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Colorectal cancers are one of the most prevalent tumour types worldwide and, despite the emergence of targeted and biologic therapies, have among the highest mortality rates. The Personalized OncoGenomics (POG) program at BC Cancer performs whole genome and transcriptome analysis (WGTA) to identify specific alterations in an individual's cancer that may be most effectively targeted. Informed using WGTA, a patient with advanced mismatch repair-deficient colorectal cancer was treated with the antihypertensive drug irbesartan and experienced a profound and durable response. We describe the subsequent relapse of this patient and potential mechanisms of response using WGTA and multiplex immunohistochemistry (m-IHC) profiling of biopsies before and after treatment from the same metastatic site of the L3 spine. We did not observe marked differences in the genomic landscape before and after treatment. Analyses revealed an increase in immune signalling and infiltrating immune cells, particularly CD8+ T cells, in the relapsed tumour. These results indicate that the observed anti-tumour response to irbesartan may have been due to an activated immune response. Determining whether there may be other cancer contexts in which irbesartan may be similarly valuable will require additional studies. [ABSTRACT FROM AUTHOR]

Summary: Background The IND.226 study was a phase Ib study to determine the recommended phase II dose of durvalumab + tremelimumab in combination with standard platinum-doublet chemotherapy. Sequential administration of multiple agents increases total chair time adding costs overall and inconvenience for patients. This cohort of the IND.226 study evaluated the safety and tolerability of durvalumab + tremelimumab given either sequentially (SEQ) or concurrently (CON). Methods Patients with advanced solid tumours were enrolled and randomised to either SEQ tremelimumab 75 mg IV over 1 h followed by durvalumab 1500 mg IV over 1 h q4wks on the same day, or CON administration over 1 h. The serum pharmacokinetic profile of SEQ versus CON of durvalumab and tremelimumab administration was also evaluated. Results 14 patients either received SEQ (n = 7pts) or CON (n = 7 pts). There were no infusion related reactions. Drug related adverse events (AEs) were mainly low grade and manageable, and comparable in frequency between SEQ/CON- fatigue (43%/57%), rash (43%/43%), pruritus (43%/29%) and nausea (14%/29%). One patient in each cohort discontinued treatment due to toxicity. The PK profiles of durvalumab and tremelimumab were similar between CON and SEQ, and to historical reference data. Conclusions Concurrent administration of durvalumab and tremelimumab over 1 h is safe with a comparable PK profile to sequential administration. [ABSTRACT FROM AUTHOR]

Background Little evidence has been generated for how best to manage patients with non-small-cell lung cancer (NSCLC) presenting with rarer clinical scenarios, including oligometastases, oligoprogression, and pseudoprogression. In each of those scenarios, oncologists have to consider how best to balance efficacy with quality of life, while maximizing the duration of each line of therapy and ensuring that patients are still eligible for later options, including clinical trial enrolment. Methods An expert panel was convened to define the clinical questions. Using case-based presentations, consensus practice recommendations for each clinical scenario were generated through focused, evidence-based discussions. Results Treatment strategies and best-practice or consensus recommendations are presented, with areas of consensus and areas of uncertainty identified. Conclusions In each situation, treatment has to be tailored to suit the individual patient, but with the intent of extending and maximizing the use of each line of treatment, while keeping treatment options in reserve for later lines of therapy. Patient participation in clinical trials examining these issues should be encouraged. [ABSTRACT FROM AUTHOR]

Using recently measured accurate relative partial ionization cross section functions for production of the C60 fragment ions C+58 through C+44 by electron impact ionization, we have determined the respective binding energies BE(C+n–C2), with n=58,...,44, using a novel self-consistent procedure. Appearance energies were determined from ionization efficiency curves. Binding energies were calculated from the corresponding appearance energies with the help of the finite heat bath theory. Then using these binding energies we calculated with transition state theory (TST), the corresponding breakdown curves, and compared these calculated ones with the ones derived from the measured cross sections. The good agreement between these breakdown curves proves the consistency of this multistep calculation scheme. As the only free parameter in this procedure is the binding energy C+58–C2, we studied the influence of different transition states chosen in the determination of this binding energy via TST theory and iterative comparison with breakdown curve measurements. Based on this study we can conclude that extremely loose transition states can be confidently excluded, and that somewhat looser transition states than those used earlier result in an upward change of the binding energy of less than 10% yielding an upper limit for the binding energy C+58–C2 of approximately 7.6 eV. © 1996 American Institute of Physics. [ABSTRACT FROM AUTHOR]

Background Gastrointestinal carcinomas are genomically complex cancers that are lethal in the metastatic setting. Whole-genome and transcriptome sequencing allow for the simultaneous characterization of multiple oncogenic pathways. Methods We report 3 cases of metastatic gastrointestinal carcinoma in patients enrolled in the Personalized Onco-Genomics program at the BC Cancer Agency. Real-time genomic profiling was combined with clinical expertise to diagnose a carcinoma of unknown primary, to explore treatment response to bevacizumab in a colorectal cancer, and to characterize an appendiceal adenocarcinoma. Results In the first case, genomic profiling revealed an IDH1 somatic mutation, supporting the diagnosis of cholangiocarcinoma in a malignancy of unknown origin, and further guided therapy by identifying epidermal growth factor receptor amplification. In the second case, a BRAF V600E mutation and wild-type KRAS profile justified the use of targeted therapies to treat a colonic adenocarcinoma. The third case was an appendiceal adenocarcinoma defined by a p53 inactivation; RAS/RAF/MEK, AKT/MTOR, Wnt, and NOTCH pathway activation; and overexpression of RET, ERBB2 (HER2), ERBB3, MET, and cell cycle regulators. Summary We show that whole-genome and transcriptome sequencing can be achieved within clinically effective timelines, yielding clinically useful and actionable information. [ABSTRACT FROM AUTHOR]

Nurse navigation is a developing facet of oncology care. The concept of patient navigation was originally created in 1990 at the Harlem Hospital Center in New York City as a strategy to assist vulnerable and socially disadvantaged populations with timely access to breast cancer care. Since the mid-1990s, navigation programs have expanded to include many patient populations that require specialized management and prompt access to diagnostic and clinical resources. Advanced non-small-cell lung cancer is ideally suited for navigation to facilitate efficient assessment in this fragile patient population and to ensure timely results of molecular tests for first-line therapy with appropriately targeted agents. At the BC Cancer Agency, nurse navigator involvement with thoracic oncology triage has been demonstrated to increase the proportion of patients receiving systemic treatment, to shorten the time to delivery of systemic treatment, and to increase the rate of molecular testing and the number of patients with molecular testing results available at time of initial consultation. Insights gained through the start-up process are briefly discussed, and a framework for implementation at other institutions is outlined. [ABSTRACT FROM AUTHOR]

Background The importance of histologic classification in selecting the appropriate systemic therapy for nonsmall- cell lung cancer (nsclc) came to attention in 2007. In British Columbia, that information was communicated through international and national meetings, our centralized cancer care program, and to the medical community at large in multidisciplinary forums. We examined the effects of those education programs on the categorization of nsclc and associated systemic treatment practices. Methods The BC Cancer Agency provides cancer care to 4.6 million residents of British Columbia. A retrospective review of all stage iiib and iv nsclc patients referred in 2007 and 2011 collected baseline characteristics, treatment, and outcomes. Histology was classified using the International Classification of Diseases for Oncology, 3rd edition, for the Canadian Cancer Registry. Results In 2007, 671 patients were referred, and 170 received chemotherapy; in 2011, the relevant figures were 680 and 197 respectively. Baseline characteristics in the cohorts were not statistically significantly different in 2007 and 2011. Histologic classifications in 2007 were 41% nonsquamous, 13% squamous, and 46% not otherwise specified (nos); in 2011, they were 63%, 17%, and 20% respectively. Exposure to pemetrexed in any line of therapy in 2007 was 22% for nonsquamous, 17% for squamous, and 10% for nos; in 2011, exposure was 39%, 3%, and 37% respectively. Exposure to epidermal growth factor receptor tyrosine kinase inhibitor (egfr tki) in 2007 was 36%, 22%, and 33%; in 2011, it was 64%, 60%, and 63%. Median overall survival duration, 2007 versus 2011, was 3.25 months versus 3.57 months with best supportive care, and 11.31 months versus 11.54 months with chemotherapy. Conclusions The specificity of nsclc histologic categorization improved in 2011 compared with 2007, with a reduction of 26 percentage points in the rate of nos disease. The proportion of patients treated with chemotherapy over time remained the same, but the use of pemetrexed and egfr tki increased. The increased accuracy in histologic classification resulted in more appropriate utilization of systemic drugs. [ABSTRACT FROM AUTHOR]

Background The importance of histologic classification in selecting the appropriate systemic therapy for nonsmall- cell lung cancer (NSCLC) came to attention in 2007. In British Columbia, that information was communicated through international and national meetings, our centralized cancer care program, and to the medical community at large in multidisciplinary forums. We examined the effects of those education programs on the categorization of NSCLC and associated systemic treatment practices. Methods The BC Cancer Agency provides cancer care to 4.6 million residents of British Columbia. A retrospective review of all stage IIIB and IV NSCLC patients referred in 2007 and 2011 collected baseline characteristics, treatment, and outcomes. Histology was classified using the International Classification of Diseases for Oncology, 3rd edition, for the Canadian Cancer Registry. Results In 2007, 671 patients were referred, and 170 received chemotherapy; in 2011, the relevant figures were 680 and 197 respectively. Baseline characteristics in the cohorts were not statistically significantly different in 2007 and 2011. Histologic classifications in 2007 were 41% nonsquamous, 13% squamous, and 46% not otherwise specified (NOS); in 2011, they were 63%, 17%, and 20% respectively. Exposure to pemetrexed in any line of therapy in 2007 was 22% for nonsquamous, 17% for squamous, and 10% for NOS; in 2011, exposure was 39%, 3%, and 37% respectively. Exposure to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) in 2007 was 36%, 22%, and 33%; in 2011, it was 64%, 60%, and 63%. Median overall survival duration, 2007 versus 2011, was 3.25 months versus 3.57 months with best supportive care, and 11.31 months versus 11.54 months with chemotherapy. Conclusions The specificity of NSCLC histologic categorization improved in 2011 compared with 2007, with a reduction of 26 percentage points in the rate of NOS disease. The proportion of patients treated with chemotherapy over time remained the same, but the use of pemetrexed and EGFR TKI increased. The increased accuracy in histologic classification resulted in more appropriate utilization of systemic drugs. [ABSTRACT FROM AUTHOR]

Phenolic compounds, which are emitted in significant amounts from biomass burning, can undergo fast reactions in atmospheric aqueous phases to form secondary organic aerosol (aqSOA). In this study, we investigate the reactions of phenol (compound with formula C6H5OH)), guaiacol (2-methoxyphenol), and syringol (2,6-dimethoxyphenol) with two major aqueous-phase oxidants - the triplet excited states of an aromatic carbonyl (³C*) and hydroxyl radical (·OH).We thoroughly characterize the low-volatility species produced from these reactions and interpret their formation mechanisms using aerosol mass spectrometry (AMS), nanospray desorption electrospray ionization mass spectrometry (nano-DESI MS), and ion chromatography (IC). A large number of oxygenated molecules are identified, including oligomers containing up to six monomer units, functionalized monomer and oligomers with carbonyl, carboxyl, and hydroxyl groups, and small organic acid anions (e.g., formate, acetate, oxalate, and malate). The average atomic oxygen-to-carbon (O = C) ratios of phenolic aqSOA are in the range of 0.85-1.23, similar to those of low-volatility oxygenated organic aerosol (LV-OOA) observed in ambient air. The aqSOA compositions are overall similar for the same precursor, but the reactions mediated by ³C* are faster than ·OH-mediated reactions and produce more oligomers and hydroxylated species at the point when 50% of the phenolic compound has reacted. Profiles determined using a thermodenuder indicate that the volatility of phenolic aqSOA is influenced by both oligomer content and O=C ratio. In addition, the aqSOA shows enhanced light absorption in the UV-visible region, suggesting that aqueous-phase reactions of phenols may contribute to formation of secondary brown carbon in the atmosphere, especially in regions influenced by biomass burning. [ABSTRACT FROM AUTHOR]

Atmospheric absorption by brown carbon aerosol may play an important role in global radiative forcing. Brown carbon arises from both primary and secondary sources, but the mechanisms and reactions of the latter are highly uncertain. One proposed mechanism is the reaction of ammonia or amino acids with carbonyl products in secondary organic aerosol (SOA). We generated SOA in situ by reacting biogenic alkenes (α-pinene, limonene, and α-humulene) with excess ozone, humidifying the resulting aerosol, and reacting the humidified aerosol with gaseous ammonia. We determined the complex refractive indices (RI) in the 360–420 nm range for these aerosols using broadband cavity enhanced spectroscopy (BBCES). The average real part (n) of the measured spectral range of the NH3-aged α-pinene SOA increased from n = 1.50 (±0.01) for the unreacted SOA to n = 1.57 (±0.01) after 1.5 h of exposure to 1.9 ppm NH3, whereas the imaginary component (k) remained below UGRAPHIC DISPLAY="INLINE" ID="UGT1" SRC="UGT1"/. For the limonene and α-humulene SOA the real part did not change significantly, and we observed a small change in the imaginary component of the RI. The imaginary component increased from k = 0.000 to an average k = 0.029 (±0.021) for α-humulene SOA, and from UGRAPHIC DISPLAY="INLINE" ID="UGT2" SRC="UGT2"/ to an average k = 0.032 (±0.019) for limonene SOA after 1.5 h of exposure to 1.3 and 1.9 ppm of NH3, respectively. Collected filter samples of the aged and unreacted α-pinene SOA and limonene SOA were analyzed off-line by nanospray desorption electrospray ionization high resolution mass spectrometry (nano-DESI/HR-MS), and in situ using a Time-of-Flight Aerosol Mass Spectrometer (ToF-AMS), confirming that the SOA reacted and that various nitrogen-containing reaction products formed. If we assume that NH3 aging reactions scale linearly with time and concentration, which will not necessarily be the case in the atmosphere, then a 1.5 h reaction with 1 ppm NH3 in the laboratory is equivalent to 24 h reaction with 63 ppbv NH3, indicating that the observed aerosol absorption will be limited to atmospheric regions with high NH3 concentrations. [ABSTRACT FROM AUTHOR]

The effect of relative humidity (RH) on the composition and concentrations of gas-phase products and secondary organic aerosol (SOA) generated from the photooxidation of isoprene under high-NOx conditions was investigated. Experiments were performed with hydrogen peroxide as the OH precursor and in the absence of seed aerosol. The relative yields of most gas-phase products were the same regardless of initial water vapor concentration with exception of hydroxyacetone and glycolaldehyde, which were considerably affected by RH. A significant change was observed in the SOA composition, with many unique condensed-phase products formed under humid (90% RH) vs. dry (<2% RH) conditions, without any detectable effect on the rate and extent of the SOA mass growth. There is a 40% reduction in the number and relative abundance of distinct particle-phase nitrogen-containing organic compounds (NOC) detected by high resolution mass spectrometry. The suppression of condensation reactions, which produce water as a product, is the most important chemical effect of the increased RH. For example, the total signal from oligomeric esters of 2-methylglyceric acid was reduced by about 60% under humid conditions and the maximum oligomer chain lengths were reduced by 7-11 carbons. Oligomers formed by addition mechanisms, without direct involvement of water, also decreased at elevated RH but to a much smaller extent. The observed reduction in the extent of condensation type oligomerization at high RH may have substantial impact on the phase characteristics and hygroscopicity of the isoprene aerosol. The reduction in the amount of organic nitrates in the particle phase has implications for understanding the budget of NOC compounds. [ABSTRACT FROM AUTHOR]

The effect of relative humidity (RH) on the composition and concentrations of gas-phase products and secondary organic aerosol (SOA) generated from the photooxidation of isoprene under high-NOx conditions was investigated. The yields of most gas-phase products were the same regardless of initial water vapor concentration with exception of hydroxyacetone and glycolaldehyde, which were considerably affected by RH. A significant change was observed in the SOA composition, with many unique condensed-phase products formed under humid (90% RH) vs. dry (<2% RH) conditions, without any observable effect on the rate and extent of the SOA mass growth. There is a 40% reduction in the number and relative abundance of distinct particle-phase organic nitrogen (ON) compounds detected by high resolution mass spectrometry. The suppression of condensation reactions, which produce water as a product, is the most important chemical effect of the increased RH. For example, the total signal from oligomeric esters of 2-methylglyceric acid was reduced by about 60% under humid conditions and the maximum oligomer chain lengths were reduced by 7-11 carbons. Oligomers formed by addition mechanisms, without direct involvement of water, also decreased at elevated RH but to a much smaller extent. The observed substantial reduction in the extent of condensation-type oligomerization at high RH may have substantial impact on the phase characteristics and hygroscopicity of the isoprene aerosol. The reduction in the amount of organic nitrates in the particle phase has implications for understanding the budget of ON compounds. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE: Physical therapists often test ball-playing skills of children with disabilities using standardized testing, which may not predict performance of ball skills in games with peers. This type of testing is used by physical therapists to determine whether children have delays in ball-handling skills. The purpose of this study was to compare ball skill performance of children with and without developmental delay in a one-to-one testing situation and in a structured game with peers. SUBJECTS: Five-year-old children with developmental delay (n=20) and 5-year-old children without disabilities (n=20) participated in the study. METHODS: We used the Peabody Developmental Motor Scales receipt and propulsion scale to test children one-to-one with a therapist and during a structured game with peers. RESULTS: Subjects without developmental delay performed better than subjects with developmental delay under both testing conditions. Children with developmental delay performed better in the one-to-one testing condition than in the game with peers. The performance of children without developmental delay did not differ under the 2 conditions. Boys performed better than girls. CONCLUSION AND DISCUSSION: Physical therapists should consider the potential effect of environment on the ball-handling skills of children with disabilities. [ABSTRACT FROM AUTHOR]

Treatment of peripheral blood mononuclear cells with 8-methoxypsoralen (8-MOP) and ultraviolet light, a procedure known as PUVA, has been found to be useful in the management of systemically disseminated cutaneous T-cell lymphoma (CTCL). In the present study we used a highly sensitive flow cytometric assay in conjunction with the hydroperoxide-sensitive dye 2',7'-dichlorofluorescein diacetate to measure intracellular hydrogen peroxide in normal lymphocytes and CTCL following PUVA treatment. Based on their laser light-scattering properties, lymphocytes were separated into three major subpopulations. We found that ultraviolet light alone caused an increase in the hydrogen peroxide content of each of the subpopulations, a response that was augmented when the cells were pretreated with 8-MOP (50 ng/ml). Cells from CTCL patients were more sensitive to the effects of 8-MOP than were normal lymphocytes. In both cell types, the production of hydrogen peroxide was found to be inhibitable by catalase. We noted an increase in hydrogen peroxide production following photopheresis; however, this was observed only 24 h after treatment. In addition, a further increase in hydrogen peroxide production was observed in lymphocytes isolated from peripheral blood that had been obtained from patients at 15 min after a second photopheresis treatment. Hydrogen peroxide is known to modulate the action of cytokines as well as the immunological responses of leukocytes. Our data suggest that the production of hydrogen peroxide by lymphocytes may be important in the action of PUVA in CTCL. [ABSTRACT FROM AUTHOR]

The combination of psoralens and ultraviolet light (UVA, 320-400 nm), referred to as PUVA, inhibits proliferation of a variety of cell types. In the present studies, we used S-180 cells to investigate the mechanism underlying the antiproliferative actions of PUVA. We found that inhibition of growth of S-180 cells by PUVA was dependent on the concentration of psoralen as well as the dose of UVA light. Neither the psoralens nor UVA light by themselves inhibited cell growth. Several clinically important psoralen analogs inhibited cell growth. The potent phototoxin 4,5',8-trimethylpsoralen was the most active psoralen analog tested, followed by 5-methoxypsoralen and 8-methoxypsoralen. The angular furocoumarin, 5-methylangelicin, was the least active inhibitor of growth. Multivariate (isobologram) analysis of the growth-inhibition curves revealed that combinations of psoralens and UVA light were not simply additive but synergistic. Similar results were observed when inhibition of DNA synthesis was used as an endpoint for the biological effects of PUVA. These studies are the first to demonstrate that psoralens and UVA light act synergistically. Our results suggest that the synergism between the psoralens and UVA light may be an important property of PUVA that contributes to its therapeutic efficacy in proliferative diseases. [ABSTRACT FROM AUTHOR]

Loads at the articulating surface of the head of the condyle were recorded in one male adult Macaca arctoides. Following surgical implantation of the pressure-sensitive foil, the monkey was given hard and soft foods to chew. Loads were recorded during incisal biting and molar chewing. The bite data showed the following: The Condylar head was loaded during molar chewing with a maximum load of 1-3 lb. The condylar head was loaded with a larger load of 3-4 lb during incisal biting. [ABSTRACT FROM AUTHOR]

Background: Walking is the most common population-wide campaign for health promotion in older people. However, the cutoff threshold for walking steps/day to identify the older people who are at risk of falling is not recommended. Therefore, the objectives were to investigate the association between all possible risk factors including physical performance, physical activity and fall incidence over the six-month in community-dwelling older people who had low-risk of falling and to identify walking threshold (steps/day) for reducing risk of fall.Methods: The older people who aged ≥60 years and had free of falling for 1 year were invited to participate in this study. They lived in five communities in Bangkok Thailand. Demographics and physical performances were collected at baseline. Walking (step/day) and 24-h physical activity (PA) were monitored for 5 consecutive days by the Actical® accelerometer wrapped on non-dominant wrists. The Physical Activity Scale for the Elderly (PASE) questionnaire was used to record activities in the past 7 days by interview. A monthly calendar was used to record fall incidence over the 6 months. Unadjusted and adjusted hazard ratio (HR) with 95% confidence interval (CI) were analyzed using the Cox's proportional hazard regression. The Kaplan Meier curve illustrated the probability to survive from fall over the 6 months.Results: Of 255, 33 older people (12.94%) reported first-fall incidence over the 6 months. Fall incidence density rate was 0.79 per 1000 person-day. Our findings showed that significant association between fall incidence and behavioral risk factors including PASE scores < 100 (HR = 3.53; 95% CI: 1.24-10.04), walking < 5000 steps/day (HR = 3.6; 95% CI: 1.76-7.31) and moderate to vigorous intensity of PA at < 60 min/week (HR = 3.66; 95% CI: 1.12-12.01). Fall incidence were related to the following risk factors: age (HR = 3.54; 95% CI: 1.37-9.11), took polypharmacy/antipsychotics (HR = 4.32; 95% CI: 2.12-8.79), presence of urinary incontinence (HR = 2.87; 95% CI: 1.45-5.68), low functional mobility by Timed Up and Go ≥13.5 s (HR = 6.43; 95% CI: 2.65-15.57).Conclusions: This study proposed walking ≥5000 steps/day as a cutoff threshold to recommend for reducing risk of falling in community-dwelling older people who had low-risk of falling. [ABSTRACT FROM AUTHOR]

Discusses research on whether increases in intracellular calcium and motility in the sperm of the sea urchin Arbacia punctulata that are mediated by egg-derived products are also mediated by ryanodine-gated intracellular calcium stores. Results of the experiments; Regulation of ryanodine receptors; Details of a schematic representation of events leading to the activation of Arbacia punctulata sperm.