Publications by authors named "Hanno Riess"

150 Publications

Evaluation of Minimal Important Difference and Responder Definition in the EORTC QLQ-PAN26 Module for Assessing Health-Related Quality of Life in Patients with Surgically Resected Pancreatic Adenocarcinoma.

Ann Surg Oncol 2021 Apr 3. Epub 2021 Apr 3.

Mayo Clinic, Scottsdale, AZ, USA.

Background: Although the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-PAN26 is widely used to assess health-related quality of life (HRQoL), its group-level minimal important difference (MID) and individual-level responder definition (RD) are not established; we calculated MID and RD using HRQoL data from the APACT trial in patients with surgically resected pancreatic cancer who received adjuvant chemotherapy.

Methods: HRQoL was assessed using EORTC QLQ-C30 and QLQ-PAN26 at baseline, during treatment, at end of treatment, and during follow-up. Distribution-based MIDs were estimated using 0.5 × baseline standard deviation (SD) and reliability-based (intraclass correlation) standard error of measurement (SEM). Anchor-based MIDs and RDs (anchor, QLQ-C30 overall health) were estimated using a linear mixed model.

Results: Overall, 772 patients completed the baseline assessment. Distribution-based MIDs (0.5 × SD) for QLQ-PAN26 scales ranged from 12 to 13, except hepatic symptoms (≈8), pancreatic pain (≈10), and sexual dysfunction (≈17); those for stand-alone items ranged from 12 to 16. The SEM values were similar. Among scales/items sufficiently correlated (r > 0.30) with the anchor, MIDs ranged from 5 to 9. Within-patient QLQ-PAN26 RD estimates varied by direction (deterioration vs. improvement) and scale/item, but all values were lower than the true possible within-patient change (e.g. 16.7 points for a two-item scale) given a one-category change on the raw scale.

Conclusions: Compared with distribution-based MIDs, anchor-based MIDs were twice as sensitive in detecting group-level changes in QLQ-PAN26 scales/items. For interpreting clinically meaningful change, RDs cannot be less than the true minimum of the scale. The group-level MID may help clinicians/researchers interpret HRQoL changes.

Trial Registration: ClinicalTrials.gov NCT01964430; Eudra CT 2013-003398-91.
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http://dx.doi.org/10.1245/s10434-021-09816-zDOI Listing
April 2021

Advanced cancer is also a heart failure syndrome: a hypothesis.

J Cachexia Sarcopenia Muscle 2021 Mar 18. Epub 2021 Mar 18.

Department of Cardiology & Berlin Institute of Health Center for Regenerative Therapies (BCRT), German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Charité-Universitätsmedizin Berlin (Campus CVK), Berlin, Germany.

We present the hypothesis that advanced stage cancer is also a heart failure syndrome. It can develop independently of or in addition to cardiotoxic effects of anti-cancer therapies. This includes an increased risk of ventricular arrhythmias. We suggest the pathophysiologic link for these developments includes generalized muscle wasting (i.e. sarcopenia) due to tissue homeostasis changes leading to cardiac wasting associated cardiomyopathy. Cardiac wasting with thinning of the ventricular wall increases ventricular wall stress, even in the absence of ventricular dilatation. In addition, arrhythmias may be facilitated by cellular wasting processes affecting structure and function of electrical cells and conduction pathways. We submit that in some patients with advanced cancer (but not terminal cancer), heart failure therapy or defibrillators may be relevant treatment options. The key points in selecting patients for such therapies may be the predicted life expectancy, quality of life at intervention time, symptomatic burden, and consequences for further anti-cancer therapies. The cause of death in advanced cancer is difficult to ascertain and consensus on event definitions in cancer is not established yet. Clinical investigations on this are called for. Broader ethical considerations must be taken into account when aiming to target cardiovascular problems in cancer patients. We suggest that focused attention to evaluating cardiac wasting and arrhythmias in cancer will herald a further evolution in the rapidly expanding field of cardio-oncology.
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http://dx.doi.org/10.1002/jcsm.12694DOI Listing
March 2021

Treatment of cancer-associated thrombosis: The evolution of anticoagulant choice and clinical insights into practical management.

Crit Rev Oncol Hematol 2021 Jan 20;157:103125. Epub 2020 Oct 20.

Hull York Medical School and Hull University Teaching Hospitals NHS Trust, Hull, United Kingdom.

Low-molecular-weight heparin (LMWH) therapy is recommended over vitamin K antagonists (VKAs) for the treatment of cancer-associated thrombosis (CAT) and extended therapy is recommended in those with active cancer to prevent recurrent thrombosis. However, the inconvenience of daily subcutaneous injections and the cost of LMWH therapy hinder long-term use. Observational data demonstrate that persistence with LMWH therapy is low in clinical practice and that many patients are switched to oral alternatives - namely VKAs and direct oral anticoagulants (DOACs). Recently, the efficacy and safety of apixaban, edoxaban, and rivaroxaban versus LMWH therapy for the treatment of CAT have been demonstrated in randomized trials. This review provides a critical evaluation of studies with DOACs in this setting and an update on the guidance regarding anticoagulant use for the treatment of CAT. In recognition of the heterogeneity of patients with cancer and the challenges of CAT, patient cases with expert clinical perspectives are presented.
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http://dx.doi.org/10.1016/j.critrevonc.2020.103125DOI Listing
January 2021

Advanced cancer is also a heart failure syndrome: a hypothesis.

Eur J Heart Fail 2021 Jan;23(1):140-144

Department of Cardiology & Berlin Institute of Health Center for Regenerative Therapies (BCRT), German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Charité-Universitätsmedizin Berlin (Campus CVK), Berlin, Germany.

We present the hypothesis that advanced stage cancer is also a heart failure syndrome. It can develop independently of or in addition to cardiotoxic effects of anti-cancer therapies. This includes an increased risk of ventricular arrhythmias. We suggest the pathophysiologic link for these developments includes generalized muscle wasting (i.e. sarcopenia) due to tissue homeostasis changes leading to cardiac wasting associated cardiomyopathy. Cardiac wasting with thinning of the ventricular wall increases ventricular wall stress, even in the absence of ventricular dilatation. In addition, arrhythmias may be facilitated by cellular wasting processes affecting structure and function of electrical cells and conduction pathways. We submit that in some patients with advanced cancer (but not terminal cancer), heart failure therapy or defibrillators may be relevant treatment options. The key points in selecting patients for such therapies may be the predicted life expectancy, quality of life at intervention time, symptomatic burden, and consequences for further anti-cancer therapies. The cause of death in advanced cancer is difficult to ascertain and consensus on event definitions in cancer is not established yet. Clinical investigations on this are called for. Broader ethical considerations must be taken into account when aiming to target cardiovascular problems in cancer patients. We suggest that focused attention to evaluating cardiac wasting and arrhythmias in cancer will herald a further evolution in the rapidly expanding field of cardio-oncology.
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http://dx.doi.org/10.1002/ejhf.2071DOI Listing
January 2021

Ventricular tachycardia, premature ventricular contractions, and mortality in unselected patients with lung, colon, or pancreatic cancer: a prospective study.

Eur J Heart Fail 2021 Jan;23(1):145-153

Division of Cardiology and Metabolism, Department of Cardiology (CVK), Charité University Medicine Berlin, Berlin, Germany.

Aims: Many cancer patients die due to cardiovascular disease and sudden death, but data on ventricular arrhythmia prevalence and prognostic importance are not known.

Methods And Results: Between 2005 and 2010, we prospectively enrolled 120 unselected patients with lung, colon, or pancreatic cancer due to one of three diagnoses: colorectal (n = 33), pancreatic (n = 54), or non-small cell lung cancer (n = 33). All were free of manifest cardiovascular disease. They were compared to 43 healthy controls similar in age and sex distribution. Each participant underwent 24 h electrocardiogram recording and cancer patients were followed for up to 12.5 years for survival (median 21 months). Ninety-six cancer patients (80%) died during follow-up [5-year survival: 27% (95% confidence interval 19-35%)]. Non-sustained ventricular tachycardia (NSVT) was more frequent in cancer patients vs. controls (8% vs. 0%, P = 0.021). The number of premature ventricular contractions (PVCs) over 24 h was not increased in cancer patients vs. controls (median 4 vs. 9, P = 0.2). In multivariable analysis, NSVT [hazard ratio (HR) 2.44, P = 0.047] and PVCs (per 100, HR 1.021, P = 0.047) were both significant predictors of mortality, independent of other univariable mortality predictors including tumour stage, cancer type, potassium concentration, prior surgery, prior cardiotoxic chemotherapy, and haemoglobin. In patients with colorectal and pancreatic cancer, ≥50 PVCs/24 h predicted mortality (HR 2.30, P = 0.0024), and was identified in 18% and 26% of patients, respectively.

Conclusions: Non-sustained ventricular tachycardia is more frequent in unselected patients with colorectal, pancreatic, and non-small cell lung cancer and together with PVCs predict long-term mortality. This raises the prospect of cardiovascular mortality being a target for future treatment interventions in selected cancers.
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http://dx.doi.org/10.1002/ejhf.2059DOI Listing
January 2021

Rivaroxaban thromboprophylaxis in ambulatory patients with pancreatic cancer: Results from a pre-specified subgroup analysis of the randomized CASSINI study.

Cancer Med 2020 09 14;9(17):6196-6204. Epub 2020 Jul 14.

Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH, USA.

Background: Pancreatic cancer patients are at risk for venous thromboembolism (VTE); the value of thromboprophylaxis has not been definitively established.

Methods: This trial randomized cancer patients initiating a new regimen and at high risk for VTE (Khorana score ≥2) to rivaroxaban 10 mg or placebo up to day 180. This analysis examined the subset of pancreatic cancer patients. The primary efficacy endpoint was the composite of symptomatic deep-vein thrombosis (DVT), asymptomatic proximal DVT, any pulmonary embolism, and VTE-related death. The primary safety endpoint was International Society on Thrombosis and Haemostasis-defined major bleeding.

Results: In total, 49/1080 (4.5%) patients enrolled had baseline VTE on screening, with higher rates (24/362 [6.6%]) in pancreatic cancer and they were not randomized. Of 841 randomized patients, 273 (32.5%) had pancreatic cancer; 155/273 (57% in each arm) completed the double-blind period. The primary endpoint occurred in 13/135 (9.6%) patients in the rivaroxaban group and in 18/138 (13.0%) in the placebo group (hazard ratio [HR] = 0.70; 95% CI, 0.34-1.43; P = .328) in up-to-day-180 period and 5/135 (3.7%) patients receiving rivaroxaban and 14/138 (10.1%) receiving placebo in the intervention period (HR = 0.35; 95% CI, 0.13-0.97; P = .034). Major bleeding was similar (2 [1.5%] receiving rivaroxaban and 3 [2.3%] receiving placebo). Correlative biomarker studies demonstrated significant decline in D-dimer (weeks 8 and 16) in patients randomized to rivaroxaban compared to placebo (P < .01).

Conclusions: In ambulatory pancreatic cancer patients, rivaroxaban did not result in significantly lower incidence of VTE or VTE-related death in the 180-day period. During the intervention period, however, rivaroxaban substantially reduced VTE without increasing major bleeding, suggesting benefit of rivaroxaban prophylaxis in this setting.

Trial Registration: ClinicalTrials.gov identifier, NCT02555878.
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http://dx.doi.org/10.1002/cam4.3269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476843PMC
September 2020

Assessing Full Benefit of Rivaroxaban Prophylaxis in High-Risk Ambulatory Patients with Cancer: Thromboembolic Events in the Randomized CASSINI Trial.

TH Open 2020 Apr 23;4(2):e107-e112. Epub 2020 May 23.

Hematology Service, Memorial Sloan Kettering Cancer Center, New York, New York, United States.

 In the CASSINI study, rivaroxaban thromboprophylaxis significantly reduced primary venous thromboembolism (VTE) endpoints during the intervention period, but several thromboembolic events designated as secondary efficacy endpoints were not included in the primary analysis. This study was aimed to evaluate the full impact of rivaroxaban thromboprophylaxis on all prespecified thromboembolic endpoints occurring on study.  CASSINI was a double-blind, randomized, placebo-controlled study in adult ambulatory patients with cancer at risk for VTE (Khorana score ≥2). Patients were screened at baseline for deep-vein thrombosis (DVT) and randomized if none was found. The primary efficacy endpoint was a composite of lower extremity proximal DVT, symptomatic upper extremity, or lower extremity distal DVT, any pulmonary embolism, and VTE-related death. This analysis evaluated all prespecified thromboembolic endpoints occurring on study to determine the full benefit of rivaroxaban prophylaxis. All endpoints were independently adjudicated.  Total thromboembolic events occurred in fewer patients randomized to rivaroxaban during the full study period (29/420 [6.9%] and 49/421 [11.6%] patients in rivaroxaban and placebo groups, respectively [hazard ratio (HR) = 0.57; 95% confidence interval (CI): 0.36-0.90;  = 0.01]; number needed to treat [NNT] = 21). Similarly, fewer patients randomized to rivaroxaban experienced thromboembolism during the intervention period (13/420 [3.1%] patients) versus placebo (38/421 [9.0%] patients; HR = 0.33; 95% CI: 0.18-0.62; < 0.001; NNT = 17).  Our findings confirm the substantial benefit of rivaroxaban thromboprophylaxis when considering all prespecified thromboembolic events, even after excluding baseline screen-detected DVT. The low NNT, coupled with prior data demonstrating a high number needed to harm, should assist clinicians in determining the risk/benefit of thromboprophylaxis in high-risk patients with cancer.
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http://dx.doi.org/10.1055/s-0040-1712143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245534PMC
April 2020

The Khorana score for prediction of venous thromboembolism in cancer patients: An individual patient data meta-analysis.

J Thromb Haemost 2020 08 8;18(8):1940-1951. Epub 2020 Jul 8.

Michael G. DeGroote Cochrane Canada and McGRADE Centres, Department of Health Research Methods, Evidence and Impact, Faculty of Health Sciences, McMaster University, Hamilton, Canada.

Background: Oncology guidelines suggest using the Khorana score to select ambulatory cancer patients receiving chemotherapy for primary venous thromboembolism (VTE) prevention, but its performance in different cancers remains uncertain.

Objective: To examine the performance of the Khorana score in assessing 6-month VTE risk, and the efficacy and safety of low-molecular-weight heparin (LMWH) among high-risk Khorana score patients.

Methods: This individual patient data meta-analysis evaluated (ultra)-LMWH in patients with solid cancer using data from seven randomized controlled trials.

Results: A total of 3293 patients from the control groups with an available Khorana score had lung (n = 1913; 58%), colorectal (n = 452; 14%), pancreatic (n = 264; 8%), gastric (n = 201; 6%), ovarian (n = 184; 56%), breast (n = 164; 5%), brain (n = 84; 3%), or bladder cancer (n = 31; 1%). The 6-month VTE incidence was 9.8% among high-risk Khorana score patients and 6.4% among low-to-intermediate-risk patients (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.1-2.2). The dichotomous Khorana score performed differently in lung cancer patients (OR 1.1; 95% CI, 0.72-1.7) than in the group with other cancer types (OR 3.2; 95% CI, 1.8-5.6; P  = .002). Among high-risk patients, LMWH decreased the risk of VTE by 64% compared with controls (OR 0.36; 95% CI, 0.22-0.58), without increasing the risk of major bleeding (OR 1.1; 95% CI, 0.59-2.1).

Conclusion: The Khorana score was unable to stratify patients with lung cancer based on their VTE risk. Among those with other cancer types, a high-risk score was associated with a three-fold increased risk of VTE compared with a low-to-intermediate risk score. Thromboprophylaxis was effective and safe in patients with a high-risk Khorana score.
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http://dx.doi.org/10.1111/jth.14824DOI Listing
August 2020

Mutations Predict Sensitivity to Adjuvant Gemcitabine in Patients with Pancreatic Ductal Adenocarcinoma: Next-Generation Sequencing Results from the CONKO-001 Trial.

Clin Cancer Res 2020 07 31;26(14):3732-3739. Epub 2020 Mar 31.

Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Purpose: We performed next-generation sequencing (NGS) in the CONKO-001 phase III trial to identify clinically relevant prognostic and predictive mutations and conducted a functional validation in The Cancer Genome Atlas (TCGA) sequencing data.

Experimental Design: Patients of the CONKO-001 trial received curatively intended surgery for pancreatic adenocarcinoma (PDAC) followed by adjuvant chemotherapy with gemcitabine (Gem) or observation only (Obs). Tissue samples of 101 patients were evaluated by NGS of 37 genes. Cox proportional hazard models were applied for survival analysis. In addition, functional genomic analyses were performed in an NGS and RNA-sequencing dataset of 146 pancreatic tumors from TCGA.

Results: The most common mutations in the CONKO cohort were (75%), (60%), (10%), (9%), as well as SWI/SNF (12%) complex alterations. In untreated patients, mutations were a negative prognostic factor for disease-free survival (DFS; HR mut vs. WT 2.434, = 0.005). With respect to gemcitabine treatment, mutations were a positive predictive factor for gemcitabine efficacy [mut: HR for DFS Gem vs. Obs, 0.235 (0.130 - 0.423; < 0.001); wt: HR for DFS Gem vs. Obs, 0.794 (0.417 - 1.513; = 0.483)] with a significant test for interaction ( = 0.003). In the TCGA dataset, mutations were associated with shortened DFS.

Conclusions: In CONKO-001, the benefit from adjuvant gemcitabine was confined to the mut patient group. This potentially clinical relevant observation needs to be confirmed in independent prospective studies. The sensitivity of TP53mut PDAC to gemcitabine in CONKO-001 provides a lead for further mechanistic investigations.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3034DOI Listing
July 2020

Landscape of Health-Related Quality of Life in Patients With Early-Stage Pancreatic Cancer Receiving Adjuvant or Neoadjuvant Chemotherapy: A Systematic Literature Review.

Pancreas 2020 03;49(3):393-407

Department of Internal Medicine, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.

Objectives: Pancreatic resection is associated with postoperative morbidity and reduced quality of life (QoL). A systematic literature review was conducted to understand the patient-reported outcome measure (PROM) landscape in early-stage pancreatic cancer (PC).

Methods: Databases/registries (through January 24, 2019) and conference abstracts (2014-2017) were searched. Study quality was assessed using the Newcastle-Ottawa Scale/Cochrane risk-of-bias tool. Searches were for general (resectable PC, adjuvant/neoadjuvant, QoL) and supplemental studies (resectable PC, European Organisation for Research and Treatment of Cancer QoL Questionnaire [QLQ] - Pancreatic Cancer [PAN26]).

Results: Of 750 studies identified, 39 (general, 22; supplemental, 17) were eligible: 32 used QLQ Core 30 (C30) and/or QLQ-PAN26, and 15 used other PROMs. Baseline QLQ-C30 global health status/QoL scores in early-stage PC were similar to all-stage PC reference values but lower than all-stage-all-cancer values. The QoL declined after surgery, recovered to baseline in 3 to 6 months, and then generally stabilized. A minimally important difference (MID) of 10 was commonly used for QLQ-C30 but was not established for QLQ-PAN26.

Conclusions: In early-stage PC, QLQ-C30 and QLQ-PAN26 are the most commonly used PROMs. Baseline QLQ-C30 global health status/QoL scores suggested a high humanistic burden. Immediately after surgery, QoL declined but seemed stable over the longer term. The QLQ-C30 MID may elucidate the clinical impact of treatment on QoL; MID for QLQ-PAN26 needs to be established.
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http://dx.doi.org/10.1097/MPA.0000000000001507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077976PMC
March 2020

Non-vitamin K Antagonist Oral Anticoagulants (NOAC) as an Alternative Treatment Option in Tumor-Related Venous Thromboembolism.

Dtsch Arztebl Int 2019 01;116(3):31-38

Department of Medicine I, Division of Hematology and Hemostaseology, University Hospital "Carl Gustav Carus" Dresden; King's Thrombosis Service, Department of Hematology, King's College London; Department of Internal Medicine, Angiology and Hemostaseology, Vivantes Klinikum im Friedrichshain Berlin; Hematology and Oncology practice, Bad Liebenwerda; II. Medical Clinic and Polyclinic, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg; (UCCH), University Medical Center Hamburg-Eppendorf; Medical Clinic II, Asklepios Klinikum Uckermark, Schwedt; Medical Department, Division of Hematology, Oncology and Tumor Immunology, Charité - Universitätsmedizin Berlin.

Background: The risk of venous thromboembolism (VTE) is 4 to 7 times higher in cancer patients than in the normal population. Moreover, cancer patients who take anticoagulants suffer more frequently from hemorrhagic complications and VTE recurrences. Patients often find low-molecular-weight heparin (LMWH) treatment unpleasant; approximately 20% stop taking LMWH during the first six months of treatment.

Methods: Based on a non-systematic literature search, an interdisciplinary group of specialists (hematology, oncology, hemostaseology, and angiology) developed a set of recommendations concerning the treatment of tumor-related thrombosis with non-vitamin K antagonist oral anticoagulants (NOAC).

Results: Patient-, tumor-, and tumor-treatment-related factors and clinical situations were identified that should be considered in therapeutic decision-making in the indi- vidual case. NOAC may be an alternative that lessens the rate of VTE recurrence (though at the cost of more hemorrhagic complications), without lessening mortality. Moreover, many factors need to be considered that can limit the utility of NOAC treatment or even make it impossible.

Conclusion: It seems likely that, in future, the treatment of tumor-related VTE will often not involve a single decision to use either NOAC or LWMH, but rather a switching of treatment in either of two directions: from LWMH to NOAC in stable phases of the underlying malignant disease, conferring better quality of life to suitable patients; or from NOAC to LWMH, e.g., in patients suffering from emesis or thrombocytopenia, to whom the greater clinical experience with LWMH, parenteral application, or stepwise dose titration can confer benefits.
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http://dx.doi.org/10.3238/arztebl.2019.0031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401514PMC
January 2019

Rivaroxaban for Thromboprophylaxis in High-Risk Ambulatory Patients with Cancer.

N Engl J Med 2019 02;380(8):720-728

From the Department of Hematology and Medical Oncology, Taussig Cancer Institute and Case Comprehensive Cancer Center, Cleveland Clinic, Cleveland (A.A.K.); the Department of Medicine, Memorial Sloan Kettering Cancer Center (G.A.S., E.M.O.), and Weill Cornell Medical College (G.A.S., E.M.O.), New York; the Thrombosis Research Institute and University College London, London (A.K.K.); University of Texas M.D. Anderson Cancer Center, Houston (S.V.-R.), and U.S. Oncology Research-Texas Oncology, Tyler (H.A.Y.) - both in Texas; the Department of Medicine, Charité Universitätsmedizin Berlin, Berlin (H.R.); the Division of Hematology-Oncology, University of California Davis School of Medicine, Sacramento (T.W.), and the Keck School of Medicine, University of Southern California, Los Angeles (H.A.L.); the Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore (M.B.S.); the University of Washington School of Medicine (D.A.G., N.M.K., G.H.L.), Advanced Cancer Research Group (N.M.K.), and Fred Hutchinson Cancer Research Center (G.H.L.), Seattle; Penn State Cancer Institute, Milton S. Hershey Medical Center, Hershey, PA (C.P.B.); the Department of Cancer Pharmacology, Levine Cancer Institute, Atrium Health, Charlotte, NC (J.N.P.); Janssen Scientific Affairs, Titusville (P.W., P.B., S.K.), and Janssen Research and Development, Raritan (U.V.) - both in New Jersey; the Department of Medicine, McMaster University, Hamilton, ON, Canada (J.E.); the Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN (R.M.); and the Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston (K.A.B.).

Background: Ambulatory patients receiving systemic cancer therapy are at varying risk for venous thromboembolism. However, the benefit of thromboprophylaxis in these patients is uncertain.

Methods: In this double-blind, randomized trial involving high-risk ambulatory patients with cancer (Khorana score of ≥2, on a scale from 0 to 6, with higher scores indicating a higher risk of venous thromboembolism), we randomly assigned patients without deep-vein thrombosis at screening to receive rivaroxaban (at a dose of 10 mg) or placebo daily for up to 180 days, with screening every 8 weeks. The primary efficacy end point was a composite of objectively confirmed proximal deep-vein thrombosis in a lower limb, pulmonary embolism, symptomatic deep-vein thrombosis in an upper limb or distal deep-vein thrombosis in a lower limb, and death from venous thromboembolism and was assessed up to day 180. In a prespecified supportive analysis involving the same population, the same end point was assessed during the intervention period (first receipt of trial agent to last dose plus 2 days). The primary safety end point was major bleeding.

Results: Of 1080 enrolled patients, 49 (4.5%) had thrombosis at screening and did not undergo randomization. Of the 841 patients who underwent randomization, the primary end point occurred in 25 of 420 patients (6.0%) in the rivaroxaban group and in 37 of 421 (8.8%) in the placebo group (hazard ratio, 0.66; 95% confidence interval [CI], 0.40 to 1.09; P = 0.10) in the period up to day 180. In the prespecified intervention-period analysis, the primary end point occurred in 11 patients (2.6%) in the rivaroxaban group and in 27 (6.4%) in the placebo group (hazard ratio, 0.40; 95% CI, 0.20 to 0.80). Major bleeding occurred in 8 of 405 patients (2.0%) in the rivaroxaban group and in 4 of 404 (1.0%) in the placebo group (hazard ratio, 1.96; 95% CI, 0.59 to 6.49).

Conclusions: In high-risk ambulatory patients with cancer, treatment with rivaroxaban did not result in a significantly lower incidence of venous thromboembolism or death due to venous thromboembolism in the 180-day trial period. During the intervention period, rivaroxaban led to a substantially lower incidence of such events, with a low incidence of major bleeding. (Funded by Janssen and others; CASSINI ClinicalTrials.gov number, NCT02555878.).
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http://dx.doi.org/10.1056/NEJMoa1814630DOI Listing
February 2019

Direct oral anticoagulants for the treatment of venous thromboembolism in cancer patients: Potential for drug-drug interactions.

Crit Rev Oncol Hematol 2018 Dec 29;132:169-179. Epub 2018 Sep 29.

Department of Vascular Medicine, Darmstadt, and Center for Thrombosis and Haemostasis, University Medical Centre, Mainz, Germany.

Patients with cancer are at high risk of developing venous thromboembolism (VTE). Although the recommended low molecular weight heparins (LMWHs) are more effective than vitamin K antagonists in treating VTE in patients with cancer, they have limitations and contraindications. Direct oral anticoagulants (DOACs) circumvent some of these limitations. Here, DOAC use for VTE treatment in patients receiving anticancer therapy is reviewed, focusing on metabolic and elimination pathways, potential drug-drug interactions and practical considerations. DOACs are typically substrates of the cytochrome P450-based metabolic pathways and/or ATP-binding cassette transporters. Although many cancer therapies influence these pathways, only a minority of these drugs interact with DOACs. Phase III DOAC trials provided encouraging safety and efficacy data for their use in cancer-associated thrombosis. Furthermore, numerous ongoing DOAC trials strive to gain a better understanding of the treatment of cancer-associated thrombosis and continue to support a role for DOACs in this setting.
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http://dx.doi.org/10.1016/j.critrevonc.2018.09.015DOI Listing
December 2018

Safety and efficacy of Nab-paclitaxel plus gemcitabine in patients with advanced pancreatic cancer suffering from cholestatic hyperbilirubinaemia-A retrospective analysis.

Eur J Cancer 2018 09 4;100:85-93. Epub 2018 Jul 4.

Division of Hematology, Oncology and Tumor Immunology, Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt Universität - Universität zu Berlin, Berlin Institute of Health, Berlin, Germany.

Introduction: Treatment of patients with advanced pancreatic carcinoma (APC) and hyperbilirubinaemia is problematic because these patients were regularly excluded from clinical studies. Nanoparticle albumin-bound paclitaxel and gemcitabine (nab-P/G) is an evidence-based treatment for patients with APC. This retrospective study investigated the safety and efficacy of nab-P/G in patients with APC and cholestatic hyperbilirubinaemia.

Methods: We screened our prospective database for patients with APC treated with nab-P/G at total bilirubin levels of ≥1.2 mg/dl. Patients were assigned into three groups according to their bilirubin level (A: 1.2-3 mg/dl, B: >3-5 mg/dl, C: >5 mg/dl). Analyses with regard to safety and survival were performed.

Results: Twenty-nine of 168 patients screened between Dec 2013 and Dec 2015 fulfilled the inclusion criteria. Most patients (83%) were male; median age was 63 [41-79] years. Nab-P/G administrations in patients with an elevated bilirubin level (median, range) did not result in unexpected toxicities assessed by predefined (non-)haematological parameters. Median overall survival (mOS) for the whole group was 11.7 (95% confidence interval [CI]: 6.8-14.0) months; for A: 11.8 (95% CI: 6.5-16.5), B: 9.2 (95% CI: 1.1 - NA) months and C 11.8 (95% CI: 5.9-20.0] months (p = 0.843). Again, mOS from the first application of nab-P/G did not differ between the groups (p = 0.13).

Conclusion: Nab-P/G administrations in our pts with cholestatic hyperbilirubinaemia suffering from APC were feasible and safe with respect to individualised dose administrations. A multicenter phase 1 trial in pts with hyperbilirubinaemia is started (AIO-PAK-0117) to confirm these findings in a prospective setting.
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http://dx.doi.org/10.1016/j.ejca.2018.06.001DOI Listing
September 2018

Immunosuppression Is Associated With Clinical Features and Relapse Risk of B Cell Posttransplant Lymphoproliferative Disorder: A Retrospective Analysis Based on the Prospective, International, Multicenter PTLD-1 Trials.

Transplantation 2018 Nov;102(11):1914-1923

Department of Hematology and Oncology, DIAKO Ev. Diakonie-Krankenhaus Bremen, Bremen, Germany.

Background: Current guideline recommendations for immunosuppression reduction after diagnosis of posttransplant lymphoproliferative disorder (PTLD) include stopping antimetabolites, reducing calcineurin inhibitors, and maintaining corticosteroids. However, the effect of immunosuppression on PTLD relapse risk after up-to-date therapy is unclear.

Methods: This is a retrospective analysis of immunosuppression, patient baseline characteristics, and relapse risk measured as landmark time to progression (TTP) starting 1 year after start of therapy in 159 patients with B cell PTLD after solid organ transplantation treated in the prospective, international, multicenter PTLD-1 trials with either sequential treatment (rituximab followed by cyclophosphamide (CHOP-21 chemotherapy) 750 mg/m intravenously [IV] day (d) 1, doxorubicin 50 mg/m IV d1, vincristine 1.4 mg/m (maximum, 2 mg) IV d1, and prednisone 50 mg/m PO d1-5, every 21 days) or risk-stratified sequential treatment (rituximab followed by rituximab or rituximab (R-CHOP-21 immunochemotherapy) 375 mg/m IV day (d) 1, cyclophosphamide 750 mg/m IV d1, doxorubicin 50 mg/m IV d1, vincristine 1.4 mg/m (max. 2 mg) IV d1, and prednisone 50 mg/m PO d1-5, every 21 days).

Results: Patient baseline characteristics at diagnosis of PTLD differed significantly depending on immunosuppression before diagnosis. Compared with immunosuppression before diagnosis, significantly fewer patients received an antimetabolite or a calcineurin inhibitor (CNI) after diagnosis of PTLD. Relapse risk measured as landmark TTP was significantly higher for patients on corticosteroids compared to all others (P = 0.010) as well as for patients on ciclosporin compared with those on tacrolimus (P = 0.002), but similar for those on antimetabolites compared with all others (P = 0.912). In a Cox regression analysis of landmark TTP, corticosteroid-containing immunosuppression after diagnosis of PTLD (P = 0.002; hazard ratio, 11.195) and age (P = 0.001; hazard ratio, 1.076/year) were identified as independent, significant risk factors for PTLD relapse.

Conclusions: In the prospective PTLD-1 trials, corticosteroid use after diagnosis of PTLD is associated with an increased risk of relapse, whereas the use of antimetabolites is not. These findings require prospective validation.
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http://dx.doi.org/10.1097/TP.0000000000002269DOI Listing
November 2018

Tumour buds determine prognosis in resected pancreatic ductal adenocarcinoma.

Br J Cancer 2018 05 14;118(11):1485-1491. Epub 2018 May 14.

Department of Medical Oncology, CONKO study group, Haematology and Tumorimmunology, Augustenburger Platz 1, Berlin, 13353, Germany.

Background: The prognostic effect of tumour budding was retrospectively analysed in a cohort of 173 patients with resected pancreatic ductal adenocarcinomas (PDACs) of the prospective clinical multicentre CONKO-001 trial.

Methods: Haematoxylin and eosin (H&E)-stained whole tissue slides were evaluated. In two independent approaches, the mean number of tumour buds was analysed according to the consensus criteria in colorectal cancer, in one 0.785 mm field of view and additionally in 10 high-power fields (HPF) (HPF = 0.238 mm).

Results: Tumour budding was significantly associated with a higher tumour grade (p < 0.001) but not with distant or lymph node metastasis. Regardless of the quantification approach, an increased number of tumour buds was significantly associated with reduced disease-free survival (DFS) and overall survival (OS) (10 HPF approach DFS: HR = 1.056 (95% CI 1.022-1.092), p = 0.001; OS: HR = 1.052 (95% CI 1.018-1.087), p = 0.002; consensus method DFS: HR = 1.037 (95% CI 1.017-1.058), p < 0.001; OS: HR = 1.040 (95% CI 1.019-1.061), p < 0.001). Recently published cut-offs for tumour budding in colorectal cancer were prognostic in PDAC as well.

Conclusions: Tumour budding is prognostic in the CONKO-001 clinical cohort of patients. Further standardisation and validation in additional clinical cohorts are necessary.
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http://dx.doi.org/10.1038/s41416-018-0093-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988658PMC
May 2018

Use of Direct Oral Anticoagulants in Patients with Cancer: Practical Considerations for the Management of Patients with Nausea or Vomiting.

Oncologist 2018 07 12;23(7):822-839. Epub 2018 Apr 12.

Cancer Research Centre, Warwick Medical School, University of Warwick, Coventry, UK.

Direct oral anticoagulants (DOACs) have proven efficacy and safety and are approved for use in the prevention and treatment of thromboembolic events in patients with venous thromboembolism (VTE) and those with atrial fibrillation (AF). There is no clear guidance on the use of DOACs in the significant proportion of these patients who have or will develop concomitant cancer. The occurrence of nausea and vomiting in these patients, despite implementation of guideline-recommended antiemetic strategies, is a particular concern because it may affect oral drug intake and consequently outcomes with anticoagulation therapy.Here, we review recent data on the incidence and management of cancer-associated nausea and vomiting and the current evidence and guidance relating to the use of DOACs in patients with cancer. On the basis of this evidence, an international working group of experts in the fields of cancer-associated thrombosis/hemostasis, hematology, and oncology discussed key issues related to the use of DOACs in patients with VTE or AF and cancer who are at risk of nausea and vomiting and developed some consensus recommendations. We present these consensus recommendations, which outline strategies for the use and management of anticoagulants, including DOACs, in patients with VTE or AF and cancer for whom oral drug intake may pose challenges. Guidance is provided on managing patients with gastrointestinal obstruction or nausea and vomiting that is caused by cancer treatments or other cancer-related factors.The recommendations outlined in this review provide a useful reference for health care professionals and will help to improve the management of anticoagulation in patients with VTE or AF and cancer.

Implications For Practice: Direct oral anticoagulants (DOACs) offer several advantages over traditional anticoagulants, including ease of administration and the lack of need for routine monitoring. However, the management of patients with an indication for anticoagulation and concomitant cancer, who are at high risk of thromboembolic events, presents several challenges for administering oral therapies, particularly with regard to the risk of nausea and vomiting. In the absence of robust data from randomized trials and specific guidelines, consensus recommendations were developed for healthcare professionals regarding the use of DOACs in patients with cancer, with a focus on the management of patients who are at risk of nausea and vomiting.
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http://dx.doi.org/10.1634/theoncologist.2017-0473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058321PMC
July 2018

End-of-Treatment Positron Emission Tomography After Uniform First-Line Therapy of B-Cell Posttransplant Lymphoproliferative Disorder Identifies Patients at Low Risk of Relapse in the Prospective German PTLD Registry.

Transplantation 2018 05;102(5):868-875

Department of Hematology and Oncology, DIAKO Ev. Diakonie-Krankenhaus Bremen, Bremen, Germany.

Background: Fluorine-18 fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET) is a recommended standard in the staging and response assessment of 18F-FDG-avid lymphoma. Posttransplant lymphoproliferative disorder (PTLD) can be detected by 18F-FDG-PET at diagnosis with high sensitivity and specificity. However, the role of response assessment by end-of-treatment (EOT) PET has only been addressed in small case series.

Methods: We performed a retrospective, multicenter study of 37 patients with CD20-positive PTLD after solid organ transplantation treated with uniform, up-to-date, first-line protocols in the prospective German PTLD registry who had received EOT 18F-FDG-PET between 2006 and 2014. Median follow-up was 5.0 years. Any nonphysiological 18F-FDG uptake (Deauville score greater 2) was interpreted as PET-positive.

Results: By computed tomography (CT) final staging, 18 of 37 patients had a complete response, 18 had a partial response and 1 patient had stable disease. EOT PET was negative in 24 of 37 patients and positive in 13 of 37 patients. The positive predictive value of EOT PET for PTLD relapse was 38%, and the negative predictive value was 92%. Time to progression (TTP) and progression-free-survival were significantly longer in the PET negative group (P = 0.019 and P = 0.013). In the 18 patients in a partial response by CT staging, we noted highly significant differences in overall survival (P = 0.001), time to progression (P = 0.007), and progression-free survival (P < 0.001) by EOT PET.

Conclusions: Even without baseline imaging, EOT PET in PTLD identifies patients at low risk of relapse and offers clinically relevant information, particularly in patients in a partial remission by CT staging.
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http://dx.doi.org/10.1097/TP.0000000000002006DOI Listing
May 2018

Dose-escalated radiotherapy for unresectable or locally recurrent pancreatic cancer: Dose volume analysis, toxicity and outcome of 28 consecutive patients.

PLoS One 2017 12;12(10):e0186341. Epub 2017 Oct 12.

Charité Universitätsmedizin Berlin, Department of Radiation Oncology, Berlin, Germany.

Purpose: The role of radiotherapy for unresectable pancreatic cancer is controversial. A benefit of additional radiotherapy is supported by some observations. A dose-effect relationship was recently found by dose escalation employing image guided and intensity modulated radiotherapy.

Methods: We retrospectively evaluated 28 consecutive patients, all with history of extensive prior therapies for unresectable locally advanced/ recurrent pancreatic cancer (LAPC/LRPC). Treatment was delivered by helical tomotherapy after daily position verification with computed tomography. Dose to the planned target volume (PTV) was 51 Gy, while the dose to the macroscopic tumor was escalated by a simultaneous integrated boost to a median cumulative dose of 66 Gy (60-66 Gy). Concomitant chemotherapy consisted mainly of capecitabine (n = 23).

Results: 10 of 28 patients presented acute toxicities > grade 2, one patient succumbed to gastrointestinal bleeding after treatment. No correlations of toxicities and dose volume histograms (DVH) of retrospectively delineated small bowel loops were observed, although average small bowel volume receiving ≥ 20 Gy was 374 ml. DVH analyses revealed a correlation of splenic parameters and acute toxicity: Vomiting, anorexia, dehydration, hematologic toxicity, fatigue, combined gastro-intestinal toxicity wit R-values between 0.392 and 0.561 (all p-values > 0.05). Only one patient developed late toxicities > grade 2. With an average follow-up time in surviving patients of 14 months median overall survival time was 19 months and median time to local recurrence 13 months. In 8 patients with available imaging of local recurrence: 5 in field recurrences, 2 marginal recurrences and one lymph node recurrence outside the high dose radiation field were observed. In univariate analysis only ΔCA-19-9 during radiotherapy was associated with local control (p = 0.029) and overall survival (p = 0.049).

Conclusion: Dose escalated normo-fractionated radiotherapy for LAPC/LRPC seems feasible and suitable to prolong local control and in consequence long-term survival. However, in-field local progression is still frequently observed and possibilities to increase the local effectiveness should be evaluated. Exposure of the spleen was predictive for acute toxicity and should be further investigated.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0186341PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638513PMC
October 2017

Rivaroxaban for Preventing Venous Thromboembolism in High-Risk Ambulatory Patients with Cancer: Rationale and Design of the CASSINI Trial. Rationale and Design of the CASSINI Trial.

Thromb Haemost 2017 11 21;117(11):2135-2145. Epub 2017 Sep 21.

Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington, United States.

Venous thromboembolism (VTE) is a frequent complication of cancer associated with morbidity, mortality, increased hospitalizations and higher health care costs. Cancer patients at increased risk for VTE can be identified using a validated risk assessment score, and the incidence of VTE can be reduced in high-risk settings using anticoagulation. Rivaroxaban is a potent, oral, direct, factor Xa inhibitor approved for the prevention and treatment of thromboembolic events, including VTE. CASSINI is a double-blind, randomized, parallel-group, multicentre study comparing rivaroxaban with placebo in adult ambulatory patients with various cancers who are initiating systemic cancer therapy and are at high risk of VTE (Khorana score ≥ 2). Patients with primary brain tumours or those at risk for bleeding are excluded. Approximately 700 patients will be randomized 1:1 to rivaroxaban 10 mg daily or placebo for up to 6 months if there is no evidence of VTE from compression ultrasonography (CU) during screening or from routine care imaging within 30 days prior to randomization. Mandatory CU will also be performed at weeks 8 and 16 (±7 days), and at study end (±3 days). The primary efficacy hypothesis is that anticoagulation with rivaroxaban reduces the composite of objectively confirmed symptomatic or asymptomatic, lower-extremity, proximal deep-vein thrombosis (DVT); symptomatic, upper-extremity DVT; symptomatic or incidental pulmonary embolism; and VTE-related death compared with placebo. The primary safety objective is to assess major bleeding events (Clinical trial information: NCT02555878).
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http://dx.doi.org/10.1160/TH17-03-0171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328370PMC
November 2017

CONKO-005: Adjuvant Chemotherapy With Gemcitabine Plus Erlotinib Versus Gemcitabine Alone in Patients After R0 Resection of Pancreatic Cancer: A Multicenter Randomized Phase III Trial.

J Clin Oncol 2017 Oct 17;35(29):3330-3337. Epub 2017 Aug 17.

Marianne Sinn, Marcus Bahra, Uwe Pelzer, Jens M. Stieler, Jana K. Striefler, Sven Bischoff, Bernd Dörken, and Hanno Riess, Charité-Universitätsmedizin Berlin; Klaus Gellert, Sana Klinikum Lichtenberg, Berlin; Torsten Liersch and Michael Ghadimi, Universitätsmedizin Göttingen, Göttingen; Helmut Messmann, Klinikum Augsburg, Augsburg; Wolf Bechstein, Universitätsklinikum Frankfurt, Frankfurt; Dirk Waldschmidt, Universitätsklinikum Köln, Köln; Lutz Jacobasch, Clinical Center, Dresden; Martin Wilhelm, Paracelsus Medical University, Nürnberg; Bettina M. Rau, Universitätsmedizin Rostock, and Municipal Hospital of Neumarkt, Rostock; Robert Grützmann, Universitätsklinikum Carl Gustav Carus, Dresden, and Universitätsklinikum Erlangen, Erlangen; Arndt Weinmann, Klinikum der Johannes Gutenberg-Universität, Mainz; Georg Maschmeyer, Ernst von Bergmann Klinikum, Potsdam; and Helmut Oettle, Clinical Center, Friedrichshafen, Germany.

Purpose Gemcitabine is standard of care in the adjuvant treatment of resectable pancreatic ductal adenocarcinoma (PDAC). The epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in combination with gemcitabine has shown efficacy in the treatment of advanced PDAC and was considered to improve survival in patients with primarily resectable PDAC after R0 resection. Patients and Methods In an open-label, multicenter trial, patients were randomly assigned to one of two study arms: gemcitabine 1,000 mg/m days 1, 8, 15, every 4 weeks plus erlotinib 100 mg once per day (GemErlo) or gemcitabine (Gem) alone for six cycles. The primary end point of the study was to improve disease-free survival (DFS) from 14 to 18 months by adding erlotinib to gemcitabine. Results In all, 436 patients were randomly assigned at 57 study centers between April 2008 and July 2013. A total of 361 instances (83%) of disease recurrence were observed after a median follow-up of 54 months. Median treatment duration was 22 weeks in both arms. There was no difference in median DFS (GemErlo 11.4 months; Gem 11.4 months) or median overall survival (GemErlo 24.5 months; Gem 26.5 months). There was a trend toward long-term survival in favor of GemErlo (estimated survival after 1, 2, and 5 years for GemErlo was 77%, 53%, and 25% v 79%, 54%, and 20% for Gem, respectively). The occurrence or the grade of rash was not associated with a better survival in the GemErlo arm. Conclusion To the best of our knowledge, CONKO-005 is the first study to investigate the combination of chemotherapy and a targeted therapy in the adjuvant treatment of PDAC. GemErlo for 24 weeks did not improve DFS or overall survival over Gem.
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http://dx.doi.org/10.1200/JCO.2017.72.6463DOI Listing
October 2017

Cytotoxic tumour-infiltrating T lymphocytes influence outcome in resected pancreatic ductal adenocarcinoma.

Eur J Cancer 2017 09 31;83:290-301. Epub 2017 Jul 31.

Universitätsmedizin Charité Berlin, CONKO Study Group, Department of Medical Oncology, Haematology and Tumorimmunology, Augustenburger Platz 1, 13353 Berlin, Germany.

Background: We studied the prognostic effect of CD3-, CD8- and CD103-positive T lymphocytes in a cohort of 165 patients with resected pancreatic ductal adenocarcinomas (PDACs) of the treatment group (adjuvant gemcitabine) and the untreated control group of the CONKO-001 study.

Methods: Immunohistochemical stainings on tissue microarrays (TMAs) against CD3, CD8 and CD103 were performed according to standard procedures.

Results: A high number of CD8-positive lymphocytes were significantly and independently associated with longer disease-free survival (DFS) and overall survival (OS) in the overall study population. Median DFS/OS were 7.4/18.1 months for patients with a low number of CD8-positive intratumoural lymphocytes (≤42 per 1 mm tissue core) and 12.7/25.2 months for patients with high numbers (>42 per 1-mm tissue core; p = 0.008/0.020; HR 0.62/0.65). The ratio of intraepithelial to total CD103-positive lymphocytes, but not total numbers of CD103-positive lymphocytes or CD103-positive intraepithelial lymphocytes, was associated with significantly improved DFS and OS in the overall study population (p = 0.022/0.009). Median DFS/OS was 5.9/15.7 for patients with a ratio of intraepithelial to total CD103-positive intratumoural lymphocytes higher than 0.3 and 11.6/24.7 for patients with a lower ratio.

Conclusion: T-lymphocyte subpopulations might be prognostic in resectable PDAC but need standardization and verification by further studies.
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http://dx.doi.org/10.1016/j.ejca.2017.06.016DOI Listing
September 2017

[Treatment and Secondary Prevention of Venous Thromboembolism - Change in Oral Anticoagulation].

Dtsch Med Wochenschr 2017 Jul 19;142(13):986-993. Epub 2017 Apr 19.

Institut für Pharmakologie und Präventive Medizin, Cloppenburg.

With the recent approval of the fourth direct non vitamin K dependent oral anticoagulant (NOAC) edoxaban the range of available NOACs for the treatment of venous thromboembolism (VTE) has expanded. Shortly thereafter, two updated guidelines for the prevention and treatment of VTE have been published. In these NOACs are listed as equal anticoagulants to low-molecular weight heparin (LMWH), or fondaparinux (FDX), and VKA for the initial or maintenance treatment of VTE. All NOACs are approved for the maintenance therapy after VTE and two NOACs (rivaroxaban and apixaban) for the initial treatment in addition in an increased dose.NOACs differ in their pharmacodynamic and pharmacokinetic properties. In patients with renal insufficiency the dose of all NOACs should be reduced similarly to NMH/FDX. In contrast to VKAs, bridging with NOACs in case of surgical interventions is generally dispensable. Similar to NMHs or FPX renal function and individual bleeding risk dependent dose intermission is generally sufficient. Conventional coagulation parameters like aPTT and INR are not suitable for the monitoring of NOACs. Only in seldom cases, laboratory monitoring with use of adjusted anti-Xa testing or diluted thrombin time (dabigatran) may be helpful.
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http://dx.doi.org/10.1055/s-0042-124132DOI Listing
July 2017

Pancreatic cancer: moving forward, step by step.

Authors:
Hanno Riess

Lancet Gastroenterol Hepatol 2017 05 28;2(5):315-316. Epub 2017 Feb 28.

Department of Hematology and Oncology, University Hospital Charité, Berlin, D-10117, Germany. Electronic address:

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http://dx.doi.org/10.1016/S2468-1253(17)30055-9DOI Listing
May 2017

Prophylaxis and Treatment of Cancer-Associated Venous Thromboembolism - Comparison Hematologist/ Oncologists versus Angiologist/Phlebologists.

Oncol Res Treat 2017 24;40(3):138-140. Epub 2017 Feb 24.

Dpt. Of Internal Medicine II, Asklepios Clinic Uckermark, Schwedt/Od., Germany.

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http://dx.doi.org/10.1159/000456670DOI Listing
September 2019

Response to Rituximab Induction Is a Predictive Marker in B-Cell Post-Transplant Lymphoproliferative Disorder and Allows Successful Stratification Into Rituximab or R-CHOP Consolidation in an International, Prospective, Multicenter Phase II Trial.

J Clin Oncol 2017 Feb 19;35(5):536-543. Epub 2016 Dec 19.

Ralf U. Trappe and Heiner Zimmermann, DIAKO Evangelisches Diakonie-Krankenhaus Bremen, Bremen; University Medical Centre Schleswig-Holstein, Kiel; Ralf U. Trappe, Petra Reinke, Ioannis Anagnostopoulos, and Hanno Riess, Charité-Universitätsmedizin Berlin, Berlin; Martin H. Dreyling and Marion Subklewe, University of Munich, Munich; Ulrich Dührsen and Andreas Hüttmann, University of Duisburg-Essen, Essen; Volker Kliem, Nephrological Centre Lower Saxony, Hann. Münden; Ingeborg A. Hauser, J.W. Goethe University Hospital, Frankfurt, Germany; Daan Dierickx, Gregor Verhoef, Thomas Tousseyn, and Olivier Gheysens, Catholic University Leuven, Leuven; Eric Van Den Neste, Cliniques Universitaires Saint-Luc, Brussels, Belgium; Franck Morschhauser, Hôpital Claude Huriez, Lille; Gilles Salles, Hospices Civils de Lyon and Université de Lyon, Pierre-Bénite; Veronique Leblond and Sylvain Choquet, Université Pierre et Marie Curie, Paris, France; Peter Mollee, University of Queensland, Brisbane, Queensland, Australia; Jan M. Zaucha, Medical University of Gdansk, Gdansk; Polish Lymphoma Research Group, Warsaw, Poland; and Corrado Tarella, European Institute of Oncology, Milan, Italy.

Purpose The Sequential Treatment of CD20-Positive Posttransplant Lymphoproliferative Disorder (PTLD-1) trial ( ClinicalTrials.gov identifier, NCT01458548) established sequential treatment with four cycles of rituximab followed by four cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy as a standard in the management of post-transplant lymphoproliferative disorder (PTLD) and identified response to rituximab induction as a prognostic factor for overall survival. We hypothesized that rituximab consolidation might be sufficient treatment for patients with a complete response after rituximab induction. Patients and Methods In this prospective, international, multicenter phase II trial, 152 treatment-naive adult solid organ transplant recipients, with CD20 PTLD unresponsive to immunosuppression reduction, were treated with four weekly doses of rituximab induction. After restaging, complete responders continued with four courses of rituximab consolidation every 21 days; all others received four courses of rituximab plus CHOP chemotherapy every 21 days. The primary end point was treatment efficacy measured as the response rate in patients who completed therapy and the response duration in those who completed therapy and responded. Secondary end points were frequency of infections, treatment-related mortality, and overall survival in the intention-to-treat population. Results One hundred eleven of 126 patients had a complete or partial response (88%; 95% CI, 81% to 93%), of whom 88 had a complete response (70%; 95% CI, 61% to 77%). Median response duration was not reached. The 3-year estimate was 82% (95% CI, 74% to 90%). Median overall survival was 6.6 years (95% CI, 5.5 to 7.6 years). The frequency of grade 3 or 4 infections and of treatment-related mortality was 34% (95% CI, 27% to 42%) and 8% (95% CI, 5% to 14%), respectively. Response to rituximab induction remained a prognostic factor for overall survival despite treatment stratification. Conclusion In B-cell PTLD, treatment stratification into rituximab or rituximab plus CHOP consolidation on the basis of response to rituximab induction is feasible, safe, and effective.
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http://dx.doi.org/10.1200/JCO.2016.69.3564DOI Listing
February 2017

Phase I/II Study of Refametinib (BAY 86-9766) in Combination with Gemcitabine in Advanced Pancreatic cancer.

Target Oncol 2017 02;12(1):97-109

Bayer HealthCare Pharmaceuticals, Inc., 100 Bayer Blvd, Whippany, NJ, 07981, USA.

Background: Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently inhibits MEK1/2, part of the MAPK signaling pathway. This phase I/II study evaluated the safety and efficacy of refametinib plus gemcitabine in patients with advanced pancreatic cancer.

Methods: Phase I comprised dose escalation, followed by phase II expansion. Refametinib and gemcitabine plasma levels were analyzed for pharmacokinetics. KRAS mutational status was determined from circulating tumor DNA.

Results: Ninety patients overall received treatment. The maximum tolerated dose was refametinib 50 mg twice daily plus standard gemcitabine (1000 mg/m weekly). The combination was well tolerated, with no pharmacokinetic interaction. Treatment-emergent toxicities included thrombocytopenia, fatigue, anemia, and edema. The objective response rate was 23% and the disease control rate was 73%. Overall response rate, disease control rate, progression-free survival, and overall survival were higher in patients without detectable KRAS mutations (48% vs. 28%, 81% vs. 69%, 8.8 vs. 5.3 months, and 18.2 vs. 6.6 months, respectively).

Conclusion: Refametinib plus gemcitabine was well tolerated, with a promising objective response rate, and had an acceptable safety profile and no pharmacokinetic interaction. There was a trend towards improved outcomes in patients without detectable KRAS mutations that deserves future investigation.
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http://dx.doi.org/10.1007/s11523-016-0469-yDOI Listing
February 2017

Resting heart rate is an independent predictor of death in patients with colorectal, pancreatic, and non-small cell lung cancer: results of a prospective cardiovascular long-term study.

Eur J Heart Fail 2016 12;18(12):1524-1534

Innovative Clinical Trials, University Medicine Gottingen (UMG), Department of Cardiology and Pneumology, Gottingen, Germany.

Aims: Patients with advanced cancer have been shown to suffer from abnormal cardiac function and impaired exercise capacity that may contribute to their impaired quality of life. As tachycardia is considered as a sign of potential early cardiac damage, we sought to determine whether resting heart rate and other ECG-derived variables have prognostic value.

Methods And Results: From 2005 to 2010, we enrolled 145 patients with histologically confirmed cancer (36 colorectal, 72 pancreatic, and 37 non-small cell lung cancer patients) and 59 healthy controls. During a mean follow-up of 27 months, 82 patients (57%) died from any cause. The mean resting heart rate of healthy subjects was 70 ± 13 b.p.m., and that of cancer patients was 79 ± 14 b.p.m. (P< 0.0001). As a sensitivity analysis, we excluded control subjects taking a beta-blocker, but resting heart rate remained increased in cancer patients vs. controls (P < 0.0001). Resting heart rate ≥75 b.p.m. [hazard ratio (HR) 1.84, 95% confidence interval (CI) 1.16-2.94; P = 0.01] significantly predicted survival in univariable analyses and remained an independent predictor of survival in a multivariate model (HR 1.67, 95% CI 1.01-2.78; P = 0.04). Furthermore, the heart rate stayed significant in a second model that included age and sex as well.

Conclusion: The present study is the first to show that resting heart rate independently of haemoglobin and tumour stage predicts survival in patients with advanced colorectal, pancreatic, and non-small cell lung cancer, and may therefore represent a therapeutic target.
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http://dx.doi.org/10.1002/ejhf.670DOI Listing
December 2016

[Direct oral anticoagulants (DOAC) in tumor patients].

Dtsch Med Wochenschr 2016 Sep 4;141(20):1446-1450. Epub 2016 Oct 4.

There is only limited data for the use of direct oral anticoagulants (DOACs) in tumor patients and no data from prospective randomised trials comparing DOACs to the current standard care: low molecular weight heparine (LMWH). Therefore, DOACs must be used with caution and should be restricted to tumor patients with (1) contraindications for LMWH (e.g. HIT II, phobia of syringe) or (2) to the situations of prolonged anticoagulation after initial therapy with LMWH. Cancer-associated disorders as well as side effects of chemotherapy as nausea and emesis have to be considered as well as potential substance-specific interactions. Data of future clinical trials in prophylaxis and treatment of venous thrombembolism in tumor patients will help to define the role of DOACs in this special patient cohort.
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http://dx.doi.org/10.1055/s-0042-112085DOI Listing
September 2016

P53 overexpression and Ki67-index are associated with outcome in ductal pancreatic adenocarcinoma with adjuvant gemcitabine treatment.

Pathol Res Pract 2016 Aug 8;212(8):726-34. Epub 2016 Jun 8.

Charité - Universitätsmedizin Berlin, Institute of Pathology, Charitéplatz 1, 10117 Berlin, Germany. Electronic address:

In pancreatic cancer there is a need for prognostic risk stratification and subsequent therapy strategies. Molecular analysis has shown in different cancers that variation in clinical behavior can be associated with specific alterations. The cell cycle regulators p16 and p53 belong to the most often alterated genes in pancreatic ductal adenocarcinoma (PDAC). We analyzed protein expression of p16, p53 and Ki67 by immunohistochemistry in 162 tumours of the CONKO-001 trial that investigated the role of adjuvant gemcitabine in pancreatic cancer patients. We could show that high proliferation of tumours and strong and consistent nuclear p53 expression by tumour cells is associated with a worse disease-free survival and overall survival in the overall study population. However, stratified analysis according to treatment arm revealed that the effect of deregulated p53 expression and high Ki67 expression was restricted to the disease free survival of patients treated with adjuvant gemcitabine. In multivariable survival analysis, p53 did not retain its prognostic status. Our study supports the important role of p53 and Ki67 expression in PDAC. They provide prognostic information in patients with adjuvant gemcitabine treatment and may contribute to treatment decision. However, these results should be validated in further studies.
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http://dx.doi.org/10.1016/j.prp.2016.06.001DOI Listing
August 2016