Efficacy of erlotinib in patients with advanced Non-small-cell Lung Cancer (NSCLC): Analysis of the Australian subpopulation of the TRUST study

Aims: The efficacy of erlotinib (Tarceva, Roche Products, Dee Why, Australia) has been demonstrated in patients with advanced non‐small‐cell lung cancer (NSCLC). Tarceva lung cancer survival treatment (TRUST) is an open‐label, single‐arm, phase IV global trial which investigated erlotinib in advanced NSCLC patients who had failed prior therapy or were unsuitable for chemo/radiotherapy. The aim of this analysis was to report the safety and efficacy of erlotinib in the Australian patient subpopulation. Methods: Patients with stage IIIB/IV NSCLC progressing after standard systemic chemotherapy or unsuitable to receive chemo/radiotherapy were eligible for the study. The patients were treated with erlotinib at 150 mg/day orally, until disease progression or unacceptable toxicity. Results: In Australia, 460 patients were recruited. Erlotinib was given as first‐line (16%), second‐line (49%) or third‐line (35%) treatment. In the intent‐to‐treat population (N = 460), the median progression‐free survival was 2.7 months (95% CI 2.3–3.4), 1‐year survival was 35% (95% CI 30–39%) and median overall survival was 6.9 months (95% CI 5.7–8.0). Tumor response rates were available for 363 patients, with a disease control rate of 58%. Of the 460 patients included in the safety analysis, 24% had one or more erlotinib‐related adverse event (AE). Rash was reported in 77% of patients, most commonly grade 1/2 (63%). Treatment‐related serious AE were reported in 7% of patients; most commonly diarrhea (2%). Dose modifications were required in 18% of patients. Conclusions: Outcomes for Australian patients confirmed the efficacy and tolerability of erlotinib for the treatment of advanced NSCLC in routine clinical practice.     

A Phase Ib,Dose-Finding Study of Erlotinib in Combination With a Fixed Dose of Pertuzumab in Patients With Advanced Non–Small-Cell Lung Cancer

BackgroundPertuzumab, a dimerization inhibitor of human epidermal growth factor receptor 2 (HER2), has demonstrated pharmacodynamic activity, with stable disease in non–small-cell lung cancer. Combining erlotinib and pertuzumab may enhance antitumor activity. This study aimed to establish the recommended dosing of the erlotinib and pertuzumab combination; assess safety, preliminary efficacy, and pharmacokinetics; and analyze biomarkers.Patients and MethodsFifteen patients with stage IIIb/IV non–small-cell lung cancer who failed chemotherapy were recruited. The patients received erlotinib (days ?8 to ?1), then combination therapy (21-day cycles for 6 cycles). Pertuzumab was given intravenous at 840 mg, then 420 mg once every three weeks, with erlotinib given daily (100 or 150 mg).ResultsNo dose-limiting toxicities were observed. Adverse events were generally grade 1/2 and manageable. The objective response rate was 20% (3/15 patients; 2 responders had mutant HER1, 1 responder had wild-type HER1), median overall progression-free survival was 9.3 weeks. High HER1, HER2, and HER3 messenger RNA expression correlated with increased progression-free survival. Combination therapy did not affect erlotinib's pharmacokinetics; however, pertuzumab mean exposures (maximum concentration, 231 mg/L; area under the concentration-time curve from 0 to 21 days, 1780 mg*d/L) were slightly higher than in previous studies.ConclusionsCombination therapy was well tolerated in patients with good performance status, with encouraging efficacy. A loading dose of pertuzumab 840 mg followed by 420 mg once every three weeks plus daily erlotinib 150 mg appears to be the most appropriate regimen for this combination.     

Cats are able to adapt protein oxidation to protein intake provided their requirement for dietary protein is met

Cats require more dietary protein than noncarnivorous species. Earlier work showed that cats lack the ability to regulate hepatic urea cycle enzymes in response to dietary protein concentration. We thus hypothesized that cats are unable to fully adapt protein oxidation to protein intake, particularly at low-protein concentrations. We used indirect respiration calorimetry to assess cats' ability to adapt substrate oxidation to diets containing different concentrations of protein, including 1 below their protein requirement. Nine cats (5 males and 4 females; 2.7 +/- 0.5 y; 4.49 +/- 0.19 kg) consumed each of 4 semipurified diets containing 7.5% [low protein (LP(3))], 14.2% [adequate protein (AP)], 27.1% [moderate protein (MP)], and 49.6% [high protein (HP)] of metabolizable energy from protein in a modified crossover design, beginning with the MP diet and then consuming the remaining diets in random order. After adaptation to each diet, cats completed a 5-d nitrogen balance trial and at least 2 12-h indirect calorimetry measurements. There was a significant effect of diet on protein oxidation (P < 0.0001), which measured 10.4 +/- 0.5, 14.1 +/- 1.0, 25.0 +/- 1.7, and 53.2 +/- 1.7% of total energy expenditure for the LP, AP, M,P and HP diets, respectively. The ratio of protein oxidation:protein intake was higher with the LP diet (1.39 +/- 0.07) than the other 3 diets (AP, 1.00 +/- 0.07; MP, 0.93 +/- 0.06; HP, 1.07 +/- 0.03; P < 0.0001), indicating a net loss of protein with the LP diet. Thus, cats are able to adapt protein oxidation to a wide range of dietary protein concentrations, provided their minimum protein requirement is met.     

Finite element modeling of the human sclera: influence on optic nerve head biomechanics and connections with glaucoma

Scleral thickness, especially near the optic nerve head (ONH), is a potential factor of interest in the development of glaucomatous optic neuropathy. Large differences in the dimensions of the sclera, the principal load-bearing tissue of the eye, have been observed between individuals. This study aimed to characterize the effects of these differences on ONH biomechanics. Eleven enucleated human globes (7 normal and 4 ostensibly glaucomatous) were imaged using high-field microMRI and segmented to produce 3-D individual-specific corneoscleral shells. An identical, idealized ONH geometry was inserted into each shell. Finite element modeling predicted the effects of pressurizing the eyes to an IOP of 30 mmHg, with the results used to characterize the effect of inter-individual differences in scleral dimensions on the biomechanics of the ONH. Measurements of the individual-specific corneoscleral shells were used to construct a 2-D axisymmetric idealized model of the corneoscleral shell and ONH. A sensitivity analysis based on this model quantified the relative importance of different geometrical characteristics of the scleral shell on the biomechanics of the ONH. Significant variations were observed in various measures of strain in the idealized lamina cribrosa (LC) across the seven normal corneoscleral shells, implying large differences in individual biomechanics due to scleral anatomy variations alone. The sensitivity analysis revealed that scleral thickness adjacent to the ONH was responsible for the vast majority of variation. Remarkably, varying peripapilary scleral thickness over the physiologically measured range changed the peak (95th percentile) first principal strain in the LC and radial displacement of the ONH canal by an amount that was equivalent to a change in IOP of 15 mmHg. Inter-individual variations in scleral thickness, particularly peripapillary scleral thickness, can result in vastly different biomechanical responses to IOP. These differences may be significant for understanding the interactions between IOP and scleral biomechanics in the pathogenesis of glaucomatous optic neuropathy. The relationship between scleral thickness and material properties needs to be studied in human eyes.     

Force required to luxate a newly placed dental implant in bone: an in vitro pilot study

Immediate loading of newly placed dental implants is a consideration when attempting to meet patients' demands. However, immediate loading may induce implant failure to osseointegrate, particularly in the case of a patient who can generate a biting force that can reach approximately 1300 Newtons (N) in the posterior jaws. The range of biting forces that prevent osseointegration of newly placed implants is currently unknown. However, it is suspected that osseointegration may fail if an implant is luxated in bone more than 50 microm, in which case fibrous tissue will be formed instead of bone. This pilot study was focused on finding the amount of horizontal off-axial force required to move a nonosseointegrated 4.3 x 13-mm implant 50 microm. The initial data show that the amount of horizontal force required to displace such an implant by 50 microm was on the order of 150 N. Assuming that the angle between the direction of the biting force and the vertical lies between 0 degrees and 20 degrees, our data show that a 4.3 x 13-mm implant may fail to osseointegrate for biting forces that are as low as 440 N. One implication of our study is that implants having smaller diameters may move and fail to osseointegrate for even lower biting forces.     

Mutations in SH3BP2, the cherubism gene, were not detected in central or peripheral giant cell tumours of the jaw

Giant cell granulomas of the jaw (GCGJ) are non-familial, generally unilateral osteoclast-rich lesions that are histopathologically indistinguishable from cherubism. Cherubism is an autosomal dominant disease that is characterised by bilateral radiolucencies of the jaw, and caused by mutations that occur in SH3BP2 exon 10. The aim of the study was to screen lesional GCGJ tissue for SH3BP2 mutations. Lesional mononuclear stromal or spindle cells were microdissected from paraffin-embedded tissue from GCGJ, and DNA was then extracted and sequenced for SH3BP2 mutations associated with cherubism. No mutations were detected in 26 GCGJ (15 central, 11 peripheral), which indicated that people with GCGJ do not harbour cherubism-related germline SH3BP2 mutations, and that GCGJ do not harbour somatic SH3BP2 mutations. This suggests that cherubism and GCGJ arise on a different genetic background, and therefore detection of SH3BP2 mutations can be a useful means of distinguishing between them.     

Understanding the autistic dental patient

Autism spectrum disorder (ASD) is one of many pervasive developmental disorders (PDD); others include Rett syndrome, childhood disintegrative disorder (also known as Heller's syndrome), pervasive developmental disorder not otherwise specified (PDD-NOS), and the higher functioning Asperger's syndrome. Because ASD is the most common of the developmental disabilities, it is not unusual for dentists to have ASD patients among their patient population. As the name indicates, ASD varies widely in its clinical manifestations; however, dentists are likely to encounter difficulties with communication and socialization. Although communication may be difficult, it is not impossible. A thorough understanding of this complex neurological disorder and displaying patience are vital for the dentist. This article seeks to familiarize readers with ASD characteristics and co-morbid conditions that may affect dental treatment and provide some management strategies for this unique population.