Phase II study of two dose schedules of C.E.R.A. (Continuous Erythropoietin Receptor Activator) in anemic patients with advanced non-small cell lung cancer (NSCLC) receiving chemotherapy

BACKGROUND: C.E.R.A. (Continuous Erythropoietin Receptor Activator) is an innovative agent with unique erythropoietin receptor activity and prolonged half-life. This study evaluated C.E.R.A. once weekly (QW) or once every 3 weeks (Q3W) in patients with anemia and advanced non-small cell lung cancer (NSCLC) receiving chemotherapy. METHODS: In this Phase II, randomized, open-label, multicenter, dose-finding study, patients (n = 218) with Stage IIIB or IV NSCLC and hemoglobin (Hb) ≤ 11 g/dL were randomized to one of six treatment groups of C.E.R.A. administered subcutaneously for 12 weeks: 0.7, 1.4, or 2.1 μg/kg QW or 2.1, 4.2, or 6.3 μg/kg Q3W. Primary endpoint was average Hb level between baseline and end of initial treatment (defined as last Hb measurement before dose reduction or transfusion, or the value at week 13). Hematopoietic response (Hb increase ≥ 2 g/dL or achievement of Hb ≥ 12 g/dL with no blood transfusion in the previous 28 days determined in two consecutive measurements within a 10-day interval) was also measured. RESULTS: Dose-dependent Hb increases were observed, although the magnitude of increase was moderate. Hematopoietic response rate was also dose dependent, achieved by 51% and 62% of patients in the 4.2 and 6.3 μg/kg Q3W groups, and 63% of the 2.1 μg/kg QW group. In the Q3W group, the proportion of early responders (defined as ≥ 1 g/dL increase in Hb from baseline during the first 22 days) increased with increasing C.E.R.A. dose, reaching 41% with the highest dose. In the 6.3 μg/kg Q3W group, 15% of patients received blood transfusion. There was an inclination for higher mean Hb increases and lower transfusion use in the Q3W groups than in the QW groups. C.E.R.A. was generally well tolerated. CONCLUSION: C.E.R.A. administered QW or Q3W showed clinical activity and safety in patients with NSCLC. There were dose-dependent increases in Hb responses. C.E.R.A. appeared to be more effective when the same dose over time was given Q3W than QW, with a suggestion that C.E.R.A. 6.3 μg/kg Q3W provided best efficacy in this study. However, further dose-finding studies using higher doses are required to determine the optimal C.E.R.A. dose regimen in cancer patients receiving chemotherapy

Genome Sequencing and Comparative Transcriptomics of the Model Entomopathogenic Fungi Metarhizium anisopliae and M. acridum

Metarhizium spp. are being used as environmentally friendly alternatives to chemical insecticides, as model systems for studying insect-fungus interactions, and as a resource of genes for biotechnology. We present a comparative analysis of the genome sequences of the broad-spectrum insect pathogen Metarhizium anisopliae and the acridid-specific M. acridum. Whole-genome analyses indicate that the genome structures of these two species are highly syntenic and suggest that the genus Metarhizium evolved from plant endophytes or pathogens. Both M. anisopliae and M. acridum have a strikingly larger proportion of genes encoding secreted proteins than other fungi, while ∼30% of these have no functionally characterized homologs, suggesting hitherto unsuspected interactions between fungal pathogens and insects. The analysis of transposase genes provided evidence of repeat-induced point mutations occurring in M. acridum but not in M. anisopliae. With the help of pathogen-host interaction gene database, ∼16% of Metarhizium genes were identified that are similar to experimentally verified genes involved in pathogenicity in other fungi, particularly plant pathogens. However, relative to M. acridum, M. anisopliae has evolved with many expanded gene families of proteases, chitinases, cytochrome P450s, polyketide synthases, and nonribosomal peptide synthetases for cuticle-degradation, detoxification, and toxin biosynthesis that may facilitate its ability to adapt to heterogenous environments. Transcriptional analysis of both fungi during early infection processes provided further insights into the genes and pathways involved in infectivity and specificity. Of particular note, M. acridum transcribed distinct G-protein coupled receptors on cuticles from locusts (the natural hosts) and cockroaches, whereas M. anisopliae transcribed the same receptor on both hosts. This study will facilitate the identification of virulence genes and the development of improved biocontrol strains with customized properties

Soluble MICA as an independent prognostic factor for the overall survival and progression-free survival of multiple myeloma patients.

Major histocompatibility complex class I-related chain A (MICA) molecules are frequently expressed in lymphoproliferative malignancies including multiple myeloma (MM). MICA activates NK cells and co-stimulates T cells by interaction with its immunoreceptor NKG2D. In contrast, soluble MICA (sMICA) molecules impair the functions of NKG2D(+) T and NK cells, which may facilitate tumor cell escape from immunosurveillance. Here, we analyzed the clinical relevance of sMICA in 97 MM patients. sMICA (mean+/-SEM pg/ml) was significantly increased (p<0.0001) in patients (429+/-20) compared to controls (230+/-20; N=43). Serial determination showed a strong correlation between increments of sMICA and paraprotein levels (r=0.543, p<0.0001, N=49). sMICA levels >305 pg/ml are associated with a poor overall (p=0.004) and progression-free survival (p=0.002). Multivariate analysis revealed sMICA as an independent predictive factor for overall (p=0.007) and progression-free survival (p=0.002). Thus, our results suggest sMICA as a potent prognostic marker in MM, which may be useful to identify risk patients

In vitro dendritic cell generation and lymphocyte subsets in myeloma patients: influence of thalidomide and high-dose chemotherapy treatment.

While vaccination with antigen-pulsed dendritic cells (DCs) represents a promising therapeutic strategy in multiple myeloma (MM), clinical benefit, so far, has been limited to individual patients. To identify potential problems with this approach, we have analyzed the influence of treatment parameters, in particular high-dose chemotherapy (HD-CTX) and thalidomide, on in vitro DC generation and peripheral blood lymphocyte subsets in MM patients. From a total of 25 MM patients, including 14 patients on thalidomide treatment and 11 after HD-CTX, in vitro DC generation from peripheral blood monocytes under serum-free condition was investigated. In addition, peripheral blood lymphocyte subsets were assessed in 17 patients including 10 patients on thalidomide treatment and 9 patients after HD-CTX. Efficient in vitro generation of DCs (median 7.1x10(6)/100 ml peripheral blood; range 0.1-42.5x10(6)/100 ml peripheral blood) expressing DC-typical surface markers was observed in 23 MM patients (92%), although reduced expression of CD1a, CD40, CD83, and HLA-DR was observed in patients treated with thalidomide. With respect to lymphocyte subsets, MM patients showed significantly (p<0.05) reduced B and CD4+ lymphocytes in the peripheral blood. This effect was most prominent within 6 months of HD-CTX and in patients receiving thalidomide (usually in combination with CTX). CD8+ lymphocytes were significantly increased in MM patients. Thus, despite the well-known deficiencies in their immune system, adequate numbers of DCs can be generated in most myeloma patients. In patients treated with thalidomide, however, it remains to be seen whether the reduced expression of co-stimulatory molecules has functional relevance

The clinical significance of soluble human leukocyte antigen class-I, ICTP, and RANKL molecules in multiple myeloma patients.

Because of the variable clinical course of multiple myeloma, the identification of prognostic parameters is of clinical interest. Therefore, we analyzed the clinical significance of serum levels of soluble human leukocyte antigen class I molecules (sHLA-I), carboxy-terminal telopeptide of type-I collagen (ICTP), and receptor activator of nuclear factor kappa B ligand (RANKL). Compared with controls, sHLA-I were threefold (p < 0.001) elevated in multiple myeloma. Increased levels of ICTP and RANKL were demonstrated in 50 and 43% of patients, respectively. sHLA-I correlated significantly with stage of disease. Serial determination of sHLA-I in 11 patients revealed significantly higher sHLA-I levels (median [range] mug/l) during active disease than during remission (700 [250-2090] versus 380 [130-920]). ICTP demonstrated an association with stages of disease and the presence of osteolytic lesions, whereas there were no differences with respect to active/remittent disease. Importantly, levels of sHLA-I > or = 1000 microg/l and ICTP > or = 5 microg/l were significantly associated with a poor overall survival. For RANKL, no significant associations were observed with disease stages, disease status, osteolytic lesions, and survival. In conclusion, sHLA-I and ICTP serum levels seem to be of prognostic significance in multiple myeloma and might be helpful to identify patients of poor prognosis

Thalidomide in combination with dexamethasone for pretreated patients with multiple myeloma: serum level of soluble interleukin-2 receptor as a predictive factor for response rate and for survival.

The aim of this study was to assess the side effects and the efficacy of thalidomide alone or in combination with dexamethasone in relapsed multiple myeloma (MM) and to evaluate possible predictive factors for response rate and survival. Twenty-nine pretreated patients were enrolled, including 13 patients with a relapse after high-dose chemotherapy. The median number of relapses was 3 (range: 1-7). Twenty-two patients received thalidomide in combination with dexamethasone and seven patients thalidomide alone. The dosage of thalidomide was 400 mg/day and the dosage of dexamethasone 20 mg/m2 daily for 4 consecutive days every 3 weeks. Cycles of dexamethasone were given until maximal decline of myeloma protein was achieved, whereas therapy with thalidomide was maintained until disease progression. Responses occurred in 62% of patients, including 5 (17%) complete remissions and 13 (45%) partial remissions. The median event-free survival (EFS) was 7.2 months and the median overall survival (OS) 26.1 months. In multivariate analysis, pretreatment serum levels of soluble interleukin-2 receptor (sIL-2R) were a significant prognostic factor for EFS, and those of beta2-microglobulin (beta2M) and sIL-2R for OS. Serum levels of sIL-2R significantly increased after 3 weeks of treatment in 89% of patients, possibly representing lymphocyte activation induced by thalidomide. Two patients died of septic complications within 3 months after starting treatment with thalidomide and dexamethasone and one patient of herpes encephalitis after 26 months of treatment with thalidomide alone. Also, one case of pneumonia and one case of deep venous thrombosis of the lower limb occurred. Other side effects were somnolence, peripheral neuropathy, and bradycardia occurring in 35, 55, 38 and 55% of patients, respectively. The combination of thalidomide and dexamethasone is an effective therapy in heavily pretreated myeloma patients with a high response rate and acceptable toxicities. A powerful predictive factor both for EFS and OS was the pretreatment serum level of sIL-2R