Anticoagulation treatment of cancer patients with deep or superficial leg vein thrombosis - a retrospective observational study of German statutory health insurance claims data (the CERTIFICAT initiative).

Background: Thrombosis is a common complication of cancer with a negative impact on quality of life and overall prognosis. Guidelines recommend low-molecular-weight heparin (LMWH) as initial and prolonged anticoagulation treatment. Little is known about current treatment patterns of these patients in ambulatory care. Patients and methods: The current retrospective observational study interrogates a large German statutory health insurance claims database in order to understand which kind of data can be extracted and analysed. An age- and sex-adjusted sample of about 4.1 million insured people from 2011 to 2016 could be used. Cancer patients with incident deep and superficial leg vein thrombosis were identified. Patients with preexisting cancer were allocated to a normal risk group; those who suffered from simultaneously diagnosed cancer and thrombosis were classified as high-risk group. Results: We identified 322,600 patients with inpatient or outpatient documented cancer diagnosis in at least two different quarters within one year. 87,755 patients were identified with an incident deep or superficial vein thrombosis. 8,201 patients suffered from both cancer and incident thrombosis. 56.9% of the patients received an anticoagulation regimen with predominant LMWH prescription, 24.2% vitamin K antagonists, 17.2% direct oral anticoagulants; in 1.7% of patients, no predominant anticoagulant drug/regime could be identified. On average, patients were prescribed anticoagulants for 4.5 months. An estimate of clinically relevant gastrointestinal bleeding could be derived (1.8% of patients). Conclusions: The dataset allows assigning detailed information of anticoagulant prescriptions in ambulatory care to well-defined groups of cancer patients. A first analysis suggests that in Germany current medical care of patients with cancer-related deep or superficial vein thrombosis does not entirely comply with guideline recommendations regarding type and duration of anticoagulation.

Serum-free light chains adjusted for renal function are a potential biomarker for post-transplant lymphoproliferative disorders.

Post-transplant lymphoproliferative disease (PTLD) is a serious complication of solid organ transplantation. As early diagnosis remains challenging, we investigated the utility of serum-free light chain (FLC) and heavy chain/light chain pairs (HLC) as diagnostic biomarkers. Pre-treatment serum FLC and HLC levels were measured in 20 patients at their first diagnosis of B cell PTLD and in 14/20 patients during follow-up. Results were compared to serum FLC/HLC levels of 90 matched PTLD-free transplanted controls. Renal dysfunction was common in both cohorts, and combined FLC levels were often elevated above the conventional upper limit of normal (45.7 mg/L). Combined FLC levels were higher in patients with PTLD than in transplant controls (p = 0.013), and levels above the conventional ULN were associated with PTLD (OR 3.2, p = 0.05). Following adjustment to cystatin C as a marker of renal function an even stronger association was found for a (dimensionless) threshold value of 37.8 (OR 8.9, p < 0.001). In addition, monoclonal proliferation (abnormal FLC ratio, using an established renal range cutoff) was more common in PTLD than in controls (3/20 vs. 2/90, p = 0.04). Following therapy, at the time of protocolised restaging, patients experiencing subsequent sustained complete remission displayed lower FLC levels than those not experiencing such remission (p = 0.053). No relationship with HLC results was seen. Elevated polyclonal FLC levels (especially when adjusted for renal function) and monoclonal proliferation are a potential biomarker for PTLD diagnosis and disease surveillance. However, prospective validation is necessary before FLC measurement should be incorporated in follow-up of transplant recipients and PTLD management.

Patients' perspectives towards malignant ascites: results of a prospective observational trial regarding expectations, characteristics and quality of life-a study of the North-Eastern-German Society of Gynecological Oncology.

PURPOSE: Malignant ascites (MA) is a frequent and common symptom in (gyneco-) oncological patients. The present trial evaluated and assessed patients' characteristics, clinical features and the possible influence of MA on QoL measurements. METHODS: A prospective observational trial was conducted from Oct 2013 until Nov 2016. Therefore an interdisciplinary questionnaire was developed. Overall 250 patients with histological confirmed MA were included with different cancer entities (gynecological, gastrointestinal). The correlation of MA caused symptoms and QoL measurements was assessed using Kendall's tau b. Multivariable logistic regression models were applied to analyze the risks of symptoms or severe limitation in daily activities. RESULTS: 125 questionnaires could be analyzed. The majority of patients with MA had diagnosis of ovarian cancer (68.8%) and were under current cancer treatment (57.6%), mostly chemotherapy. Over 50% reported abdominal tension as major symptom, around 56% of the patients had MA when cancer was firstly diagnosed. Regression analysis showed that patients with MA above 2l were significantly more likely to be harmed in everyday activities. However, the age, gender, type of malignancy and the current treatment (chemotherapy vs. no chemotherapy) had no significant influence. CONCLUSION: MA has a significantly impact on QoL measurements in cancer patients and might influence everyday activities including basic needs like eating, walking and body care. There is a high need for more information and education of patients with MA.

[Bridging anticoagulation in patients receiving vitamin K antagonists : Current status]. / Überbrückende Antikoagulation bei Patienten unter Vitamin-K-Antagonisten : Eine Bestandsaufnahme.

Approximately 30% of patients receiving oral anticoagulation using vitamin K antagonists (VKA) require surgery within 2 years. In this context, a clinical decision on the need and the mode of a peri-interventional bridging with heparin is needed. While a few years ago, bridging was almost considered a standard of care, recent study results triggered a discussion on which patients will need bridging at all. Revisiting the currently available recommendations and study results the conclusion can be drawn that the indications for bridging with heparin must nowadays be taken more narrowly and considering the individual patient risk of bleeding and thromboembolism. Bridging with heparin is only needed in patients with a very high risk of thromboembolism. This overview aims to give guidance for a risk-adapted peri-interventional approach to management of patients with a need for long-term anticoagulation using VKA.

[Bridging anticoagulation in patients receiving vitamin K antagonists : Current status]. / Überbrückende Antikoagulation bei Patienten unter Vitamin-K-Antagonisten : Eine Bestandsaufnahme.

Approximately 30% of patients receiving oral anticoagulation using vitamin K antagonists (VKA) require surgery within 2 years. In this context, a clinical decision on the need and the mode of a peri-interventional bridging with heparin is needed. While a few years ago, bridging was almost considered a standard of care, recent study results triggered a discussion on which patients will need bridging at all. Revisiting the currently available recommendations and study results the conclusion can be drawn that the indications for bridging with heparin must nowadays be taken more narrowly and considering the individual patient risk of bleeding and thromboembolism. Bridging with heparin is only needed in patients with a very high risk of thromboembolism. This overview aims to give guidance for a risk-adapted peri-interventional approach to management of patients with a need for long-term anticoagulation using VKA.

Radiation Dosage for Percutaneous PAD Treatment is Different in Cardiovascular Disciplines: Results From an Eleven Year Population Based Registry in the Metropolitan Area of Hamburg.

OBJECTIVE: The worldwide prevalence of peripheral artery disease (PAD) has evolved to an intervention as the primary treatment option and therefore radiation is used with escalating incidence. Dose area product (DAP) correlates well with the total energy imparted to the patient during fluoroscopic interventions. This study aims to determine whether there are any associations among stage of disease, gender, age, and expertise on the radiation dose in single endovascular treatments of PAD. METHODS: This study was a prospective, mandatory, population based cross-sectional registry design. In total, 24,000 invasive percutaneous endovascular treatments of PAD conducted in the metropolitan area of Hamburg (Germany) were consecutively collected between January 2004 and December 2015. DAP was analysed by discipline conducting the procedure, Fontaine classification, patient gender, and age. RESULTS: Statistically significant differences in median DAP values were found. The lowest median DAP values were observed in surgical centres (7.1 vs. 18.0 Gy*cm2, p<.001) and in endovascular revascularisations (ER) following multidisciplinary consultation (11.6 vs. 23.4 Gy*cm2, p<.001). Considering the treatment of intermittent claudication, men had statistically significantly higher DAP values compared with women. Furthermore, lower median DAP values were observed in higher age groups, with lowest dosages in octogenarians. CONCLUSION: This is the first large population based study on DAP during ER for PAD. Several significant differences in median DAP values were observed, although patient stratification was comparable. Pre-operative therapy strategy planning can lead to lower DAP values, emphasising the importance of further vascular research and quality improvement projects targeting this topic. To date, available evidence is limited and therefore there is no accepted range of DAP levels. However, the ever increasing use of fluoroscopic interventions means that further investigation into radiation exposure to patients and healthcare professionals is required in order to keep DAP levels low.

International prognostic index, type of transplant and response to rituximab are key parameters to tailor treatment in adults with CD20-positive B cell PTLD: clues from the PTLD-1 trial.

Tailoring treatment by patient strata based on the risk of disease progression and treatment toxicity might improve outcomes of patients with posttransplant lymphoproliferative disorder (PTLD). We analysed the cohort of 70 patients treated in the international, multicenter phase II PTLD-1 trial (NCT01458548) to identify such factors. Of the previously published scoring systems in PTLD, the international prognostic index (IPI), the PTLD prognostic index and the Ghobrial score were predictive for overall survival. None of the scoring systems had a considerable effect on the risk for disease progression. Age and ECOG performance status were the baseline variables with the highest prognostic impact in the different scoring systems. Baseline variables not included in the scoring systems that had an impact on overall survival and disease progression were the type of transplant and the response to rituximab at interim staging. Thoracic organ transplant recipients who did not respond to rituximab monotherapy were at particularly high risk for death from disease progression with subsequent CHOP-based chemotherapy. Patients in complete remission after four courses of rituximab and patients in partial remission with low-risk IPI had a low risk of disease progression. We speculate that chemotherapy might not be necessary in this patient cohort.

A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial.

BACKGROUND: This double-blind, phase 3 study assessed the efficacy and safety of ganitumab combined with gemcitabine as first-line treatment of metastatic pancreatic cancer. PATIENTS AND METHODS: Patients with previously untreated metastatic pancreatic adenocarcinoma were randomly assigned 2 : 2 : 1 to receive intravenous gemcitabine 1000 mg/m(2) (days 1, 8, and 15 of each 28-day cycle) plus placebo, ganitumab 12 mg/kg, or ganitumab 20 mg/kg (days 1 and 15 of each cycle). The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), safety, and efficacy by levels of circulating biomarkers. RESULTS: Overall, 322 patients were randomly assigned to placebo, 318 to ganitumab 12 mg/kg, and 160 to ganitumab 20 mg/kg. The study was stopped based on results from a preplanned futility analysis; the final results are reported. Median OS was 7.2 months [95% confidence interval (CI), 6.3-8.2] in the placebo arm, 7.0 months (95% CI, 6.2-8.5) in the ganitumab 12-mg/kg arm [hazard ratio (HR), 1.00; 95% CI, 0.82-1.21; P = 0.494], and 7.1 months (95% CI, 6.4-8.5) in the ganitumab 20-mg/kg arm (HR, 0.97; 95% CI, 0.76-1.23; P = 0.397). Median PFS was 3.7, 3.6 (HR, 1.00; 95% CI, 0.84-1.20; P = 0.520), and 3.7 months (HR, 0.97; 95% CI, 0.77-1.22; P = 0.403), respectively. No unexpected toxicity was observed with ganitumab plus gemcitabine. The circulating biomarkers assessed [insulin-like growth factor-1 (IGF-1), IGF-binding protein-2, and -3] were not associated with a treatment effect on OS or PFS by ganitumab. CONCLUSION: Ganitumab combined with gemcitabine had manageable toxicity but did not improve OS, compared with gemcitabine alone in unselected patients with metastatic pancreatic cancer. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01231347.

α-Smooth muscle actin expression and desmoplastic stromal reaction in pancreatic cancer: results from the CONKO-001 study.

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.

A comprehensive analysis of the cellular and EBV-specific microRNAome in primary CNS PTLD identifies different patterns among EBV-associated tumors.

Primary central nervous system (pCNS) posttransplant lymphoproliferative disorder (PTLD) is a complication of solid organ transplantation characterized by poor outcome. In contrast to systemic PTLD, Epstein-Barr virus (EBV)-association of pCNS PTLD is almost universal, yet viral and cellular data are limited. To identify differences in the pattern of EBV-association of pCNS and systemic PTLD, we analyzed the expression of latent and lytic EBV transcripts and the viral and cellular microRNAome in nine pCNS (eight EBV-associated) and in 16 systemic PTLD samples (eight EBV-associated). Notably although 15/16 EBV-associated samples exhibited a viral type III latency pattern, lytic transcripts were also strongly expressed. Members of the ebv-miR-BHRF1 and ebv-miR-BART clusters were expressed in virtually all EBV-associated PTLD samples. There were 28 cellular microRNAs differentially expressed between systemic and pCNS PTLD. pCNS PTLD expressed lower hsa-miR-199a-5p/3p and hsa-miR-143/145 (implicated in nuclear factor kappa beta and c-myc signaling) as compared to systemic PTLD. Unsupervised nonhierarchical clustering of the viral and cellular microRNAome distinguished non-EBV-associated from EBV-associated samples and identified a separate group of EBV-associated pCNS PTLD that displayed reduced levels of B cell lymphoma associated oncomiRs such as hsa-miR-155, -21, -221 and the hsa-miR-17-92 cluster. EBV has a major impact on viral and cellular microRNA expression in EBV-associated pCNS PTLD.

SPARC expression in resected pancreatic cancer patients treated with gemcitabine: results from the CONKO-001 study.

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.

Intensity-modulated and image-guided radiotherapy in patients with locally advanced inoperable pancreatic cancer after preradiation chemotherapy.

BACKGROUND: Radiotherapy (RT) in patients with pancreatic cancer is still a controversial subject and its benefit in inoperable stages of locally advanced pancreatic cancer (LAPC), even after induction chemotherapy, remains unclear. Modern radiation techniques such as image-guided radiotherapy (IGRT) and intensity-modulated radiotherapy (IMRT) may improve effectiveness and reduce radiotherapy-related toxicities. METHODS: Patients with LAPC who underwent radiotherapy after chemotherapy between 09/2004 and 05/2013 were retrospectively analyzed with regard to preradiation chemotherapy (PRCT), modalities of radiotherapy, and toxicities. Progression-free (PFS) and overall survival (OS) were estimated by Kaplan-Meier curves. RESULTS: 15 (68%) women and 7 men (median age 64 years; range 40-77) were identified. Median duration of PRCT was 11.1 months (range 4.3-33.0). Six patients (27%) underwent conventional RT and 16 patients (73%) advanced IMRT and IGRT; median dosage was 50.4 (range 9-54) Gray. No grade III or IV toxicities occurred. Median PFS (estimated from the beginning of RT) was 5.8 months, 2.6 months in the conventional RT group (conv-RT), and 7.1 months in the IMRT/IGRT group (P = 0.029); median OS was 11.0 months, 4.2 months (conv-RT), and 14.0 months (IMRT/IGRT); P = 0.141. Median RT-specific PFS for patients with prolonged PRCT > 9 months was 8.5 months compared to 5.6 months for PRCT < 9 months (P = 0.293). This effect was translated into a significantly better median RT-specific overall survival of patients in the PRCT > 9 months group, with 19.0 months compared to 8.5 months in the PRCT < 9 months group (P = 0.049). CONCLUSIONS: IGRT and IMRT after PRCT are feasible and effective options for patients with LAPC after prolonged preradiation chemotherapy.

[Prophylaxis and treatment of venous thromboembolism in cancer patients. Clinical value of low-molecular-weight heparins]. / Prophylaxe und Therapie venöser Thromboembolien bei Tumorerkrankungen. Stellenwert niedermolekularer Heparine.

Venous thromboembolism (VTE) is a common complication in patients with cancer. Because of their improved subcutaneous bioavailability and reliable antithrombotic efficiency low-molecular-weight heparins (LMWH) are preferably used for prevention and treatment of cancer-related VTE. Thromboprophylaxis with LMWH is well established in patients undergoing cancer surgery and hospitalized cancer patients, while outpatient prophylaxis remains contentious. LMWH are recommended over unfractionated heparins and vitamin K antagonists for initial treatment and secondary prophylaxis (3-6 months) after cancer-related VTE. Long-term secondary prophylaxis should be considered for patients with ongoing active malignancy and low bleeding risk. Due to absence of clinical studies in cancer patients, the use of novel oral anticoagulants is currently not recommended.

[Multimodal treatment of pancreatic cancer]. / Multimodale Therapie des Pankreaskarzinoms.

Adenocarcinoma of the exocrine pancreas is one of the most aggressive types of solid tumor and stands at fourth position in the tumor death frequency scale due to a high mortality rate. Effective screening methods are not available and only radical surgery offers a curative option. With adjuvant chemotherapy the median survival time can be prolonged up to 23 months and approximately 25 % of patients are still alive after 5 years. Of these patients approximately 75-80 % are already in a palliative therapy situation at the time of diagnosis. In the last 5 years treatment options have been increased by the introduction of new chemotherapeutic drugs. For patients with metastasized disease median survival times of 6-12 months can currently be achieved depending on the general performance status at diagnosis but less than 5 % of these patients are still alive after 5 years. Neoadjuvant treatment strategies, radiation and immunotherapy do not play a role in evidence-based clinical practice. Despite progress in the understanding of cancer biology and new treatment options, non-resectable adenocarcinoma of the pancreas remains a disease with a very poor prognosis.

Hepatic arterial infusion with oxaliplatin and 5-FU/folinic acid for advanced biliary tract cancer: a phase II study.

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(2) and folinic acid (F) 170 mg/m(2) with 5-FU (F) 600 mg/m(2). 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.

[Spontaneous hematoma and hip pain in a 65-year old patient]. / Spontane Hämatomneigung und Hüftschmerzen bei einer 65-jährigen Patientin.

The case of a 65-year-old woman with acquired hemophilia is reported. Acquired hemophilia is characterized by the development of inhibitors directed against coagulation factors. Impairment of plasmatic hemostasis leads to a severe bleeding tendency in individuals without a preexisting coagulation defect with considerable mortality. Pathophysiology, diagnostic work-up, and treatment are summarized and discussed.