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Abstract: Quitting smoking after a diagnosis of cancer results in greater response to treatment and decreased risk of disease recurrence and second primary cancers. The objective of this study was to evaluate the potential cost‐effectiveness of two smoking cessation approaches: the current basic smoking cessation program consisting of screening for tobacco use, advice, and referral; and a best practice smoking cessation program that includes the current basic program with the addition of pharmacological therapy, counseling, and follow‐up. A Markov model was constructed that followed 65‐year‐old smokers with cancer over a lifetime horizon. Transition probabilities and mortality estimates were obtained from the published literature. Costs were obtained from standard costing sources in Ontario and reports. Probabilistic and deterministic sensitivity analyses were conducted to address parameter uncertainties. For smokers with cancer, the best practice smoking cessation program was more effective and more costly than the basic smoking cessation program. The incremental cost‐effectiveness ratio of the best practice smoking cessation program compared to the basic smoking cessation program was $3367 per QALY gained and $5050 per LY gained for males, and $2050 per QALY gained and $4100 per LY gained for females. Results were most sensitive to the hazard ratio of mortality for former and current smokers, the probability of quitting smoking through participation in the program and smoking‐attributable costs. The study results suggested that a best practice smoking cessation program could be a cost‐effective option. These findings can support and guide implementation of smoking cessation programs. [ABSTRACT FROM AUTHOR]

Background older patients are commonly believed to derive less benefit from cancer drugs, even if they fulfil clinical trial eligibility [Talarico et al. (2004, J Clin Oncol, 22(22):4626–31)]. We aim to examine if novel oncology drugs provide differential age-based treatment outcomes for patients on clinical trials. Methods a systematic review of randomised control trials (RCTs) cited for clinical efficacy evidence in novel oncology drug approvals by the Food and Drug Administration, European Medicines Agency and Health Canada between 2006 and 2017 was conducted. Studies reporting age-based subgroup analyses for overall or progression-free survival (OS/PFS) were included. Hazard ratios (HRs) and confidence intervals (CIs) for age-based subgroups were extracted. Meta-analyses with random effects were conducted, examining patient subgroups <65 and ≥65 years separately and pooled HRs of studies primary endpoints (OS or PFS) compared to examine if differences existed between age-based subgroups. Sensitivity analyses were conducted for cancer type, primary endpoint and systemic treatment. Results one-hundred-two RCTs, including 65,122 patients, met the inclusion criteria. One study reported age-based toxicity and none reported age-based quality of life (QOL) results. Pooled HRs [95% CIs] for patients <65 and ≥65 years were 0.61 [0.57–0.65] and 0.65 [0.61–0.70], respectively, with no difference between them (P = 0.14). Sensitivity analyses revealed similar results. Conclusion our results suggest that older and young patients, who fulfil clinical trial eligibility, may derive similar relative survival benefits from novel oncology drugs. There is, however, a need to report age-based toxicity and QOL results to support patient discussions regarding the balance of treatment benefit and harm, to encourage informed decision-making. [ABSTRACT FROM AUTHOR]

Objectives: Tracking population-based quality indicators of supportive and aggressive end of life (EOL) care may provide insight into the success of EOL interventions and health resource utilization. We examined patterns of EOL care in patients with gynecologic cancers over 14 years in Ontario, Canada. Methods: We conducted a population-based, retrospective cohort study of gynecologic cancer decedents in Ontario from 2005 to 2018 using linked administrative healthcare data (Ontario Cancer Registry, Discharge Abstract Database, Ontario Health Insurance Plan physician billing claims, homecare databases). Quality indices included emergency department (ED) use, admissions to hospital or intensive care unit (ICU), chemotherapy in the last 14 days of life, physician or palliative care home visits, and death in hospital, as well as previously defined aggregate measures of aggressive or supportive care. Descriptive statistics and crude incidence rates of each indicator were calculated. A multivariable logistic regression model was created to examine the relationship between sociodemographic and patient factors and receipt of aggressive and supportive care. Results: The cohort included 1 7,405 women; 51% died of ovarian cancer, 30% uterine cancer, 12% cervical cancer, and 6.5% vulvar or vaginal cancers (VVC). During the study period, death rates in hospitals decreased from 48% to 39%, while supportive care indices increased from 47% to 71%, and aggressive care indices remained stable (18%). Within the last 30 days of life, 53% were hospitalized, 5.6% were admitted to ICU, and 64% accessed palliative homecare, while within the last 14 days of life, 33% visited the ED, and 4.5% received chemotherapy. Patients with VVC demonstrated lower rates of both aggressive (11%) and supportive care (58%) compared to other cancer subtypes. On multivariable analyses, patients were significantly more likely to receive aggressive EOL care if they were <50 years of age, had a modified Deyo-Charlson Comorbidity Index score of 0, had uterine or ovarian cancer, or lived in a smaller community (<100,000) or a neighborhood in the lowest three income quintiles. Patients were less likely to receive supportive EOL care if they were ≥70 years of age, had a non-ovarian gynecologic malignancy, or lived in the lowest two income quintiles. Conclusions: Women dying with gynecologic cancers in Ontario were less likely to experience death in hospitals over time. Although access to supportive care has been increasing, the majority were still hospitalized, and a significant proportion continued to receive aggressive care in the final 30 days of life. A 5.6% rate of ICU admission exceeds a previously-determined Canadian oncologic quality benchmark of 2%, presenting an opportunity to improve the establishment of goals of care. Patients who live in rural and low-income communities may experience inequitable access to quality EOL care, and interventions are needed to address this issue. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Esophageal adenocarcinoma (EAC) incidence is increasing rapidly. Esophageal cancer has the second lowest 5-year survival rate of people diagnosed with cancer in Canada. Given the poor survival and the potential for further increases in incidence, phase-specific cost estimates constitute an important input for economic evaluation of prevention, screening, and treatment interventions. The study aims to estimate phase-specific net direct medical costs of care attributable to EAC, costs stratified by cancer stage and treatment, and predictors of total net costs of care for EAC.Methods: A population-based retrospective cohort study was conducted using Ontario Cancer Registry-linked administrative health data from 2003 to 2011. The mean net costs of EAC care per 30 patient-days (2016 CAD) were estimated from the payer perspective using phase of care approach and generalized estimating equations. Predictors of net cost by phase of care were based on a generalized estimating equations model with a logarithmic link and gamma distribution adjusting for sociodemographic and clinical factors.Results: The mean net costs of EAC care per 30 patient-days were $1016 (95% CI, $955-$1078) in the initial phase, $669 (95% CI, $594-$743) in the continuing care phase, and $8678 (95% CI, $8217-$9139) in the terminal phase. Overall, stage IV at diagnosis and surgery plus radiotherapy for EAC incurred the highest cost, particularly in the terminal phase. Strong predictors of higher net costs were receipt of chemotherapy plus radiotherapy, surgery plus chemotherapy, radiotherapy alone, surgery alone, and chemotherapy alone in the initial and continuing care phases, stage III-IV disease and patients diagnosed with EAC later in a calendar year (2007-2011) in the initial and terminal phases, comorbidity in the continuing care phase, and older age at diagnosis (70-74 years), and geographic region in the terminal phase.Conclusions: Costs of care vary by phase of care, stage at diagnosis, and type of treatment for EAC. These cost estimates provide information to guide future resource allocation decisions, and clinical and policy interventions to reduce the burden of EAC. [ABSTRACT FROM AUTHOR]

Background Our objectives were to evaluate the temporal changes in CMR-based strain imaging, and examine their relationship with left ventricular ejection fraction (LVEF), in patients treated with trastuzumab. Patients and methods In this prospective longitudinal observational study, 41 women with HER2+ breast cancer treated with chemotherapy underwent serial CMR (baseline, 6, 12, and 18 months) after initiation of trastuzumab (treatment duration 12 months). LVEF and LV strain (global longitudinal[GLS] and circumferential[GCS]) measurements were independently measured by 2 blinded readers. Results Of the 41 patients, 56% received anthracycline-based chemotherapy. Compared to baseline (60.4%, 95%CI 59.2–61.7%), there was a small but significant reduction in LVEF at 6 months (58.4%, 95%CI 56.7–60.0%, p  = 0.034) and 12 months (57.9%, 95%CI 56.4–59.7%, p  = 0.012), but not at 18 months (60.2%, 95%CI 58.2–62.2%, p  = 0.93). Similarly, compared to baseline, GLS and GCS decreased significantly at 6 months ( p  = 0.024 and < 0.001, respectively) and 12 months ( p  = 0.002 and < 0.001, respectively) with an increase in LV end-diastolic volume, but not at 18 months. There were significant correlations between the temporal (6 month-baseline) changes in LVEF, and all global strain measurements (Pearson's r  = −0.60 and r  = −0.75 for GLS and GCS, respectively, all p  < 0.001). Conclusion There was a significant reduction in LV strain during trastuzumab treatment, which correlated with a concurrent subtle decline in LVEF and was associated with an increase in LV end-diastolic volume. LV strain assessment by CMR may be a promising method to monitor for subclinical myocardial dysfunction in breast cancer patients receiving chemotherapy. Future studies are needed to determine its prognostic and therapeutic implications. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to determine if clinical benefits of novel anticancer drugs, measured by the ASCO Value Framework and European Society of Medical Oncology (ESMO) Magnitude of Clinical Benefit Scale, have increased over time in parallel with increasing costs. Methods: Anticancer drugs from phase III randomized controlled trials cited for clinical efficacy evidence in drug approvals between January 2006 to December 2015 were identified and scored using both frameworks. For each drug, the monthly price and incremental anticancer drug costs were calculated. Relationships between cost and year of approval were examined using generalized linear regressions models. Ordinary least square models were used to evaluate relationships between ASCO and ESMO scores and year of approval. Spearman correlation coefficients between costs and clinical benefit scores were calculated. Results: In total, 42 randomized controlled trials were included. Both monthly prices and incremental anticancer drug costs were significantly associated with year of approval and showed an average annual increase of 9% and 21%, respectively. The predicted mean incremental anticancer drug cost increased from $30,447 in 2006 to $161,141 in 2015 (greater than five-fold increase). Both ASCO and ESMO scores were not statistically associated with year of approval or correlated with monthly prices or incremental anticancer drug costs. Conclusion: Over the past decade, costs of novel oncology drugs have increased, while clinical benefits of these medications have not experienced a proportional positive change. The incremental anticancer drug costs have increased at a much greater rate than monthly prices, indicating that the increase in anticancer drug costs may be higher than commonly reported. [ABSTRACT FROM AUTHOR]

Objectives While there is wide support for patient engagement in health technology assessment, determining what constitutes meaningful (as opposed to tokenistic) engagement is complex. This paper explores reviewer and payer perceptions of what constitutes meaningful patient engagement in the Pan-Canadian Oncology Drug Review process. Methods Qualitative interview study comprising 24 semi-structured telephone interviews. A qualitative descriptive approach, employing the technique of constant comparison, was used to produce a thematic analysis. Results Submissions from patient advocacy groups were seen as meaningful when they provided information unavailable from other sources. This included information not collected in clinical trials, information relevant to clinical trade-offs and information about aspects of lived experience such as geographic differences and patient and carer priorities. In contrast, patient submissions that relied on emotional appeals or lacked transparency about their own methods were seen as detracting from the meaningfulness of patient engagement by conflating health technology assessment with other functions of patient advocacy groups such as fundraising or public awareness campaigns, and by failing to provide credible information relevant to deliberations. Conclusions This study suggests that misalignment of stakeholder expectations remains an issue even for a well-regarded health technology assessment process that has promoted patient engagement since its inception. Support for the technical capacity of patient groups to participate in health technology assessment is necessary but not sufficient to address this issue fully. There is a fundamental tension between the evidence-based nature of health technology assessment and the experientially oriented culture of patient advocacy. Divergent notions of what constitutes evidence and how it should be used must also be addressed. [ABSTRACT FROM AUTHOR]

Background: There is a paucity of information about treatment and mortality trends after acute myocardial infarction (AMI) for cancer survivors (CS).Methods: In this population-based study, the authors compared temporal trends of treatments and outcomes (mortality, nonfatal cardiovascular outcomes), among CS and patients without cancer (the noncancer patient [NCP] group) with AMI in Ontario (Canada) using inverse probability treatment weight (IPTW)-adjusted modeling.Results: Of 270,089 patients with AMI (22,907 CS, 247,182 NCP, 1995-2013; median follow-up, 10.1 and 11.0 years, respectively), the use of invasive coronary strategies and pharmacotherapies increased and mortality declined for CS and NCP (all Ptrend  < .001). At 30 days after AMI, there was no difference between CS and NCP in the receipt of coronary angiography (incidence risk ratio [IRR], 0.98; 95% confidence interval [CI], 0.96-1.01; P = .23), percutaneous coronary intervention (IRR, 0.98; 95% CI, 0.94-1.02; P = .29), or bypass (IRR, 0.93; 95% CI, 0.85-1.02; P = .11). At 90 days after AMI, there was no difference in the receipt of β-blockers, clopidogrel, or nitrates; but CS were less often prescribed angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers and statins. CS had higher all-cause mortality at 30 days (adjusted hazard ratio [HR] 1.12; 95% CI, 1.07-1.17; P < .001), at 1 year (1.16; 95% CI, 1.12-1.20; P < .001), and long term (HR, 1.21; 95% CI, 1.17-1.25; P < .001) and had a greater risk of heart failure (HR, 1.08; 95% CI, 1.03-1.14; P = .001), but not myocardial re-infarction (HR, 0.98; 95% CI, 0.95-1.01; P = .22) or stroke (HR, 1.06; 95% CI, 0.97-1.16; P = .18).Conclusions: Among CS and NCP with AMI in Ontario, similar improvements in mortality and receipt of treatments were observed between 1995 and 2013. However, compared with NCP, CS had a higher risk of mortality and heart failure. Cancer 2018;124:1269-78. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Resource and cost issues are a growing concern in health care. Thus, it is important to have an accurate estimate of the economic burden of care. Previous work has estimated the economic burden of cancer care for Canada; however, there is some concern this estimate is too low. The objective of this analysis was to provide a comprehensive revised estimate of this burden. Methods: We used a case--control prevalence-based approach to estimate direct annual cancer costs from 2005 to 2012. We used patient-level administrative health care data from Ontario to correctly attribute health care costs to cancer. We employed the net cost method (cost difference between patients with cancer and control subjects without cancer) to account for costs directly and indirectly related to cancer and its sequelae. Using average patient-level cost estimates from Ontario, we applied proportions from national health expenditures data to obtain the economic burden of cancer care for Canada. All costs were adjusted to 2015 Canadian dollars. Results: Costs of cancer care rose steadily over our analysis period, from $2.9 billion in 2005 to $7.5 billion in 2012, mostly owing to the increase in costs of hospital-based care. Most expenditures for health care services increased over time, with chemotherapy and radiation therapy expenditures accounting for the largest increases over the study period. Our cost estimates were larger than those in the Economic Burden of Illness in Canada 2005-2008 report for every year except 2005 and 2006. Interpretation: The economic burden of cancer care in Canada is substantial. Further research is needed to understand how the economic burden of cancer compares to that of other diseases. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) presentation is heterogeneous necessitating a variety of therapeutic interventions with varying efficacies and associated prognoses. Poor prognostic patients often undergo non-curative palliative interventions including transarterial chemoembolization (TACE), sorafenib, chemotherapy, or purely supportive care. The decision to pursue one of many palliative interventions for HCC is complex and an economic evaluation comparing these interventions has not been done. This study evaluates the cost-effectiveness of non-curative palliative treatment strategies such as TACE alone or TACE+sorafenib, sorafenib alone, and non-sorafenib chemotherapy compared with no treatment or best supportive care (BSC) among patients diagnosed with HCC between 2007 and 2010 in a Canadian setting. Using person-level data, we estimated effectiveness in life years and quality-adjusted life years (QALYs) along with total health care costs (2013 US dollars) from the health care payer’s perspective (3% annual discount). A net benefit regression approach accounting for baseline covariates with propensity score adjustment was used to calculate incremental net benefit to generate incremental cost-effectiveness ratio (ICER) and uncertainty measures. Among 1,172 identified patients diagnosed with HCC, 4.5%, 7.9%, and 5.6%, received TACE alone or TACE+sorafenib, sorafenib, and non-sorafenib chemotherapy clone, respectively. Compared with no treatment or BSC (81.9%), ICER estimates for TACE alone or TACE+sorafenib was $6,665/QALY (additional QALY: 0.47, additional cost: $3,120; 95% CI: -$18,800-$34,500/QALY). The cost-effectiveness acceptability curve demonstrated that if the relevant threshold was $50,000/QALY, TACE alone or TACE+sorafenib, non-sorafenib chemotherapy, and sorafenib alone, would have a cost-effectiveness probability of 99.7%, 46.6%, and 5.5%, respectively. Covariates associated with the incremental net benefit of treatments are age, sex, comorbidity, and cancer stage. Findings suggest that TACE with or without sorafenib is currently the most cost-effective active non-curative palliative treatment approach to HCC. Further research into new combination treatment strategies that afford the best tumor response is needed. [ABSTRACT FROM AUTHOR]

Puerariae Lobatae Radix (PLR) exerts cyto-protective effect against oxidative stress due to its high isoflavonoid content. In this study, the ultrasonic-assisted extraction condition for the maximum recovery of isoflavonoids with high cyto-protective effect was optimised by response surface methodology (RSM). A second-order polynomial fitted the experimental data (R 2 : 0.9736; p-value <0.0001). The optimal extraction parameters were determined as: extraction time 16.02 min, ethanol concentration 41.41% and liquid-to-solid ratio 44.35 mL/g. Practical experiments with extraction time 16.00 min, ethanol concentration 41.00% and liquid-to-solid ratio 44.00 mL/g were carried out in triplicate. This subsequently yielded a cell viability of 82.90 ± 0.78% against hydrogen peroxide-induced oxidative stress on EA.hy926, and was comparable to the predicted of 85.60%. Five chemical constituents in the extract were identified to exert cyto-protective effect. Taken together, this method successfully integrated RSM and the partial least squares regression method to optimise the PLR extract with highest cyto-protective activity. [ABSTRACT FROM AUTHOR]

BACKGROUND The objective of this study was to determine the impact of modeling cancer drug wastage in economic evaluations because wastage can result from single-dose vials on account of body surface area- or weight-based dosing. METHODS Intravenous chemotherapy drugs were identified from the pan-Canadian Oncology Drug Review (pCODR) program as of January 2015. Economic evaluations performed by drug manufacturers and pCODR were reviewed. Cost-effectiveness analyses and budget impact analyses were conducted for no-wastage and maximum-wastage scenarios (ie, the entire unused portion of the vial was discarded at each infusion). Sensitivity analyses were performed for a range of body surface areas and weights. RESULTS Twelve drugs used for 17 indications were analyzed. Wastage was reported (ie, assumptions were explicit) in 71% of the models and was incorporated into 53% by manufacturers; this resulted in a mean incremental cost-effectiveness ratio increase of 6.1% (range, 1.3%-14.6%). pCODR reported and incorporated wastage for 59% of the models, and this resulted in a mean incremental cost-effectiveness ratio increase of 15.0% (range, 2.6%-48.2%). In the maximum-wastage scenario, there was a mean increase in the incremental cost-effectiveness ratio of 24.0% (range, 0.0%-97.2%), a mean increase in the 3-year total incremental budget costs of 26.0% (range, 0.0%-83.1%), and an increase in the 3-year total incremental drug budget cost of approximately CaD $102 million nationally. Changing the mean body surface area or body weight caused 45% of the drugs to have a change in the vial size and/or quantity, and this resulted in increased drug costs. CONCLUSIONS Cancer drug wastage can increase drug costs but is not uniformly modeled in economic evaluations. Cancer 2017;123:3583-90. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Patients with early-stage hepatocellular carcinoma ( HCC) are potential candidates for curative treatments such as radiofrequency ablation ( RFA), surgical resection ( SR), or liver transplantation ( LT), which have demonstrated a significant survival benefit. We aimed to estimate the cost-effectiveness of curative and combination treatment strategies among patients diagnosed with HCC during 2002-2010. This study used Ontario Cancer Registry-linked administrative data to estimate effectiveness and costs (2013 USD) of the treatment strategies from the healthcare payer's perspective. Multiple imputation by logistic regression was used to handle missing data. A net benefit regression approach of baseline important covariates and propensity score adjustment were used to calculate incremental net benefit to generate incremental cost-effectiveness ratio ( ICER) and uncertainty measures. Among 2,222 patients diagnosed with HCC, 10.5%, 14.1%, and 10.3% received RFA, SR, and LT monotherapy, respectively; 0.5-3.1% dual treatments; and 0.5% triple treatments. Compared with no treatment (53.2%), transarterial chemoembolization ( TACE) + RFA (average $2,465, 95% CI: −$20,000-$36,600/quality-adjusted life years [ QALY]) or RFA monotherapy ($15,553, 95% CI: $3,500-$28,500/ QALY) appears to be the most cost-effective modality with lowest ICER value. The cost-effectiveness acceptability curve showed that if the relevant threshold was $50,000/ QALY, RFA monotherapy and TACE+ RFA would have a cost-effectiveness probability of 100%. Strategies using LT delivered the most additional QALYs and became cost-effective at a threshold of $77,000/ QALY. Our findings found that TACE+ RFA dual treatment or RFA monotherapy appears to be the most cost-effective curative treatment for patients with potential early stage of HCC in Ontario. These findings highlight the importance of identifying and measuring differential benefits, costs, and cost-effectiveness of alternative HCC curative treatments in order to evaluate whether they are providing good value for money in the real world. [ABSTRACT FROM AUTHOR]

Objectives: The current standard therapy for locally advanced squamous cell carcinoma of the head and neck (LASCCHN) is platinum-based chemotherapy plus concurrent radiotherapy (CRT), but several systemic therapies have been evaluated. We performed a Bayesian network meta-analysis (NMA) with random effects to enable direct and indirect comparisons of all existing treatment modalities for LASCCHN simultaneously.Material and Methods: A systematic review was conducted using MEDLINE, EMBASE, ASCO abstracts, ASTRO abstracts and the Cochrane Central of Registered Trials using Cochrane methodology to identify randomized controlled trials (RCTs) up to June 2016. Only abstracts that involved the same definitive radiotherapy in the arms for the RCT were included.Results: Sixty-five RCTs involving 13,574 patients and 16 different treatment strategies were identified. Chemotherapy plus concurrent radiation (CRT) was superior to RT with a HR of 0.74 (95%CR 0.69-0.79) for OS in the NMA. Only 3 trials compared RT alone to concurrent therapy with an EGFR antibody (ERT), demonstrating a superior OS (HR 0.75, 95% CR 0.60-0.94), but this difference was not statistically significant when interpreted in a NMA (HR 0.84, 95%CR 0.65-1.08). ERT was not superior to CRT (HR 1.19, 95%CR 0.93-1.54), and the addition of neo-adjuvant taxane-based chemotherapy to CRT was not beneficial (HR 0.86, 95% CR 0.70-1.07).Conclusion: The addition of either adjuvant or neoadjuvant chemotherapy to the CRT backbone does not confer an OS benefit in the treatment of LASCCHN. Similarly, ERT does not confer an OS benefit for patients who are eligible for CRT. [ABSTRACT FROM AUTHOR]

Background: It is unclear which regimen is the most efficacious among the available therapies for advanced gastric cancer in the second-line setting. We performed a network meta-analysis to determine their relative benefits. Methods: We conducted a systematic review of randomized controlled trials (RCTs) through the MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases and American Society of Clinical Oncology abstracts up to June 2014 to identify phase III RCTs on advanced gastric cancer in the second-line setting. Overall survival (OS) data were the primary outcome of interest. Hazard ratios (HRs) were extracted from the publications on the basis of reported values or were extracted from survival curves by established methods. A Bayesian network meta-analysis was performed with WinBUGS to compare all regimens simultaneously. Results: Eight RCTs (2439 patients) were identified and contained extractable data for quantitative analysis. Network meta-analysis showed that paclitaxel plus ramucirumab was superior to single-agent ramucirumab [OS HR 0.51, 95 % credible region (CR) 0.30-0.86], paclitaxel (OS HR 0.81, 95 % CR 0.68-0.96), docetaxel (OS HR 0.56, 95 % CR 0.33-0.94), and irinotecan (OS HR 0.71, 95 % CR 0.52-0.99). Paclitaxel plus ramucirumab also had an 89 % probability of being the best regimen among all these regimens. Single-agent ramucirumab, paclitaxel, docetaxel, and irinotecan were comparable to each other with respect to OS and were superior to best supportive care. Conclusions: This is the first network meta-analysis to compare all second-line regimens reported in phase III gastric cancer trials. The results suggest the paclitaxel plus ramucirumab combination is the most effective therapy and should be the reference regimen for future comparative trials. [ABSTRACT FROM AUTHOR]

Purpose Cancer drug wastage occurs when a parenteral drug within a fixed vial is not administered fully to a patient. This study investigated the extent of drug wastage, the financial impact on the hospital budget, and the cost savings associated with current mitigation strategies. Methods We conducted a cross-sectional study in three University of Toronto-affiliated hospitals of various sizes. We recorded the actual amount of drug wasted over a 2-week period while using current mitigation strategies. Single-dose vial cancer drugs with the highest wastage potentials were identified (14 drugs). To calculate the hypothetical drug wastage with no mitigation strategies, we determined how many vials of drugs would be needed to fill a single prescription. Results The total drug costs over the 2weeks ranged from$50,257 to $716,983 in the three institutions. With existing mitigation strategies, the actual drug wastage over the 2 weeks ranged from $928 to $5,472, which was approximately 1% to 2% of the total drug costs. In the hypothetical model with no mitigation strategies implemented, the projected drug cost wastage would have been $11,232 to $149,131, which accounted for 16% to 18% of the total drug costs. As a result, the potential annual savings while using current mitigation strategies range from 15% to 17%. Conclusion The financial impact of drug wastage is substantial. Mitigation strategies lead to substantial cost savings, with the opportunity to reinvest those savings. More research is needed to determine the appropriate methods to minimize risk to patients while using the cost-saving mitigation strategies. [ABSTRACT FROM AUTHOR]

Purpose Palliative care inpatient units (PCUs) can improve symptoms, family perception of care, and lower per-diem costs compared with usual care. In March 2013, Johns Hopkins Medical Institutions (JHMI) added a PCU to the palliative care (PC) program. We studied the financial impact of the PC program on JHMI from March 2013 to March 2014. Methods This study considered three components of the PC program: PCU, PC consultations, and professional fees. Using 13 months of admissions data, the team calculated the per-day variable cost pre-PCU (ie, in another hospital unit) and after transfer to the PCU. These fees were multiplied by the number of patients transferred to the PCU and by the average length of stay in the PCU. Consultation savings were estimated using established methods. Professional fees assumed a collection rate of 50%. Results The total positive financial impact of the PC program was $3,488,863.17. There were 153 transfers to the PCU, 60% with cancer, and an average length of stay of 5.11 days. The daily loss pretransfer to the PCU of $1,797.67 was reduced to $1,345.34 in the PCU(225%). The PCUsaved JHMI $353,645.17 in variable costs, or $452.33 per transfer. Cost savings for PC consultations in the hospital, 60% with cancer, were estimated at $2,765,218. $370,000 was collected in professional fees savings. Conclusion The PCU and PC program had a favorable impact on JHMI while providing expert patient-centered care. As JHMI moves to an accountable care organization model, value-based patient-centered care and increased intensive care unit availability are desirable. [ABSTRACT FROM AUTHOR]

A fetus of Chinese descent presented with ultrasound features of anemia at 20 weeks’ gestation. Father had low a mean corpuscular volume (MCV) level. Multiplex gap-polymerase chain reaction (gap-PCR) excluded common α-thalassemia (α-thal) deletions and mutations and PCR sequencing of the α1- and α2-globin genes were negative. The fetus had a normal karyotype. Array comparative genomic hybridization (aCGH) showed a single copy loss of 189.87 kb in chromosome 11p15.4, involving the whole β-globin gene cluster, inherited from the father. Multiplex ligation-dependent probe amplification (MLPA) confirmed the deletion included the ε-globin gene, confirming the diagnosis of heterozygous (εγδβ)0-thalassemia [(εγδβ)0-thal], also inherited from the father. The fetus had a worsening anemic conditionin uteroand required a transfusion at 26 weeks’ gestation, raising the hemoglobin (Hb) level from 5.3 to 12.6g/dL. A cesarean-section was subsequently performed at 32 weeks’ gestation because of reduced fetal movements, and a 1650g baby girl with good Apgar scores was delivered. Hemoglobin at birth was 12.8g/dL, gradually dropping to 6.8 g/dL, requiring three neonatal transfusions. Her condition gradually stabilized after 2 months with Hb stable at 8.0 g/dL. Family screening by MLPA showed that the paternal grandmother carried the same deletion. The deletion in this case is distinct and is the reported first case. The deletion transmitted across three successive generations with great phenotypic variation. The final adult phenotype of (εγδβ)0-thal is usually mild, therefore, with accurate prenatal diagnosis this condition is salvageable byin uteroand early neonatal transfusions, preventing adverse pregnancy and neonatal outcomes. [ABSTRACT FROM AUTHOR]

Background: There are limited data on the effects of trastuzumab on the right ventricle (RV). Therefore, we sought to evaluate the temporal changes in right ventricular (RV) structure and function as measured by cardiovascular magnetic resonance (CMR), and their relationship with left ventricular (LV) structure and function in breast cancer patients treated with trastuzumab. Methods: Prospective, longitudinal, observational study involving 41 women with HER2+ breast cancer who underwent serial CMR at baseline, 6, 12, and 18 months after initiation of trastuzumab. A single blinded observer measured RV parameters on de-identified CMRs in a random order. Linear mixed models were used to investigate temporal changes in RV parameters. Results: Of the 41 women (age 52 ± 11 years), only one patient experienced trastuzumab-induced cardiotoxicity. Compared to baseline, there were small but significant increases in the RV end-diastolic volume at 6 months (p = 0.002) and RV end-systolic volume at 6 and 12 months (p < 0.001 for both), but not at 18 months (p = 0.82 and 0.13 respectively). RV ejection fraction (RVEF), when compared to baseline (58.3%, 95% CI 57.1-59.5%), showed corresponding decreases at 6 months (53.9%, 95% CI 52.5-55.4%, p < 0.001) and 12 months (55%, 95% CI 53.8-56.2%, p < 0.001) that recovered at 18 months (56.6%, 95% CI 55.1-58.0%, p = 0.08). Although the temporal pattern of changes in LVEF and RVEF were similar, there was no significant correlation between RVEF and LVEF at baseline (r = 0.29, p = 0.07) or between their changes at 6 months (r = 0.24, p = 0.17). Conclusion: In patients receiving trastuzumab without overt cardiotoxicity, there is a subtle but significant deleterious effect on RV structure and function that recover at 18 months, which can be detected by CMR. Furthermore, monitoring of LVEF alone may not be sufficient in detecting early RV injury. These novel findings provide further support for CMR in monitoring early cardiotoxicity. Trial registration: ClinicalTrials.gov Identifier: NCT01022086. Date of registration: November 27, 2009. [ABSTRACT FROM AUTHOR]

Objective: To review the available evidence and make recommendations regarding use of systemically administered drugs in combination or in sequence with radiation (RT) and/or surgery for cure and/or organ preservation in patients with locally advanced nonmetastatic (Stage III to IVB) squamous cell carcinoma of the head and neck (LASCCHN). Method: Recognizing the Meta-analysis of Chemotherapy in Head and Neck Cancer (MACH-NC) group reports have de facto guided practice since 2000, we searched for systematic reviews in the MEDLINE, EMBASE and Cochrane Database of Systematic Reviews published from January 2000 to February 2015 in reference to 4 research questions. A search was also conducted for randomized trials (RCTs) up to February 2015 not included in the meta-analyses. Result: The MACH-NC reports, 5 additional meta-analyses, and 30 RCTs not included by MACH-NC were identified. For chemotherapy, MACH-NC findings showing improved overall survival with concomitant chemoRT did not require modification. High-dose cisplatin was most commonly studied. We confirmed this benefit with cisplatin monotherapy in patients treated with with postoperative concurrent chemoRT. Other than cetuximab, no targeted agents and radiosensitizers studied in RCTs were shown effective. TPF induction chemotherapy was superior to PF for tumor response and larynx preservation but not survival. Larynx preservation was reported with both CRT and induction chemotherapy approaches. Conclusion: ChemoRT with cisplatin at least 40 mg/m² per week given as radical or postoperative adjuvant remains a standard treatment approach for LASCCHN that improves overall survival but increases toxicity. 5-FU plus platinum is supported by less data but may be a reasonable alternative for patients unsuitable for cisplatin. Of note, stratification of outcomes by HPV-status was not available but outcomes for oropharynx cancer appeared similar to other subsites in chemoRT RCTs. No RCTs have yet demonstrated superiority or non-inferiority of cetuximab-RT to CRT. In view of this, cetuximab-RT is suggested only for patients not candidates for CRT. Taxane-based triplet induction chemotherapy is superior to doublets for rapid tumour downsizing and for larynx preservation, but does not improve overall survival and should be used with primary G-CSF prophylaxis. Further investigation of induction approaches for larynx preservation may be warranted. [ABSTRACT FROM AUTHOR]

Objectives To assess the cost-effectiveness of gemcitabine (G), G + 5-fluorouracil, G + capecitabine, G + cisplatin, G + oxaliplatin, G + erlotinib, G + nab-paclitaxel (GnP), and FOLFIRINOX in the treatment of advanced pancreatic cancer from a Canadian public health payer’s perspective, using data from a recently published Bayesian network meta-analysis. Methods Analysis was conducted through a three-state Markov model and used data on the progression of disease with treatment from the gemcitabine arms of randomized controlled trials combined with estimates from the network meta-analysis for the newer regimens. Estimates of health care costs were obtained from local providers, and utilities were derived from the literature. The model estimates the effect of treatment regimens on costs and quality-adjusted life-years (QALYs) discounted at 5% per annum. Results At a willingness-to-pay (WTP) threshold of greater than $30,666 per QALY, FOLFIRINOX would be the most optimal regimen. For a WTP threshold of $50,000 per QALY, the probability that FOLFIRINOX would be optimal was 57.8%. There was no price reduction for nab-paclitaxel when GnP was optimal. Conclusions From a Canadian public health payer’s perspective at the present time and drug prices, FOLFIRINOX is the optimal regimen on the basis of the cost-effectiveness criterion. GnP is not cost-effective regardless of the WTP threshold. [ABSTRACT FROM AUTHOR]

Background Cystic fibrosis ( CF) is a rare condition in Asians. Since 1985, only about 30 Chinese patients have been reported with molecular confirmation. Method Using our in-house next-generation sequencing ( NGS) pipeline for childhood bronchiectasis, we identified disease-causing CFTR mutations in CF patients in Hong Kong. After identifying p.I1023R in multiple patients, haplotype analysis was performed with genome-wide microarray to ascertain the likelihood of this being a founder mutation. We also assessed the processing and gating activity of the mutant protein by Western hybridization and patch-clamp test. Results Molecular diagnoses were confirmed in four patients, three of whom shared a missense mutation: CFTR:c.3068T>G:p.I1023R. The results suggested that p.I1023R is a founder mutation in southern Han Chinese. In addition, the processing and gating activity of the mutant protein was assessed by gel electrophoresis and a patch-clamp test. The mutant protein exhibited trafficking defects, suggesting that the dysfunction is caused by reduced cell surface expression of the fully glycosylated proteins. Conclusion Together with other previously reported mutations, the specific founder mutation presented herein suggests a unique CFTR mutation spectrum in the southern Chinese populations, and this finding has vital implications for improving molecular testing and mutation-specific treatments for Chinese patients with CF. [ABSTRACT FROM AUTHOR]

The genus Rosa (roses) has long been used in traditional or folk medicine worldwide for the treatment of various types of arthritis including rheumatoid arthritis and osteoarthritis. The active constituents of Rosa spp., such as flavonoids, triterpenoids, and phytosterols, could act on different targets in the NF-κB signalling pathway, inhibit pro-inflammatory enzymes (e.g. MMPs and COX-2), lower the production of inflammatory cytokines and chemokines (e.g. TNF-α, IL-1β, IL-6, CCL5), and reduce oxidative stress, which in turn suppress inflammatory processes. Preclinical and clinical studies have demonstrated that these species possess analgesic, anti-arthritic, anti-inflammatory, anti-oxidative and bone-preserving activities. This review presents comprehensive overview of the mode and mechanism of action of various extracts, preparations, and active constituents from this genus. The dynamic beneficial effects of the products prepared from this genus in arthritis management are summarized. The Rosa genus is a treasure waiting for further exploration by researchers interested in the development of safe and effective anti-arthritic agents. [ABSTRACT FROM AUTHOR]

Neointimal hyperplasia (NIH) and inward wall remodeling cause arterial restenosis and failure of bypass vein grafts. Previous studies from our group suggest that transforming growth factor (TGF) β promotes these pathologies via regulating cell kinetics at the early stage and matrix metabolism at the late stage. Although these temporal TGFβ effects may result from its signaling in different cell groups, the responsible cell type has not been identified. In the current study, we evaluated the effect of smooth muscle cell (SMC)-specific TGFβ signaling through its type I receptor TGFBR1 on NIH and wall remodeling of the injured femoral arteries (FAs). An inducible Cre/loxP system was employed to delete SMC Tgfbr1 (Tgfbr1iko). Mice not carrying the Cre allele (Tgfbr1f/f) served as controls. The injured FAs were evaluated on d3, d7, and d28 postoperatively. Tgfbr1iko attenuated NIH by 92%, but had insignificant influence on arterial caliber when compared with Tgfbr1f/f controls on d28. This attenuation correlated with greater cellularity and reduced collagen content. Compared with Tgfbr1f/f FAs, however, Tgfbr1iko FAs exhibited persistent neointimal cell proliferation and cell apoptosis, with both events at a greater rate on d28. Tgfbr1iko FAs additionally contained fewer SMCs and more inflammatory infiltrates in the neointima and displayed a thicker adventitia than did Tgfbr1f/f FAs. More MMP9 proteins were detected in the adventitia of Tgfbr1iko FAs than in that of Tgfbr1f/f controls. Our results suggest that disruption of SMC Tgfbr1 inhibits arterial NIH in the short term, but the overall vascular phenotype may not favor long-term performance of the injured arteries. [ABSTRACT FROM AUTHOR]

Aim The aim is to evaluate the impact of cisplatin dose modification on outcomes of human papillomavirus (HPV)-related (HPV+) and HPV-unrelated (HPV−) locally advanced head and neck cancer (LAHNC) treated with chemoradiotherapy (CRT). Patients and methods A pooled analysis was conducted of stage III/IV oropharyngeal cancer (OPC), carcinoma of unknown primary (CUP) and laryngo-hypopharyngeal cancer (LHC) patients treated with single-agent cisplatin CRT in 2000–2012 from two tertiary academic cancer centres. HPV status was determined by p16 staining and/or in situ hybridisation. LHC was assumed to be HPV−. Unknown HPV status OPC/CUPs were excluded. Overall survival (OS) was calculated. Multivariable analysis (MVA) evaluated the impact of cisplatin dose intensity on survival for HPV+ and HPV− cohorts separately. Results A total of 404 HPV+ and 255 HPV− LAHNC (481 OPC, 18 CUP, 160 LHC) patients were included. Median follow-up was 4.3 (0.5–11.9) years. Three-year OS for cisplatin <200, =200, and >200 mg/m 2 subgroups were 52%, 60%, and 72% ( P = 0.001) for the HPV− and 91%, 90%, and 91% ( P = 0.30) for the HPV+ patients. MVA confirmed a survival benefit with cisplatin >200 mg/m 2 for the HPV− (hazard ratio [HR] 0.5, 95% confidence interval [CI]: 0.3–0.7, P < 0.001) but not for HPV+ (HR 0.6, 95% CI: 0.4–1.1, P = 0.104). There was a superior OS trend in the HPV+ T4 or N3 high-risk subset ( N = 107) with cisplatin >200 mg/m 2 (HR 0.5, 95% CI: 0.2–1.1, P = 0.07). Conclusions A survival benefit of cisplatin dose >200 mg/m 2 is evident for HPV− LAHNC patients, but not for HPV+ cohort overall, although the T4 or N3 subset may benefit from a higher cumulative cisplatin dose. [ABSTRACT FROM AUTHOR]

Hydrops fetalis is commonly due to Hb Bart’s (γ4) disease in South East Asia. Here, we report an unusual case of hydrops fetalis due to congenital dyserythropoietic anemia (CDA) associated with compound heterozygosity forKrüppel-like factor 1(KLF1) gene mutations. Fetal cardiomegaly was first detected on routine mid-trimester scan in a pregnant woman with normal mean corpuscular volume (MCV) and Rhesus positive status. The fetus subsequently developed hydrops fetalis, and cordocentesis showed severe fetal anemia with a hemoglobin (Hb) level of 3.4 g/dL. Common causes of fetal anemia including Hb Bart’s disease, parvovirus infection, and red cell antibodies were excluded. In view of the marked increase in erythroblasts at various stages of erythropoiesis, the diagnosis of CDA was suspected. We screened the couple for previously reportedKLF1gene mutations, showing that the mother was heterozygous for the c.525_526insCGGCGCC, p.Gly176Argfs*179 mutation, and her husband heterozygous for c.1012C>A, p.Pro338Thr mutation. The fetus was a compound heterozygote for these two KLF1 mutations. After counseling, repeated intrauterine transfusions were given at 27, 29, and 34 weeks’ gestation; the hydrops fetalis was resolved. The baby was delivered at 34 weeks’ gestation and required monthly blood transfusions but was otherwise thriving. Bone marrow aspiration at 10 months of age showed the features of ineffective erythropoiesis, compatible with CDA. In conclusion, hydrops fetalis can rarely be due to CDA associated with a compound heterozygous mutation forKLF1gene mutations, and be managed by repeated intrauterine transfusions. Our present report adds to the wide clinical spectrum of KLF1 mutations. [ABSTRACT FROM AUTHOR]

Aims. This study aims to investigate the possible synergistic interactions of the Danshen-Sanqi combination on vascular disease via their anti-inflammatory activities. Methods. Nine combination ratios of Danshen-Sanqi extracts were screened in the RAW264.7 cell line and their anti-inflammatory effects were examined in lipopolysaccharide- (LPS-) induced nitric oxide (NO), tumor necrosis factor (TNF), and monocyte chemoattractant protein-1 (MCP-1) generation pathways. The interaction between Danshen and Sanqi on each target was analysed using combination index (CI) and isobologram models. Additionally, the anti-inflammatory activities of key bioactive compounds from Danshen and Sanqi were tested using the same models. The compounds from each herb that exerted the most potent activity were combined to evaluate their possible synergistic/antagonistic interactions. Results. Danshen-Sanqi 8 : 2 was found to be the optimal ratio and exerted a synergistic effect in inhibiting NO, TNF, and MCP-1 when the concentrations were higher than 1.24, 1.89, and 2.17 mg/mL, respectively. Although dihydrotanshinone I (DT) and ginsenoside Rd (Rd) from Danshen and Sanqi, respectively, exhibited the greatest individual bioactivity in the assays, antagonistic effects were observed for the DT-Rd combination 7 : 3. Conclusion. This study provided scientific evidence to support the traditional use of the Danshen-Sanqi combination for vascular disease through their synergistic interactions on anti-inflammatory pathways. [ABSTRACT FROM AUTHOR]

Background: Cancer is a major public health issue and represents a significant economic burden to health care systems worldwide. The objective of this analysis was to estimate phase-specific, 5-year and lifetime net costs for the 21 most prevalent cancer sites, and remaining tumour sites combined, in Ontario, Canada. Methods: We selected all adult patients diagnosed with a primary cancer between 1997 and 2007, with valid ICD-O site and histology codes, and who survived 30 days or more after diagnosis, from the Ontario Cancer Registry (N = 394,092). Patients were linked to treatment data from Cancer Care Ontario and administrative health care databases at the Institute for Clinical and Evaluative Sciences. Net costs (i.e., cost difference between patients and matched non-cancer control subjects) were estimated by phase of care and sex, and used to estimate 5-year and lifetime costs. Results: Mean net costs of care (2009 CAD) were highest in the initial (6 months post-diagnosis) and terminal (12 months pre-death) phases, and lowest in the (3 months) pre-diagnosis and continuing phases of care. Phase-specific net costs were generally lowest for melanoma and highest for brain cancer. Mean 5-year net costs varied from less than $25,000 for melanoma, thyroid and testicular cancers to more than $60,000 for multiple myeloma and leukemia. Lifetime costs ranged from less than $55,000 for lung and liver cancers to over $110,000 for leukemia, multiple myeloma, lymphoma and breast cancer. Conclusions: Costs of cancer care are substantial and vary by cancer site, phase of care and time horizon analyzed. These cost estimates are valuable to decision makers to understand the economic burden of cancer care and may be useful inputs to researchers undertaking cancer-related economic evaluations. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discusses various reports within the issue on topics including one related to complementary and alternative medicine (CAM), the other on use of beta-amyloid for treating Alzheimer's disease and the third on the treatment of depression.

Dietary fiber like konjac glucomannan (KGM) is important in maintaining good human health. There is no established method for quantifying the average degree of acetylation DA of this polysaccharide. Polysaccharides are notoriously difficult to dissolve. In this study, KGM could not be fully dissolved in common solvents and was characterized in the solid state. ATR-FTIR spectroscopy enabled a fast qualitative assessment of acetylation, selective to the outer layer of KGM particles, and identifying excipients like magnesium stearate. Average DA was quantified for the first time with solid-state 13C NMR in KGM: semi-quantitative measurements on the same arbitrary scale by cross polarization (1 to 2 days) were calibrated with a few longer single-pulse excitation measurements (approximately 1 week). DA values ranged from 4 to 8% of the hexoses in the backbone, in agreement with previously reported values. This method could be used for quality control and standardization of KGM products. [Display omitted] [ABSTRACT FROM AUTHOR]

Purpose Patients with unresectable wild-type KRAS metastatic colorectal cancer benefit from fluoropyrimidines (FP), oxaliplatin (O), irinotecan (I), bevacizumab (Bev), and epithelial growth factor receptor inhibitors (EGFRI). The most cost-effective regimen remains unclear. Methods A Markov model was constructed to examine the costs and outcomes of three treatment strategies: strategy A (reference strategy): EGFRI monotherapy in third line ([3L]; ie, first-line [1L]: Bev + FOLFIRI [FP + I] or FOLFOX [FP + O]; second line [2L]: FOLFIRI/ FOLFOX; 3L: EGFRI); strategy B: EGFRI and I in 3L (ie, 1L: Bev + FOLFIRI/FOLFOX; 2L: FOLFIRI/FOLFOX; 3L: EGFRI + I); and strategy C: EGFRI in 1L (ie, 1L: EGFRI + FOLFIRI/ FOLFOX; 2L: Bev + FOLFIRI/FOLFOX; 3L: best supportive care). Efficacy data of the treatments were obtained from the literature. Health system resource use information was derived from chart review and the literature. Using Euro-QOL 5 Dimensions, utilities were obtained by surveying medical oncologists and costs from the Ontario Ministry of Health and the literature. The perspective of the Canadian public health care system was used over a 5-year time horizon with a 5% discount in 2012 Canadian dollars. Results Al l three strategies had similar efficacy, but strategy C was most expensive. The incremental cost-effectiveness ratios (ICERs) for strategies B and C compared with A were 119,623 and 3,176,591, respectively. The model was primarily driven by the acquisition cost of the drugs. Strategy B was most cost effective when the willingness-to-pay threshold was > $130,000 per quality-adjusted life-year. Sensitivity analysisshowed that strategy C would be cost-effective only when the progression-free survival of EGFRI is better than Bev in 1Lwith hazard ratio < 0.23 at willingness-to-pay of $150,000 per quality-adjusted life-year. Conclusion First-line use of EGFRI in metastatic colorectal cancer is not cost effective at its current pricing relative to Bev. [ABSTRACT FROM AUTHOR]

Microtubules play a crucial role in the generation, migration and differentiation of nascent neurons in the developing vertebrate brain. Mutations in the constituents of microtubules, the tubulins, are knownto cause an array of neurological disorders, including lissencephaly, polymicrogyria and microcephaly. In this study we explore the genetic and cellular mechanisms that cause TUBB5-associated microcephaly by exploiting two new mouse models: a conditional E401K knock-in, and a conditional knockout animal. These mice present with profound microcephaly due to a loss of upper-layer neurons that correlates with massive apoptosis and upregulation of p53. This phenotype is associated with a delay in cell cycle progression and ectopic DNA elements in progenitors, which is dependent on the dosage of functional Tubb5. Strikingly, we report ectopic Sox2-positive progenitors and defects in spindle orientation in our knock-in mouse line, which are absent in knockout animals. Thiswork sheds light on the functional repertoire of Tubb5, reveals that the E401K mutation acts by a complex mechanism, and demonstrates that the cellular pathology driving TUBB5-associated microcephaly is cell death. [ABSTRACT FROM AUTHOR]

Background: The late cardiac effect of adjuvant trastuzumab and its potential interaction with anthracycline have not been well-studied on a population level. Methods: In this retrospective population-based cohort study, female breast cancer patients in Ontario, diagnosed between 2003 and 2009, were identified by the Ontario Cancer Registry and linked to administrative databases to ascertain demographics, cardiac risk factors, comorbidities, and use of adjuvant trastuzumab and other chemotherapy. Patients with pre-existing heart failure (HF) were excluded. The main endpoint was new diagnosis of HF. Analyses included Kaplan-Meier (KM) survival analysis, multivariable piecewise Cox regression, and competing risk and propensity score analyses. All statistical tests were two-sided. Results: Nineteen thousand seventy-four women with breast cancer treated with adjuvant chemotherapy were identified, of whom 3371 (17.7%) also received adjuvant trastuzumab. Anthracycline use was 84.9% overall. After a median follow-up of 5.9 years, patients treated with trastuzumab and chemotherapy were more likely to develop HF than patients on chemotherapy alone (5-year cumulative incidences of 5.2% vs 2.5%; log-rank P < .001). After adjusting for confounders, adjuvant trastuzumab remained independently associated with incident HF in the first 1.5 years (HR = 5.77, 95% CI = 4.38 to 7.62, P < .001), but not thereafter (HR = 0.87, 95% CI = 0.57 to 1.33, P = .53). Anthracycline use did not increase the risk of HF with trastuzumab synergistically, neither within (P interaction = .92) nor beyond 1.5 years (P interaction = .23). Conclusion: Adjuvant trastuzumab was associated with increased risk of new incidence of HF in breast cancer survivors during the period of adjuvant treatment but not thereafter. Routine intensive monitoring may not be necessary after completing adjuvant therapy. [ABSTRACT FROM AUTHOR]

We here report an unusual case of Hb Bart’s (γ4) disease. Thalassemia screening of a couple showed that the wife was an α0-thalassemia (α0-thal) carrier and her husband’s mean corpuscular volume (MCV) was normal. Chorionic villus sampling (CVS) was performed at 13 weeks’ gestation for positive Down syndrome screening and chromosomal study of the cultured CVS showed a normal karyotype. Ultrasound examination at 22 weeks’ gestation showed fetal cardiomegaly and raised middle cerebral artery peak systolic velocity. Cordocentesis confirmed fetal anemia and showed Hb Bart’s disease. Multiplex gap-polymerase chain reaction (gap-PCR) for α-thal deletions on DNA extracted from the CVS showed the presence of a homozygous α0-thal − −SEA(Southeast Asian) deletion. The husband was found to be a carrier of the α+-thal −α3.7(rightward) deletion. Non paternity was excluded by fluorescent PCR using short tandem repeat (STR) markers on chromosomes 13, 18 and 21. Ade novoterminal deletion of chromosome 16 was excluded by array comparative genomic hybridization (aCGH). Detection of uniparental disomy (UPD), using STR markers on chromosome 16 showed maternal uniparental isodisomy from 16pter to 16p13.2, and uniparental heterodisomy from 16p13.13 to 16qter. [ABSTRACT FROM PUBLISHER]

Background: Epithelial growth factor receptor inhibitors (EGFRis) and bevacizumab (BEV) are used in combination with chemotherapy for the treatment of metastatic colorectal cancer (mCRC). However, few randomized controlled trials (RCTs) have directly compared their relative efficacy on progression-free survival (PFS) and overall survival (OS). Methods: We conducted a systematic review of first-line RCTs comparing (1) EGFRis vs. BEV, with chemotherapy in both arms (2) EGFRis + chemotherapy vs. chemotherapy alone, or (3) BEV + chemotherapy vs. chemotherapy alone, using Cochrane methodology. Data on and PFS and OS were extracted using the Parmar method. Pairwise meta-analyses and Bayesian network meta-analyses (NMA) were conducted to estimate the direct, indirect and combined PFS and OS hazard ratios (HRs) comparing EGFRis to BEV. Results: Seventeen RCTs contained extractable data for quantitative analysis. Combining direct and indirect data using an NMA did not show a statistical difference between EGFRis versus BEV (PFS HR = 1.11 (95% CR: 0.92–1.36) and OS HR = 0.91 (95% CR: 0.75–1.09)). Direct meta-analysis (3 RCTs), indirect (14 RCTs) and combined (17 RCTs) NMA of PFS HRs were concordant and did not show a difference between EGFRis and BEV. Meta-analysis of OS using direct evidence, largely influenced by one trial, showed an improvement with EGFRis therapy (HR = 0.79 (95% CR: 0.65–0.98)), while indirect and combined NMA of OS did not show a difference between EGFRis and BEV Successive inclusions of trials over time in the combined NMA did not show superiority of EGFRis over BEV. Conclusions: Our findings did not support OS or PFS benefits of EGFRis over BEV in first-line mCRC. [ABSTRACT FROM AUTHOR]

ABSTRACT The development of the mammalian brain requires the generation, migration, and differentiation of neurons, cellular processes that are dependent on a dynamic microtubule cytoskeleton. Mutations in tubulin genes, which encode for the structural subunits of microtubules, cause detrimental neurological disorders known as the tubulinopathies. The disease spectra associated with different tubulin genes are overlapping but distinct, an observation believed to reflect functional specification of this multigene family. Perturbation of the β-tubulin TUBB2B is known to cause polymicrogyria, pachygyria, microcephaly, and axon guidance defects. Here we provide a detailed analysis of the expression pattern of its murine homolog Tubb2b. The generation and characterization of BAC-transgenic eGFP reporter mouse lines has revealed that it is highly expressed in progenitors and postmitotic neurons during cortical development. This contrasts with the 8-week-old cortex, in which Tubb2b expression is restricted to macroglia, and expression is almost completely absent in mature neurons. This developmental transition in neurons is mirrored in the adult hippocampus and the cerebellum but is not a universal feature of Tubb2b; its expression persists in a population of postmitotic neurons in the 8-week-old retina. We propose that the dynamic spatial and temporal expression of Tubb2b reflects specific functional requirements of the microtubule cytoskeleton. J. Comp. Neurol. 523:2161-2186, 2015. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background Concurrent chemoradiotherapy followed by adjuvant chemotherapy (CRT-A) is often the regimen of choice in locoregionally advanced nasopharyngeal carcinoma (NPC). Many alternative regimens have been reported in the literature, however, it is unknown how effective these regimens are compared to each other due to the lack of direct comparisons. Our objective was to perform a network meta-analysis (NMA) to determine the relative survival benefits of these treatments for locoregionally advanced NPC. Methods We performed a systematic review following the Cochrane methodology, using MEDLINE, EMBASE and CENTRAL to identify all randomised controlled trials (RCTs) that compared different chemoradiotherapy regimens for locoregionally advanced NPC. Overall survival (OS) was the primary outcome of interest, and hazard ratios (HRs) were extracted using the Parmar method. Bayesian NMAs with random effects were conducted using WinBUGS. Results Twenty-five RCTs (5576 patients) were included in this review. All together, these trials compared seven different regimens: radiotherapy (RT), concurrent chemoradiotherapy (CRT), neoadjuvant followed by CRT (N-CRT), CRT-A, RT-A, N-RT and N-RT-A. All regimens that contained CRT performed significantly better than RT. CRT-A did not improve survival compared to CRT alone (0.98; 95% credible regions: 0.71–1.34). For N-CRT versus CRT, the HR was 1.03 (0.69–1.47). When CRT-A was compared against N-CRT, the resulting HR was 0.96 (0.64–1.48). Conclusions Adjuvant chemotherapy does not appear to improve survival following CRT. The efficacies of CRT, CRT-A and N-CRT all appeared to be similar. Further studies are warranted to determine the value of additional chemotherapy phases in specific patient subgroups. [ABSTRACT FROM AUTHOR]

Objectives: Percutaneous endoscopic gastrostomy (PEG) placement is essential for the provision of enteral nutrition in select head and neck cancer (HNC) patients. Minimally invasive tube placement is facilitated through one of two techniques, push or pull, but there have been conflicting results regarding safety profiles of these procedures. The objectives of this study were to determine the association of PEG insertion technique with gastrostomy tube complications, including stomal metastases.Methods: A multi-institutional retrospective cohort study of patients with HNC undergoing PEG insertion by either the pull (gastroscope assisted) or push (fluoroscopy assisted) technique was performed. Tube-related complications included infection, dislodgement, deterioration, leak, and other. Adjusted analysis was performed via a multivariable logistic regression model.Results: 1,575 patients were included across three institutions. Tube-related complications occurred in 36% of patients, the most common being peristomal leak (13%) and infection (16%). The push technique (OR 2.66, 95% CI: 1.42-4.97), and the presence of T4 disease (OR 4.62, 95% CI: 1.58-13.51), were associated with a greater risk of developing any tube-related complication. Infection rates were similar between pull and push cohorts. All detected stoma metastases occurred with the pull technique, with an overall prevalence of 0.32% amongst the cohort.Conclusions: The push technique is associated with a greater risk of developing any tube-related complication, but the rate of stomal metastases may be higher with the pull technique. There is potential for quality improvement measures to improve tube-related complications associated with either technique. [ABSTRACT FROM AUTHOR]

Pembrolizumab monotherapy has replaced chemotherapy as first-line treatment for patients with metastatic non-small-cell lung cancer with tumor programmed death-ligand 1 expression ≥ 50%. The benefit of chemotherapy combined with pembrolizumab, as compared to pembrolizumab monotherapy, remains uncertain. This systematic review and network meta-analysis aimed to compare these therapies through a network of randomized controlled trials. Endpoints evaluated were progression-free survival (PFS) and overall survival (OS) expressed as hazard ratio (HR) and restricted mean survival time (RMST) through reconstruction of individual patient data from Kaplan-Meier curves, and objective response rate and adverse events. Four trials were included. Through HR and RMST, combination therapy demonstrated longer PFS and similar OS as compared to pembrolizumab monotherapy. Combination therapy was associated with an increase in response rate and adverse events. Thus, combination therapy can be considered when rapid response or prevention of rapid progression is needed. Further evidence to directly compare these therapies is required. [Display omitted] • A network meta-analysis allows for the indirect comparison of treatments. • Restricted mean survival time is a robust survival measure for immunotherapies. • Combining chemotherapy and pembrolizumab may improve progression-free survival. • Pembrolizumab with or without chemotherapy have similar overall survival. • This combination can be considered for rapid response or prevention of rapid progression. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Puerariae Lobatae Radix (PLR) and Puerariae Thomsonii Radix (PTR) are traditional Chinese medicines used for the treatment of diabetes and cardiovascular diseases. These two herbs are used interchangeably in clinical practice, even though they possess significantly different chemical profiles. In the case of Pueraria species, the misidentification is related to the multiple Chinese common names in clinical practice and variable pharmaceutical Latin names in different versions of the Pharmacopoeia of the People׳s Republic of China. In addition, there is lack of evidence demonstrating how the differences in the chemical profile would impact on the pharmacological activity of the two herbs. Therefore, the aim of this study was to compare the microscopic, phytochemical profiles and anti-diabetic activity of PLR and PTR so that the two species can be differentiated. Materials and methods The microscopic characteristics of the PLR and PTR were observed and measured by an optical microscope. The major compounds were quantified by ultra-performance liquid chromatography (UPLC) and total flavonoid content (TFC) colorimetric assay. The free radical scavenging capacity was assessed by 2,2-diphenyl-2-picrylhydrazyl (DPPH) antioxidant assays. Anti-diabetic activity was determined by the inhibition of porcine pancreatic α-amylase and rat intestinal α-glucosidase activities. Results Microscopic results illustrated that the size of xylem vessels (PLR: 0.1390±0.0184 mm; PTR: 0.0471±0.0109 mm), number of fibre per bundle (PLR: 32.6800±2.8780; PTR: 16.5900±0.9982) and the size of fibre (PLR: 0.0075±0.0003 mm 2 ; PTR: 0.0025±0.0002 mm 2 ) in PLR were significantly greater than that in PTR ( p <0.01). PLR possessed a significantly lower total starch content (PLR: 0.5288±1.2559 mg starch/g DM; PTR: 76.7954±2.9905 mg starch/g DM) and total dietary fibre content (PLR: 4.2886±0.3466 g/100 g DM; PTR: 12.4148±0.4541 g/100 g DM) as compared to PTR. Isoflavonoids including puerarin, daidzin, genistin and daidzein were the major chemical constituents in both species. However, the average content of puerarin in PLR was found to be eleven times greater than that in PTR. Furthermore, the TFC, DPPH free radical scavenging capacity, anti-α-amylase and anti-α-glucosidase in the PLR extracts were 4.42, 4.91, 3.10 and 4.22 times greater than in the PTR extracts. Conclusions This study provides a comprehensive investigation on the two medicinal valuable Pueraria species and allows differences to be ascertained. This information can be used to update monographs which will help practitioners and dispensers differentiate the herbs. Further study on the interchangeable use of PLR and PTR in clinical practice is urgently warranted. [ABSTRACT FROM AUTHOR]

The dried roots of Pueraria lobata (Puerariae Lobatae Radix; PLR) and Pueraria thomsonii (Puerariae Thomsonii Radix; PTR) are medicinal herbs that are used interchangeably in clinical practice, even though their chemical profiles are different. Therefore, the aim of this study was to develop a rapid and non-destructive method for the quality control of Pueraria species using Raman spectroscopy in combination with partial least squares analysis. Partial least squares-discriminant analysis (PLS-DA) was used to differentiate PLR from PTR, whereas partial least squares regression (PLSR) was used to predict the total phenolic content (TPC) and antioxidant capacities of the Pueraria species. Raman spectroscopy revealed that spectral characteristics of starch and polyphenols differentiated the two species, with the PLS-DA model giving 100% classification accuracy for the tested samples. A significantly higher TPC ( p < 0.001), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging activity ( p < 0.001) and cupric reducing antioxidant capacity (CUPRAC; p < 0.001) were observed for PLR as compared to PTR. The high ratio of performance to deviation values (TPC: 9.84; ABTS: 7.11; CUPRAC: 7.13) indicated the PLSR models were robust for predicting TPC and antioxidant capacities. The loading plot revealed that the content of starch and polyphenols were important factors in differentiating PLR from PTR and predicting TPC and antioxidant capacities. The results demonstrate that Raman spectroscopy coupled with chemometrics is a rapid method for the quality control of PLR and PTR. These methods can be applied as a template for the quality control of other herbal medicines and products to promote the correct identification of herbs for clinical practice. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]