Health-related quality of life in patients with light chain amyloidosis treated with bortezomib, cyclophosphamide, and dexamethasone ± daratumumab: Results from the ANDROMEDA study.

In the phase 3 ANDROMEDA trial, patients treated with daratumumab, bortezomib, cyclophosphamide, and dexamethasone (D-VCd) had significantly higher rates of organ and hematologic response compared with patients who received VCd alone. Here, we present patient-reported outcomes (PROs) from the ANDROMEDA trial. PROs were assessed through cycle 6 using three standardized questionnaires. Treatment effect through cycle 6 was measured by a repeated-measures, mixed-effects model. The magnitude of changes in PROs versus baseline was generally low, but between-group differences favored the D-VCd group. Results were generally consistent irrespective of hematologic, cardiac, or renal responses. More patients in the D-VCd group experienced meaningful improvements in PROs; median time to improvement was more rapid in the D-VCd group versus the VCd group. After cycle 6, patients in the D-VCd group received daratumumab monotherapy and their PRO assessments continued, with improvements in health-related quality of life (HRQoL) reported through cycle 19. PROs of subgroups with renal and cardiac involvement were consistent with those of the intent-to-treat population. These results demonstrate that the previously reported clinical benefits of D-VCd were achieved without decrement to patients' HRQoL and provide support of D-VCd in patients with AL amyloidosis.

Structure-activity relationships for lipoprotein lipase agonists that lower plasma triglycerides in vivo.

The risk of cardiovascular events increases in individuals with elevated plasma triglyceride (TG) levels, therefore advocating the need for efficient TG-lowering drugs. In the blood circulation, TG levels are regulated by lipoprotein lipase (LPL), an unstable enzyme that is only active as a non-covalently associated homodimer. We recently reported on a N-phenylphthalimide derivative (1) that stabilizes LPL in vitro, and moderately lowers triglycerides in vivo (Biochem. Biophys. Res. Commun.2014, 450, 1063). Herein, we establish structure-activity relationships of 51 N-phenylphthalimide analogs of the screening hit 1. In vitro evaluation highlighted that modifications on the phthalimide moiety were not tolerated and that lipophilic substituents on the central phenyl ring were functionally essential. The substitution pattern on the central phenyl ring also proved important to stabilize LPL. However, in vitro testing demonstrated rapid degradation of the phthalimide fragment in plasma which was addressed by replacing the phthalimide scaffold with other heterocyclic fragments. The in vitro potency was retained or improved and substance 80 proved stable in plasma and efficiently lowered plasma TGs in vivo.

Food effects on abiraterone pharmacokinetics in healthy subjects and patients with metastatic castration-resistant prostate cancer.

Food effect on abiraterone pharmacokinetics and safety on abiraterone acetate coadministration with low-fat or high-fat meals was examined in healthy subjects and metastatic castration-resistant prostate cancer (mCRPC) patients. Healthy subjects (n = 36) were randomized to abiraterone acetate (single dose, 1000 mg) + low-fat meal, + high-fat meal, and fasted state. mCRPC patients received repeated doses (abiraterone acetate 1000 mg + 5 mg prednisone twice daily; days 1-7) in a modified fasting state followed by abiraterone acetate plus prednisone within 0.5 hours post-low-fat (n = 6) or high-fat meal (n = 18; days 8-14). In healthy subjects, geometric mean (GM) abiraterone area under plasma concentration-time curve (AUC) increased ∼5- and ∼10-fold, respectively, with low-fat and high-fat meals versus fasted state (GM [coefficient of variation], 1942 [48] and 4077 [37] ng · h/mL vs 421 [67] ng · h/mL, respectively). In mCRPC patients, abiraterone AUC was ∼2-fold higher with a high-fat meal and similar with a low-fat meal versus modified fasting state (GM [coefficient of variation]: 1992 [34] vs 973 [58] ng · h/mL and 1264 [65] vs 1185 [90] ng · h/mL, respectively). Adverse events (all grade ≤ 3) were similar, with high-fat/low-fat meals or fasted/modified fasting state. Short-term dosing with food did not alter abiraterone acetate safety.

Control of HPV infection and related cancer through vaccination.

Human papillomavirus (HPV), the most common sexually transmitted virus, and its associated diseases continue to cause significant morbidity and mortality in over 600 million infected individuals. Major progress has been made with preventative vaccines, and clinical data have emerged regarding the efficacy and cross-reactivity of the two FDA approved L1 virus like particle (VLP)-based vaccines. However, the cost of the approved vaccines currently limits their widespread use in developing countries which carry the greatest burden of HPV-associated diseases. Furthermore, the licensed preventive HPV vaccines only contain two high-risk types of HPV (HPV-16 and HPV-18) which can protect only up to 75 % of all cervical cancers. Thus, second generation preventative vaccine candidates hope to address the issues of cost and broaden protection through the use of more multivalent L1-VLPs, vaccine formulations, or alternative antigens such as L1 capsomers, L2 capsid proteins, and chimeric VLPs. Preventative vaccines are crucial to controlling the transmission of HPV, but there are already hundreds of millions of infected individuals who have HPV-associated lesions that are silently progressing toward malignancy. This raises the need for therapeutic HPV vaccines that can trigger T cell killing of established HPV lesions, including HPV-transformed tumor cells. In order to stimulate such antitumor immune responses, therapeutic vaccine candidates deliver HPV antigens in vivo by employing various bacterial, viral, protein, peptide, dendritic cell, and DNA-based vectors. This book chapter will review the commercially available preventive vaccines, present second generation candidates, and discuss the progress of developing therapeutic HPV vaccines.

Emerging human papillomavirus vaccines.

INTRODUCTION: Identification of human papillomavirus (HPV) as the etiologic factor of cervical, anogenital, and a subset of head and neck cancers has stimulated the development of preventive and therapeutic HPV vaccines to control HPV-associated malignancies. Excitement has been generated by the commercialization of two preventive L1-based vaccines, which use HPV virus-like particles (VLPs) to generate capsid-specific neutralizing antibodies. However, factors such as high cost and requirement for cold chain have prevented widespread implementation where they are needed most. AREAS COVERED: Next generation preventive HPV vaccine candidates have focused on cost-effective stable alternatives and generating broader protection via targeting multivalent L1 VLPs, L2 capsid protein, and chimeric L1/L2 VLPs. Therapeutic HPV vaccine candidates have focused on enhancing T cell-mediated killing of HPV-transformed tumor cells, which constitutively express HPV-encoded proteins, E6 and E7. Several therapeutic HPV vaccines are in clinical trials. EXPERT OPINION: Although progress is being made, cost remains an issue inhibiting the use of preventive HPV vaccines in countries that carry the majority of the cervical cancer burden. In addition, progression of therapeutic HPV vaccines through clinical trials may require combination strategies employing different therapeutic modalities. As research in the development of HPV vaccines continues, we may generate effective strategies to control HPV-associated malignancies.

Comparison of noninvasive cardiac output measurements using the Nexfin monitoring device and the esophageal Doppler.

STUDY OBJECTIVE: To evaluate the validity of cardiac output (CO) measurements obtained using the Nexfin device in comparison to those obtained with the esophageal Doppler in steady-state conditions and after phenylephrine administration. DESIGN: Prospective observational study. SETTING: Operating room of a North American academic medical center. PATIENTS: 25 ASA physical status 1, 2, and 3 patients referred for abdominal or orthopedic surgeries. INTERVENTIONS: After endotracheal intubation, patients who presented with a 20% or greater decrease in mean arterial pressure (MAP) received an intravenous (IV) bolus of 100 µg of phenylephrine. If MAP was still 20% lower than the patient's baseline level at least 10 minutes after the first vasopressor treatment, a second bolus of 100 µg of phenylephrine was given. MEASUREMENTS: CO was measured simultaneously by esophageal Doppler (CO(ED)) and Nexfin (CO(NXF)) at baseline and when blood pressure peaked after an IV 100 µg phenylephrine bolus. Comparisons were then made between the two devices to evaluate the ability of the Nexfin device to track changes in CO. MAIN RESULTS: 66 pairs of data were obtained. Mean CO(ED) and CO(NXF) were 4.7 ± 1.8 L/min and 5.6 ± 2.0 L/min, respectively. There was a significant relationship between CO(ED) and CO(NXF) (r(2) = 0.82; P < 0.001). The agreement between CO(ED) and CO(NXF) was 0.88 ± 0.86 L/min (Bland Altman). The mean percent error (Critchley and Critchley) of CO(NXF) versus CO(ED) was 37%. Trending analysis found a 94% concordance between changes in CO(ED) and CO(NXF) after phenylephrine administration. CONCLUSIONS: Intraoperative CO measurement using the Nexfin device has a strong correlation with CO measured by esophageal Doppler.

Synthesis, biological evaluation, and structure-activity relationships of 2-[2-(benzoylamino)benzoylamino]benzoic acid analogues as inhibitors of adenovirus replication.

2-[2-Benzoylamino)benzoylamino]benzoic acid (1) was previously identified as a potent and nontoxic antiadenoviral compound (Antimicrob. Agents Chemother. 2010, 54, 3871). Here, the potency of 1 was improved over three generations of compounds. We found that the ortho, ortho substituent pattern and the presence of the carboxylic acid of 1 are favorable for this class of compounds and that the direction of the amide bonds (as in 1) is obligatory. Some variability in the N-terminal moiety was tolerated, but benzamides appear to be preferred. The substituents on the middle and C-terminal rings were varied, resulting in two potent inhibitors, 35g and 35j, with EC(50) = 0.6 µM and low cell toxicity.

Predicting fluid responsiveness with stroke volume variation despite multiple extrasystoles.

OBJECTIVE: To investigate the ability of a new stroke volume variation algorithm to predict fluid responsiveness during general anesthesia and mechanical ventilation in animals with multiple extrasystoles. DESIGN: Prospective laboratory animal experiment. SETTING: Investigational laboratory. SUBJECTS: Eight instrumented pigs. INTERVENTIONS: Eight anesthetized and mechanically ventilated pigs were monitored with an arterial line and a pulmonary artery catheter. Multiple extrasystoles were induced by right ventricular pacing (25% of heart beats). Arterial pressure waveforms were recorded and stroke volume variation was computed from the new and from the standard algorithm. The new stroke volume variation algorithm is designed to restore the respiratory component of the arterial pressure waveform despite multiple ectopic heart beats. Cardiac output was measured before and after 56 fluid boluses (7 mL/kg of 6% hydroxy ethyl starch) performed at different volemic states. MEASUREMENTS AND MAIN RESULTS: A positive response to fluid boluses (>15% increase in cardiac output) was observed in 21 of 56 boluses. The new stroke volume variation was higher in responders than in nonresponders (19% ± 5% vs. 12% ± 3%, p < .05), whereas the standard stroke volume variation was similar in the two groups (29% ± 8% vs. 26% ± 11%, p = .4). Receiver operating characteristic curve analysis showed that the new stroke volume variation was an accurate predictor of fluid responsiveness (sensitivity = 86%, specificity = 85%, best cutoff value = 14%, area under the curve = 0.892 ±, whereas the standard stroke volume variation was not (area under the curve = 0.596 ± 0.077). CONCLUSIONS: In contrast to the standard stroke volume variation, the new stroke volume variation algorithm was able to predict fluid responsiveness in animals with multiple ventricular extrasystoles.

The impact of phenylephrine, ephedrine, and increased preload on third-generation Vigileo-FloTrac and esophageal doppler cardiac output measurements.

BACKGROUND: Cardiac output (CO) monitoring based on pulse contour analysis (Vigileo-FloTrac) has the potential to be used for goal-directed fluid therapy in the perioperative setting. However, factors such as vasopressor usage may impact Vigileo-FloTrac's reliability in tracking CO changes. We tested third-generation Vigileo-FloTrac system's ability to accurately measure the changes in CO induced by vasopressor administration and increased preload in comparison with esophageal Doppler measurements. METHODS: In 33 anesthetized patients, CO was monitored simultaneously by the third-generation Vigileo-FloTrac and esophageal Doppler. Hemodynamic challenges included phenylephrine (to increase vasomotor tone), ephedrine (to increase myocardial contractility and heart rate), and whole-body tilting (to increase preload). Measurements were performed before and after each intervention. RESULTS: Overall, 176 pairs of CO measurements were obtained. The difference between paired pulse contour and Doppler measurements of CO was 0.14 ± 2.13 L/min (mean ± SD), and the percentage error (2 SD of the difference divided by the mean CO of the reference method) was 66%. The trending ability of pulse contour versus Doppler was 23% (concordance, the percentage of the total number of data points that are in 1 of the 2 quadrants of agreement) after phenylephrine treatment, 69% (concordance) after ephedrine treatment, and 96% (concordance) after whole-body tilting. CONCLUSIONS: The pulse contour method of measuring CO, as implemented in the third-generation Vigileo-FloTrac device, accurately tracks changes in CO when preload changes. However, the pulse contour method does not accurately track changes in CO induced with phenylephrine and ephedrine.