High-dose Bendamustine-EAM followed by autologous stem cell rescue results in long-term remission rates in lymphoma patients, without renal toxicity.

BACKGROUND: Autologous stem cell transplantation (ASCT) following BEAM (BCNU, etoposide, cytarabine, melphalan) conditioning is standard of care in relapsed low- and high-grade B-cell lymphoma (DLBCL) and other lymphoproliferative disorders, but BCNU is associated with interstitial pneumonia and an increased mortality. A less toxic regimen might improve the outcome of patients with lymphoma after transplantation. OBJECTIVES: We investigated the role of bendamustine replacing BCNU in the BEAM regimen in patients with lymphoma undergoing ASCT. PATIENTS/METHODS: The conditioning regimen BendaEAM consisted of bendamustine, cytarabine, etoposide, and melphalan and was used in patients with Hodgkin's disease (HD) and Non-Hodgkin lymphoma (NHL). RESULTS: Forty-one patients with HD (n = 9) or NHL (n = 32) were consecutively treated with Benda-BEAM replacing BCNU. No pulmonary or renal toxicities occurred, and no patient died related to transplant. After a median follow-up of 55 months, CR rate was 56%, 18 patients (44%) showed progression after a median time of 7 months after transplantation (range: 2-29 months), and 11 patients (24%) have died, all due to lymphoma progression. The 1-, 2-, and 4-year PFS are 73.2%, 58.6%, and 55.6% and the 1-, 2-, and 4-year OS 85.4%, 78.0%, and 72.6%, respectively. CONCLUSION: BendaEAM seems to be feasible with a promising response rate and acceptable toxicity.

Probability of remaining in unsustained complete remission after steroid therapy withdrawal in patients with primary warm-antibody reactive autoimmune hemolytic anemia.

BACKGROUND: Primary warm autoimmune hemolytic anemia (WAIHA) is a rare autoimmune disorder frequently responding to corticosteroid first-line treatment and effective second-line treatment options such as splenectomy or anti-CD20 antibody therapy. Disease management is frequently hampered by a lack of evidence. METHODS: We have investigated the probability of sustained treatment-free remission after steroid induction to facilitate clinical decision making regarding timing and necessity of second-line treatments. Response data from 31 patients with primary WAIHA initially treated with steroids were retrospectively analyzed. All patients responded by achieving a hemoglobin of at least 10 mg/dl. RESULTS: After steroid tapering and final withdrawal, 9 of 30 patients remained in unsustained complete remission (CR). The probability of remaining in CR after steroid treatment only was 38.2 % (2 SD 20.6 %) at 15 months. The median remission duration was 100 + months with a range of 12 + to 163 + months. Of note, none of the remaining patients still on steroids achieved CR beyond 15 + months. CONCLUSION: These data indicate that a considerable proportion of patients do not need further treatment and that relapses will not occur after 15 months in CR.

Psyche at the end of life: Psychiatric symptoms are prevalent in patients admitted to a palliative care unit.

OBJECTIVE: Our aim was to evaluate the frequency and treatment of psychiatric symptoms in patients at palliative care units (PCUs). METHOD: Patients admitted to one of five participating PCUs in Austria were included. The short version of the Patient Health Questionnaire (PHQ-D) was used to evaluate their mental health status. Pain intensity was rated on a numeric rating scale (NRS) from 0 to 10 by patients and physicians. Patients with a previously diagnosed psychiatric disorder were compared to those without or with newly diagnosed psychiatric symptoms, based on PHQ-D results. Pain and psychopharmacological medication were assessed. Opioid doses were converted into oral morphine equivalents (OMEs). RESULTS: Some 68 patients were included. Previously undetected psychiatric symptoms were identified in 38% (26 of 68), preexisting psychiatric comorbidities were evident in 25% (17), and no psychiatric symptoms were observed in 37% (25). Patients with a preexisting psychiatric comorbidity received antidepressants and benzodiazepines significantly more often than patients without or with previously undetected psychiatric symptoms (p < 0.001). Patient and physician median NRS ratings of pain intensity correlated significantly (p = 0.001). Median NRS rating showed no significant difference between patients with preexisting, previously undetected, or without psychiatric symptoms. OMEs did not differ significantly between preexisting, without, or previously undetected psychiatric symptoms. Patients with undetected and preexisting psychiatric comorbidities had a greater impairment in their activities of daily living than patients without psychiatric symptoms (p = 0.003). SIGNIFICANCE OF RESULTS: Undetected psychiatric comorbidities are common in patients receiving palliative care. Screening for psychiatric symptoms should be integrated into standard palliative care to optimize treatment and reduce the psychosocial burden of the disease.

[A case report of the difficulty treating an endstage oncologic ENT patient with parenteral nutrition]. / Ein Fallbericht über die Problematik der Ernährung am Lebensende eines onkologischen HNO-Patienten.

The occurrence of cachexia at the end of life of patients suffering from cancer is a common seen problem. Within the last years new definitions, diagnostic criteria and classification systems of cachexia have been developed to improve the clinical practice. Still therapeutic interventions are limited; the role of parenteral nutrition (PN) remains controversial. PN cannot be generally recommended in patients with incurable malignancies, not even in ill-nourished patients with inadequate oral or enteral nutrition due to a changed metabolism. Treating a cachectic endstage patient suffering from head-neck-cancer we were faced with different problems.

High spontaneous granulocyte/macrophage-colony formation in patients with myelofibrosis.

Unstimulated methylcellulose cultures in 25 myelofibrosis (MF) patients were performed to better understand the role of cytokines in the proliferation of MF cells. Compared to controls MF patients show a variable but highly increased spontaneous CFU-GM formation (66 vs 4.8/10(5) PBMNC). There was a marked reduction of autonomous CFU-GM growth by the cytokine-synthesis-inhibiting molecule IL-10 as well as by antibodies against GM-CSF whereas antibodies against IL-3, G-CSF, M-CSF and IL-1ß showed heterogeneous effects. Spontaneous CFU-GM growth >100/10(5) PBMNC predicted shorter survival. Constitutive release of GM-CSF seems to contribute to proliferation of MF cells in vitro and possibly in vivo.

Prediction of venous thromboembolism in patients with cancer by measuring thrombin generation: results from the Vienna Cancer and Thrombosis Study.

PURPOSE: Patients with cancer are at increased risk of venous thromboembolism (VTE). Laboratory tests measuring the overall thrombophilic tendency might be useful to assess VTE risk. The aim of this study was to investigate thrombin generation, a key process in hemostasis, as predictor of cancer-associated VTE. PATIENTS AND METHODS: The Vienna Cancer and Thrombosis Study (CATS) is a prospective observational cohort study of patients with newly diagnosed cancer or progression of disease after remission. The study end point is occurrence of objectively confirmed symptomatic or fatal VTE within a follow-up period of 2 years. Thrombin generation was measured with a commercially available assay. RESULTS: One thousand thirty-three patients with malignancies of the breast (n = 151), lung (n = 148), upper (n = 44) and lower gastrointestinal tract (n = 125), pancreas (n = 67), kidney (n = 34), prostate (n = 122), and brain (n = 134) or lymphoma (n = 126), multiple myeloma (n = 26), and other tumor types (n = 56) were observed for a median observation period of 517 days. VTE occurred in 77 patients (7.5%). Patients with elevated peak thrombin (defined as values ≥ 611 nM thrombin, representing the 75th percentile of the total study population) had an increased risk of VTE with a hazard ratio of 2.1 (95% CI, 1.3 to 3.3, P = .002) in multivariable analysis including age, sex, surgery, chemotherapy, and radiotherapy. The cumulative probability of developing VTE after 6 months was significantly higher in patients with elevated peak thrombin than in those with lower peak thrombin (11% v 4%; log-rank test: P = .002). CONCLUSION: Measurement of thrombin generation may help identify patients with cancer at high risk of VTE.

Circulating procoagulant microparticles in cancer patients.

Accumulating evidence indicates that microparticles (MPs) are important mediators of the interaction between cancer and the hemostatic system. We conducted a large prospective cohort study to determine whether the number of circulating procoagulant MPs is elevated in cancer patients and whether the elevated MP levels are predictive of occurrence of venous thrombembolism (VTE). We analyzed plasma samples of 728 cancer patients from the ongoing prospective observational Vienna Cancer and Thrombosis Study. Study endpoint was the occurrence of symptomatic VTE. Sixty-five age- and sex-matched healthy controls were recruited for defining the cut-off point for elevated MPs (4.62 nanomolar phosphatidylserine [nM PS]), which was set at the 95th percentile of MP levels in healthy controls. The measurement of MPs was performed after capture onto immobilized annexin V, and determination of their procoagulant activity was quantified with a prothrombinase assay. During a median observation period of 710 days, 53 patients developed VTE. MP levels (nM PS) were significantly higher in cancer patients than in healthy controls (median [25th-75th percentile], 3.95 [1.74-7.96] vs. 1.19 [0.81-1.67], p<0.001). Multivariate analysis including age, sex, surgery, chemo- and radiotherapy showed no statistically significant association of the hazard ratio of elevated MPs with VTE (0.95 [95% CI, 0.55-1.64], p=0.856). In conclusion, MP levels were elevated in cancer patients compared to healthy individuals in this study. However, elevated MP levels were not predictive of VTE.

Prediction of venous thromboembolism in cancer patients.

The risk of venous thromboembolism (VTE) is increased in cancer patients. To improve prediction of VTE in cancer patients, we performed a prospective and observational cohort study of patients with newly diagnosed cancer or progression of disease after remission. A previously developed risk scoring model for prediction of VTE that included clinical (tumor entity and body mass index) and laboratory (hemoglobin level and thrombocyte and leukocyte count) parameters was expanded by incorporating 2 biomarkers, soluble P-selectin, and D-Dimer. Of 819 patients 61 (7.4%) experienced VTE during a median follow-up of 656 days. The cumulative VTE probability in the original risk model after 6 months was 17.7% in patients with the highest risk score (≥ 3, n = 93), 9.6% in those with score 2 (n = 221), 3.8% in those with score 1 (n = 229), and 1.5% in those with score 0 (n = 276). In the expanded risk model, the cumulative VTE probability after 6 months in patients with the highest score (≥ 5, n = 30) was 35.0% and 10.3% in those with an intermediate score (score 3, n = 130) as opposed to only 1.0% in patients with score 0 (n = 200); the hazard ratio of patients with the highest compared with those with the lowest score was 25.9 (8.0-84.6). Clinical and standard laboratory parameters with addition of biomarkers enable prediction of VTE and allow identification of cancer patients at high or low risk of VTE.

[Comorbidity oriented oncology - an overview]. / Komorbiditätsorientierte Onkologie - ein Uberblick.

Increasing life expectancy results in an increased number of elderly cancer patients. Comorbidities and functional impairment influence the patient's course of disease and the choice of antineoplastic treatment. The Comprehensive Geriatric Assessment (CGA) supports the appraisal of the patient's individual health characteristics, especially due to the fact that chronologic age does not always correlate with the patient's health. Next to the appraisal of comorbidities and functional impairment, nutritional state, cognitive impairment, psychological state, social support, quality of life and the patient's medication are recorded. The Society of Geriatric Oncology (SIOG) recommends the CGA in cancer patients older than seventy years. While planning a systemic antineoplastic therapy, renal, hepatic, cardiac and bone marrow insufficiencies have to be considered. Renal and hepatic impairment often cause in dose reduced antineoplastic treatment, whereas in patients with cardiac insufficiency liposomale substances and in patients with decreased bone marrow function growth factors are available. Additionally to the oncological treatment, an early involvement of palliative care specialists should be considered.

D-dimer and prothrombin fragment 1 + 2 predict venous thromboembolism in patients with cancer: results from the Vienna Cancer and Thrombosis Study.

PURPOSE: Venous thromboembolism (VTE) is a well-recognized complication of cancer. Laboratory parameters might be useful to assess the VTE risk in patients with cancer. The aim of this study was to investigate D-dimer and prothrombin fragment 1 + 2 (F 1 + 2), which reflect activation of blood coagulation and fibrinolysis, for prediction of cancer-associated VTE. PATIENTS AND METHODS: In a prospective, observational, cohort study of 821 patients with newly diagnosed cancer or progression of disease who did not recently receive chemotherapy, radiotherapy, or surgery were enrolled and followed for a median of 501 days (interquartile range, 255 to 731 days). The malignancies in these patients were as follows: breast (n = 132), lung (n = 119), stomach (n = 35), lower gastrointestinal tract (n = 106), pancreas (n = 46), kidney (n = 22), and prostate (n = 101) cancers; high-grade glioma (n = 102); malignant lymphoma (n = 94); multiple myeloma (n = 17); and other tumor types (n = 47). The study end point was occurrence of objectively confirmed symptomatic or fatal VTE. RESULTS: VTE occurred in 62 patients (7.6%). The cutoff level for elevated D-dimer and elevated F 1 + 2 was set at the 75th percentile of the total study population. In multivariable analysis that included elevated D-dimer, elevated F 1 + 2, age, sex, surgery, chemotherapy, and radiotherapy, the hazard ratios (HRs) of VTE in patients with elevated D-dimer (HR, 1.8; 95% CI, 1.0 to 3.2; P = .048) and elevated F 1 + 2 (HR, 2.0; 95% CI, 1.2 to 3.6; P = .015) were statistically significantly increased. The cumulative probability of developing VTE after 6 months was highest in patients with both elevated D-dimer and elevated F 1 + 2 (15.2%) compared with patients with nonelevated D-dimer and nonelevated F 1 + 2 (5.0%; P < .001). CONCLUSION: High D-dimer and F 1 + 2 levels independently predict occurrence of VTE in patients with cancer.

High plasma levels of soluble P-selectin are predictive of venous thromboembolism in cancer patients: results from the Vienna Cancer and Thrombosis Study (CATS).

Cancer patients are at high risk for venous thromboembolism (VTE). Laboratory parameters with a predictive value for VTE could help stratify patients into high- or low-risk groups. The cell adhesion molecule P-selectin was recently identified as risk factor for VTE. To investigate soluble P-selectin (sP-selectin) in cancer patients as risk predictor for VTE, we performed a prospective cohort study of 687 cancer patients and followed them for a median (IQR) of 415 (221-722) days. Main tumor entities were malignancies of the breast (n = 125), lung (n = 86), gastrointestinal tract (n = 130), pancreas (n = 42), kidney (n = 19), prostate (n = 72), and brain (n = 80); 91 had hematologic malignancies; 42 had other tumors. VTE occurred in 44 (6.4%) patients. In multivariable analysis, elevated sP-selectin (cutoff level, 53.1 ng/mL, 75th percentile of study population) was a statistically significant risk factor for VTE after adjustment for age, sex, surgery, chemotherapy, and radiotherapy (hazard ratio = 2.6, 95% confidence interval, 1.4-4.9, P = .003). The cumulative probability of VTE after 6 months was 11.9% in patients with sP-selectin above and 3.7% in those below the 75th percentile (P = .002). High sP-selectin plasma levels independently predict VTE in cancer patients. Measurement of sP-selectin at diagnosis of cancer could help identify patients at increased risk for VTE.

Risk of recurrence after a first venous thromboembolic event in young women.

BACKGROUND AND OBJECTIVES: Few data are available on the long-term risk of recurrence of venous thromboembolism (VTE) and on the impact of established thrombosis risk factors in young women. We aimed to study the recurrence rate and the predictive value of laboratory and clinical thrombosis risk factors in young women. DESIGN AND METHODS: Three-hundred and sixty-one women with a first objectively confirmed VTE under 45 years of age (median age 29.6 years, interquartile range 21.9-36.9) known to our outpatient department were included in this retrospective analysis. These women were re-examined with regard to recurrence of thrombosis and laboratory thrombosis risk factors. RESULTS: Within a median observation period of 11.3 years, recurrent VTE occurred in 141 patients (39.2%). The cumulative probability of recurrence was 10.9% after 2 years, 29% after 10 years and 56% after 20 years. There were no significant associations between recurrence of VTE and laboratory risk factors such as natural inhibitor deficiency, factor V Leiden, the G20210A prothrombin variation, elevated factor VIII or hyperhomocysteinemia. Even women with more than one risk factor were not found to have a higher risk of recurrent VTE. Among the clinical characteristics only an increased body mass index (p=0.03) was associated with a higher probability of recurrence. INTERPRETATION AND CONCLUSIONS: The risk of recurrent VTE in young women is higher than previously expected and remains constant over at least 20 years. Neither clinical features nor laboratory parameters help predict this risk. Thus, also in young women VTE should be regarded as a chronic disease.

Venous thromboembolism and survival in patients with high-grade glioma.

Patients with malignancy, particularly patients with high-grade glioma (HGG; WHO grade III/IV), have an increased risk of venous thromboembolism (VTE). It has been suggested that VTE predicts survival in cancer patients. The aim of our study was to investigate the occurrence of symptomatic VTE and its impact on survival in patients with HGG. Consecutive patients (n = 63; 36 female, 27 male; median age, 58 years) who had neurosurgical intervention between October 2003 and December 2004 were followed after surgery until October 2005. Objectively confirmed VTE was recorded as an event. All patients had received thrombosis prophylaxis with low-molecular-weight heparin (LMWH) during the immediate postoperative period. Subsequently, 56 patients received radiochemotherapy, 6 radiotherapy, and 1 chemotherapy only. Patients were followed over a median time period of 348 days. Fifteen patients (24%) developed VTE. Pulmonary embolism was diagnosed in nine patients (60%) and was fatal twice. The cumulative probability of VTE was 21% after three months and 26% after 12 months. The highest frequency of VTE was observed in patients with biopsy and subtotal tumor resection (n = 37; multivariate hazard ratio, 3.58; 95% CI = 0.98-13.13; P = 0.054) compared with patients with total resection. Survival did not significantly differ among patients with and without VTE and was 53% after 12 months in both groups. Patients with HGG, particularly those with biopsy and subtotal resection, are at high risk to develop VTE postoperatively. Thrombosis was not associated with a significant reduction of survival.

Venous thromboembolism--a manifestation of the metabolic syndrome.

BACKGROUND AND OBJECTIVES: The metabolic syndrome, defined by abdominal obesity, elevation of blood pressure, fasting glucose and triglycerides and low levels of high-density lipoprotein cholesterol is associated with atherosclerotic disease. It induces a pro-inflammatory and prothrombotic state. Despite its high prevalence, data on the association with venous thromboembolism (VTE) are scarce. The aim of our study was to elucidate the association of the metabolic syndrome with the risk of VTE. DESIGN AND METHODS: We conducted a case-control study to investigate the presence of the metabolic syndrome defined according to guidelines of the National Cholesterol Education Program, in high-risk patients with objectively confirmed recurrent VTE, who had had at least one unprovoked event of deep venous thrombosis or pulmonary embolism. Age and sex-matched healthy individuals served as controls. RESULTS: A total of 116 patients and 129 controls were enrolled. The prevalence of the metabolic syndrome was statistically significantly higher in patients (40/116, 35%) than in controls (26/129, 20%, p=0.012). The unadjusted odds ratio (OR) of the metabolic syndrome for VTE was 2.1 (95% CI [1.2-3.7], p=0.012) and remained statistically significant after adjustment for established thrombosis risk factors, sex and age (OR=2.2, 95% CI [1.1-4.3], p=0.020). Individuals with the metabolic syndrome (n=66) had significantly higher levels of high-sensitivity C-reactive protein (median, [interquartile range]: 0.312 mg/dL, [0.142-0.751] vs. 0.153 mg/dL, [0.073-0.330], p<0.001), fibrinogen (390 mg/dL, [342-432] vs. 343 mg/dL, [310-394], p<0.001) and factor VIII activity (182%, [157-216] vs. 159%, [133-199], p=0.005) compared to those without (n=179). INTERPRETATION AND CONCLUSIONS: The metabolic syndrome may contribute to the development of VTE and is associated with a two-fold increased risk of VTE.

Preeclampsia and pregnancy loss in women with a history of venous thromboembolism and prophylactic low-molecular-weight heparin (LMWH) during pregnancy.

Limited data are available regarding complications of pregnancy and pregnancy outcome under prophylaxis with low-molecular-weight heparin (LMWH) in women with a history of thromboembolism (TE). We retrospectively evaluated pregnancy complications in a cohort of 80 women. All had a history of TE (76 venous, two arterial and two venous and arterial) and received prophylactic LMWH during 86 pregnancies. The rate of preeclampsia and stillbirth in these women was compared to that of a control group of 313 women without a history of TE and LMWH. Prophylaxis was started at a median of 10 weeks of gestation and usually continued until six weeks post partum. In 94% of the cases the outcome of pregnancy was favourable with a live birth. Four pregnancies (4.7%) ended in miscarriage. Two (2.3%) pregnancies were complicated by a thromboembolic event (one deep leg vein thrombosis and PRIND, respectively). One patient developed HELLP-syndrome. Severe preeclampsia occurred in three (3.8%) and stillbirth in one (1.3%) of the patients (n = 80), whereas this was the case in four (1.3%, odds ratio 3.01; 95% confidence interval (CI) 0.66-13.73, p = 0.15) and 10 (3.2%, OR = 0.38; 95% CI 0.05-3.04, p = 0.72) control women. Mean birth weight and standard deviation of infants was 3,160 +/- 930 g in patients and 3,300 +/- 540 g in controls (p = 0.11). We conclude that a favourable pregnancy outcome in women with a history of thromboembolism who use prophylactic LMWH during pregnancy can be expected. There was a trend towards a higher risk of preeclampsia, and these women should be carefully monitored for this complication.