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  • 1
    Abstract: Colorectal mixed adenoneuroendocrine carcinomas are rare and clinically aggressive neoplasms with considerable morphological heterogeneity. Data on their genomic characteristics and molecular associations to either conventional colorectal adenocarcinomas or poorly differentiated neuroendocrine neoplasms is still scarce, hampering optimized patient treatment and care. Tissue from 19 colorectal mixed adenoneuroendocrine carcinomas and eight colorectal poorly differentiated neuroendocrine neoplasms (neuroendocrine carcinomas) was microdissected and subjected to next-generation sequencing using a colorectal adenocarcinoma-specific panel comprising 196 amplicons covering 32 genes linked to colorectal adenocarcinoma, and poorly differentiated neuroendocrine neoplasm tumorigenesis. Mixed adenoneuroendocrine carcinomas were also examined for microsatellite instability and MLH-1 promoter methylation status. In three mixed adenoneuroendocrine carcinomas, exocrine and endocrine components were analyzed separately. Genetic testing of colorectal mixed adenoneuroendocrine carcinomas identified 43 somatic mutations clustering in 13/32 genes. Sixteen (84%) tumors harbored at least one somatic mutation, two tumors (11%) displayed high microsatellite instability. Compared with colorectal adenocarcinomas, mixed adenoneuroendocrine carcinomas were more frequently BRAF (37%; P=0.006), and less frequently KRAS (21%; P=0.043) and APC (16%; P=0.001) mutated. Point mutations in neuroendocrine neoplasm-related genes like RB1 or RET were not detected, but one tumor harbored a heterozygous RB1 deletion. Separately analyzed adenocarcinoma and neuroendocrine carcinoma components revealed a shared mutational trunk of driver genes involved in colorectal adenocarcinoma carcinogenesis. Colorectal neuroendocrine carcinomas were similar in their mutation profile to colorectal adenocarcinomas, but compared with mixed adenoneuroendocrine carcinomas, had a higher rate of APC mutations (P=0.027). Our data indicate that colorectal mixed adenoneuroendocrine carcinomas and neuroendocrine carcinomas are genetically closely related to colorectal adenocarcinomas, suggesting that the cells giving rise to these tumors primarily have an intestinal coinage. The identification of BRAF mutations and the frequently present KRAS wild-type status principally render some mixed adenoneuroendocrine carcinomas eligible to targeted treatment strategies used for colorectal adenocarcinomas.
    Type of Publication: Journal article published
    PubMed ID: 28059096
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  • 2
    Abstract: Somatostatin receptor 2A expression is a feature of well-differentiated neuroendocrine neoplasms and is important for their diagnosis and therapy. Little is known about somatostatin receptor 2A expression in poorly differentiated neuroendocrine neoplasms in relation to TP53 and RB1 status and how these features may contribute to the separation of well from poorly differentiated neuroendocrine neoplasms with a proliferation index above 20%. This study investigates the expression of somatostatin receptors, p53 and Rb1, and TP53 alterations in pancreatic and extrapancreatic well and poorly differentiated neuroendocrine neoplasms (Ki67-index 〉20%). Thirty-seven poorly differentiated neuroendocrine neoplasms of pancreatic (n=12) and extrapancreatic origin (n=25) as well as 10 well-differentiated neuroendocrine neoplasms of the pancreas (n=9) and rectum (n=1) with a Ki67-index 〉20% were immunostained for synaptophysin, chromogranin A, Ki67, CD56, p53, Rb1, ATRX, DAXX, progesterone receptor, somatostatin receptor 2A, somatostatin receptor 5, and cytokeratin 20, and sequenced for TP53, exons 5-9. Somatostatin receptor 2A was positive in 6/37 of poorly differentiated and in 8/10 of well-differentiated neuroendocrine neoplasms. One well-differentiated and two poorly differentiated neuroendocrine neoplasms expressed somatostatin receptor 5. Abnormal nuclear p53 and Rb1 staining was found in 29/37 and 22/37 poorly differentiated neuroendocrine neoplasms, respectively, whereas all well-differentiated neuroendocrine neoplasms showed normal p53 and Rb1 expression. TP53 gene alterations were restricted to poorly differentiated neuroendocrine neoplasms (24/34) and correlated well with p53 expression. All cases were progesterone receptor negative. Somatostatin receptor 2A expression is not limited to well-differentiated neuroendocrine neoplasms but also occurs in 16% of poorly differentiated neuroendocrine neoplasms from various sites. Most poorly differentiated neuroendocrine neoplasms are characterized by TP53 alterations and Rb1 loss, usually in the absence of somatostatin receptor 2A expression. In the pancreas, these criteria contribute to separate well-differentiated neuroendocrine neoplasms with a Ki67-index above 20% from poorly differentiated neuroendocrine neoplasms.
    Type of Publication: Journal article published
    PubMed ID: 28059098
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  • 3
    Abstract: PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is associated with a dismal prognosis and poor therapeutic response to current chemotherapy regimens in unselected patient populations. Recently, it has been shown that PDAC may be stratified into functionally and therapeutically relevant molecular subgroups and that some of these subtypes can be recapitulated by immunohistochemistry for KRT81 (QM/squamous/basal like) and HNF1A (non-QM, overlap with exocrine/ADEX subtype). EXPERIMENTAL DESIGN: We validated the different outcome of the HNF1A / KRT81 PDAC subtypes in two independent cohorts of surgically treated patients and examined the treatment response to chemotherapy in a third cohort of unresectable patients. The first two cohorts included 262 and 130 patients, respectively, and the third independent cohort comprised advanced-stage PDAC patients who were either treated with FOLFIRINOX (64 patients) or Gemcitabine (61 patients). RESULTS: In both cohorts with resected PDAC the HNF1A-positive subtype showed the best, the KRT81-positive subtype the worst and the double negative subtype an intermediate survival (p 〈0.013 and 〈0.009, respectively). In the chemotherapy cohort the survival difference between the double negative and the HNF1A-positive subtype was lost, while the dismal prognosis of KRT81-positive PDAC patients was retained (p 〈0.021). Patients with a KRT81-positive subtype did not benefit from FOLFIRINOX-therapy, while those with HNF1A-positive tumors responded better compared to Gemcitabine-based treatment (p 〈0.038). CONCLUSIONS: Immunohistochemical stratification recapitulating molecular subtypes of PDAC using HNF1A and KRT81 is associated with significantly differing outcomes and responses to chemotherapy. These results may pave the way towards future pretherapeutic biomarker based stratification of PDAC patients.
    Type of Publication: Journal article published
    PubMed ID: 29101303
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  • 4
    Abstract: Esophageal squamous cell carcinoma (ESCC) is the most common esophageal cancer associated with poor prognosis and additional therapeutic strategies must be implemented to optimize ESCC treatment. Meanwhile, the important biologic role and potential prognostic and therapeutic implications of a tumors immunologic microenvironment (IM) have been recognized in various cancers.In order to investigate the contexture and the prognostic relevance of the IM in ESCC, we immunohistochemically evaluated the extent of overall/intraepithelial TILs (CD3+/CD8+) and of PD-1 / PD-L1 expression in a cohort of 125 therapy-naive ESCCs, additionally assessing PD-L1 copy number status via fluorescence in-situ hybridization.High intraepithelial CD3+ TILs (CD3ihigh) and high PD-L1 expression on tumor cells (PD-L1high) were each significantly associated with improved overall- (OS) (CD3+: p = 0.019; PD-L1: p = 0.028), disease specific- (DSS) (CD3+: p = 0.05; PD-L1: p = 0.006) and disease free survival (DFS) (CD3+: p = 0.009; PD-L1: p 〈 0.001). CD3ihigh- and PD-L1high cases were significantly associated with one another (p 〈 0.001). Subgrouping of ESCC revealed decreased OS (p = 0.031), DSS (p = 0.012) and DFS (p 〈 0.001) for CD3ilow/PD-L1low cancers.Our data not only associate CD3ihigh- and PD-L1high ESCC with a beneficial outcome, but also demonstrate PD-L1high- and CD3ihigh status to be closely intertwined. Furthermore, our study demarcates a prognostically unfavorable, "non-immunoreactive" CD3ilow / PD-L1low ESCC-subgroup, potentially forming the basis for an immune-based stratification of ESCC.
    Type of Publication: Journal article published
    PubMed ID: 28657901
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  • 5
    Abstract: The UICC TNM (tumour-node-metastasis) staging system for pancreatic ductal adenocarcinoma (PDAC) has been a matter of debate over decades because survival prediction based on T stages was weak and unreliable. To improve staging, the recently published 8th TNM edition (2016) introduced a conceptually completely changed strictly size-based T staging system and a refined N stage for PDAC. To investigate the clinical value of the novel TNM classification, we compared the prognostic impact of pT and pN stage between the 7th and 8th edition in two well-characterised independent German PDAC cohorts from different decades, including a total number of 523 patients. Former UICC T staging (7th edition 2009) resulted in a clustering of pT3 cases (72% and 85% of cases per cohort, respectively) and failed to show significant prognostic differences between the four stages in one of the investigated cohorts (p = 0.074). Application of the novel size-based T stage system resulted in a more equal distribution of cases between the four T categories with a predominance of pT2 tumours (65% and 60% of cases). The novel pT staging algorithm showed greatly improved discriminative power with highly significant overall differences between the four pT stages in both investigated cohorts in univariate and multivariate analyses (p 〈 0.001, each). In contrast, no prognostic differences were observed between the recently introduced pN1 and pN2 categories in both cohorts (p = 0.970 and p = 0.061). pT stage of resected PDAC patients according to the novel UICC staging protocol (8th edition) significantly improves patient stratification, whereas introduction of an extended N stage protocol does not demonstrate high clinical relevance in our cohorts.
    Type of Publication: Journal article published
    PubMed ID: 28802189
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  • 6
    Abstract: The determination of prognosis in patients with esophageal squamous cell carcinoma (ESCC) is primarily based on staging according to the TNM-classification, whereas conventional grading is of minor clinical importance because of its deficiencies in prognostic patient stratification. Recently, a novel, highly prognostic grading scheme based on budding activity and cell nest size has been proposed for squamous cell carcinoma (SCC) of both pulmonary as well as oral origin. In order to investigate the utility and transferability of this approach to ESCC, we evaluated budding activity and cell nest size, as well as other histomorphologic characteristics, in a cohort of 135 primarily resected tumors and correlated the results with clinicopathologic and outcome parameters. High budding activity and small cell nest size showed a strong association with reduced overall, disease-specific, and disease-free survival (P〈0.001, respectively) in ESCC. The combination of both markers in a 3-step grading system showed excellent prognostic separation of well-differentiated (G1), moderately differentiated (G2), and poorly differentiated (G3) carcinomas (P〈0.001). The hazard ratio for disease-free survival in multivariate analysis under inclusion of stage was 2.97 for G2 and 5.42 for G3 ESCC (P〈0.001). World Health Organization-based grading had no prognostic impact. Taken together, our data prove the value of tumor budding and cell nest size as excellent outcome predictors in ESCC and validate the utility of a previously established grading scheme proposed for oral and pulmonary SCC in this tumor entity. Ultimately, these combined efforts may result in a universal grading system for SCC regardless of the site of origin.
    Type of Publication: Journal article published
    PubMed ID: 28505009
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  • 7
    Publication Date: 2018-02-10
    Description: In the light of novel cancer immune therapies, the status of antitumor inflammatory response and its regulation has gained much attention in patients with lung cancer. Ample datasets exist for non-small-cell lung cancer, but those for pulmonary neuroendocrine tumors are scarce and controversial. Here, tumor-associated inflammation, CD8+ cell infiltration and PD-L1 status were evaluated in a cohort of 57 resected carcinoids and 185 resected neuroendocrine carcinomas of the lung (58 large cell carcinomas and 127 small cell carcinomas). Data were correlated with clinicopathological factors and survival. Moderate or high tumor-associated inflammation was detected in 4 carcinoids (7%) and in 37 neuroendocrine carcinomas (20%). PD-L1 immunoreactivity was seen in immune cells of 73 (39%) neuroendocrine carcinomas, while tumor cells were labeled in 21 (11%) cases. Inflammatory cells and tumor cells in carcinoids lacked any PD-L1 expression. In neuroendocrine carcinomas, PD-L1 positivity in immune cells, but not in tumor cells, was associated with intratumoral CD8+ cell infiltration ( P 〈 0.001), as well as with the severity of tumor-associated inflammation ( P 〈 0.001). In neuroendocrine carcinomas, tumor-associated inflammation and PD-L1 positivity in immune cells correlated with prolonged survival and the latter factor was also an independent prognosticator ( P 〈 0.01, hazard ratio 0.4 for overall survival, P 〈 0.001 hazard ratio 0.4 for disease-free survival). Taken together, in neuroendocrine tumors, antitumor inflammatory response and PD-L1 expression are largely restricted to neuroendocrine carcinomas, and in this tumor entity, PD-L1 expression in inflammatory cells is positively correlated to patient survival.
    Print ISSN: 1351-0088
    Electronic ISSN: 1479-6821
    Topics: Medicine
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  • 8
    Publication Date: 2018-01-17
    Description: Purpose: Pancreatic ductal adenocarcinoma (PDAC) is associated with a dismal prognosis and poor therapeutic response to current chemotherapy regimens in unselected patient populations. Recently, it has been shown that PDAC may be stratified into functionally and therapeutically relevant molecular subgroups and that some of these subtypes can be recapitulated by IHC for KRT81 [quasi-mesenchymal (QM)/squamous/basal-like] and HNF1A (non-QM, overlap with exocrine/ADEX subtype). Experimental Design: We validated the different outcome of the HNF1A/KRT81 PDAC subtypes in two independent cohorts of surgically treated patients and examined the treatment response to chemotherapy in a third cohort of unresectable patients. The first two cohorts included 262 and 130 patients, respectively, and the third independent cohort comprised advanced-stage PDAC patients who were treated with either FOLFIRINOX (64 patients) or gemcitabine (61 patients). Results: In both cohorts with resected PDAC, the HNF1A-positive subtype showed the best, the KRT81-positive subtype the worst, and the double-negative subtype an intermediate survival ( P 〈 0.013 and P 〈 0.009, respectively). In the chemotherapy cohort, the survival difference between the double-negative and the HNF1A-positive subtype was lost, whereas the dismal prognosis of KRT81-positive PDAC patients was retained ( P 〈 0.021). Patients with a KRT81-positive subtype did not benefit from FOLFIRINOX therapy, whereas those with HNF1A-positive tumors responded better compared with gemcitabine-based treatment ( P 〈 0.038). Conclusions: IHC stratification recapitulating molecular subtypes of PDAC using HNF1A and KRT81 is associated with significantly different outcomes and responses to chemotherapy. These results may pave the way toward future pretherapeutic biomarker-based stratification of PDAC patients. Clin Cancer Res; 24(2); 351–9. ©2017 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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