Prognostic value of ploidy, cell proliferation kinetics, and conventional clinicopathologic criteria in patients with colorectal carcinoma: a prospective study.

PURPOSE: The aim of this study was to obtain additional biologic determinants that may be of use in segregating into subgroups with different prognosis patients with similarly staged colorectal cancers. METHODS: Between 1989 and 1991, a prospective study of prognostic factors has been performed in a group of 98 consecutive, unselected patients who underwent curative resections for primary untreated large bowel carcinoma. The fate of all patients is known at three years after operation. Clinical and pathologic data were recorded at the time of presentation and operation, and patients have been the subjects of regular follow-up. Tumor DNA content was determined by flow cytometry, and cell proliferative activity was determined by autoradiography with tritiated thymidine labeling index (LI). RESULTS: Univariate analysis revealed that the most important predictors of survival (P < 0.001) were the presence of positive lymph nodes, the presence of preoperative complications, Dukes stage, and LI. The multivariate analysis showed that Dukes stage (P < 0.002) and LI (P < 0.0001) were the only factors significantly related to survival. Disease-free survival was influenced significantly by Dukes stage (P < 0.001), LI, according to the classification in the two groups of high and low proliferative activity, respectively, (P < 0.0001), LI, calculated as a continuous variable (P < 0.0002), and the presence of lymph node metastases (P < 0.003). Outcome (favorable/unfavorable) was influenced significantly by Dukes stage (P < 0.0001) and LI (P < 0.0001). Concordance for each patient between Dukes stage and outcome was 73.1 percent and between LI, calculated as a continuous variable, and outcome was 74.1 percent. If, on the other hand, Dukes stage and LI are used together, concordance with outcome reaches 89.2 percent. CONCLUSION: We can conclude that, from a practical point of view, LI is an essential factor that must be combined with pathologic variables for a better prediction of patient outcome

Preclinical and clinical phase I studies of a new recombinant Filgrastim (BK0023) in comparison with Neupogen®

BACKGROUND: Filgrastim or methionyl-granulocyte colony-stimulating factor (Met-G-CSF), is a recombinant therapeutic protein widely used to treat severe neutropenia caused by myelosuppressive drugs in patients with nonmyeloid malignancies. In addition to its role in the regulation of granulopoiesis, treatment with G-CSF is considered the standard approach to mobilize CD34 positive (CD34+) mononuclear cells for reconstituting hemopoietic ability for bone marrow transplantation. An intended biosimilar filgrastim (coded BK0023) was produced in GMP conditions by E.coli fermentation according to an original recombinant process and showed physico-chemical properties and purity profile similar to Neupogen®, a commercial preparation of filgrastim. The aim of the present study was to demonstrate the comparability of BK0023 to Neupogen® in terms of both in vitro biological activities and in vivo toxicology, pharmacokinetics and pharmacodynamics. METHODS: Cell proliferation and radioligand binding assays were conducted in NFS-60 cells to compare the biological activity and functional interaction with the G-CSF receptor in vitro, while preclinical in vivo studies, including pharmacokinetics and pharmacodynamics after repeated dose were performed in normal and neutropenic rats. A phase I study was carried out in healthy male volunteers treated by multiple-dose subcutaneous administration of BK0023 and Neupogen® to evaluate their pharmacodynamic effects as well as their pharmacokinetic and safety profile and to demonstrate their pharmacodynamic equivalence and pharmacokinetic bioequivalence. RESULTS: The results reported in this work demonstrate that BK0023 is comparable in terms of biological activity, efficacy and safety to Neupogen®. CONCLUSIONS: BK0023 has the same pharmacokinetic profile, efficacy and safety as the reference commercial filgrastim Neupogen® and therefore could be further developed to become a convenient option to treat neutropenia in oncological patients

Sex differences in the daily rhythmicity of morphine consumption after major abdominal surgery.

Objective: The sex of the patients has been shown to affect postoperative pain and morphine consumption; still a clear understanding able to explain the reasons behind this difference struggles to emerge. Our research aimed to investigate one specific aspect of the variability in morphine consumption between sexes. Previous studies have shown that circadian rhythm can influence opioid consumption. Furthermore, circadian rhythm is different between female and male. Our analysis investigated the presence of differences in daily rhythmicity of morphine consumption between males and females. Design: This is a secondary analysis of data collected during 2 years long multi-center clinical trial (NCT01233 752). Settings: Clinical data were collected in two Italian hospitals: IRCCS Foundation Policlinico S. Matteo (Pavia) and San Gerardo Hospital (Monza). Patients: The authors recorded data about morphine consumption in 157 patients who underwent major abdominal surgery, who received morphine intravenous patient-controlled analgesia (IV-PCA) as postoperative analgesia. Interventions: The authors analyzed the daily periodicity of effective boluses delivered by morphine IV-PCA with Poisson multilevel models, adjusted by the time of start for each pump. An effective bolus was defined as a correctly delivered bolus oflmg of morphine. The authors also evaluated the interactions among the time of the day and sex, age (0.001) in our study population. Consumption was higher around 2 am (rate 0.4 mg/min-patient) and lower around 12 pm (rate 0.05 mg/minpatient). Global consumption was not associated with the pump start time, age, or sex. The daily periodicity of morphine consumption was different between males and females (p = 0.004), with males consuming more morphine during the night. Conclusions: Our analysis confirmed the presence of daily rhythm for morphine consumption in patients treated with IV-PCA morphine after major abdominal surgery. A difference in the daily periodicity was observed between sexes. No difference emerged in daily periodicity for the categories of age and BMI

Feasibility and challenges of independent research on drugs: the Italian medicines agency (AIFA) experience

Key points * National Health Service (NHS) is becoming increasingly aware of the need to support independent research to answer some important questions for patient care in areas of scant commercial interest. * This article reports the main features and strategies of the independent research programme on drugs launched by the Italian Medicines Agency (AIFA) in 2005. * In the three bids launched between 2005 and 2007, a total of 151 studies have been approved for funding for a total of about 78 million Euro. * In this article we describe the Italian legislative framework under which the programme was launched, the types of research funded and discuss how the supported studies could contribute, in an international framework, to the knowledge needed on drug efficacy, effectiveness and safety