Background. The pilot phase IIb VIKING study suggested that dolutegravir (DTG), a human immunodeficiency virus (HIV) integrase inhibitor (INI), would be efficacious in INI-resistant patients at the ...50 mg twice daily (BID) dose. Methods. VIKING-3 is a single-arm, open-label phase III study in which therapy-experienced adults with INI-resistant virus received DTG 50 mg BID while continuing their failing regimen (without raltegravir or elvitegravir) through day 7, after which the regimen was optimized with ≥1 fully active drug and DTG continued. The primary efficacy endpoints were the mean change from baseline in plasma HIV-1 RNA at day 8 and the proportion of subjects with HIV-1 RNA <50 c/mL at week 24. Results. Mean change in HIV-1 RNA at day 8 was -1.43 log₁₀ c/mL, and 69% of subjects achieved <50 c/mL at week 24. Multivariate analyses demonstrated a strong association between baseline DTG susceptibility and response. Response was most reduced in subjects with Q148 + ≥2 resistance-associated mutations. DTG 50 mg BID had a low (3%) discontinuation rate due to adverse events, similar to INI-naive subjects receiving DTG 50 mg once daily. Conclusions. DTG 50 mg BID-based therapy was effective in this highly treatment-experienced population with INI-resistant virus. Clinical Trials Registration. www.clinicaltrials.gov (NCT01328041) and http://www.gsk-clinicalstudywww.gsk-clinicalstudyregister.com (112574).
Purpose
Continuing employment or returning to work (RTW) as a cancer survivor can be meaningful and financially necessary, yet challenging. However, there is a lack of qualitative research on RTW ...experiences and financial wellbeing of people with advanced colorectal cancer (CRC-A). This study aimed to fill this gap.
Methods
Adults treated for CRC-A were recruited 0.5–2 years post-surgery (or post-diagnosis of CRC-A for palliative chemotherapy participants). Semi-structured telephone interviews, exploring RTW and finances, were subjected to framework analysis. Demographic, clinical, and quality of life data (FACT-C, Distress Thermometer, COST measure) were collected to characterise the sample and inform the framework analysis.
Results
Analysis of 38 interviews revealed five overarching themes:
work as a struggle
,
work as my identity
,
work as my saviour
,
work as a financial necessity
, and
employer and colleague response.
Many survivors with CRC-A desired to, and had the capacity to, continue work or RTW, yet faced unique challenges from compounded stigma of both cancer and toileting issues. Inability to RTW negatively impacted financial and psychosocial wellbeing. Workplace support was an important facilitator of RTW.
Conclusion
For survivors with CRC-A, continuing or RTW is fraught with challenges, including physical functioning challenges, financial anxiety, and unsupportive workplace environments. Survivors require psychosocial, financial, and employer support to manage these difficulties. This paper recommends a multiprong approach, including education programmes (facilitated through workers’ union groups, human resource institutions, and/or large consumer CRC groups) and policies, to support workers and for employers to understand the unique challenges of employees with CRC-A.
Recently, the Data collection of Adverse events of Anti-HIV Drugs Group (D:A:D) described results from their international observational cohort of 33,347 HIV-1-infected individuals, suggesting ...unexpected increased risk of myocardial infarction (MI) associated with abacavir (ABC) therapy relative rate 1.9, 95% confidence interval (CI): 1.47 to 2.45; P = 0.0001. To contribute to the scientific question, we summarized GlaxoSmithKline HIV clinical trial data to determine if a similar signal emerged.
We compiled data from GlaxoSmithKline-sponsored clinical trials with > or = 24 weeks of combination antiretroviral therapy comprising 14,174 HIV-infected adults who received ABC (n = 9502; 7641 person-years) or not (n = 4672; 4267 person-years).
Baseline demographics and HIV disease characteristics, including lipids and glucose values, were similar. MI rates were comparable among subjects exposed n = 16 (0.168%; CI: 0.096 to 0.273; 2.09 per 1000 person-years) or not n = 11 (0.235%; CI: 0.118 to 0.421; 2.57 per 1000 person-years) to ABC-containing therapy. Results of 12 trials with randomization to ABC or not were consistent (2.15 per 1000 person-years vs. 4.10 per 1000 person-years).
In this pooled summary, we observed few MI events overall and no excess risk of MI with ABC therapy. It is unclear why results from this data set seem discrepant to the Data collection of Adverse events of Anti-HIV Drugs data set, particularly, as the non-ABC MI event rate is similar. Further data are needed to evaluate any association between ABC and increased risk of MI.
Modern treatments, including surgery and palliative chemotherapy without surgery, enable longer survival for people with advanced/recurrent colorectal cancer (CRC). Qualitative research comparing the ...physical and psychosocial outcomes of these different treatments is lacking. This study therefore aimed to explore and compare the physical and psychosocial challenges and survivorship experiences of people who receive different treatments for advanced CRC, through a qualitative study.
Adults with CRC who have undergone treatment for advanced/recurrent CRC were recruited 0.5–2 years post-surgery or, for palliative chemotherapy participants, 0.5–2 years post-diagnosis of advanced CRC. Qualitative semi-structured telephone interviews, analysed via framework analysis, explored quality of life (QoL) experiences. Demographic, clinical, and QoL data (Functional Assessment of Cancer Therapy – Colorectal (FACT-C), Distress Thermometer) were collected to characterise the sample and inform the framework analysis.
A diverse sample of 38 participants (22 female) participated, with ages ranging 27–84 (Median = 59), FACT-C 56–132 (Median = 102), and distress 0–10 (median = 3). Analysis of interviews revealed three overarching themes: 1) the overwhelming impact of protracted, complex illness; 2) compounding and interacting effects of multiple treatments, impacts, and multimorbidity; and 3) the long haul is unpredictable, bumpy, and wearing. These themes reveal that people with advanced CRC experience many challenges due to the complex nature of the illness, its treatment, and side effects.
Survivors require continued multi-disciplinary supportive care throughout follow-up to manage survivorship challenges. Guideline-led survivorship care and routine monitoring of physical and psychosocial wellbeing throughout follow up is imperative to manage patient expectations and support advanced CRC survivors.
•Survivors of advanced colorectal cancer experience many challenges in survivorship.•Pelvic exenteration survivors may require tailored care for their unique challenges.•Treatment complexity makes survival an unpredictable, bumpy, and wearing long haul.•We need tailored services to meet the needs of advanced colorectal cancer survivors.
Qualitative research examining healthcare experiences and needs of people with advanced (metastatic or recurrent) colorectal cancer CRC-A is limited. This study aimed to fill this gap in CRC-A ...survivors treated with surgical or palliative chemotherapy, through a qualitative study.
Australian adults treated for CRC-A were recruited 0.5–2 years post-surgery or post-diagnosis of CRC-A (for palliative chemotherapy groups). Semi-structured telephone interviews, analysed via framework analysis, explored healthcare experiences. Demographic, clinical, and quality of life data characterised the sample and informed framework analyses. Data was compared against the Institute of Medicine's framework for quality healthcare.
Interviews from 38 participants (22 female) of median age 59 years (range 27–84) revealed six overarching themes relating to the safety, effectiveness, timeliness, patient-centredness, efficiency, and equity of CRC-A care: 1) Early experiences influence later perceptions; 2) Trusting the system, trusting the professionals; 3) The benefits of multidisciplinary care co-ordination; 4) Feeling lost in follow-up; 5) Whose role is it anyway? Gaps in responsibility for survivorship care; and 6) Useful or useless? Perceptions of psychosocial support.
Healthcare systems for CRC-A can be improved through delivery of repeated information, upskilling general practitioners and/or implementing written survivorship care plans or survivorship clinics, to ensure quality healthcare.
•Advanced colorectal cancer survivors may feel lost in follow-up.•There is confusion about which doctor is responsible for survivorship challenges.•Repeated information delivery may help survivors to feel supported and informed.•Multidisciplinary care can be beneficial, yet burdensome for survivors.•GPs can provide quality care co-ordination following upskilling and training.
To study patients with coronary artery disease (CAD) scheduled for coronary angioplasty and to examine platelet activation in response to mental stress as a potential mechanism involved in the ...association between psychosocial factors and cardiac outcomes. Psychosocial factors have been identified as risk factors for CAD and adverse cardiac outcomes, although the underlying mechanisms are poorly understood.
Markers of platelet activation and platelet reactivity in response to experimentally induced mental stress (mental arithmetic and anger recall) were examined, using flow cytometry analysis and beta-thromboglobulin (BTG) assays among 249 CAD patients (age = 60.3 +/- 9.0 years, 15% women) who were scheduled to undergo elective percutaneous coronary intervention.
Mental stress-induced increases in platelet activation (CD41 (GP IIb/IIIa), p = .002; percent of mononuclear cells positive for CD41, p = .01; CD62P (P-selectin) expression, p = .005; and percent platelets positive for CD62P, p < .001). The degree of platelet reactivity was not related to demographic, clinical, or psychological variables, or cardiovascular hemodynamic changes.
Experimentally induced mental stress induced platelet activation in patients with CAD. This mechanism may partially explain the link between psychosocial variables and the development of adverse cardiac outcomes in patients with CAD.
While opioids are effective in carefully selected patients with chronic non-cancer pain (CNCP), they are associated with potential risks. Therefore, treatment recommendations for the safe and ...effective use of opioids in this patient population are needed.
A multidisciplinary expert panel was convened by the Pain Association of Singapore to develop practical evidence-based recommendations on the use of opioids in the management of CNCP in the local population. This article discusses specific recommendations for various common CNCP conditions.
Available data demonstrate weak evidence for the long-term use of opioids. There is moderate evidence for the short-term benefit of opioids in certain CNCP conditions. Patients should be carefully screened and assessed prior to starting opioids. An opioid treatment agreement must be established, and urine drug testing may form part of this agreement. A trial duration of up to 2 months is necessary to determine efficacy, not only in terms of pain relief, but also to document improvement in function and quality of life. Regular reviews are essential with appropriate dose adjustments, if necessary, and routine assessment of analgesic efficacy, aberrant behaviour and adverse effects. The reasons for discontinuation of opioid therapy include side effects, lack of efficacy and aberrant drug behaviour.
Due to insufficient evidence, the task force does not recommend the use of opioids as first-line treatment for various CNCP. They can be used as secondor third-line treatment, preferably as part of a multimodal approach. Additional studies conducted over extended periods are required.
Studies of the allelotype of human cancers have provided valuable insights into those chromosomes targeted for genetic inactivation during tumorigenesis. We present the comprehensive allelotype of 82 ...xenografted pancreatic or biliary cancers using 386 microsatellite markers and spanning the entire genome at an average coverage of 10 cM. Allelic losses were nonrandomly distributed across the genome and most prevalent for chromosome arms 9p, 17p, and 18q (>60%), sites of the known tumor suppressor genes CDKN2A, TP53, and MADH4. Moderate rates of loss (at any one locus) were noted for chromosome arms 3p, 6q, 8p, 17q, 18p, 21q, and 22q (40-60%). A mapping of individual loci of allelic loss revealed 11 "hot spots" of loss of heterozygosity (>30%) in addition to loci near known tumor suppressor genes, corresponding to 3p, 4q, 5q, 6q, 8p, 12q, 14q, 21q, 22q, and the X chromosome. The average genomic fractional allelic loss was 15.3% of all tested markers for the 82 xenografted cancers, with allelic loss affecting as little as 1.5% to as much as 32.1% of tested loci, a remarkable 20-fold range. We determined the chromosome location (in cM) of each of the 386 markers used based on mapping data available from the National Center for Biotechnology Information, and we provide the first distance-based estimates of chromosome material lost in a human epithelial cancer. Specifically, we found that the cumulative size of allelic losses ranged from 58 to 1160 cM, with an average loss of 561.32 cM/tumor. We compared the genomic fractional allelic loss of each xenografted cancer with known clinicopathological features for each patient and found a significant correlation with smoking status (P < 0.01). These findings offer new loci for investigation of the genetic alterations common to pancreaticobiliary cancers and aid the understanding of mechanisms of allelic loss in human carcinogenesis.
Guidelines published by the National Kidney Foundation in 2002 categorize renal failure into 5 stages of increasing severity. The relation of this classification to risk stratification for operative ...mortality in patients with nonemergent coronary artery bypass grafting (CABG) has not been clarified. We examined the effect of chronic kidney disease (CKD) severity on CABG operative mortality in patients with nonemergent CABG. Data reporting to the California CABG outcomes reporting program is mandated in California. Data from 121 hospitals on patients undergoing CABG in 2003 and 2004 were analyzed, including clinical characteristics, CKD stage, and operative mortality. CKD stage 1 and 2 were combined to form the reference group because data on urinary markers of renal failure were not available. Excluding patients with emergent or salvage acuity for CABG, 37,735 isolated CABGs were performed. Of these, 27,132 patients (71.9%) had glomerular filtration rate (GFR) ≥60 ml/min/1.73 m2 ; 8,861 (23.5%) had stage 3 CKD (GFR 30 to 59); 669 (1.8%) had stage 4 CKD (GFR 15 to 29); and 1,073 (2.8%) had stage 5 CKD (GFR <15 or on dialysis). In separate multivariate analyses, GFR and CKD stage were each significantly and independently associated with operative mortality (both p <0.0001). Operative mortality increased significantly with each stage of CKD (all p <0.01). Compared with the reference group, stage 3, (odds ratio OR 1.18, p = 0.0374), stage 4 (OR 2.23, p <0.0001), and stage 5 (OR 4.39, p <0.0001) had increasingly higher operative mortality. In conclusion, CKD stage based on National Kidney Foundation guidelines is an important predictor in risk stratification for operative mortality in patients undergoing nonemergent CABG.
Using physiologically based pharmacokinetic modeling, we predicted the magnitude of drug-drug interactions (DDIs) for studies with rifampicin and seven CYP3A4 probe substrates administered i.v. (10 ...studies) or orally (19 studies). The results showed a tendency to underpredict the DDI magnitude when the victim drug was administered orally. Possible sources of inaccuracy were investigated systematically to determine the most appropriate model refinement. When the maximal fold induction (Indmax) for rifampicin was increased (from 8 to 16) in both the liver and the gut, or when the Indmax was increased in the gut but not in liver, there was a decrease in bias and increased precision compared with the base model (Indmax = 8) geometric mean fold error (GMFE) 2.12 vs. 1.48 and 1.77, respectively. Induction parameters (mRNA and activity), determined for rifampicin, carbamazepine, phenytoin, and phenobarbital in hepatocytes from four donors, were then used to evaluate use of the refined rifampicin model for calibration. Calibration of mRNA and activity data for other inducers using the refined rifampicin model led to more accurate DDI predictions compared with the initial model (activity GMFE 1.49 vs. 1.68; mRNA GMFE 1.35 vs. 1.46), suggesting that robust in vivo reference values can be used to overcome interdonor and laboratory-to-laboratory variability. Use of uncalibrated data also performed well (GMFE 1.39 and 1.44 for activity and mRNA). As a result of experimental variability (i.e., in donors and protocols), it is prudent to fully characterize in vitro induction with prototypical inducers to give an understanding of how that particular system extrapolates to the in vivo situation when using an uncalibrated approach.
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