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.

FCGR2A and FCGR3A polymorphisms and clinical outcome in metastatic colorectal cancer patients treated with first-line 5-fluorouracil/folinic acid and oxaliplatin +/- cetuximab.

BACKGROUND: Polymorphisms of genes encoding the Fcy receptors (Fc fragment of IgG receptor 2A (FCGR2A) and 3A (FCGR3A)), which influence their affinity for the Fc fragment, have been linked to the pharmacodynamics of monoclonal antibodies. Most studies have been limited by small samples sizes and have reported inconsistent associations between the FCGR2A and the FCGR3A polymorphisms and clinical outcome in metastatic colorectal cancer (mCRC) patients treated with cetuximab. We investigated the association of these polymorphisms and clinical outcome in a large cohort of mCRC patients treated with first-line 5-fluorouracil/folinic acid and oxaliplatin (Nordic FLOX) +/- cetuximab in the NORDIC-VII study (NCT00145314). METHODS: 504 and 497 mCRC patients were evaluable for the FCGR2A and FCGR3A genotyping, respectively. Genotyping was performed on TaqMan ABI HT 7900 (Applied Biosystems, Foster City, CA, USA) with pre-designed SNP genotyping assays for FCGR2A (rs1801274) and FCGR3A (rs396991). RESULTS: The response rate for patients with the FCGR2A R/R genotype was significantly increased when cetuximab was added to Nordic FLOX (31% versus 53%, interaction P = 0.03), but was not significantly different compared to the response rate of patients with the FCGR2A H/H or H/R genotypes given the same treatment. A larger increase in response rate with the addition of cetuximab to Nordic FLOX in patients with KRAS mutated tumors and the FCGR2A R/R genotype was observed (19% versus 50%, interaction P = 0.04). None of the FCGR3A polymorphisms were associated with altered response when cetuximab was added to Nordic FLOX (interaction P = 0.63). Neither of the FCGR polymorphisms showed any significant associations with progression-free survival or overall survival. CONCLUSION: Patients with KRAS mutated tumors and the FCGR2A R/R polymorphism responded poorly when treated with chemotherapy only, and experienced the most benefit of the addition of cetuximab in terms of response rate.

Patterns of Palliative Chemotherapy and Survival in Patients With Pancreatic Cancer Focusing on Age: A Nationwide Real-World Danish Registry Study.

OBJECTIVES: The aim of this study was to identify patterns of palliative chemotherapy (CTh) and the associated overall survival (OS) in patients with pancreatic cancer, with specific focus on age. METHODS: Between May 1, 2011, and April 30, 2016, 4260 patients were registered in the Danish Pancreatic Cancer Database. The 1715 patients receiving palliative CTh were retrieved. Age was grouped into less than 70, 70 to less than 75, and 75 years or more. RESULTS: Of the 1715 patients receiving first-line CTh, 586 (34%) underwent second-line CTh and 151 (9%) third-line CTh. First-line gemcitabine resulted in a significant worse survival compared with combination CTh, hazard ratio 1.51. For combination CTh, OS differed between the age groups, P < 0.01. The median OS in the less than 70 years (n = 547), 70 to less than 75 years (n = 163), and 75 years or more (n = 67) groups were 9.3, 9.6, and 7.2 months, respectively. No differences in survival were observed among patients receiving first-line gemcitabine (P = 0.35). CONCLUSIONS: Our findings are useful in treatment-related decision making in patients with pancreatic cancer. A significant survival benefit was observed for all patients after first-line combination CTh. The effect of combination CTh was most prominent among patients aged less than 75 years. By age, no differences in survival were observed in those receiving gemcitabine.

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

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.

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.

Initial treatment and survival in 4163 Danish patients with pancreatic cancer: A nationwide unselected real-world register study.

BACKGROUND: Nationwide register data on the effect of primary treatment on survival in an unselected population of patients with pancreatic cancer (PC) have not been reported before. The study aim was to investigate the overall survival (OS) related to initial treatment with resection, chemotherapy, or best supportive care (BSC) in all patients diagnosed with PC in Denmark from 2011 to 2016. METHODS: From 1 May 2011 to 30 April 2016, 4260 patients with PC were identified in the Danish Pancreatic Cancer Database. Ninety-seven patients (2%) were excluded, 56 because of treatment with preoperative chemotherapy, 39 because of incorrect registration of diagnosis or treatment, and 2 because of loss to follow-up; thus, 4163 patients were included. RESULTS: The 718 patients (17%) receiving resection had a median overall survival (mOS) of 21.9 months (range 20.0-24.2). In the chemotherapy group of 1746 patients (42%), those treated with FOLFIRINOX had the longest mOS of 10.0 months (9.2-11.0), whereas those treated with gemcitabine had the shortest mOS of 5.1 months (4.8-5.6). The 1697 patients (41%) receiving BSC had a mOS of only 1.6 months (1.5-1.7). CONCLUSIONS: The resected PC cohort had an OS comparable with that reported in randomised controlled trials (RCTs). The mOS of the chemotherapy-treated patients was slightly shorter compared with the results from RCTs and reflects the unselected population in this study. During the last decade, a larger fraction of patients received anticancer treatment, but the BSC group was still large and showed extremely poor OS.

Half body irradiation of patients with multiple bone metastases: a phase II trial.

AIM OF STUDY: The primary aim of this study was to evaluate the effect of half-body irradiation (HBI) on pain and quality of life in cancer patients with multiple bone metastases. The secondary aim was to evaluate side effects of the treatment. PATIENTS AND METHODS: A total of 44 patients received lower (n = 37), upper (n = 5), or sequential HBI (n = 2). The dose for lower HBI was 8 Gy in one fraction and for upper HBI 7 Gy in one fraction, with reduction of the lung dose to 6 Gy in one fraction by partial shielding. The majority of patients (n = 41) were males with prostate cancers (93%). Outcome and side effects were measured by the EORTC Quality of Life Questionnaire C30 (QLQ-C30), and by the doctors' toxicity scores in the medical record. Pain relief was defined as a reduction of more than 10 points on the QLQ-C30 scale. Evaluations were performed before and 2, 4, 8, 16, and 24 weeks after treatment. RESULTS: Relief of pain was observed in 76% of the patients receiving HBI with 8.8% of the patients experiencing complete pain relief with no residual pain in the treated field. For most patients, the pain relief was lasting throughout the follow-up period. About one third of the patients were able to reduce their intake of analgesics. Grade 1-2 diarrhoea was the most common side effect observed in 49% of the patients two weeks after treatment. Mild pulmonary symptoms (grade 1-2) were observed in four of seven patients receiving upper HBI. No clear effect was observed on the patients' global quality of life. CONCLUSION: Single fraction HBI is safe and effective providing long lasting pain reduction in 76% of patients with multiple bone metastases.

Effects of current parenteral nutrition treatment on health-related quality of life, physical function, nutritional status, survival and adverse events exclusively in patients with advanced cancer: A systematic literature review.

BACKGROUND: The aim was to evaluate the effects of current parenteral nutrition (PN) treatment on clinical outcomes in patients with advanced cancer. METHODS: This review was conducted according to the PRISMA guidelines (PROSPERO ID: 4201707915). RESULTS: Two underpowered randomized controlled trials and six observational studies were retrieved (n = 894 patients). Health-related quality of life and physical function may improve during anti-neoplastic treatment in who PN treatment is the only feeding opportunity, but not necessarily in patients able to feed enterally. Nutritional status may improve in patients regardless of anti-neoplastic treatment and gastrointestinal function. PN treatment was neither superior to fluid in terminal patients nor to dietary counselling in patients able to feed enterally in regards to survival. The total incidence of adverse events was low. CONCLUSION: Current PN treatment in patients with advanced cancer is understudied and the level of evidence is weak.

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.

Haemostatis activity in rectal cancer patients exposed to preoperative radiotherapy: a clinical prospective cohort study.

To investigate whether markers of haemostasis activity increased during preoperative radiotherapy and whether postoperative marker levels were increased in irradiated rectal cancer patients when compared with nonirradiated rectal and colon cancer patients. In 45 rectal cancer patients, we measured plasma levels of prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin complex, and D-dimer during radiotherapy. Postoperative levels of F1 + 2, thrombin-antithrombin complex, and D-dimer in irradiated patients were compared with postoperative levels in 123 nonirradiated colon and rectal cancer patients. A small oscillation in F1 + 2 levels was observed during radiotherapy among long-term low-intensity radiotherapy recipients. Postoperative levels of F1 + 2 and D-dimer were significantly higher among patients who received short-term high-intensity radiotherapy. This study provided no evidence for activation of the haemostatic system during preoperative radiotherapy in patients with rectal cancer. Some evidence was provided for increased postoperative haemostatic activity among rectal cancer patients who received short-term high-intensity radiotherapy, when compared with patients who received long-term low-intensity radiotherapy, and nonirradiated patients.