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

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.

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

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.

MyHealth: specialist nurse-led follow-up in breast cancer. A randomized controlled trial - development and feasibility.

Background: Traditionally, women treated for breast cancer (BC) have been followed up through regular oncologist-led visits in outpatient clinics, focusing on detection of recurrences, new primary BC, symptom management, and psychological support. However, this follow-up routine is expensive and its effectiveness has been questioned. Consequently, alternative follow-up programs have been tested. The Guided Self-Determination method (GSD), which facilitates partnership between health-care provider and patient, has been shown to improve self-management in patients with chronic conditions, including cancer. Patient-reported outcomes (PRO) is another increasingly used tool to improve patient-provider communication, symptom monitoring and control. In combination, GSD and PRO may have the potential to meet the objectives of BC follow-up. To test this, we developed the MyHealth study, a randomized controlled trial comparing a nurse-led follow-up program based on GSD, collection of PRO, and patient navigation with routine oncologist-led follow-up. Here we describe how we developed the intervention and are currently testing the feasibility of the MyHealth protocol in terms of recruitment, adherence to the intervention, collection of PRO, and patient navigation. Material and methods: We have invited the first 25 consecutively enrolled patients to test the MyHealth intervention. This consists of (1) 3-5 initial GSD appointments with a nurse, (2) collection of PRO, and (3) symptom management and patient navigation. The randomized trial was launched in January 2017 and is still recruiting. Results of the feasibility study: Of 32 patients invited, 25 accepted participation. At 18-month follow-up, two patients have withdrawn, 143 PRO questionnaires have been completed (mean 5.7/patient) resulting in 59 nurse contacts (mean 2.4 per patient) and 14 project physician contacts (mean 0.6 per patient). Conclusion: A high recruitment rate and response rate to PRO indicate that follow-up led by specialist nurses, based on collection of PRO is feasible and acceptable for patients treated for early stage BC.

The potential diagnostic value of serum microRNA signature in patients with pancreatic cancer.

Biomarkers for early diagnosis of patients with pancreatic cancer (PC) are needed. Our aim was to identify panels of miRNAs in serum in combination with CA 19-9 for use in the diagnosis of PC. Four hundred seventeen patients with PC were included prospectively from Denmark (n = 306) and Germany (n = 111). Controls included 59 patients with chronic pancreatitis (CP) and 248 healthy subjects (HS). MiRNAs were analyzed in pretreatment serum samples from 3 cohorts: discovery cohort (754 human miRNAs, TaqMan(®) Human MicroRNA assay, Applied Biosystem; PC n = 133, controls n = 72); training cohort (34 miRNAs, real-time qPCR using the Fluidigm BioMark™ System; PC n = 198, controls n = 184); validation cohort (13 miRNAs, real-time qPCR using the Fluidigm BioMark™ System; PC n = 86, controls n = 51). We found that 34 miRNAs in serum from PC patients in the discovery cohort were expressed differently than in controls. These miRNAs were tested in the training cohort, and four diagnostic panels were constructed that included 5 or 12 miRNAs (miR-16, -18a, -20a, -24, -25, -27a, -29c, -30a.5p, -191, -323.3p, -345 and -483.5p). Diagnostic accuracy of detecting PC in the training cohort was AUC (Index I 0.85; II 0.87; III 0.85; IV 0.95; CA 19-9 0.93); specificity (I 0.71; II 0.76; III 0.66; IV 0.90 (fixed sensitivity at 0.85); CA 19-9 0.93). Combining serum CA 19-9 and Index II best discriminated Stages I and II PC from HS [AUC 0.93 (0.90-0.96), sensitivity 0.77 (0.69-0.84), specificity 0.94 (0.90-0.96) and accuracy 0.88 (0.84-0.91)]. In conclusion, we identified four diagnostic panels based on 5 or 12 miRNAs in serum that could distinguish patients with PC from HS and CP.

Positron emission tomography/computed tomography and biomarkers for early treatment response evaluation in metastatic colon cancer.

BACKGROUND: Treatment options for metastatic colon cancer (mCC) are widening. We prospectively evaluated serial 2-deoxy-2-[18F]fluoro-d-glucose positron-emission tomography/computed tomography (PET/CT) and measurements of tissue inhibitor of metalloproteinases-1 (TIMP-1), carcinoembryonic antigen (CEA), and liberated domain I of urokinase plasminogen activator receptor (uPAR(I)) for early assessment of treatment response in mCC patients. METHODS: Thirty-three mCC patients scheduled for first-line chemotherapy with capecitabine and oxaliplatin (CAPOX) and bevacizumab participated; 27 were evaluated by PET/CT before treatment, after one and four treatment series. Morphological and metabolic response was independently assessed according to Response Evaluation Criteria in Solid Tumors and European Organization for Research and Treatment of Cancer PET criteria. Plasma TIMP-1, plasma uPAR(I), and serum CEA were determined. RESULTS: Metabolic response after one treatment course predicted the ability of CAPOX and bevacizumab to induce morphological response after four treatment series with a sensitivity of 80%, specificity of 69%, and odds ratio of 13.9 (95% confidence interval [CI] 1.9; 182). Early metabolically stable or progressive disease was associated with shorter progression-free survival (hazard ratio [HR] = 3.2 [CI 1.3; 7.8]). Biomarker levels at early evaluation were associated with shorter OS (TIMP-1 per unit increase on a log-2-transformed ng/mL scale: HR = 2.6 [CI 1.4; 4.9]; uPAR(I) per 25 fmol/mL increase: HR = 1.5 [CI 1.1; 2.1]). CONCLUSION: This monocentric study demonstrated predictive value of early metabolic PET response and prognostic value of TIMP-1 and uPAR(I) levels in mCC treated with CAPOX and bevacizumab. Results support investigation of PET/CT, TIMP-1, and uPAR(I) guided early treatment adaptation in mCC.

Duration of Adjuvant Doublet Chemotherapy (3 or 6 months) in Patients With High-Risk Stage II Colorectal Cancer.

PURPOSE: As oxaliplatin results in cumulative neurotoxicity, reducing treatment duration without loss of efficacy would benefit patients and healthcare providers. PATIENTS AND METHODS: Four of the six studies in the International Duration of Adjuvant Chemotherapy (IDEA) collaboration included patients with high-risk stage II colon and rectal cancers. Patients were treated (clinician and/or patient choice) with either fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX) and randomly assigned to receive 3- or 6-month treatment. The primary end point is disease-free survival (DFS), and noninferiority of 3-month treatment was defined as a hazard ratio (HR) of < 1.2- v 6-month arm. To detect this with 80% power at a one-sided type one error rate of 0.10, a total of 542 DFS events were required. RESULTS: 3,273 eligible patients were randomly assigned to either 3- or 6-month treatment with 62% receiving CAPOX and 38% FOLFOX. There were 553 DFS events. Five-year DFS was 80.7% and 83.9% for 3-month and 6-month treatment, respectively (HR, 1.17; 80% CI, 1.05 to 1.31; P [for noninferiority] .39). This crossed the noninferiority limit of 1.2. As in the IDEA stage III analysis, the duration effect appeared dependent on the chemotherapy regimen although a test of interaction was negative. HR for CAPOX was 1.02 (80% CI, 0.88 to 1.17), and HR for FOLFOX was 1.41 (80% CI, 1.18 to 1.68). CONCLUSION: Although noninferiority has not been demonstrated in the overall population, the convenience, reduced toxicity, and cost of 3-month adjuvant CAPOX suggest it as a potential option for high-risk stage II colon cancer if oxaliplatin-based chemotherapy is suitable. The relative contribution of the factors used to define high-risk stage II disease needs better understanding.

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

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.

Outcomes After Radiotherapy Alone for Metastatic Spinal Cord Compression in Patients with Oligo-metastatic Breast Cancer.

BACKGROUND/AIM: Patients with oligo-metastatic breast cancer are a unique patient subgroup with more favourable outlook than most patients with metastatic disease. Prognostic factors in these patients with metastatic spinal cord compression (MSCC) were evaluated. PATIENTS AND METHODS: In 159 patients irradiated for MSCC from oligo-metastatic breast cancer, seven characteristics were retrospectively analyzed including age, interval between breast cancer diagnosis and irradiation of MSCC, time developing motor deficits, ambulatory status, involved vertebrae, performance score (ECOG-PS) and radiotherapy regimen. RESULTS: Improvement of motor function was significantly associated with time developing motor deficits (p=0.017), post-radiotherapy ambulatory status with pre-radiotherapy ambulation (p=0.012) and ECOG-PS 1-2 (p=0.029). Radiation doses of 39-40 Gy (equivalent doses) resulted in 1- and 2-year local control of 100% and 95%. On multivariate analyses, higher doses were associated with local control (p=0.011). Pre-radiotherapy ambulatory status (p=0.001) and ECOG-PS 1-2 (p=0.002) were associated with survival. CONCLUSION: Significant prognostic factors were identified for patients with MSCC from oligo-metastatic breast cancer. Higher radiation doses improved local control.

Less pitfalls and variation in population based cancer survival comparisons within the European Union: Lessons from colorectal cancer patients in neighbouring regions in Denmark and Germany - The Fehmarn Belt project.

BACKGROUND: International comparisons of cancer registry based survival are often used as a marker of the performance of health care services on cancer. These are debated for comparability, validity and lack of detail with respect to prognostic factors. With a view to cross border collaborative cancer research and care in the European Union (EU), we used the established routine registration systems for cancer in the neighbouring regions Zealand, Denmark, and Schleswig-Holstein, Germany, to study if available routine registration suffices for the study of diagnosis, treatment and follow-up for colorectal cancer patients. The aim was to assess to which extent differences in survival between the regions could be explained. METHODS: Colorectal cancer patients recorded 2004-2010 in Schleswig-Holstein (colon: 10,631; rectum 5683) and region Zealand (colon: 3205; rectum 1747) were studied. Excluding cases aged 90+ or only known from death certificates, one- and four-year relative survival by stage for the periods 2004-2006 and 2007-2009 (one-year) were calculated. FINDINGS: A high proportion of patients in Schleswig-Holstein were known only from death certificates (colon 11%; rectum 6.9%) compared to <0.3% in region Zealand. Colon cancer incidence (asr-e) (men 36; women 28) and mortality (men 12; women 8.7) in Schleswig-Holstein were 10 per 100,000 lower than in Zealand; minor differences were seen for rectum cancer. One and four-year overall survival increased in both regions but was superior in Schleswig-Holstein. For patients with reported stage I-III, negligible differences in survival were seen; with further restriction to patients with treatment reported, even so in stage IV patients 2007-2009. INTERPRETATION: Improved data quality and comparability than presently used in the large international survival studies is needed. If stage and treatment is taken into account, more valid international comparisons of cancer survival are possible. Reporting and follow-up must be improved and cases only known from death certificates (DCO) minimised. A high proportion DCO (excluded from analyses) may produce higher survival, whereas a low the opposite. Co-morbidity and socio-economic status should be included alongside other prognostic variables in survival studies. Barriers towards proper follow-up and monitoring of outcome e.g. privacy legislation must be considered with a view to future patient mobility.

Tissue microRNAs as predictors of outcome in patients with metastatic colorectal cancer treated with first line Capecitabine and Oxaliplatin with or without Bevacizumab.

PURPOSE: We tested the hypothesis that expression of microRNAs (miRNAs) in cancer tissue can predict effectiveness of bevacizumab added to capecitabine and oxaliplatin (CAPEOX) in patients with metastatic colorectal cancer (mCRC). EXPERIMENTAL DESIGN: Patients with mCRC treated with first line CAPEOX and bevacizumab (CAPEOXBEV): screening (n = 212) and validation (n = 121) cohorts, or CAPEOX alone: control cohort (n = 127), were identified retrospectively and archival primary tumor samples were collected. Expression of 754 miRNAs was analyzed in the screening cohort using polymerase chain reaction (PCR) arrays and expression levels were related to time to disease progression (TTP) and overall survival (OS). Significant miRNAs from the screening study were analyzed in all three cohorts using custom PCR arrays. In situ hybridization (ISH) was done for selected miRNAs. RESULTS: In the screening study, 26 miRNAs were significantly correlated with outcome in multivariate analyses. Twenty-two miRNAs were selected for further study. Higher miR-664-3p expression and lower miR-455-5p expression were predictive of improved outcome in the CAPEOXBEV cohorts and showed a significant interaction with bevacizumab effectiveness. The effects were strongest for OS. Both miRNAs showed high expression in stromal cells. Higher expression of miR-196b-5p and miR-592 predicted improved outcome regardless of bevacizumab treatment, with similar effect estimates in all three cohorts. CONCLUSIONS: We have identified potentially predictive miRNAs for bevacizumab effectiveness and additional miRNAs that could be related to chemotherapy effectiveness or prognosis in patients with mCRC. Our findings need further validation in large cohorts, preferably from completed randomized trials.

Diagnostic and Prognostic Impact of Circulating YKL-40, IL-6, and CA 19.9 in Patients with Pancreatic Cancer.

PURPOSE: We tested the hypothesis that high plasma YKL-40 and IL-6 associate with pancreatic cancer and short overall survival. PATIENTS AND METHODS: In all, 559 patients with pancreatic cancer from prospective biomarker studies from Denmark (n = 448) and Germany (n = 111) were studied. Plasma YKL-40 and IL-6 were determined by ELISAs and serum CA 19.9 by chemiluminescent immunometric assay. RESULTS: Odds ratios (ORs) for prediction of pancreatic cancer were significant for all biomarkers, with CA 19.9 having the highest AUC (CA 19.9: OR = 2.28, 95% CI 1.97 to 2.68, p<0.0001, AUC = 0.94; YKL-40: OR = 4.50, 3.99 to 5.08, p<0.0001, AUC = 0.87; IL-6: OR = 3.68, 3.08 to 4.44, p<0.0001, AUC = 0.87). Multivariate Cox analysis (YKL-40, IL-6, CA 19.9, age, stage, gender) in patients operated on showed that high preoperative IL-6 and CA 19.9 (dichotomized according to normal values) were independently associated with short overall survival (CA 19.9: HR = 2.51, 1.22-5.15, p = 0.013; IL-6: HR = 2.03, 1.11 to 3.70, p = 0.021). Multivariate Cox analysis of non-operable patients (Stage IIB-IV) showed that high pre-treatment levels of each biomarker were independently associated with short overall survival (YKL-40: HR = 1.30, 1.03 to 1.64, p = 0.029; IL-6: HR = 1.71, 1.33 to 2.20, p<0.0001; CA 19.9: HR = 1.54, 1.06 to 2.24, p = 0.022). Patients with preoperative elevation of both IL-6 and CA 19.9 had shorter overall survival (p<0.005) compared to patients with normal levels of both biomarkers (45% vs. 92% alive after 12 months). CONCLUSIONS: Plasma YKL-40 and IL-6 had less diagnostic impact than CA 19.9. Combination of pretreatment YKL-40, IL-6, and CA 19.9 may have clinical value to identify pancreatic cancer patients with the poorest prognosis.