, endoscopy, therapy, and supportive care. There was strong consensus that all individuals younger than 50 should undergo CRC risk stratification and prompt symptom assessment. All newly diagnosed eoCRC patients should receive germline genetic testing, ideally before surgery. On the basis of current evidence, endoscopic, surgical, and oncologic treatment of eoCRC should not differ from later-onset CRC, except for individuals with pathogenic or likely pathogenic germline variants. The evidence on chemotherapy is not sufficient to recommend changes to established therapeutic protocols. Fertility preservation and sexual health are important to address in eoCRC survivors. The DIRECt group highlighted areas with knowledge gaps that should be prioritized in future research efforts, including age at first screening for the general population, use of fecal immunochemical tests, chemotherapy, endoscopic therapy, and post-treatment surveillance for eoCRC patients. CONCLUSIONS: The DIRECt group produced the first consensus recommendations on eoCRC. All statements should be considered together with the accompanying comments and literature reviews. We highlighted areas where research should be prioritized. These guidelines represent a useful tool for clinicians caring for patients with eoCRC.
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Neoplasias Colorrectales , Endoscopía , Humanos , Pruebas Genéticas , Neoplasias Colorrectales/diagnósticoRESUMEN
BACKGROUND/OBJECTIVES: Death domain-associated protein (DAXX) and/or α-thalassemia/mental retardation X-linked (ATRX) chromatin remodeling genes mutations and alternative lengthening of telomeres (ALT) activation are associated with more aggressive behavior of non-functional pancreatic neuroendocrine tumors (NF-PanNETs). We aimed to evaluate the reliability of such markers on endoscopic-ultrasound fine-needle biopsy (EUS-FNB) specimens. METHODS: Patients who underwent EUS-FNB and subsequent surgical resection for PanNETs between January 2017 and December 2019 were retrospectively identified. Immunohistochemistry (IHC) to evaluate DAXX/ATRX expression and fluorescence in situ hybridization (FISH) for ALT status were performed. Primary outcome was the concordance rate of markers expression between EUS-FNB and surgical specimens. Secondary aims were association between markers and lesion aggressiveness, their diagnostic performance in predicting aggressiveness, and agreement of preoperative and post-surgical Ki67-based grading. RESULTS: Forty-one NF-PanNETs (mean diameter 36.1 ± 26.5 mm) were included. Twenty-four showed features of lesion aggressiveness. Concordance of expressions of DAXX, ATRX, and ALT status between EUS-FNB and surgical specimens were 95.1% (κ = 0.828; p < 0.001), 92.7% (κ = 0.626; p < 0.001), and 100% (κ = 1; p < 0.001), respectively. DAXX/ATRX loss and ALT-positivity were significantly (p < 0.05) associated with metastatic lymphnodes and lymphovascular invasion. The combination of all tumor markers (DAXX/ATRX loss + ALT-positivity + grade 2) reached an accuracy of 73.2% (95%CI 57.1-85.8) in identifying aggressive lesions. Pre- and post-operative ki-67-based grading was concordant in 80.5% of cases (k = 0.573; p < 0.001). CONCLUSION: DAXX/ATRX expression and ALT status can be accurately evaluated in a preoperative setting on EUS-FNB samples, potentially improving the identification of patients with increased risk and poorer prognosis.
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Discapacidad Intelectual , Tumores Neuroendocrinos , Neoplasias Pancreáticas , Talasemia alfa , Humanos , Proteína Nuclear Ligada al Cromosoma X/genética , Proteína Nuclear Ligada al Cromosoma X/metabolismo , Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/cirugía , Estudios Retrospectivos , Biopsia con Aguja Fina , Hibridación Fluorescente in Situ , Reproducibilidad de los Resultados , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/cirugía , Telómero/genética , Telómero/metabolismo , Telómero/patología , Chaperonas Moleculares/genética , Proteínas Co-Represoras/genéticaRESUMEN
Target-oriented agents improve metastatic colorectal cancer (mCRC) survival in combination with chemotherapy. However, the majority of patients experience disease progression after first-line treatment and are eligible for second-line approaches. In such a context, antiangiogenic and anti-Epidermal Growth Factor Receptor (EGFR) agents as well as immune checkpoint inhibitors have been approved as second-line options, and RAS and BRAF mutations and microsatellite status represent the molecular drivers that guide therapeutic choices. Patients harboring K- and N-RAS mutations are not eligible for anti-EGFR treatments, and bevacizumab is the only antiangiogenic agent that improves survival in combination with chemotherapy in first-line, regardless of RAS mutational status. Thus, the choice of an appropriate therapy after the progression to a bevacizumab or an EGFR-based first-line treatment should be evaluated according to the patient and disease characteristics and treatment aims. The continuation of bevacizumab beyond progression or its substitution with another anti-angiogenic agents has been shown to increase survival, whereas anti-EGFR monoclonals represent an option in RAS wild-type patients. In addition, specific molecular subgroups, such as BRAF-mutated and Microsatellite Instability-High (MSI-H) mCRCs represent aggressive malignancies that are poorly responsive to standard therapies and deserve targeted approaches. This review provides a critical overview about the state of the art in mCRC second-line treatment and discusses sequential strategies according to key molecular biomarkers.
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Neoplasias Colorrectales/terapia , Medicina de Precisión/métodos , Proteínas ras/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores Farmacológicos/química , Biomarcadores Farmacológicos/metabolismo , Ensayos Clínicos Fase III como Asunto , Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Humanos , Mutación , Ensayos Clínicos Controlados Aleatorios como Asunto , Proteínas ras/metabolismoRESUMEN
The 2019 WHO classification of digestive system tumors significantly reformed the classificatory definition of serrated lesions of the colorectal mucosa and added new essential diagnostic criteria for both conventional adenomas and hereditary gastrointestinal polyposis syndromes. Histopathological examination of colorectal adenocarcinoma precursors lesions represents an important segment of daily clinical practice in a pathology department and is essential for the implementation of current colorectal adenocarcinoma secondary prevention strategies. This overview will focus on a schematic histopathological and molecular classification of precursor lesions arising within colorectal mucosa.
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Adenocarcinoma , Adenoma , Pólipos del Colon , Neoplasias Colorrectales , Adenocarcinoma/genética , Adenoma/genética , Pólipos del Colon/genética , Neoplasias Colorrectales/genética , Humanos , MutaciónRESUMEN
PURPOSE: The impact of acute histopathological changes (HC) of the rectum on development of late clinical proctitis (LCP) after external radiotherapy (RT) for prostate cancer is poorly explored and was the primary end point of this prospective study. METHODS: In 70 patients, 15 HC of early rectal biopsies after RT were identified, whereby RT was conventional 2D RT in 41 cases and conformational 3D RT in 29. Associations of HC in anterior and posterior rectal walls (ARW, PRW) with LCP, acute endoscopic (AEP) and acute clinical proctitis (ACP) were statistically evaluated considering as explicative variables the patient general characteristics and the HC. RESULTS: The mean patients' follow-up was 123.5 months (24-209). The median prostatic dose was 72â¯Gy (2â¯Gy/fraction). For the 41 and 29 patients the ARW and PRW doses were 64 and 49â¯Gy vs. 63 and 50â¯Gy, respectively. The incidence of LCPâ¯≥ grade 2â¯at 10 years was 12.9%. The univariate (pâ¯= 0.02) and Kaplan-Meyer methods (pâ¯= 0.007) showed that the gland (or crypts) loss in the ARW was significantly associated with LCP. AEP and ACP occurred in 14.3 and 55.7% of cases. At multivariate level AEP significantly correlated with hemorrhoids (pâ¯= 0.014) and neutrophilia in ARW (pâ¯= 0.042). CONCLUSIONS: Early after RT, substantial gland loss in ARW is predictive of LCP. To reduce this complication with conventional fractionation, we suggest keeping the mean dose to ARW ≤48-52â¯Gy.
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Adenocarcinoma/radioterapia , Órganos en Riesgo/efectos de la radiación , Proctitis/patología , Neoplasias de la Próstata/radioterapia , Traumatismos por Radiación/patología , Radioterapia Conformacional/efectos adversos , Radioterapia de Alta Energía/efectos adversos , Recto/efectos de la radiación , Enfermedad Aguda , Adenocarcinoma/cirugía , Anciano , Terapia Combinada , Fraccionamiento de la Dosis de Radiación , Relación Dosis-Respuesta en la Radiación , Estudios de Seguimiento , Humanos , Incidencia , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Órganos en Riesgo/patología , Proctitis/diagnóstico , Proctitis/epidemiología , Proctitis/etiología , Proctoscopía , Estudios Prospectivos , Prostatectomía , Neoplasias de la Próstata/cirugía , Traumatismos por Radiación/diagnóstico , Traumatismos por Radiación/epidemiología , Traumatismos por Radiación/etiología , Protección Radiológica/instrumentación , Dosificación Radioterapéutica , Radioterapia Conformacional/métodos , Radioterapia de Intensidad Modulada/efectos adversos , Recto/patología , Factores de TiempoRESUMEN
The pathologist emerged in the personalized medicine era as a central actor in the definition of the most adequate diagnostic and therapeutic algorithms. In the last decade, gastrointestinal oncology has seen a significantly increased clinical request for the integration of novel prognostic and predictive biomarkers in histopathological reports. This request couples with the significant contraction of invasive sampling of the disease, thus conferring to the pathologist the role of governor for both proper pathologic characterization and customized processing of the biospecimens. This overview will focus on the most commonly adopted immunohistochemical and molecular biomarkers in the routine clinical characterization of gastrointestinal neoplasms referring to the most recent published recommendations, guidelines and expert opinions.
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Neoplasias Gastrointestinales , Patología Molecular/métodos , Biomarcadores de Tumor , Neoplasias Gastrointestinales/diagnóstico , Neoplasias Gastrointestinales/patología , Humanos , Inmunohistoquímica , Terapia Molecular Dirigida , Medicina de Precisión/métodos , PronósticoRESUMEN
BACKGROUND AND AIMS: EUS-guided through-the-needle biopsy (TTNB) sampling has been reported to improve diagnostic yield compared with cytology for the evaluation of pancreatic cystic lesions (PCLs). The number of macroscopically visible tissue samples needed to reach an adequate diagnosis is still unknown. METHODS: This is a retrospective, single-center study on consecutive patients with PCLs with risk features (cyst >3 cm, thickened wall, cyst growth during follow-up, and mural nodules) who underwent TTNB sampling. The capability of differentiating mucinous versus nonmucinous cysts, ability to obtain a cyst-lining epithelium, definition of the grade of dysplasia, and specific diagnosis of cyst histotype were evaluated for 1, 2, or 3 TTNB macroscopically visible specimens. RESULTS: Sixty-one patients were evaluated. A 100% histologic adequacy was reached by 2 samples (P = .05 versus 1). Compared with cytology, 1 TTNB specimen improved the possibility of defining cyst histotype (P < .0001), whereas 2 specimens increased all 4 diagnostic categories (P < .003). Two specimens also increased diagnostic yield compared with 1 sample (P < .085). The collection of a third sample did not improve the value of any diagnostic categories. A specific diagnosis was reached in 74% of patients with 2 histologic samples. The diagnostic reliability of TTNB sampling compared with surgical histology was 90%, with a 22.9% rate of adverse events. CONCLUSIONS: Two TTNB macroscopically visible specimens reached 100% histologic adequacy and a specific diagnosis in 74% of patients. The collection of a third specimen did not add any additional information and should be avoided to possibly decrease the risk of adverse events.
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Biopsia por Aspiración con Aguja Fina Guiada por Ultrasonido Endoscópico/instrumentación , Quiste Pancreático/patología , Adulto , Anciano , Anciano de 80 o más Años , Diseño de Equipo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Estudios Retrospectivos , Instrumentos Quirúrgicos , Adulto JovenRESUMEN
Renal cell carcinomas with t(6;11) chromosome translocation involving the TFEB gene are indolent neoplasms which often occur in young patients. In this study, we report seven cases of renal cell carcinoma with TFEB rearrangement, two of whom had histologically proven metastasis. Patients (4F, 3M) ranged in age from 19 to 55 years (mean 37). One patient developed paratracheal and pleural metastases 24 months after surgery and died of disease after 46 months; another one recurred with neoplastic nodules in the perinephric fat and pelvic soft tissue. Histologically, either cytological or architectural appearance was peculiar in each case whereas one tumor displayed the typical biphasic morphology. By immunohistochemistry, all tumors labelled for cathepsin K, Melan-A and CD68 (KP1 clone). HMB45 and PAX8 staining were detected in six of seven tumors. All tumors were negative for CD68 (PG-M1 clone), CKAE1-AE3, CK7, CAIX, and AMACR. Seven pure epithelioid PEComa/epithelioid angiomyolipomas, used as control, were positive for cathepsin K, melanocytic markers, and CD68 (PG-M1 and KP1) and negative for PAX8. Fluorescence in situ hybridization results showed the presence of TFEB gene translocation in all t(6;11) renal cell carcinomas with a high frequency of split TFEB fluorescent signals (mean 74%). In the primary and metastatic samples of the two aggressive tumors, increased gene copy number was observed (3-5 fluorescent signals per neoplastic nuclei) with a concomitant increased number of CEP6. Review of the literature revealed older age and larger tumor size as correlating with aggressive behavior in these neoplasms. In conclusion, we present the clinical, morphological and molecular features of seven t(6;11) renal cell carcinomas, two with histologically demonstrated metastasis. We report the high frequency of split signals by FISH in tumors with t(6;11) chromosomal rearrangement and the occurrence of TFEB gene copy number gains in the aggressive cases, analyzing either the primary or metastatic tumor. Finally, we demonstrate the usefulness of CD68 (PG-M1) immunohistochemical staining in distinguishing t(6;11) renal cell carcinoma from pure epithelioid PEComa/epithelioid angiomyolipoma.
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Antígenos CD/análisis , Antígenos de Diferenciación Mielomonocítica/análisis , Biomarcadores de Tumor/análisis , Carcinoma de Células Renales/química , Carcinoma de Células Renales/secundario , Neoplasias Renales/química , Neoplasias Renales/patología , Adulto , Angiomiolipoma/química , Angiomiolipoma/patología , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Carcinoma de Células Renales/genética , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 6/genética , Diagnóstico Diferencial , Femenino , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Neoplasias Renales/genética , Masculino , Persona de Mediana Edad , Neoplasias de Células Epitelioides Perivasculares/química , Neoplasias de Células Epitelioides Perivasculares/patología , Translocación GenéticaAsunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis , Neoplasias Colorrectales , Humanos , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales/genética , Mutación , Homólogo 1 de la Proteína MutL/genética , Metilación de ADN , Inestabilidad de Microsatélites , Reparación de la Incompatibilidad de ADNRESUMEN
AIMS: PD-1/PD-L1 checkpoint immunotherapy has been proposed recently as a promising treatment in relapsed/refractory disease, used eventually in combination with traditional chemotherapy in different cancer settings. To date, no data are available concerning PD-L1 expression in ampulla of Vater carcinoma and its pre-invasive lesions. METHODS AND RESULTS: We assessed the immunohistochemical expression of PD-L1 in a series of 26 ampullary adenocarcinomas, 50 ampullary dysplastic lesions and 10 normal duodenal mucosa samples. Moreover, in all cases DNA mismatch repair proteins status was investigated. PD-L1 was expressed in seven of 26 (26.9%) invasive carcinomas and three of 50 (6.0%) dysplastic samples. Most of the PD-L1-positive tumours (seven of 10) were intestinal-type and poorly differentiated (G3). The number of PD-L1-positive stromal lymphoid cells was significantly higher in dysplastic and invasive lesions than in the normal samples (P = 0.011). Nineteen dysplastic lesions and eight invasive carcinomas did not show any evident epithelial or stromal PD-L1 expression. Four of the carcinomas were mismatch repair-deficient and two of these were PD-L1-positive. Furthermore, mismatch repair-deficient lesions showed a significantly higher average of PD-L1-positive stromal lymphoid cells than those of neoplastic PD-L1-negative samples (62.8 versus 21.6; P < 0.001). CONCLUSIONS: The present results suggest a role of the PD-1/PD-L1 axis in ampullary adenocarcinomas, and therefore this may also prompt consideration of checkpoint immunotherapy as a novel promising treatment for these tumours.
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Adenocarcinoma/patología , Ampolla Hepatopancreática/patología , Antígeno B7-H1/biosíntesis , Biomarcadores de Tumor/análisis , Adenocarcinoma/inmunología , Adulto , Anciano , Ampolla Hepatopancreática/inmunología , Antígeno B7-H1/análisis , Biomarcadores de Tumor/inmunología , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/patología , Neoplasias del Conducto Colédoco/inmunología , Neoplasias del Conducto Colédoco/patología , Neoplasias Duodenales/inmunología , Neoplasias Duodenales/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Lesiones Precancerosas/inmunología , Lesiones Precancerosas/patologíaRESUMEN
BACKGROUND: Inflammatory breast cancer (IBC) is the most rare and aggressive variant of breast cancer (BC); however, only a limited number of specific gene signatures with low generalization abilities are available and few reliable biomarkers are helpful to improve IBC classification into a molecularly distinct phenotype. We applied a network-based strategy to gain insight into master regulators (MRs) linked to IBC pathogenesis. METHODS: In-silico modeling and Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNe) on IBC/non-IBC (nIBC) gene expression data (n = 197) was employed to identify novel master regulators connected to the IBC phenotype. Pathway enrichment analysis was used to characterize predicted targets of candidate genes. The expression pattern of the most significant MRs was then evaluated by immunohistochemistry (IHC) in two independent cohorts of IBCs (n = 39) and nIBCs (n = 82) and normal breast tissues (n = 15) spotted on tissue microarrays. The staining pattern of non-neoplastic mammary epithelial cells was used as a normal control. RESULTS: Using in-silico modeling of network-based strategy, we identified three top enriched MRs (NFAT5, CTNNB1 or ß-catenin, and MGA) strongly linked to the IBC phenotype. By IHC assays, we found that IBC patients displayed a higher number of NFAT5-positive cases than nIBC (69.2% vs. 19.5%; p-value = 2.79 10(-7)). Accordingly, the majority of NFAT5-positive IBC samples revealed an aberrant nuclear expression in comparison with nIBC samples (70% vs. 12.5%; p-value = 0.000797). NFAT5 nuclear accumulation occurs regardless of WNT/ß-catenin activated signaling in a substantial portion of IBCs, suggesting that NFAT5 pathway activation may have a relevant role in IBC pathogenesis. Accordingly, cytoplasmic NFAT5 and membranous ß-catenin expression were preferentially linked to nIBC, accounting for the better prognosis of this phenotype. CONCLUSIONS: We provide evidence that NFAT-signaling pathway activation could help to identify aggressive forms of BC and potentially be a guide to assignment of phenotype-specific therapeutic agents. The NFAT5 transcription factor might be developed into routine clinical practice as a putative biomarker of IBC phenotype.
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Regulación Neoplásica de la Expresión Génica , Neoplasias Inflamatorias de la Mama/metabolismo , Biología de Sistemas/métodos , Factores de Transcripción/metabolismo , Algoritmos , Biomarcadores de Tumor , Ciclo Celular , Estudios de Cohortes , Biología Computacional , Femenino , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Inmunohistoquímica , Análisis de Secuencia por Matrices de Oligonucleótidos , Fenotipo , beta Catenina/metabolismoRESUMEN
BACKGROUND: INI1 (Integrase interactor 1), also known as SMARCB1, is the most studied subunit of chromatin remodelling complexes. Its role in colorectal tumorigenesis is not known. METHODS: We examined SMARCB1/INI1 protein expression in 134 cases of colorectal cancer (CRC) and 60 matched normal mucosa by using tissue microarrays and western blot and categorized the results according to mismatch repair status (MMR), CpG island methylator phenotype, biomarkers of tumor differentiation CDX2, CK20, vimentin and p53. We validated results in two independent data sets and in cultured CRC cell lines. RESULTS: Herein, we show that negative SMARCB1/INI1 expression (11% of CRCs) associates with loss of CDX2, poor differentiation, liver metastasis and shorter patients' survival regardless of the MMR status or tumor stage. Unexpectedly, even CRCs displaying diffuse nuclear INI1 staining (33%) show an adverse prognosis and vimentin over-expression, in comparison with the low expressing group (56%). The negative association of SMARCB1/INI1-lack of expression with a metastatic behavior is enhanced by the TP53 status. By interrogating global gene expression from two independent cohorts of 226 and 146 patients, we confirm the prognostic results and identify a gene signature characterized by SMARCB1/INI1 deregulation. Notably, the top genes of the signature (BCR, COMT, MIF) map on the long arm of chromosome 22 and are closely associated with SMARCB1/INI1. CONCLUSION: Our findings suggest that SMARCB1/INI1-dysregulation and genetic hot-spots on the long arm of chromosome 22 might play an important role in the CRC metastatic behavior and be clinically relevant as novel biomarkers.
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Ensamble y Desensamble de Cromatina/genética , Proteínas Cromosómicas no Histona/metabolismo , Cromosomas Humanos Par 22/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Proteínas de Unión al ADN/metabolismo , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Factores de Transcripción/metabolismo , Anciano , Biomarcadores de Tumor/metabolismo , Diferenciación Celular , Proteínas Cromosómicas no Histona/genética , Estudios de Cohortes , Proteínas de Unión al ADN/genética , Femenino , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/secundario , Masculino , Pronóstico , Proteína SMARCB1 , Análisis de Supervivencia , Análisis de Matrices Tisulares , Factores de Transcripción/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Dasatinib is a second-generation multityrosine kinase inhibitor used in the first-line and second-line treatment of Philadelphia chromosome-positive leukaemia. The most frequent type of Dasatinib-induced intestinal injury is haemorrhagic colitis; other morphologic patterns include apoptotic colopathy, CD8+ T-cell-mediated colitis and non-specific colitis. Aim of this study is to describe a novel Crohn's-like histopathologic pattern of Dasatinib-induced colitis. Four patients developed diarrhoea during Dasatinib treatment; colonoscopy was performed and biopsy sets were taken for histological analysis. All patients showed patchy, chronic active inflammation with cryptitis and microgranulomas (two patients). Ileal and rectal biopsies showed either no or mild, focal inflammation. An increase in lamina propria eosinophils was seen (two patients) and apoptoses were seen (three patients). Complete remission was observed after interruption of treatment. Dasatinib-induced colitis and Crohn's disease may share histologic features including microgranulomas, which can potentially lead to misdiagnosis if no information on treatment is provided.
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Colitis Ulcerosa , Colitis , Enfermedad de Crohn , Humanos , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/patología , Dasatinib/efectos adversos , Colitis/inducido químicamente , Colitis/diagnóstico , Colitis/patología , Inflamación/patología , Biopsia , Colitis Ulcerosa/patología , Mucosa Intestinal/patologíaRESUMEN
Ribonucleoprotein (RNP) condensates are crucial for controlling RNA metabolism and splicing events in animal cells. We used spatial proteomics and transcriptomic to elucidate RNP interaction networks at the centrosome, the main microtubule-organizing center in animal cells. We found a number of cell-type specific centrosome-associated spliceosome interactions localized in subcellular structures involved in nuclear division and ciliogenesis. A component of the nuclear spliceosome BUD31 was validated as an interactor of the centriolar satellite protein OFD1. Analysis of normal and disease cohorts identified the cholangiocarcinoma as target of centrosome-associated spliceosome alterations. Multiplexed single-cell fluorescent microscopy for the centriole linker CEP250 and spliceosome components including BCAS2, BUD31, SRSF2 and DHX35 recapitulated bioinformatic predictions on the centrosome-associated spliceosome components tissue-type specific composition. Collectively, centrosomes and cilia act as anchor for cell-type specific spliceosome components, and provide a helpful reference for explore cytoplasmic condensates functions in defining cell identity and in the origin of rare diseases.
RESUMEN
A rhabdoid colorectal tumor (RCT) is a rare cancer with aggressive clinical behavior. Recently, it has been recognized as a distinct disease entity, characterized by genetic alterations in the SMARCB1 and Ciliary Rootlet Coiled-Coil (CROCC). We here investigate the genetic and immunophenotypic profiling of 21 RCTs using immunohistochemistry and next-generation sequencing. Mismatch repair-deficient phenotypes were identified in 60% of RCTs. Similarly, a large proportion of cancers exhibited the combined marker phenotype (CK7-/CK20-/CDX2-) not common to classical adenocarcinoma variants. More than 70% of cases displayed aberrant activation of the mitogen-activated protein kinase (MAPK) pathway with mutations prevalently in BRAF V600E. SMARCB1/INI1 expression was normal in a large majority of lesions. In contrast, ciliogenic markers including CROCC and γ-tubulin were globally altered in tumors. Notably, CROCC and γ-tubulin were observed to colocalize in large cilia found on cancer tissues but not in normal controls. Taken together, our findings indicate that primary ciliogenesis and MAPK pathway activation contribute to the aggressiveness of RCTs and, therefore, may constitute a novel therapeutic target.
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Cilios , Neoplasias Colorrectales , Humanos , Cilios/genética , Cilios/metabolismo , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Quinasas Activadas por Mitógenos/genética , Tubulina (Proteína) , Neoplasias Colorrectales/patología , Proteínas del CitoesqueletoRESUMEN
BACKGROUND: Adult pancreatoblastoma (PBL) is a rare pancreatic malignancy, with recent evidence suggesting a possible link to familial adenomatous polyposis (FAP). This study aims to review the latest evidence and explore a possible association between adult PBL and FAP. METHODS: Two independent literature reviews were conducted: (1) on PBL and FAP, and (2) on PBL in the adult population not diagnosed with FAP. RESULTS: Out of 26 articles on PBL and FAP screened, 5 were selected for systematic review, including 1 additional case. We identified eight FAP-related PBL cases, with a median age of 40 (IQR: 34-50). Of these, seven (87%) occurred in adults. We found 65 cases of adult PBL not FAP-related; thus, 7 out of 65 cases (10.7%) of adult PBL reported in the literature are associated with a clinical diagnosis of FAP or were carriers of APC germline pathogenic variants (GPVs). CONCLUSION: Data suggest a non-random association between adult PBL and FAP. Further research is essential to optimise surveillance protocols and develop more effective treatment strategies.
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Poliposis Adenomatosa del Colon , Neoplasias Pancreáticas , Adulto , Humanos , Poliposis Adenomatosa del Colon/genética , Mutación de Línea Germinal , Neoplasias Pancreáticas/epidemiología , Neoplasias Pancreáticas/genéticaRESUMEN
BACKGROUND & AIMS: Multiple colorectal adenomas (MCRAs) can result from APC (AFAP) or biallelic MUTYH (MAP) mutations, but most patients are wild type and referred to as non-APC/MUTYH polyposis (NAMP). We aim to examine the risk of colorectal cancer (CRC) and the role of endoscopy in managing patients with MCRAs, with a specific focus on clinical features and genotype. METHODS: Records of MRCAs between 2000 and 2022 were retrospectively analysed. Patients were divided according to the genotype (MAP vs. NAMP) and the number of categorised polyps' burden (group 1: 10-24, group 2: 25-49, and group 3: 50-99 adenomas). Predictors of outcome were CRC-free survival (CRC-FS) and Surgery free-survival (S-FS). RESULTS: 220 patients were enrolled (NAMP n = 178(80.0%)). CRC at diagnosis was more frequent in group 3 (p = 0.01), without significant differences between the genotypes (p = 0.20). At a follow-up of 83(41-164) months, 15(7%) patients developed CRC during surveillance. CRC-FS was not correlated to genotype (p = 0.07) or polyps' number (p = 0.33), while S-FS was similar in MAP and NAMP (p = 0.22) and lower in groups 2 and 3 (p = 0.0001). CONCLUSIONS: MAP and NAMP have the same CRC risk and no difference in treatment. Endoscopic surveillance compared favorably with surgery in avoiding CRC risk, even in patients with more severe colorectal polyposis.
RESUMEN
Organic (such as parasites or vegetable remnants) and inorganic substances may be encountered during routine pathology diagnostic work up of endoscopic gastrointestinal biopsy samples and major resections, causing possible diagnostic conundrums for the young and not so young pathologists. The main aim of this review is the description of the most frequent oddities one can encounter as foreign bodies, in gastrointestinal pathology, on the basis of the current literature and personal experience. The types of encountered substances are divided into four principal categories: parasites (helminths such as Enterobius vermicularis, Strongyloides, Schistosoma, and Anisakis, and protozoa such as Entamoeba, Giardia and some intestinal coccidia); drugs and pharmaceutical fillers (found as deposits and as bystanders, innocent or not); seeds (possibly confused with worms) and plant remnants; pollutants (secondary to post-resection or post-biopsy contamination of the sample). An ample library of images is provided in order to consent easy referencing for diagnostic routine.
Asunto(s)
Giardiasis , Parasitosis Intestinales , Animales , Enterobius , Giardia , Giardiasis/parasitología , Humanos , Parasitosis Intestinales/diagnóstico , Parasitosis Intestinales/parasitologíaRESUMEN
Metastasis is a process by which cancer cells escape from the location of the primary tumor invading normal tissues at distant organs. Chromosomal instability (CIN) is a hallmark of human cancer, associated with metastasis and therapeutic resistance. The centrosome plays a major role in organizing the microtubule cytoskeleton in animal cells regulating cellular architecture and cell division. Loss of centrosome integrity activates the p38-p53-p21 pathway, which results in cell-cycle arrest or senescence and acts as a cell-cycle checkpoint pathway. Structural and numerical centrosome abnormalities can lead to aneuploidy and CIN. New findings derived from studies on cancer and rare genetic disorders suggest that centrosome dysfunction alters the cellular microenvironment through Rho GTPases, p38, and JNK (c-Jun N-terminal Kinase)-dependent signaling in a way that is favorable for pro-invasive secretory phenotypes and aneuploidy tolerance. We here review recent data on how centrosomes act as complex molecular platforms for Rho GTPases and p38 MAPK (Mitogen activated kinase) signaling at the crossroads of CIN, cytoskeleton remodeling, and immune evasion via both cell-autonomous and non-autonomous mechanisms.
Asunto(s)
Centrosoma/metabolismo , Inflamación/patología , Metástasis de la Neoplasia/patología , Aneuploidia , Animales , Ciclo Celular/fisiología , Puntos de Control del Ciclo Celular/fisiología , Centrosoma/fisiología , Inestabilidad Cromosómica/fisiología , Citoesqueleto/fisiología , Humanos , Inflamación/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/genética , Sistema de Señalización de MAP Quinasas/fisiología , Microtúbulos/metabolismo , Metástasis de la Neoplasia/genética , Neoplasias/metabolismo , Transducción de Señal , Microambiente Tumoral , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/fisiología , Proteínas de Unión al GTP rho/metabolismoRESUMEN
Breast cancer is a complex and highly heterogeneous disease consisting of various subtypes. It is classified into human epidermal growth receptor 2 (HER-2)-enriched, luminal A, luminal B and basal-like/triple negative (TNBC) breast cancer, based on histological and molecular features. At present, clinical decision-making in breast cancer is focused only on the assessment of tumor cells; nevertheless, it has been recognized that the tumor microenvironment (TME) plays a critical biologic role in breast cancer. This is constituted by a large group of immune and non-immune cells, but also by non-cellular components, such as several cytokines. TME is deeply involved in angiogenesis, immune-evasion strategies, and propensity for early metastatic spread, impacting on prognosis and prediction of response to specific treatments. In this review, we focused our attention on the early morphological changes of tumor microenvironment (tumor vasculature features, presence of immune and non-immune cells infiltrating the stroma, levels of cytokines) during breast cancer development. At the same time, we correlate these characteristics with early metastatic propensity (defined as synchronous metastasis or early recurrence) with particular attention to breast cancer subtypes.