A survey on IVIVC/IVIVR development in the pharmaceutical industry - Past experience and current perspectives.

The present work aimed to describe the current status of IVIVC/IVIVR development in the pharmaceutical industry, focusing on the use and perception of specific approaches as well as successful and failed case studies. Two questionnaires have been distributed to 13 EFPIA partners of the Oral Biopharmaceutics Tools Initiative and to the Pharmacokinetics Working Party of the European Medicines Agency in order to capture the perspectives and experiences of industry scientists and agency members, respectively. Responses from ten companies and three European Agencies were received between May 21st 2014 and January 19th 2016. The majority of the companies acknowledged the importance of IVIVC/IVIVR throughout the drug development stages and a well-balanced rate of return on investment. However, the IVIVC/IVIVR approach seemed to be underutilized in regulatory submissions. Four of the ten companies stated to have an internal guidance related to IVIVC/IVIVR modelling, whereas three felt that an overall strategy is not necessary. Successful models mainly served to support formulation development and to provide a better mechanistic understanding. There was not yet much experience with safe-space IVIVRs as well as the use of physiologically based modelling in the field of IVIVC. At the same time, the responses from both industry and agencies indicated that there might be a need for a regulatory framework to guide the application of these novel approaches. The relevance of IVIVC/IVIVR for oral IR drug products was recognized by most of the companies. For IR formulations, relationships other than Level A correlation were more common outcomes among the provided case studies, such as multiple Level C correlation or safe-space IVIVR, which could be successfully used for requesting regulatory flexibility. Compared to the responses from industry scientists, there was a trend towards a higher appreciation of the BCS among the regulators, but a less positive attitude towards the utility of non-compendial dissolution methods for establishing a successful IVIVC/IVIVR. The lack of appropriate in vivo data and regulatory uncertainty were considered the major difficulties in IVIVC/IVIVR development. The results of this survey provide unique insights into current IVIVC/IVIVR practices in the pharmaceutical industry. Pursuing an IVIVC/IVIVR should be generally encouraged, considering its high value from both industry and regulators' perspective.

Aesthetic and functional outcome after breast conserving surgery - Comparison between conventional and oncoplastic resection.

BACKGROUND: Recent studies implicate that oncoplastic breast cancer surgery provides better aesthetic outcome than conventional resection. Several factors have been associated with poor aesthetic outcome. This study aims to compare patient-reported aesthetic and functional outcome after conventional and oncoplastic resection and to evaluate prognostic factors for poor aesthetic outcome in a population-based setting. METHODS: 637 patients having breast conserving treatment (BCT) due to unilateral primary breast cancer at a single hospital district during 2010 were included. Aesthetic and functional outcome were evaluated using two questionnaires three years after surgery. RESULTS: Questionnaires were returned by 379 (59%) patients; 293 (77%) of these had conventional and 86 (23%) oncoplastic resection. Patients in oncoplastic resection group had larger tumour diameter (p < 0.001), larger resection specimens (p < 0.001), and more often multifocal tumours (p = 0.032), node positive cancer (p = 0.029) and lower quadrant tumour localization (p = 0.007). Aesthetic outcome according to BCTOS questionnaire was good in 284 (75%) patients; 52 (61%) patients in the oncoplastic group and 230 patients (81%) in the conventional resection group, p < 0.001. Larger tumour diameter (p = 0.033), multifocality (p = 0.022), weight of resection specimen (<0.001) and oncoplastic surgery (p < 0.001) were predicting poor aesthetic outcome, when all patients were included. Tumour multifocality (p = 0.013) remained predictor of poor aesthetic outcome in conventional resection group but not in oncoplastic resection group. CONCLUSIONS: Patient satisfaction to aesthetic outcome after BCT is high. Conventional resection provides good aesthetic outcome in appropriately selected patients. Oncoplastic resection enables BCT in patients with larger and multifocal tumours with favourable aesthetic outcome.

Feasibility of Day Surgery in Patients With Breast Conservation and Sentinel Node Biopsy: A Randomized Controlled Trial.

BACKGROUND AND AIMS: The aim of this study was to analyze feasibility of day surgery in breast cancer patients with breast conserving surgery and sentinel node biopsy. MATERIAL AND METHODS: The study was a randomized controlled trial comparing day surgery with one night hospital stay in breast cancer patients with breast conserving surgery and sentinel node biopsy. A total of 40 patients with ⩽3-cm tumor and clinically N0 were randomized to one night stay group and 38 patients to day surgery group. Within discharge, patients and their relatives were given questionnaires in order to evaluate their experience regarding the duration of hospital stay. RESULTS: Randomized groups were similar regarding patient age and tumor stage. A total of 18 (47%) day surgery group patients were discharged the same day. The most common reason for overnight hospital stay was axillary clearance, 9 (24%). None of the patients in the day surgery group, but 2 patients in the overnight hospital stay group had re-operation due to complications. Perception and preference results were analyzed both according to randomization and actual treatment groups. Patients in both groups had rather similar experiences on the first postoperative day. Also, spouse's or relative's perception after discharge was similar in both groups. CONCLUSION: Day surgery was well received by the patients and their relatives. Day surgery appears as feasible in patients with breast conservation and sentinel node biopsy.

Oral biopharmaceutics tools - time for a new initiative - an introduction to the IMI project OrBiTo.

OrBiTo is a new European project within the IMI programme in the area of oral biopharmaceutics tools that includes world leading scientists from nine European universities, one regulatory agency, one non-profit research organization, four SMEs together with scientists from twelve pharmaceutical companies. The OrBiTo project will address key gaps in our knowledge of gastrointestinal (GI) drug absorption and deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery. This will be achieved through novel prospective investigations to define new methodologies as well as refinement of existing tools. Extensive validation of novel and existing biopharmaceutics tools will be performed using active pharmaceutical ingredient (API), formulations and supporting datasets from industry partners. A combination of high quality in vitro or in silico characterizations of API and formulations will be integrated into physiologically based in silico biopharmaceutics models capturing the full complexity of GI drug absorption. This approach gives an unparalleled opportunity to initiate a transformational change in industrial research and development to achieve model-based pharmaceutical product development in accordance with the Quality by Design concept. Benefits include an accelerated and more efficient drug candidate selection, formulation development process, particularly for challenging projects such as low solubility molecules (BCS II and IV), enhanced and modified-release formulations, as well as allowing optimization of clinical product performance for patient benefit. In addition, the tools emerging from OrBiTo are expected to significantly reduce demand for animal experiments in the future as well as reducing the number of human bioequivalence studies required to bridge formulations after manufacturing or composition changes.

Minor histocompatibility antigens as determinants for graft-versus-host disease after allogeneic haematopoietic stem cell transplantation.

Minor histocompatibility antigens (minor H antigens) are genetically polymorphic peptides that have been shown to elicit immune response when mismatched between donor and recipient of haematopoietic stem cell transplantation (HSCT). Depending on the expression profiles, mismatches in these genes may either lead to harmful graft-versus-host (GvH) reaction or desired graft-versus-leukaemia (GvL) effect. We analysed retrospectively the effect of HLA-restricted matching 11 established autosomal minor H antigens on the risk of graft-versus-host disease and relapse in 311 HLA-matched sibling HSCT of a single centre. Increased incidence of chronic GvH disease was shown to be associated with mismatches in the HA-8 and ACC-1. The mRNA expression profiles in a large set of healthy and malignant tissue samples of minor H antigen genes demonstrated in silico that the expression profiles of HA-8 and ACC-1 were surprisingly different: HA-8 gene was expressed in practically all tissues, whereas ACC-1 gene had a restricted profile. The results demonstrated that mismatches in minor H antigens HA-8 and ACC-1 predisposed to chronic graft-versus-host disease (GvHD).

Effect of exercise on bone structural traits, physical performance and body composition in breast cancer patients--a 12-month RCT.

In this 12-month RCT, we examined whether aerobic impact exercise training (3x/week) could facilitate breast cancer survivors' recovery by enhancing their bone structural strength, physical performance and body composition. After the adjuvant chemo- and/ or radiotherapy, 86 patients were randomly assigned into the training or control group. Structural bone traits were assessed with pQCT at the tibia and with DXA at the femoral neck. Agility (figure-8 running), jump force and power (force platform), grip strength and cardiovascular fitness (2-km walk test) were also assessed. Training effects on outcome variables were estimated by two-way factorial ANCOVA using the study group and menopausal status as fixed factors. Bone structural strength was better maintained among the trainees. At the femoral neck, there was a small but significant 2% training effect in the bone mass distribution (p=0.05). At the tibial diaphysis, slight 1% to 2% training effects (p=0.03) in total cross-sectional area and bone structural strength were observed (p=0.03) among the postmenopausal trainees. Also, 3% to 4% training effects were observed in the figure-8 running time (p=0.03) and grip strength (p=0.01). In conclusion, vigorous aerobic impact exercise training has potential to maintain bone structural strength and improve physical performance among breast cancer survivors.

Very rapid dissolution is not needed to guarantee bioequivalence for biopharmaceutics classification system (BCS) I drugs.

Currently, the EMEA, FDA, and WHO as regulatory authorities accept rapidly dissolving (>85% dissolved in 30 min) biopharmaceutics classification system (BCS) I drug products for biowaiver candidates. In the draft EMEA guideline the requirement has been set tighter, that is, the drug product should be very rapidly dissolving (>85% dissolved in 15 min) to be eligible for a biowaiver. Pharmacokinetic modeling of 32 BCS I drugs was performed to demonstrate that very rapid dissolution is not necessary to guarantee bioequivalence for them. Rapid dissolution and similar dissolution profiles are sufficient criteria for all BCS I drugs.

A multi-component exercise regimen to prevent functional decline and bone fragility in home-dwelling elderly women: randomized, controlled trial.

SUMMARY: This study showed that combination of strength, balance, agility and jumping training prevented functional decline and bone fragility in home-dwelling elderly women. The finding supports the idea that it is possible to maintain good physical functioning by multi-component exercise program and thus postpone the age-related functional problems. INTRODUCTION: This 1-year randomized, controlled exercise intervention trial assessed the effects of two different training programs and their combination on physical functioning and bone in home-dwelling elderly women. METHODS: One hundred and forty-nine healthy women aged 70-78 years were randomly assigned into: group 1-resistance training (RES), group 2-balance-jumping training (BAL), group 3-combination of resistance and balance-jumping training (COMB), and group 4-controls (CON). Self-rated physical functioning, leg extensor force, dynamic balance, and bone mass and structure were measured. RESULTS: Self-rated physical functioning improved in the COMB group, but was reduced in the CON group; the mean inter-group difference was 10% (95% CI: 0-22%). Mean increase in the leg extensor force was higher in the RES (14%; 4-25%) and COMB (13%; 3-25%) compared with the CON groups. Dynamic balance improved in the BAL (6%; 1-11%) and in the COMB (8%; 3-12%) groups. There were no inter-group differences in BMC at the proximal femur. In those COMB women who trained at least twice a week, the tibial shaft structure weakened 2% (0-4%) less than those in the CON group. CONCLUSIONS: Strength, balance, agility, and jumping training (especially in combination) prevented functional decline in home-dwelling elderly women. In addition, positive effects seen in the structure of the loaded tibia indicated that exercise may also play a role in preventing bone fragility.

A comparison of intrapartum automated fetal electrocardiography and conventional cardiotocography--a randomised controlled study.

OBJECTIVE: To examine whether intrapartum monitoring by means of automatic ST analysis (STAN) of fetal electrocardiography could reduce the rate of neonatal acidemia and the rate of operative intervention during labour, compared with monitoring by means of cardiotocography (CTG). DESIGN: Randomised controlled trial. SETTING: Labour ward in tertiary-level university hospital. SAMPLE: A total of 1483 women in active labour with singleton term fetus in cephalic presentation. METHODS: Women were randomly assigned to be monitored either by STAN or by CTG. Fetal blood sampling (FBS) was optional in both groups. MAIN OUTCOME MEASURES: Neonatal acidemia (umbilical artery pH <7.10), neonatal metabolic acidosis (umbilical artery pH <7.05 and base excess <-12 mmol/l) and operative interventions: caesarean section rate, vacuum outlet (VO) rate and FBS rate. RESULTS: There were no statistically significant differences between the STAN group and CTG group in the incidence of neonatal acidemia (5.8 versus 4.7%) or metabolic acidosis (1.7 versus 0.7%). The caesarean section rate (6.4 versus 4.7%) and the VO rate (9.5 versus 10.7%) were also similar in the STAN and CTG groups. The incidence of FBS was lower (P < 0.001) in the STAN group (7.0%) than in the CTG group (15.6%). CONCLUSIONS: Intrapartum fetal monitoring by means of automatic STAN did not improve the neonatal outcome or decrease the caesarean section rate. However, the need for FBS during labour was lower in the STAN group.

Specific binding of baculoviruses displaying gp64 fusion proteins to mammalian cells.

Viral vectors displaying specific ligand binding moieties have raised an increasing interest in the area of targeted gene therapy. In this report, we describe baculovirus vectors displaying either a functional single chain antibody fragment (scFv) specific for the carcinoembryonic antigen (CEA) or the synthetic IgG binding domains (ZZ) derived from protein A of Staphylococcus aureus. In addition, the vectors were engineered to incorporate a reporter gene encoding the enhanced green fluorescent protein (EGFP) under the transcriptional regulation of the cytomegalovirus (CMV) IE promoter. Display of the targeting moieties on the viral surface was achieved through fusion to the N-terminus of gp64, the major envelope protein of the Autographa californica nuclear polyhedrosis virus (AcNPV). Specific binding of the gp64 fusion viruses to mammalian target cells was demonstrated by using monoclonal anti-gp64 antibodies followed by fluorescence and/or confocal microscopy. The anti-CEA scFv displaying baculovirus was shown to bind specifically to CEA expressing cells (PC-3). Similarly, the virus displaying the ZZ domains of protein A was targeted to BHK cells via binding of an appropriate IgG antibody. In all cases, the reporter gene was expressed in the transduced mammalian cells as shown by fluorescence microscopy and flow cytometric analyses.

Baculoviral display of functional scFv and synthetic IgG-binding domains.

Viral vectors displaying specific ligand binding moities such as scFv fragments or intact antibodies hold promise for the development of targeted gene therapy vectors. In this report we describe baculoviral vectors displaying either functional scFv fragments or the synthetic Z/ZZ IgG binding domain derived from protein A. Display on the baculovirus surface was achieved via fusion of the scFv fragment or Z/ZZ domain to the N-terminus of gp64, the major envelope protein of the Autographa californica nuclear polyhedrosis virus, AcNPV. As examples of scFv fragments we have used a murine scFv specific for the hapten 2-phenyloxazolone and a human scFv specific for carcinoembryonic antigen. In principle, the Z/ZZ IgG binding domain displaying baculoviruses could be targeted to specific cell types via the binding of an appropriate antibody. We envisage applications for scFv and Z/ZZ domain displaying baculoviral vectors in the gene therapy field.

Feasibility of a 2-km walking test for fitness assessment in a population study.

A simple 2-km Walking Test has been developed for determining the cardiorespiratory fitness of healthy adults. In the present study the following aspects of the feasibility of this test for population assessment were investigated: participation willingness, the percentage of test qualified subjects, the percentage of acceptable test performances and the resources needed for field test administration. A representative sample was drawn from the 27 to 65-year-old population in a rural municipality in northeastern Finland. Subjects were recruited on the basis of the results of health questionnaires and interviews. One fourth of the volunteers were excluded from the test because of health problems. The 2-km walking tests were administered outdoors in the municipality center. More than 50% of the subjects successfully completed two consecutive walking tests. This study indicated that the 2-km Walking Test is a feasible alternative as a measure of cardiovascular fitness for large population groups and could potentially be used in exercise related health promotion programmes.

Reflection and transmission measurements with an integrating sphere and Fourier-transform infrared spectrometer.

A method of measuring the total reflection and transmission spectra of scattering materials with an integrating sphere and a Fourier-transform infrared spectrometer is studied. The reflectance measurement system is considered in a specific case where the incident beam overfills the back side port of the sphere, and the correction functions for measured spectra are derived for this case. Correction formulas are based on the energy balance between incident radiation and absorbed or escaped radiation in the system. The absorption spectrum of the material is calculated from the corrected spectra. The optical properties of paper samples and radiating surfaces of infrared dryers in the 0.4-20-microm wavelength range are determined. The correction formulas are compared with previous work presented in the literature.

Diagnostic significance of pleural fluid lactate concentrations.

Lactate concentrations in the pleural fluid and plasma of 57 patients with pleural effusions were measured by an enzymatic method. The mean pleural fluid lactate concentrations were significantly higher in patients with empyemas and rheumatoid arthritis than in patients with tuberculosis, cancer, non-specific pleural effusions and congestive heart failure. Pleural fluid lactate concentrations correlated significantly with pleural fluid lactate dehydrogenase activities and inversely with pleural fluid glucose concentrations. An elevated pleural fluid lactate concentration is not diagnostic for empyema, as most patients with rheumatoid arthritis and some with tuberculosis and cancer also show high values.

Adenosine deaminase in the diagnosis of pleural effusions.

The activity of adenosine deaminase (ADA) was determined in serum and pleural fluid of 90 patients with pleural effusions of various aetiology. Tuberculous pleural effusions, empyemas and rheumatoid pleural effusions demonstrated significantly higher activities of ADA than parapneumonic , nonspecific and malignant pleural effusions and effusions in systemic lupus erythematosus and congestive heart failure. In tuberculosis, empyema and rheumatoid arthritis ADA activity was significantly higher in pleural fluid than in serum, indicating a local synthesis of ADA by cells within the pleural cavity in these diseases.

Aetiology and detection of congenital nasal deformities.

A total of 4724 newborns were screened for congenital nasal deformities with two simple tests which were performed by specialized nurses. Altogether 91 (1.9%) pathological cases were found. The parturients' external features and the course of the deliveries showed no differences from those of a control group, nor did the groups differ regarding features of the newborns. On the other hand, in the nasal deformity group, highly significantly (P less than 0.001) more cases of stuffy nose were found already during the first days after birth. In this study, no evidence of birth trauma as the cause of congenital nasal deformities was found. It is proposed that at least the majority of them originated during intrauterine life. The screening method was quite valid: every newborn who failed the screen tests showed some kind of nasal pathology and, on the other hand, those who passed had only minor deviations of the septum.

External, asymptomatic laryngocele without known predisposing factors in a middle-aged man.

A laryngocele is an air-filled swelling of the upper pouch (the sacculus) of the laryngeal ventricle of Morgagni, which may herniate through the thyro-hyoid membrane to form a mass which is palpable subcutaneously in the neck. The condition is rare, but is found at times in individuals with laryngeal malignancy and in individuals who have been pre-disposed to it by increased internal laryngeal pressure. When the condition is discovered it is always an indication for a thorough examination of the larynx, with follow-up, bearing in mind the possibility of malignancy.