Lung Cancer Oncogene-Directed Therapy, Fertility, and Pregnancy.

INTRODUCTION: Alterations in the highly actionable lung cancer oncogenes, EGFR, ALK, and ROS1, occur across the age spectrum. Pregnancy and plans for motherhood consequently overlap with diagnoses of advanced oncogene-driven NSCLC. Guidelines for cytotoxic agents and pregnancy are well established. Nevertheless, accessible data on targeted lung cancer therapy during pregnancy or egg retrieval has not been collated previously, nor have the issues of reproduction in the setting of specific oncogene-addicted advanced NSCLC been widely discussed. METHODS: We performed a narrative review of ex vivo placenta perfusion studies, pharmacologic characteristics, mutagenicity, animal embryo-fetal development studies, and case reports of pathways to motherhood, pregnancies, and egg retrieval while on EGFR-, ALK-, or ROS1-targeted therapy. RESULTS: EGFR inhibitors may reduce female fertility while on therapy owing to decrease in corpora lutea. Odds of pregnancy in women on EGFR and ALK inhibitors may be reduced owing to potential increase in postimplantation loss found in animals. Crizotinib and entrectinib exhibit in vitro mutagenic potential. Several effects on human pregnancies have been noted; however, 11 EGFR and ALK tyrosine kinase inhibitor-exposed infants have been documented free of substantial adverse health effects by ages 4 months to 2 years. Successful gestational surrogacy has been reported in two women treated with crizotinib. Adoption and termination approaches have also been undertaken by some patients. CONCLUSIONS: Reproduction may not be out of reach for some patients with advanced NSCLC. Additional explorations of the impact and optimal timing of targeted therapy in egg capture and pregnancy are needed. Wider scientific and societal discussion about the issues of reproduction in advanced NSCLC is warranted.

Role of rodent models in advancing precision medicine for Parkinson's disease.

With a current lack of disease-modifying treatments, an initiative toward implementing a precision medicine approach for treating Parkinson's disease (PD) has emerged. However, challenges remain in how to define and apply precision medicine in PD. To accomplish the goal of optimally targeted and timed treatment for each patient, preclinical research in a diverse population of rodent models will continue to be an essential part of the translational path to identify novel biomarkers for patient diagnosis and subgrouping, understand PD disease mechanisms, identify new therapeutic targets, and screen therapeutics prior to clinical testing. This review highlights the most common rodent models of PD and discusses how these models can contribute to defining and implementing precision medicine for the treatment of PD.

Targeting alpha-synuclein via the immune system in Parkinson's disease: Current vaccine therapies.

Parkinson's disease (PD) is the second most common neurodegenerative disorder and is defined pathologically by the abnormal accumulation of the presynaptic protein alpha-synuclein (aSyn) in the form of Lewy bodies and Lewy neurites and loss of midbrain dopaminergic neurons in the substantia nigra pars compacta. Because of aSyn's involvement in both sporadic and familial forms of PD, it has become a key target for the development of novel therapeutics. Aberrant aSyn is associated with multiple mechanisms of neuronal dysfunction and degeneration including inflammation, impaired mitochondrial function, altered protein degradation systems, and oxidative stress. Inflammation, in particular, has emerged as a potential significant contributor early in the disease making it an attractive target for disease modification and neuroprotection. Thus, immunotherapies targeting aSyn are currently being investigated in pre-clinical and clinical trials. The focus of this review is to highlight the role of aSyn in neuroinflammation and discuss the current status of aSyn-directed immunotherapies in pre-clinical and clinical trials for PD.

Variation in Toxicity Reporting Methods for Early Phase Lung Cancer Treatment Trials at Oncology Conferences.

INTRODUCTION: Phase I and II trials provide the initial human safety and tolerability data for new drugs. Nevertheless, the methods for presenting toxicity data are not standardized. Clinicians often first encounter these data at professional conferences. We sought to characterize how the burden of adverse events (AEs) is reported at the largest professional conference in clinical oncology. METHODS: We collected toxicity data from all lung cancer-associated phase I and II trial presentations and posters at the American Society for Clinical Oncology annual meetings from 2017 to 2019. We captured the various AE features, including the minimum incidence used for reporting; whether AEs found were treatment emergent or treatment related, grouped by organ system or separated by individual descriptors; whether combined or separated across dose levels when a dose-escalation component was included; and whether dose-limiting toxicities, serious AE, dose-reduction rules, and denominators for laboratory tests were described. RESULTS: A total of 209 trials were analyzed. There was wide variability in toxicity reporting practices. Six different thresholds for reporting AEs of any grade were used. Treatment-related AEs were reported twice as frequently as treatment-emergent AEs. Toxicities were as likely to be reported across dose levels as by dose level. Terms such as dose-limiting toxicity and serious AE were rarely defined. Dose-reduction rules and denominators for laboratory tests were never defined. CONCLUSIONS: Standardization of methods for reporting toxicities could improve the quality and ease of comparability of data on adverse effects in early phase therapeutic trials. A minimal AE data disclosure template is proposed.

Congenital melanocytic nevi in young children: Histopathologic features and clinical outcomes.

BACKGROUND: Although only large congenital melanocytic nevi (CMN) are associated with a significantly high risk for malignant transformation, CMN of all sizes are prone to changes in clinical appearance in early childhood and thus are often biopsied or excised. While CMNs typically exhibit benign behavior, atypical histopathologic findings might be common and may prompt additional unnecessary procedures. OBJECTIVE: To assess the prevalence and associated clinical outcomes of atypical histopathologic features in CMN in children. METHODS: A single center retrospective study was conducted with patients 0-35 months of age with CMN diagnosed by histopathology between 1993-2013. RESULTS: One hundred seventy-nine patients with a total of 197 CMNs were identified. Cytologic atypia, architectural disorder, or pagetoid spread were present in 73% of CMN. With a mean follow up of 7.3 years, no cases of melanoma or CMN-related deaths were identified. LIMITATIONS: Our findings were based on a largely Caucasian population and might not apply to darker skin types. Our findings might not apply to older children or adults with CMN. CONCLUSION: Atypical histopathologic features of cytologic atypia, architectural disorder, and pagetoid spread are common in benign CMN of young children.

Using Seroprevalence and Immunisation Coverage Data to Estimate the Global Burden of Congenital Rubella Syndrome, 1996-2010: A Systematic Review.

BACKGROUND: The burden of Congenital Rubella Syndrome (CRS) is typically underestimated in routine surveillance. Updated estimates are needed following the recent WHO position paper on rubella and recent GAVI initiatives, funding rubella vaccination in eligible countries. Previous estimates considered the year 1996 and only 78 (developing) countries. METHODS: We reviewed the literature to identify rubella seroprevalence studies conducted before countries introduced rubella-containing vaccination (RCV). These data and the estimated vaccination coverage in the routine schedule and mass campaigns were incorporated in mathematical models to estimate the CRS incidence in 1996 and 2000-2010 for each country, region and globally. RESULTS: The estimated CRS decreased in the three regions (Americas, Europe and Eastern Mediterranean) which had introduced widespread RCV by 2010, reaching <2 per 100,000 live births (the Americas and Europe) and 25 (95% CI 4-61) per 100,000 live births (the Eastern Mediterranean). The estimated incidence in 2010 ranged from 90 (95% CI: 46-195) in the Western Pacific, excluding China, to 116 (95% CI: 56-235) and 121 (95% CI: 31-238) per 100,000 live births in Africa and SE Asia respectively. Highest numbers of cases were predicted in Africa (39,000, 95% CI: 18,000-80,000) and SE Asia (49,000, 95% CI: 11,000-97,000). In 2010, 105,000 (95% CI: 54,000-158,000) CRS cases were estimated globally, compared to 119,000 (95% CI: 72,000-169,000) in 1996. CONCLUSIONS: Whilst falling dramatically in the Americas, Europe and the Eastern Mediterranean after vaccination, the estimated CRS incidence remains high elsewhere. Well-conducted seroprevalence studies can help to improve the reliability of these estimates and monitor the impact of rubella vaccination.

Characterization of the Risks of Adverse Outcomes Following Rubella Infection in Pregnancy.

Although most infections with the rubella virus result in relatively minor sequelae, rubella infection in early pregnancy may lead to severe adverse outcomes for the fetus. First recognized in 1941, congenital rubella syndrome (CRS) can manifest with a diverse range of symptoms, including congenital cataracts, glaucoma, and cardiac defects, as well as hearing and intellectual disability. The gestational age of the fetus at the time of the maternal rubella infection impacts the probability and severity of outcomes, with infection in early pregnancy increasing the risks of spontaneous termination (miscarriage), fetal death (stillbirth), birth defects, and reduced survival for live-born infants. Rubella vaccination continues to change the epidemiology of rubella and CRS globally, but no models currently exist to evaluate the economic benefits of rubella management. This systematic review provides an overall assessment of the weight of the evidence for the outcomes associated with rubella infections in the first 20 weeks of pregnancy. We identified, evaluated, and graded 31 studies (all from developed countries) that reported on the pregnancy outcomes of at least 30 maternal rubella infections. We used the available evidence to estimate the increased risks of spontaneous termination, fetal death, infant death, and CRS as a function of the timing of rubella infection in pregnancy and decisions about induced termination. These data support the characterization of the disability-adjusted life years for outcomes associated with rubella infection in pregnancy. We find significant impacts associated with maternal rubella infections in early pregnancy, which economic analyses will miss if they only focus on live births of CRS cases. Our estimates of fetal loss from increased induced terminations due to maternal rubella infections provide context that may help to explain the relatively low numbers of observed CRS cases per year despite potentially large burdens of disease. Our comprehensive review of the weight of the evidence of all pregnancy outcomes demonstrates the importance of including all outcomes in models that characterize rubella-related disease burdens and costs.

Systematic Review of the Manifestations of Congenital Rubella Syndrome in Infants and Characterization of Disability-Adjusted Life Years (DALYs).

Congenital rubella syndrome (CRS) continues to cause disability among unvaccinated populations in countries with no or insufficient rubella vaccine coverage to prevent transmission. We systematically reviewed the literature on birth outcomes associated with CRS to estimate the duration, severity, and frequency of combinations of morbidities. We searched PubMed, the Science Citation Index, and references from relevant articles for studies in English with primary data on the frequency of CRS manifestations for ≥20 cases and identified 65 studies representing 66 study populations that met our inclusion criteria. We abstracted available data on CRS cases with one or more hearing, heart, and/or eye defect following maternal rubella infection during the period of 0-20 weeks since the last menstrual period. We assessed the quality and weight of the available evidence using a modified Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Most of the evidence originates from studies in developed countries of cohorts of infants identified with CRS in the 1960s and 1970s, prior to the development of standardized definitions for CRS and widespread use of vaccine. We developed estimates of undiscounted disability-adjusted life years (DALYs) lost per CRS case for countries of different income levels. The estimates ranged from approximately 19 to 39 for high-income countries assuming optimal treatment and from approximately 29 to 39 DALYs lost per CRS case in low- and lower- middle-income countries assuming minimal treatment, with the lower bound based on 2010 general global burden of disease disability weights and the upper bound based on 1990 age-specific and treatment-specific global burden of disease disability weights. Policymakers and analysts should appreciate the significant burden of disability caused by CRS as they evaluate opportunities to manage rubella.

The estimated mortality impact of vaccinations forecast to be administered during 2011-2020 in 73 countries supported by the GAVI Alliance.

INTRODUCTION: From August to December 2011, a multidisciplinary group with expertise in mathematical modeling was constituted by the GAVI Alliance and the Bill & Melinda Gates Foundation to estimate the impact of vaccination in 73 countries supported by the GAVI Alliance. METHODS: The number of deaths averted in persons projected to be vaccinated during 2011-2020 was estimated for ten antigens: hepatitis B, yellow fever, Haemophilus influenzae type B (Hib), Streptococcus pneumoniae, rotavirus, Neisseria meningitidis serogroup A, Japanese encephalitis, human papillomavirus, measles, and rubella. Impact was calculated as the difference in the number of deaths expected over the lifetime of vaccinated cohorts compared to the number of deaths expected in those cohorts with no vaccination. Numbers of persons vaccinated were based on 2011 GAVI Strategic Demand Forecasts with projected dates of vaccine introductions, vaccination coverage, and target population size in each country. RESULTS: By 2020, nearly all GAVI-supported countries with endemic disease are projected to have introduced hepatitis B, Hib, pneumococcal, rotavirus, rubella, yellow fever, N. meningitidis serogroup A, and Japanese encephalitis-containing vaccines; 55 (75 percent) countries are projected to have introduced human papillomavirus vaccine. Projected use of these vaccines during 2011-2020 is expected to avert an estimated 9.9 million deaths. Routine and supplementary immunization activities with measles vaccine are expected to avert an additional 13.4 million deaths. Estimated numbers of deaths averted per 1000 persons vaccinated were highest for first-dose measles (16.5), human papillomavirus (15.1), and hepatitis B (8.3) vaccination. Approximately 52 percent of the expected deaths averted will be in Africa, 27 percent in Southeast Asia, and 13 percent in the Eastern Mediterranean. CONCLUSION: Vaccination of persons during 2011-2020 in 73 GAVI-eligible countries is expected to have substantial public health impact, particularly in Africa and Southeast Asia, two regions with high mortality. The actual impact of vaccination in these countries may be higher than our estimates because several widely used antigens were not included in the analysis. The quality of our estimates is limited by lack of data on underlying disease burden and vaccine effectiveness against fatal disease outcomes in developing countries. We plan to update the estimates annually to reflect updated demand forecasts, to refine model assumptions based on results of new information, and to extend the analysis to include morbidity and economic benefits.

Assessment of the 2010 global measles mortality reduction goal: results from a model of surveillance data.

BACKGROUND: In 2008 all WHO member states endorsed a target of 90% reduction in measles mortality by 2010 over 2000 levels. We developed a model to estimate progress made towards this goal. METHODS: We constructed a state-space model with population and immunisation coverage estimates and reported surveillance data to estimate annual national measles cases, distributed across age classes. We estimated deaths by applying age-specific and country-specific case-fatality ratios to estimated cases in each age-country class. FINDINGS: Estimated global measles mortality decreased 74% from 535,300 deaths (95% CI 347,200-976,400) in 2000 to 139,300 (71,200-447,800) in 2010. Measles mortality was reduced by more than three-quarters in all WHO regions except the WHO southeast Asia region. India accounted for 47% of estimated measles mortality in 2010, and the WHO African region accounted for 36%. INTERPRETATION: Despite rapid progress in measles control from 2000 to 2007, delayed implementation of accelerated disease control in India and continued outbreaks in Africa stalled momentum towards the 2010 global measles mortality reduction goal. Intensified control measures and renewed political and financial commitment are needed to achieve mortality reduction targets and lay the foundation for future global eradication of measles. FUNDING: US Centers for Disease Control and Prevention (PMS 5U66/IP000161).

Strategic planning for measles control: using data to inform optimal vaccination strategies.

BACKGROUND: In response to repeated requests for assistance in evaluating the health benefit and cost implications of adjustments to national measles immunization strategies, the World Health Organization (WHO) has developed the Measles Strategic Planning (MSP) tool to harness routinely available data to estimate effectiveness and cost effectiveness of vaccination strategies. METHOD: The MSP tool estimates measles incidence and mortality through a country-specific cohort model, using a probability of infection dependent on population immunity levels. This method approximates measles transmission dynamics without requiring detailed data that would prohibit use in low- and middle-income countries. Coupled with cost data, the tool estimates incremental costs and cost effectiveness of user-defined vaccination strategies over 5-10 year planning periods. RESULTS: The MSP tool produces valid estimates of measles incidence in settings with low to moderate vaccination coverage. Early adopters report that the tool facilitates decision making by minimizing the amount of time required to assess the impact of vaccination strategies on population immunity. CONCLUSIONS: By clearly illustrating what vaccination strategies can effectively protect against measles at the least cost to immunization programs, the MSP tool supports evidence-based decision making for effective and comprehensive measles control.

Global eradication of measles: an epidemiologic and economic evaluation.

BACKGROUND: Measles remains an important cause of morbidity and mortality in children in developing countries. Due to the success of the measles mortality reduction and elimination efforts thus far, the WHO has raised the question of whether global eradication of measles is economically feasible. METHODS: The cost-effectiveness of various measles mortality reduction and eradication scenarios was evaluated vis-à-vis the current mortality reduction goal in six countries and globally. Data collection on costs of measles vaccination were conducted in six countries in four regions: Bangladesh, Brazil, Colombia, Ethiopia, Tajikistan, and Uganda. The number of measles cases and deaths were projected from 2010 to 2050 using a dynamic, age-structured compartmental model. The incremental cost-effectiveness ratios were then calculated for each scenario vis a vis the baseline. RESULTS: Measles eradication by 2020 was the found to be the most cost-effective scenario, both in the six countries and globally. Eradicating measles by 2020 is projected to cost an additional discounted $7.8 billion and avert a discounted 346 million DALYs between 2010 and 2050. CONCLUSIONS: In conclusion, the study found that, compared to the baseline, reaching measles eradication by 2020 would be the most cost-effective measles mortality reduction scenario, both for the six countries and on a global basis.

The cost-effectiveness of supplementary immunization activities for measles: a stochastic model for Uganda.

Supplemental Immunization Activities (SIAs) have become an important adjunct to measles control efforts in countries that endeavor to achieve higher levels of population immunity than can be achieved in a growing routine immunization system. Because SIAs are often supported with funds that have alternative uses, decision makers need to know how cost-effective they are compared with other options. This study integrated a dynamic stochastic model of measles transmission in Uganda (2010-2050) with a cost model to compare a strategy of maintaining Uganda's current (2008) levels of the first dose of routine measles-containing vaccine (MCV1) coverage at 68% with SIAs with a strategy using the same levels of MCV1 coverage without SIAs. The stochastic model was fitted with parameters drawn from district-level measles case reports from Uganda, and the cost model was fitted to administrative data from the Ugandan Expanded Program on Immunization and from the literature. A discount rate of 0.03, time horizon of 2010-2050, and a societal perspective on costs were assumed. Costs expressed in US dollars (2010) included vaccination costs, disease treatment costs including lost productivity of mothers, as well as costs of outbreaks and surveillance. The model estimated that adding on triennial SIAs that covered 95% of children aged 12-59 months to a system that achieved routine coverage rates of 68% would have an incremental cost-effectiveness ratio (ICER) of $1.50 ($US 2010) per disability-adjusted life year averted. The ICER was somewhat higher if the discount rate was set at either 0 or 0.06. The addition of SIAs was found to make outbreaks less frequent and lower in magnitude. The benefit was reduced if routine coverage rates were higher. This cost-effectiveness ratio compares favorably to that of other commonly accepted public health interventions in sub-Saharan Africa.

Assessing the cost-effectiveness of measles elimination in Uganda: local impact of a global eradication program.

BACKGROUND: Measles control has succeeded worldwide, and many countries have substantially reduced incidence and mortality. This has led to consideration of the feasibility of measles elimination in Uganda within the context of global eradication. Before an elimination program is initiated, it is important to consider its potential economic impact, including its cost-effectiveness. METHODS: Incremental cost-effectiveness ratios (ICERs) were estimated for measles mortality reduction and measles elimination in Uganda. A dynamic age-structured compartmental model of measles transmission was used to simulate scenarios and estimate health outcomes and costs. The main outcome measures were costs, measles cases, measles deaths, disability-adjusted life-years (DALYs), and ICERs measured as cost per DALY averted through either the year 2030 or 2050. RESULTS: Measles elimination by 2020 averted 130,232 measles cases, 3520 measles deaths, and 106,330 DALYs through the year 2030, compared with the next best scenario (95% mortality reduction by 2015), and it was the most cost-effective strategy, with ICERs of $556 per DALY averted (2030 time horizon) and $284 per DALY averted (2050 time horizon). CONCLUSIONS: Measles elimination in Uganda, as part of a global eradication program, is projected to be highly cost-effective and should be considered among the available policy options for dealing with the disease.

Alert tones are frequently inaudible among patients with implantable cardioverter-defibrillators.

BACKGROUND: Current management guidelines for patients with Medtronic Sprint Fidelis ICD leads (Medtronic Inc., Minneapolis, MN, USA) include prominent use of Patient Alert, a feature in which the ICD generator emits audible beeps at two programmable frequencies. Because hearing loss is highly prevalent beyond the sixth decade of life, the utility of this feature is unclear. Therefore, we conducted a survey of patients' ability to hear the Medtronic Patient Alert. METHODS: During visits to an outpatient device clinic, patients with Medtronic ICDs were evaluated for their ability to hear ICD tones. RESULTS: The patient group consisted of 102 patients. Patients older than 70 years comprised 68% of the sample, with 16% between 60 and 70, and 17% younger than 60 years. Of the 102 patients, 59% (56% of males and 70% of females) were able to hear at least one tone. Ability to hear ICD tones decreased with advancing age. Among patients over 60 and 70 years, 52% and 43%, respectively (P < 0.001 vs. patients below 60 and 70 years), could hear at least one tone. CONCLUSIONS: The Patient Alert feature is not useful among a large proportion of ICD patients. Patients with Sprint Fidelis leads should be evaluated for their ability to hear audible ICD tones. For patients who cannot hear the Patient Alert feature, a wireless remote monitoring and/or daily application of a magnet by a caregiver should be considered. Device manufacturers should include nonauditory alert technologies such as wireless remote monitoring and vibratory stimulation in future devices.