Carboplatin dosage: prospective evaluation of a simple formula based on renal function.

A dosage formula has been derived from a retrospective analysis of carboplatin pharmacokinetics in 18 patients with pretreatment glomerular filtration rates (GFR) in the range of 33 to 136 mL/min. Carboplatin plasma clearance was linearly related to GFR (r = 0.85, P less than .00001) and rearrangements of the equation describing the correlation gave the dosage formula dose (mg) = target area under the free carboplatin plasma concentration versus time curve (AUC) x (1.2 x GFR + 20). In a prospective clinical and pharmacokinetic study the formula was used to determine the dose required to treat 31 patients (GFR range, 33 to 135 mL/min) with 40 courses of carboplatin. The target AUC was escalated from 3 to 8 mg carboplatin/mL/min. Over this AUC range the formula accurately predicted the observed AUC (observed/predicted ratio 1.24 +/- 0.11, r = 0.886) and using these additional data, the formula was refined. Dose (mg) = target AUC x (GFR + 25) is now the recommended formula. AUC values of 4 to 6 and 6 to 8 mg/mL. min gave rise to manageable hematological toxicity in previously treated and untreated patients, respectively, and hence target AUC values of 5 and 7 mg/mL min are recommended for single-agent carboplatin in these patient groups. Pharmacokinetic modeling demonstrated that the formula was reasonably accurate regardless of whether a one- or two-compartment model most accurately described carboplatin pharmacokinetics, assuming that body size did not influence nonrenal clearance. The validity of this assumption was demonstrated in 13 patients where no correlation between surface area and nonrenal clearance was found (r = .31, P = .30). Therefore, the formula provides a simple and consistent method of determining carboplatin dose in adults. Since the measure of carboplatin exposure in the formula is AUC, and not toxicity, it will not be influenced by previous or concurrent myelosuppressive therapy or supportive measures. The formula is therefore applicable to combination and high-dose studies as well as conventional single-agent therapy, although the target AUC for carboplatin will need to be redefined for combination chemotherapy.

Cardiovascular Risk Factor Knowledge among Monolingual Hispanics.

Hispanics in the United States have worse cardiovascular disease (CVD) risk factor profiles than non-Hispanic Whites. Cardiovascular health literacy is important for health promotion but is not well characterized among monolingual Spanish-speaking Hispanics outside of health care settings. We recruited Hispanic participants (N=235) from a community-based health fair in Denver, Colorado. A total of 182 participants (77%) completed a subsequent language-congruent telephone survey to assess CVD risk-factor knowledge. Of these, 174 self-identified as monolingual Spanish-speaking, and constituted the analysis cohort. Cardiovascular disease risk knowledge score was defined as the number of established risk factors an individual participant could name (out of 10 pre-specified), and multivariable regression analyses were conducted to determine factors independently associated with knowledge. The mean knowledge score for the cohort was 2.2 ± 1.1 out of 10. This suggests an unmet need for tailored educational interventions beyond simple screening events.

A Point-of-Care Algorithm to Guide Proper Device Selection for Ambulatory Electrocardiography.

In the outpatient setting, ambulatory electrocardiography is the most frequently used diagnostic modality for the evaluation of patients in whom cardiac arrhythmias or conduction abnormalities are suspected. Proper selection of the device type and monitoring duration is critical for optimizing diagnostic yield and cost-effective resource utilization. However, despite guidance from major professional societies, the lack of systematic guidance for proper test selection in many institutions results in the need for repeat testing, which leads to not only increased resource utilization and cost of care, but also suboptimal patient care. To address this unmet need at our own institution, we formed a multidisciplinary panel to develop a concise, yet comprehensive algorithm, incorporating the most common indications for ambulatory electrocardiography, to efficiently guide clinicians to the most appropriate test option for a given clinical scenario, with the goal of maximizing diagnostic yield and optimizing resource utilization. The algorithm was designed as a single-page, color-coded flowchart to be utilized both as a rapid reference guide in printed form, and a decision support tool embedded within the electronic medical records system at the point of order entry. We believe that systematic adoption of this algorithm will optimize diagnostic efficiency, resource utilization, and importantly, patient care and satisfaction.

A Pilot Study and Ecological Model of Smoking Cues to Inform Mobile Health Strategies for Quitting Among Low-Income Smokers.

One crucial factor that leads to disparities in smoking cessation between groups with higher and lower socioeconomic status is more prevalent socioenvironmental smoking cues in low-income communities. Little is known about how these cues influence socioeconomically disadvantaged smokers in real-world scenarios and how to design interventions, especially mobile phone-based interventions, to counteract the impacts of various types of smoking cues. We interviewed 15 current smokers living in low-income communities and scanned their neighborhoods to explore smoking-related experiences and identify multilevel cues that may trigger them to smoke. Findings suggest four major types of smoking cues influence low-income smokers-internal, habitual, social, and environmental. We propose an ecological model of smoking cues to inform the design of mobile health (mHealth) interventions for smoking cessation. We suggest that user-triggered strategies will be most useful to address internal cues; server-triggered strategies will be most suitable in changing perceived social norms of smoking and routine smoking activities to address social and habitual cues; and context-triggered strategies will be most effective for counteracting environmental cues. The pros and cons of each approach are discussed regarding their cost-effectiveness, the potential to provide personalized assistance, and scale.

The paradox-breaking panRAF plus SRC family kinase inhibitor, CCT3833, is effective in mutant KRAS-driven cancers.

BACKGROUND: KRAS is mutated in ∼90% of pancreatic ductal adenocarcinomas, ∼35% of colorectal cancers and ∼20% of non-small-cell lung cancers. There has been recent progress in targeting G12CKRAS specifically, but therapeutic options for other mutant forms of KRAS are limited, largely because the complexity of downstream signaling and feedback mechanisms mean that targeting individual pathway components is ineffective. DESIGN: The protein kinases RAF and SRC are validated therapeutic targets in KRAS-mutant pancreatic ductal adenocarcinomas, colorectal cancers and non-small-cell lung cancers and we show that both must be inhibited to block growth of these cancers. We describe CCT3833, a new drug that inhibits both RAF and SRC, which may be effective in KRAS-mutant cancers. RESULTS: We show that CCT3833 inhibits RAF and SRC in KRAS-mutant tumors in vitro and in vivo, and that it inhibits tumor growth at well-tolerated doses in mice. CCT3833 has been evaluated in a phase I clinical trial (NCT02437227) and we report here that it significantly prolongs progression-free survival of a patient with a G12VKRAS spindle cell sarcoma who did not respond to a multikinase inhibitor and therefore had limited treatment options. CONCLUSIONS: New drug CCT3833 elicits significant preclinical therapeutic efficacy in KRAS-mutant colorectal, lung and pancreatic tumor xenografts, demonstrating a treatment option for several areas of unmet clinical need. Based on these preclinical data and the phase I clinical unconfirmed response in a patient with KRAS-mutant spindle cell sarcoma, CCT3833 requires further evaluation in patients with other KRAS-mutant cancers.

Elements of Social Convoy Theory in Mobile Health for Palliative Care: Scoping Review.

BACKGROUND: Mobile health (mHealth) provides a unique modality for improving access to and awareness of palliative care among patients, families, and caregivers from diverse backgrounds. Some mHealth palliative care apps exist, both commercially available and established by academic researchers. However, the elements of family support and family caregiving tools offered by these early apps is unknown. OBJECTIVE: The objective of this scoping review was to use social convoy theory to describe the inclusion and functionality of family, social relationships, and caregivers in palliative care mobile apps. METHODS: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Review guidelines, a systematic search of palliative care mHealth included (1) research-based mobile apps identified from academic searches published between January 1, 2010, and March 31, 2019 and (2) commercially available apps for app stores in April 2019. Two reviewers independently assessed abstracts, app titles, and descriptions against the inclusion and exclusion criteria. Abstracted data covered app name, research team or developer, palliative care element, target audience, and features for family support and caregiving functionality as defined by social convoy theory. RESULTS: Overall, 10 articles describing 9 individual research-based apps and 22 commercially available apps were identified. Commercially available apps were most commonly designed for both patients and social convoys, whereas the majority of research apps were designed for patient use only. CONCLUSIONS: Results suggest there is an emerging presence of apps for patients and social convoys receiving palliative care; however, there are many needs for developers and researchers to address in the future. Although palliative care mHealth is a growing field, additional research is needed for apps that embrace a team approach to information sharing, target family- and caregiver-specific issues, promote access to palliative care, and are comprehensive of palliative needs.

Advancing evidence-based digital health through an innovative research environment: an academic-industry collaboration case report.

The proliferation of technology enthuses clinicians, researchers, and entrepreneurs to revolutionize health care and care delivery. Intersecting in the field of digital health, academic-industry collaboration (AIC) play a critical role in advancing evidence-based innovations into real world application. AIC models vary, but historically have not included the strong emphasis on rapid research and discovery that the digital health field demands. Due to the voluminous availability of real time patient and client data, academic health centers offer a rich interdisciplinary environment to develop, pilot and evaluate innovations in pragmatic settings. Despite the opportunity between academic health centers and industry to advance digital health innovation through rapid research, limited evidence exists of such collaboration. The purpose of this case report is to examine an AIC facilitating research of new health technologies within an academic health center. This paper presents a case report involving collaboration between diverse technology industry partners and an academic health center that encompasses a university health system (UCHealth), a university technology transfer office (CU Innovations), an innovation center (CARE Innovation Center), and research collaborators (mHealth Impact Laboratory). Case assertions discuss the lessons learned and recommendations when implementing such collaboration in practice. The principal finding is that academic health centers offer an innovative environment for AIC in digital health. Collaborations between academia and industry provide much promise in ensuring health innovations are scientifically sound while meeting the needs of a rapidly evolving technical climate.

Racial Differences in Cardiovascular Biomarkers in the General Population.

Background The incidence and clinical manifestations of cardiovascular disease (CVD) differ between blacks and whites. Biomarkers that reflect important pathophysiological pathways may provide a window to allow deeper understanding of racial differences in CVD. Methods and Results The study included 2635 white and black participants from the Dallas Heart Study who were free from existing CVD. Cross-sectional associations between race and 32 biomarkers were evaluated using multivariable linear regression adjusting for age, traditional CVD risk factors, imaging measures of body composition, renal function, insulin resistance, left ventricular mass, and socioeconomic factors. In fully adjusted models, black women had higher lipoprotein(a), leptin, d-dimer, osteoprotegerin, antinuclear antibody, homoarginine, suppression of tumorigenicity-2, and urinary microalbumin, and lower adiponectin, soluble receptor for advanced glycation end products and N-terminal pro-B-type natriuretic peptide versus white women. Black men had higher lipoprotein(a), leptin, d-dimer, high-sensitivity C-reactive protein, antinuclear antibody, symmetrical dimethylarginine, homoarginine, high-sensitivity cardiac troponin T, suppression of tumorigenicity-2, and lower adiponectin, soluble receptor for advanced glycation end products, and N-terminal pro-B-type natriuretic peptide versus white men. Adjustment for biomarkers that were associated with higher CVD risk, and that differed between blacks and whites, attenuated the risk for CVD events in black women (unadjusted hazard ratio 2.05, 95% CI 1.32, 3.17 and adjusted hazard ratio 1.15, 95% CI 0.69, 1.92) and black men (unadjusted hazard ratio 2.39, 95% CI 1.64, 3.46, and adjusted hazard ratio 1.21, 95% CI 0.76, 1.95). Conclusions Significant racial differences were seen in biomarkers reflecting lipids, adipokines, and biomarkers of endothelial function, inflammation, myocyte injury, and neurohormonal stress, which may contribute to racial differences in the development and complications of CVD.

Identifying Familial Hypercholesterolemia Using a Blood Donor Screening Program With More Than 1 Million Volunteer Donors.

Importance: Familial hypercholesterolemia is an autosomal-dominant disorder that often causes premature coronary artery disease. Unfortunately, familial hypercholesterolemia remains largely undiagnosed. Objective: To estimate the prevalence of familial hypercholesterolemia in a population of blood donors. Design: This analysis of deidentified data from blood donors 16 years and older who donated to Carter BloodCare, one of the largest independent blood programs in the United States, between January 2002 and December 2016. Carter BloodCare, which serves a population of about 8 million in Texas, routinely measures total nonfasting serum cholesterol levels as part of a donor health screening program. Data analysis occurred from October 2017 to March 2019. Exposure: Blood donation. Main Outcomes and Measures: Familial hypercholesterolemia was defined using the Make Early Diagnosis to Prevent Early Death general population criteria, with total nonfasting serum cholesterol thresholds of 270, 290, 340, and 360 mg/dL for donors younger than 20 years, 20 to 29 years, 30 to 39 years, and 40 years or older, respectively (to convert cholesterol values to mmol/L, multiply by 0.0259). For repeated donors, the maximum observed total cholesterol level was used for analyses. Results: The study included 1 178 102 individual donors with a total of 3 038 420 blood donations. Of all individual donors (median total cholesterol level, 183 [interquartile range (IQR), 157-212] mg/dL; median age, 32 [IQR, 19-47] years; 619 583 [52.6%] women), a total of 3473 individuals (or 1 in every 339) met criteria for familial hypercholesterolemia. This group had a median (IQR) total cholesterol of 332 (297-377) mg/dL. Estimated prevalence was higher at younger ages (<30 years: 1:257) compared with older ages (≥30 years: 1:469; P < .001) and in men (1:327) compared with women (1:351; P = .03). Among 2219 repeated donors who met familial hypercholesterolemia criteria at least once, 3116 of 10 833 total donations (28.8%) met FH criteria. Conclusions and Relevance: The prevalence of familial hypercholesterolemia using the Make Early Diagnosis to Prevent Early Death criteria in a large cohort of blood donors was similar to the estimated prevalence of this disorder in the general population. The blood donor screening program could be a novel strategy to detect and notify individuals with potential familial hypercholesterolemia, particularly younger individuals in whom early detection and treatment is especially helpful, as well as guide cascade screening.

The impact of effective systemic therapies on surgery for stage IV melanoma.

INTRODUCTION: The outcomes of patients with metastatic melanoma have significantly improved with the introduction of effective systemic therapies (ESTs). The role of surgery in the context of ESTs for stage IV melanoma is evolving. We sought to characterise the changing patterns of surgery and oncological outcomes in patients with stage IV melanoma treated before and after the establishment of ESTs. METHODS: Patients undergoing surgical resection of stage IV melanoma were identified from our institutional database from 2003 to 2015. Patients were grouped into two cohorts, those referred before EST (2003-2007) and after EST (2011-2015). Clinicopathological variables, patterns of surgery and oncological outcomes in the two groups were compared. RESULTS: A total of 138 patients underwent surgery for stage IV melanoma (n = 69 in each cohort). We observed no significant difference in the ratio of operations/patients performed. However, the pattern of operations altered, with a significant decrease in in-transit excisions (0.9% vs. 19.4%, p < 0.001) and an increase in abdominal metastasectomies (21.1% vs. 4.2%, p < 0.001), in the after-EST cohort. Novel indications for surgical intervention were noted in the after-EST cohort, with a significant increase in potentially curative operations for residual oligometastatic disease (15.9% vs. 4.3%, p = 0.045). Survival after surgery was prolonged in the after-EST cohort (median 16 months vs. 6 months, p < 0.001), with the stage at initial metastasectomy (stage 4a, hazard ratio [HR] 0.45 (0.28-0.73), p = 0.001) and treatment with immune checkpoint inhibitors (HR 0.38 (0.25-0.60), p < 0.001) associated with prolonged survival. DISCUSSION: Surgery remains important in the management of stage IV melanoma, with evolving indications and patterns of intervention after the introduction of ESTs. The combination of judicious surgery and EST may improve oncological outcomes.

Adjuvant bevacizumab for melanoma patients at high risk of recurrence: survival analysis of the AVAST-M trial.

Background: Bevacizumab is a recombinant humanised monoclonal antibody to vascular endothelial growth factor shown to improve survival in advanced solid cancers. We evaluated the role of adjuvant bevacizumab in melanoma patients at high risk of recurrence. Patients and methods: Patients with resected AJCC stage IIB, IIC and III cutaneous melanoma were randomised to receive either adjuvant bevacizumab (7.5 mg/kg i.v. 3 weekly for 1 year) or standard observation. The primary end point was detection of an 8% difference in 5-year overall survival (OS) rate; secondary end points included disease-free interval (DFI) and distant metastasis-free interval (DMFI). Tumour and blood were analysed for prognostic and predictive markers. Results: Patients (n=1343) recruited between 2007 and 2012 were predominantly stage III (73%), with median age 56 years (range 18-88 years). With 6.4-year median follow-up, 515 (38%) patients had died [254 (38%) bevacizumab; 261 (39%) observation]; 707 (53%) patients had disease recurrence [336 (50%) bevacizumab, 371 (55%) observation]. OS at 5 years was 64% for both groups [hazard ratio (HR) 0.98; 95% confidence interval (CI) 0.82-1.16, P = 0.78). At 5 years, 51% were disease free on bevacizumab versus 45% on observation (HR 0.85; 95% CI 0.74-0.99, P = 0.03), 58% were distant metastasis free on bevacizumab versus 54% on observation (HR 0.91; 95% CI 0.78-1.07, P = 0.25). Forty four percent of 682 melanomas assessed had a BRAFV600 mutation. In the observation arm, BRAF mutant patients had a trend towards poorer OS compared with BRAF wild-type patients (P = 0.06). BRAF mutation positivity trended towards better OS with bevacizumab (P = 0.21). Conclusions: Adjuvant bevacizumab after resection of high-risk melanoma improves DFI, but not OS. BRAF mutation status may predict for poorer OS untreated and potential benefit from bevacizumab. Clinical Trial Information: ISRCTN 81261306; EudraCT Number: 2006-005505-64.

Evidence of hepatitis A virus infection in the patients with acute encephalitis syndrome in Gorakhpur region, North India.

The etiological agent remained unidentified in a large number of patients hospitalized for acute encephalitis syndrome (AES) in 2008-2009 in Uttar Pradesh and Bihar, north India. All patients were found to present with fever and altered sensorium, while 28%, 19% and 13% showed hepatomegaly, splenomegaly and meningeal signs, respectively. Involvement mostly of children with abnormal hepatic features prompted us to undertake an exploratory study on viral hepatitis A to determine its association, if any, with hepatic derangements. AES patients (n = 2515) and healthy children (n = 167) were investigated for the presence of serum anti-hepatitis A virus (anti-HAV) IgM and anti-Japanese encephalitis (anti-JE) virus IgM by ELISA. Cerebrospinal fluids (CSFs, n = 595) and rectal swabs (n = 182) were examined for anti-HAV IgM and/or HAV RNA. Anti-HAV IgM was detected in the sera of 14.6% patients as against 6.6% of healthy children (p = 0.0042). Anti-JE virus IgM positivity was Keywords: acute encephalitis syndrome; cerebrospinal fluid; hepatitis A virus; anti-HAV IgM; non-Japanese encephalitis.

Cryptic lineage differentiation among Indo-Pacific bottlenose dolphins (Tursiops aduncus) in the northwest Indian Ocean.

Phylogeography can provide insight into the potential for speciation and identify geographic regions and evolutionary processes associated with species richness and evolutionary endemism. In the marine environment, highly mobile species sometimes show structured patterns of diversity, but the processes isolating populations and promoting differentiation are often unclear. The Delphinidae (oceanic dolphins) are a striking case in point and, in particular, bottlenose dolphins (Tursiops spp.). Understanding the radiation of species in this genus is likely to provide broader inference about the processes that determine patterns of biogeography and speciation, because both fine-scale structure over a range of kilometers and relative panmixia over an oceanic range are known for Tursiops populations. In our study, novel Tursiops spp. sequences from the northwest Indian Ocean (including mitogenomes and two nuDNA loci) are included in a worldwide Tursiops spp. phylogeographic analysis. We discover a new 'aduncus' type lineage in the Arabian Sea (off India, Pakistan and Oman) that diverged from the Australasian lineage ∼261 Ka. Effective management of coastal dolphins in the region will need to consider this new lineage as an evolutionarily significant unit. We propose that the establishment of this lineage could have been in response to climate change during the Pleistocene and show data supporting hypotheses for multiple divergence events, including vicariance across the Indo-Pacific barrier and in the northwest Indian Ocean. These data provide valuable transferable inference on the potential mechanisms for population and species differentiation across this geographic range.

Neurotoxicity from immune-checkpoint inhibition in the treatment of melanoma: a single centre experience and review of the literature.

Background: Treatment with immune checkpoint inhibitors (ICPi) has greatly improved survival for patients with advanced melanoma in recent years. Anti-CTLA-4 and anti-PD1 antibodies have been approved following large Phase III trials. Immune-related neurological toxicity of varying severity has been reported in the literature. The cumulative incidence of neurotoxicity among ipilimumab, nivolumab and pembrolizumab is reported as <1% in published clinical trials. We aimed to identify the incidence of neurotoxicity in our institution across anti-CTLA4 and anti-PD-1 antibodies, including the combination of ipilimumab with nivolumab. We also review the existing literature and propose an investigation and management algorithm. Methods: All patients with advanced melanoma treated with ipilimumab, nivolumab, pembrolizumab or the combination of ipilimumab and nivolumab (ipi + nivo), managed at the Royal Marsden Hospital between September 2010 and December 2015, including patients on (published) clinical trials were included. Medical records for each patient were reviewed and information on neurotoxicity recorded. A systematic search strategy was performed to collate existing reports of neurological toxicity. Results: In total, 413 immunotherapy treatment episodes in 352 patients were included, with median follow-up of 26.7 months. Ten cases of neurotoxicity were recorded, affecting 2.8% of patients overall, ranging from grade 1 to 4, affecting both central and peripheral nervous systems. A rate of 14% was noted with ipi + nivo. Three of five patients commenced on corticosteroids responded to these. Six patients had made a full recovery at the time of reporting. A favorable radiological response was found in 7 of the 10 cases. Unusual presentations are described in detail. Conclusions: Neurological toxicity is not uncommon, and may be more frequent in patients treated with combination ipi + nivo. Patterns of presentation and response to treatment are varied. A prompt and considered approach is required to optimize outcomes in this group of patients.

Thyroid abnormalities following the use of cytotoxic T-lymphocyte antigen-4 and programmed death receptor protein-1 inhibitors in the treatment of melanoma.

CONTEXT: Checkpoint inhibitors are emerging as important cancer therapies but are associated with a high rate of immune side effects, including endocrinopathy. OBJECTIVE: To determine the burden of thyroid dysfunction in patients with melanoma treated with immune checkpoint inhibitors and describe the clinical course. DESIGN AND PATIENTS: Consecutive patients with melanoma treated with either ipilimumab, nivolumab, pembrolizumab or the combination of ipilimumab and nivolumab were identified. Baseline thyroid function tests were used to exclude those with pre-existing thyroid abnormalities, and thyroid function tests during treatment used to identify those with thyroid dysfunction. RESULTS: Rates of overt thyroid dysfunction were in keeping with the published phase 3 trials. Hypothyroidism occurred in 13·0% treated with a programmed death receptor-1 (PD-1) inhibitor and 22·2% with a combination of PD-1 inhibitor and ipilimumab. Transient subclinical hyperthyroidism was observed in 13·0% treated with a PD-1 inhibitor, 15·9% following a PD-1 inhibitor, and 22·2% following combination treatment with investigations suggesting a thyroiditic mechanism rather than Graves' disease, and a high frequency of subsequent hypothyroidism. Any thyroid abnormality occurred in 23·0% following ipilimumab, 39·1% following a PD-1 inhibitor and 50% following combination treatment. Abnormal thyroid function was more common in female patients. CONCLUSION: Thyroid dysfunction occurs commonly in patients with melanoma treated with immune checkpoint inhibitors, with rates, including subclinical dysfunction, occurring in up to 50%.