Comparison of the effects of two drying methods on polymorphism of theophylline

Processing-induced transformations in drug formulation may induce adverse biopharmaceutical changes in the finished product. During the drying phase of wet granulation, theophylline monohydrate transforms either the stable (form I), or a polymorphic, metastable (form I(*)) form of anhydrous theophylline. We investigated the effect of two drying methods (multichamber microscale fluid bed dryer MMFD) or variable temperature X-ray powder diffractometer (VT-XRPD) on the relative amounts of the different theophylline forms remaining in the dried granules. Granules were analyzed using XRPD and near-infrared spectroscopy. Form I(*) was the predominant form of theophylline after drying at 40-50 degrees C with both drying techniques. Although drying at temperatures over 50 degrees C produced mostly form I, more than 20% of form I(*) remained even at 90 degrees C when drying in MMFD. In these conditions, humidity had little influence on the amount of form I(*) in the granules. In contrast, drying in a VT-XRPD at 60 degrees C produced form I already during the first 15min. Using additional drying methods, including MMFD, during the preformulation stage can be more informative about the possible polymorphic transformations and their underlying mechanisms, such as triboelectrification or recrystallization, in drug ingredients during the manufacturing process.     

Resectability,conversion, metastasectomy and outcome according to RAS and BRAF status for metastatic colorectal cancer in the prospective RAXO study

Background Outcomes after metastasectomy for metastatic colorectal cancer (mCRC) vary with RAS and BRAF mutational status, but their effects on resectability and conversion rates have not been extensively studied.Methods This substudy of the prospective RAXO trial included 906 patients recruited between 2011 and 2018. We evaluated repeated centralised resectability assessment, conversion/resection rates and overall survival (OS), according to RAS and BRAF status.Results Patients included 289 with RAS and BRAF wild-type (RAS and BRAFwt), 529 with RAS mutated (RASmt) and 88 with BRAF mutated (BRAFmt) mCRC. Metastatic prevalence varied between the RAS and BRAFwt/RASmt/BRAFmt groups, for liver (78%/74%/61%), lung (24%/35%/28%) and peritoneal (15%/15%/32%) metastases, respectively. Upfront resectability (32%/29%/15%), conversion (16%/13%/7%) and resection/local ablative therapy (LAT) rates (45%/37%/17%) varied for RASa and BRAFwt/RASmt/BRAFmt, respectively. Median OS for patients treated with resection/LAT (n = 342) was 83/69/30 months, with 5-year OS-rates of 67%/60%/24%, while systemic therapy-only patients (n = 564) had OS of 29/21/15 months with 5-year OS-rates of 11%/6%/2% in RAS and BRAFwt/RASmt/BRAFmt, respectively. Resection/LAT was associated with improved OS in all subgroups.Conclusions There were significant differences in resectability, conversion and resection/LAT rates according to RAS and BRAF status. OS was also significantly longer for RAS and BRAFwt versus either mutant. Patients only receiving systemic therapy had poorer long-term survival, with variation according to molecular status.Clinical trial registration {"type":"clinical-trial","attrs":{"text":"NCT01531621","term_id":"NCT01531621"}}NCT01531621/EudraCT2011-003158-24Subject terms: Metastasis, Colorectal cancer, Surgical oncology, Prognostic markers     

Short mandible, maxilla and cranial base are common in patients with neurofibromatosis 1

Neurofibromatosis type 1 (NF1) is an autosomal-dominant neuro-cutaneous-skeletal syndrome. Neurofibromatosis type 1 is one of the Rasopathies, and at the cellular level NF1 results in a hyperactive Ras pathway. In the current investigation, our aim was to study lateral skull X-rays (cephalograms) to assess NF1-related craniofacial morphology. A total of 85 Finnish patients with NF1, including four patients with plexiform neurofibroma of the 5th cranial nerve, and their age- and gender-matched controls, were enrolled in the study. The results showed that patients with NF1 typically had a short mandible, maxilla, and cranial base compared with healthy controls, irrespective of age, but the results were statistically significant only in adults. The length of the mandible, the maxilla and the cranial base correlated with the height of patients under 19 yr of age, but this correlation was absent in adult patients. Thus, a tall adult patient with NF1 may have short jaws and a short cranial base. In conclusion, the NF1 gene apparently influences the growth of craniofacial bones, thus contributing to the craniofacial morphology in NF1.     

Dehydration studies using a novel multichamber microscale fluid bed dryer with in-line near-infrared measurement

The purpose of this research was to study the effect of two process parameters (temperature and moisture content) on dehydration behavior of different materials using a novel multichamber microscale fluid bed dryer with a process air control unit and in-line near-infrared (NIR) spectroscopy. The materials studied were disodium hydrogen phosphates with three different levels of hydrate water and wet theophylline granules. Measured process parameters of fluid bed drying were logged, including in-line NIR signals. Off-line analyses consisted of X-ray powder diffraction patterns, Fourier transform NIR spectra and moisture contents of studied materials. During fluid bed drying, the stepwise dehydration of materials was observed by the water content difference of inlet and outlet air, the pressure difference over the bed, and the in-line NIR spectroscopy. The off-line analysis confirmed the state of solid materials. The temperature and the moisture content of the process air were demonstrated to be significant factors for the solid-state stability of theophylline. The presented setup is a material and cost-saving approach for studying the influence of different process parameters on dehydration behavior during pharmaceutical processing.     

Overall Survival and Metastasis Resections in Patients with Metastatic Colorectal Cancer Using Electronic Medical Records

Purpose

Treatment for patients with metastatic colorectal cancer is chemotherapy commonly combined with monoclonal antibodies against vascular endothelial growth factor (bevacizumab) or epidermal growth factor receptor (cetuximab or panitumumab), the efficacy of which has been proven in randomized controlled trials. The objective of the current retrospective study was to analyze the impact of targeted therapy, adverse events, and dose reduction on overall survival (OS) and metastasis resection rates.

Methods

A hospital-based electronic informatics center was used to gather clinical data and outcome information in a “real-life” setting in a single academic hospital. A total of 178 patients were included in 2010–2013.

Results

In patients whose tumors expressed the KRAS wild type, the longest median OS was observed with irinotecan-based chemotherapy combined with bevacizumab (38 months), or with cetuximab (41 months). In the KRAS-mutated group, the longest median OS was observed with oxaliplatin with or without bevacizumab (34 months). Beneficial liver metastasis resections were observed in 12 out of 20 patients. Patients with KRAS wild-type tumors who received cetuximab were the most likely to undergo surgery. Age was a negative predictor of OS. Patients whose chemotherapy dose was reduced to below 80% had lower OS compared to those remaining above 80%. Treatment delays in chemotherapy did not affect OS. Pulmonary embolism and infections were common but did not have an impact on OS.

Conclusions

A hospital-based electronic informatics center provides comparable OS results, even though adverse events were frequently observed in the present study.

     

Health-related quality of life outcomes in adolescent Scheuermann’s kyphosis patients treated with posterior spinal fusion: A comparison with age- and sex-matched controls

Purpose:To assess the health-related quality of life and radiographic outcomes of surgically treated adolescent Scheuermann’s kyphosis patients after minimum of 2-year follow-up and to compare the health-related quality of life with age- and sex-matched healthy controls.Methods:Twenty-two consecutive adolescents (mean age = 16.7 years) undergoing posterior spinal fusion for Scheuermann’s kyphosis were included and matched by age and sex with two healthy controls. The health-related quality of life was evaluated using the Scoliosis Research Society-24 questionnaire. Radiographic parameters were measured for comparison preoperatively and at 6 months and 2-year follow-ups. The health-related quality of life parameters were compared with healthy controls at 2 years of follow-up.Results:The mean maximal thoracic kyphosis improved from 79° (range = 75°–90°) to 55° (range = 45°–75°) (p < 0.001), and the mean lumbar lordosis was reduced from 71° (range = 51°–107°) to 52° (range = 34°–68°) (p < 0.001) after 2 years postoperatively. Incidence of proximal junctional kyphosis (PJK) was 18%. The scores of the Scoliosis Research Society-24 improved, with statistical significance observed in pain and self-image domains from preoperative to 2-year follow-up (p = 0.002 in both domains). The self-image and function were significantly lower in the operated patients at their 2-year follow-up visit compared to controls (p = 0.023 for self-image and p < 0.001 for function).Conclusion:Instrumented posterior spinal fusion improves the health-related quality of life of Scheuermann’s kyphosis patients during the 2-year follow-up. The greatest improvement is observed in pain and self-image domains. The health-related quality of life in pain and activity domains reaches the level of healthy individuals, while function and self-image remain at a statistically lower level.     

The effect of TLS point cloud sampling on tree detection and diameter measurement accuracy

Terrestrial laser scanning (TLS) is a vital technique for collecting data with millimetre-level detail from the surrounding forest or individual trees. The downside of the technique is the vast amount of data it can collect, which requires efficient data processing methods. An increasing number of manual and automatic methods have been developed in recent years and most of them use point cloud sampling to fasten the processing. The challenge in the sampling procedures is the point density of TLS, which decreases rapidly as a function of distance from the scanner location. Therefore, traditional sampling procedures are not suitable for processing TLS point clouds. The present study focuses on evaluating two sampling procedures (presented in Puttonen et al. 2013) that aim to reduce the point density without losing the characteristics of the full point cloud. The study goal was to assess the effect of these two sampling procedures in tree detection and diameter at breast height (1.3 m, DBH) measurement accuracies in two sample cases. The results demonstrated that the point cloud sampling could be effectively used without losing accuracy in tree detection. However, for measurement of single-tree attributes, the use of full point cloud is recommended. Further evaluation of the methods is required with more diverse data set and due to the manual processing applied here. The automatic approach is mandatory if the approach is to be considered for more operational use.     

The effect of relative humidity on CaCl2 nanoparticles studied by soft X-ray absorption spectroscopy

Ca- and Cl-containing nanoparticles are common in atmosphere, originating for example from desert dust and sea water. The properties and effects on atmospheric processes of these aerosol particles depend on the relative humidity (RH) as they are often both hygroscopic and deliquescent. We present here a study of surface structure of free-flying CaCl₂ nanoparticles (CaCl₂-NPs) in the 100 nm size regime prepared at different humidity levels (RH: 11–85%). We also created mixed nanoparticles by aerosolizing a solution of CaCl₂ and phenylalanine (Phe), which is a hydrophobic amino acid present in atmosphere. Information of hydration state of CaCl₂-NPs and production of mixed CaCl₂ + Phe nanoparticles was obtained using soft X-ray absorption spectroscopy (XAS) at Ca 2p, Cl 2p, C 1s, and O 1s edges. We also report Ca 2p and Cl 2p X-ray absorption spectra of an aqueous CaCl₂ solution. The O 1s X-ray absorption spectra measured from hydrated CaCl₂-NPs resemble liquid-like water spectrum, which is heavily influenced by the presence of ions. Core level spectra of Ca²⁺ and Cl⁻ ions do not show a clear dependence of % RH, indicating that the first coordination shell remains similar in all measured hydrated CaCl₂-NPs, but they differ from aqueous solution and solid CaCl₂.

Hydration state and surface composition of free-flying nanoparticles originating from aerosolized solutions of CaCl₂ and CaCl₂ and Phenylalanine are probed using X-ray absorption spectroscopy.     

The characterization of fluidization behavior using a novel multichamber microscale fluid bed

In the preformulation stage, there is a special need to determine the process behavior of materials with smaller amounts of samples. The purpose of this study was to assemble a novel automated multichamber microscale fluid bed module with a process air control unit for the characterization of fluidization behavior in variable conditions. The results were evaluated on the basis of two common computational methods, the minimum fluidization velocity, and the Geldart classification. The materials studied were different particle sizes of glass beads, microcrystalline cellulose, and silicified microcrystalline cellulose. During processing, the different characteristic fluidization phases (e.g., plugging, bubbling, slugging, and turbulent fluidization) of the materials were observed by the pressure difference over the bed. When the moisture content of the process air was increased, the amount of free charge carriers increased and the fine glass beads fluidized on the limited range of velocity. The silicification was demonstrated to improve the fluidization behavior with two different particle sizes of cellulose powders. Due to the interparticle (e.g., electrostatic) forces of the fine solids, the utilization of the computational predictions was restricted. The presented setup is a novel approach for studying process behavior with only a few grams of materials.