29 Elevated Flt3L predicts long-term survival in patients with high-grade gastroenteropancreatic neuroendocrine neoplasms

BackgroundGastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) are a rare and heterogeneous family of tumors arising from the disseminated neuroendocrine system of the gastrointestinal tract and pancreas. Clinical management of high-grade GEP-NEN is challenging due to disease heterogeneity, illustrating the need for reliable biomarkers facilitating patient stratification and guiding treatment decisions. FMS-like tyrosine kinase 3 ligand (Flt3L) is emerging as a prognostic or predictive surrogate marker of host tumoral immune response and might enable stratification of patients with otherwise comparable tumor features.MethodsWe used RNAseq data from human foregut-derived pancreatic and gastric GEP-NEN to evaluate Flt3L gene expression in tumor tissue. The data set (n=54) represented the full range of NEN grades and differentiation, and expression levels were compared to healthy control tissue as well. We also analyzed circulating Flt3L levels in serum samples of a separate cohort of G2/G3 GEP-NEN (n=59) an healthy controls (n=4). The study was approved by the local ethics committee at Charité Universitätsmedizin Berlin, Germany (ethical approval number EA1/229/17) and patient informed consent was obtained.ResultsWe detected a prominent induction of Flt3L gene expression in individual G2 and G3 NEN, but not in G1 neuroendocrine tumors (NET). Flt3L mRNA expression levels in tumor tissue predicted disease related survival of patients with highly proliferative G2 and G3 NEN more accurately than the conventional criteria of grading or NEC/NET differentiation. High level Flt3L mRNA expression was associated with increased expression of genes related to immunogenic cell death, lymphocyte effector function and dendritic cell maturation, suggesting a less tolerogenic (more proinflammatory) phenotype of tumors with Flt3L induction. Importantly, circulating levels of Flt3L were also elevated in high grade NEN and correlated with patients´ progression-free and disease-related survival, thereby reflecting the results observed in tumor tissue.ConclusionsOur results suggest Flt3L as a surrogate marker of an inflammatory tumor microenvironment. Therefore, we propose Flt3L as a prognostic biomarker for high grade GEP-NEN. Flt3L measurements in serum, which can be easily be incorporated into clinical routine, may hold the promise to guide patient stratification and tailor treatment decisions and should be further evaluated, especially in the context of immunotherapies.Ethics ApprovalThe study was approved by the local ethics committee at Charité Universitätsmedizin Berlin, Germany (ethical approval number EA1/229/17) and patient informed consent was obtained.

Plasma Prokineticin 1, a prognostic biomarker in colorectal cancer patients with curative resection: a retrospective cohort study

Background Prokineticin 1 (PROK1) was reported as an angiogenic factor, which is associated with tumor progression, cell invasion, and metastasis in colorectal cancer. Although the association between PROK1 expression in primary cancer lesion and patient prognosis was reported, it is unclear whether plasma PROK1 concentration may be a predictive factor in colorectal cancer patients. This study investigated the association between PROK1 concentration in plasma and prognosis in colorectal cancer patients. Methods We measured preoperative PROK1 plasma levels using ELISA method, while PROK1 expression in primary cancer lesion was evaluated using immunohistochemistry (IHC). The association between plasma PROK1 levels and cancer-related survival rate (CRS) was evaluated. Additionally, we examined whether simultaneous PROK1 expression in both primary cancer lesions and plasma was correlated with CRS. The cancer-related survival rate was calculated using the Kaplan-Meier method, and survival estimates were compared using the log-rank test. Results We have gathered eligible 130 CRC patients retrospectively. Out of 130 patients, 61 (46.9%) were positive on IHC in primary cancer, and 69 (53.1%) were negative, while 43 (33.1%) had high-value PROK1 in plasma. Out of these 43, 30 (25.4%) also had concomitant higher IHC expression in primary cancer. The plasma PROK1 levels tended to increase with advancing stages. The plasma PROK1-positive group had a lower 5-year CRS than the negative group (63.6% vs. 88.2%; P = 0.006). Additionally, simultaneous PROK1 expression was associated with a more significant decrease of 5-year CRS than both negative groups in all stages (76.2% vs. 92.5%; P = 0.003) and stage III (59.3% vs. 84.5%; P = 0.047). Multivariate analysis showed simultaneous PROK1 expression was independently associated with worse CRS (HR, 1.97; 95% CI 1.20‑3.24, P < 0.01). Conclusion PROK1 expression in preoperative plasma reflects poor prognosis in patients undergoing curative resection for colorectal cancer. The plasma PROK1 level may be a potential predictive marker, especially in stage III colorectal cancer patients.

Elevated Flt3L Predicts Long-Term Survival in Patients with High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms

Background: The clinical management of high-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) is challenging due to disease heterogeneity, illustrating the need for reliable biomarkers facilitating patient stratification and guiding treatment decisions. FMS-like tyrosine kinase 3 ligand (Flt3L) is emerging as a prognostic or predictive surrogate marker of host tumoral immune response and might enable the stratification of patients with otherwise comparable tumor features. Methods: We evaluated Flt3L gene expression in tumor tissue as well as circulating Flt3L levels as potential biomarkers in a cohort of 54 patients with GEP-NEN. Results: We detected a prominent induction of Flt3L gene expression in individual G2 and G3 NEN, but not in G1 neuroendocrine tumors (NET). Flt3L mRNA expression levels in tumor tissue predicted the disease-related survival of patients with highly proliferative G2 and G3 NEN more accurately than the conventional criteria of grading or NEC/NET differentiation. High level Flt3L mRNA expression was associated with the increased expression of genes related to immunogenic cell death, lymphocyte effector function and dendritic cell maturation, suggesting a less tolerogenic (more proinflammatory) phenotype of tumors with Flt3L induction. Importantly, circulating levels of Flt3L were also elevated in high grade NEN and correlated with patients’ progression-free and disease-related survival, thereby reflecting the results observed in tumor tissue. Conclusions: We propose Flt3L as a prognostic biomarker for high grade GEP-NEN, harnessing its potential as a marker of an inflammatory tumor microenvironment. Flt3L measurements in serum, which can be easily be incorporated into clinical routine, should be further evaluated to guide patient stratification and treatment decisions.

Fused in Sarcoma (FUS) Expression May Predict Survival Outcomes of Patients With Advanced Squamous Cell Cervical Carcinoma

Because of its role in preserving DNA/RNA stability, there is an increasing number of studies addressing the relationship between Fused in Sarcoma (FUS) expression and cancer. However, the disparity in FUS/FUS oncogenic vs. tumor-suppressive roles may be attributed to the complex molecular pathways associated with FUS regulation in different cancer types, and its role in cervical carcinogenesis remains largely unexplored. Methods: We determined FUS protein expression in specimens of 61 patients with advanced cervical cancer. Long-term (> 10 years) clinical follow-up data for these patients were available, and we determined disease-free, cancer-related and overall survival as related to FUS expression. Results: There were no significant associations between FUS expression and patients’ age, tumor grade, and acute/late toxicity events related to treatment (either radiation alone or chemoradiation). However, multivariate Cox regression analysis for disease-free survival (recurrence), overall survival (death) and cancer-related survival showed that patients with high average FUS expression fared significantly better than their counterparts with low average FUS expression, both in terms of disease-free survival (HR = 0.31; 95%CI 0.12 to 0.77; p = 0.01) and cancer-related survival (HR = 0.41; 95%CI 0.17 to 0.98; p = 0.04). Conclusions: Our study shows that high FUS protein expression in advanced cervical cancer specimens is a potent harbinger of better prognosis, and can as such be used in clinical practice to help characterize patients and, possibly, plan treatment and follow-up strategies.

Prognostic Value of Long Non-Coding RNA Long Intergenic Non-Protein Coding RNA 1586 in Pancreatic Cancer

This study investigated the prognostic value of the long non-coding RNA (lncRNA) LINC01586 in pancreatic cancer. Three pancreatic cancer patients who received pancreaticoduodenectomies in our department in January 2019 were retrospectively selected. Cancer tissue and adjacent tissue samples were collected for high-throughput sequencing of lncRNAs. Among them, 221 lncRNAs were up-regulated and 235 were down-regulated. The expression of LINC01586 was decreased in pancreatic cancer patients (logFC = -3.308). An additional 74 tissue specimens were collected from pancreatic cancer patients from January 2011 to December 2016 for low-throughput validation. Patient samples were categorized into overexpression and low expression groups, based on the median LINC01586 expression level. The LINC01586 low expression group exhibited larger tumor size than the overexpression group (P < 0.001), while the low expression group exhibited a lower cancer-related survival rate than the overexpression group (one-year cancer-related survival rate: 55.6% vs. 89.2%, P < 0.001). Further analysis confirmed that low expression of LINC01586 was associated with poor prognosis for pancreatic cancer patients (OR = 0.169, 95% CI 0.066-0.437, P = 0.000). KEGG signaling pathway analysis was used to enrich LINC01586 target genes, and were mainly related to two metabolic pathways: insulin secretion (P = 0.011) and dopaminergic synapses (P = 0.0129), with SNAP25 as the core gene. The expression of LINC01586 and SNAP25were positively correlated in pancreatic cancer (R = 0.81 and P < 0.001). Together, our results indicate that LINC01586 may be used as a biomarker for prognosis predictions in pancreatic cancer patients, and its low expression is associated with poor prognosis.

Five Decades of Enucleations for Uveal Melanoma in One Center: More Tumors with High Risk Factors, No Improvement in Survival over Time

<b><i>Background:</i></b> In order to improve medical care for uveal melanoma (UM) patients, we need to monitor disease and survival to guide our research efforts. We analyzed the data of UM patients who underwent an enucleation at the Leiden University Medical Center over the last five decades and investigated trends in patient and tumor characteristics and survival. <b><i>Methods:</i></b> Data were collected from charts and pathology reports from all patients who underwent an enucleation for UM between 1973 and 2019 (<i>n</i> = 1,212), of which 1,066 were primary enucleations; data were analyzed according to five time periods: 1973–1979 (<i>n</i> = 209), 1980–1989 (<i>n</i> = 148), 1990–1999 (<i>n</i> = 174), 2000–2009 (<i>n</i> = 280), and 2010–2019 (<i>n</i> = 401). <b><i>Results:</i></b> Over time, mean patient age at the time of enucleation for UM increased from 54.9 to 64.7 years (<i>p</i> &#x3c; 0.001), more tumors showed histopathological involvement of the ciliary body (<i>p</i> &#x3c; 0.001), and were classified in a high TNM/AJCC class (<i>p</i> &#x3c; 0.001). Overall, the 5- and 10-year UM-related survival rates were 0.68 and 0.59, respectively. Over time, survival showed no change in patients with tumors in AJCC stages I or III, with recently a slightly worse survival in stage II UM (<i>p</i> = 0.02). <b><i>Conclusion:</i></b> Between 1973 and 2019, we found similar rates of UM-related survival following enucleation, although we noticed a strong increase in more unfavorable patient and tumor characteristics over time, such as an older age and larger tumor size. The lack of improvement indicates that more research should take place to develop adjuvant treatments to prevent metastases and efficient treatments once metastases develop.

Standard versus eversion-modified double-staple technique for low colorectal anastomoses after resection of rectal cancer

Purpose The double-staple technique, performed as either the standard procedure or after eversion of the rectal stump, is a well-established method of performing low colorectal anastomoses following the resection of rectal cancer. Eversion of the tumor-bearing ano-rectal stump was proposed to allow the linear stapler to be fired at a safe distance of clearance from the tumor. We conducted this study to compare the results of the standard versus the eversion-modified double-staple technique. Methods The subjects of this retrospective study were 753 consecutive patients who underwent low stapled colorectal anastomosis after resection of rectal cancer. The patients were divided into two groups according to the method of anastomosis used: Group A comprised 165 patients (22%) treated with the modified eversion technique and group B comprised 588 patients (78%) treated with the standard technique. The primary endpoints of the study were postoperative mortality, surgery-related morbidity, the number of sampled lymph nodes in the mesorectum, and late disease-related survival. Results Postoperative mortality was 1.2% in group A and 1.7% in group B (p = 0.66). Postoperative morbidity was 12% in group A and 11% in group B (p = 0.75). The mean number of sampled lymph nodes in the mesorectum was 23 (range 17–27) in group A and 24 (range 19–29) in group B (p = 0.06). The 5-year disease-related survival was 73% in group A and 74% in group B (p = 0.75). Conclusion The standard and eversion-modified double-staple techniques yield comparable results.