Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial.

The Dutch-Belgian Cooperative Trial Group for Hematology Oncology Group-65/German-speaking Myeloma Multicenter Group-HD4 (HOVON-65/GMMG-HD4) phase III trial compared bortezomib (BTZ) before and after high-dose melphalan and autologous stem cell transplantation (HDM, PAD arm) compared with classical cytotoxic agents prior and thalidomide after HDM (VAD arm) in multiple myeloma (MM) patients aged 18-65 years. Here, the long-term follow-up and data on second primary malignancies (SPM) are presented. After a median follow-up of 96 months, progression-free survival (censored at allogeneic transplantation, PFS) remained significantly prolonged in the PAD versus VAD arm (hazard ratio (HR)=0.76, 95% confidence interval (95% CI) of 0.65-0.89, P=0.001). Overall survival (OS) was similar in the PAD versus VAD arm (HR=0.89, 95% CI: 0.74-1.08, P=0.24). The incidence of SPM were similar between the two arms (7% each, P=0.73). The negative prognostic effects of the cytogenetic aberration deletion 17p13 (clone size ⩾10%) and renal impairment at baseline (serum creatinine >2 mg dl-1) on PFS and OS remained abrogated in the PAD but not VAD arm. OS from first relapse/progression was similar between the study arms (HR=1.02, P=0.85). In conclusion, the survival benefit with BTZ induction/maintenance compared with classical cytotoxic agents and thalidomide maintenance is maintained without an increased risk of SPM.

von Willebrand disease and aging: an evolving phenotype.

BACKGROUND: Because the number of elderly von Willebrand disease (VWD) patients is increasing, the pathophysiology of aging in VWD has become increasingly relevant. OBJECTIVES: To assess age-related changes in von Willebrand factor (VWF) and factor VIII (FVIII) levels and to compare age-related differences in bleeding phenotype between elderly VWD patients and those < 65 years. We also studied co-morbidity in elderly patients. PATIENTS/METHODS: We included VWD patients with VWF levels ≤ 30 U dL(-1) in the nationwide cross-sectional 'Willebrand in the Netherlands' (WiN-) study. Patients reported bleeding episodes and treatment of VWD in the year preceding inclusion and during life. This was compared between VWD patients older (n = 71) and younger (16-64 years, n = 593) than 65 years. In elderly patients, age-related changes in VWF and FVIII levels were studied longitudinally by including all historically measured levels. All medical records were examined for co-morbidity. RESULTS: In elderly type 1 patients, a decade age increase was associated with a 3.5 U dL(-1) (95% CI, -0.6 to 7.6) VWF:Ag increase and 7.1 U dL(-1) (95% CI, 0.7 to 13.4) FVIII:C increase. This increase was not observed in elderly type 2 patients. Elderly type 2 patients reported significantly more bleeding symptoms in the year preceding inclusion than younger patients (16/27, 59% vs. 87/221, 39%; P = 0.048), which was not observed in type 1 VWD. CONCLUSIONS: von Willebrand factor parameters and bleeding phenotype evolve with increasing age in VWD. VWF and FVIII levels increase with age in type 1 patients with no mitigation in bleeding phenotype. In type 2 patients VWF parameters do not increase with age and in these patients aging is accompanied by increased bleeding.

Measuring clinical bleeding using a standardized daily report form and a computer algorithm for adjudication of WHO bleeding grades.

INTRODUCTION: Bleeding is increasingly considered an important end point in clinical platelet transfusion studies. Accurate recording and adjudication into well-defined bleeding grades, however, remains a major challenge. METHODS: We developed a computer algorithm for automatic adjudication. The algorithm's results were compared to those of three independent adjudicators. RESULTS: For one of 1186 bleeding days, the clinical report form (CRF) was filled out incorrectly, and the algorithm therefore missed one grade-1 skin bleed. For two bleeding days, the adjudicators incorrectly classified a grade-2 skin bleed as grade-1 while the algorithm correctly classified these days. The algorithm saved approximately six person-hours of adjudication time for the adjudication of 1186 days from 60 patients. DISCUSSION: The algorithm can be an invaluable tool for adjudicating large amounts of bleeding data.

Cardiac catheterization and intervention in haemophilia patients: prospective evaluation of the 2009 institutional guideline.

Ageing haemophilia patients are increasingly confronted with ischaemic heart disease (IHD). Treatment is complex because of the delicate equilibrium between bleeding and thrombosis. In 2009, we developed an institutional guideline on how to treat IHD in this patient population. The aim of this study was to evaluate feasibility and safety of this guideline. Haemophilia patients who underwent coronary angiography or percutaneous coronary intervention between January 2009 and June 2012 were included in the current case series. Nine diagnostic or therapeutic cardiac catheterizations were performed in six haemophilia patients. One patient with moderate haemophilia B was included, whereas the other patients had mild haemophilia A. In six of nine procedures, access to the circulation was gained via the radial artery. Only bare-metal stents were implanted, after which dual antiplatelet treatment was given for at least 4 weeks. During cardiac catheterization/intervention and dual antiplatelet treatment, clotting factor levels were corrected. No thrombotic or clinically relevant bleeding complications occurred. In one patient, a low-titre inhibitor recurred 10 months after catheterization. In-stent restenosis was diagnosed in one patient. This case series indicates that treatment according to the guideline is feasible and safe. Furthermore, based on the case series and developments in new guidelines for non-haemophilic patients with IHD, some adjustments on the 2009 guideline are proposed.

The observation of bleeding complications in haemato-oncological patients: stringent watching, relevant reporting.

BACKGROUND: The reported percentage of haemato-oncological patients experiencing bleeding complications is highly variable, ranging from 5 to 70%, posing a major problem for comparison of clinical platelet transfusion trials using bleeding complications as a primary endpoint. In a pilot study we assessed the impact of the design of scoring of bleeding on the percentage of patients with WHO grade 2 or higher bleeding grades. STUDY DESIGN AND METHODS: We performed a prospective, observational study using a rigorous bleeding observation system in thrombocytopenic patients with haemato-oncological disorders. Endpoints of the study were the percentage of patients and days with bleeding WHO grade ≥ 2 comparing designs in which skin bleeding represent a continuation of a previous bleed or a new bleed. RESULTS: In four participating hospitals 64 patients suffering 870 evaluable thrombocytopenic days (platelet count < 80 × 10(9) L(-1)) were included. At least one episode of bleeding grade ≥ 2 occurred in 36 patients (56%). Most grade 2 bleeding complications occurred mucocutaneously. The percentage of days with bleeding of grade ≥ 2 was 16% but decreases to 8% when only newly developed skin bleeding was included. CONCLUSION: Rigorous daily observation results in a bleeding incidence that is comparable to recent reportings applying the same method. The results of this study show that censoring for stable skin bleeding has a profound effect on bleeding incidence per day. The clinical relevance of rigorous or clinically judged bleeding scores as an endpoint remains to be defined.

Treatment of hereditary angioedema with nanofiltered C1-esterase inhibitor concentrate (Cetor®): multi-center phase II and III studies to assess pharmacokinetics, clinical efficacy and safety.

From 1997, plasma-derived C1-inhibitor concentrate (Cetor®) has been available to HAE and AAE patients. Recently, a virus reducing 15 nm nanofiltration step has been introduced in the production process. A randomized, double-blind controlled cross-over study was performed to compare the pharmacokinetics (PK) of nanofiltered (C1-INH-NF) with conventional C1-inhibitor (C1-INH). Efficacy and safety were investigated in an open-label, on-demand and a prophylactic study. No differences in pharmacokinetic parameters between C1-INH and C1-INH-NF were found (13 non-symptomatic HAE patients). Both C1-inhibitor products equally increased plasma C4 levels. In the on-demand study, 14 acute angioedema attacks in 8 patients were analyzed. In the prophylactic study, 1 AAE and 5 HAE patients experienced in total 31 attacks during 748 observation days. In total 180,000 units of C1-INH-NF were administered. No product-related adverse events occurred, and no anti-C1-antibodies were induced. Nanofiltration in the production process of C1-inhibitor did not affect the pharmacokinetics, efficacy, and safety.

Gynaecological and obstetric bleeding in moderate and severe von Willebrand disease.

A nation-wide cross-sectional study was initiated to assess gynaecological and obstetrical symptoms in an unselected cohort of women with moderate and severe von Willebrand disease (VWD) in the Netherlands. A total of 423 women aged ≥16 years were included. Bleeding severity was measured using the Tosetto Bleeding Score (BS). Menorrhagia, defined as occurrence of ≥2 menorrhagia symptoms, was reported by 81%. Of all VWD women, 78% received any kind of treatment for menorrhagia and 20% underwent a hysterectomy predominantly because of severe menstrual bleeding. Over half of the women reported more blood loss than can be expected with a normal delivery. In 52% of reported pregnancy losses curettage was needed because of bleeding. Mean number of live births was 1.9, which is comparable with the general Dutch population. In conclusion, women with moderate or severe VWD frequently have menorrhagia in need of treatment, and 20% of the VWD women underwent a hysterectomy. Bleeding complications occurred in over 50% of the women after childbirth or pregnancy loss. Progeny seems not to be affected in women with moderate or severe VWD.

An ultrapure plasma-derived monoclonal antibody-purified factor IX concentrate (Nonafact®), results of phase III and IV clinical studies.

Nonafact(®), an ultrapure, monoclonal antibody-purified factor IX concentrate (FIX) was developed to minimize risk of thrombotic complications and viral transmission. To investigate the pharmacokinetics, efficacy and safety, phase III/IV studies were performed in the Netherlands and Poland from 1996 to 2007. The mean half-life, in vivo response and recovery of Nonafact(®) were 18.7 (SD 2.0) h, 1.1 (SD 0.2) IU dL(-1) per IU kg(-1) b.w. of FIX infused and 49% (SD 10%), respectively. Eleven surgical procedures were performed in eight patients. During two surgeries, both high-risk, blood loss was observed. No postoperative bleeding occurred. The in vivo recovery of FIX was higher than expected. In the phase III follow-up study, 26 previously treated patients (PTP) were included with a median follow-up of 1130 days. From the 1617 minor bleedings, 80.5% was stopped after a single infusion. In the phase IV study thirteen patients were treated for a median study period of 737 days. In the two follow-up studies the investigators rated the effect of Nonafact(®) as excellent/good in 95% of major bleedings. Surgeries for which Nonafact(®) was given prophylactically were without bleeding problems. In total more than 10 million units of Nonafact(®) were used during almost 120 person-years. Only one minor adverse event was reported. No inhibitors, viral transmissions and thrombogenic events occurred. In conclusion, Nonafact(®) is safe and provides excellent haemostasis in haemophilia B patients treated for spontaneous bleeding or undergoing surgical procedures. Due to the excellent in vivo recovery characteristic, treatment with Nonafact(®) is cost saving compared to other FIX products.

Paraneoplastic cerebellar degeneration preceding the diagnosis of Hodgkin's lymphoma.

Paraneoplastic cerebellar degeneration (PCD) can present as a severe and (sub)acute cerebellar syndrome. PCD can accompany different kinds of neoplasms including small cell lung cancer, adenocarcinoma of the breast and ovary, and Hodgkin's lymphoma. A 34-year-old patient is described with acute dysarthria, gait ataxia and diplopia. Despite extensive laboratory and radiological evaluations in this patient with rapidly deteriorating cerebellar syndrome, the diagnosis of a paraneoplastic syndrome was only made after several months, when an anti-Tr antibody was detected in his serum. The search for Hodgkin's disease as concomitant disorder was then started and resulted in stage II B disease. The patient was successively treated with six courses of etoposide, bleomycin, vinblastine and dexamethasone and radiotherapy, which resulted in a complete remission of the Hodgkin's disease. After starting therapy the cerebellar degeneration stabilised. The pathogenesis of neuronal damage in central nervous system paraneoplastic disorders such as the one we describe is not completely understood. Antitumour therapy is assumed to be the important cornerstone in stabilising the neurological condition. Improvement of the cerebellar syndrome in anti-Tr autoantibody paraneoplastic disease is a rare achievement. Early recognition of the concomitant disorders (anti-Tr autoantibody disease and Hodgkin's lymphoma) is of crucial importance.

Exclusion of venous thromboembolism: evaluation of D-Dimer PLUS for the quantitative determination of D-dimer.

The objective of this study was to evaluate if D-Dimer PLUS (Dade Behring, USA), a rapid fully automated assay, could be used as an initial screening test in the diagnosis of venous thromboembolism (VTE). Samples from 274 consecutive symptomatic patients with suspected pulmonary embolism (n=229; 79% outpatients, 21% inpatients), deep venous thrombosis (n=37; 84% outpatients, 16% inpatients) or suspected for both complications (n=8) were tested with this D-dimer assay with a Sysmex CA-1500 Coagulation Analyzer. Clinical probability for pulmonary embolism (PE) or deep venous thrombosis (DVT) was staged according to a pretest risk score proposed by Wells. Final diagnosis of PE and/or DVT was established by spiral-computed tomography of the pulmonary arteries or compression ultrasonography, respectively. PE was diagnosed in 13.5% of the patients, whereas DVT was confirmed in 17.7% of the patients. The optimal cut-off value for exclusion of venous thromboembolism was 130 mug/l, and sensitivity, specificity and negative predictive value (NPV) were 95.0% (95% CI: 92.4-97.6), 30.4% (95% CI: 25.0-35.8) and 97.2% (95% CI: 95.2-99.2), respectively. In fact, two patient with PE were missed using D-Dimer PLUS; both cases were outpatients. In conclusion, this assay appears to be safe when implemented in an algorithm based on clinical assessment, D-dimer concentration, and radiological diagnostic techniques to stratify the risk for PE or DVT. However, higher sensitivities and negative predictive values were claimed in the scarce published reports for the D-Dimer PLUS assay than found in this study.

[Diagnostic image (97). A woman with septicemia due to the small intestinal infarction]. / Diagnose in beeld (97). Een vrouw met sepsis door dunnedarminfarcering.

A 69-year-old woman who was treated for a spindle cell carcinoma of the upper jaw developed tumour emboli causing ischaemia and infarction of fingertips, small intestine, spleen, pancreas and kidneys.

Effects of dopamine depletion on the morphology of medium spiny neurons in the shell and core of the rat nucleus accumbens.

Nucleus accumbens receives a dense dopaminergic innervation which is important in regulating motivated states of behavior such as goal-directed actions, stimulus-reward associations and reinforcement of addictive substances. The shell and core territories of this nucleus each receive functionally and morphologically distinct dopaminergic inputs and lesions of the ascending pathways totally deprive the core but not the shell of dopaminergic fibers. Medium spiny neurons are the principal targets of dopaminergic terminals. The present study explored whether the loss of dopamine inputs can affect these neurons and whether cells in the shell and core would be equally susceptible to such a loss. Intracellular injection in fixed slices and neuronal reconstruction were used to analyze the dendritic trees of 62 neurons in the shell and core of animals that received a unilateral, chronic 6-hydroxydopamine lesion of the medial forebrain bundle. In the dopamine-depleted core, dendrites are significantly shorter (16% decrease) than in the intact core and in both the dopamine-depleted core and lateral shell, dendrites are less spiny than in respective control regions. Dopamine loss in the medial shell is associated with significantly more tortuous dendrites that are lower in spine density. However, the number of spines is not reduced which may mean that the increase recorded for segment length, although insignificant in tests, could be responsible for the change in spine density. These data suggest that the loss of dopamine can affect accumbal neuronal morphology and, moreover, can affect neuronal structures differentially in the shell and core.

Pyrite Group: An Unusual Member: Cu0.60Ni0.14Co0.03Fe0.23S2.

An investigation of villamaninite from the type locality indicates that former analyses were of aggregates rather than of individual minerals. A redefinition embraces a larger range of solid solution, the end-member of which has the highest content of copper so far attributed to a member of the pyrite family.