Novel computational biology modeling system can accurately forecast response to neoadjuvant therapy in early breast cancer.

BACKGROUND: Generalizable population-based studies are unable to account for individual tumor heterogeneity that contributes to variability in a patient's response to physician-chosen therapy. Although molecular characterization of tumors has advanced precision medicine, in early-stage and locally advanced breast cancer patients, predicting a patient's response to neoadjuvant therapy (NAT) remains a gap in current clinical practice. Here, we perform a study in an independent cohort of early-stage and locally advanced breast cancer patients to forecast tumor response to NAT and assess the stability of a previously validated biophysical simulation platform. METHODS: A single-blinded study was performed using a retrospective database from a single institution (9/2014-12/2020). Patients included: ≥ 18 years with breast cancer who completed NAT, with pre-treatment dynamic contrast enhanced magnetic resonance imaging. Demographics, chemotherapy, baseline (pre-treatment) MRI and pathologic data were input into the TumorScope Predict (TS) biophysical simulation platform to generate predictions. Primary outcomes included predictions of pathological complete response (pCR) versus residual disease (RD) and final volume for each tumor. For validation, post-NAT predicted pCR and tumor volumes were compared to actual pathological assessment and MRI-assessed volumes. Predicted pCR was pre-defined as residual tumor volume ≤ 0.01 cm3 (≥ 99.9% reduction). RESULTS: The cohort consisted of eighty patients; 36 Caucasian and 40 African American. Most tumors were high-grade (54.4% grade 3) invasive ductal carcinomas (90.0%). Receptor subtypes included hormone receptor positive (HR+)/human epidermal growth factor receptor 2 positive (HER2+, 30%), HR+/HER2- (35%), HR-/HER2+ (12.5%) and triple negative breast cancer (TNBC, 22.5%). Simulated tumor volume was significantly correlated with post-treatment radiographic MRI calculated volumes (r = 0.53, p = 1.3 × 10-7, mean absolute error of 6.57%). TS prediction of pCR compared favorably to pathological assessment (pCR: TS n = 28; Path n = 27; RD: TS n = 52; Path n = 53), for an overall accuracy of 91.2% (95% CI: 82.8% - 96.4%; Clopper-Pearson interval). Five-year risk of recurrence demonstrated similar prognostic performance between TS predictions (Hazard ratio (HR): - 1.99; 95% CI [- 3.96, - 0.02]; p = 0.043) and clinically assessed pCR (HR: - 1.76; 95% CI [- 3.75, 0.23]; p = 0.054). CONCLUSION: We demonstrated TS ability to simulate and model tumor in vivo conditions in silico and forecast volume response to NAT across breast tumor subtypes.

Genetics of pain perception, COMT and postoperative pain management in children.

BACKGROUND: Effective perioperative analgesia is lacking for children owing to interindividual variations and underdosing of opioids caused by fear of adverse effects. We investigated the role of COMT SNPs on postoperative pain management in children. METHODS: One hundred and forty nine children undergoing adenotonsillectomy were enrolled. The associations of four COMT SNPs (rs6269, rs4633, rs4818 and rs4680) with postoperative pain were analyzed and outcome measures included maximum pain scores, need for postoperative opioid interventions and postoperative morphine requirements. RESULTS: We detected an association of postoperative opioid intervention need with all four COMT SNPs. Minor allele carriers of COMT SNPs were approximately three-times more likely to require analgesic interventions than homozygotes of major alleles (p-value range: 0.0031-0.0127; odds ratio range: 2.6-3.1). In addition, significant association was detected between maximum Face, Leg, Activity, Consolability, Cry (FLACC) pain scores and three COMT SNPs (rs6269, rs4633 and rs4680). Haplotype 1 (ATCA: 51.3%) and Haplotype 2 (GCGG: 36.2%) are more frequent. Haplotype 2 was associated with higher odds of intravenous analgesic intervention need in postanesthesia recovery unit with an odds ratio of 2.6 (95% CI: 1.2-5.4; p-value = 0.022). CONCLUSION: COMT SNPs may play a significant role in interindividual variation in postoperative pain perception and postoperative morphine requirements in children. Original submitted 16 August 2013; Revision submitted 13 December 2013.

Codeine-related adverse drug reactions in children following tonsillectomy: a prospective study.

OBJECTIVES/HYPOTHESIS: To prospectively determine factors associated with codeine's adverse drug reactions (ADRs) at home in a large homogenous population of children undergoing outpatient tonsillectomy. STUDY DESIGN: Prospective, genotype blinded, observational study with a single group and repeated ADR measures documented by parents at home. METHODS: A total of 249 children 6 to 15 years of age scheduled for tonsillectomy were enrolled. The primary outcome was number of daily codeine-related ADRs. We examined the number and type of ADR by race and by days and further modeled factors potentially associated with ADR risk in a subcohort of white children. Sedation following a dose of codeine was a secondary outcome measure. Parents recorded their children's daily ADRs and sedation scores during postoperative days (POD) 0 to 3 at home. RESULTS: Diaries were returned for 134 children, who were given codeine. A total of 106 (79%) reported at least one ADR. The most common ADRs were nausea, lightheadedness/dizziness for white children and nausea, and vomiting for African American children. In a subcohort of white children ≤ 45 kg, increased ADR risk was associated with the presence of one or more full function CYP2D6 alleles (P < 0.001), POD (P < 0.001), and sex (P = 0.027). Increased pain intensity (P = 0.009) and PODs 0 and 1 (P = 0.001) contributed to a higher sedation risk. Neither obstructive apnea nor predicted CYP2D6 phenotype were associated with sedation risk. CONCLUSIONS: Our results provide evidence that multiple factors are associated with codeine-related ADRs and support the FDA recommendation to avoid codeine's routine use following tonsillectomy in children.

OCT1 genetic variants influence the pharmacokinetics of morphine in children.

AIM: Large interindividual variability in morphine disposition could contribute to unpredictable variability in morphine analgesia and adverse events. Caucasian children have more adverse effects and slower morphine clearance than African-American children. To study variations in intravenous morphine pharmacokinetics in children, we examined the influence of genetic polymorphisms in OCT1. METHODS: In 146 children undergoing adenotonsillectomy, 146 concentration-time profiles (2-4 measurements per patient) were available. Population pharmacokinetic analysis characterized the profiles in NONMEM(®) and tested OCT1 variants as covariates. RESULTS: Allometrically scaled post hoc Bayesian morphine clearance in homozygotes of loss-of-function OCT1 variants (n = 9, OCT1*2-*5/*2-*5) was significantly lower (20%) than in wild-type (n = 85, OCT1*1/*1) and heterozygotes (n = 52, OCT1*1/*2-*5; p < 0.05). CONCLUSION: Besides bodyweight, OCT1 genotypes play a significant role in intravenous morphine pharmacokinetics. Relatively high allelic frequencies of defective OCT1 variants among Caucasians may explain their lower morphine clearance and possibly higher frequencies of adverse events compared with African-American children. Original submitted 21 December 2012; Revision submitted 7 May 2013.

Morphine clearance in children: does race or genetics matter?

OBJECTIVE: Interindividual variability in analgesic response and adverse effects of opioids because of narrow therapeutic indices are major clinical problems. Morphine is an opioid commonly used in children to manage perioperative pain. Al-though size and age often are considered primary covariates for morphine pharmacokinetic models, the impact of other factors important in personalizing care such as race and genetic variations on morphine disposition is not well documented. DESIGN: Genotype blinded clinical observational pharmacokinetic study. One hundred forty-six African American and Caucasian children scheduled for elective outpatient adenotonsillectomy were enrolled in our prospective genotype blinded observational study with standard perioperative clinical care. SETTING: Tertiary care pediatric institution. INTERVENTIONS: Morphine bolus for intraoperative analgesia in children and pharmacokinetic analyses in different races. MAIN OUTCOME MEASURES: Pharmacokinetics and pharmacogenetics of intravenous morphine in a homogeneous pediatric outpatient surgical pain population were evaluated. RESULTS: The authors observed that African American children have higher morphine clearance than Caucasian children. The increased clearance is directed toward the formation of morphine-3-glucuronide formation, rather than the formation of morphine-6-glucuronide. Common uridine diphosphate glucuronosyl transferase (UGT) 2B7 genetic variations (2161C>T and 802C>T) were not associated with observed racial differences in morphine's clearance although the wild type of the UGT2B7 isozyme is more prevalent in the African Americans. CONCLUSIONS: Race of the child is an important factor in perioperative intravenous morphine's clearance and its potential role in personalizing analgesia with morphine needs further investigation.

Propofol clearance in morbidly obese children and adolescents: influence of age and body size.

BACKGROUND AND OBJECTIVE: Given the alarming increase in obesity among children undergoing surgery, the main aim of this study was to characterize propofol clearance in a cohort of morbidly obese children and adolescents in relation to their age and body weight characteristics. METHODS: A prospective pharmacokinetic study in morbidly obese children and adolescents undergoing elective surgery was conducted. Serial blood samples were collected and nonlinear mixed-effects modelling using NONMEM(®) was performed to characterize propofol pharmacokinetics with subsequent evaluation of age and body size descriptors. RESULTS: Twenty obese and morbidly obese children and adolescents with a mean age of 16 years (range 9-18 years), a mean total body weight (TBW) of 125 kg (range 70-184 kg) and a mean body mass index of 46 kg/m(2) (range 31-63 kg/m(2)) were available for pharmacokinetic modelling using a two-compartment pharmacokinetic model (n = 294 propofol concentration measurements). Compared with lean body weight and ideal body weight, TBW proved to be the most predictive covariate for clearance [CL (L/min) = 1.70 × (TBW/70)(0.8)]. Central volume of distribution, peripheral volume and intercompartmental clearance were 45.2 L, 128 L and 1.75 L/min, respectively, with no predictive covariates identifiable. CONCLUSION: In the population pharmacokinetic model for propofol in morbidly obese children and adolescents, TBW proved to be the most significant determinant for clearance. As a result, it is anticipated that dosage of propofol for maintenance of anaesthesia in morbidly obese children and adolescents should be based on TBW using an allometric function.

Race and unequal burden of perioperative pain and opioid related adverse effects in children.

BACKGROUND: Interindividual variability in pain perception and analgesic response is a major problem in perioperative practice. Adult studies suggest pain management is influenced by patient's race. The objective of this study is to evaluate the influence of race on perioperative pain treatment in children. METHODS: Prospective observational study evaluating effect of race on analgesia and opioid related adverse effects after tonsillectomy in African American and Caucasian children. A sample of 194 healthy children between 6 and 15 years of age were included. Race was self-identified by parents. All participants received standard perioperative care with a standard anesthetic and an intraoperative dose of morphine. Analgesia outcomes included maximum postoperative pain scores, postoperative opioid requirement, and analgesic interventions. Safety outcomes included incidences of opioid related adverse effects. RESULTS: African American children experienced significantly more postoperative pain than Caucasian children as measured by postoperative opioid requirement (P = .0011), maximum postoperative pain scores (P < .0001), and analgesic interventions (P < .0001) in the recovery room. Although Caucasian children received relatively less opioids perioperatively, they had significantly higher opioid related adverse effects (P = .039). African American children with obstructive sleep apnea were more likely to have prolonged post anesthesia recovery unit stay due to inadequate pain control. CONCLUSIONS: After similar uses of intraoperative morphine for tonsillectomy, there was an unequal burden of increased pain in African American children and increased opioid adverse effects in Caucasian children in the recovery room. Though Caucasian children received relatively less opioids perioperatively, they had higher incidences of opioid related adverse effects than African American children.

Propofol Clearance in Morbidly Obese Children and Adolescents : Influence of Age and Body Size.

BACKGROUND AND OBJECTIVE: Given the alarming increase in obesity among children undergoing surgery, the main aim of this study was to characterize propofol clearance in a cohort of morbidly obese children and adolescents in relation to their age and body weight characteristics. METHODS: A prospective pharmacokinetic study in morbidly obese children and adolescents undergoing elective surgery was conducted. Serial blood samples were collected and nonlinear mixed-effects modelling using NONMEM® was performed to characterize propofol pharmacokinetics with subsequent evaluation of age and body size descriptors. RESULTS: Twenty obese and morbidly obese children and adolescents with a mean age of 16 years (range 9-18 years), a mean total body weight (TBW) of 125 kg (range 70-184 kg) and a mean body mass index of 46kg/m2 (range 31-63 kg/m2) were available for pharmacokinetic modelling using a two-compartment pharmacokinetic model (n = 294 propofol concentration measurements). Compared with lean body weight and ideal body weight, TBW proved to be the most predictive covariate for clearance [CL (L/min)= 1.70 × (TBW/70)0.8]. Central volume of distribution, peripheral volume and intercompartmental clearance were 45.2 L, 128 L and 1.75 L/min, respectively, with no predictive covariates identifiable. CONCLUSION: In the population pharmacokinetic model for propofol in morbidly obese children and adolescents, TBW proved to be the most significant determinant for clearance. As a result, it is anticipated that dosage of propofol for maintenance of anaesthesia in morbidly obese children and adolescents should be based on TBW using an allometric function. TRIAL REGISTRATION NUMBER (CLINICALTRIALS.GOV): NCT00948597.