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CONKO-006 was designed for patients with pancreatic adenocarcinoma with postsurgical R1 residual status to evaluate the efficacy and safety of the combination of gemcitabine and sorafenib (GemSorafenib) compared with those of gemcitabine + placebo (GemP) for 12 cycles. This randomised, double-blind, placebo-controlled, multicenter study was planned to detect an improvement in recurrence-free survival (RFS) from 42% to 60% after 18 months. Secondary objectives were overall survival (OS), safety and duration of treatment. 122 patients were included between 02/2008 and 09/2013; 57 were randomised to GemSorafenib and 65 to GemP. Patient characteristics were wellbalanced (GemSorafenib/GemP) in terms of median age (63/63 years), tumour size (T3/T4: 97/97%), and nodal positivity (86/85%). Grade 3/4 toxicities comprised diarrhoea (GemSorafenib: 12%; GemP: 2%), elevated gamma-glutamyl transferase (GGT) (19%; 9%), fatigue (5%; 2%) and hypertension (5%; 2%), as well as neutropenia (18%; 25%) and thrombocytopenia (9%; 2%). By August 2017, 118 (97%) RFS event had occurred. There were no difference in RFS (median GemSorafenib: 8.5 versus GemP: 9.4 months; p = 0.730) nor OS (median GemSorafenib: 17.6 versus GemP: 17.5 months; p = 0.481). Landmark analyses suggest that patients who received more than six cycles of postoperative chemotherapy had significantly longer OS (p = 0.021). CONKO-006 is the first randomised clinical trial to include exclusively patients with PDAC with postsurgical R1 status thus far. Sorafenib added to gemcitabine did neither improve RFS nor OS. However, postoperative treatment exceeding six months seemed to prolong survival and should be further investigated in these high-risk patients. German Tumor Study Registry (Deutsches Krebsstudienregister), DRKS00000242. • Patients with R1 resection of pancreatic ductal adenocarcinoma (PDAC) relapsed in more than 90%. • Gemcitabine + sorafenib is not effective in the postoperative treatment of PDAC. • Adjuvant gemcitabine exceeding 6 months may be beneficial in R1-resected PDAC not suitable for mFOLFIRINOX. [ABSTRACT FROM AUTHOR]

Background High expression of human equilibrative nucleoside transporter 1 (hENT1) is considered to predict survival in patients treated with adjuvant gemcitabine for pancreatic cancer. A standard evaluation system for immunohistochemical analysis (antibody, scoring system) has not yet been established. Methods CONKO-001, a prospective randomised phase III study investigated the role of adjuvant gemcitabine (gem) as compared to observation (obs). Tumour samples of 156 patients were analysed by immunohistochemistry with the rabbit monoclonal antibody SP120 (Ventana Medical Systems) for expression of hENT1. Kaplan–Meier analyses for median disease-free survival (DFS) and overall survival (OS) were performed in dependence of hENT1 expression measured analogously to Farrell et al. 2009 and Poplin et al. 2013. Results For the 88 gem and 68 obs patients, median DFS/OS was 12.9/22.7 months and 6.2/19.1 months. High hENT1 expression was not associated with improved median DFS (Farrell: no hENT1 22.2 months, low hENT1 13.7 months, high hENT1 12.1 months, p = 0.248; Poplin: low hENT1 13.2 months versus high hENT1 11.5 months, p = 0.5) or median OS (Farrell: no hENT1 21.7 months, low hENT1 24.7 months, high hENT1 19.5, p = 0.571; Poplin: low hENT1 24.4 months versus high hENT1 19.7 months, p = 0.92;) in the gem group or in the obs group (median DFS Farrell: no hENT1 5.1 months, low hENT1 6.2 months, high hENT1 7.5 months, p = 0.375; Poplin: low hENT1 6.2 months versus high hENT1 5.9 months, p = 0.83; median OS Farrell: no hENT1 20.2 months, low hENT1 17.7 months, high HENT1 19.1 months, p = 0.738; Poplin: low hENT1 17.7 months versus high hENT1 20.4 months, p = 0.65) measured by the Farrell or Poplin Score. Conclusions We cannot confirm a predictive role of hENT1 measured by the clone SP120 rabbit antibody in our study population. Reproducible standard procedures are urgently needed prior to the implementation or exclusion of hENT1 as a predictive biomarker in the treatment of pancreatic cancer. Trial registration ISRCTN34802808. [ABSTRACT FROM AUTHOR]

Background: Previous investigations in pancreatic cancer suggest a prognostic role for α-smooth muscle actin (α-SMA) expression and stromal density in the peritumoural stroma. The aim of this study was to further validate the impact of α-SMA expression and stromal density in resectable pancreatic cancer patients treated with adjuvant gemcitabine compared with untreated patients.Methods: CONKO-001 was a prospective randomised phase III study investigating the role of adjuvant gemcitabine as compared with observation. Tissue samples of 162 patients were available for immunohistochemistry on tissue microarrays to evaluate the impact of α-SMA expression and stromal density impact on patient outcome.Results: High α-SMA expression in tumour stroma was associated with worse patient outcome (DFS: P=0.05, OS: P=0.047). A dense stroma reaction was associated with improved disease-free survival (DFS) and overall survival (OS) in the overall study population (DFS: P=0.001, OS: P=0.001). This positive prognostic impact was restricted to patients with no adjuvant treatment (DFS: P<0.001, OS: P<0.001). In multivariable analysis, α-SMA and stromal density expression were independently predictive factors for survival.Conclusions: Our data confirm the negative prognostic impact of high α-SMA expression in pancreatic cancer patients after curatively intended resection. In contrast to former investigations, we found a positive prognostic impact for a dense stroma. This significant influence was restricted to patients who received no adjuvant therapy. [ABSTRACT FROM AUTHOR]

Background:Previous investigations in pancreatic cancer suggest a prognostic role for α-smooth muscle actin (α-SMA) expression and stromal density in the peritumoural stroma. The aim of this study was to further validate the impact of α-SMA expression and stromal density in resectable pancreatic cancer patients treated with adjuvant gemcitabine compared with untreated patients.Methods:CONKO-001 was a prospective randomised phase III study investigating the role of adjuvant gemcitabine as compared with observation. Tissue samples of 162 patients were available for immunohistochemistry on tissue microarrays to evaluate the impact of α-SMA expression and stromal density impact on patient outcome.Results:High α-SMA expression in tumour stroma was associated with worse patient outcome (DFS: P=0.05, OS: P=0.047). A dense stroma reaction was associated with improved disease-free survival (DFS) and overall survival (OS) in the overall study population (DFS: P=0.001, OS: P=0.001). This positive prognostic impact was restricted to patients with no adjuvant treatment (DFS: P<0.001, OS: P<0.001). In multivariable analysis, α-SMA and stromal density expression were independently predictive factors for survival.Conclusions:Our data confirm the negative prognostic impact of high α-SMA expression in pancreatic cancer patients after curatively intended resection. In contrast to former investigations, we found a positive prognostic impact for a dense stroma. This significant influence was restricted to patients who received no adjuvant therapy. [ABSTRACT FROM AUTHOR]

Strong stromal and cytoplasmic SPARC expression was associated with worse DFS and OS in the overall study population of CONKO-001. The negative prognostic impact was restricted to patients who received adjuvant treatment with gemcitabine. Our data implements the role of SPARC in a more general context: High SPARC expression is associated with a decreased DFS and OS in patients treated with gemcitabine (or chemotherapy in general?)Background Previous investigations in pancreatic cancer suggested a prognostic role for secreted protein acidic and rich in cysteine (SPARC) expression in the peritumoral stroma but not for cytoplasmic SPARC expression. The aim of this study was to evaluate the impact of SPARC expression in pancreatic cancer patients treated with gemcitabine compared with untreated patients. Patients and methods CONKO-001 was a prospective randomized phase III study investigating the role of adjuvant gemcitabine when compared with observation. Tissue samples of 160 patients were available for SPARC immunohistochemistry on tissue microarrays to evaluate its impact on patient outcome. Results Strong stromal SPARC expression was associated with worse disease-free survival (DFS) and overall survival (OS) in the overall study population (DFS: P = 0.005, OS: P = 0.033). Its negative prognostic impact was restricted to patients treated with gemcitabine (DFS: P = 0.007, OS: P = 0.006). High cytoplasmic SPARC expression also was associated with worse patient outcome (DFS: P = 0.041, OS: P = 0.011). Again the effect was restricted to patients treated with gemcitabine (DFS: P = 0.002, OS: P = 0.003). In multivariable analysis, SPARC expression was independently predictive of patient outcome. Conclusions Our data confirm the prognostic significance of SPARC expression after curatively intended resection. The negative prognostic impact was restricted to patients who received adjuvant treatment with gemcitabine, suggesting SPARC as a predictive marker for response to gemcitabine. [ABSTRACT FROM PUBLISHER]

Background: Effective and tolerable chemotherapy with gemcitabine and cisplatin for advanced biliary tract cancer (BTC) has been established recently. However, overall prognosis is still poor, and additional therapeutic approaches are needed for patients with locally advanced, irresectable and/or pretreated tumors. Hepatic arterial infusion (HAI) of chemotherapy represents a safe and well-established treatment modality, but data on its use in patients with BTC are still sparse. Methods: Patients with irresectable BTC predominant to the liver were included in a prospective, open phase II study investigating HAI provided through interventionally implanted port catheters. Intraarterial chemotherapy consisted of biweekly oxaliplatin (O) 85 mg/m and folinic acid (F) 170 mg/m with 5-FU (F) 600 mg/m. Results: Between 2004 and 2010, 37 patients were enrolled. A total of 432 cycles of HAI were applied with a median of 9 (range 1-46) cycles. Objective response rate was 16 %, and tumor control was achieved in 24 of 37 (65 %) patients. Median progression-free survival was 6.5 months (range 0.5-26.0; 95 % CI 4.3-8.7), median overall survival was 13.5 (range 0.9-50.7; 95 % CI 11.1-15.9) months. The most frequent adverse event was sensory neuropathy grade 1/2 in 10/14 patients. Conclusions: Using a minimal invasive technique, repetitive HAI with OFF is feasible and results in clinically relevant tumor control with low toxicity in patients with liver predominant advanced BTC. [ABSTRACT FROM AUTHOR]

For a zero-mean Gaussian process, the covariances of zero crossings can be expressed as the sum of quadrivariate normal orthant probabilities. In this paper, we demonstrate the evaluation of zero crossing covariances using one-dimensional integrals. Furthermore, we provide asymptotics of zero crossing covariances for large time lags and derive bounds and approximations. Based on these results, we analyze the variance of the empirical zero crossing rate. We illustrate the applications of our results by autoregressive (AR) fractional Gaussian noise and fractionally integrated autoregressive moving average (FARIMA) processes. [ABSTRACT FROM AUTHOR]

Abstract: In order to develop fast and robust methods for extracting qualitative information from non-linear time series, Bandt and Pompe have proposed to consider time series from the pure ordinal viewpoint. On the basis of counting ordinal patterns, which describe the up-and-down in a time series, they have introduced the concept of permutation entropy for quantifying the complexity of a system behind a time series. The permutation entropy only provides one detail of the ordinal structure of a time series. Here we present a method for extracting the whole ordinal information. [Copyright &y& Elsevier]

• Cancer-associated thrombosis is a major health problem that affects morbidity and mortality of people with cancer. • Surgical and systemic pharmacological anticancer treatments have a significant impact on the thrombotic risk of patients. • Primary thromboprophylaxis may be considered in high-risk ambulatory cancer patients using validated risk models. • Anticoagulant treatment of VTE in cancer patients is effective but may be associated with increased bleeding. • LMWH or DOACs are effective treatments and generally safe options for cancer-associated thrombosis. [ABSTRACT FROM AUTHOR]

Purpose: Comparison of meniscal T1rho- and T2*-relaxation times in professional female volleyball players and healthy controls to determine if relaxation times are prolonged in athletes due to compositional meniscal alterations based on extensive and repetitive joint loading.Methods: The right knee of 20 asymptomatic professional female volleyball players and 20 female controls were examined at 3T MRI. T1rho- and T2*-measurements were performed in sagittal orientation. For quantitative measurements, two readers independently defined two consecutive central slices with the greatest area of the anterior and posterior horn of the lateral (AHLAT; PHLAT) and medial meniscus (AHMED; PHMED). Both readers repeated measurements after a six-week interval on the original MR images. Statistical analysis included intraclass correlation coefficient (ICC), Wilcoxon signed-rank-, Shapiro-Wilk- & Kolmogorov-Smirnov- and Mann-Whitney U-tests.Results: Mean T1rho-relaxation times in the PHMED were significantly prolonged in professional female volleyball players when compared to controls (24.2 ± 4.0 vs 21.1 ± 2.6 ms; p < 0.005). There were no significant differences for the remaining three meniscal horns. T2*-relaxation times revealed no significant differences between athletes and controls. Prolonged T1rho-relaxation times in the PHMED of female volleyball players did not correlate with significant change in T2*-relaxation times within all meniscal subregions. Reproducibility levels were excellent in all segments (Interobserver-ICC: 0.93-0.97 and intraobserver-ICC: 0.97-0.99).Conclusion: T1rho-relaxation times were significantly increased in the PHMED of female volleyball players, potentially indicating a predilection to early degenerative meniscal changes. T1rho may serve as a sensitive biomarker at detecting early compositional meniscal alterations in athletes. [ABSTRACT FROM AUTHOR]