First-time-in-human randomized clinical trial in healthy volunteers and haemodialysis patients with SNF472, a novel inhibitor of vascular calcification.

AIMS: SNF472 is a calcification inhibitor being developed for the treatment of cardiovascular calcification in haemodialysis (HD) and in calciphylaxis patients. This study investigated the safety, tolerability and pharmacokinetics (PK) of intravenous (IV) SNF472 in healthy volunteers (HV) and HD patients. METHODS: This is a first-time-in-human, double-blind, randomized, placebo-controlled Phase I study to assess the safety, tolerability and PK of SNF472 after ascending single IV doses in HV and a single IV dose in HD patients. A pharmacodynamic analysis was performed to assess the capability of IV SNF472 to inhibit hydroxyapatite formation. RESULTS: Twenty HV and eight HD patients were enrolled. The starting dose in HV was 0.5 mg kg-1 and the dose ascended to 12.5 mg kg-1 . The dose selected for HD patients was 9 mg kg-1 . Safety analyses support the safety and tolerability of IV SNF472 in HD patients and HV. Most treatment-emergent adverse events were mild in intensity. No clinically significant effects were observed on vital signs or laboratory tests. PK results were similar in HD patients and HV and indicate a lack of significant dialysability. Pharmacodynamic analyses demonstrated that SNF472 administration reduced hydroxyapatite crystallization potential in HD patients who received IV SNF472 9 mg kg-1 by 80.0 ± 2.4% (mean ± standard error of the mean, 95% CI, 75.3-84.8) compared to placebo (8.7 ± 21.0%, P < 0.001, 95% CI, -32.4 to 49.7). CONCLUSION: The results from this study showed acceptable safety and tolerability, and lack of significant dialysability of IV SNF472. It is a potential novel treatment for cardiovascular calcification in end-stage renal disease and calciphylaxis warranting further human studies.

Clinical outcomes with pemetrexed-based systemic therapies in RET-rearranged lung cancers.

BACKGROUND: RET rearrangements are targetable, oncogenic lung cancer drivers. While previous series have shown durable clinical benefit with pemetrexed-based therapies in ALK- and ROS1-rearranged lung cancers, the benefits of pemetrexed-based treatments in patients with RET-rearranged lung cancers relative to other genomic subsets have not previously been explored. PATIENTS AND METHODS: A retrospective review of patients with pathologically confirmed stage IIIB/IV lung adenocarcinomas and evidence of a RET, ROS1, or ALK rearrangement, or a KRAS mutation was conducted. Patients were eligible if they received treatment with pemetrexed alone or in combination. The primary outcome of progression-free survival (PFS), and secondary outcomes of overall response rate (ORR, RECIST v1.1), time to progression (TTP), and time to treatment discontinuation were compared between RET-rearranged and groups of ROS1-rearranged, ALK-rearranged, and KRAS-mutant lung cancers. RESULTS: We evaluated 104 patients. Patients with RET-rearranged lung cancers (n = 18) had a median PFS of 19 months [95% confidence interval (CI) 12-not reached (NR)] that was comparable with patients with ROS1- (23 months, 95% CI 14-NR, n = 10) and ALK-rearranged (19 months, 95% CI 15-36, n = 36) lung cancers, and significantly improved compared with patients with KRAS-mutant lung cancers (6 months, 95% CI 5-9, P < 0.001, n = 40). ORR (45%), median TTP (20 months, 95% CI 17-NR), and median time to treatment discontinuation (21 months, 95% CI 6-NR) in patients with RET-rearranged lung cancers were not significantly different compared with patients with ALK- and ROS1-rearranged lung cancers, and improved compared with patients with KRAS-mutant lung cancers. CONCLUSION: Durable benefits with pemetrexed-based therapies in RET-rearranged lung cancers are comparable with ALK- and ROS1-rearranged lung cancers. When selecting therapies for patients with RET-rearranged lung cancers, pemetrexed-containing regimens should be considered.

Rovibrational hybrid fs/ps CARS using a volume Bragg grating for N2 thermometry.

Coherent anti-Stokes Raman scattering (CARS) spectra of N2 in the hybrid femtosecond/picosecond regime have been recorded with 0.7 cm(-1) resolution. The Q-branch rovibrational structure has been resolved, making it suitable for gas-phase simultaneous rotational and vibrational thermometry applications. Resolving this spectral structure requires synchronization of a narrowband picosecond probe pulse with a broadband femtosecond pair of pump and Stokes pulses. It is achieved using a single femtosecond ytterbium-laser source and a volume Bragg grating in a compact experimental arrangement.

Small bowel metastasis from embryonal rhabdomyosarcoma of the extremity- a case report.

Rhabdomyosarcoma is the most common soft tissue tumour in children and adolescents, but extremely rare in adults with comparatively worse outcomes. Metastatic disease is not uncommon, but intra-abdominal metastases are exceedingly rare. We report an unusual case of ileal metastases from an upper extremity rhabdomyosarcoma in a 17-year-old male who presented with abdominal pain during a routine follow-up visit. Laparotomy and ileocecectomy for a perforated ileal mass confirmed metastatic embryonal rhabdomyosarcoma with 1 out of 14 positive lymph node metastases. This case demonstrates that, although rare, intra-abdominal metastases should be considered when patients with a rhabdomyosarcoma present with abdominal complaints.

Small bowel metastasis from embryonal rhabdomyosarcoma of the extremity- a case report.

Rhabdomyosarcoma is the most common soft tissue tumour in children and adolescents, but extremely rare in adults with comparatively worse outcomes. Metastatic disease is not uncommon, but intra-abdominal metastases are exceedingly rare. We report an unusual case of ileal metastases from an upper extremity rhabdomyosarcoma in a 17-year-old male who presented with abdominal pain during a routine follow-up visit. Laparotomy and ileocecectomy for a perforated ileal mass confirmed metastatic embryonal rhabdomyosarcoma with 1 out of 14 positive lymph node metastases. This case demonstrates that, although rare, intra-abdominal metastases should be considered when patients with a rhabdomyosarcoma present with abdominal complaints.

Expression and regulation of CCL15 by human airway smooth muscle cells.

BACKGROUND: Structural cells are an important reservoir of chemokines that coordinate the influx of various immune cells to the lungs of asthmatics. Airway smooth muscle cells (ASMC) are an important source of these chemokines. CCL15 is a recently described chemo-attractant for neutrophils, eosinophils, monocytes and lymphocytes. OBJECTIVE: To determine the production and the regulation of CCL15 by ASMC and to investigate its production in asthmatic airways. METHODS: Human ASMC were obtained from main bronchial airway segments of patients with mild, moderate and severe asthma. To induce chemokine production, cells were incubated with IL-4, IL-13, TNF-α or IFN-γ in presence or absence of dexamethasone, mithramycin A (SP-1 inhibitor) or the IKK-2 inhibitor, AS602868. CCL15 mRNA expression was evaluated by real-time PCR. Immunoreactive CCL15 was detected by immuno-fluorescence and CCL15 protein concentration in the supernatant was measured using ELISA. RESULTS: CCL15 is constitutively expressed in human ASMC and is strongly up-regulated by TNF-α. This up-regulation is inhibited by dexamethasone, mithramycin A and AS602868. TNF-α-induced CCL15 levels can be synergistically enhanced by the presence of IFN-γ, at both the transcriptional and translation level. This synergism is NF-κB-dependent. Asthmatic biopsies demonstrated higher expression of CCL15 compared with non-asthmatic controls. CONCLUSION AND CLINICAL RELEVANCE: Our results show that ASMC are a potent source of CCL15 in the airways and may directly participate in the recruitment of inflammatory cells to asthmatic airways. Targeting the production of CCL15 by ASMC might reduce the inflammatory response within the airways of asthmatic patients.

Host status of commercial mango cultivars to Thaumatotibia leucotreta (Lepidoptera: Tortricidae) in South Africa.

The objective of this study was to determine the host status of commercially cultivated mango fruit, Mangifera indica L. (Anacardiaceae) to Thaumatotibia leucotreta (Meyrick) (Lepidoptera: Tortricidae) in South Africa. T. leucotreta was monitored with parapheromone traps in mango orchards in Limpopo and Mpumalanga from 2007 to 2010. Fruit were inspected for the presence of T leucotreta eggs in mango orchards. Mango fruit of the cultivars 'Tommy Atkins', 'Kent', 'Keitt', and 'Sensation' were artificially infested with T. leucotreta eggs on the tree to determine if the larvae were able to develop in fruit. Mature fruit of these cultivars were harvested and were then exposed to T leucotreta eggs and the larval development monitored. Before harvest, fruit were inspected for natural infestations and a packhouse survey was conducted during the 2009-2010 season to determine if any infested fruit were present. T. leucotreta was present in all mango orchards where monitoring was done with traps but no eggs were found on the fruit, which suggests the presence of antixenosis. Development occurred in mature harvested fruit of all cultivars that had been exposed to T. leucotreta eggs. Depending on the cultivar, between 0 and 5.05% of immature fruit on the tree supported development and demonstrate antibiosis. No naturally infested fruit were found in the orchards or during the packhouse survey. Mango in South Africa is not a natural host for T. leucotreta. Mature mango fruit is an acceptable host for T. leucotreta larval development under artificial conditions. The latex plays an important role in the resistance mechanism of mango fruit to T. leucotreta.

Developing a systems approach for Thaumatotibia leucotreta (Lepidoptera: Tortricidae) on 'Hass' avocado in South Africa.

Thaumatotibia leucotreta (Meyrick) (Lepidoptera: Tortricidae) is pest of the avocado, Persea americana (Mill.) (Lauraceae), in South Africa and is regarded as a phytosanitary threat. The objective of this study was to develop a systems approach for T. leucotreta on 'Hass' avocado that will mitigate the pest risk. T. leucotreta males were monitored with pheromone traps, and numbers declined during the winter. Field studies indicated that most of eggs were laid during January in the Deerpark area, and during harvest, only 0.029 lesions produced live larvae. Survival of larvae in fruit infested on the tree and left to develop after harvest varied and depended on the time of infestation before harvest. Fruit firmness was measured and fifth instars were only present in soft fruit. Fenpropathrin and a granulovirus were effective in reducing the infestation levels. Bags used to cover fruit also reduced infestation levels. Lesions caused by T. leucotreta were visible from two weeks after infestation and fruit with lesions can be sorted. The mean infestation rate per orchard was 0.003 lesions per fruit which makes T. leucotreta on Hass amenable to the alternative treatment efficacy approach and maximum pest limit. In the case of T. leucotreta on Hass, poor host status, production, preharvest and postharvest measures were studied and low infestation levels were observed; all these elements would make a systems approach an option. Furthermore, inspection and certification as well as shipping and distribution measures could be added.

Multi-frequency detection of a dielectric object using flexible contactless RF sensors for tissue diagnosis.

The aim of this paper is to experimentally assess the capacity of radio-frequency flexible sensors to localize a dielectric object inside a fluid, which could be used as a non contact sensor detected to the detection or the monitoring a local modification of a tissue, such as a tumor or a lesion. The used sensor is an MRI-like antenna, which consists in a flat, flexible and low cost multi-turn split resonator (MTLR), which features a geometrically pre-determined resonance frequency. The MTLR is used here as a transmit and receive sensor monitored by a distant loop coil. The complex impedance changes observed at the ends of the monitoring coil is known to be linked to the dielectric properties of the resonator environment. If a dielectric object is placed close to the resonator, the complex impedance is altered. In this work, an experimental set up is used to assess the relevance of such a measurement scheme to detect the presence of a dielectric inclusion embedded in another dielectric medium. The setup includes a spherical object of 1.5 cm diameter filled with various NaCl solutions moved vertically inside a tank filled with deionized water by means of a three axis robotic arm, to create an electrical conductivity contrast between the inclusion and the media, and three 2 cm diameter MTLR sensors featuring 30, 47 and 70 MHz resonance frequencies, respectively. The sensors are operated through the use of monitoring coils connected to a network analyzer, and measurements are carried out at each position of the spherical object. The resulting sensor responses are plotted and used for the assessment of sensor performances. In addition, a method to combine the multi-frequency data provided by the three different sensors is proposed. Two different metrics regarding the spatial resolution (SR) and the peak signal to noise ratio (PSNR) are computed to characterize the single sensor performances, as well as the enhancement provided by the proposed multi-frequency approach.

Therapeutic landscape of metastatic non-small-cell lung cancer in Canada in 2020.

Lung cancer is the most commonly diagnosed cancer in Canada and remains associated with high mortality. Nevertheless, recent advances in the fields of immuno-oncology and precision medicine have led to significant improvements in clinical outcome in metastatic non-small-cell lung cancer (nsclc). Those improvements were facilitated by a greater understanding of the biologic classification of nsclc, which catalyzed discoveries of novel therapies. Here, we present a comprehensive review of the recent avalanche of practice-changing trials in metastatic nsclc, and we offer an approach to the management of this disease from a Canadian perspective. We begin with an overview of the pathologic and molecular characterization of metastatic nsclc. Next, we review the indications for currently approved immune checkpoint inhibitors, and we provide an approach to the management of disease with a driver mutation. Finally, we address future avenues in both diagnostics and therapeutics for patients with advanced and metastatic nsclc.

Erratum: Therapeutic landscape of metastatic non-small-cell lung cancer in Canada in 2020.

[This corrects the article DOI: 10.3747/co.27.5953.].

Consensus recommendations for optimizing biomarker testing to identify and treat advanced EGFR-mutated non-small-cell lung cancer.

The advent of personalized therapy for non-small-cell lung carcinoma (nsclc) has improved patient outcomes. Selection of appropriate targeted therapy for patients with nsclc now involves testing for multiple biomarkers, including EGFR. EGFR mutation status is required to optimally treat patients with nsclc, and thus timely and accurate biomarker testing is necessary. However, in Canada, there are currently no standardized processes or methods in place to ensure consistent testing implementation. That lack creates challenges in ensuring that all appropriate biomarkers are tested for each patient and that the medical oncologist receives the results for making informed treatment decisions in a timely way. An expert multidisciplinary working group was convened to create consensus recommendations about biomarker testing in advanced nsclc in Canada, with a primary focus on EGFR testing. Recognizing that there are biomarkers beyond EGFR that require timely identification, the expert multidisciplinary working group considered EGFR testing in the broader context of integration into complex lung biomarker testing. Primarily, the panel of experts recommends that all patients with nonsquamous nsclc, regardless of stage, should undergo comprehensive reflex biomarker testing at diagnosis with targeted next-generation sequencing. The panel also considered the EGFR testing algorithm and the challenges associated with the pre-analytic, analytic, and post-analytic elements of testing. Strategies for funding testing by reducing silos of single biomarker testing for EGFR and for optimally implementing the recommendations presented here and educating oncology professionals about them are also discussed.

Femtosecond time resolved coherent anti-Stokes Raman spectroscopy of H(2)-N(2) mixtures in the Dicke regime: Experiments and modeling of velocity effects.

In this paper, we present measurements and modeling of femtosecond time resolved coherent anti-Stokes Raman spectroscopy (CARS) signal in H(2)-N(2) mixtures at low densities. Three approaches have been used to model the CARS response. The first is the usual sum of Voigt profiles. In the second approach, the speed dependent Voigt profile is used. In the last approach, a model of the temporal CARS signal is developed, which takes into account the velocity changes induced by collisions and the speed dependence of the collisional parameters. The velocity changes are modeled using the Keilson and Storer memory function; the radiator speed dependences of the collisional parameters are determined from their temperature dependences. The results obtained are consistent with previous studies in the frequency domain, showing that the changes of the velocity have important effects for the H(2)/N(2) system in the Dicke narrowing density regime.

Imaging of a dielectric inclusion using a contactless radio-frequency inductive probe for tissue diagnosis.

In this paper, a contactless radio-frequency (RF) inductive probe is used to spatially localize and characterize a complex dielectric organic inclusion in a fluid. The effect of dielectric properties (DP) of this organic material is investigated experimentally and by numerical computations.The used RF probe is a 135 MHz 3 cm diameter and 10 cm long, cylindrical bracelet resonator, placed close to a water tank filled with deionized water which includes a 1.5 cm diameter inclusion filled of air or NaCl solutions and placed in arbitrary positions. The water tank and the inclusion are used to model an organic material including a tumor. The RF probe is used as a transmit and receive sensor. It induces a magnetic field inside the water tank, which, by reciprocity, conveys information about the DP of the investigated material. The impedance changes at the end of the RF probe are directly related to the modifications of the magnetic field, and are measured by means of a network analyzer. A complex fit of the impedance frequency response around the resonance frequency gives access to two quantities proportional to the electrical conductivity and dielectric constant of the inclusion. The inclusion is moved into the water tank along the three axes by means of a robotic arm, so that two three dimensional maps of the equivalent dielectric quantities in function of the inclusion position are sensed by the probe. Then, the inclusion is filled with different conductive NaCl solutions from 0.1 to 1.1 S/m in order to test the ability of the probe to sense the modifications of the dielectric properties of the inclusion. Experimental as well as computation results obtained using the Distributed Point Source Method (DPSM) validate the ability of the proposed probe to localize the inclusion as deep as 1 cm into the water, and the ability of the probe to sense the dielectric property changes of the inclusion.

Bronchoalveolar lavage fluid neutrophilia is associated with the severity of pulmonary lesions during equine asthma exacerbations.

BACKGROUND: The severe form of equine asthma is associated with pathological changes of the peripheral airways and pulmonary parenchyma that are only partly described. Also, the relationship between these structural alterations and the percentage of neutrophils found within the airway lumen, assessed by bronchoalveolar lavage fluid (BALF) cytology, remains ill-defined. OBJECTIVE: To examine the histological lesions associated with equine asthma during disease exacerbation and remission, and their relationship with lung function and BALF neutrophilia. STUDY DESIGN: Observational retrospective study. METHODS: Peripheral lung tissues, BALF cytology and lung function data from 61 horses (22 controls, 24 asthma exacerbations and 15 asthma remission) were obtained from an equine pulmonary tissue bank. Two pathologists semi-quantitatively assessed histological features, including airway wall inflammation, interstitial fibrosis, mucus cell hyperplasia, mucostasis, peribronchiolar metaplasia, presence of granuloma and the overall severity of these lesions. RESULTS: Mucostasis, mucus cell hyperplasia, peribronchiolar metaplasia and interstitial fibrosis were associated with disease exacerbation (P≤0.05), and these changes were all attenuated during remission. Airway wall inflammation was greater in horses with asthma in exacerbation compared with horses with asthma in remission and control horses (P≤0.05). Acute (neutrophilic) airway wall inflammation was more frequently detected in asthmatic cases compared with control horses (P<0.0001) and was associated with BALF neutrophilia >5% in control horses (P = 0.002). The degree of bronchiolar inflammation was higher in asthmatic horses in remission stabled and treated pharmacologically compared with those kept on pasture (P = 0.04). MAIN LIMITATIONS: Samples obtained from a convenient cohort of horses were studied. CONCLUSIONS: Severely asthmatic horses present parenchymal and peribronchial/peribronchiolar lesions possibly contributing to the obstructive nature of the disease.

Development of a Semiquantitative Histological Score for the Diagnosis of Heaves Using Endobronchial Biopsy Specimens in Horses.

BACKGROUND: Remodeling of the peripheral airways persists during the asymptomatic phase of heaves. Assessing the histology of large bronchi could facilitate the diagnosis of heaves during remission of the disease. HYPOTHESIS: Airway inflammation and remodeling in endobronchial biopsy (EBB) specimens differentiate horses with heaves from controls, independently of their clinical status (exacerbation or remission). ANIMALS: Fourteen healthy horses and 24 horses with heaves. METHODS: A 14-point scoring system assessing central bronchial wall inflammation and remodeling was developed. The score was validated by 2 pathologists using specimens obtained from 18 horses (6 controls, 6 with heaves exacerbation, and 6 with heaves remission) in which lung function had been assessed with impulse oscillometry. Clinical and research application of the score was evaluated using biopsy specimens obtained from 20 additional horses (8 controls, 6 with heaves exacerbation, and 6 with heaves remission). RESULTS: The score was repeatable (interclass correlation coefficient = 69%). It differentiated horses with heaves in exacerbation (mean ± SD: 6.2 ± 2.2) from those in remission (4.0 ± 1.0) and controls (3.6 ± 1.7, P < 0.0001). The histological scores of horses with heaves correlated with the ratio of respiratory resistance (R) at 5 and 10 Hz (R5 : R10 ratio, r = 0.65, P = 0.03), a parameter assessing airway obstruction. CONCLUSIONS AND CLINICAL SIGNIFICANCE: The proposed histological scoring system correlates with the degree of airway obstruction measured by impulse oscillometry. However, it does not discriminate horses with heaves in remission from controls. Evaluation of EBB specimens might be considered in future research and clinical studies of respiratory diseases in horses.

Patient package inserts. II. Toward a rational patient package insert.

Analysis of the response to a questionnaire on various aspects of drug information showed several significant trends. The importance of the physician as an information source varied directly with age and inversely with educational level of patients. The doctor's importance as a source of information was also greater for those who visited physicians' offices or clinics more and if they were on long-term treatment. Younger persons, those with higher levels of education, and those who were not in regular contact with a physician placed greater importance on non-physician sources. Persons consulting physicians regularly desired less information and knew less about drugs than those who did not regularly see a physician. These findings suggest that the educational role of the physician could be improved and should be directed particularly at the low-income, older patient. In the design of the package insert, particular attention should be given to self-prescribed medications where no other information sources will be operating.

Commentary: Patient package inserts. I. Nature, notions, and needs.

A total of 137 completed questionnaires were obtained from several population samples in an attempt to assess drug knowledge, information sources, and views on drug information with particular attention to the possible role of a patient-oriented package insert. The results indicated that the study population was variably informed and could make fairly accurate assessments by this knowledge. Responders placed great importance on the doctor and pharmacist as preferred and actual drug information sources. The mass media were accorded little prominence. Great emphasis was placed on the adequate provision of information, and this appears to be a crucial function in an adequate doctor-patient relationship. The results appear to indicate a favorable climate for establishing a patient-oriented package insert that should have summarized as well as detailed information to complement the doctor and pharmacist as primary information sources.

Serial serum digoxin concentrations and quantitative electrocardiographic changes.

Four elderly female patients in sinus rhythm and with mild congestive cardiac failure were treated with digoxin and studied over a 6-month period. There were significant linear correlations between serum digoxin concentrations and several quantitative electrocardiographic (ECG) parameters. T-wave amplitude was the most important ECG variable. ECG changes reverted to baseline values when digoxin was discontinued. These findings suggest that quantitative ECG changes are potentially useful in clinical and research situations involving digitalis glycosides.

Commentary. The normal volunteer in clinical investigation: how rigid should selection criteria be?

Twenty-nine healthy young male volunteers were screened by history, physical examination, urinalysis, 24 different blood tests, and electrocardiography for admission to a Phase I drug study. The protocol submitted to, and approved by, the FDA listed the normal ranges for the local laboratories and stipulated that the test results for any volunteers accepted should all be within these ranges. During screening 46 abnormal values were found in the laboratory tests. Only 4 subjects had all their test data within "normal" range, a result that could have been anticipated simply form the number of tests performed. These findings indicate the need for deciding on realistic protocol criteria for studies involving healthy volunteers.