Serum miR-338-3p and miR-199b-5p are associated with the absolute neutrophil count in patients with resectable pancreatic cancer

Background: Several peripheral blood cell counts and immune ratios, such as the systemic immune-inflammation index (SII = platelet x neutrophil count/lymphocyte count) have prognostic value in patients with resectable pancreatic cancer (PDAC). Circulating microRNAs (miRNAs) are involved in various aspects of cancer and inflammation. We aimed to identify measurable circulating miRNAs in PDAC patients correlating with systemic inflammation parameters. Methods: A total of 42 PDAC patients was included in this study: twelve in the discovery (n = 6 SII low; n = 6 SII high) and 30 patients in the validation cohort (n = 19 SII low, n = 11 SII high). MiRNAs isolated from preoperative serum samples were measured with a 352 miRNA panel in the discovery cohort and individual miRNA primers in the validation cohort, using RT-qPCR (ID3EAL assays, MiRXES). Results: Only in the discovery cohort miR-328-3p, miR-338-3p, miR-1258 and miR-199b-5p were upregulated in high compared to low SII patients (fold difference ≥ 2, P<0.05). In the total cohort (n = 42) correlations were found between miR-338-3p (r = 0.48, P = 0.002) and miR-199b-5p (r = 0.44, P = 0.005) and the absolute neutrophil count. Conclusion: Circulating miR-338-3p and miR-199b-5p are correlated to the neutrophil count in the blood of PDAC patients, suggesting a potential role of circulating miRNAs in cancer immune evasion and systemic inflammation

The American Orthopaedic Foot and Ankle Society Ankle-Hindfoot Scale; Translation and validation of the Dutch language version for ankle fractures

Objectives The American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Scale is among the most commonly used instruments for measuring outcome of treatment in patients who sustained a complex ankle or hindfoot injury. It consists of a patient-reported and a physician-reported part. A validated, Dutch version of this instrument is currently not available. The aim of this study was to translate the instrument into Dutch and to determine the measurement properties of the AOFAS Ankle-Hindfoot Scale Dutch language version (DLV) in patients with a unilateral ankle fracture. Setting Multicentre (two Dutch hospitals), prospective observational study. Participants In total, 142 patients with a unilateral ankle fracture were included. Ten patients were lost to follow-up. Primary and secondary outcome measures Patients completed the subjective (patient-reported) part of the AOFAS Ankle-Hindfoot Scale-DLV. A physician or trained physician-assistant completed the physician-reported part. For comparison and evaluation of the measuring characteristics, the Foot Function Index and the Short Form-36 were completed by the patient. Descriptive statistics (including floor and ceiling effects), reliability (ie, internal consistency), construct validity, reproducibility (ie, test-retest reliability, agreement and smallest detectable change) and responsiveness were determined. Results The AOFAS-DLV and its subscales showed good internal consistency (Cronbach's α >0.90). Construct validity and longitudinal validity were proven to be adequate (76.5% of predefined hypotheses were confirmed). Floor effects were not present. Ceiling effects were present from 6 months onwards, as expected. Responsiveness was adequate, with a smallest detectable change of 12.0 points. Conclusions The AOFAS-DLV is a reliable, valid and responsive measurement instrument for evaluating functional outcome in patients with a unilateral ankle fracture. This implies that the questionnaire is suitable to compare different treatment modalities within this population or to compare outcome across hospitals. Trial registration The Netherlands Trial Register (NTR5613

Immune-related circulating miR-125b-5p and miR-99a-5p reveal a high recurrence risk group of pancreatic cancer patients after tumor resection

Clinical follow-up aided by changes in the expression of circulating microRNAs (miRs) may improve prognostication of pancreatic ductal adenocarcinoma (PDAC) patients. Changes in 179 circulating miRs due to cancer progression

Serum mir-373-3p and mir-194-5p are associated with early tumor progression during folfirinox treatment in pancreatic cancer patients

In this study, we explored the predictive value of serum microRNA (miRNA) expression for early tumor progression during FOLFIRINOX chemotherapy and its association with overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDAC). A total of 132 PDAC patients of all disease stages were included in this study, of whom 25% showed progressive disease during FOLFIRINOX according to the RECIST criteria. MiRNA expression was analyzed in serum collected before the start and after one cycle of chemotherapy. In the discovery cohort (n = 12), a 352-miRNA RT-qPCR panel was used. In the validation cohorts (total n = 120), miRNA expression was detected using individual RT-qPCR miRNA primers. Before the start of FOLFIRINOX, serum miR-373-3p expression was higher in patients with progressive disease compared to patients with disease control after FOLFIRINOX (Log2 fold difference (FD) 0.88, p = 0.006). MiR-194-5p expression after one cycle of FOLFIRINOX was lower in patients with progressive disease (Log2 FD −0.29, p = 0.044). Both miRNAs were predictors of early tumor progression in a multivariable model including disease stage and baseline CA19-9 level (miR-373-3p odds ratio (OR) 3.99, 95% CI 1.10–14.49; miR-194-5p OR 0.91, 95% CI 0.83–0.99). MiR-373-3p and miR-194-5p did not show an association with OS after adjustment for disease stage, baseline CA19-9, and chemotherapy response. In conclusion, high serum miR-373-3p before the start and low serum miR-194-5p after one cycle are associated with early tumor progression during FOLFIRINOX.</p

Circulating TP53 mutations are associated with early tumor progression and poor survival in pancreatic cancer patients treated with FOLFIRINOX

Background: Biomarkers predicting treatment response may be used to stratify pancreatic ductal adenocarcinoma (PDAC) patients for therapy. The aim of this study was to identify circulating tumor DNA (ctDNA) mutations that associate with tumor progression during FOLFIRINOX chemotherapy, and overall survival (OS). Methods: Circulating cell-free DNA was analyzed with a 57 gene next-generation sequencing panel using plasma samples of 48 PDAC patients of all disease stages. Patients received FOLFIRINOX as initial treatment. Chemotherapy response was determined on CT scans as disease control (n = 30) or progressive disease (n = 18) within eight cycles of FOLFIRINOX, based on RECIST 1.1 criteria. Results: Detection of a TP53 ctDNA mutation before start of FOLFIRINOX [odds ratio (OR) 10.51, 95% confidence interval (CI) 1.40–79.14] and the presence of a homozygous TP53 Pro72Arg germline variant (OR 6.98, 95% CI 1.31–37.30) were predictors of early tumor progression during FOLFIRINOX in multivariable analysis. Five patients presented with the combination of a TP53 ctDNA mutation before start of FOLFIRINOX and the homozygous Pro72Arg variant. All five patients showed progression during FOLFIRINOX. The combination of the TP53 mutation and TP53 germline variant was associated with shorter survival (median OS 4.4 months, 95% CI 2.6–6.2 months) compared with patients without any TP53 alterations (median OS 13.0 months, 95% CI 8.6–17.4 months). Conclusion: The combination of a TP53 ctDNA mutation before start of FOLFIRINOX and a homozygous TP53 Pro72Arg variant is a promising biomarker, associated with early tumor progression during FOLFIRINOX and poor OS. The results of this exploratory study need to be validated in an independent cohort

Preoperative serum ADAM12 levels as a stromal marker for overall survival and benefit of adjuvant therapy in patients with resected pancreatic and periampullary cancer

Background: We evaluated the stroma marker A Disintegrin And Metalloprotease 12 (ADAM12) as a preoperative prognostic and treatment-predictive marker for overall survival (OS) in pancreatic ductal adenocarcinoma (PDAC) and periampullary cancers. Methods: Materials were derived from the prospective nationwide Dutch Pancreas Biobank (2015–2017). We included patients who underwent resection because of PDAC/periampullary cancer or non-invasive IPMN (control group) and had a preoperative serum sample available. ADAM12 levels were dichotomized using a pre-defined cut-off (316 pg/mL). Univariable and multivariable Cox regression analyses (backward selection) were performed. Results: Median ADAM12 levels were 161 (IQR 79–352) pg/mL in 215 PDAC and periampullary adenocarcinomas. High ADAM12 levels (>316 pg/mL) predicted poor OS in the total group of pancreatic and periampullary adenocarcinomas (P = 0.04), but not after adjustment. In distal cholangiocarcinoma (n = 33), high ADAM12 levels predicted poor OS in univariable analysis (P = 0.02), but not in PDAC (P = 0.63). PDAC patients (n = 135) with high ADAM12 levels benefited from adjuvant treatment (median OS 27 vs 14 months, P = 0.02), whereas those with low levels did not (21 vs 21 months, P = 0.87). Conclusion: High circulating ADAM12 levels, as a proxy for activated stroma, predict survival benefit from adjuvant chemotherapy in PDAC, requiring validation in future studies