Azacitidine in combination with intensive induction chemotherapy in older patients with acute myeloid leukemia: The AML-AZA trial of the Study Alliance Leukemia.

DNA methylation changes are a constant feature of acute myeloid leukemia. Hypomethylating drugs such as azacitidine are active in acute myeloid leukemia (AML) as monotherapy. Azacitidine monotherapy is not curative. The AML-AZA trial tested the hypothesis that DNA methyltransferase inhibitors such as azacitidine can improve chemotherapy outcome in AML. This randomized, controlled trial compared the efficacy of azacitidine applied before each cycle of intensive chemotherapy with chemotherapy alone in older patients with untreated AML. Event-free survival (EFS) was the primary end point. In total, 214 patients with a median age of 70 years were randomized to azacitidine/chemotherapy (arm-A) or chemotherapy (arm-B). More arm-A patients (39/105; 37%) than arm-B (25/109; 23%) showed adverse cytogenetics (P=0.057). Adverse events were more frequent in arm-A (15.44) versus 13.52 in arm-B, (P=0.26), but early death rates did not differ significantly (30-day mortality: 6% versus 5%, P=0.76). Median EFS was 6 months in both arms (P=0.96). Median overall survival was 15 months for patients in arm-A compared with 21 months in arm-B (P=0.35). Azacitidine added to standard chemotherapy increases toxicity in older patients with AML, but provides no additional benefit for unselected patients.

Results in using the Freiburger monosyllabic speech test in noise without and with hearing aids.

The Freiburger Speech Test (FST) has been the gold standard in speech testing by word recognition score in Germany for many years. Recently, it has been demonstrated that for an amount of 104 test-persons there is no significant deviation within the lists. The objective of this study was to determine the percentiles of the distinct measuring situations in quiet and with noise (e.g. applied in hearing aid fitting) and the average benefit using hearing aids. In this prospective study, 623 patients with SNHL and equipped with hearing aids for at least 3 months have been investigated by means of the Freiburger monosyllabic test (FBE) without and with hearing aids and in quiet or with noise (CCITT noise, 65/60 dB signal-noise ratio) in free field conditions at 65 dB to determine the ratio of intelligibility. To investigate the different diagnostic conditions a linear mixed model was applied. The dependent binary variable corresponds to the number of understood syllables. The average age of all subjects was about 72.6 years. The average rate of understanding in the FBE without hearing aids and in quiet was 38.5 %, with hearing aids and in quiet 67.7 %, without hearing aids and with noise 22.4 %, and with hearing aids and with noise 39.8 %. All results were presented with the depending confidence intervals. The extent of hearing loss and the quality of hearing aid fitting can be successfully measured using the FST in quiet and with background noise (CCITT noise). In quiet, an average hearing improving gain of 29.2 % points and with noise a gain of 17.4 % points could be estimated with a successful hearing aid fitting.

[Evaluation of the Freiburg monosyllabic speech test in background noise]. / Evaluation des Freiburger Einsilbertests im Störschall.

BACKGROUND: The Freiburg speech test has been the gold standard in speech audiometry in Germany for many years. Previously, however, this test had not been evaluated in assessing the effectiveness of a hearing aid in background noise. Furthermore, the validity of particular word lists used in the test has been questioned repeatedly in the past, due to a suspected higher variation within these lists as compared to the other word list used. PATIENTS AND METHODS: In this prospective study, two groups of subjects [normal hearing control subjects and patients with SNHL (sensorineural hearing loss) that had been fitted with hearing aid] were examined. In a first group, 113 control subjects with normal age- and gender-related pure tone thresholds were assessed by means of the Freiburg monosyllabic test under free-field conditions at 65 dB. The second group comprised 104 patients that had been fitted with hearing aids at least 3 months previously to treat their SNHL. Members of the SNHL group were assessed by means of the Freiburg monosyllabic test both with and without hearing aids, and in the presence or absence of background noise (CCITT-noise; 65/60 dB signal-noise ratio, in accordance with the Comité Consultatif International Téléphonique et Télégraphique), under free-field conditions at 65 dB. RESULTS: The first (control) group exhibited no gender-related differences in the Freiburg test results. In a few instances, inter-individual variability of responses was observed, although the reasons for this remain to be clarified. Within the second (patient) group, the Freiburg test results under the four different measurement conditions differed significantly from each other (p>0.05). This group exhibited a high degree of inter-individual variability between responses. In light of this, no significant differences in outcome could be assigned to the different word lists employed in the Freiburg speech test. CONCLUSION: The Freiburg monosyllabic test is able to assess the extent of hearing loss, as well as the effectiveness of a fitted hearing aid, in the presence or absence of background-noise (CCITT-noise). The present study could not evidence statistically significant differences in outcome when using the different word lists in this test battery.

Plerixafor for PBSC mobilisation in myeloma patients with advanced renal failure: safety and efficacy data in a series of 21 patients from Europe and the USA.

We describe 20 patients with myeloma and 1 with primary amyloidosis from 15 centres, all with advanced renal failure, most of whom had PBSC mobilised using plerixafor following previous failed mobilisation by conventional means (plerixafor used up-front for 4 patients). For 15 patients, the plerixafor dose was reduced to 0.16 mg/kg/day, with a subsequent dose increase in one case to 0.24 mg/kg/day. The remaining six patients received a standard plerixafor dosage at 0.24 mg/kg/day. Scheduling of plerixafor and apheresis around dialysis was generally straightforward. Following plerixafor administration, all patients underwent apheresis. A median CD34+ cell dose of 4.6 × 10(6) per kg was achieved after 1 (n=7), 2 (n=10), 3 (n=3) or 4 (n=1) aphereses. Only one patient failed to achieve a sufficient cell dose for transplant: she subsequently underwent delayed re-mobilisation using G-CSF with plerixafor 0.24 mg/kg/day, resulting in a CD34+ cell dose of 2.12 × 10(6)/kg. Sixteen patients experienced no plerixafor toxicities; five had mild-to-moderate gastrointestinal symptoms that did not prevent apheresis. Fifteen patients have progressed to autologous transplant, of whom 12 remain alive without disease progression. Two patients recovered endogenous renal function post autograft, and a third underwent successful renal transplantation. Plerixafor is highly effective in mobilising PBSC in this difficult patient group.

Induction therapy of AML with ara-C plus daunorubicin versus ara-C plus gemtuzumab ozogamicin: a randomized phase II trial in elderly patients.

BACKGROUND: Chemotherapy for elderly patients with acute myeloid leukemia (AML) results in a median overall survival (OS) of ≤ 1 year. Elderly patients often present with cardiac comorbidity. Gemtuzumab ozogamicin (GO) is active in elderly (≥ 60 years) patients with relapsed AML with low cardiac toxicity. PATIENTS AND METHODS: This randomized phase II study compared a standard combination of ara-C and daunorubicin (DNR; 7+3) versus ara-C plus gemtuzumab ozogamicin (7+GO) as the first course of induction therapy. Primary objectives were comparison of blast clearance on day 16, event-free survival (EFS), and remission duration. OS, complete remission (CR), and tolerability were secondary objectives. RESULTS: One hundred and nineteen patients with de novo AML, treatment-related AML, AML with a history of myelodysplastic syndrome (MDS), or high-risk MDS entered the study. Median age of 115 patients (intent-to-treat population) was 69 years. Protocol outlined a second course 7+3 for patients without blast clearance and two courses of high-dose ara-C consolidation upon CR. Both treatments were equally effective in blast clearance, CR, EFS, remission duration, or OS (median: 7+3, 9 months; 7+GO, 10 months). Induction death rate was higher in the GO group due to veno-occlusive disease. CONCLUSION: The study did not show significant superiority of 7+GO over standard 7+3.

Lenograstim after autologous peripheral blood progenitor cell transplantation: results of a double-blind, randomized trial.

A phase III, randomized, double-blind, placebo-controlled, multi-center trial was conducted in order to compare the incidence of microbiologically defined infections occurring after high-dose chemotherapy (HDT) and ASCT in 98 patients given lenograstim (Granocyte) and 94 patients given placebo after transplantation. Hematopoietic recovery, the use of i.v. antibiotics, the numbers of red blood cell and platelet transfusions, the days spent in hospital, and the days on parenteral nutrition were also compared. The incidence of infections until neutrophil recovery was significantly less in patients who received lenograstim after HDT and ASCT as compared to patients who received placebo (66 of 98 vs 86 of 94 patients, P<0.001). Lenograstim also significantly reduced the use of i.v. antibiotics (P<0.001) and the median duration of i.v. antibiotic treatment (8 days vs 10 days, P=0.04), improved neutrophil recovery (absolute neutrophil count >0.5 x 10(9)/l: 11 days vs 15 days, P<0.001) and reduced the number of days spent in hospital (15 days vs 17 days, P<0.001). The administration of lenograstim after HDT and ASCT significantly reduces the incidence of microbiologically defined infections until neutrophil recovery. It also leads to less use of antibiotics and earlier discharge from hospital.

[Laparoscopic splenectomy by the "Essen-manoeuvre" for treatment of benign and malignant haematological diseases]. / Die laparoskopische Splenektomie mit dem "Essener Manöver" zur Behandlung benigner und maligner hämatologischer Erkrankungen.

Despite its early description, laparoscopic splenectomy has not yet reached the level of a standard operation as a therapeutic option for haematological disease, especially for malignant disorders. We performed laparoscopic splenectomies in a modified 4 port technique and dissection of the splenic vessels by the "Essen-Manoeuvre" and report on 68 attempted laparoscopic splenectomies for benign (n = 42) and malignant (n = 26) haematological disorders. Conversion rate was 9 %, 30-days-mortality was 1.4 %, perioperative morbidity was 11 %, respectively. Accessory spleens were found and resected in 17 % of our patients. Laparoscopic splenectomy is a new minimally invasive option for patients with benign and malignant haematological disease fraught with a special risk of intraoperative bleeding.

[AIDS and non-Hodgkin's lymphoma: initial cardiac manifestations of highly malignant B-cell lymphoma 18 years after HIV infection]. / AIDS und Non-Hodgkin Lymphome--kardiale Erstmanifestation eines hochmalignen B-Zellymphoms nach 18 Jahren HIV-Infektion.

HISTORY AND FINDINGS: A 35-year-old man who, as a result of intravenous drug abuse, had become infected with HIV 18 years previously, was admitted with signs of right-heart failure. Three months earlier a systolic murmur had first been heard in the 5th intercostal space parasternally. INVESTIGATIONS: Transesophageal echocardiography (TEE) demonstrated a 3 x 2 cm right atrial tumour, moderate to severe tricuspid regurgitation and pulmonary hypertension. Blood cultures grew Streptococcus. DIAGNOSIS, TREATMENT AND COURSE: Endocarditis with atrial thrombi and recurrent pulmonary emboli was diagnosed and treated with antibiotics and anticoagulants. Three weeks later the TEE showed an increase in the atrial tumour. Computed tomography of skull, thorax and abdomen did not demonstrate any significantly enlarged lymph nodes. Exploratory thoracotomy revealed an infiltrating highly malignant centroblastic non-Hodgkin's lymphoma (NHL) of almost the entire free wall of the right atrium. After two courses of chemotherapy (CHOP protocol) the size of the tumour had significantly decreased. CONCLUSION: The differential diagnosis of a right atrial tumour can be difficult in patients with HIV or AIDS. Even if the site is atypical and there is no lymphadenopathy, a lymphoma should be considered. In case of doubt a histological diagnosis via an exploratory thoracotomy should be performed.

Long-term survival after induction therapy with idarubicin and cytosine arabinoside for de novo acute myeloid leukemia.

We treated 153 patients with de novo acute myeloid leukemia (AML) with two induction courses of conventional-dose cytosine arabinoside (ara-C) and idarubicin (AIDA) followed by either a third course of AIDA, high-dose ara-C or bone-marrow transplantation. The complete remission (CR) rate for all patients was 63.4%, with a higher CR rate for patients with a normal (versus unfavorable) karyotype (73.2% vs 52.5%; P=0.038). The probability of overall survival (OS) was 30.7% after 5 years (26.3% after 7 years). Improved OS at 5 years could be observed for patients up to 50 years old versus patients older than 50 years of age (37.6% vs 19.9%; P=0.001) and patients with a normal (versus unfavorable) karyotype (42.9% vs 14.1%; P=0.0016). Disease-free survival (DFS) after 5 years was 33.2% for all 97 CR patients and was significantly better for patients with a normal (versus unfavorable) karyotype (44.3% vs 12.3%; P= 0.003). Multivariate analysis revealed that the age for OS (P < 0.02) and the karyotype for both OS (P<0.03) and DFS (P< 0.05) were independent prognostic factors. In conclusion, AIDA is an effective and well-tolerated induction regimen (even in elderly patients) with a 5-year survival of more than 30% when combined with ara-C-containing postremission therapy. The karyotype is the most powerful prognostic factor for predicting the outcome of patients treated with this protocol.

Quantitative analysis of postnatal myelin sheath development in the dorsal funiculus of rat.

Postnatal development of myelin sheaths in the dorsal funiculus of rats has been studied qualitatively by light microscopy and morphometry. A distinction is made between Goll's tract and Burdach's tract, and, furthermore, inside Goll's tract the cervical, thoracic and lumbar areas are compared. The induction of myelinization is influenced by a critical range of axon thicknesses. Between the 15th and 20th days of postnatal maturation there is a minimal growth reaction in the dorsal funiculus, but after the 20th day up to the 120th day extensive growth of the myelin sheath can be seen. Burdach's tract shows earlier and faster development of the myelin sheath than Goll's tract cervically, which leads to the conclusion that epicritical sensitivity matures earlier in the upper extremity. Concerning Goll's tract in the lumbar area of the dorsal funiculus, faster maturation than in the thoracic and cervical areas can be seen.