Elementary Derivative Tasks and Neural Net Multiscale Analysis of Tasks

Neural nets are known to be universal approximators. In particular, formal neurons implementing wavelets have been shown to build nets able to approximate any multidimensional task. Such very specialized formal neurons may be, however, difficult to obtain biologically and/or industrially. In this paper we relax the constraint of a strict ``Fourier analysis'' of tasks. Rather, we use a finite number of more realistic formal neurons implementing elementary tasks such as ``window'' or ``Mexican hat'' responses, with adjustable widths. This is shown to provide a reasonably efficient, practical and robust, multifrequency analysis. A training algorithm, optimizing the task with respect to the widths of the responses, reveals two distinct training modes. The first mode induces some of the formal neurons to become identical, hence promotes ``derivative tasks''. The other mode keeps the formal neurons distinct.Comment: latex neurondlt.tex, 7 files, 6 figures, 9 pages [SPhT-T01/064], submitted to Phys. Rev.

Modelling the prevalence of Salmonella carrier pigs at slaughtering age: influence of management systems and of the Salmonella status of replacement gilts

To reduce Salmonella contamination of pork food cham at the farm level, control actions can aim at preventmg the introduction of the bactena into herds or/and at preventing the in-herd transmission. Our aim is to estimate the influence of (i) the decontamination efficiency and (ii) the Salmonella status of replacement gilts on the prevalence of carrier pigs at slaughtering age. We developed a stochastic mathematical model to simulate the pig population dynamics and the Salmonella transmiss1on withrn a farrow-to-finish herd. Results show a different prevalence of carnage in groups of delivered pigs according to the scenarios tested

Interest of pet imaging in multiple myeloma

The interest of 18Fluoro-deoxyglucose (FDG) positron emission tomography (PET) imaging in the management of patients with multiple myeloma (MM) for the workup at diagnosis and for therapeutic evaluation has recently been demonstrated. FDG-PET is a powerful imaging tool for bone lesions detection at initial diagnosis with high sensitivity and specificity values. The independent pejorative prognostic value on progression-free survival (PFS) and overall survival (OS) of baseline PET-derived parameters (presence of extra-medullary disease (EMD), number of focal bone lesions (FLs), and maximum standardized uptake values [SUVmax]) has been reported in several large independent prospective studies. During therapeutic evaluation, FDG-PET is considered as the reference imaging technique, because it can be performed much earlier than MRI which lacks specificity. Persistence of significant FDG uptake after treatment, notably before maintenance therapy, is an independent pejorative prognostic factor, especially for patients with a complete biological response. So FDG-PET and medullary flow cytometry are complementary tools for detection of minimal residual disease before maintenance therapy. However, the definition of PET metabolic complete response should be standardized. In patients with smoldering multiple myeloma, the presence of at least one hyper-metabolic lytic lesions on FDG-PET may be considered as a criterion for initiating therapy. FDG-PET is also indicated for initial staging of a solitary plasmacytoma so as to not disregard other bone or extra-medullary localizations. Development of nuclear medicine offer new perspectives for MM imaging. Recent PET tracers are willing to overcome limitations of FDG. (11)C-Methionine, which uptake reflects the increased protein synthesis of malignant cells seems to correlate well with bone marrow infiltration. Lipid tracers, such as Choline or acetate, and some peptide tracers, such as (68) Ga-Pentixafor, that targets CXCR4 (chemokine receptor-4, which is often expressed with high density by myeloma cells), are other promising PET ligands. 18F-fludarabine and immuno-PET targeting CD138 and CD38 also showed promising results in preclinical models

Exposure-Response and Population Pharmacokinetic Analyses of a Novel Subcutaneous Formulation of Daratumumab Administered to Multiple Myeloma Patients

We report the population pharmacokinetic (PK) and exposure-response analyses of a novel subcutaneous formulation of daratumumab (DARA) using data from 3 DARA subcutaneous monotherapy studies (PAVO Part 2, MMY1008, COLUMBA) and 1 combination therapy study (PLEIADES). Results were based on 5159 PK samples from 742 patients (DARA 1800 mg subcutaneously, n = 487 [monotherapy, n = 288; combination therapy, n = 199]; DARA 16 mg/kg intravenously, n = 255 [all monotherapy, in COLUMBA]; age, 33-92 years; weight, 28.6-147.6 kg). Subcutaneous and intravenous DARA monotherapies were administered once every week for cycles 1-2, once every 2 weeks for cycles 3-6, and once every 4 weeks thereafter (1 cycle is 28 days). The subcutaneous DARA combination therapy was administered with the adaptation of corresponding standard-of-care regimens. PK samples were collected between cycle 1 and cycle 12. Among monotherapy studies, throughout the treatment period, subcutaneous DARA provided similar/slightly higher trough concentrations (Ctrough) versus intravenous DARA, with lower maximum concentrations and smaller peak-to-trough fluctuations. The PK profile was consistent between subcutaneous DARA monotherapy and combination therapies. The exposure-response relationship between daratumumab PK and efficacy or safety end points was similar for subcutaneous and intravenous DARA. Although the ≤65-kg subgroup reported a higher incidence of neutropenia, no relationship was found between the incidence of neutropenia and exposure, which was attributed, in part, to the preexisting imbalance in neutropenia between subcutaneous DARA (45.5%) and intravenous DARA (19%) in patients ≤50 kg. A flat relationship was observed between body weight and any grade and at least grade 3 infections. The results support the DARA 1800-mg subcutaneous flat dose as an alternative to the approved intravenous DARA 16 mg/kg.The clinical studies and the analyses presented here were supported by research funding from Janssen Research & Development, LLC

Analysis of data collected in the European Society for Blood and Marrow Transplantation (EBMT) Registry on a cohort of lymphoma patients receiving plerixafor

Plerixafor + granulocyte-colony stimulating factor (G-CSF) is administered to patients with lymphoma who are poor mobilizers of hematopoietic stem cells (HSCs) in Europe. This international, multicenter, non-interventional registry study (NCT01362972) evaluated long-term follow-up of patients with lymphoma who received plerixafor for HSC mobilization versus other mobilization methods. Propensity score matching was conducted to balance baseline characteristics between comparison groups. The following mobilization regimens were compared: G-CSF + plerixafor (G + P) versus G-CSF alone; G + P versus G-CSF + chemotherapy (G + C); and G-CSF + plerixafor + chemotherapy (G + P + C) versus G + C. The primary outcomes were progression-free survival (PFS), overall survival (OS), and cumulative incidence of relapse (CIR). Overall, 313/3749 (8.3%) eligible patients were mobilized with plerixafor-containing regimens. After propensity score matching, 70 versus 36 patients were matched in the G + P versus G-CSF alone cohort, 124 versus 124 in the G + P versus G + C cohort, and 130 versus 130 in the G + P + C versus G + C cohort. For both PFS and OS, the upper bound of confidence interval for the hazard ratio was >1.3 for all comparisons, implying that non-inferiority was not demonstrated. No major differences in PFS, OS, and CIR were observed between the plerixafor and comparison groups

Melflufen and dexamethasone in heavily pretreated relapsed and refractory multiple myeloma

PURPOSE Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need. PATIENTS AND METHODS Patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing. RESULTS Of 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class–refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class–refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade $ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4. CONCLUSION Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class–refractory and extramedullary disease

Melphalan 140mg/m2 or 200mg/m2 for autologous transplantation in myeloma: results from the Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study. A report by the EBMT Chronic Malignancies Working Party

Melphalan at a dose of 200mg/m2 is standard conditioning prior to autologous haematopoietic stem cell transplantation for multiple myeloma, but a dose of 140mg/m2 is often used in clinical practice in patients perceived to be at risk of excess toxicity. To determine if melphalan 200 and melphalan 140 are equally effective and tolerable in clinically relevant patient subgroups we analysed 1964 first single autologous transplantation episodes using a series of Cox proportional-hazards models. Overall survival, progression-free survival, cumulative incidence of relapse, non-relapse mortality, haematopoietic recovery and second primary malignancy rates were not significantly different between the melphalan 140 (n=245) and melphalan 200 (n=1719) groups. Multivariable subgroup analysis showed that disease status at transplantation interacted with overall survival, progression-free survival, and cumulative incidence of relapse, with a significant advantage associated with melphalan 200 in patients transplanted in less than partial response (adjusted hazard ratios for melphalan 200 versus melphalan 140: 0.5, 0.54, and 0.56). In contrast, transplantation in very good partial or complete response significantly favoured melphalan 140 for overall survival (adjusted hazard ratio: 2.02). Age, renal function, prior proteasome inhibitor treatment, gender, or Karnofsky score did not interact with overall/progression-free survival or relapse rate in the melphalan dose groups. There were no significant survival or relapse rate differences between melphalan 200 and melphalan 140 patients with high-risk or standard-risk chromosomal abnormalities. In conclusion, remission status at the time of transplantation may favour melphalan 200 or melphalan 140 for key transplant outcomes (NCT01362972)