Methodology and results of real-world cost-effectiveness of carfilzomib in combination with lenalidomide and dexamethasone in relapsed multiple myeloma using registry data.

OBJECTIVE: To predict the real-world (RW) cost-effectiveness of carfilzomib in combination with lenalidomide and dexamethasone (KRd) versus lenalidomide and dexamethasone (Rd) in relapsed multiple myeloma (MM) patients after one to three prior therapies. METHODS: A partitioned survival model that included three health states (progression-free, progressed disease and death) was built. Progression-free survival (PFS), overall survival (OS) and time to discontinuation (TTD) data for the Rd arm were derived using the Registry of Monoclonal Gammopathies in the Czech Republic; the relative treatment effects of KRd versus Rd were estimated from the phase 3, randomised, ASPIRE trial, and were used to predict PFS, OS and TTD for KRd. The model was developed from the payer perspective and included drug costs, administration costs, monitoring costs, palliative care costs and adverse-event related costs collected from Czech sources. RESULTS: The base case incremental cost effectiveness ratio for KRd compared with Rd was €73,156 per quality-adjusted life year (QALY) gained. Patients on KRd incurred costs of €117,534 over their lifetime compared with €53,165 for patients on Rd. The QALYs gained were 2.63 and 1.75 for patients on KRd and Rd, respectively. CONCLUSIONS: Combining the strengths of randomised controlled trials and observational databases in cost-effectiveness models can generate policy-relevant results to allow well-informed decision-making. The current model showed that KRd is likely to be cost-effective versus Rd in the RW and, therefore, the reimbursement of KRd represents an efficient allocation of resources within the healthcare system.

Minimal model assessment of hepatic insulin extraction during an oral test from standard insulin kinetic parameters.

In this article, a first aim was to develop a minimal modeling approach to noninvasively assess hepatic insulin extraction in 204 healthy subjects studied with a standard meal by coupling the already available meal C-peptide minimal model with a new insulin model. The ingredients of this model are posthepatic IDR, which in turn is described in terms of pancreatic ISR and hepatic insulin extraction HE, and a linear monocompartmental model of insulin kinetics. Even if ISR is provided by the C-peptide minimal model, the simultaneous assessment of HE and insulin kinetics is critical, since compensations may arise between parameters describing these two processes. Therefore, as a second aim of this study, a method was developed to predict standard values of insulin kinetic parameters in an individual on the basis of the individual's anthropometric characteristics. The statistical analysis, based on linear regression of insulin kinetic parameters estimated from IM-IVGTT data performed on the same subjects, demonstrated that insulin kinetic parameters can be accurately predicted from age and body surface area. Once kinetic parameters of the new insulin model were fixed to these values, HE profile and indexes during a meal were reliably estimated in each individual, indicating a significant suppression during the meal since the overall index of HE, equal to 60 +/- 1% in the basal state, is reduced to 40 +/- 1% during a meal. However, standard parameters provide an approximation of the individual one; thus, the third aim was to define the impact on estimated indexes of using standard instead of individually estimated values. Our results showed that the 25% uncertainty affecting as an average insulin kinetic parameters of an individual, when they are predicted from age and body surface area, translates into a similar relative uncertainty in the individual's hepatic insulin extraction indexes.

HtrA1-dependent proteolysis of TGF-beta controls both neuronal maturation and developmental survival.

Transforming growth factor-beta (TGF-beta) signalling controls a number of cerebral functions and dysfunctions including synaptogenesis, amyloid-beta accumulation, apoptosis and excitotoxicity. Using cultured cortical neurons prepared from either wild type or transgenic mice overexpressing a TGF-beta-responsive luciferase reporter gene (SBE-Luc), we demonstrated a progressive loss of TGF-beta signalling during neuronal maturation and survival. Moreover, we showed that neurons exhibit increasing amounts of the serine protease HtrA1 (high temperature responsive antigen 1) and corresponding cleavage products during both in vitro neuronal maturation and brain development. In parallel of its ability to promote degradation of TGF-beta1, we demonstrated that blockage of the proteolytic activity of HtrA1 leads to a restoration of TGF-beta signalling, subsequent overexpression of the serpin type -1 plasminogen activator inhibitor (PAI-1) and neuronal death. Altogether, we propose that the balance between HtrA1 and TGF-beta could be one of the critical events controlling both neuronal maturation and developmental survival.

Cell-cycle molecules in mesothelioma: an overview.

Cell cycle progression is mediated by a group of proteins named cyclins that activate a highly conserved family of protein kinases, the cyclin-dependent kinases (CDKs). CDKs are also regulated by related proteins called cdk inhibitors, grouped into two families: the INK4 inhibitors (p16, p15, p19 and p18) and the Cip/Kip inhibitors (p21, p27). Moreover, several tumour suppressor genes (such as Retinoblastoma gene and p53 gene) are implicated in the regulation of the molecular mechanism of cell division. Several studies report the importance of cell cycle regulator proteins in the pathogenesis and the prognosis of mesothelioma. This article will review the most recent data from the literature about the expression and the diagnostic and prognostic significance of cell cycle molecules in mesothelioma.

Bone marrow and sentinel lymph node biopsy in patients with breast cancer: from staging to ultrastaging?

Bone marrow (BM) biopsy has been suggested as an independent prognostic tool to improve staging in patients with breast cancer. Two hundred and ten consecutive patients operated for breast cancer from June 2000 to June 2005 who signed an informed consent were enrolled in this protocol. Patients underwent SLN biopsy, and lymph nodes were analysed with serial sections and stained with hematossilin-eosin and immunohistochemistry. At the end of the procedure a BM aspirate from the iliac crest was obtained and 5-10 cc of blood collected. A CEA specific nested reverse transcriptase (RT) polymerase chain reaction (PCR) assay was used to examine BM samples. Results were blinded to both patients and clinicians. The median age of the patients was 56 years (range 34-80), and the median tumor diameter 1,5 cm (range 0.2-4.5). BM aspirates were unsuccessful in ten patients, and RT-PCR was not technically feasible in seventeen women, leaving 183 patients available for analysis of results and follow up. SLN biopsy allowed diagnoses of occult metastases (micrometastases and isolated tumor cells) in 16% of patients (29/183). 25% of T1N0 patients (23/92), 35% of T2N0 patients (6/17), and 44% of N1-2 patients (32/72) were BM+ (p = 0.03). At a median follow up of 35 months 5/122 in the BM- group and 6/61 in the BM+ group have relapsed (p = 0.2), while 1/122 and 4/61 have died of disease (p = 0.04) In conclusion, ultrastaging of breast cancer patients may identify a substantial subgroup of patients N-/BM- who may not require adjuvant chemotherapy, as well as a subgroup N-/BM+ with a decreased survival who may need more aggressive therapies. Further follow-up is needed to confirm this hypothesis, and several studies are under way.

[The Urovac bladder evacuator: comparison with traditionally used devices]. / Evacuatore vescicale Urovac: confronto con i dispositivi tradizionalmente usati.

Bladder evacuation device "Urovac": comparison with the conventional most used devices. We evaluated a new technique for bladder evacuation primarily during Turp using a disposable device called Urovac. This device proved to be better for evacuation of prostatic chips than both the Ellik evacuation and Toomey syringe.