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OBJECTIVE: To develop and externally validate an updated artificial intelligence (AI) prediction system for stratifying the risk of lymph node metastasis (LNM) in T2 colorectal cancer (CRC). SUMMARY BACKGROUND DATA: Recent technical advances allow complete local excision of T2 CRC, traditionally treated with surgical resection. Yet, the widespread adoption of this approach is hampered by the inability to stratify the risk of LNM. METHODS: Data from pT2 CRC patients undergoing surgical resection between April 2000 and May 2022 at one Japanese and one Italian center were analyzed. Primary goal was AI system development for accurate LNM prediction. Predictors encompassed seven variables: age, sex, tumor size and location, lympho-vascular invasion, histological differentiation, and carcinoembryonic antigen level. The tool's discriminating power was assessed via Area Under the Curve (AUC), sensitivity, and specificity. RESULTS: Out of 735 initial patients, 692 were eligible. Training and validation cohorts comprised of 492 and 200 patients, respectively. The AI model displayed an AUC of 0.75 in the combined validation dataset. Sensitivity for LNM prediction was 97.8% and specificity was 15.6%. The Positive and the Negative Predictive Value were 25.7% and 96% respectively. The False Negative (FN) rate was 2.2%, the False Positive was 84.4%. CONCLUSIONS: Our AI model, based on easily accessible clinical and pathological variables, moderately predicts LNM in T2 CRC. However, the risk of FN needs to be considered. The training of the model including more patients across Western and Eastern centers -differentiating between colon and rectal cancers- may improve its performance and accuracy.
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BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is an aggressive disease with increasing incidence and its genetic alterations could be the target of systemic therapies. AIMS: To elucidate if radiomics extracted from computed tomography (CT) may non-invasively predict ICC genetic alterations. METHODS: All consecutive patients with a diagnosis of a mass-forming ICC (01/2016-06/2022) were considered. Inclusion criteria were availability of a high-quality contrast-enhanced CT and molecular profiling by NGS or FISH for FGFR2 fusion/rearrangement. The CT scan at diagnosis was considered. Genetic analyses were performed on surgical specimens (resectable patients) or biopsies (unresectable ones). The radiomic features were extracted using the LifeX software. Multivariate predictive models of the commonest genetic alterations were built. RESULTS: In the 90 enrolled patients (58 NGS/32 FISH, median age 65 years), the most common genetic alterations were FGFR2 (20/90), IDH1 (10/58), and KRAS (9/58). At internal validation, the combined clinical-radiomic models achieved the best performance for the prediction of FGFR2 (AUC = 0.892) and IDH1 status (AUC = 0.819), outperforming the pure clinical and radiomic models. The radiomic model for predicting KRAS mutations achieved an AUC = 0.767 (vs. 0.660 of the clinical model) without further improvements with the addition of clinical features. CONCLUSIONS: CT-based radiomics provides a reliable non-invasive prediction of ICC genetic status with a major impact on therapeutic strategies.
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BACKGROUND AND AIM: VETC (vessel that encapsulate tumor cluster) is a peculiar vascular phenotype observed in hepatocellular carcinoma (HCC), associated with distant metastases and poor outcome. VETC has been linked to the Tie2/Ang2 axis and is characterized by lymphocytes poor (cold) tumor microenvironment (TME). In this setting the role of Tumor Associated Macrophages (TAMs) has never been explored. Aim of the study is to investigate the presence and features of TAMs in VETC+ HCC and the possible interplay between TAMs and endothelial cells (ECs). METHODS: The series under study included 42 HCC. Once separated according to the VETC phenotype (21 VETC+; 21 VETC-) we stained consecutive slides with immunohistochemistry for CD68, CD163 and Tie2. Slides were then scanned and QuPath used to quantify morphological features. RESULTS: VETC+ cases were significantly (p < 0.001) enriched with large, lipid rich CD163+ TAMs (M2 oriented) that were spatially close to ECs; HCC cells significantly (p: 0.002) overexpressed Tie2 with a polarization toward ECs. CONCLUSIONS: The pro-metastatic attitude of VETC is sustained by a strict morphological relationship between immunosuppressive M2-TAMs, ECs and Tie2-expressing HCC cells.
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Different factors, not limited to the lung, influence the progression of ILDs. A "treatable trait" strategy was recently proposed for ILD patients as a precision model of care to improve outcomes. However, no data have been published so far on the prevalence of TTs in ILD. A prospective, observational, cohort study was conducted within the ILD Program at the IRCCS Humanitas Research Hospital (Milan, Italy) between November 2021 and November 2023. TTs were selected according to recent literature and assigned during multidisciplinary discussion (MDD) to one of the following categories: pulmonary, etiological, comorbidities, and lifestyle. Patients were further divided into four groups according to their post-MDD diagnosis: idiopathic ILD, sarcoidosis, connective tissue disease-ILD, and other ILD. The primary study outcome was the prevalence of each TT in the study population. A total of 116 patients with ILD [63.9% male; median (IQR) age: 69 (54-78) years] were included in the study. All the TTs identified in the literature were found in our cohort, except for intractable chronic cough. We also recognized differences in TTs across the ILD groups, with less TTs in patients with sarcoidosis. This analysis provides the first ancillary characterization of TTs in ILD patients in a real setting to date.
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The incidence of rectal cancer (RC) is increasing in the population aged ≤ 49 (early-onset RC-EORC). EORC patients are more likely to present with locally advanced disease at diagnosis than late-onset RC (LORC; aged ≥ 50) patients. As a consequence, more EORC patients undergo neoadjuvant therapies. The response to treatment in EORC patients is still unknown. This study aims to explore the effect of age of onset on the pathological response to neoadjuvant therapies in sporadic locally advanced RC (LARC) patients. Based on an institutional prospectively maintained database, LARC patients undergoing neoadjuvant therapies and radical surgery between January 2010 and December 2022 were allocated to the EORC and LORC groups. The primary endpoint was the rate of incomplete response (Dworak 0-2). A total of 326 LORC and 79 EORC patients were included. Pre-neoadjuvant tumor features were comparable. A significantly higher rate of incomplete response was observed in EORC patients (49% vs. 35%; p = 0.028). From multivariable analysis, early age of onset, smoking and extramural invasion presented as independent risk factors for a worse response. This study demonstrates that an early age of onset is related to a worse response and calls for different multimodal strategies in this group of patients.
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BACKGROUND & AIMS: AXL and MERTK expression on circulating monocytes modulated immune responses in patients with cirrhosis (CD14+HLA-DR+AXL+) and acute-on-chronic liver failure (CD14+MERTK+). AXL expression involved enhanced efferocytosis, sustained phagocytosis, but reduced tumor necrosis factor-α/interleukin-6 production and T-cell activation, suggesting a homeostatic function. Axl was expressed on murine airway in tissues contacting the external environment, but not interstitial lung- and tissue-resident synovial lining macrophages. Here, we assessed AXL expression on tissue macrophages in patients with cirrhosis. METHODS: Using multiplexed immunofluorescence we compared AXL expression in liver biopsies in cirrhosis (n = 22), chronic liver disease (n = 8), non-cirrhotic portal hypertension (n = 4), and healthy controls (n = 4). Phenotype and function of isolated primary human liver macrophages were characterized by flow cytometry (cirrhosis, n = 11; control, n = 14) ex vivo. Also, AXL expression was assessed on peritoneal (n = 29) and gut macrophages (n = 16) from cirrhotic patients. Regulation of AXL expression was analyzed in vitro and ex vivo using primary hepatic stellate cells (HSCs), LX-2 cells, and GAS6 in co-culture experiments. RESULTS: AXL was expressed on resident (CD68+) but not tissue-infiltrating (MAC387+) liver macrophages, hepatocytes, HSCs, or sinusoidal endothelial cells. Prevalence of hepatic CD68+AXL+ cells significantly decreased with cirrhosis progression: (healthy, 90.2%; Child-Pugh A, 76.1%; Child-Pugh B, 64.5%; and Child-Pugh C, 18.7%; all P < .05) and negatively correlated with Model for End-Stage Liver Disease and C-reactive protein (all P < .05). AXL-expressing hepatic macrophages were CD68highHLA-DRhighCD16highCD206high. AXL expression also decreased on gut and peritoneal macrophages from cirrhotic patients but increased in regional lymph nodes. GAS6, enriched in the cirrhotic liver, appeared to be secreted by HSCs and down-regulate AXL in vitro. CONCLUSIONS: Decreased AXL expression on resident liver macrophages in advanced cirrhosis, potentially in response to activated HSC-secreted GAS6, suggests a role for AXL in the regulation of hepatic immune homeostasis.
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Enfermedad Hepática en Estado Terminal , Células Estrelladas Hepáticas , Animales , Humanos , Ratones , Tirosina Quinasa c-Mer/metabolismo , Células Endoteliales/patología , Células Estrelladas Hepáticas/patología , Antígenos HLA-DR/metabolismo , Homeostasis , Cirrosis Hepática/patología , Macrófagos/metabolismo , Índice de Severidad de la Enfermedad , Tirosina Quinasa del Receptor Axl/metabolismoRESUMEN
Primary large B-cell lymphoma of immune-privileged sites (IP-LBCL) is a rare malignant hematological neoplasm. Involvement of the cerebellum is even rarer and its diagnosis is often difficult to make due to its non-specific clinical and radiological presentation. METHODS: We reported 3 cases of cerebellar IP-LBCL followed at our hospital and reviewed the medical literature to unravel the peculiarities of this poorly studied entity. OUTCOMES: Analyzing our cases and reviewing the literature, we could collect and study 26 cases of cerebellar IP-LBCL. To the best of our knowledge, this is the largest cohort of such patients currently published. CONCLUSION: Cerebellar IP-LBCL presents more often in adult females with cerebellum-related focal neurological signs such as ataxia, headache, and nausea. Histological confirmation is mandatory for a correct diagnosis and treatment and all cases feature diffuse large B-cell lymphoma histopathology. Compared to other encephalic IP-LBCL, cerebellar cases seem to include a higher number of cases with germinal center B-cell phenotype and better survival. These differences may be related to a different immune microenvironment and especially immunoregulation that distinguishes the cerebellum from other areas of the CNS.
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We here report the first case of anti-proteinase 3-positive anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis following the severe acute respiratory syndrome coronavirus 2 Pfizer-BioNTech vaccine presenting with prominent liver involvement and alveolar haemorrhage. Two weeks after vaccination, a 49-year-old man developed inflammatory arthralgias and hypertransaminasaemia. Two months later, fever and haemoptysis appeared; the patient tested positive for anti-proteinase 3 autoantibodies. High-dose steroids and rituximab were started, and complete remission was achieved. Systemic autoimmune diseases, including ANCA-associated vasculitis, should always be considered in the differential diagnosis of hypertransaminasaemia, especially when the clinical context is suspicious.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , COVID-19 , Masculino , Humanos , Persona de Mediana Edad , Anticuerpos Anticitoplasma de Neutrófilos , Vacunas contra la COVID-19/efectos adversos , SARS-CoV-2 , COVID-19/diagnóstico , COVID-19/prevención & control , Mieloblastina , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/diagnóstico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/etiología , Vacunación , HígadoRESUMEN
In recent years, immunohistochemical protein expression was studied as a surrogate to the molecular classification of bladder cancer, although no tissue biomarkers are available for clinical use to predict survival or the response to neoadjuvant chemotherapy (CT) in UC, as the literature produced conflicting results. This retrospective study included TURB specimens harboring foci of HG pT2 muscle-invasive bladder carcinoma (MIBC) from 251 patients who subsequently underwent radical cystectomy. We performed immunohistochemical analysis on tumor samples, for relevant gene-expression-based markers for basal type (CD44, CK5/6) and luminal type (CK20 and pPARγ). Piescore, investigated in both non-muscle-invasive (NMI) and muscle-invasive (MI) components of the tumor, divided basal and luminal UC-types when at least three of the four markers were consistent with a specific phenotype, mixed types if one/two luminal and basal markers were present simultaneously, and neu-like types when all four markers investigated were negative. Eighteen selected cases were also investigated with RT-PCR to validate, and to increase the specificity of, the immunohistochemical results. We observe an immunophenotypical difference in the NMI and MI components in 96/251 UC patients (38.25%): half of tumors (44/96 cases) have a transition to basal, 36.46% (35/96 cases) to neu-like, 12.5% (12/96 cases) to mixed, and 5.2% (5/96 cases) to luminal phenotypes. Mixed tumors in the NMI component are more likely to change phenotype than other groups, particularly compared with basal tumors, which demonstrate greater stability (only 8/96 cases, p < 0.00001). The transition of luminal tumors to basal display a better OS compared with the transition toward neu-like tumors (p = 0.027). Overall, the phenotypical switch does not affect lymphovascular invasion, pT, DFS, or OS compared with non-switched cases. In the MI component, the presence of CD44 expression, irrespective of score-related phenotype, shows a protective effect in papillary-type UC (OS p = 0.008, HR 0.453, PFS p = 0.07, HR 0.599), and in UC naïve for CT (p = 0.0479). Piescore immunophenotyping reveals an intratumoral phenotypical transition between the NMI and MI components of the same tumor. The molecular change is a common event in the mixed and luminal categories, but not in basal tumors, which show better phenotypical stability. This phenomenon could partially explain the sensitivity of a subset of luminal UC to chemotherapy: good responders could be "non-real" luminal UC, which acquire nasal markers, such as CD44.
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Neuroendocrine tumors (NETs) are neoplasms derived from neuroendocrine cells. One of their main features is to often remain asymptomatic and clinically undetectable. High Mobility Group A (HMGA) proteins belong to a family of non-histone chromatinic proteins able to modulate gene expression through the interaction with DNA and transcription factors. They are overexpressed in most of the human malignancies, playing a critical role in carcinogenesis. However, their expression levels and their role in neuroendocrine carcinogenesis has not been exhaustively evaluated until now. Therefore, in this study, we have addressed the validity of using the expression of HMGA1 as a diagnostic marker and have investigated its role in NET carcinogenesis. The expression of HMGA1 has been evaluated by qRT-PCR and immunohistochemistry, using NET tissue microarrays, in a cohort of gastroenteropancreatic (GEP)-NET samples. The expression levels of HMGA1 have been then correlated with the main clinical features of NET samples. Finally, the contribution of HMGA1 overexpression to NET development has been addressed as far as the modulation of proliferation and migration abilities of NET cells is concerned. Here, we report that HMGA1 is overexpressed in GEP-NET samples, at both mRNA and protein levels, and that the silencing of HMGA1 protein expression interferes with the ability of NET cells to proliferate and migrate through the downregulation of Cyclin E, Cyclin B1 and EZH2. These results propose the HMGA proteins as new diagnostic and prognostic markers.
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Proteínas HMGA , Proteína HMGA1a/metabolismo , Tumores Neuroendocrinos , Carcinogénesis , Proteínas HMGA/genética , Proteína HMGA1a/genética , Humanos , Neoplasias Intestinales , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/metabolismo , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas , Neoplasias Gástricas , Factores de TranscripciónRESUMEN
Renal medullary carcinoma (RMC) is a rare entity with poor prognosis bearing inactivating genomic alterations in SMARCB1/INI1 resulting in the loss of expression of INI1 and occurring in young patients with sickle cell trait or sickle cell disease. Recently, rare examples with histological characteristics of RMC have been described in older patients without hemoglobinopathies and provisionally termed "Renal cell carcinoma unclassified with medullary phenotype" (RCCU-MP). Fluorescence in situ Hybridization (FISH) can detect alterations in SMARCB1/INI1 consisting mostly in inactivating translocation of one allele and deletion of the second. To date, only seven further cases of RCCU-MP have been described in the literature. Here we report the second Italian case of RCCU-MP, a 62-year-old man presenting with persistent dull back pain and incidentally discovering a 13 cm mass in the right kidney. The nomenclature of this entity is still debated and might be updated as a variant of medullary carcinoma in the upcoming WHO classification. In the meantime, we encourage awareness of these extraordinarily rare neoplasms with poor outcomes.
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Background: We have recently reported the downregulation of the Metallophosphoesterase-domain-containing protein 2 (MPPED2) gene and its cognate long non-coding RNA, MPPED2-AS1, in papillary thyroid carcinomas. Functional studies supported a tumor suppressor role of both these genes in thyroid carcinogenesis. We then decided to investigate their role in breast carcinogenesis. Methods: In order to verify MPPED2 expression, 45 human breast carcinoma samples have been investigated by quantitative real-time polymerase chain reaction (qRT-PCR). Then, MPPED2 has been transfected in several human breast carcinoma cell lines, analyzing its role in cell proliferation, migration and invasion. To study the regulation of MPPED2 expression the methylation of its promoter was investigated by targeted bisulfite sequencing. Results: MPPED2 expression was decreased in breast cancer samples, and this was confirmed by the analysis of data available in The Cancer Genome Atlas (TCGA). Interestingly, the hypermethylation of MPPED2 promoter likely accounted for its downregulation in breast cancer. Additionally, MPPED2-AS1 was also found downregulated in breast cancer tissues and, intriguingly, its expression decreased the hypermethylation of the MPPED2 promoter by inhibiting DNA methyltransferase 1 (DNMT1). Furthermore, the restoration of MPPED2 expression reduced cell proliferation, migration and invasion capability of breast carcinoma cell lines. Conclusion: Taken together, these results propose MPPED2 downregulation as a critical event in breast carcinogenesis.
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In colorectal cancer (CRC), RHAMM is an independent adverse prognostic factor. The aim of the study was therefore to investigate on the role of RHAMM as a potential direct driver of cell proliferation and migration in CRC cell lines and to identify pathways dependent on RHAMM in human CRC. Proliferation, cell cycle alterations and invasive capacity were tested in two RHAMM- and control- knockdown CRC cell lines by flow cytometry and in vitro assays. Tumorigenicity and metastasis formation was assessed in immunodeficient mice. RNA-Seq and immunohistochemistry was performed on six RHAMM+/- primary CRC tumors. In vitro, silencing of RHAMM inhibited CRC cell migration and invasion by 50% (p<0.01). In vivo, RHAMM knockdown resulted in slower growth, lower tumor size (p<0.001) and inhibition of metastasis (p<0.001). Patients with RHAMM-high CRC had a worse prognosis (p=0.040) and upregulated pathways for cell cycle progression and adhesion turnover. RHAMM overexpression is correlated with increased migration and invasion of CRC cells, leads to larger, fast growing tumors, and its downregulation essentially abolishes metastasis in mouse models. RHAMM is therefore a promising therapeutic target in all CRC stages as its inhibition affects growth and dissemination of the primary CRC as well as the metastases.
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OBJECTIVES: Breast cancer represents the second leading cause of cancer mortality among American women and accounts for more than 40â 000 deaths annually. High-mobility group A1 (HMGA1) expression has been implicated in the pathogenesis and progression of human malignant tumours, including breast carcinomas. The aim of this study was to evaluate HMGA1 detection as an indicator for the diagnosis and prognosis of human breast carcinoma. METHODS: HMGA1 expression has been analysed by immunohistochemistry in a large series of breast carcinoma resections (1338) combined on a tissue microarray mainly including the ductal carcinoma variant. The results were then correlated with clinicopathological parameters of patients. RESULTS: HMGA1 overexpression was found in the large majority of breast carcinoma samples and its overexpression positively correlated with HER-2/neu amplification and progesterone receptor, while a negative correlation was found with oestrogen receptor. Conversely, no HMGA1 expression was found in normal breast tissues. CONCLUSIONS: The data reported here indicate that HMGA1 is overexpressed in human breast carcinomas and its levels are associated with a particular endocrine status.
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Biomarcadores de Tumor/análisis , Neoplasias de la Mama/química , Carcinoma Ductal de Mama/química , Proteínas HMGA/análisis , Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patología , Carcinoma Ductal de Mama/cirugía , Femenino , Amplificación de Genes , Humanos , Inmunohistoquímica , Clasificación del Tumor , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Receptor ErbB-2/genética , Receptores de Estrógenos/análisis , Receptores de Progesterona/análisis , Análisis de Matrices Tisulares , Regulación hacia ArribaRESUMEN
Hepatocellular carcinoma (HCC) is currently the sixth most common type of cancer with a high mortality rate and an increasing incidence worldwide. Its etiology is usually linked to environmental, dietary or life-style factors. HCC most commonly arises in a cirrhotic liver but interestingly an increasing proportion of HCCs develop in the non-fibrotic or minimal fibrotic liver and a shift in the underlying etiology can be observed. Although this process is yet to be completely understood, this changing scenario also has impact on the material seen by pathologists, presenting them with new diagnostic dilemmas. Histopathologic criteria for diagnosing classical, progressed HCC are well established and known, but with an increase in detection of small and early HCCs due to routine screening programs, the diagnosis of these small lesions in core needle biopsies poses a difficult challenge. These lesions can be far more difficult to distinguish from one another than progressed HCC, which is usually a clear cut hematoxylin and eosin diagnosis. Furthermore lesions thought to derive from progenitor cells have recently been reclassified in the WHO. This review summarizes recent developments and tries to put new HCC biomarkers in context with the WHOs reclassification. Furthermore it also addresses the group of tumors known as combined hepatocellular-cholangiocellular carcinomas.
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Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/patología , Carcinoma Hepatocelular/patología , Colangiocarcinoma/patología , Neoplasias Hepáticas/patología , Neoplasias Complejas y Mixtas/patología , Lesiones Precancerosas/patología , Animales , Neoplasias de los Conductos Biliares/química , Neoplasias de los Conductos Biliares/clasificación , Neoplasias de los Conductos Biliares/epidemiología , Conductos Biliares Intrahepáticos/química , Biomarcadores de Tumor/análisis , Biopsia , Carcinoma Hepatocelular/química , Carcinoma Hepatocelular/clasificación , Carcinoma Hepatocelular/epidemiología , Colangiocarcinoma/química , Colangiocarcinoma/clasificación , Colangiocarcinoma/epidemiología , Diagnóstico Diferencial , Humanos , Inmunohistoquímica , Neoplasias Hepáticas/química , Neoplasias Hepáticas/clasificación , Neoplasias Hepáticas/epidemiología , Clasificación del Tumor , Neoplasias Complejas y Mixtas/química , Neoplasias Complejas y Mixtas/clasificación , Neoplasias Complejas y Mixtas/epidemiología , Lesiones Precancerosas/química , Lesiones Precancerosas/clasificación , Lesiones Precancerosas/epidemiología , Valor Predictivo de las PruebasRESUMEN
AIM: To determine calprotectin release before and after colorectal cancer operation and compare it to tumor and histopathological parameters. METHODS: The study was performed on patients with diagnosed colorectal cancer admitted for operation. Calprotectin was measured in a single stool sample before and three months after the operation using an enzyme-linked immunosorbent assay (ELISA). Calprotectin levels greater than or equal to 50 µg/g were considered positive. The compliance for collecting stool samples was assessed and the value of calprotectin was correlated to tumor and histopathological parameters of intra- and peri-tumoral inflammation. Surgical specimens were fixed in neutral buffered formalin and stained with hematoxylin and eosin. Staging was performed according to the Dukes classification system and the 7(th) edition tumor node metastasis classification system. Intra- and peri-tumoral inflammation was graded according to the Klintrup criteria. Immunohistochemical quantification was performed for MPO, CD45R0, TIA-1, CD3, CD4, CD8, CD57, and granzyme B. Statistical significance was measured using Wilcoxon signed rank test, Kruskal Wallis test and Spearman's rank correlation coefficient as appropriate. RESULTS: Between March 2009 and May 2011, 80 patients with colorectal cancer (46 men and 34 women, with mean age of 71 ± 11.7 years old) were enrolled in the study. Twenty-six patients had rectal carcinoma, 29 had left-side tumors, 23 had right-side tumors, and 2 had bilateral carcinoma. In total, 71.2% of the patients had increased levels of calprotectin before the operation (median 205 µg/g, range 50-2405 µg/g) and experienced a significant decrease three months after the operation (46 µg/g, range 10-384 µg/g, P < 0001). The compliance for collecting stool samples was 89.5%. Patients with T3 and T4 tumors had significantly higher values than those with T1 and T2 cancers (P = 0.022). For all other tumor parameters (N, M, G, L, V, Pn) and location, no significant difference in calprotectin concentration was found. Furthermore, the calprotectin levels and histological grading of both peri- and intra-tumoral inflammation was not correlated. Additional testing with specific markers for lymphocytes and neutrophils also revealed no statistically significant correlation. CONCLUSION: Fecal calprotectin decreases significantly after colorectal cancer operation. Its value depends exclusively on the individual T-stage, but not on other tumor or histopathological parameters.
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Biomarcadores de Tumor/metabolismo , Carcinoma/metabolismo , Neoplasias Colorrectales/metabolismo , Heces/química , Complejo de Antígeno L1 de Leucocito/metabolismo , Anciano , Anciano de 80 o más Años , Biopsia , Carcinoma/patología , Carcinoma/cirugía , Colectomía , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/cirugía , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Cooperación del Paciente , Valor Predictivo de las Pruebas , Suiza , Factores de Tiempo , Resultado del TratamientoRESUMEN
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. The lack of effective therapeutic options for advanced stage HCCs combined with an increasing incidence rate calls for the identification of early stage HCC molecular markers. SH2 Domain Containing 4A (SH2D4A) gene maps to human chromosome 8p21.3 and encodes for SH(2)A. The chromosomal region containing SH2D4A is frequently lost in colorectal, lung and HCC cancers. Our study aimed to investigate SH2D4A involvement in HCC pathogenesis combining mRNA expression, protein and clinical data. Transcriptome analysis performed on 37 HCC needle biopsies (matched with their corresponding non-neoplastic parenchyma) and five normal liver donor samples revealed that SH2D4A is downregulated in HCC. Results were confirmed by quantitative real-time-polymerase chain reaction (qRT-PCR), 25 out of 37 (67.6%) fresh frozen samples showed SH2D4A downregulation (p = 0.026). Furthermore, combining qRT-PCR and immunohistochemistry data we demonstrated a direct correlation between SH2D4A mRNA and SH(2)A protein levels. The analysis of a tissue microarray (TMA) containing 336 specimens confirmed that SH(2)A is frequently reduced in HCC (56.8%) as well as in cirrhotic nodules (50.5%) compared to normal liver samples (31.1%). To conclude, our study revealed that SH2D4A is frequently downregulated in HCC samples thus corroborating its putative role as a tumour suppressor gene. In addition, we provide new evidence for SH2D4A involvement in HCC pathogenesis demonstrating for the first time its deregulation in cirrhotic nodules.
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Carcinoma Hepatocelular/genética , Cirrosis Hepática/genética , Neoplasias Hepáticas/genética , Proteínas de la Membrana/genética , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/epidemiología , Regulación hacia Abajo , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Péptidos y Proteínas de Señalización Intracelular , Cirrosis Hepática/epidemiología , Cirrosis Hepática/patología , Neoplasias Hepáticas/epidemiología , Masculino , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Análisis de Matrices TisularesRESUMEN
The differentiation of colorectal cancer from primary tumors at other sites can be challenging. Often a panel of immunohistochemical protein markers is needed to distinguish between these entities. Protein expression differs significantly in colorectal cancer depending on mismatch repair status and is also heterogeneous among mismatch repair-proficient or -deficient tumors. The aim of this study was to systematically analyze the diagnostic and prognostic role of the commonly used multi-marker phenotype CK20/CK7/CDX2 on a large series of colorectal cancers stratified by mismatch repair status. The immunohistochemical analysis of CK20, CK7 and CDX2 was performed on 1197 mismatch repair-proficient and 223 mismatch repair-deficient colorectal cancers using a tissue microarray. Multi-marker combinations of CK20/CK7/CDX2 were explored. Univariate and multivariable analysis of the markers was evaluated for their association with several clinico-pathological end points namely T stage, N stage, tumor grade, vascular invasion, intratumoral lymphocytes and survival. Multi-marker phenotypes with CK20 and CDX2 negativity were more frequently found in mismatch repair-deficient than in mismatch repair-proficient colorectal cancer (19.3 vs 7.5% and 21.6 vs 6.7%, respectively; P<0.001). In both colorectal cancer subsets loss of CK20 was associated with higher tumor grade (P<0.001) and with presence of intratumoral lymphocytes (P<0.001 and P=0.02, respectively). In the proficient mismatch repair subset CK20 overexpression was an independent adverse prognostic factor (P=0.041) and CDX2 underexpression was linked to tumor progression. Loss of CDX2 and CK20 is more frequently encountered in mismatch repair-deficient colorectal cancer, which should be taken into consideration to differentiate between primary and metastatic colorectal cancer in daily practice. Although associated with lower tumor grade, CK20 overexpression is an independent adverse prognostic factor in mismatch repair-proficient colorectal cancer.
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Adenocarcinoma/diagnóstico , Biomarcadores de Tumor/metabolismo , Neoplasias Colorrectales/diagnóstico , Proteínas de Homeodominio/metabolismo , Queratina-20/metabolismo , Queratina-7/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidad , Anciano , Biomarcadores de Tumor/genética , Factor de Transcripción CDX2 , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/mortalidad , Reparación de la Incompatibilidad de ADN , Análisis Mutacional de ADN , ADN de Neoplasias/genética , Diagnóstico Diferencial , Femenino , Técnica del Anticuerpo Fluorescente Directa , Proteínas de Homeodominio/genética , Humanos , Técnicas para Inmunoenzimas , Queratina-20/genética , Queratina-7/genética , Masculino , Análisis de Matrices TisularesRESUMEN
BACKGROUND: The long-term outcome of chronic hepatitis C (CHC) has not been well studied, both for untreated and interferon-treated children. The aim of this study was to evaluate the long-term outcome of disease in a large series of children with CHC. METHODS: Clinical, biochemical, virological, and histological features were evaluated in all children (age, 2-18 years) with CHC who did not have concomitant disease and who attended at our hospital's liver unit during the period of 1986-2004. RESULTS: One hundred twenty-five children with CHC were studied. All patients remained free of symptoms throughout the period of observation. On the basis of transaminase levels during the first year of positivity for antibodies to hepatitis C virus (HCV), children were divided into 2 groups: patients with hypertransaminasemia (100 patients, all of whom had detectable HCV RNA), and those with normal transaminases (25 patients; 16 had viremia and 9 did not have viremia). Sustained clearance of viremia was achieved in 38% of the patients treated with interferon, compared with 12% of untreated children (P<.05). A sustained response to therapy was obtained in 64.7% of children infected with an HCV genotype other than genotype 1 and in 24.2% of those infected with HCV genotype 1 (P<.05). Histological lesions were mild in all 64 patients who underwent liver biopsy. No linear correlation was found between duration of disease and progression of fibrosis. Examination of a follow-up liver biopsy specimen revealed cirrhosis only in 1 (4.7%) of 21 children. CONCLUSIONS: Children with CHC were symptom free and had a morphologically mild liver disease. Interferon therapy may be effective for patients infected with HCV genotypes other than genotype 1, whereas lower response rates are expected for HCV genotype 1-infected children. The real impact of therapy on long-term outcome remains to be established.
Asunto(s)
Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Adolescente , Niño , Preescolar , Femenino , Genotipo , Hepacivirus/genética , Anticuerpos contra la Hepatitis C/sangre , Hepatitis C Crónica/virología , Humanos , Interferón alfa-2 , Interferón-alfa/uso terapéutico , Estudios Longitudinales , Masculino , Proteínas Recombinantes , Factores de Tiempo , Resultado del Tratamiento , ViremiaRESUMEN
Hepatocyte paraffin 1 (Hep Par 1) is a monoclonal antibody developed from hepatic tissue from a failed liver allograft. Several studies have shown that Hep Par 1 is a useful marker to differentiate hepatocellular carcinoma (HCC) from other types of adenocarcinoma metastatic to the liver. The aim of our study was the systematic investigation of the epidemiology of Hep Par 1 expression in 3,940 tissue samples using the tissue microarray technique. Strong Hep Par 1 expression was found most frequently in 35 (73%) of 48 HCCs. In nonhepatic tumors, strong Hep Par 1 expression was detected in adenocarcinoma of the lung (2/50), gallbladder (3/31), pancreas (2/48), stomach (3/74), small intestine (1/11), adenoma of the colon with high-grade dysplasia (1/49), adrenal gland carcinoma (1/6), paraganglioma (1/9), and malignant melanoma (2/48). Our data suggest that Hep Par 1 is a highly specific marker for HCC, although several nonhepatic tumors occasionally can show some Hep Par 1 positivity.