Non-alcoholic fatty liver disease (NAFLD), encompassing fatty liver and its progression into nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), is one of the rapidly rising health concerns worldwide. SIRT6 is an essential nuclear sirtuin that regulates numerous pathological processes including insulin resistance and inflammation, and recently it has been implicated in the amelioration of NAFLD progression. SIRT6 overexpression protects from formation of fibrotic lesions. However, the underlying molecular mechanisms are not fully delineated. Moreover, new allelic variants of SIRT6 (N308K/A313S) were recently associated with the longevity in Ashkenazi Jews by improving genome maintenance and DNA repair, suppressing transposons and killing cancer cells. Whether these new SIRT6 variants play different or enhanced roles in liver diseases is currently unknown. In this study, we aimed to clarify how these new centenarian-associated SIRT6 genetic variants affect liver metabolism and associated diseases. We present evidence that overexpression of centenarian-associated SIRT6 variants dramatically altered the metabolomic and secretomic profiles of unchallenged immortalized human hepatocytes (IHH). Most amino acids were increased in the SIRT6 N308K/A313S overexpressing IHH when compared to IHH transfected with the SIRT6 wild-type sequence. Several unsaturated fatty acids and glycerophospholipids were increased, and ceramide tended to be decreased upon SIRT6 N308K/A313S overexpression. Furthermore, we found that overexpression of SIRT6 N308K/A313S in a 3D hepatic spheroid model formed by the co-culture of human immortalized hepatocytes (IHH) and hepatic stellate cells (LX2) inhibited collagen deposition and fibrotic gene expression in absence of metabolic or dietary challenges. Hence, our findings suggest that novel longevity associated SIRT6 N308K/A313S variants could favor the prevention of NASH by altering hepatocyte proteome and lipidome.
- MeSH
- hepatocelulární karcinom * metabolismus patologie MeSH
- hepatocyty metabolismus patologie MeSH
- kolagen metabolismus MeSH
- lidé MeSH
- nádory jater * metabolismus patologie MeSH
- nealkoholová steatóza jater * genetika metabolismus patologie MeSH
- senioři nad 80 let MeSH
- sirtuiny * genetika metabolismus MeSH
- století lidé MeSH
- Check Tag
- lidé MeSH
- senioři nad 80 let MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Background: The prognostic value of Immunoscore was evaluated in Stage II/III colon cancer (CC) patients, but it remains unclear in Stage I/II, and in early-stage subgroups at risk. An international Society for Immunotherapy of Cancer (SITC) study evaluated the pre-defined consensus Immunoscore in tumors from 1885 AJCC/UICC-TNM Stage I/II CC patients from Canada/USA (Cohort 1) and Europe/Asia (Cohort 2). METHODS: Digital-pathology is used to quantify the densities of CD3+ and CD8+ T-lymphocyte in the center of tumor (CT) and the invasive margin (IM). The time to recurrence (TTR) was the primary endpoint. Secondary endpoints were disease-free survival (DFS), overall survival (OS), prognosis in Stage I, Stage II, Stage II-high-risk, and microsatellite-stable (MSS) patients. RESULTS: High-Immunoscore presented with the lowest risk of recurrence in both cohorts. In Stage I/II, recurrence-free rates at 5 years were 78.4% (95%-CI, 74.4−82.6), 88.1% (95%-CI, 85.7−90.4), 93.4% (95%-CI, 91.1−95.8) in low, intermediate and high Immunoscore, respectively (HR (Hi vs. Lo) = 0.27 (95%-CI, 0.18−0.41); p < 0.0001). In Cox multivariable analysis, the association of Immunoscore to outcome was independent (TTR: HR (Hi vs. Lo) = 0.29, (95%-CI, 0.17−0.50); p < 0.0001) of the patient’s gender, T-stage, sidedness, and microsatellite instability-status (MSI). A significant association of Immunoscore with survival was found for Stage II, high-risk Stage II, T4N0 and MSS patients. The Immunoscore also showed significant association with TTR in Stage-I (HR (Hi vs. Lo) = 0.07 (95%-CI, 0.01−0.61); P = 0.016). The Immunoscore had the strongest (69.5%) contribution χ2 for influencing survival. Patients with a high Immunoscore had prolonged TTR in T4N0 tumors even for patients not receiving chemotherapy, and the Immunoscore remained the only significant parameter in multivariable analysis. CONCLUSION: In early CC, low Immunoscore reliably identifies patients at risk of relapse for whom a more intensive surveillance program or adjuvant treatment should be considered.
- Publikační typ
- časopisecké články MeSH
BACKGROUND: In this study, we evaluated the prognostic value of Immunoscore in patients with stage I-III colon cancer (CC) in the Asian population. These patients were originally included in an international study led by the Society for Immunotherapy of Cancer (SITC) on 2681 patients with AJCC/UICC-TNM stages I-III CC. METHODS: CD3+ and cytotoxic CD8+ T-lymphocyte densities were quantified in the tumor and invasive margin by digital pathology. The association of Immunoscore with prognosis was evaluated for time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS). RESULTS: Immunoscore stratified Asian patients (n = 423) into different risk categories and was not impacted by age. Recurrence-free rates at 3 years were 78.5%, 85.2%, and 98.3% for a Low, Intermediate, and High Immunoscore, respectively (HR[Low-vs-High] = 7.26 (95% CI 1.75-30.19); p = 0.0064). A High Immunoscore showed a significant association with prolonged TTR, OS, and DFS (p < 0.05). In Cox multivariable analysis stratified by center, Immunoscore association with TTR was independent (HR[Low-vs-Int+High] = 2.22 (95% CI 1.10-4.55) p = 0.0269) of the patient's gender, T-stage, N-stage, sidedness, and MSI status. A significant association of a High Immunoscore with prolonged TTR was also found among MSS (HR[Low-vs-Int+High] = 4.58 (95% CI 2.27-9.23); p ≤ 0.0001), stage II (HR[Low-vs-Int+High] = 2.72 (95% CI 1.35-5.51); p = 0.0052), low-risk stage-II (HR[Low-vs-Int+High] = 2.62 (95% CI 1.21-5.68); p = 0.0146), and high-risk stage II patients (HR[Low-vs-Int+High] = 3.11 (95% CI 1.39-6.91); p = 0.0055). CONCLUSION: A High Immunoscore is significantly associated with the prolonged survival of CC patients within the Asian population.
- Publikační typ
- časopisecké články MeSH
Cílem následujícího sdělení je podat přehled problematiky využití imunohistochemických metod u karcinomu endometria. Diskutováno je zejména využití imunohistochemie v diferenciální diagnostice základních histologických typů karcinomu endometria; rozlišení mezi primárním serózním karcinomem endometria a postižením při high grade serózním karcinomu jiného primárního zdroje; v diagnostice nediferencovaného / dediferencovaného karcinomu endometria a v diagnostice nádorů s neuroendokrinní diferenciací. Samostatně je zdůrazněna problematika hodnocení exprese p53 v kontextu diferenciální diagnostiky, ale i prognózy a predikce karcinomu endometria jako pomocného markeru při subtypizaci těchto nádorů.
The goal of this manuscript is to provide an overview of the significance of immunohistochemical methods in diagnosing endometrial carcinoma. The main points discussed include: the use of immunohistochemistry in the differential diagnosis of the main histological types of endometrial carcinoma, the difference between primary serous endometrial carcinoma and the involvement with high grade serous carcinoma of another primary source, the diagnosis of undifferentiated/dedifferentiated endometrial carcinoma, and diagnosing tumours with neuroendocrine differentiation. The role of p53 expression evaluation is also emphasized as a special area of interest, not only in the context of differential diagnosis, but also from the point of view of the prognosis and prediction of endometrial carcinoma as an ancillary marker for subtypization of these tumours.
- MeSH
- diferenciální diagnóza MeSH
- endometroidní karcinom diagnóza genetika MeSH
- exprese genu MeSH
- imunohistochemie MeSH
- karcinom * diagnóza genetika MeSH
- lidé MeSH
- nádorový supresorový protein p53 MeSH
- nádory endometria * diagnóza genetika klasifikace MeSH
- staging nádorů MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
PURPOSE: The purpose of this study was to evaluate the prognostic value of Immunoscore in patients with stage III colon cancer (CC) and to analyze its association with the effect of chemotherapy on time to recurrence (TTR). METHODS: An international study led by the Society for Immunotherapy of Cancer evaluated the predefined consensus Immunoscore in 763 patients with American Joint Committee on Cancer/Union for International Cancer Control TNM stage III CC from cohort 1 (Canada/United States) and cohort 2 (Europe/Asia). CD3+ and cytotoxic CD8+ T lymphocyte densities were quantified in the tumor and invasive margin by digital pathology. The primary end point was TTR. Secondary end points were overall survival (OS), disease-free survival (DFS), prognosis in microsatellite stable (MSS) status, and predictive value of efficacy of chemotherapy. RESULTS: Patients with a high Immunoscore presented with the lowest risk of recurrence, in both cohorts. Recurrence-free rates at 3 years were 56.9% (95% CI, 50.3% to 64.4%), 65.9% (95% CI, 60.8% to 71.4%), and 76.4% (95% CI, 69.3% to 84.3%) in patients with low, intermediate, and high immunoscores, respectively (hazard ratio [HR; high v low], 0.48; 95% CI, 0.32 to 0.71; P = .0003). Patients with high Immunoscore showed significant association with prolonged TTR, OS, and DFS (all P < .001). In Cox multivariable analysis stratified by participating center, Immunoscore association with TTR was independent (HR [high v low], 0.41; 95% CI, 0.25 to 0.67; P = .0003) of patient's sex, T stage, N stage, sidedness, and microsatellite instability status. Significant association of a high Immunoscore with prolonged TTR was also found among MSS patients (HR [high v low], 0.36; 95% CI, 0.21 to 0.62; P = .0003). Immunoscore had the strongest contribution χ2 proportion for influencing survival (TTR and OS). Chemotherapy was significantly associated with survival in the high-Immunoscore group for both low-risk (HR [chemotherapy v no chemotherapy], 0.42; 95% CI, 0.25 to 0.71; P = .0011) and high-risk (HR [chemotherapy v no chemotherapy], 0.5; 95% CI, 0.33 to 0.77; P = .0015) patients, in contrast to the low-Immunoscore group (P > .12). CONCLUSION: This study shows that a high Immunoscore significantly associated with prolonged survival in stage III CC. Our findings suggest that patients with a high Immunoscore will benefit the most from chemotherapy in terms of recurrence risk.
- MeSH
- adjuvantní chemoterapie MeSH
- antigeny CD3 metabolismus MeSH
- antitumorózní látky terapeutické užití MeSH
- časové faktory MeSH
- CD8-pozitivní T-lymfocyty * metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- lokální recidiva nádoru imunologie MeSH
- mikrosatelitní nestabilita MeSH
- míra přežití MeSH
- mutace MeSH
- nádory tračníku farmakoterapie genetika imunologie patologie MeSH
- počet lymfocytů MeSH
- prediktivní hodnota testů MeSH
- přežití po terapii bez příznaků nemoci MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- staging nádorů MeSH
- tumor infiltrující lymfocyty MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
The importance of the expression profile of claudins in the molecular classification of breast cancer (BC) is currently under investigation. Claudins, together with cadherins, serve an important role in the epithelial-mesenchymal transition and influence the chemosensitivity of cancer cells. Adjuvant chemotherapy is administered following surgical resection in selected cases of BC. Previous neoadjuvant chemotherapy may change the molecular profile of a tumour and subsequently also its chemosensitivity. In the current study, the expression of claudin-1, -3 and -4, E- and N-cadherin and the standard BC biomarkers [oestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and marker of proliferation Ki-67 (Ki-67)] in formalin-fixed, paraffin-embedded sections from 62 patients with invasive BC was analysed using immunohistochemistry prior to and following neoadjuvant chemotherapy. The results revealed increased expression of claudin-1 (P=0.03) and decreased expression of claudin-3 (P=0.005), PR (P<0.001) and Ki-67 (P=0.01) following the neoadjuvant therapy. No significant changes in the expression of ER, claudin-4 or E- and N-cadherin were observed following therapy. Furthermore, an association between the expression of claudin-1 and the standard BC markers (P<0.05) was identified. A high expression of claudin-1 was more frequently observed in the triple-negative BC cohort than in the cohort with positive ER, PR and/or HER2 before (P=0.04) and after chemotherapy (P=0.02). The expression of N-cadherin was associated with the expression of ER, PR, HER2 and tumour grade (P<0.05). A positive association between the expression of claudin-3 and E-cadherin (P=0.005) was observed. No association was found between the expression of E- and N-cadherin. In conclusion, significant changes in the expression of claudin-1 and -3 but not in the expression of claudin-4, E- and N-cadherin were observed in samples taken from patients with BC following chemotherapy. These findings indicate that claudins-1 and -3 serve a role in the response of BC to chemotherapy.
- Publikační typ
- časopisecké články MeSH
BACKGROUND: The objective of this study was to investigate serum levels of immunosuppressive cytokines TGF beta 1 and VEGF and count of immune cells in peripheral blood in stage II and III colorectal cancer patients. METHODS: Blood samples were collected from 22 colorectal patients and 25 healthy controls before the start of treatment. All patients were examined by a clinical immunologist to exclude patients with immune disorders and autoimmune diseases. TGF beta 1 and VEGF were measured by ELISA, and anti-tumor cellular immunity cells (CD4, CD8, B cells, NK cells) were measured by flow cytometry. RESULTS: TGF beta 1 and VEGF plasma levels were significantly increased in stage II and III colorectal patients compared with control group (both p < 0.0001). A decrease in the cellular immunity was shown in the absolute numbers of cytotoxic T lymphocytes (CD8+ ; p = 0.0240), helper T lymphocytes (CD4+ ; p = 0.0019), and natural killer cells (CD16 + CD56+; p < 0.0001) in both stage II and stage III patients. On the contrary, B lymphocyte (CD19+) serum levels were increased in colon cancer patients (p < 0.0001) compared to the control group. CONCLUSIONS: Our results show peripheral blood levels of TGF beta and VEGF were significantly increased in colorectal patients and changes in cellular anticancer immunity in comparison to control group. These results will be compared with results from Immunoscore.
- MeSH
- adenokarcinom imunologie MeSH
- B-lymfocyty imunologie MeSH
- buněčná imunita MeSH
- buňky NK imunologie MeSH
- CD4-pozitivní T-lymfocyty imunologie MeSH
- CD8-pozitivní T-lymfocyty imunologie MeSH
- kolorektální nádory imunologie MeSH
- krevní oběh MeSH
- lidé středního věku MeSH
- lidé MeSH
- počet lymfocytů MeSH
- staging nádorů MeSH
- transformující růstový faktor beta1 krev MeSH
- vaskulární endoteliální růstový faktor A krev MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: The estimation of risk of recurrence for patients with colon carcinoma must be improved. A robust immune score quantification is needed to introduce immune parameters into cancer classification. The aim of the study was to assess the prognostic value of total tumour-infiltrating T-cell counts and cytotoxic tumour-infiltrating T-cells counts with the consensus Immunoscore assay in patients with stage I-III colon cancer. METHODS: An international consortium of 14 centres in 13 countries, led by the Society for Immunotherapy of Cancer, assessed the Immunoscore assay in patients with TNM stage I-III colon cancer. Patients were randomly assigned to a training set, an internal validation set, or an external validation set. Paraffin sections of the colon tumour and invasive margin from each patient were processed by immunohistochemistry, and the densities of CD3+ and cytotoxic CD8+ T cells in the tumour and in the invasive margin were quantified by digital pathology. An Immunoscore for each patient was derived from the mean of four density percentiles. The primary endpoint was to evaluate the prognostic value of the Immunoscore for time to recurrence, defined as time from surgery to disease recurrence. Stratified multivariable Cox models were used to assess the associations between Immunoscore and outcomes, adjusting for potential confounders. Harrell's C-statistics was used to assess model performance. FINDINGS: Tissue samples from 3539 patients were processed, and samples from 2681 patients were included in the analyses after quality controls (700 patients in the training set, 636 patients in the internal validation set, and 1345 patients in the external validation set). The Immunoscore assay showed a high level of reproducibility between observers and centres (r=0·97 for colon tumour; r=0·97 for invasive margin; p<0·0001). In the training set, patients with a high Immunoscore had the lowest risk of recurrence at 5 years (14 [8%] patients with a high Immunoscore vs 65 (19%) patients with an intermediate Immunoscore vs 51 (32%) patients with a low Immunoscore; hazard ratio [HR] for high vs low Immunoscore 0·20, 95% CI 0·10-0·38; p<0·0001). The findings were confirmed in the two validation sets (n=1981). In the stratified Cox multivariable analysis, the Immunoscore association with time to recurrence was independent of patient age, sex, T stage, N stage, microsatellite instability, and existing prognostic factors (p<0·0001). Of 1434 patients with stage II cancer, the difference in risk of recurrence at 5 years was significant (HR for high vs low Immunoscore 0·33, 95% CI 0·21-0·52; p<0·0001), including in Cox multivariable analysis (p<0·0001). Immunoscore had the highest relative contribution to the risk of all clinical parameters, including the American Joint Committee on Cancer and Union for International Cancer Control TNM classification system. INTERPRETATION: The Immunoscore provides a reliable estimate of the risk of recurrence in patients with colon cancer. These results support the implementation of the consensus Immunoscore as a new component of a TNM-Immune classification of cancer. FUNDING: French National Institute of Health and Medical Research, the LabEx Immuno-oncology, the Transcan ERAnet Immunoscore European project, Association pour la Recherche contre le Cancer, CARPEM, AP-HP, Institut National du Cancer, Italian Association for Cancer Research, national grants and the Society for Immunotherapy of Cancer.
- MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- lokální recidiva nádoru etiologie MeSH
- nádory tračníku klasifikace diagnóza imunologie MeSH
- prognóza MeSH
- proporcionální rizikové modely MeSH
- reprodukovatelnost výsledků MeSH
- senioři MeSH
- staging nádorů MeSH
- tumor infiltrující lymfocyty MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
We report six cases of anastomosing hemangioma of the ovary. All lesions were unilateral and arose in 43 to 81 year old females. In all but one patient, the tumor was asymptomatic and represented incidental finding. The exception was a tumor associated with massive ascites and elevated CA 125. The tumors were, on cut section, spongy and dark violet in color. The size of tumors ranged from 0.5 to 3.5 cm. All lesions showed the same histological features and consisted of capillary sized anastomosing vessels with sinusoid-like pattern intermingled with sporadic medium sized vessels. Interestingly, in all cases there were areas of luteinized cells at the tumor periphery, which ranged from rare small nests to multiple and commonly confluent areas. In one tumor, components of mature adipose tissue were present. Immunohistochemically, all tumors were CD31 and CD34 positive. Other markers examined were negative, including; estrogen receptor, progesterone receptor, androgen receptor, and D2-40. Proliferative activity (Ki-67 index) was very low in all cases. Anastomosing hemangioma is a rare entity, only 8 lesions occurring in ovary has been described from its initial description in 2009. We report six additional cases with their clinicopathological correlation.
- MeSH
- dospělí MeSH
- hemangiom patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádorové biomarkery analýza MeSH
- nádory vaječníků patologie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Publikační typ
- abstrakt z konference MeSH
