Publications by authors named "Julia S Johansen"

134 Publications

Cell-free DNA promoter hypermethylation as a diagnostic marker for pancreatic ductal adenocarcinoma - An external validation study.

Pancreatology 2021 May 8. Epub 2021 May 8.

Department of Gastrointestinal Surgery, Aalborg University Hospital, Denmark; Department of Clinical Medicine, Aalborg University, Denmark; Clinical Cancer Research Center, Aalborg University Hospital, Denmark.

Background: We recently identified a diagnostic prediction model based on promoter hypermethylation of eight selected genes in plasma cell-free (cf) DNA, which showed promising results as a diagnostic biomarker for pancreatic ductal adenocarcinoma (PDAC). The aim of the present study was to validate this biomarker profile in an external patient cohort and examine any additional effect of serum CA 19-9.

Methods: Patients with PDAC (n = 346, stage I-IV) and chronic pancreatitis (n = 25) were included. Methylation-specific PCR of a 28-gene panel was performed on serum cfDNA samples. The previously developed diagnostic prediction model (age>65 years, BMP3, RASSF1A, BNC1, MESTv2, TFPI2, APC, SFRP1 and SFRP2) was validated alone and in combination with serum CA 19-9 in this external patient cohort.

Results: Patients with PDAC had a higher number of hypermethylated genes (mean 8.11, 95% CI 7.70-8.52) than patients with chronic pancreatitis (mean 5.60, 95% CI 4.42-6.78, p = 0.011). Validation of the diagnostic prediction model yielded an AUC of 0.77 (95% CI 0.69-0.84). The combination of serum CA 19-9 and our test had an AUC of 0.93 (95% CI 0.89-0.96) in the primary study and 0.85 (95% CI 0.79-0.91) in the validation study.

Conclusion: In this validation study, PDAC was associated with a higher number of hypermethylated genes in serum cfDNA than chronic pancreatitis. Our diagnostic test was superior to the predictive value of serum CA 19-9 alone in both the primary and the validation study. The combination of our test with CA 19-9 may serve as a clinically useful diagnostic biomarker for PDAC.
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http://dx.doi.org/10.1016/j.pan.2021.05.003DOI Listing
May 2021

Lack of association of CD44-rs353630 and CHI3L2-rs684559 with pancreatic ductal adenocarcinoma survival.

Sci Rep 2021 Apr 7;11(1):7570. Epub 2021 Apr 7.

Department of Biology, University of Pisa, Via Derna 1, 56126, Pisa, Italy.

Although pancreatic ductal adenocarcinoma (PDAC) survival is poor, there are differences in patients' response to the treatments. Detection of predictive biomarkers explaining these differences is of the utmost importance. In a recent study two genetic markers (CD44-rs353630 and CHI3L2-rs684559) were reported to be associated with survival after PDAC resection. We attempted to replicate the associations in 1856 PDAC patients (685 resected with stage I/II) from the PANcreatic Disease ReseArch (PANDoRA) consortium. We also analysed the combined effect of the two genotypes in order to compare our results with what was previously reported. Additional stratified analyses considering TNM stage of the disease and whether the patients received surgery were also performed. We observed no statistically significant associations, except for the heterozygous carriers of CD44-rs353630, who were associated with worse OS (HR = 5.01; 95% CI 1.58-15.88; p = 0.006) among patients with stage I disease. This association is in the opposite direction of those reported previously, suggesting that data obtained in such small subgroups are hardly replicable and should be considered cautiously. The two polymorphisms combined did not show any statistically significant association. Our results suggest that the effect of CD44-rs353630 and CHI3L2-rs684559 cannot be generalized to all PDAC patients.
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http://dx.doi.org/10.1038/s41598-021-87130-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027406PMC
April 2021

Circulating Protein Biomarkers for Use in Pancreatic Ductal Adenocarcinoma Identification.

Clin Cancer Res 2021 May 18;27(9):2592-2603. Epub 2021 Mar 18.

Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumors. Most patients are diagnosed at an advanced stage where curative surgery is not an option. The aim of this study was to identify a panel of circulating proteins that could distinguish patients with PDAC from non-PDAC individuals.

Experimental Design: We investigated 92 proteins known to be involved in inflammation, development, and progression of PDAC using the Olink immuno-oncology panel in serum samples from 701 patients with PDAC (stage I-IV), 102 patients with nonmalignant pancreatic diseases, and 180 healthy blood donors. Patients were included prospectively between 2008 and 2018. Plasma carbohydrate antigen 19-9 (CA19-9) was measured in all samples. The protein panels with the best diagnostic performances were developed by two bioinformaticians working independently, using LASSO and Ridge regression models.

Results: Two panels of proteins (index I, containing 9 proteins + CA19-9, and index II, containing 23 proteins + CA19-9) were identified. Index I was able to discriminate patients with PDAC from all patients with non-PDAC, with a ROC AUC value of 0.92 [95% confidence interval (CI), 0.89-0.96] in the discovery cohort and 0.92 (95% CI, 0.87-0.97) in the replication cohort. For index II, the AUC value was 0.96 (95% CI, 0.95-0.98) in the discovery cohort and 0.93 (95% CI, 0.90-0.96) in the replication cohort. All nine serum proteins of index I were found in index II.

Conclusions: This study identified two circulating protein indices with the potential to discriminate between individuals with and without PDAC.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4215DOI Listing
May 2021

Noninvasive prognostic biomarker potential of quantifying the propeptides of Type XI collagen alpha-1 chain (PRO-C11) in patients with pancreatic ductal adenocarcinoma.

Int J Cancer 2021 07 22;149(1):228-238. Epub 2021 Mar 22.

Biomarkers & Research, Nordic Bioscience, Herlev, Denmark.

Type XI collagen has been associated with tumor fibrosis and aggressiveness in patients with pancreatic ductal adenocarcinoma (PDAC). The propeptide on Type XI collagen is released into the circulation after proteolytic processing at either amino acid 253 or 511. This allows for a noninvasive biomarker approach to quantify Type XI collagen production. We developed two ELISA-based biomarkers, targeting the two enzymatic cleavage sites (PRO-C11-253 and PRO-C11-511). In a discovery cohort including serum from patients with PDAC (n = 39, Stages 1-4), chronic pancreatitis (CP, n = 12) and healthy controls (n = 20), PRO-C11-511, but not PRO-C11-253, was significantly upregulated in patients with PDAC and CP compared to healthy controls. Furthermore, PRO-C11-511 levels >75th percentile were associated with poor overall survival (OS) (HR, 95% CI: 3.40, 1.48-7.83). The PRO-C11-511 biomarker potential was validated in serum from 686 patients with PDAC. Again, high levels of PRO-C11-511 (>75th percentile) were associated with poor OS (HR, 95% CI: 1.68, 1.40-2.02). Furthermore, PRO-C11-511 remained significant after adjusting for clinical risk factors (HR, 95% CI: 1.50, 1.22-1.86). In conclusion, quantifying serum levels of Type XI collagen with PRO-C11-511 predicts poor OS in patients with PDAC. This supports that Type XI collagen is important for PDAC biology and that PRO-C11-511 has prognostic noninvasive biomarker potential for patients with PDAC.
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http://dx.doi.org/10.1002/ijc.33551DOI Listing
July 2021

Geriatric assessment and intervention in older vulnerable patients undergoing surgery for colorectal cancer: a protocol for a randomised controlled trial (GEPOC trial).

BMC Geriatr 2021 01 30;21(1):88. Epub 2021 Jan 30.

Department of Medicine, Copenhagen University Hospital, Herlev and Gentofte, Borgmester Ib Juuls Vej 1, DK-2730, Herlev, Denmark.

Background: The incidence of colorectal cancer (CRC) increases with age. Older patients are a heterogeneous group ranging from fit to frail with various comorbidities. Frail older patients with CRC are at increased risk of negative outcomes and functional decline after cancer surgery compared to younger and fit older patients. Maintenance of independence after treatment is rarely investigated in clinical trials despite older patients value it as high as survival. Comprehensive geriatric assessment (CGA) is an evaluation of an older persons' medical, psychosocial, and functional capabilities to develop an overall plan for treatment and follow-up. The beneficial effect of CGA is well documented in the fields of medicine and orthopaedic surgery, but evidence is lacking in cancer surgery. We aim to investigate the effect of CGA on physical performance in older frail patients undergoing surgery for CRC.

Methods: GEPOC is a single centre randomised controlled trial including older patients (≥65 years) undergoing surgical resection for primary CRC. Frail patients (≤14/17 points using the G8 screening tool) will be randomised 1:1 to geriatric intervention and exercise (n = 50) or standard of care along (n = 50) with their standard surgical procedure. Intervention includes preoperative CGA, perioperative geriatric in-ward review and postoperative follow-up. All patients in the intervention group will participate in a pre- and postoperative resistance exercise programme (twice/week, 2 + 12 weeks). Primary endpoint is change in 30-s chair stand test. Assessment of primary endpoint will be performed by physiotherapists blinded to patient allocation. Secondary endpoints: changes in health related quality of life, physical strength and capacity (handgrip strength, gait speed and 6 min walking test), patient perceived quality of recovery, complications to surgery, body composition (Dual-energy X-ray absorptiometry and bioelectric impedance), serum biomarkers, readmission, length of stay and survival.

Discussion: This ongoing trial will provide valuable knowledge on whether preoperative CGA and postoperative geriatric follow-up and intervention including an exercise program can counteract physical decline and improve quality of life in frail CRC patients undergoing surgery.

Trial Registration: Prospectively registered at Clinicaltrials.gov NCT03719573 (October 2018).
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http://dx.doi.org/10.1186/s12877-021-02045-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847583PMC
January 2021

Prognostic value of blood-based fibrosis biomarkers in patients with metastatic colorectal cancer receiving chemotherapy and bevacizumab.

Sci Rep 2021 01 13;11(1):865. Epub 2021 Jan 13.

Biomarkers and Research, Nordic Bioscience, Herlev Hovedgade 205-207, 2730, Herlev, Denmark.

A desmoplastic colorectal cancer stroma, characterized by excess turnover of the cancer-associated fibroblast derived collagens type III and VI, can lead to reduced drug-uptake and poor treatment response. We investigated the association between biomarkers of collagen type III and VI and overall survival (OS) in patients with metastatic colorectal cancer (mCRC). Serum samples were collected from 252 patients with mCRC prior to treatment with bevacizumab and chemotherapy. Serum concentrations of biomarkers reflecting formation of collagen type III (PRO-C3) and VI (PRO-C6) and degradation of collagen type VI (C6M and C6Mα3) were determined by ELISA. The biomarkers were evaluated for associations with OS, individually, combined, and after adjusting for carcinoembryonic antigen (CEA), lactate dehydrogenase (LDH) and performance status (PS). High baseline levels (> median) of each collagen biomarker were significantly associated with shorter OS (PRO-C3: HR = 2.0, 95%CI = 1.54-2.63; PRO-C6: HR = 1.6, 95%CI = 1.24-2.11; C6M: HR = 1.4, 95%CI = 1.05-1.78; C6Mα3: HR = 1.6, 95%CI = 1.16-2.07). PRO-C3 and PRO-C6 remained significant after adjustment for CEA, LDH and PS. Weak correlations were seen between the collagen biomarkers (r = 0.03-0.59) and combining all improved prognostic capacity (HR = 3.6, 95%CI = 2.30-5.76). Collagen biomarkers were predictive of shorter OS in patients with mCRC. This supports that collagen- and CAF biology is important in CRC.
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http://dx.doi.org/10.1038/s41598-020-79608-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806753PMC
January 2021

Pre-treatment serum vitamin D deficiency is associated with increased inflammatory biomarkers and short overall survival in patients with pancreatic cancer.

Eur J Cancer 2021 02 17;144:72-80. Epub 2020 Dec 17.

Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark; Department of Medicine, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

Background: Vitamin D deficiency and inflammation are associated with increased mortality. We investigated the relationship between pre-treatment serum vitamin D levels, inflammatory biomarkers (IL-6, YKL-40 and CRP) and overall survival (OS) in pancreatic ductal adenocarcinoma (PDAC) patients.

Methods: Pre-treatment serum vitamin D, IL-6, YKL-40 and CRP levels were determined in 1,267 patients with PDAC enrolled from July 2008 to September 2018 in the prospective BIOPAC study (NCT03311776). The patients were grouped according to vitamin D levels: sufficient >50 nmol/L, insufficient 25-50 nmol/L and deficient <25 nmol/L.

Results: Across all tumour stages, vitamin D-deficient patients had the highest median levels of IL-6 (8.3 pg/mL, range 0.7-91), YKL-40 (177 ng/ml, range 25-5279) and CRP (15.5 mg/L, range 0.8-384). The resected stage I and II patients with vitamin D deficiencies had a shorter median OS, 18.3 months (95% CI, 12.1-31.5 months) than those with sufficient levels, 29.7 months (95% CI, 22.3-36.1 months), and the hazard ratio for death was 1.55 (95% CI, 1.04-2.31; p = 0.03). In advanced PDAC, there was no significant difference in OS between the vitamin D groups.

Conclusions: Vitamin D deficiency was associated with increased inflammatory biomarkers in all PDAC stages. The resected stage I and II patients with sufficient vitamin D levels had a higher OS than those with a vitamin D deficiency. However, there was no correlation between vitamin D levels and survival in advanced PDAC. Future studies need to investigate vitamin D supplementation effects on survival in PDAC.
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http://dx.doi.org/10.1016/j.ejca.2020.10.038DOI Listing
February 2021

Cetuximab plus irinotecan administered biweekly with reduced infusion time to heavily pretreated patients with metastatic colorectal cancer and related RAS and BRAF mutation status.

Int J Cancer 2020 Dec 17. Epub 2020 Dec 17.

Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.

Metastatic colorectal cancer (mCRC) is treated with cetuximab 250 mg/m administered weekly over 1 hour or biweekly (q2w) over 3.5 hours when combined with irinotecan. This prospective study investigated cetuximab 500 mg/m plus irinotecan 180 mg/m administered q2w over 1.5 hours independent of RAS or BRAF mutation status in mCRC patients in a third-line setting. The intention-to-treat population included 181 patients. No patients had complete response, 18% had partial responses (PR) and 48% stable disease (SD). For cetuximab, a relative dose intensity of ≥90% was reached in 78% and for irinotecan in 67% of the patients. Grade 3 to 4 toxicities were pain (17%), fatigue (9%), neutropenia (8%), diarrhea (8%), rash (8%), infection (7%) and hypersensitivity (3%). No deaths occurred. Next-generation sequencing in 96.7% of the patients revealed that 50.3% had RAS and BRAF wild type (WT), with a mutation type (MT) in 45.1% of the RAS and 4.4% of the BRAF genes. In patients with RAS-WT and RAS-MT tumors, a PR was obtained in 32% and 4% (P = .000003) and an SD in 43% and 53%, respectively, with a superior PFS (6.2 vs 3.7 months; hazard ratio [HR] 2.12, P = .00001) and OS (12.9 vs 8.8 months; HR 1.71, P = .0008). Treatment efficacy was poor in 7.4% of patients with an RAS mutation outside KRAS exon 2 and in 38% of patients with KRAS exon 2 mutations. Administration of cetuximab and irinotecan q2w, shortening treatment time from 3.5 to 1.5 hours, is recommended as standard therapy.
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http://dx.doi.org/10.1002/ijc.33448DOI Listing
December 2020

Prognostic and predictive value of circulating DNA for hepatic arterial infusion of chemotherapy for patients with colorectal cancer liver metastases.

Mol Clin Oncol 2020 Dec 24;13(6):77. Epub 2020 Sep 24.

Department of Experimental Clinical Oncology, Aarhus University Hospital, 8200 Aarhus N, Denmark.

Hepatic arterial infusion (HAI) of chemotherapy is an experimental treatment option for patients with colorectal cancer liver metastases (CRCLM). The current study aimed to investigate the predictive and prognostic value of cell free DNA (cfDNA) in patients with CRCLM receiving HAI with oxaliplatin and systemic capecitabine. Plasma samples from 62 patients were investigated who were included into a single arm phase II study investigating HAI treatment for patients with CRCLM. The clinical outcome of the trial has been presented previously. In brief, treatment consisted of intrahepatic infusion of oxaliplatin 100 mg/m every second week with concomitant oral capecitabine 3,500 mg/m every second week for up to 12 cycles. Blood samples were drawn at baseline and follow-up and plasma was analyzed for cell free DNA using a direct fluorescent assay. The baseline level of plasma cfDNA was 0.92 ng/µl (95% CI 0.84-1.00). Patients with a baseline value of cfDNA above the 75th quartile had a median overall survival of 2.4 years (95% CI 0.7-2.8), compared with 3.9 years (95% CI 2.8-5.9) for patients below the 75th quartile (P=0.02). The baseline level of cfDNA was significantly lower (0.91 ng/µl, 95% CI 0.76-0.98) in patients who achieved an objective response compared to non-responders (1.79 ng/µl; 95% CI 0.99-2.57; P=0.02). The current study demonstrated a possible prognostic and predictive value of cfDNA for patients with CRCLM undergoing HAI with oxaliplatin and concomitant capecitabine.
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http://dx.doi.org/10.3892/mco.2020.2147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523269PMC
December 2020

Serum IL6 as a Prognostic Biomarker and IL6R as a Therapeutic Target in Biliary Tract Cancers.

Clin Cancer Res 2020 11 15;26(21):5655-5667. Epub 2020 Sep 15.

Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Purpose: Biliary tract cancer (BTC) is a heterogeneous group of rare gastrointestinal malignancies with dismal prognosis often associated with inflammation. We assessed the prognostic value of IL6 and YKL-40 compared with CA19-9 before and during palliative chemotherapy. We also investigated in mice whether IL6R inhibition in combination with gemcitabine could prolong chemosensitivity.

Experimental Design: A total of 452 Danish participants with advanced (locally advanced and metastatic) BTC were included from six clinical trials (February 2004 to March 2017). Serum CA19-9, IL6, and YKL-40 were measured before and during palliative treatment. Associations between candidate biomarkers and progression-free survival (PFS) and overall survival (OS) were analyzed by univariate and multivariate Cox regression. Effects of inhibiting IL6R and YKL-40 were assessed , and of IL6R inhibition .

Results: High pretreatment levels of CA19-9, IL6, and YKL-40, and increasing levels during treatment, were associated with short PFS and OS in patients with advanced BTC. IL6 provided independent prognostic information, independent of tumor location and in patients with normal serum CA19-9. ROC analyses showed that IL6 and YKL-40 were predictive of very short OS (OS < 6 months), whereas CA19-9 was best to predict OS > 1.5 years. Treatment with anti-IL6R and gemcitabine significantly diminished tumor growth when compared with gemcitabine monotherapy in an transplant model of BTC.

Conclusions: Serum IL6 and YKL-40 are potential new prognostic biomarkers in BTC. IL6 provides independent prognostic information and may be superior to CA19-9 in certain contexts. Moreover, anti-IL6R should be considered as a new treatment option to sustain gemcitabine response in patients with BTC.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2700DOI Listing
November 2020

Elevated serum YKL-40, IL-6, CRP, CEA, and CA19-9 combined as a prognostic biomarker panel after resection of colorectal liver metastases.

PLoS One 2020 5;15(8):e0236569. Epub 2020 Aug 5.

Transplantation and Liver Surgery, Abdominal Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Background: The inflammatory biomarkers, YKL-40 and interleukin-6 (IL-6), are elevated in patients with metastatic colorectal cancer. We examined their associations with relapse-free survival and overall survival in combination with serum C-reactive protein (CRP), carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9) in patients with colorectal liver metastases.

Methods: Altogether 441 consecutive patients undergoing liver resection at Helsinki University Hospital between 1998 and 2013 were included in the study. Pre- and postoperative YKL-40 and IL-6 were determined from serum samples with commercially available enzyme-linked immunosorbent assay (ELISA) kits, and CRP, CEA, and CA19-9 by routine methods. Associations between these biomarkers and relapse-free and overall survival were examined using Cox regression analysis.

Results: Patients with 2-5 elevated biomarkers were at an increased risk of relapse compared to those with 0-1 elevated biomarkers, preoperatively (HR 1.37, 95% CI 1.1-1.72) or postoperatively (HR 1.54, 95% CI 1.23-1.92). Patients with 2-5 elevated biomarkers were also at an increased risk of death compared to those with 0-1 elevated biomarkers, preoperatively (HR 1.76, 95% CI 1.39-2.24) or postoperatively (HR 1.83, 95% CI 1.44-2.33).

Conclusion: The results suggest that a protein panel of the inflammatory biomarkers YKL-40, IL-6, and CRP, and the cancer biomarkers CEA and CA19-9 might identify patients that benefit from more aggressive treatment and surveillance, although the additional value of IL-6 and CRP in this aspect is limited.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236569PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406016PMC
October 2020

Prognosis and Reclassification by YKL-40 in Stable Coronary Artery Disease.

J Am Heart Assoc 2020 03 2;9(5):e014634. Epub 2020 Mar 2.

Department of Cardiology Rigshospitalet University of Copenhagen København Denmark.

Background The inflammatory biomarker YKL-40 has previously been studied as a potential risk marker in cardiovascular disease. We aimed to assess the prognostic reclassification potential of serum YKL-40 in patients with stable coronary artery disease. Methods and Results The main study population was the placebo group of the CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease) trial. The primary outcome was a composite of acute myocardial infarction, unstable angina pectoris, cerebrovascular disease, and all-cause mortality. We used Cox proportional hazards regression models adjusted for C-reactive protein level and baseline cardiovascular risk factors. Improvement in prediction by adding serum YKL-40 to the risk factors was calculated using the Cox-Breslow method and c-statistic. A total of 2200 patients were randomized to placebo, with a follow-up duration of 10 years. YKL-40 was associated with an increased risk of the composite outcome (hazard ratio per unit increase in (YKL-40) 1.13, 95% CI 1.03-1.24, =0.013) and all-cause mortality (hazard ratio 1.32, 95% CI 1.17-1.49, <0.0001). Considering whether a composite-outcome event was more likely to have, or not have, occurred to date, we found 68.4% of such predictions to be correct when based on the standard predictors, and 68.5% when serum YKL-40 was added as a predictor. Equivalent results were obtained with c-statistics. Conclusions Higher serum YKL-40 was independently associated with an increased risk of adverse cardiovascular outcomes and mortality. Addition of YKL-40 did not improve risk prediction in patients with stable coronary artery disease. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00121550.
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http://dx.doi.org/10.1161/JAHA.119.014634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335588PMC
March 2020

Prognostic impact of Charlson's Age-Comorbidity Index and other risk factors in patients with pancreatic cancer.

Eur J Cancer Care (Engl) 2020 May 6;29(3):e13219. Epub 2020 Jan 6.

Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.

Objectives: Few studies have evaluated the impact of risk factors and comorbidity on overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDAC). The aim was to investigate the prognostic importance of Charlson's age-comorbidity index (CACI) and other risk factors on prognosis in a clinical real-world cohort of PDAC patients.

Methods: A total of 1,159 patients with PDAC who had received at least one cycle of adjuvant or palliative chemotherapy were included from the Danish BIOPAC study. We analysed OS according to CACI, tobacco smoking, alcohol intake, performance status (PS), BMI and diabetes. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for OS using Cox proportional hazards regression.

Results: At the end of follow-up, 994 (86%) patients had died. The median OS was 298 days for all patients (range 3-3010) and shortest in patients with stage IV. No association with short OS was seen for CACI > 2, diabetes, alcohol abuse, tobacco smoking, hypertension, and high BMI. Multivariate analysis showed that stage (IV vs. I: HR = 9.05, 95% CI 5.17-15.84), PS (2 vs. 0: HR = 3.67, 2.92-4.61) and treatment with angiotensin-converting enzyme inhibitors (yes vs. no: HR = 1.31, 1.06-1.61) were independent negative prognostic factors.

Conclusions: We found that CACI, diabetes, tobacco smoking, alcohol abuse, hypertension, and high BMI were not associated with OS in a real-world cohort of patients with PDAC treated with chemotherapy. Only stage and PS were prognostic parameters.
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http://dx.doi.org/10.1111/ecc.13219DOI Listing
May 2020

Antitumour immunity invoked by hepatic arterial infusion of first-line oxaliplatin predicts durable colorectal cancer control after liver metastasis ablation: 8-12 years of follow-up.

Int J Cancer 2020 04 7;146(7):2019-2026. Epub 2020 Jan 7.

Department of Oncology, Akershus University Hospital, Lørenskog, Norway.

In colorectal cancer (CRC), hepatic arterial infusion (HAI) chemotherapy may convert primarily unresectable CRC liver metastases (CLM) into resectability, although the risk of metastatic recurrence remains high after CLM ablation. We investigated the role of antitumour immunity invoked by first-line oxaliplatin-HAI for long-term CLM outcome. In a prospective study cohort of primarily unresectable CLM, we assessed patients' fms-related tyrosine kinase 3 ligand (FLT3LG) in serum, reflecting opportune intratumoural immune activity, at baseline and following 1-3 sequences of oxaliplatin-HAI. The end points were CLM resectability and overall survival. Patients who presented an immediate twofold increment of circulating FLT3LG during the treatment and at its completion were scored as CLM resectable (16.4% with both features), were alive at final follow-up 8-12 years later. All patients experienced FLT3LG increase during the treatment course, but those who remained unresectable or had the disease converted but presented a slow and gradual FLT3LG accretion, later died of the metastatic disease. These data provide further support to our previous findings that tumour-directed immunity invoked by oxaliplatin-containing therapy predicts excellent outcome of early advanced CRC if macroscopic tumour ablation is rendered possible by the 'classic' tumour response to the cytotoxic treatment.
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http://dx.doi.org/10.1002/ijc.32847DOI Listing
April 2020

Prognostic Value of Combined Detection of Serum IL6, YKL-40, and C-reactive Protein in Patients with Unresectable Pancreatic Cancer.

Cancer Epidemiol Biomarkers Prev 2020 01 4;29(1):176-184. Epub 2019 Nov 4.

Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

Background: IL6 and YKL-40 (also known as chitinase 3-like 1 protein, CHI3L1) are produced by pancreatic cancer cells and macrophages and activate inflammation. C-reactive protein (CRP) is synthesized mainly in hepatic cells and primarily stimulated by IL6. The aim of this study was to determine the prognostic value of combined detection of serum IL6, YKL-40, and CRP in patients with pancreatic cancer receiving palliative chemotherapy.

Methods: In all, 592 patients with unresectable pancreatic cancer from five hospitals in Denmark were included in the BIOPAC biomarker study between 2008 and 2017. Pretreatment and longitudinal serum values of IL6 and YKL-40 were determined. Baseline CRP and CA19-9 values were available for the whole cohort. Patients were dichotomized as low versus high using cutoffs for IL6 of >4.92 pg/mL, YKL-40 of >95% age-corrected percentile, and CRP of >10 mg/L. The main outcome was overall survival.

Results: Combined elevations of serum IL6, YKL-40, and CRP were associated with worse survival in contrast to an isolated high concentration of a single marker. Serum IL6, YKL-40, and CRP were higher in patients with advanced stage disease and in patients with poor performance status. Higher IL6 and YKL-40 levels at the time of tumor progression and serum IL6 measured over time were associated with shorter overall survival.

Conclusions: Combined high baseline serum levels of IL6, YKL-40, and CRP are associated with poor survival.

Impact: Assessment of systemic inflammation via measurements of IL6, YKL-40, and CRP may be important for pancreatic cancer prognostication.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0672DOI Listing
January 2020

Clinical value of serum hyaluronan and propeptide of type III collagen in patients with pancreatic cancer.

Int J Cancer 2020 05 11;146(10):2913-2922. Epub 2019 Nov 11.

Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

Hyaluronan (HA) and collagen are highly expressed in pancreatic cancer (PC) stroma. HA and collagen accumulation increase tumor interstitial fluid pressure, compromising blood flow and drug penetration. The aim of this biomarker study was to determine the clinical utility of serum HA and the propeptide of type III collagen (PRO-C3) in patients with PC. A cohort from the Danish BIOPAC study (NCT03311776) including patients with histologically confirmed pancreatic ductal adenocarcinoma (n = 809), ampullary carcinoma (n = 44), distal biliary tract cancer (n = 31), chronic pancreatitis (n = 15), intraductal papillary mucinous neoplasm (n = 41), duodenal adenoma (n = 7) and no cancer (n = 25). Healthy controls were available for serum HA (n = 141) and PRO-C3 (n = 8). The main outcome was overall survival (OS) of patients with PC in relation to pretreatment serum HA and PRO-C3 levels. Patients with PC had higher baseline serum HA and PRO-C3 than healthy subjects and patients with benign conditions. Pretreatment serum baseline HA and PRO-C3 in patients with PC were associated with poorer survival and PRO-C3 remained prognostic also after adjusting for age, performance status, stage, the presence of liver and peritoneum metastasis, and CA19-9. Detection of HA and PRO-C3 may be useful in differentiating between malignant and benign pancreatic conditions. Serum HA and PRO-C3 were prognostic for OS in patients with PC.
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http://dx.doi.org/10.1002/ijc.32751DOI Listing
May 2020

Measured and genetically predicted plasma YKL-40 levels and melanoma mortality.

Eur J Cancer 2019 11;121:74-84

Department of Clinical Biochemistry, The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Denmark. Electronic address:

Purpose: High plasma levels of YKL-40 might be associated with mortality in patients with melanoma, and it is unknown if YKL-40 is causally related to mortality.

Experimental Design: We studied two cohorts: 2618 patients with melanoma from hospital clinics and 1413 general population patients with melanoma, totalling 4031 patients followed up for mortality end-points for up to 20 years. All were genotyped for CHI3L1 rs4950928, highly predictive of lifelong plasma YKL-40, and plasma YKL-40 levels were measured in 2165 patients. We tested the hypotheses that measured and genetically predicted high plasma YKL-40 are associated with increased mortality in patients with melanoma.

Results: For the hospital melanoma cohort, age- and sex-adjusted hazard ratios for death in individuals with measured plasma YKL-40 in the 96-100th percentile versus 1-95th percentile and per 10-percentile increase were 1.52 (95% confidence interval, 1.07-2.16) and 1.07 (1.02-1.11), respectively, most pronounced for patients with localised melanomas. Each C-allele of the CHI3L1 rs4950928 genotype was associated with plasma YKL-40 level increases of 32% in the hospital melanoma cohort (p = 6 × 10) and 43% in the general population melanoma cohort (p = 7 × 10). Multifactorially adjusted ratios for these increases in the combined cohorts were 1.04 (1.00-1.09) observationally for measured plasma YKL-40 and 0.98 (0.86-1.12) for the genetically predicted plasma YKL-40.

Conclusion: Measured, but not genetically predicted, increasing plasma YKL-40 was associated with increased mortality in patients with melanoma. Plasma YKL-40 is a marker but less likely to be a cause of increased mortality in patients with melanoma.
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http://dx.doi.org/10.1016/j.ejca.2019.08.025DOI Listing
November 2019

Genome-wide cell-free DNA fragmentation in patients with cancer.

Nature 2019 06 29;570(7761):385-389. Epub 2019 May 29.

Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Cell-free DNA in the blood provides a non-invasive diagnostic avenue for patients with cancer. However, characteristics of the origins and molecular features of cell-free DNA are poorly understood. Here we developed an approach to evaluate fragmentation patterns of cell-free DNA across the genome, and found that profiles of healthy individuals reflected nucleosomal patterns of white blood cells, whereas patients with cancer had altered fragmentation profiles. We used this method to analyse the fragmentation profiles of 236 patients with breast, colorectal, lung, ovarian, pancreatic, gastric or bile duct cancer and 245 healthy individuals. A machine learning model that incorporated genome-wide fragmentation features had sensitivities of detection ranging from 57% to more than 99% among the seven cancer types at 98% specificity, with an overall area under the curve value of 0.94. Fragmentation profiles could be used to identify the tissue of origin of the cancers to a limited number of sites in 75% of cases. Combining our approach with mutation-based cell-free DNA analyses detected 91% of patients with cancer. The results of these analyses highlight important properties of cell-free DNA and provide a proof-of-principle approach for the screening, early detection and monitoring of human cancer.
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http://dx.doi.org/10.1038/s41586-019-1272-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774252PMC
June 2019

Increased serological, cancer-associated protein biomarker levels at diagnosis of large bowel adenoma: Risk of subsequent primary malignancy?

Acta Oncol 2019 7;58(sup1):S42-S48. Epub 2018 Dec 7.

a Department of Surgical Gastroenterology, Center for Surgical Research , Hvidovre Hospital , Hvidovre , Denmark.

Background: Blood-based, cancer-associated biomarkers may detect subjects at risk of having neoplastic diseases. The aim of the present study was to evaluate whether elevated serological protein biomarker levels may identify adenoma patients, who are at increased risk of being diagnosed with subsequent primary malignancy.

Methods: Levels of CEA, CA19-9, TIMP-1 and YKL-40 were determined in blood samples collected prior to diagnostic bowel endoscopy due to symptoms of colorectal neoplasia. Follow-up time was ten years, and identified adenoma patients, who were diagnosed with subsequent primary intra- or extra-colonic malignant diseases. The biomarker levels were also determined in 400 subjects, who underwent diagnostic colonoscopy, had clean colorectum and were without apparent co-morbidity; these levels were used as reference levels. In the present study, biomarkers were interpreted as elevated when levels were above the reference intervals adjusting for age and gender. The 1-year and 5-years cumulative incidences were calculated.

Results: Primary malignancies were identified in 175 (19%) of the 923 subjects diagnosed with adenomas at the primary bowel endoscopy. In detail, 20 of the 175 subjects were diagnosed with colorectal cancer (CRC) and 155 subjects with extra-colonic cancers. Thirty patients were diagnosed with malignancy within the first year. Three groups were established: 0: no elevated biomarkers; 1: 1 of the 4 biomarkers elevated; and 2: ≥2 biomarkers elevated. The cumulative 5-years incidence of malignancy was: 0: 6.9%; 1: 11.8%; and 2: 17.5% (p = .0009).

Conclusion: Elevated blood-based, cancer-associated protein biomarker levels in subjects diagnosed with adenomas at large bowel endoscopy identifies subjects at increased risk of being diagnosed with subsequent primary malignancy.
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http://dx.doi.org/10.1080/0284186X.2018.1540885DOI Listing
August 2019

Stromal Content Is Correlated With Tissue Site, Contrast Retention, and Survival in Pancreatic Adenocarcinoma.

JCO Precis Oncol 2018 16;2018. Epub 2018 Jan 16.

Department of Medicine, University of California, San Francisco, USA.

Purpose: Desmoplastic stroma is a cardinal feature of primary pancreatic ductal adenocarcinoma (PDAC), but its effects on the biology, prognosis and therapeutic outcomes are not known. We developed an automated method to assess tumor stroma density (TSD) and investigated computed tomography (CT)-correlates of stroma in PDAC.

Patients And Methods: We collected PDAC samples from rapid autopsy and resection series and digitally annotated samples to quantify TSD. A series of resected patients also underwent preoperative multiphasic CT.

Results: Automated and manual assessments of TSD were highly correlated (ρ= 0.65, < 0.001). Solid organ metastases had a lower median TSD than primary tumors ( < 0.001). Patients with high TSD enjoyed prolonged recurrence free survival (RFS) ( = 0.003; HR = 0.51) and overall survival ( = 0.008, HR = 0.57). In another independent dataset, patients with high TSD had decreased risk for recurrence ( = 0.003, HR = 0.03) and death ( 0.003, HR = 0.03) at time of resection, however the protective effect diminished over time. Patients with normalized portovenous phase CT tumor enhancement ratio ≥0.40 had a longer RFS following resection ( = 0.020). Normalized portovenous phase CT tumor enhancement ratio was significantly correlated with TSD ( = 0.003).

Conclusions: Objective quantitative assessment of stroma in PDAC revealed several clinically relevant observations. Firstly, stroma was less abundant in metastatic PDAC, the cause of most PDAC mortality. Secondly, high stromal content correlates with favorable outcome in resected cases, implying a protective effect of stroma and suggesting careful consideration of active stromal depletion therapies. Finally, standard multiphase CT imaging correlates with stroma content as well as clinical outcome, indicating that non-invasive assessment of stroma is a feasible sensitivity enrichment approach in PDAC.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262879PMC
http://dx.doi.org/10.1200/PO.17.00121DOI Listing
January 2018

Total cell-free DNA, carcinoembryonic antigen, and C-reactive protein for assessment of prognosis in patients with metastatic colorectal cancer.

Tumour Biol 2018 Nov;40(11):1010428318811207

4 Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Hellerup, Denmark.

In late-stage metastatic colorectal cancer, difficult treatment decisions should incorporate a thorough evaluation of the patient's general condition and subject for shared decision making. Assessment of the individual patients' prognosis is valuable in this setting. The aim was to analyze the prognostic value of plasma levels of total cell-free DNA, carcinoembryonic antigen and C-reactive protein in 97 heavily pretreated patients with metastatic colorectal cancer. Patients received irinotecan, cetuximab, and everolimus in a phase-2 clinical trial ( clinicaltrials.gov NCT01387880). Plasma samples were used for DNA purification and quantification of total cell-free DNA by droplet digital polymerase chain reaction. Serum carcinoembryonic antigen and C-reactive protein were analyzed by routine methods. Clinical endpoints were overall survival and progression-free survival. A total of 82 patients had blood samples available for quantification of total cell-free DNA. Patients with pre-treatment cell-free DNA levels higher than the median total cell-free DNA (9800 alleles per milliliter plasma) had a significantly shorter overall survival of 4.3 months (95% confidence interval: 3.6-5.8) compared to patients with cell-free DNA levels below the median with an overall survival of 11.3 months (95% confidence interval: 8.0-14.8, p < 0.0001). When using the upper normal limit from a previously analyzed normal control group, the median overall survival was 11.3 (95% confidence interval: 7.3-14.8) and 4.3 (95% confidence interval: 3.7-6.1) months, respectively (p < 0.0001). Serum carcinoembryonic antigen and C-reactive protein had similar prognostic value with short overall survival and progression-free survival in patients with elevated levels compared to those within normal range. A high-risk profile of elevated cell-free DNA, carcinoembryonic antigen, and C-reactive protein was described, but in combined Cox regression multivariate analysis, only total cell-free DNA preserved a strong prognostic value. In conclusion, total cell-free DNA in plasma, carcinoembryonic antigen, and C-reactive protein could all contribute to assessment of patients' prognosis and potentially aid in clinical decision making in patients with metastatic colorectal cancer.
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http://dx.doi.org/10.1177/1010428318811207DOI Listing
November 2018

Age-dependent differences in first-line chemotherapy in patients with metastatic colorectal cancer: the DISCO study.

Acta Oncol 2018 Nov 30;57(11):1445-1454. Epub 2018 Oct 30.

b Department of Oncology , Herlev and Gentofte Hospital, Copenhagen University Hospital , Herlev , Denmark.

Objectives: First-line chemotherapy for metastatic colorectal cancer (mCRC) is effective and feasible in selected older patients. We investigated age-dependent differences in treatment and outcomes in patients with mCRC in clinical practice.

Material And Methods: A retrospective study of 654 patients with mCRC referred to first-line chemotherapy in 2008-2014. Patients were divided into two age groups: 50-69 and ≥70 (older patients). Binary outcomes were analyzed by logistic regression. Progression-free survival (PFS) and overall survival (OS) were analyzed by Cox proportional hazards regression, CRC-specific and other-cause mortality with Fine and Gray proportional hazard model for the sub-distribution of a competing risk.

Results: After adjusting for performance status (PS) and comorbidity, older patients were more likely to receive monotherapy (adjusted odds ratio (aOR) = 9.00, 95% confidence interval (CI) 4.52-17.91), lower doses, and no additional targeted therapy (aOR = 1.89, 95% CI 1.28-2.78) than younger patients. Yet, older patients experienced more toxicity and hospitalizations (aOR = 1.53, 95% CI 1.08-2.17). Among those treated, older patients had shorter PFS (hazard ratio (HR) = 1.32, 95% CI 1.11-1.57), but after adjusting for PS and comorbidity, PFS was similar. No significant difference was found in CRC mortality (HR = 1.15, 95% CI 0.95-1.40) between age groups. Poor PS was associated with shorter OS and PFS and higher CRC mortality.

Conclusions: In the DISCO study, older patients with mCRC received less aggressive first-line chemotherapy. Yet, they experienced more toxicity. Younger and older patients had similar CRC mortality. Shorter PFS and higher CRC mortality were observed in patients with poor PS.
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http://dx.doi.org/10.1080/0284186X.2018.1531299DOI Listing
November 2018

Serum Biomarker Signature-Based Liquid Biopsy for Diagnosis of Early-Stage Pancreatic Cancer.

J Clin Oncol 2018 10 14;36(28):2887-2894. Epub 2018 Aug 14.

Linda D. Mellby and Andreas P. Nyberg, Immunovia AB; Christer Wingren and Carl A.K. Borrebaeck, Lund University, Lund, Sweden; Julia S. Johansen, University of Copenhagen, Copenhagen; Børge G. Nordestgaard and Stig E. Bojesen, Copenhagen University Hospital, Herlev, Denmark; and Breeana L. Mitchell, Brett C. Sheppard, and Rosalie C. Sears, Oregon Health and Science University, Portland, OR.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 5-year survival of < 10% because of diffuse symptoms leading to late-stage diagnosis. That survival could increase significantly if localized tumors could be detected early. Therefore, we used multiparametric analysis of blood samples to obtain a novel biomarker signature of early-stage PDAC. The signature was derived from a large patient cohort, including patients with well-defined early-stage (I and II) PDAC. This biomarker signature was validated subsequently in an independent patient cohort.

Patients And Methods: The biomarker signature was derived from a case-control study, using a Scandinavian cohort, consisting of 16 patients with stage I, 132 patients with stage II, 65 patients with stage III, and 230 patients with stage IV PDAC, and 888 controls. This signature was validated subsequently in an independent case-control cohort in the United States with 15 patients with stage I, 75 patients with stage II, 15 patients with stage III, and 38 patients with stage IV PDAC, and 219 controls. An antibody microarray platform was used to identify the serum biomarker signature associated with early-stage PDAC.

Results: Using the Scandinavian case-control study, a biomarker signature was created, discriminating samples derived from patients with stage I and II from those from controls with a receiver operating characteristic area under the curve value of 0.96. This signature, consisting of 29 biomarkers, was then validated in an independent case-control study in the United States. The biomarker signature could discriminate patients with stage I and II PDAC from controls in this independent patient cohort with a receiver operating characteristic area under the curve value of 0.96.

Conclusion: This serum biomarker signature might represent a tenable approach to detecting early-stage, localized PDAC if these findings are supported by a prospective validation study.
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http://dx.doi.org/10.1200/JCO.2017.77.6658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161836PMC
October 2018

Measuring KRAS Mutations in Circulating Tumor DNA by Droplet Digital PCR and Next-Generation Sequencing.

Transl Oncol 2018 Oct 4;11(5):1220-1224. Epub 2018 Aug 4.

Department of Clinical Biochemistry, Aarhus University Hospital, Denmark. Electronic address:

Measuring total cell-free DNA (cfDNA) or cancer-specific mutations herein has presented as new tools in aiding the treatment of cancer patients. Studies show that total cfDNA bears prognostic value in metastatic colorectal cancer (mCRC) and that measuring cancer-specific mutations could supplement biopsies. However, limited information is available on the performance of different methods. Blood samples from 28 patients with mCRC and known KRAS mutation status were included. cfDNA was extracted and quantified with droplet digital polymerase chain reaction (ddPCR) measuring Beta-2 Microglobulin. KRAS mutation detection was performed using ddPCR (Bio-Rad) and next-generation sequencing (NGS, Ion Torrent PGM). Comparing KRAS mutation status in plasma and tissue revealed concordance rates of 79% and 89% for NGS and ddPCR. Strong correlation between the methods was observed. Most KRAS mutations were also detectable in 10-fold diluted samples using the ddPCR. We find that for detection of KRAS mutations in ctDNA ddPCR was superior to NGS both in analysis success rate and concordance to tissue. We further present results indicating that lower amount of plasma may be used for detection of KRAS mutations in mCRC.
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http://dx.doi.org/10.1016/j.tranon.2018.07.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6085225PMC
October 2018

Systematic literature review of IL-6 as a biomarker or treatment target in patients with gastric, bile duct, pancreatic and colorectal cancer.

Oncotarget 2018 Jul 3;9(51):29820-29841. Epub 2018 Jul 3.

Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.

Gastrointestinal cancer (GI) is a major health problem. Patients with gastric, pancreatic, colorectal, bile duct and gall bladder cancer often have advanced disease at the time of diagnosis and are generally difficult to cure, resulting in a dismal prognosis for most patients. Inflammation plays an important role in the development and growth of cancer, which has led to a growing interest in the pro-inflammatory cytokine interleukin 6 (IL-6). The aim of the present review was to evaluate the clinical use of IL-6 as a biomarker or therapeutic target in patients with GI cancer. We did a systematic review of studies (1993-2018), to assess the clinical use of IL-6 as a diagnostic, prognostic or predictive tumor biomarker or as a potential therapeutic target. This review includes 48 studies and 5316 patients. Circulating IL-6 levels appear to be an independent prognostic biomarker in patients with GI cancer, with high IL-6 levels associated with short overall survival (OS). The results for colorectal cancer were too ambiguous to give conclusive results. IL-6 seemed to be a marker for some of the clinical characteristics of GI cancer, and may have a role in the diagnostic workup in general practice. No published studies have examined the use of IL-6 as a therapeutic target in pancreatic, gastric, bile duct or colorectal cancer. In conclusion, high circulating IL-6 was associated with short OS in most studies in GI cancer patients. Whether inhibition of IL-6 would decrease GI cancer symptoms and increase quality of life is unknown.
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http://dx.doi.org/10.18632/oncotarget.25661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6049875PMC
July 2018

Prognostic role of carcinoembryonic antigen and carbohydrate antigen 19-9 in metastatic colorectal cancer: a BRAF-mutant subset with high CA 19-9 level and poor outcome.

Br J Cancer 2018 06 6;118(12):1609-1616. Epub 2018 Jun 6.

Department of Oncology, Oslo University Hospital, Oslo, Norway.

Background: Mutation status of RAS and BRAF, as well as serum levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9), are biomarkers used in clinical management of patients with gastrointestinal cancers. This study aimed to examine the prognostic role of these biomarkers in a patient population that started first-line chemotherapy for unresectable metastatic colorectal cancer (mCRC) in the NORDIC-VII study.

Methods: CEA and CA 19-9 were measured in serum samples from 545 patients obtained before the start of chemotherapy. Four hundred and ninety-four patients had detectable levels of carbohydrate antigen 19-9 (CA 19-9). RAS (exons 2-4) and BRAF (V600E) mutation status were available from 440 patients. Overall survival (OS) was estimated in patient groups defined by serum CEA or CA 19-9 levels using cut-off values of 5 µg/L and 35 kU/L, respectively, in the total population and in subgroups according to RAS and BRAF mutation status.

Results: For both CEA and CA 19-9, elevated serum levels were associated with reduced OS in adjusted analyses which included RAS and BRAF mutation status, baseline World Health Organization performance status, and levels of alkaline phosphatase and C-reactive protein. The negative prognostic information provided by an elevated CA 19-9 level was particularly marked in patients with BRAF mutation (hazard ratio = 4.35, interaction P = 0.003, in an adjusted model for OS).

Conclusions: High baseline serum concentrations of CEA and CA 19-9 provide independent information of impaired prognosis in mCRC. In patients with BRAF-mutant tumours, elevated serum CA 19-9 may identify a subgroup with highly aggressive disease and could contribute to improving therapeutic decisions.
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http://dx.doi.org/10.1038/s41416-018-0115-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008450PMC
June 2018

Plasma YKL-40 as a biomarker for bevacizumab efficacy in patients with newly diagnosed glioblastoma in the phase 3 randomized AVAglio trial.

Oncotarget 2018 Jan 4;9(6):6752-6762. Epub 2017 Dec 4.

Department of Oncology, Herlev University Hospital, Herlev and Gentofte Hospital, Copenhagen, Denmark.

YKL-40 is a glycoprotein with pro-angiogenic functions. We hypothesized that patients with newly diagnosed glioblastoma and low baseline plasma YKL-40 levels derive greater benefit from first-line bevacizumab. Plasma samples were collected from 563 patients in the randomized, phase 3 AVAglio trial who received bevacizumab or placebo plus radiotherapy/temozolomide. Raw plasma YKL-40 concentrations were converted to age-corrected percentiles of normal healthy YKL-40 levels and divided into quartiles (Q). The impact of baseline plasma YKL-40 level on survival was investigated using Cox regression analyses. Patients with low baseline plasma YKL-40 (≤Q1) had an improved progression-free survival hazard ratio (HR) for bevacizumab versus placebo (0.37, 95% confidence interval [CI]: 0.25-0.55) compared with high plasma YKL-40 (> Q1) (0.71, 95% CI: 0.57-0.87). Overall survival HRs were comparable between the subgroups (≤ Q1: 0.69, 95% CI: 0.44-1.09; (> Q1: 0.88, 95% CI: 0.68-1.13). A trend for improved progression-free survival HR with low versus high YKL-40 was observed in proneural glioblastoma (0.41, 95% CI: 0.13-1.28 vs 0.80, 95% CI: 0.45-1.40, respectively), but not for proliferative/mesenchymal subtypes. Elevated plasma YKL-40 (> 90th percentile of normal) was an independent negative prognostic factor. In conclusion, the predictive value of baseline plasma YKL-40 level as a biomarker for bevacizumab efficacy in glioblastoma may be limited to patients with proneural tumors. Independent validation studies are required to confirm these results.
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http://dx.doi.org/10.18632/oncotarget.22886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805511PMC
January 2018

Ultrasensitive plasma ctDNA assay for detection, prognosis, and assessment of therapeutic response in patients with unresectable pancreatic ductal adenocarcinoma.

Oncotarget 2017 Nov 26;8(58):97769-97786. Epub 2017 Oct 26.

Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.

Precision oncology requires sensitive and specific clinical biomarkers. Carbohydrate Antigen 19-9 (CA19-9) is widely used in pancreatic ductal adenocarcinoma (PDA) but lacks sensitivity and specificity. Nearly all PDAs harbor somatic mutations, nominating circulating tumor DNA (ctDNA) as an alternative disease biomarker, however, variable clinical performance has limited its clinical utility. We applied an ultrasensitive, PCR mutation enrichment, next generation sequencing ctDNA assay in a large cohort of patients with unresectable PDA ( = 189) recruited to the BIOPAC study between 2008-2015. Baseline and longitudinal serum CA19-9 and plasma ctDNA were correlated with time to progression (TTP) and overall survival (OS). Baseline ctDNA detection rate was 93.7% (86.4% in patients with non-elevated CA19-9). ctDNA and CA19-9 were positively correlated yet independently associated with TTP and OS (ctDNA = 0.0018 and 0.0014; CA19-9 = 0.0294 and 0.0007, respectively). A generated model quantitating longitudinal ctDNA correctly assessed greater than 80% of patient responses. Quantitative detection of ctDNA is an informative prognostic biomarker, complementary to CA19-9 in patients with unresectable PDA. Longitudinal ctDNA may inform therapeutic decision making and provides a kinetically dynamic and quantitative metric of patient response.
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http://dx.doi.org/10.18632/oncotarget.22080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716690PMC
November 2017

Plasma MicroRNA Profiles in Patients with Early Rheumatoid Arthritis Responding to Adalimumab plus Methotrexate vs Methotrexate Alone: A Placebo-controlled Clinical Trial.

J Rheumatol 2018 01 15;45(1):53-61. Epub 2017 Nov 15.

From the Department of Autoimmunology and Biomarkers, Statens Serum Institut, Copenhagen; Department of Rheumatology, Frederiksberg Hospital, Frederiksberg; Institute of Regional Health Research-Center Sønderjylland, University of Southern Denmark, Odense; Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Centre of Head and Orthopedics, Rigshospitalet, Glostrup; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen; The DANBIO Registry and Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Centre of Head and Orthopedics, Rigshospitalet, Glostrup; Department of Medicine and Oncology, Herlev and Gentofte Hospital, Herlev; Faculty of Health Sciences, University of Copenhagen, Copenhagen; Department of Rheumatology, King Christian 10th Hospital for Rheumatic Diseases, Gråsten; Department of Rheumatology, Aarhus University Hospital, Aarhus; Department of Rheumatology, Odense University Hospital, Odense; Department of Clinical Genetics, Odense University Hospital, Odense; Institute of Clinical Research, University of Southern Denmark, Odense; Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark.

Objective: The aim was to identify plasma (i.e., cell-free) microRNA (miRNA) predicting antitumor necrosis and/or methotrexate (MTX) treatment response in patients enrolled in an investigator-initiated, prospective, double-blinded, placebo-controlled trial (The OPERA study, NCT00660647).

Methods: We included 180 disease-modifying antirheumatic drug-naive patients with early rheumatoid arthritis (RA) randomized to adalimumab (ADA; n = 89) or placebo (n = 91) in combination with MTX. Plasma samples before and 3 months after treatment initiation were analyzed for 91 specific miRNA by quantitative reverse transcriptase-polymerase chain reaction on microfluidic dynamic arrays. A linear mixed-effects model was used to test for associations between pretreatment miRNA and changes in miRNA expression and American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean (28 joints) remission at 3 and 12 months, applying false discovery rate correction for multiple testing. Using leave-one-out cross validation, we built predictive multivariate miRNA models and estimated classification performances using receiver-operating characteristics (ROC) curves.

Results: In the ADA group, a higher pretreatment level of miR-27a-3p was significantly associated with remission at 12 months. The level decreased in remitting patients between pretreatment and 3 months, and increased in nonremitting patients. No associations were found in the placebo group receiving only MTX. Two multivariate miRNA models were able to predict response to ADA treatment after 3 and 12 months, with 63% and 82% area under the ROC curves, respectively.

Conclusion: We identified miR-27a-3p as a potential predictive biomarker of ACR/EULAR remission in patients with early RA treated with ADA in combination with MTX. We conclude that pretreatment plasma-miRNA profiles may be of predictive value, but the results need confirmation in independent cohorts.
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http://dx.doi.org/10.3899/jrheum.170266DOI Listing
January 2018

Cell-Free DNA in Metastatic Colorectal Cancer: A Systematic Review and Meta-Analysis.

Oncologist 2017 09 4;22(9):1049-1055. Epub 2017 Aug 4.

Department of Oncology, Danish Colorectal Cancer Center South, Vejle Hospital, Vejle, Denmark.

Background: Circulating DNA can be detected and quantified in the blood of cancer patients and used for detection of tumor-specific genetic alterations. The clinical utility has been intensively investigated for the past 10 years. The majority of reports focus on analyzing the clinical potential of tumor-specific mutations, whereas the use of total cell-free DNA (cfDNA) quantification is somehow controversial and sparsely described in the literature, but holds important clinical information in itself. The purpose of the present report was to present a systematic review and meta-analysis of the prognostic value of total cfDNA in patients with metastatic colorectal cancer (mCRC) treated with chemotherapy. In addition, we report on the overall performance of cfDNA as source for mutation detection.

Materials And Methods: A systematic literature search of PubMed and Embase was performed by two independent investigators. Eligibility criteria were (a) total cfDNA analysis, (b) mCRC, and (c) prognostic value during palliative treatment. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines were followed, and meta-analysis applied on both aggregate data extraction and individual patients' data.

Results: Ten eligible cohorts were identified, including a total of 1,076 patients. Seven studies used quantitative polymerase chain reaction methods, two BEAMing [beads, emulsification, amplification, and magnetics] technology, and one study digital droplet polymerase chain reaction. The baseline levels of cfDNA was similar in the presented studies, and all studies reported a clear prognostic value in favor of patients with lowest levels of baseline cfDNA. A meta-analysis revealed a combined estimate of favorable overall survival hazard ratio (HR) in patients with levels below the median cfDNA (HR = 2.39, 95% confidence interval 2.03-2.82,  < .0001).

Conclusion: The total cfDNA levels are high in patients with mCRC and bear strong prognostic information, which should be tested prospectively by using a predefined cut-off value based on normal values in healthy cohorts. Finally, the potential use of cfDNA for detection of tumor-specific mutations was emphasized in a large individual patients' data meta-analysis.

Implications For Practice: Reliable prognostic markers could help to guide patients and treating physicians regarding the relevance and choice of systemic therapy. Small fragments of circulating cell-free DNA (cfDNA) can be measured in a simple blood sample. This report presents the first meta-analysis of the prognostic value of total cfDNA measurement in patients with metastatic colorectal cancer. Data from 1,076 patients confirmed that patients with the lowest pre-treatment levels of cfDNA had a significantly higher chance of longer survival than those with higher levels. Cell-free DNA analysis can also be used for detection of tumor-specific mutations, and hold potential as a valuable tool in colorectal cancer treatment.
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http://dx.doi.org/10.1634/theoncologist.2016-0178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5599199PMC
September 2017
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