Exosomes are membrane vesicles which offer potential as blood derived biomarkers for malign tumors in clinical practice. Pancreatic cancer is counted among cancer diseases with the highest mortality. ...The present work seeks to assess whether pancreatic carcinomas release exosomes which express c-Met (proto-oncogene mesenchymal-epithelial transition factor) and PD-L1 (programmed cell death 1 ligand 1), and whether the detection of such expression in serum has diagnostic or prognostic meaning for the affected patients. Exosome isolation was performed on culture media of one benign pancreatic cell line and ten pancreatic carcinoma cell lines as well as on serum samples from 55 patients with pancreatic ductal adenocarcinoma (PDAC), 26 patients with chronic pancreatitis and 10 patients with benign serous cyst adenoma of the pancreas. Exosomes were bound to latex beads and stained with antibodies against c-Met or PD-L1. Analysis of fluorescence intensity was performed by flow cytometry. In terms of c-Met, the mean fluorescence intensity of PDAC-patients was significantly higher than the fluorescence intensity of the comparative patients with benign disease (
< 0.001). A diagnostic test based on c-Met resulted in a sensitivity of 70%, a specificity of 85% and a diagnostic odds ratio of 13:2. The specificity of the test can be further improved by combining it with the established tumor marker carbohydrate antigen 19-9 (CA 19-9). In addition, c-Met-positive patients showed a significantly shorter postoperative survival time (9.5 vs. 21.7 months,
< 0.001). In terms of PD-L1, no significant difference between fluorescence intensity of PDAC-patients and comparative patients was detectable. However, PD-L1-positive PDAC-patients also showed a significantly shorter postoperative survival time (7.8 vs. 17.2 months,
= 0.043). Thus, both markers can be considered as negative prognostic factors.
Pancreatic ductal adenocarcinoma (PDAC) responds poorly to checkpoint blockade, such as anti-CTLA-4 and anti-PD-1. Galectin-9, a β-galactoside-binding lectin, promotes immune suppression through ...T-cell inhibition, and programming of tolerogenic macrophages. Of all cancers tested, PDAC showed the highest expression of LGALS9 (galectin-9) mRNA. We analyzed formalin-fixed and paraffin-embedded specimens from 83 patients with PDAC stained for galectin-9. Using flow cytometry, we determined galectin-9 expression on immune cells from tumor and matched blood samples from 12 patients with resectable PDAC. Furthermore, we analyzed galectin-9 serum levels by enzyme-linked immunosorbent assay using serum samples from 70 patients with PDAC, from 36 individuals with benign pancreatic disease, and from 28 healthy controls. Galectin-9 was highly expressed in human PDAC compared with normal pancreas and present on both tumor and immune cells. Tumor-infiltrating immune cells, especially CD3
T cells, showed upregulation of galectin-9 compared with immune cells from matched blood. Blood γδ T cells from PDAC patients had higher galectin-9 expression than γδ T cells from healthy individuals. Galectin-9 polarized macrophages toward a protumoral M2 phenotype leading to suppressed T-cell cytokine secretion. Furthermore, serum concentration of galectin-9 was able to discriminate PDAC from benign pancreatic disease and healthy individuals, and was prognostic for stage IV patients. Galectin-9 is a new biomarker for the detection of PDAC.
Cancer is one of the leading causes of death worldwide. This life-threatening disease requires novel strategies for the early detection and therapy response prediction. Circulating DNA was first ...described 70 years ago. However, only the recent evolution in the PCR-based sequencing techniques allow the minimally invasive molecular profiling of circulating mutant DNA from small-volume "liquid biopsies" such as blood, urine, or saliva. In this article, we aim to summarize the fast-growing evidence for cfDNA and exosomal DNA as minimally invasive diagnostic markers in solid tumors and to highlight their opposing diagnostic advantages and disadvantages.
Background
Intraoperative bile analysis during pancreatoduodenectomy (PD) is performed routinely at specialized centers worldwide. However, it remains controversial if and how intraoperative ...bacterobilia during PD affects morbidity and its management. The aim of the study was a systematic review and meta-analysis of intraoperative bacterobilia and its impact on patient outcome after PD.
Methods
Five relevant outcomes of interest were defined, and a systematic review of the literature with meta-analysis was performed according to the PRISMA guidelines.
Results
A total of 28 studies (8523 patients) were included. The median incidence of bacterobilia was 58% (interquartile range 51–67%). The most frequently isolated bacteria were Enterococcus species (51%), Klebsiella species (28%), and
Escherichia coli
(27%). Preoperative biliary drainage was significantly associated with bacterobilia (86 vs. 25%; RR 3.27; 95% confidence interval (CI) 2.42–4.42;
p
< 0.001). The incidence of surgical site infections (SSI) was significantly increased in cases with bacterobilia (RR 2.84; 95% CI 2.17–3.73;
p
< 0.001). Postoperative pancreatic fistula, overall postoperative morbidity, and mortality were not significantly influenced. Identical bacteria in bile and the infectious sources were found in 48% (interquartile range 34–59%) of the cases.
Conclusions
Bacterobilia is detected during almost every second PD and is associated with an increased rate of SSI. The microbiome from intraoperative bile and postoperative infectious sources match in ~50% of patients, providing the option of early administration of calculated antibiotics and the determination of resistance patterns.
Molecular reprogramming of stromal microarchitecture by tumour-derived extracellular vesicles (EVs) is proposed to favour pre-metastatic niche formation. We elucidated the role of extravesicular ...tissue inhibitor of matrix metalloproteinase-1 (TIMP1
) in pro-invasive extracellular matrix (ECM) remodelling of the liver microenvironment to aid tumour progression in colorectal cancer (CRC). Immunohistochemistry analysis revealed a high expression of stromal TIMP1 in the invasion front that was associated with poor progression-free survival in patients with colorectal liver metastases. Molecular analysis identified TIMP1
enrichment in CRC-EVs as a major factor in the induction of TIMP1 upregulation in recipient fibroblasts. Mechanistically, we proved that EV-mediated TIMP1 upregulation in recipient fibroblasts induced ECM remodelling. This effect was recapitulated by human serum-derived EVs providing strong evidence that CRC release active EVs into the blood circulation of patients for the horizontal transfer of malignant traits to recipient cells. Moreover, EV-associated TIMP1 binds to HSP90AA, a heat-shock protein, and the inhibition of HSP90AA on human-derived serum EVs attenuates TIMP1
-mediated ECM remodelling, rendering EV-associated TIMP1 a potential therapeutic target. Eventually, in accordance with REMARK guidelines, we demonstrated in three independent cohorts that EV-bound TIMP1 is a robust circulating biomarker for a non-invasive, preoperative risk stratification in patients with colorectal liver metastases.
The tumor edge of colorectal cancer and its adjacent peritumoral tissue is characterized by an invasion front‐specific expression of genes that contribute to angiogenesis or epithelial‐to‐mesenchymal ...transition. Dysregulation of these genes has a strong impact on the invasion behavior of tumor cells. However, the invasion front‐specific expression of microRNA (miRNA) still remains unclear. Therefore, the aim of the present study was to investigate miRNA expression patterns at the invasion front of colorectal liver metastases. Laser microdissection of colorectal liver metastases was performed to obtain separate tissue compartments from the tumor center, tumor invasion front, liver invasion front and pure liver parenchyma. Microarray expression analysis revealed 23 miRNA downregulated in samples from the tumor invasion front with respect to the same miRNA in the liver, the liver invasion front or the tumor center. By comparing samples from the liver invasion front with samples from pure liver parenchyma, the tumor invasion front and the tumor center, 13 miRNA were downregulated. By quantitative RT‐PCR, we validated the liver invasion front‐specific downregulation of miR‐19b, miR‐194, let‐7b and miR‐1275 and the tumor invasion front‐specific downregulation of miR‐143, miR‐145, let‐7b and miR‐638. Univariate analysis demonstrated that enhanced expression of miR‐19b and miR‐194 at the liver invasion front, and decreased expression of let‐7 at the tumor invasion front, is an adverse prognostic marker of tumor recurrence and overall survival. In conclusion, the present study suggests that invasion front‐specific downregulation of miRNA in colorectal liver metastases plays a pivotal role in tumor progression. (Cancer Sci 2011; 102: 1799–1807)
Exosomes are small membrane vesicles of endocytic origin with a size of 50–100 nm. They can contain microRNAs, mRNAs, DNA fragments, and proteins, which are shuttled from a donor cell to recipient ...cells. Many different cell types including immune cells, mesenchymal cells, and cancer cells release exosomes. There is emerging evidence that cancer-derived exosomes contribute to the recruitment and reprogramming of constituents associated with tumor environment. Here, we discuss different mechanisms associated with biogenesis, payload, and transport of exosomes. We highlight the functional relevance of exosomes in cancer, as related to tumor microenvironment, tumor immunology, angiogenesis, and metastasis. Exosomes may exert an immunosuppressive function as well as trigger an anti-tumor response by presenting tumor antigens to dendritic cells. Exosomes may serve as cancer biomarkers and aid in the treatment of cancer.
Abstract
Background
Colorectal cancer stands as a prevalent cause of cancer-related mortality, necessitating effective treatment strategies. Acute colonic obstruction occurs in approximately 20% of ...patients and represents a surgical emergency with substantial morbidity and mortality. The optimal approach for managing left-sided colon cancer with acute colonic obstruction remains debatable, with no consensus on whether emergency resection or bridge-to-surgery, involving initial decompressing stoma and subsequent elective resection after recovery, should be employed. Current studies show a decrease in morbidity and short-term mortality for the bridge-to-surgery approach, yet it remains unclear if the long-term oncological outcome is equivalent to emergency resection.
Methods
This prospective, randomized, multicenter trial aims to investigate the management of obstructive left-sided colon cancer in a comprehensive manner. The study will be conducted across 26 university hospitals and 40 academic hospitals in Germany. A total of 468 patients will be enrolled, providing a cohort of 420 evaluable patients, with an equal distribution of 210 patients in each treatment arm. Patients with left-sided colon cancer, defined as cancer between the left splenic flexure and > 12 cm ab ano and obstruction confirmed by X-ray or CT scan, are eligible. Randomization will be performed in a 1:1 ratio, assigning patients either to the oncological emergency resection group or the bridge-to-surgery group, wherein patients will undergo diverting stoma and subsequent elective oncological resection after recovery. The primary endpoint of this trial will be 120-day mortality, allowing for consideration of the time interval between diverting stoma and resection.
Discussion
The findings derived from this trial possess the potential to reshape the current clinical approach of emergency resection for obstructive left-sided colon cancer by favoring the bridge-to-surgery practice, provided that a reduction in morbidity can be achieved without compromising the oncological long-term outcome.
Trial registration
German Clinical Trials Register (DRKS) under the identifier DRKS00031827. Registered on May 15, 2023.
Protocol: 28.04.2023, protocol version 2.0F.
Tumor infiltrating T lymphocytes in colorectal cancer (CRC) have prognostic impact, but the role of natural killer (NK) cells in CRC tissue is unclear. The contribution of intratumoral cytokines and ...chemokines in shaping the composition of the inflammatory lymphocytic infiltrate is also unclear.
In this study, localization and densities of NK and T cells within primary CRC, CRC liver metastases, adenomas, and normal tissues were analyzed on whole tissue sections from 112 patients. In a subset of these patients, the most important 50 cytokines and chemokines were quantified in paired serum, primary CRC and adjacent mucosa samples and in CRC liver metastases and correlated with NK and T-cell infiltration, respectively.
The various compartments displayed characteristic differences like significantly higher chemokine concentrations in CRC tissue. Most importantly, despite high local chemokine levels, NK cells were generally scarce within CRC tumor tissues, independent of human leukocyte antigen (HLA) class I expression. Adjacent normal mucosa contained normal levels of NK cells. In contrast, corresponding T-cell numbers varied substantially and were positively correlated with higher chemokine levels.
Our findings indicate a distinct regulation of NK cells versus T cells in the CRC tumor microenvironment. NK-cell migration into CRC tumor tissue is obviously impaired early during tumor development by mechanisms that do not affect T-cell infiltration.
CRC with liver metastases is a major contributor to cancer-related mortality. Despite advancements in liver resection techniques, patient survival remains a concern due to high recurrence rates. This ...study seeks to uncover prognostic biomarkers that predict overall survival in patients undergoing curative hepatic resection for CRC liver metastases.
Prospectively collected serum samples from a cohort of 49 patients who received curative hepatic resection for CRC liver metastases were studied. The patients are part of a cohort, previously analyzed for perioperative complications (see methods). Various preoperative serum markers, clinical characteristics, and factors were analyzed. Univariate and multivariate Cox regression analyses were conducted to determine associations between these variables and disease-free survival as well as overall survival.
For disease-free survival, univariate analysis highlighted the correlation between poor outcomes and advanced primary tumor stage, high ASA score, and synchronous liver metastases. Multivariate analysis identified nodal-positive primary tumors and synchronous metastases as independent risk factors for disease-free survival. Regarding overall survival, univariate analysis demonstrated significant links between poor survival and high preoperative IL-8 levels, elevated neutrophil-lymphocyte ratio (NLR), and presence of metastases in other organs. Multivariate analysis confirmed preoperative IL-8 and having three or more liver metastases as independent risk factors for overall survival. The impact of IL-8 on survival was particularly noteworthy, surpassing the influence of established clinical factors.
This study establishes preoperative IL-8 levels as a potential prognostic biomarker for overall survival in patients undergoing curative liver resection for CRC liver metastases. This study underscores the importance of incorporating IL-8 and other biomarkers into clinical decision-making, facilitating improved patient stratification and tailored treatment approaches. Further research and validation studies are needed to solidify the clinical utility of IL-8 as a prognostic marker.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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