430 research outputs found
Assessment of pathological response to therapy using lipid mass spectrometry imaging.
In many cancers, the establishment of a patient's future treatment regime often relies on histopathological assessment of tumor tissue specimens in order to determine the extent of the 'pathological response' to a given therapy. However, histopathological assessment of pathological response remains subjective. Here we use MALDI mass spectrometry imaging to generate lipid signatures from colorectal cancer liver metastasis specimens resected from patients preoperatively treated with chemotherapy. Using these signatures we obtained a unique pathological response score that correlates with prognosis. In addition, we identify single lipid moieties that are overexpressed in different histopathological features of the tumor, which have potential as new biomarkers for assessing response to therapy. These data show that computational methods, focusing on the lipidome, can be used to determine prognostic markers for response to chemotherapy and may potentially improve risk assessment and patient care
MRNA expression profiles of colorectal liver metastases as a novel biomarker for early recurrence after partial hepatectomy
Background: Identification of specific risk groups for recurrence after surgery for isolated colorectal liver metastases (CRLM) remains challenging due to the heterogeneity of the disease. Classical clinicopathologic parameters have limited prognostic value. The aim of this study was to identify a gene expression signature measured in CRLM discriminating early from late recurrence after partial hepatectomy. Methods: CRLM from two patient groups were collected: I) with recurrent disease ≤12 months after surgery (N = 33), and II) without recurrences and disease free for ≥36 months (N = 30). The patients were clinically homogeneous; all had a low clinical risk score (0-2) and did not receive (neo-) adjuvant chemotherapy. Total RNA was hybridised to Illumina arrays, and processed for analysis. A leave-one-out cross validation (LOOCV) analysis was performed to identify a prognostic gene expression signature. Results: LOOCV yielded an 11-gene profile with prognostic value in relation to recurrent disease ≤12 months after partial hepatectomy. This signature had a sensitivity of 81.8%, with a specificity of 66.7% for predicting recurrences (≤12 months) versus no recurrences for at least 36 months after surgery (X2 P < 0.0001). Conclusion: The current study yielded an 11-gene signature at mRNA level in CRLM discriminating early from late or no relapse after partial hepatectomy
Histopathological growth patterns of colorectal liver metastasis exhibit little heterogeneity and can be determined with a high diagnostic accuracy
Colorectal liver metastases (CRLM) exhibit distinct histopathological growth patterns (HGPs) that are indicative of prognosis following surgical treatment. This study aims to assess the reliability and replicability of this histological biomarker. Within and between metastasis HGP concordance was analysed in patients who underwent surgery for CRLM. An independent cohort was used for external validation. Within metastasis concordance was assessed in CRLM with ≥ 2 tissue blocks. Similarly, concordance amongst multiple metastases was determined in patients with ≥ 2 resected CRLM. Diagnostic accuracy [expressed in area under the curve (AUC)] was compared by number of blocks and number of metastases scored. Interobserver agreement (Cohen’s k) compared to the gold standard was determined for a pathologist and a PhD candidate witho
Immunosenescence in wild animals:Meta-analysis and outlook
Immunosenescence, the decline in immune defense with age, is an important mortality source in elderly humans but little is known of immunosenescence in wild animals. We systematically reviewed and meta-analysed evidence for age-related changes in immunity in captive and free-living populations of wild species (321 effect sizes in 62 studies across 44 species of mammals, birds and reptiles). As in humans, senescence was more evident in adaptive (acquired) than innate immune functions. Declines were evident for cell function (antibody response), the relative abundance of naive immune cells and an in vivo measure of overall immune responsiveness (local response to phytohaemagglutinin injection). Inflammatory markers increased with age, similar to chronic inflammation associated with human immunosenescence. Comparisons across taxa and captive vs free-living animals were difficult due to lack of overlap in parameters and species measured. Most studies are cross-sectional, which yields biased estimates of age-effects when immune function co-varies with survival. We therefore suggest longitudinal sampling approaches, and highlight techniques from human cohort studies that can be incorporated into ecological research. We also identify avenues to address predictions from evolutionary theory and the contribution of immunosenescence to age-related increases in disease susceptibility and mortality
Semiautomated isolation and molecular characterisation of single or highly purified tumour cells from CellSearch enriched blood samples using dielectrophoretic cell sorting
Background: Molecular characterisation of single circulating tumour cells (CTCs) holds considerable promise for predictive biomarker assessment and to explore CTC heterogeneity. We evaluate a new method, the DEPArray system, that allows the dielectrophoretic manipulation and isolation of single and 100% purified groups of CTCs from pre-enriched blood samples and explore the feasibility of their molecular characterisation.Methods:Samples containing known numbers of two cell populations were used to assess cell loss during sample loading. Cultured breast cancer cells were isolated from spiked blood samples using CellSearch CTC and Profile kits. Single tumour cells and groups of up to 10 tumour cells were recovered with the DEPArray system and subjected to transcriptional and mutation analysis.Results:On average, 40% cell loss was observed when loading samples to the DEPArray system. Expected mutations in clinically relevant markers could be obtained for 60% of single recovered tumour cells and all groups of tumour cells. Reliable gene expression profiles were obtained from single cells and groups of up to 10 cells for 2 out of 3 spiked breast cancer cell lines.Conclusion:We describe a semiautomated workflow for the isolation of small groups of 1 to 10 tumour cells from whole blood samples and provide proof of principle for the feasibility of their comprehensive molecular characterisation
Enrichment of the tumour immune microenvironment in patients with desmoplastic colorectal liver metastasis
Background: Patients with resected colorectal liver metastasis (CRLM) who display only the desmoplastic histopathological growth pattern (dHGP) exhibit superior survival compared to patients with any non-desmoplastic growth (non-dHGP). The aim of this study was to compare the tumour microenvironment between dHGP and non-dHGP. Methods: The tumour microenvironment was investigated in three cohorts of chemo-naive patients surgically treated for CRLM. In cohort A semi-quantitative immunohistochemistry was performed, in cohort B intra
Salvage treatment for recurrences after first resection of colorectal liver metastases: the impact of histopathological growth patterns
The majority of patients recur after resection of colorectal liver metastases (CRLM). Patients with CRLM displaying a desmoplastic histopathological growth pattern (dHGP) have a better prognosis and lower probability of recurrence than patients
with non-dHGP CRLM. The current study evaluates the impact of HGP type on the pattern and treatment of recurrences after
first resection of CRLM. A retrospective cohort study was performed, including patients with known HGP type after complete
resection of CRLM. All patients were treated between 2000 and 2015. The HGP was determined on the CRLM resected at
first partial hepatectomy. The prognostic value of HGPs, in terms of survival outcome, in the current patient cohort were
previously published. In total 690 patients were included, of which 492 (71%) developed recurrent disease. CRLM displaying
dHGP were observed in 103 patients (21%). Amongst patients with dHGP CRLM diagnosed with recurrent disease, more
liver-limited recurrences were seen (43% vs. 31%, p=0.030), whereas patients with non-dHGP more often recurred at multiple locations (34% vs. 19%, p=0.005). Patients with dHGP CRLM were more likely to undergo curatively intended local
treatment for recurrent disease (adjusted odds ratio: 2.37; 95% confidence interval (CI) [1.46–3.84]; p<0.001) compared
to patients with non-dHGP. The present study demonstrates that liver-limited disease recurrence after complete resection o
Angiogenic desmoplastic histopathological growth pattern as a prognostic marker of good outcome in patients with colorectal liver metastases
Abstract
Background In patients with resectable colorectal liver metastases (CRLM), distinct histopathological growth patterns
(HGPs) develop at the interface between the tumour and surrounding tissue. The desmoplastic (d) HGP is characterised by
angiogenesis and a peripheral fibrotic rim, whereas non-angiogenic HGPs co-opt endogenous sinusoidal hepatic vasculature.
Evidence from previous studies has suggested that patients with dHGP in their CRLM have improved prognosis as compared
to patients with non-desmoplastic HGPs. However, these studies were relatively small and applied arbitrary cut-off values
for the determination of the predominant HGP. We have now investigated the
Decreased expression of ABAT and STC2 hallmarks ER-positive inflammatory breast cancer and endocrine therapy resistance in advanced disease
Background: Patients with Estrogen Receptor α-positive (ER+) Inflammatory Breast Cancer (IBC) are less responsive to endocrine therapy compared with ER+ non-IBC (nIBC) patients. The study of ER+ IBC samples might reveal biomarkers for endocrine resistant breast cancer. Materials & methods: Gene expression profiles of ER+ samples from 201 patients were explored for genes that discriminated between IBC and nIBC. Classifier genes were applied onto clinically annotated expression data from 947 patients with ER+ breast cancer and validated with RT-qPCR for 231 patients treated with first-line tamoxifen. Relationships with metastasis-free survival (MFS) and progression-free survival (PFS) following adjuvant and first-line endocrine treatment, respectively, were investigated using Cox regression analysis. Results: A metagene of six genes including the genes encoding for 4-aminobutyrate aminotransferase (ABAT) and Stanniocalcin-2 (STC2) were identified to distinguish 22 ER+ IBC from 43 ER+ nIBC patients and remained discriminatory in an independent series of 136 patients. The metagene and two genes were not prognostic in 517 (neo)adjuvant untreated lymph node-negative ER+ nIBC breast cancer patients. Only ABAT was related to outcome in 250 patients treated with adjuvant tamoxifen. Three independent series of in total 411 patients with advanced disease showed increased metagene scores and decreased expression of ABAT and STC2 to be correlated with poor first-line endocrine therapy outcome. The biomarkers remained predictive for first-line tamoxifen treatment outcome in multivariate analysis including traditional factors or published signatures. In an exploratory analysis, ABAT and STC2 protein expression levels had no relation with PFS after first-line tamoxifen. Conclusions: This study utilized ER+ IBC to identify a metagene including ABAT and STC2 as predictive biomarkers for endocrine therapy resistance
Histopathological growth patterns as biomarker for adjuvant systemic chemotherapy in patients with resected colorectal liver metastases
Adjuvant systemic chemotherapy (CTx) is widely administered in patients with colorectal liver metastases (CRLM). Histopathological growth patterns (HGPs) are an independent prognostic factor for survival after complete resection. This study
evaluates whether HGPs can predict the efectiveness of adjuvant CTx in patients with resected CRLM. Two main types of
HGPs can be distinguished; the desmoplastic type and the non-desmoplastic type. Uni- and multivariable analyses for overall
survival (OS) and disease-free survival (DFS) were performed, in both patients treated with and without preoperative chemotherapy. A total of 1236 patients from two tertiary centers (Memorial Sloan Kettering Cancer Center, New York, USA; Erasmus MC Cancer Institute, Rotterdam, The Netherlands) were included (period 2000–2016). A total of 656 patients (53.1%)
patients received preoperative chemotherapy. Adjuvant CTx was only associated with a superior OS in non-desmoplastic
patients that had not been pretreated (adjusted hazard ratio (HR) 0.52, 95% confdence interval (CI) 0.37–0.73, p<0.001),
and not in desmoplastic patients (adjusted HR 1.78, 95% CI 0.75–4.21, p=0.19). In pretreated patients no signifcant efect
of adjuvant CTx was observed, neither in the desmoplastic group (adjusted HR 0.83, 95% CI 0.49–1.42, p=0.50) nor in
the non-desmoplastic group (adjusted HR 0.96, 95% CI 0.71–1.29, p=0.79). Similar results were found for DFS, with a
superior DFS in non-desmoplastic patients treated with adjuvant CTx (HR 0.71, 95% CI 0.55–0.93, p<0.001) that were not
pretreated. Adjuvant CTx seems to improve OS and DFS after resection of non-desmoplastic CRLM. However, this efect
was only observed in patients that were not treated with chemotherap
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