Pancreatic cancer is an extremely aggressive disease; although progress has been made in the last few years, the prognosis of these patients remains dismal. FOLFIRINOX is now considered a standard ...treatment in first-line setting, since it demonstrated an improved overall and progression-free survival vs gemcitabine alone. However, the enthusiasm over the benefit of this three-drug regimen is tempered by the associated increased toxicity profile, and many efforts have been made to improve the feasibility of this schedule. After a more recent phase Ⅲ trial showing an improved outcome over gemcitabine, the combination of gemcitabine/nab-paclitaxel emerged as another standard first-line treatment. However, this treatment is also associated with more side effects. In addition, despite initial promising data on the predictive role of SPARClevels, recent studies showed that these levels are not associated with nab-paclitaxel efficacy. The choice to use this treatment over FOLFIRINOX is therefore a topic of debate, also because no validated biomarkers to guide FOLFIRINOX treatment are available. In the era of actionable mutations and target agents it would be desirable to identify molecular factors or biomarkers to predict response to therapy in order to maximize the efficacy of treatment and avoid useless toxic effects for non-responding patients. However, until today the milestone of treatment for pancreatic cancer remains chemotherapy combinations, without predictive or monitoring tools existing to optimize therapy. This review analyzes the state-of-the-art treatments, promises and limitations of targeted therapies, ongoing trials and future perspectives, including potential role of microR NAs as predictive biomarkers.
The aim of the study was to identify plasma microRNA (miRNA) biomarkers for stratifying and monitoring patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) treated ...with FOLFIRINOX, and to investigate their functional roles.
FOLFIRINOX has become a standard therapy for patients with advanced PDAC and can be used to potentially downstage disease. However, only a subset of patients respond, and biomarkers to guide decision-making are urgently needed.
We used microarray-based profiling to discover deregulated miRNAs in pre- and postchemotherapy plasma samples from patients based on their progression-free survival (PFS) after FOLFIRINOX. Nine candidate plasma miRNAs were validated in an independent cohort (n = 43). The most discriminative plasma miRNA was correlated with clinicopathological factors and survival, and also investigated in an additional cohort treated with gemcitabine plus nab-paclitaxel. Expression patterns were further evaluated in matched tumor tissues. In vitro studies explored its function, key downstream gene-targets, and interaction with 5-fluorouracil, irinotecan, and oxaliplatin.
Plasma miR-181a-5p was significantly downregulated in non-progressive patients after FOLFIRINOX. In multivariate analysis, this decline correlated with improved PFS and overall survival, especially when combined with CA19-9 decline hazard ratio (HR) = 0.153, 95% confidence interval (CI), 0.067-0.347 and HR = 0.201, 95% CI, 0.070-0.576, respectively. This combination did not correlate with survival in patients treated with gemcitabine plus nab-paclitaxel. Tissue expression of miR-181a-5p reflected plasma levels. Inhibition of miR-181a-5p coupled with oxaliplatin exposure in pancreatic cell lines decreased cell viability.
Plasma miR-181a-5p is a specific biomarker for monitoring FOLFIRINOX response. Decline in plasma miR-181a-5p and CA19-9 levels is associated with better prognosis after FOLFIRINOX and may be useful for guiding therapeutic choices and surgical exploration.
This study examined the correlation between pancreatic microbiome and patients characteristics. Furthermore, we compared different duodenal materials to examine their reflection of the pancreatic ...microbiome.
Patients undergoing pancreatic surgery were included in the study. Characteristics of those patients were prospectively registered and sterile pancreatic biopsies were collected during surgery. After completion of the resection, duodenal fluid, -tissue and -swab were collected. Bacterial DNA was extracted and analyzed with IS-pro assay.
Paired samples of 51 patients were available for evaluation, including pancreatic biopsies from all patients, 22 duodenal fluids, 21 duodenal swabs and 11 duodenal tissues. The pancreatic microbiome consisted mostly of Proteobacteria followed by Firmicutes, Actinobacteria, Fusobacteria and Verrucomicrobia (FAFV) and Bacteroidetes. On species level, Enterococcus faecalis, Escherichia coli, and Enterobacter-Klebsiella were most abundant. In pancreatic biopsies, the total bacterial load and Proteobacteria load were significantly higher in patients with biliary drainage (54618.0 vs 5623.5; 9119.0 vs 2067.1). Patients who used proton pump inhibitors had a significantly higher total bacterial load (115964.7 vs 8495.8), more FAFV (66862.9 vs 1890.1), more Proteobacteria (24245.9 vs 2951.4) and more Bacteroidetes (542.5 vs 25.8). The head of the pancreas contained significantly more bacteria (21193.4 vs 2096.8) and more FAFV (5225.7 vs 19.0) compared to the tail, regardless of biliary drainage. Furthermore, the microbiome of all duodenal materials showed a weak correlation with the pancreatic microbiome.
Biliary drainage, use of proton pump inhibitors, and anatomic location of the pancreatic biopsy influence the pancreatic microbiome. Furthermore, the duodenal microbiome does not suffice as a surrogate for the pancreatic microbiome.
Background
Duodenal adenocarcinoma (DA) is a rare tumor for which survival data per treatment modality and disease stage are unclear. This systematic review and meta-analysis aims to summarize the ...current literature on patient outcome after surgical, (neo)adjuvant, and palliative treatment in patients with DA.
Methods
A systematic search was performed according to the preferred reporting items for systematic reviews and meta-analyses guidelines, to 25 April 2017. Primary outcome was overall survival (OS), specified for treatment strategy or disease stage. Random-effects models were used for the calculation of pooled odds ratios per treatment modality. Included papers were also screened for prognostic factors.
Results
A total of 26 observational studies, comprising 6438 patients with DA, were included. Of these, resection with curative intent was performed in 71% (range 53–100%) of patients, and 29% received palliative treatment (range 0–61%). The pooled 5-year OS rate was 46% after curative resection, compared with 1% in palliative-treated patients (OR 0.04, 95% confidence interval CI 0.02–0.09,
p
< 0.0001). Both segmental resection and pancreaticoduodenectomy allowed adequate assessment of lymph node involvement and resulted in similar OS. Lymph node involvement correlated with worse OS (pooled 5-year survival rate 21% for nodal metastases vs. 65% for node-negative disease; OR 0.17, 95% CI 0.11–0.27,
p
< 0.0001). In the current literature, no survival benefit for adjuvant therapy after curative resection was found.
Conclusion
Resection with curative intent, either pancreaticoduodenectomy or segmental resection, and lack of nodal metastases, favors survival for DA. Further studies exploring multimodality (neo)adjuvant therapy are warranted to investigate their benefit.
Blood-based liquid biopsies, including tumor-educated blood platelets (TEPs), have emerged as promising biomarker sources for non-invasive detection of cancer. Here we demonstrate that particle-swarm ...optimization (PSO)-enhanced algorithms enable efficient selection of RNA biomarker panels from platelet RNA-sequencing libraries (n = 779). This resulted in accurate TEP-based detection of early- and late-stage non-small-cell lung cancer (n = 518 late-stage validation cohort, accuracy, 88%; AUC, 0.94; 95% CI, 0.92–0.96; p < 0.001; n = 106 early-stage validation cohort, accuracy, 81%; AUC, 0.89; 95% CI, 0.83–0.95; p < 0.001), independent of age of the individuals, smoking habits, whole-blood storage time, and various inflammatory conditions. PSO enabled selection of gene panels to diagnose cancer from TEPs, suggesting that swarm intelligence may also benefit the optimization of diagnostics readout of other liquid biopsy biosources.
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•Tumor-educated platelet (TEP) RNA profiles allow for blood-based cancer diagnostics•Inflammatory conditions only minimally confound TEP-based cancer detection•Swarm intelligence algorithms enable efficient selection of biomarker gene panels•TEP gene panels enable support vector machine-based classification of lung cancer
Best et al. use particle-swarm optimization algorithms and RNA-seq of tumor-educated platelets from patients to generate RNA sets capable of identifying patients with non-small-cell lung cancer, including those having early stage, from individuals without cancer, including those having inflammatory conditions.
Background: An important focus of post-stroke physical therapy is to improve walking and walking capacity. However, many people after stroke experience difficulties with gait-related participation, ...which includes more than walking capacity alone. Gait-related participation involves walking with a participation goal and requires to deal with changes in the environment during walking and perform dual tasks, for example.Objective: To explore barriers and facilitators for gait-related participation from the perspective of people after stroke. This knowledge can contribute to the development of effective interventions to improve gait-related participation.Methods: Semi-structured interviews were conducted to investigate how people after stroke experience gait-related participation. Audio-recorded interviews were transcribed, anonymized, and analyzed thematically. Barriers and facilitators were categorized according to the International Classification of Functioning, Disability and Health (ICF) framework.Results: Twenty-one people after stroke participated. Median age was 65 years, median time since stroke 16 weeks. Barriers were reported in movement-related functions, cognitive functions, mobility, personal factors, and environmental factors. Facilitators were found on participation level and in personal and environmental factors, such as motivation and family support.Conclusion: People after stroke who were physically able to walk independently still described multiple barriers to gait-related participation in all components of the ICF framework.
•Landscape configuration defines mangrove and mudflat connectivity.•Macrobenthic communities are influenced by backyard mangrove forests.•Seascape consideration is critical in integrative, ...cross-habitat conservation.
Understanding the connectivity among seascape habitats is an important emerging topic in marine ecology and coastal management. Mangroves are known to provide many ecosystem services such as coastal protection and carbon cycling, but their functional relationships with adjacent benthic intertidal communities are less clear. We examined how spatial adjacency to mangroves affects macrobenthic communities of intertidal mudflats in a tropical estuarine ecosystem. In the Bijagós Archipelago, Guinea-Bissau, benthic macrofauna assemblages were compared among sampling locations with different connectivities between intertidal mudflats and mangrove stands. We explored how a single mangrove connectivity index (MCI), combining mangrove tidal basin size and the distance to the mangrove edge, affected macrobenthic composition, and compared this effect to sediment properties. In addition, we used structural equation modelling (SEM) and ordination to determine how different environmental predictors directly and indirectly affected macrobenthic communities. MCI strongly affected macrobenthic composition and species abundance, and SEM revealed that this effect contained both a direct component and an indirect component through mudflat NDVI (normalized difference vegetation index, an indicator for microphytobenthos). Sediment properties (grain size, organic matter) affected macrobenthos independently from MCI, nevertheless sediment properties were also affected by MCI. We show the importance of accounting for the seascape structure of tidal basins when investigating the connectivity between mangroves and macrobenthic communities of intertidal mudflats. As benthic macrofauna is a key food source for endangered fish and waders in these systems, our findings provide strong arguments for the integrative conservation of intertidal mudflats and mangroves at the seascape scale.
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