Introduction: Cancer-associated venous thromboembolism (CAT) is a frequent and medical relevant problem. Guidelines recommend treatment with low molecular weight heparins (LMWH) or direct oral factor-Xa inhibitors as rivaroxaban for ≥3 months. Patient's preference and convenience is an important factor to guide treatment decision and to support treatment adherence. No data are available so far about patient-reported outcome in CAT. METHODS:CONKO-011/AIO-SUP-0115/ass. was an open-label, prospective, multicenter German phase III trial for cancer patients with newly diagnosed venous thromboembolism (VTE) randomized to rivaroxaban (Riva) or site-specific LMWH. Primary endpoint was patient-reported treatment satisfaction, measured by the Anti-Clot Treatment Scale (ACTS). The 12-item ACTS Burdens scale (primary endpoint after 4 weeks) and the 3-item ACTS Benefits scale were analyzed at 4, 8 and 12 weeks. Secondary endpoints included recurrent VTE, major/clinically relevant bleeding, safety, compliance, overall mortality at 3 and 6 months, quality of life measured by the Treatment Satisfaction Questionnaire for Medication II (TSQM II) and Spitzer Index. RESULTS:Between 03/2016 and 06/2019, 247 (123 Riva/124 LMWH) patients were randomized. Mean ACTS Burdens scores after 4 weeks were 52.8 versus 51.2 in favor of rivaroxaban (p = 0.019) with mean score differences ranging from 3.3 (week 8; p = 0.001) to 2.4 (week 12; p = 0.006). The treatment effect of ACTS burden was consistent over treatment time (p < 0.001). More patients on LMWH requested to stop study treatment preterm (19.4% versus 11.1%). CONCLUSION:Oral treatment with rivaroxaban led to an improvement in patient-reported treatment satisfaction, particularly in reducing anticoagulation-related burden, resulting in less patient-requested treatment stops. .

Zusammenfassung Bei Tumorpatienten sind symptomatische und sogenannte inzidentelle tiefe Venenthrombosen und Lungenembolien häufig. Es wird eine prolongierte, regelhaft über 3 Monate hinausgehende Antikoagulation empfohlen, wobei die therapiebedingte Zunahme eines bei Malignompatienten vorbestehend erhöhten Blutungsrisikos besonderer Berücksichtigung bedarf. Zusätzlich zu der bisher empfohlenen parenteralen Gabe niedermolekularer Heparine von Tumorpatienten stehen nun auch orale Faktor-Xa-Inhibitoren mit hohem Evidenzniveau gleichwertig für die Initialtherapie und Sekundärprophylaxe zur Verfügung. Die individuelle Entscheidung über Art, Dauer und Intensität der Antikoagulation sollte neben den tumorentitätsspezifischen Risiken für Blutungen und Rezidivthrombosen auch präparatespezifische Charakteristika, Therapiekosten und die Patientenpräferenz einbeziehen.

INTRODUCTION:The number of patients requiring anticoagulation, e.g., for cardiovascular diseases, is increasing, even in patients with immune thrombocytopenia (ITP). However, detailed guidelines and studies are lacking. In clinical trials in ITP, patients taking anticoagulants are usually excluded and patients with thrombocytopenia are often excluded from anticoagulation studies. Our main goal was to highlight factors influence anticoagulation decision-making in clinical routine. METHODS:We conducted a survey to explore the preferred management of anticoagulation therapy in patients with ITP. It presented common patient scenarios and elicited factors influencing decisions regarding whether to initiate anticoagulation therapy. RESULTS:We surveyed 235 colleagues in Germany, Austria, and Switzerland. A total of 210 respondents specialized in hematology; 13 had advanced training in hemostaseology. About half (110/210; 55%) of participants treat 5-10 patients with ITP per month. The recommended platelet thresholds for antithrombotic therapy were similar among patients with ITP. Most participants recommended a minimum platelet count of 50 × 109/L for anticoagulation therapy in most scenarios. However, there was great variability in individual practice patterns among the respondents. The psychosocial status of patients was important for decision making. CONCLUSION:Deciding on anticoagulation therapy in patients with ITP remains challenging. Our survey illustrated the diverse perspectives of medical professionals in managing anticoagulation therapy in ITP. A platelet count >50 × 109/L was considered safe. In patients with lower platelet counts, other influencing factors such as bleeding tendency, comorbidities, and psychosocial status become relevant. Our findings emphasize the importance of balanced clinical judgment, need for evidence-based guidelines, and open discussions with patients to optimize treatment strategies.

Abstract:Active cancer by itself but also chemotherapy is associated with an increased risk of cardiovascular disease (CVD) and especially coronary artery disease (CAD) and atrial fibrillation (AF). The frequency of CVD, CAD, and AF varies depending on comorbidities (particularly in older patients), cancer type, and stage, as well as the anticancer therapeutic being taken. Many reports exist for anticancer drugs being associated with CVD, CAD, and AF, but robust data are often lacking. Because of this, each patient needs an individual structured approach concerning thromboembolic and bleeding risk, drug-drug interactions, as well as patient preferences to evaluate the need for anticoagulation therapy and targeting optimal symptom control. Interruption of specific cancer therapy should be avoided to reduce the potential risk of cancer progression. Nevertheless, additional factors like thrombocytopenia and anticoagulation in the elderly and frail patient with cancer cause additional challenges which need to be addressed in daily clinical management. Therefore, the aim of these recommendations is to summarize the available scientific data on antithrombotic therapy (both antiplatelet and anticoagulant therapy) in cancer patients with CVD and in cases of missing data providing guidance for optimal careful decision-making in daily routine.

Patients with cancer are prone to develop venous thromboembolism (VTE) with negative impact on quality of life, morbidity, and mortality. Treatment of established VTE is often complex in patients with cancer. Treatment of cancer-associated VTE (CAT) basically comprises initial and maintenance treatment, for 3 to 6 months, secondary preventions, and treatment in special situations. Therapeutic anticoagulation is the treatment of choice in CAT. In addition to the efficacy and safety of low-molecular-weight heparin (LMWH) that had been recommended for decades, direct oral anti-factor Xa inhibitors, a subgroup of direct oral anticoagulants (DOACs), demonstrated their advantages along with the accompanying concerns in several randomized controlled treatment trials of CAT. The latest guidelines, such as the German AWMF-S2k Guideline "Diagnostics and Therapy of Venous Thrombosis and Pulmonary Embolism," agree with each other on most aspects with respect to the treatment of CAT. Encompassing recent clinical studies, and meta-analyses, as well as the focus on some special management aspects of CAT, the objective of this review is to present a current overview and recommendations for the treatment of CAT.

In the recently updated German S2k Guideline "Diagnostics and Therapy of Venous Thrombosis and Pulmonary Embolism," a new chapter was incorporated about recurrent venous thromboembolism (VTE) in patients on anticoagulation treatment. Despite the high efficacy of anticoagulation in most patients, approximately 2% experience a recurrent VTE event while receiving anticoagulant drugs. The proper diagnosis of the recurrent VTE is important and possible only with the knowledge of localization and thrombus burden of the primary VTE event. Possible reasons for recurrent VTE events in patients on anticoagulation are non-adherence to medication, sub-therapeutic drug levels due to resorption disorders or drug interactions, or concomitant disease with high thrombogenicity. Cancer is the most common underlying disease, but it is important to investigate and understand possible other causes whenever a breakthrough VTE event occurs. This results in the recommendation that in patients with VTE recurrence on therapeutic anticoagulation, in particular, the presence of malignant disease, antiphospholipid syndrome, and rare diseases like paroxysmal nocturnal hemoglobinuria or Behçet's disease should be considered. For VTE recurrence during heparin therapy, heparin-induced thrombocytopenia type II needs to be ruled out, even if platelet counts are within the normal range. Although the mechanisms of recurrence on anticoagulation can be evaluated in a certain degree, clinical evidence for the management of recurrent VTE in anticoagulated patients is minimal and mainly based on expert opinion. Switching anticoagulant medication and intensifying anticoagulant treatment are possible options.

AbstractEven after decades of research, pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease and responses to conventional treatments remain mostly poor. Subclassification of PDAC into distinct biological subtypes has been proposed by various groups to further improve patient outcome and reduce unnecessary side effects. Recently, an immunohistochemistry (IHC)‐based subtyping method using cytokeratin‐81 (KRT81) and hepatocyte nuclear factor 1A (HNF1A) could recapitulate some of the previously established molecular subtyping methods, while providing significant prognostic and, to a limited degree, also predictive information. We refined the KRT81/HNF1A subtyping method to classify PDAC into three distinct biological subtypes. The prognostic value of the IHC‐based method was investigated in two primary resected cohorts, which include 269 and 286 patients, respectively. In the second cohort, we also assessed the predictive effect for response to erlotinib + gemcitabine. In both PDAC cohorts, the new HNF1A‐positive subtype was associated with the best survival, the KRT81‐positive subtype with the worst, and the double‐negative with an intermediate survival (p < 0.001 and p < 0.001, respectively) in univariate and multivariate analyses. In the second cohort (CONKO‐005), the IHC‐based subtype was additionally found to have a potential predictive value for the erlotinib‐based treatment effect. The revised IHC‐based subtyping using KRT81 and HNF1A has prognostic significance for PDAC patients and may be of value in predicting treatment response to specific therapeutic agents.

BACKGROUND:Body wasting in patients with cancer can affect the heart. OBJECTIVES:The frequency, extent, and clinical and prognostic importance of cardiac wasting in cancer patients is unknown. METHODS:This study prospectively enrolled 300 patients with mostly advanced, active cancer but without significant cardiovascular disease or infection. These patients were compared with 60 healthy control subjects and 60 patients with chronic heart failure (ejection fraction <40%) of similar age and sex distribution. RESULTS:Cancer patients presented with lower left ventricular (LV) mass than healthy control subjects or heart failure patients (assessed by transthoracic echocardiography: 177 ± 47 g vs 203 ± 64 g vs 300 ± 71 g, respectively; P < 0.001). LV mass was lowest in cancer patients with cachexia (153 ± 42 g; P < 0.001). Importantly, the presence of low LV mass was independent of previous cardiotoxic anticancer therapy. In 90 cancer patients with a second echocardiogram after 122 ± 71 days, LV mass had declined by 9.3% ± 1.4% (P < 0.001). In cancer patients with cardiac wasting during follow-up, stroke volume decreased (P < 0.001) and resting heart rate increased over time (P = 0.001). During follow-up of on average 16 months, 149 patients died (1-year all-cause mortality 43%; 95% CI: 37%-49%). LV mass and LV mass adjusted for height squared were independent prognostic markers (both P < 0.05). Adjustment of LV mass for body surface area masked the observed survival impact. LV mass below the prognostically relevant cutpoints in cancer was associated with reduced overall functional status and lower physical performance. CONCLUSIONS:Low LV mass is associated with poor functional status and increased all-cause mortality in cancer. These findings provide clinical evidence of cardiac wasting-associated cardiomyopathy in cancer.

Im Rahmen einer Malignom-Erkrankung ist das Risiko fur venose thromboembolische Ereignisse (VTE) um das bis zu 7-Fache erhoht. Die Leitlinien empfehlen in dieser Patientengruppe nach einer stattgehabten Thrombose oder Lungenembolie eine langfristige Antikoagulation mit niedermolekularem Heparin. Die Rezidivprophylaxe mit einem direkten oralen Antikoagulans scheint jedoch vergleichbar effektiv und sicher zu sein, wie eine aktuelle prospektive Studie zeigte.

AbstractBackgroundMaintaining the ability to perform self‐care is a critical goal in patients with cancer. We assessed whether the patient‐reported ability to walk 4 m and wash oneself predict survival in patients with pre‐terminal cancer.MethodsWe performed a prospective observational study on 169 consecutive hospitalized patients with cancer (52% female, 64 ± 12 years) and an estimated 1–12 months prognosis at an academic, inpatient palliative care unit. Patients answered functional questions for ‘today’, ‘last week’, and ‘last month’, performed patient‐reported outcomes (PROs), and physical function assessments.ResultsNinety‐two (54%) patients reported the ability to independently walk 4 m and 100 (59%) to wash ‘today’. The median number of days patients reported the ability to walk 4 m and wash were 6 (IQR 0–7) and 7 (0–7) days (‘last week’); and 27 (5–30) and 26 (10–30) days (‘last month’). In the last week, 32% of patients were unable to walk 4 m on every day and 10% could walk on 1–3 days; 30% were unable to wash on every day and 10% could wash on 1–3 days. In the last months, 14% of patients were unable to walk 4 m on every day and 10% could only walk on 1–10 days; 12% were unable to wash on every day and 11% could wash on 1–10 days. In patients who could walk ‘today’ average 4 m gait speed was 0.78 ± 0.28 m/s. Patients who reported impaired walking and washing experienced more symptoms (dyspnoea, exertion, and oedema) and decreased physical function (higher Eastern Cooperative Oncology Group Performance Status, and lower Karnofsky Performance Status and hand‐grip strength [unable vs. able to walk ‘today’: 205 ± 87 vs. 252 ± 78 Newton, P = 0.001; unable vs. able to wash ‘today’: 204 ± 86 vs. 250 ± 80 Newton, P = 0.001]). During the 27 months of observation, 152 (90%) patients died (median survival 46 days). In multivariable Cox proportional hazards regression analyses, all tested parameters were independent predictors of survival: walking 4 m ‘today’ (HR 0.63, P = 0.015), ‘last week’ (per 1 day: HR 0.93, P = 0.011), ‘last month’ (per 1 day: HR 0.98, P = 0.012), 4 m gait speed (per 1 m/s: HR 0.45, P = 0.002), and washing ‘today’ (HR 0.67, P = 0.024), ‘last week (per 1 day HR 0.94, p=0.019), and ‘last month’ (per 1 day HR 0.99, P = 0.040). Patients unable to walk and wash experienced the shortest survival and most reduced functional status.ConclusionsIn patients with pre‐terminal cancer, the self‐reported ability to walk 4 m and wash were independent predictors of survival and associated with decreased functional status.

Drug Prescribing for Patients with Chronic Kidney Disease in General Practice: a Cross-Sectional Study

Objective This article aims to investigate the reality of anticoagulation treatment for cancer patients with thrombosis in the outpatient sector of Germany. Methods For the analysis period 2012 to 2015, anonymized data from 4.1 million statutory insured patients were analyzed. Cancer patients with incident thrombosis and an outpatient prescription of anticoagulant drugs were identified and evaluated for three subsequent quarters with regard to anticoagulant use. Results A total of 7,313 cancer patients with incident thrombosis (ICD-10: I80*) were evaluated. About, 90% of patients with thromboses were diagnosed and treated in the ambulatory sector. More than 80% of the prescriptions were issued by general practitioners. And 57% of patients were anticoagulated predominantly (>50% of the time) with different low-molecular-weight heparins (LMWHs), 24% predominantly with vitamin K antagonists (VKAs), and 17% with direct oral anticoagulants (DOACs). Anticoagulants were prescribed for an average of 4.5 months. LMWH had a substantially longer prescription period (90-135 days) than VKA (53 days) or DOAC (47 days). Gastrointestinal bleeding in conjunction with hospitalization was documented in 1.76% of patients with a range of 1.3 to 3% for the different LMWHs. Conclusion The prescription practice documented by this representative and comprehensive evaluation demonstrates an anticoagulation duration in accordance with the guidelines, although the choice of the respective anticoagulant was often not in compliance with the contemporary label or guidelines.

Immunostimulatory regimens are a game changer in the fight against cancer, but still only a minority of patients achieve clinical benefit. Combination with immunomodulatory drugs and agents converting otherwise non-immunogenic forms of cell death into bona fide “immunogenic cell death” (ICD) could improve the efficacy of these novel therapies. The aim of our study was to investigate conventional Amphotericin B (AmB) as an enhancer of antitumor immune responses. In tumor cell line models, AmB induced ICD with its typical hallmarks of calreticulin (CALR) expression and release of high mobility group box 1 (HMGB1) as well as Adenosine 5’-triphosphate (ATP). Interestingly, in contrast to non-ICD inducing treatments, ICD induction led to up-regulation of PD-L1-expression by ICD experiencing cells, resulting in decreased maturation of dendritic cells (DCs). Blocking this PD-L1 expression on tumor cells could unleash full ICD effects on antigen presenting cells. Even at sub-toxic concentrations, AmB was able to enhance CALR on leukemic blasts, particularly on phagocytic monoblastic THP-1 cells, which also showed features of “M1-like” differentiation after AmB exposure. The ability of AmB to increase the immunogenicity of tumor cells was confirmed in vivo in a mouse vaccination experiment. In conclusion, we demonstrate that AmB can promote antitumor immune responses in a dose-dependent manner by ICD induction, surface translocation of CALR on leukemic blasts even at sub-toxic concentrations, and “M1-like” polarization of phagocytic cells, making it noteworthy as potential booster for cancer immunotherapy. We additionally report for the first time that PD-L1 expression may be a feature of ICD, possibly as a negative feedback mechanism regulating the maturation status of DCs and thus indirectly affecting T-cell priming.

BACKGROUND:Primary objective of this present trial was to define the maximum tolerable dose of lapatinib in combination with oxaliplatin, 5-fluorouracil, and folinic acid (OFF) in refractory pancreatic cancer. The secondary objective was to assess the safety and efficacy of lapatinib plus OFF.METHODS:We conducted a phase I trial using an accelerated dose escalation design in patients with refractory pancreatic cancer. Lapatinib was given on days 1 to 42 in combination with folinic acid 200 mg/m2 day + 5-fluorouracil 2000 mg/m2 (24 h) on days 1, 8, 15, and 22, and oxaliplatin 85 mg/m2 days 8 and 22 of a 43-day cycle (OFF). Toxicity and efficacy were evaluated.RESULTS:In total, eighteen patients were enrolled: dose level 1 (1000 mg) was assigned to seven patients, dose level 2 (1250 mg), five patients; and dose level 3 (1500 mg), six patients. Dose-limiting toxicities were diarrhea and/or neutropenic enterocolitis observed in two of six patients: one diarrhea III°, one diarrhea IV°, as well as neutropenic enterocolitis. The maximum tolerable dose of lapatinib was 1250 mg OD.CONCLUSIONS:The combination of lapatinib 1250 mg OD with platinum-containing chemotherapy is safe and feasible in patients with refractory pancreatic cancer and warrants further investigation.

Symptomatic as well as so-called incidental deep venous thromboses and pulmonary embolisms are frequent complications in cancer patients. A prolonged anticoagulation, regularly for more than three months, considering the treatment-associated enhancement of a preexisting increased cancer-associated bleeding risk, is recommended. In addition to parenteral application of low molecular weight heparins now oral factor Xa inhibitors became an equally good, high-level evidence-based option for initial treatment and secondary prophylaxis. The individual choice of kind, duration and intensity of anticoagulation needs to consider the cancer type associated risks of bleeding and recurrent thromboembolism, as well as characteristics of anticoagulant drugs, treatment costs and patient's preference.