18 research outputs found
ΠΠ°ΠΊΠΎΠ½ΠΎΠΌΠ΅ΡΠ½ΠΎΡΡΠΈ ΡΠ°ΡΠΏΡΠ΅Π΄Π΅Π»Π΅Π½ΠΈΡ Π°Π½ΠΎΠΌΠ°Π»ΡΠ½ΡΡ ΠΊΠΎΠ½ΡΠ΅Π½ΡΡΠ°ΡΠΈΠΉ Π³Π΅Π»ΠΈΡ Π² ΠΏΠ°Π»Π΅ΠΎΠ·ΠΎΠΉΡΠΊΠΈΡ ΠΎΡΠ»ΠΎΠΆΠ΅Π½ΠΈΡΡ ΠΠΎΠ½Π±Π°ΡΡΠ°
ΠΡΠ΄Π²ΠΈΡΠ΅Π½Ρ ΠΊΠΎΠ½ΡΠ΅Π½ΡΡΠ°ΡΡΡ Π³Π΅Π»ΡΡ Ρ Π²ΡΠ»ΡΠ½ΠΈΡ
Ρ ΡΠΎΠ·ΡΠΈΠ½Π΅Π½ΠΈΡ
Π³Π°Π·Π°Ρ
Ρ Π²ΡΠ³ΡΠ»ΡΠ½ΠΎ-ΠΏΠΎΡΠΎΠ΄Π½ΠΎΠΌΡ ΠΌΠ°ΡΠΈΠ²Ρ ΠΠΎΠ½Π±Π°ΡΡ ΠΏΡΠΈΡΡΠΎΡΠ΅Π½Ρ Π΄ΠΎ Π·ΠΎΠ½ Π·ΡΠ»Π΅Π½ΡΠ²Π°Π½Π½Ρ ΠΠΎΠ½Π±Π°ΡΡ Π· ΠΡΠΈΠ°Π·ΠΎΠ²ΡΡΠΊΠΈΠΌ Ρ ΠΠΎΡΠΎΠ½Π΅Π·ΡΠΊΠΈΠΌ ΠΊΡΠΈΡΡΠ°Π»ΡΡΠ½ΠΈΠΌΠΈ ΠΌΠ°ΡΠΈΠ²Π°ΠΌΠΈ Ρ ΠΠΎΠ»ΠΎΠ²Π½ΠΎΡ Π°Π½ΡΠΈΠΊΠ»ΡΠ½Π°Π»Ρ. ΠΠΈΠ·'ΡΠ½ΠΊΡΠΈΠ²Π½Ρ ΡΠ΅ΠΊΡΠΎΠ½ΡΡΠ½Ρ ΠΏΠΎΡΡΡΠ΅Π½Π½Ρ Π³Π»ΠΈΠ±ΠΎΠΊΠΎΠ³ΠΎ Π·Π°ΠΊΠ»Π°Π΄Π΅Π½Π½Ρ ΡΠ»ΡΠΆΠΈΠ»ΠΈ, ΠΉΠΌΠΎΠ²ΡΡΠ½ΠΎ, ΡΠ»ΡΡ
Π°ΠΌΠΈ ΡΡΠ°Π½Π·ΠΈΡΡ Π³Π΅Π»ΡΡ Π²ΡΠ΄ ΠΊΡΠΈΡΡΠ°Π»ΡΡΠ½ΠΈΡ
ΠΏΠΎΡΡΠ΄ ΡΡΠ½Π΄Π°ΠΌΠ΅Π½ΡΡ Π² ΠΏΠ°Π»Π΅ΠΎΠ·ΠΎΠΉΡΡΠΊΡ Π²ΡΠ΄ΠΊΠ»Π°Π΄ΠΈ ΠΠΎΠ½Π±Π°ΡΡ, Ρ ΠΏΡΠ΄Π²ΠΈΡΠ΅Π½ΠΈΠΉ Π²ΠΌΡΡΡ Π³Π΅Π»ΡΡ ΠΌΠΎΠΆΠ΅ ΡΠ»ΡΠΆΠΈΡΠΈ ΡΠ½Π΄ΠΈΠΊΠ°ΡΠΎΡΠΎΠΌ ΡΠ»ΡΡ
ΡΠ² ΡΡΠ°Π½Π·ΠΈΡΡ Π³Π°Π·ΡΠ² Π· Π³Π»ΠΈΠ±ΠΎΠΊΠΈΡ
Π³ΠΎΡΠΈΠ·ΠΎΠ½ΡΡΠ² ΠΠΎΠ½Π΅ΡΡΠΊΠΎΠ³ΠΎ Π²ΡΠ³ΡΠ»ΡΠ½ΠΎΠ³ΠΎ Π±Π°ΡΠ΅ΠΉΠ½Ρ.Elevated concentrations of helium in free and dissolved gases in coal-rock mass of the Donets Coal Basin are confined to the junction zones of the Donets Coal Basin with the Priazovie and Voronezh crystalline core-areas and Glavnaya (Principal) Anticline. Deep-laid disjunctive dislocations were probably the ways for transit of helium from crystalline basement rocks into Paleozoic deposits of the Basin. Elevated concentrations of helium can also serve as indicators of the ways for transit of gases from deep levels of the Donets Coal Basin
Neoadjuvant chemotherapy affects molecular classification of colorectal tumors
The recent discovery of 'molecular subtypes' in human primary colorectal cancer has revealed correlations between subtype, propensity to metastasize and response to therapy. It is currently not known whether the molecular tumor subtype is maintained after distant spread. If this is the case, molecular subtyping of the primary tumor could guide subtype-targeted therapy of metastatic disease. In this study, we classified paired samples of primary colorectal carcinomas and their corresponding liver metastases (n = 129) as epithelial-like or mesenchymal-like, using a recently developed immunohistochemistry-based classification tool. We observed considerable discordance (45%) in the classification of primary tumors and their liver metastases. Discordant classification was significantly associated with the use of neoadjuvant chemotherapy. Furthermore, gene expression analysis of chemotherapy-exposed versus chemotherapy naive liver metastases revealed expression of a mesenchymal program in pre-treated tumors. To explore whether chemotherapy could cause gene expression changes influencing molecular subtyping, we exposed patient-derived colonospheres to six short cycles of 5-fluorouracil. Gene expression profiling and signature enrichment analysis subsequently revealed that the expression of signatures identifying mesenchymal-like tumors was strongly increased in chemotherapy-exposed tumor cultures. Unsupervised clustering of large cohorts of human colon tumors with the chemotherapy-induced gene expression program identified a poor prognosis mesenchymal-like subgroup. We conclude that neoadjuvant chemotherapy induces a mesenchymal phenotype in residual tumor cells and that this may influence the molecular classification of colorectal tumor
Practical and Robust Identification of Molecular Subtypes in Colorectal Cancer by Immunohistochemistry
Surgical oncolog
Practical and robust identification of molecular subtypes in colorectal cancer by immunohistochemistry
URPOSE: Recent transcriptomic analyses have identified four distinct molecular subtypes of colorectal cancer (CRC) with evident clinical relevance. However, the requirement for sufficient quantities of bulk tumor and difficulties in obtaining high quality genome-wide transcriptome data from formalin-fixed paraffin-embedded tissue are obstacles towards widespread adoption of this taxonomy. Here, we develop an immunohistochemistry-based classifier to validate the prognostic and predictive value of molecular CRC subtyping in a multi-center study. EXPERIMENTAL DESIGN: Tissue microarrays from 1076 CRC patients from four different cohorts were stained for five markers (CDX2, FRMD6, HTR2B, ZEB1 and KER) by immunohistochemistry and assessed for microsatellite instability. An automated classification system was trained on one cohort using quantitative image analysis or semi-quantitative pathologist scoring of the cores as input, and applied to three independent clinical cohorts. RESULTS: This classifier demonstrated 87% concordance with the gold-standard transcriptome-based classification. Application to three validation datasets confirmed the poor prognosis of the mesenchymal-like molecular CRC subtype. In addition, retrospective analysis demonstrated the benefit of adding cetuximab to bevacizumab and chemotherapy in patients with RAS wild type metastatic cancers of the canonical epithelial-like subtypes. CONCLUSION: This study shows that a practical and robust immunohistochemical-assay can be employed to identify molecular CRC subtypes and uncover subtype-specific therapeutic benefit. Finally, the described tool is available online for rapid classification of CRC samples, both in the format of an automated image analysis pipeline to score tumour core staining, and as a classifier based on semi-quantitative pathology scoring
Practical and robust identification of molecular subtypes in colorectal cancer by immunohistochemistry
URPOSE: Recent transcriptomic analyses have identified four distinct molecular subtypes of colorectal cancer (CRC) with evident clinical relevance. However, the requirement for sufficient quantities of bulk tumor and difficulties in obtaining high quality genome-wide transcriptome data from formalin-fixed paraffin-embedded tissue are obstacles towards widespread adoption of this taxonomy. Here, we develop an immunohistochemistry-based classifier to validate the prognostic and predictive value of molecular CRC subtyping in a multi-center study. EXPERIMENTAL DESIGN: Tissue microarrays from 1076 CRC patients from four different cohorts were stained for five markers (CDX2, FRMD6, HTR2B, ZEB1 and KER) by immunohistochemistry and assessed for microsatellite instability. An automated classification system was trained on one cohort using quantitative image analysis or semi-quantitative pathologist scoring of the cores as input, and applied to three independent clinical cohorts. RESULTS: This classifier demonstrated 87% concordance with the gold-standard transcriptome-based classification. Application to three validation datasets confirmed the poor prognosis of the mesenchymal-like molecular CRC subtype. In addition, retrospective analysis demonstrated the benefit of adding cetuximab to bevacizumab and chemotherapy in patients with RAS wild type metastatic cancers of the canonical epithelial-like subtypes. CONCLUSION: This study shows that a practical and robust immunohistochemical-assay can be employed to identify molecular CRC subtypes and uncover subtype-specific therapeutic benefit. Finally, the described tool is available online for rapid classification of CRC samples, both in the format of an automated image analysis pipeline to score tumour core staining, and as a classifier based on semi-quantitative pathology scoring
Associations of non-pedunculated T1 colorectal adenocarcinoma outcome with consensus molecular subtypes, immunoscore, and microsatellite status: a multicenter case-cohort study
Advanced colorectal cancer (CRC) consensus molecular subtype 4 (CMS4) or CRC with a low immunoscore is associated with shorter survival times. Non-metastatic CRC with microsatellite instability (MSI) is associated with a lower risk of recurrence. We evaluated outcome (lymph node metastases [LNM] or cancer recurrence) in these tumor subtypes in patients with surgically-removed non-pedunculated T1 CRC by performing a multicenter case-cohort study. We included all patients in 13 hospitals in the Netherlands from 2000-2014 (nn=n651). We randomly selected a subgroup of patients (nn=n223) and all patients with LNM or recurrence (nn=n63), and median follow-up of 44 months. We centrally reviewed tumor-slides, and constructed and immunostained tissue microarrays determining MSI, CMS (MSI/CMS1, CMS2/3, or CMS4), and immunoscore (I-low/I-high). We used weighted Cox proportional hazard models to evaluate the association of MSI, CMS, and immunoscore with LNM or recurrence, adjusting for conventional histologic risk factors. In the randomly selected subgroup of patients, 7.1% of tumors were MSI/CMS1, 91.0% CMS2/3, 1.8% CMS4, and 25% I-low. In the case-cohort, patients with CMS4 tumors had an increased risk for LNM or recurrence compared with patients with tumors of other CMSs (adjusted hazard ratio [HR], 3.97; 95% CI, 1.12-14.06; Pn=n0.03). Albeit not significant, tumors with MSI had a lower risk for LNM or recurrence than other tumor subtypes (adjusted HR, 0.52; 95% CI, 0.12-2.30; Pn=n0.39), whereas tumors with a low immunoscore had an increased risk for LNM or recurrence (adjusted HR, 1.30; 95% CI, 0.68-2.48; Pn=n0.43). In conclusion, in a case-cohort study of patients with non-pedunculated T1 CRC, MSI, and immunoscore were not significantly associated with adverse outcome after surgery. CMS4 substantially increased the risk of adverse outcome. However, CMS4 is rare in T1 CRCs, limiting its value for determining the risk in patients