Real-world treatment patterns and outcomes in refractory metastatic colorectal cancer.

AIM: To investigate treatment patterns and outcomes of metastatic colorectal cancer (mCRC) patients beyond second progression (PD2) since regorafenib and TAS-102 became available in Hong Kong. METHODS: The clinical records of consecutive mCRC patients who were treated beyond PD2 at Department of Clinical Oncology, Queen Mary Hospital between June 2013 and February 2018, were retrospectively reviewed. RESULTS: Of 176 PD2 patients (76.7% Eastern Cooperative Oncology Group performance status 0/1 and a median follow-up time of 6.6 [range, 0.4-37.2] months), 104 (59%) underwent palliative care only and 72 (41%) received active third-line (3L) treatment: regorafenib (n = 22), TAS-102 (n = 6), chemotherapy + antiepidermal growth factor receptor (n = 12), chemotherapy + antivascular endothelial growth factor (n = 28) or clinical trials (n = 4). Patients on active 3L treatment had significantly longer OS than those on palliative care only: 11.7 versus 5.5 months (adjusted hazard ratio = 0.41, 95% confidence interval: 0.28-0.61, P < 0.001). For those on active treatment, OS was significantly associated with the time from diagnosis of metastasis to PD2 (P < 0.001) and post-3L treatments (P = 0.009). When analyzing treatment eligibility according to trial criteria, half of the eligible patients (54/109) did not receive active treatment, but both eligible and ineligible patients achieved better OS when receiving active 3L treatment versus palliative care only (P < 0.001 and P = 0.002). No unexpected toxicity was reported. CONCLUSION: Active 3L and beyond treatment significantly prolonged OS versus palliative care, even in selected "trial ineligible" patients. Given a high rate of palliation only care in eligible patients, improved patient access to medicine and counseling may be needed to maximize outcomes.

The real-world use of regorafenib for metastatic colorectal cancer: multicentre analysis of treatment pattern and outcomes in Hong Kong.

PURPOSE OF THE STUDY: To evaluate the benefits and tolerability of regorafenib in the real-world setting, we performed a multicentre analysis in Hong Kong. STUDY DESIGN: Individual patient data were retrieved from three leading oncology centres in Hong Kong for analyses. All patients with metastatic colorectal cancer (mCRC) treated with regorafenib after failure of all standard systemic options were included. RESULTS: From July 2013 to December 2015, 45 consecutive patients treated with regorafenib for mCRC were analysed. The median age was 63. Twenty patients were started at 160 mg, while the other 25 patients were started at a lower dose. The median progression-free survival was 15.6 weeks (95% CI 13.1 to 18.1 weeks) and the median overall survival was 30.4 weeks (95% CI 16.6 to 44.3 weeks). Among the 31 evaluable patients, only 1 patient (3.2%) achieved partial response and another 10 patients (32.3%) had stable disease. The commonest grade 3 non-haematological adverse event (AE) was hand-foot skin reaction (26.7%) and the commonest grade 3 or 4 haematological AE was anaemia (8.9%). Notably, patients who were started on a lower dose of regorafenib had significantly lower risk of grade 3 treatment-emergent AEs. Overall, 78.3% of the patients had dose reduction during the first and second cycles. Patients older than 65 years were more likely to experience cycle suspension and require dose reduction. CONCLUSIONS: Our study confirmed the efficacy and tolerability of regorafenib in the real-world setting. It also suggested that individualised dosing of regorafenib in patients with mCRC might result in better clinical outcomes.

Effects of 18-month low-magnitude high-frequency vibration on fall rate and fracture risks in 710 community elderly--a cluster-randomized controlled trial.

UNLABELLED: This study is a prospective cluster-randomized controlled clinical trial involving 710 elderly subjects to investigate the long-term effects of low-magnitude high-frequency vibration (LMHFV) on fall and fracture rates, muscle performance, and bone quality. The results confirmed that LMHFV is effective in reducing fall incidence and enhancing muscle performance in the elderly. INTRODUCTION: Falls are direct causes of fragility fracture in the elderly. LMHFV has been shown to improve muscle function and bone quality. This study is to investigate the efficacy of LMHFV in preventing fall and fractures among the elderly in the community. METHODS: A cluster-randomized controlled trial was conducted with 710 postmenopausal females over 60 years. A total of 364 participants received daily 20 min LMHFV (35 Hz, 0.3 g), 5 days/week for 18 months; 346 participants served as control. Fall or fracture rate was taken as the primary outcome. Also, quadriceps muscle strength, balancing abilities, bone mineral density (BMD), and quality of life (QoL) assessments were done at 0, 9, and 18 months. RESULTS: With an average of 66.0% compliance in the vibration group, 18.6% of 334 vibration group subjects reported fall or fracture incidences compared with 28.7% of 327 in the control (adjusted HR = 0.56, p = 0.001). The fracture rate of vibration and control groups were 1.1 and 2.3 % respectively (p = 0.171). Significant improvements were found in reaction time, movement velocity, and maximum excursion of balancing ability assessment, and also the quadriceps muscle strength (p < 0.001). No significant differences were found in the overall change of BMD. Minimal adverse effects were documented. CONCLUSION: LMHFV is effective in fall prevention with improved muscle strength and balancing ability in the elderly. We recommend its use in the community as an effective fall prevention program and to decrease related injuries.

Microfluidic fabrication of 6-methoxyethylamino numonafide-eluting magnetic microspheres.

Recently, 6-methoxyethylamino numonafide (MEAN) exhibited potent inhibition of hepatocellular carcinoma (HCC) cell growth and less systemic toxicity than amonafide. MEAN may serve as an ideal candidate for the treatment of HCC; however, liver-directed, selective infusion methods may be critical to maximize the MEAN dose delivered to the targeted tumors. This study describes the microfluidic fabrication of MEAN-eluting ultrasmall superparamagnetic iron oxide (USPIO) nanocluster-containing alginate microspheres (MEAN-magnetic microspheres) intended for selective transcatheter delivery to HCC. The resulting drug delivery platform was mono-disperse, microsphere sizes were readily controlled based on channel flow rates during synthesis procedures, and drug release rates from the microspheres could be readily controlled with the introduction of USPIO nanoclusters. The MR relaxivity properties of the microspheres suggest the feasibility of in vivo imaging after administration, and these microspheres exhibited potent therapeutic effects significantly inhibiting cell growth inducing apoptosis in hepatoma cells.

Photochemically crosslinked collagen annulus plug: a potential solution solving the leakage problem of cell-based therapies for disc degeneration.

Intra-disc injection of mesenchymal stem cells (MSCs) to treat disc degeneration may lead to unfavorable complications, particularly osteophyte formation. Development of an effective method to block the injection portal, prevent the leakage of injected cells and materials and, hence, prevent osteophyte formation is of the utmost importance before MSC-based therapies can be applied in a clinical setting. Here we seek to alleviate the cell leakage problem and the associated complication osteophyte formation by developing an injectable annulus plug to block the injection portal during intra-disc delivery. Specifically, we fabricated a needle-shaped collagen plug by photochemical crosslinking and successfully delivered it intra-discally, in association with MSCs in collagen microsphere carriers, using a custom-made delivery device. The mechanical performance of the plug and its effectiveness in reducing cell leakage were evaluated ex vivo under compression and in torsion push-out tests. The results demonstrate that the plug survived physiologically relevant loadings and significantly reduced leakage and enhanced retention of the injected materials. Finally, a pilot in vivo study in rabbits was conducted to evaluate the performance of the plug. Microcomputed tomography imaging and histology revealed that the plug significantly reduced osteophyte formation. This work suggests the potential of the annulus plug as an adjunct or annulus closure device for intra-disc delivery of cells and materials.

Rethinking hospital general ward ventilation design using computational fluid dynamics.

Indoor ventilation with good air quality control minimises the spread of airborne respiratory and other infections in hospitals. This article considers the role of ventilation in preventing and controlling infection in hospital general wards and identifies a simple and cost-effective ventilation design capable of reducing the chances of cross-infection. Computational fluid dynamic (CFD) analysis is used to simulate and compare the removal of microbes using a number of different ventilation systems. Instead of the conventional corridor air return arrangement used in most general wards, air return is rearranged so that ventilation is controlled from inside the ward cubicle. In addition to boosting the air ventilation rate, the CFD results reveal that ventilation performance and the removal of microbes can be significantly improved. These improvements are capable of matching the standards maintained in a properly constructed isolation room, though at much lower cost. It is recommended that the newly identified ventilation parameters be widely adopted in the design of new hospital general wards to minimise cross-infection. The proposed ventilation system can also be retrofitted in existing hospital general wards with far less disruption and cost than a full-scale refurbishment.

Nano-silver-modified PQC/DNA biosensor for detecting E. coli in environmental water.

To meet the requirement of World Health Organization for zero tolerance of E. coli cell in 100mL drinking water, a new procedure based on photodeposition of nano-Ag at TiO(2)-coated piezoelectric quartz crystal (PQC) electrode was developed to fabricate a highly sensitive PQC/DNA biosensor. Enhancement of 3.3 times for binding of complementary DNA has been shown and attributed to the following effects arising from the nano-Ag coating. First, a large increase in the active surface area and packing density of neutravidin enhances the maximum neutravidin load to 1.8 times of a normal electrode. Second, the functional activity of neutravidin is enhanced by chemical interaction with nano-Ag to give rise to an increase in the binding ratio between neutravidin and biotinylated DNA probe from 1.00:1.76 to 1.00:3.01. Third, the stronger binding leads to a higher stability of the biotinylated DNA probes bound and increase in hybridization with the complementary DNA. Under the optimized conditions for flow analysis with online PCR product denaturing and hybridization, a detection limit of eight E. coli cells are obtained which require sampling at least 800mL water to detect a single E. coli cell in 100mL water.

HMG CoA reductase-inhibitor-related myopathy and the influence of drug interactions.

We report four cases of rhabdomyolysis and severe, disabling myopathy associated with HMG CoA reductase-inhibitor therapy. Patient developed symptoms following the addition of roxithromycin to combination lipid-lowering therapy with simvastatin and gemfibrozil. Patients 2 and 3 became symptomatic after developing acute on chronic renal impairment while taking simvastatin. The muscle biopsy of patient 3 revealed a necrotizing myopathy and the presence of inclusion bodies. Patient 4 developed symptoms within 4 weeks of starting cerivastatin monotherapy. The four cases illustrate the importance of considering the potential for drug interactions and making appropriate dosage adjustments for renal insufficiency in patients receiving HMG CoA reductase therapy.

Delivery of medication by iontophoresis to treat post-burn hypertrophic scars: investigation of a new electronic technique.

At present, direct current (DC) and pulsed direct current (PDC) methods are used for iontophoresis. Although the DC field has high efficiency, it exhibits some side-effects. The PDC field has little side-effects, but the efficiency is lower. In this study, a new iontophoretic drug device was designed for providing the maximal efficiency with the minimal side-effects. Tests of animal and human models showed that the permeation rate of the new field was higher than that of PDC and DC fields, and side-effects were lower than that of the DC field.

On-line respiratory artefact removal via adaptive FIR filters in rheopneumographic measurement.

Impedance rheopneumography is a simple non-invasive technique that can reflect the vascular condition in the human pulmonary circulatory system. However, the much larger and almost in-banding respiratory artefact present has greatly restricted its usefulness to only respiratory patients of a less severe type, in view of the existing practice of requiring the subject to stop breathing momentarily during measurement. Conventional fixed or adaptive filtering cannot satisfactorily remove the artefact in view of the non-time stationary characteristic of the latter. In the paper, a fast adaptive FIR filter design method, which is based on the filter coefficient look-up table (CLT) concept, is presented as a solution. The CLT is constructed with the coefficients indexed to the cut-off frequency to separate the two components of the plethysmogram. An on-line fast Fourier transform is calculated to track the cut-off frequency. This filter can adaptively change its coefficients, not only for different subjects, but also for the same subject during long-term monitoring. Results show that this filter design is capable of providing an almost respiratory artefact-free signal for a majority of patients. The high speed of implementation also renders it a possibility for real-time monitoring applications.

Circuit model-based analysis of the impedance rheopneumogram.

Impedance rheopneumography, like other applications of electrical bio-impedance, is receiving increasing attention as a simple, non-invasive tool for clinical diagnosis of the pulmonary circulation. However, one major drawback of this method lies in the difficulty in computing accurately the time domain parameters therefrom for diagnostic purposes. This paper presents a model-oriented analysis technique based on physiological consideration of both the arterial and venous pathways of the pulmonary circulatory system. The technique involves a combination of a two-segment model and a modified form of the 'Windkessel' model, the summed response of which is curve-fitted to measurement data via the non-linear method of Marquardt to obtain the system parameters. A simple illustrative application is also given to explain the changes in wave morphology for a subject under measurement in the supine and sit-up positions. The result suggests that this technique shows promise of providing useful physiological information and better insight of system behaviour than existing technique.

Post-traumatic stress disorder: an overview.

An overview of post-traumatic stress disorder, including a brief historical survey, and its epidemiology, nosology, etiology, clinical presentation, treatment, prognosis as well as a short vignette, highlights the fact that this disorder prevails in times of war and peace. Early intervention is emphasized as the key to successful treatment. The timeliness for Canadian mental health professionals to review this disorder is also mentioned.

Real-time drift suppressor for ECG.

By introducing poles close to the zeros of the transfer function (1 - Z-N), a drift filter is formed which involves only simple addition and shifting operations and is therefore capable of real-time application with moderate speed microprocessors. A normal ECG with moderate baseline fluctuations showed satisfactory drift suppression with minimal observable T-wave distortion.

Real time microprocessor-based 50 Hz notch filter for ECG.

High performance analogue notch filters are difficult to realize in practice. Their real time digital counterparts, when implemented on an inexpensive microprocessor with no additional hardware, also have limitations of their own. To overcome these limitations, we have developed a new type of 50 Hz notch filter with its poles close to the zero of the transfer function 1 + Z-N. This new type of digital notch filter can be used for suppression of 50 Hz noise in the ECG. The filter is simple to design and easy to implement on most 8-bit microprocessors. It has a high execution speed, low analogue to digital noise, low recursive noise and good frequency response with no overshoot or ringing. It is capable of suppressing 50 Hz noise by at least 40 db. Its finite bandwidth of 4 Hz causes about 2% attenuation on the QRS peak, which is acceptable for almost all practical applications. One possible drawback is that multiple notches occur at higher frequencies. However, this has hardly any effect on the ECG because of the limited notch bandwidth.

Potentiation of radiotherapy by cis-dichlorodiammine platinum (II) in advanced cervical carcinoma.

Forty-five patients with Stages II and III cervical carcinoma were randomized to receive either radiation or cis-dichlorodiammine platinum (II) (cis-DPP) with radiation. Cis-DPP was administered in bolus injections of 25 mg/m2 at weekly intervals until completion of radium application. Complete response was noted in 11/20 (55%) patients in the radiochemotherapy group compared to 5/25 (20%) patients in the radiation group (P less than 0.025). No enhanced toxicities were observed with the addition of cis-DPP to radiation. The combined use of cis-DPP and radiotherapy offers promising potential in improving local-regional control of advanced cervical carcinoma.

Physical locus of the DNA polymerase gene and genetic maps of bacteriophage T5 mutants.

Segments of DNA that contained the DNA polymerase gene of bacteriophage T5 were isolated. The physical locus of the gene was identified by transforming Escherichia coli with purified DNA fragments generated by restriction enzyme digestions, and the transformed cells were used to rescue amber mutants of T5 with mutations in the gene for DNA polymerase. The method is applicable to any other gene that has mutations with low reversion frequencies. We studied the following mutations of the T5 DNA polymerase gene, reading from left to right by the standard convention (D. J. McCorquodale, Crit. Rev. Microbiol. 4:101-159, 1975): D7, D8, aml, ts5E-ts53, am6, and D9. These loci were found to reside within three pieces of DNA with a total length of 3,600 base pairs. Because the structural gene for T5 DNA polymerase is estimated to be 2,600 base pairs long, the whole structural gene may reside in these segments. These are located 58.3 to 61.3% of the distance from the left end of the DNA. The left-end piece of the DNA (1,100 base pairs) containing the polymerase gene has loci D7 and D8, and the right-end piece (1,600 base pairs) has locus D9, according to the results of the transformation assay. These results are consistent with the genetic map.

Concurrent radiochemotherapy in the treatment of gynaecologic neoplasms.

Chemotherapy with adriamycin and/or cisplatinum in standard dosages concurrent with full radiation produced an accelerated local-regional tumour control leading to complete response in 12 of 14 patients who had advanced primary or recurrent gynaecologic neoplasms. The continuation of chemotherapy thereafter did not however prevent the development nor arrest progression of metastases outside the irradiated field. Epidermitis and myelosupression were the enhanced side effects but were tolerable and manageable. Radiochemotherapy can be applicable in situations where rapid shrinkage of the tumour bulk is required. Its other useful potentials deserve further evaluation.