Front Physiol. 2021 Jul 29;12:713016. doi: 10.3389/fphys.2021.713016. eCollection 2021.

ABSTRACT

Background: Human adaptive response to exercise interventions is often described as group average and SD to represent the typical response for most individuals, but studies reporting individual responses to exercise show a wide range of responses. Objective: To characterize the physiological effects and inter-individual variability on fat mass and other health-related and physical performance outcomes after 12 weeks of high-intensity interval training (HIIT) and dietary energy restriction in overweight/obese adult women. Methods: Thirty untrained adult overweight and obese women (age = 27.4 ± 7.9 years; BMI = 29.9 ± 3.3 kg/m2) successfully completed a 12-week supervised HIIT program and an individually prescribed home hypocaloric diet (75% of daily energy requirements) throughout the whole intervention. High and low responders to the intervention were those individuals who were able to lose ≥ 10 and < 10% of initial absolute fat mass (i.e., kilograms), respectively. Results: The prevalence for high and low responders was 33% (n = 11) and 66% (n = 19), respectively. At the whole group level, the intervention was effective to reduce the absolute fat mass (30.9 ± 7.2 vs. 28.5 ± 7.2 kg; p < 0.0001), body fat percentage (39.8 ± 4.3 vs. 37.8 ± 4.9%; p < 0.0001), and total body mass (76.7 ± 10.1 vs. 74.4 ± 9.9 kg; p < 0.0001). In addition, there were improvements in systolic blood pressure (SBP; Δ% = -5.1%), diastolic blood pressure (DBP; Δ% = -6.4%), absolute VO2peak (Δ% = +14.0%), relative VO2peak (Δ% = +13.8%), peak power output (PPO; Δ% = +19.8%), anaerobic threshold (AT; Δ% = +16.7%), maximal ventilation (VE; Δ% = +14.1%), and peak oxygen pulse (O2 pulse; Δ% = +10.4%). However, at the individual level, a wide range of effects were appreciated on all variables, and the magnitude of the fat mass changes did not correlate with baseline body mass or fat mass. Conclusion: A 12-week supervised HIIT program added to a slight dietary energy restriction effectively improved fat mass, body mass, blood pressure, and cardiorespiratory fitness (CRF). However, a wide range of inter-individual variability was observed in the adaptative response to the intervention. Furthermore, subjects classified as low responders for fat mass reduction could be high responders (HiRes) in many other health-related and physical performance outcomes. Thus, the beneficial effects of exercise in obese and overweight women go further beyond the adaptive response to a single outcome variable such as fat mass or total body mass reduction.

PMID:34393829 | PMC:PMC8358598 | DOI:10.3389/fphys.2021.713016

Expert Rev Clin Immunol. 2021 Aug 16. doi: 10.1080/1744666X.2021.1968833. Online ahead of print.

ABSTRACT

INTRODUCTION: : Juvenile idiopathic arthritis (JIA) is a chronic disease characterized by persistent joint inflammation. JIA is the most common pediatric chronic rheumatic disease and no curative therapy is currently available. Methotrexate (MTX) is an important treatment for JIA even though a high inter-individual variability in response is observed in patients. Among the factors of this variability, genetics and epigenetics might play an important role.

AREAS COVERED: : This review summarizes the results of pharmacogenetic and pharmacoepigenetic studies regarding MTX response in JIA. Studies considering epigenetic factors in JIA patients are still very limited, therefore this review includes also studies performed in adult patients with rheumatoid arthritis. Moreover, the relevance of biomarkers measured in blood or urine of JIA patients in relation to MTX treatment is discussed.

EXPERT OPINION: : Nowadays, even though many pharmacogenomics studies have been published, a specific genetic marker predictor of MTX efficacy or adverse events has not yet been identified. Encouraging results are available and great expectations rely on the study of epigenetics. Future studies are needed in order to identify genetic and epigenetic biomarkers that can be implemented in the clinical practice.

PMID:34392756 | DOI:10.1080/1744666X.2021.1968833

EBioMedicine. 2021 Aug 12;70:103532. doi: 10.1016/j.ebiom.2021.103532. Online ahead of print.

ABSTRACT

BACKGROUND: The underlying pathology of inguinal hernia is still not fully known; thus, further investigations of genetic backgrounds is needed. Here, we aimed to identify genetic factors attributing to inguinal hernias and explore the polygenic architecture of which some components are population-specific, while others are more common among populations.

METHODS: We performed a genome-wide association study (GWAS) on subjects with inguinal hernias using BioBank Japan (BBJ) data with 1,983 cases and 172,507 controls, followed by a trans-ethnic meta-analysis with UK Biobank (UKBB) data. We performed downstream analyses in order to identify the mechanisms underlying inguinal hernias supported by genetic findings.

FINDINGS: We identified a locus closest to ELN, which encodes elastin, at the GWAS significant level. The trans-ethnic meta-analysis revealed 23 additional significant loci, including five loci newly identified not significant in BBJ or UKBB GWAS: TGFB2, RNA5SP214/VGLL2, LOC646588, HMCN2, and ATP5F1CP1/CDKN3. Downstream analyses revealed the overlap of GWAS significant signals in extracellular components, including elastin fiber formation. We also found a highly shared polygenic architecture across different populations (trans-ethnic genetic-effect correlation = 0•77, standard error = 0•26) and population-specific lead variants in ELN, indicating the critical role of elastin in inguinal hernias.

INTERPRETATION: We identified a significant locus of the ELN gene in the Japanese population and five additional loci across different populations. Downstream analyses revealed highly shared genetic architectures across populations and highlighted the important roles of extracellular components in the development of inguinal hernias. These findings deepen our understanding of the mechanisms underlying inguinal hernia.

FUNDING: The Japan Agency for Medical Research and Development (AMED) (Grant Number: JP19km0605001).

PMID:34392144 | DOI:10.1016/j.ebiom.2021.103532

Ann Oncol. 2021 Aug 12:S0923-7534(21)03974-0. doi: 10.1016/j.annonc.2021.08.1745. Online ahead of print.

ABSTRACT

IMPORTANCE: The severity of oxaliplatin (L-OHP)-induced peripheral sensory neuropathy (PSN) exhibits substantial interpatient variability, and some patients suffer from long-term, persisting PSN.

OBJECTIVE: To identify single-nucleotide polymorphisms (SNPs) predicting L-OHP-induced PSN using a genome-wide association study (GWAS) approach.

DESIGN, SETTING, PARTICIPANTS: A large prospective GWAS including 1,379 patients with stage II/III colon cancer who received L-OHP-based adjuvant chemotherapy (mFOLFOX6/CAPOX) under the phase II (JOIN/JFMC41) or the phase III (ACHIVE/JFMC47) trial.

MAIN OUTCOMES AND MEASURES: First, GWAS comparison of worst grade PSN (grade 0/1 vs. 2/3) was performed. Next, to minimize the impact of ambiguity in PSN grading, extreme PSN phenotypes were selected and analyzed by GWAS. SNPs that could predict time to recovery from PSN were also evaluated. In addition, SNPs associated with L-OHP-induced allergic reactions (AR) and time to disease recurrence were explored.

RESULTS: No SNPs exceeded the genome-wide significance (p < 5.0 × 10-8) in either GWAS comparison of worst grade PSN, extreme PSN phenotypes, or time to recovery from PSN. Association study focusing on AR or time to disease recurrence also failed to reveal any significant SNPs.

CONCLUSION AND RELEVANCE: Our results highlight the challenges of utilizing SNPs for predicting susceptibility to L-OHP-induced PSN in daily clinical practice.

PMID:34391895 | DOI:10.1016/j.annonc.2021.08.1745

Lancet. 2021 Aug 14;398(10300):578. doi: 10.1016/S0140-6736(21)00879-5.

NO ABSTRACT

PMID:34391494 | DOI:10.1016/S0140-6736(21)00879-5

Lancet. 2021 Aug 14;398(10300):578-579. doi: 10.1016/S0140-6736(21)00874-6.

NO ABSTRACT

PMID:34391493 | DOI:10.1016/S0140-6736(21)00874-6

Malar J. 2021 Aug 14;20(1):341. doi: 10.1186/s12936-021-03869-x.

ABSTRACT

BACKGROUND: The relapsing nature of Plasmodium vivax infection is a major barrier to its control and elimination. Factors such as adequate dosing, adherence, drug quality, and pharmacogenetics can impact the effectiveness of radical cure of P. vivax and need to be adequately evaluated. CYP2D6 pathway mediates the activation of primaquine (primaquine) into an active metabolite(s) in hepatocytes, and impaired activity has been linked to a higher risk of relapse.

CASES PRESENTATION: Three patients diagnosed with P. vivax malaria presented repeated relapses after being initially treated with chloroquine (25 mg/kg) and primaquine (3.5 mg/kg in 14 days) at a non-endemic travel clinic. Recurring episodes were subsequently treated with a higher dose of primaquine (7 mg/kg in 14 days), which prevented further relapses in two patients. However, one patient still presented two episodes after a higher primaquine dose and was prescribed 300 mg of chloroquine weekly to prevent further episodes. Impaired CYP2D6 function was observed in all of them.

CONCLUSION: Lack of response to primaquine was associated with impaired CYP2D6 activity in three patients presenting multiple relapses followed in a non-endemic setting. Higher primaquine dosage was safe and effectively prevented relapses in two patients and should be further investigated as an option in Latin America. It is crucial to investigate the factors associated with unsuccessful radical cures and alternative therapeutic options.

PMID:34391426 | DOI:10.1186/s12936-021-03869-x

Clin Pharmacol Ther. 2021 Aug 14. doi: 10.1002/cpt.2397. Online ahead of print.

ABSTRACT

Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious drug-related adverse event. To identify pharmacogenomic markers of MRONJ associated with bisphosphonate therapy, we conducted a genome-wide association study (GWAS) meta-analysis followed by functional analysis of 5,008 individuals of European ancestry treated with bisphosphonates which includes the largest number of MRONJ cases to date (444 cases and 4,564 controls). Discovery GWAS was performed in randomly selected 70% of the cancer patients and replication GWAS was performed in the remaining 30% of the cancer patients treated with intravenous bisphosphonates followed by meta-analysis of all 3,639 cancer patients. GWAS was also performed in 1,369 osteoporosis patients treated with oral bisphosphonates. The lead SNP, rs2736308 on chromosome 8, was associated with an increased risk of MRONJ with an odds ratio (OR) of 2.71 and 95% confidence interval (CI) of 1.90 - 3.86 (p = 3.57*10-8 ) in the meta-analysis of cancer patients. This SNP was validated in the MRONJ GWAS in osteoporosis patients, with OR of 2.82 (1.55-4.09) (p = 6.84*10-4 ). The meta-analysis combining cancer and osteoporosis patients yielded the same lead SNP rs2736308 on chromosome 8 as the top SNP (OR: 2.74, 95% CI: 2.09-3.39, p = 9.65*10-11 ). This locus is associated with regulation of the BLK, CTSB, and FDFT1 genes, which had been associated with bone mineral density. FDFT1 encodes a membrane-associated enzyme which is implicated in the bisphosphonates pathway. This study provides insights into the potential mechanism of MRONJ.

PMID:34390503 | DOI:10.1002/cpt.2397

Biochem Pharmacol. 2021 Aug 10:114726. doi: 10.1016/j.bcp.2021.114726. Online ahead of print.

ABSTRACT

Migration and invasion promote tumor cell metastasis, which is the leading cause of cancer death. At present there are no effective treatments. Epidemiological studies have suggested that ω-3 polyunsaturated fatty acids (PUFA) may decrease cancer aggressiveness. In recent studies epoxide metabolites of ω-3 PUFA exhibited anti-cancer activity, although increased in vivo stability is required to develop useful drugs. Here we synthesized novel stabilized ureido-fatty acid ω-3 epoxide isosteres and found that one analogue - p-tolyl-ureidopalmitic acid (PTU) - inhibited migration and invasion by MDA-MB-231 breast cancer cells in vitro and in vivo in xenografted nu/nu mice. From proteomics analysis of PTU-treated cells major regulated pathways were linked to the actin cytoskeleton and actin-based motility. The principal finding was that PTU impaired the formation of actin protrusions by decreasing the secretion of Wnt5a, which dysregulated the Wnt/planar cell polarity (PCP) pathway and actin cytoskeletal dynamics. Exogenous Wnt5a restored invasion and Wnt/PCP signalling in PTU-treated cells. PTU is the prototype of a novel class of agents that selectively dysregulate the Wnt/PCP pathway by inhibiting Wnt5a secretion and actin dynamics to impair MDA-MB-231 cell migration and invasion.

PMID:34389322 | DOI:10.1016/j.bcp.2021.114726

Pharmacopsychiatry. 2021 Aug 13. doi: 10.1055/a-1525-2820. Online ahead of print.

ABSTRACT

INTRODUCTION: The atypical antipsychotic quetiapine is known to induce weight gain and other metabolic complications. The underlying mechanisms are multifactorial and poorly understood with almost no information on the effect of dosage. Concerns were thus raised with the rise in low-dose quetiapine off-label prescription (i. e.,<150 mg/day).

METHODS: In this study, we evaluated the influence of quetiapine dose for 474 patients included in PsyMetab and PsyClin studies on weight and metabolic parameter evolution. Weight, blood pressure, lipid, and glucose profiles were evaluated during a follow-up period of 3 months after treatment initiation.

RESULTS: Significant dose-dependent metabolic alterations were observed. The daily dose was found to influence weight gain and increase the risk of undergoing clinically relevant weight gain (≥7% from baseline). It was also associated with a change in plasma levels of cholesterol (total cholesterol, LDL cholesterol, and HDL cholesterol) as well as with increased odds of developing hypertriglyceridemia, as well as total and LDL hypercholesterolemia. No impact of a dose increase on blood pressure and plasma glucose level was observed.

DISCUSSION: The dose-dependent effect highlighted for weight gain and lipid alterations emphasizes the importance of prescribing the minimal effective dose. However, as the effect size of a dose increase on metabolic worsening is low, the potential harm of low-dose quetiapine should not be dismissed. Prescriptions must be carefully evaluated and regularly questioned in light of side effect onset.

PMID:34388836 | DOI:10.1055/a-1525-2820

Biomed Pharmacother. 2021 Aug 10;142:112009. doi: 10.1016/j.biopha.2021.112009. Online ahead of print.

ABSTRACT

Genetic factors that affect variability in metformin response have been poorly studied in the Latin American population, despite its being the initial drug therapy for type 2 diabetes, one of the most prevalent diseases in that region. Metformin pharmacokinetics is carried out by members of the membrane transporters superfamily (SLCs), being the multidrug and toxin extrusion protein 1 (MATE1), one of the most studied. Some genetic variants in MATE1 have been associated with reduced in vitro metformin transport. They include rs77474263 p.[L125F], a variant present at a frequency of 13.8% in Latin Americans, but rare worldwide (less than 1%). Using exome sequence data and TaqMan genotyping, we revealed that the Mexican population has the highest frequency of this variant: 16% in Mestizos and 27% in Amerindians, suggesting a possible Amerindian origin. To elucidate the metformin pharmacogenetics, a children cohort was genotyped, allowing us to describe, for the first time, a MATE1 rs77474263 TT homozygous individual. An additive effect of the L125F variant was observed on blood metformin accumulation, revealing the highest metformin and lactate serum levels in the TT homozygote, and intermediate metformin values in the heterozygotes. Moreover, a molecular dynamics analysis suggested that the genetic variant effect on metformin efflux could be due to a decreased protein permeability. We conclude that pharmacogenetics could be useful in enhancing metformin pharmacovigilance in populations having a high frequency of the risk genotype, especially considering that these populations also have a higher susceptibility to the diseases for which metformin is the first-choice drug.

PMID:34388523 | DOI:10.1016/j.biopha.2021.112009

Cell. 2021 Aug 6:S0092-8674(21)00879-5. doi: 10.1016/j.cell.2021.07.020. Online ahead of print.

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is characterized by notorious resistance to current therapies attributed to inherent tumor heterogeneity and highly desmoplastic and immunosuppressive tumor microenvironment (TME). Unique proline isomerase Pin1 regulates multiple cancer pathways, but its role in the TME and cancer immunotherapy is unknown. Here, we find that Pin1 is overexpressed both in cancer cells and cancer-associated fibroblasts (CAFs) and correlates with poor survival in PDAC patients. Targeting Pin1 using clinically available drugs induces complete elimination or sustained remissions of aggressive PDAC by synergizing with anti-PD-1 and gemcitabine in diverse model systems. Mechanistically, Pin1 drives the desmoplastic and immunosuppressive TME by acting on CAFs and induces lysosomal degradation of the PD-1 ligand PD-L1 and the gemcitabine transporter ENT1 in cancer cells, besides activating multiple cancer pathways. Thus, Pin1 inhibition simultaneously blocks multiple cancer pathways, disrupts the desmoplastic and immunosuppressive TME, and upregulates PD-L1 and ENT1, rendering PDAC eradicable by immunochemotherapy.

PMID:34388391 | DOI:10.1016/j.cell.2021.07.020

Clin Transl Sci. 2021 Aug 13. doi: 10.1111/cts.13122. Online ahead of print.

ABSTRACT

Psychotropic drugs can induce strong metabolic adverse effects, potentially increasing morbidity and/or mortality of patients. Metabolomic profiling, by studying the levels of numerous metabolic intermediates and products in the blood, allows a more detailed examination of metabolism dysfunctions. We aimed to identify blood metabolomic markers associated with weight gain in psychiatric patients. Sixty-two patients starting a treatment known to induce weight gain were recruited. Two hundred six selected metabolites implicated in various pathways were analyzed in plasma, at baseline and after one month of treatment. Additionally, 15 metabolites of the kynurenine pathway were quantified. This latter analysis was repeated in a confirmatory cohort of 24 patients. Among the 206 metabolites, a plasma metabolomic fingerprint after one month of treatment embedded 19 compounds from different chemical classes (amino acids, acylcarnitines, carboxylic acids, catecholamines, nucleosides, pyridine and tetrapyrrole) potentially involved in metabolic disruption and inflammation processes. The predictive potential of such early metabolite changes on 3 months of weight evolution was then explored using a linear mixed-effects model. Of these 19 metabolites, short-term modifications of kynurenine, hexanoylcarnitine, and biliverdin, as well as kynurenine/tryptophan ratio at one month, were associated with 3 months weight evolution. Alterations of the kynurenine pathway were confirmed by quantification, in both exploratory and confirmatory cohorts. Our metabolomic study suggests a specific metabolic dysregulation after one month of treatment with psychotropic drugs known to induce weight gain. The identified metabolomic signature could contribute in the future to the prediction of weight gain in patients treated with psychotropic drugs.

PMID:34387942 | DOI:10.1111/cts.13122

Curr Protoc. 2021 Aug;1(8):e226. doi: 10.1002/cpz1.226.

ABSTRACT

The Pharmacogenomics Knowledgebase (PharmGKB) is an integrated online knowledge resource for the understanding of how genetic variation contributes to variation in drug response. Our focus includes not only pharmacogenomic information useful for clinical implementation (e.g., drug dosing guidelines and annotated drug labels), but also information to catalyze scientific research and drug discovery (e.g., variant-drug annotations and drug-centered pathways). As of April 2021, the annotated content of PharmGKB spans 715 drugs, 1761 genes, 227 diseases, 165 clinical guidelines, and 784 drug labels. We have manually curated data from more than 9000 published papers to generate the content of PharmGKB. Recently, we have also implemented an automated natural language processing (NLP) tool to broaden our coverage of the pharmacogenomic literature. This article contains a basic protocol describing how to navigate the PharmGKB website to retrieve information on how genes and genetic variations affect drug efficacy and toxicity. It also includes a protocol on how to use PharmGKB to facilitate interpretation of findings for a pharmacogenomic variant genotype or metabolizer phenotype. PharmGKB is freely available at http://www.pharmgkb.org. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Navigating the homepage of PharmGKB and searching by drug Basic Protocol 2: Using PharmGKB to facilitate interpretation of pharmacogenomic variant genotypes or metabolizer phenotypes.

PMID:34387941 | DOI:10.1002/cpz1.226

PeerJ. 2021 Jul 23;9:e11149. doi: 10.7717/peerj.11149. eCollection 2021.

ABSTRACT

BACKGROUND: Some single nucleotide polymorphisms (SNPs) in the cytochrome P450 (CYP)2B6 gene lead to decreased enzyme activity and have an impact on drug metabolism. The present study was designed to investigate the patterns of genetic distinction across a hypervariable region of the CYP2B6 gene, known to contain important SNPs, i.e. rs4803419 and rs3745274, among five major ethnic groups of the Pakistani population.

METHODS: Arlequin v3.5.DnaSPv6.12. and network 5 resources were used to analyze population genetic variance in the partial CYP2B6 gene sequences obtained from 104 human samples belonging to Punjabi, Pathan, Sindhi, Seraiki and Baloch ethnicities of Pakistan. The partial CYP2B6 gene region analyzed in the current study is previously known to possess important SNPs.

RESULTS: The data analyses revealed that genetic variance among samples mainly came from differentiation within the ethnic groups. However, significant genetic variation was also found among the various ethnic groups. The high pairwise Fst genetic distinction was observed between Seraiki and Sindhi ethnic groups (Fst = 0.13392, P-value = 0.026) as well as between Seraiki and Balochi groups (Fst = 0.04303, P-value = -0.0030). However, the degree of genetic distinction was low between Pathan and Punjabi ethnic groups. Some SNPs, including rs3745274 and rs4803419, which are previously shown in strong association with increased plasma Efavirenz level, were found in high frequency. Besides, a novel SNP, which was not found in dbSNP and Ensemble databases, was identified in the Balochi ethnicity. This novel SNP is predicted to affect the CYP2B6 splicing pattern.

CONCLUSION: These results may have significant implications in Pakistani ethnicities in the context of drugs metabolized by CYP2B6, especially in Seraiki and Balochi ethnicity. The novel heterogeneous SNP, found in the present study, might lead to altered drug-metabolizing potential of CYP2B6 and, therefore, may be implicated in non-responder phenomenon.

PMID:34386299 | PMC:PMC8312491 | DOI:10.7717/peerj.11149

Pharmgenomics Pers Med. 2021 Aug 5;14:955-962. doi: 10.2147/PGPM.S316556. eCollection 2021.

ABSTRACT

PURPOSE: Inefficacy and safety concerns are main medications' problems, especially in the case of poly-therapies, when drug-drug interactions may alter the expected drug disposition. Ongoing efforts are aimed to establish drug selection processes aimed to preemptive evaluation of a plethora of factors affecting patient's specific drug response, including pharmacogenomic markers, in order to minimize prescription of improper medications. In previous years, we established at the University Hospital Sant'Andrea of Rome, Italy, a Precision Medicine Service based on a multi-disciplinary experts' team. The team is in charge to produce a drug therapy counselling report, including pharmacogenomic, pharmacokinetic and pharmacodynamic considerations. In this study, we aimed to evaluate the performance of this established "manual" process of therapy selection with a novel bioinformatic tool, the Drug-PIN system.

PATIENTS AND METHODS: A total of 200 patients diagnosed with Major Depressive Disorders or a depressive episode in Bipolar Disorder, with at least three previous failed treatments, who underwent pharmacogenomic profiling and therapy counselling in the Sant'Andrea Hospital from 2017 to 2020. The baseline poly-therapy of these patients was re-evaluated and optimized by Drug-PIN. Results of the Drug-PIN poly-therapy evaluation/optimization were compared with the results of the original poly-therapy evaluation/optimization by therapy counselling. To compare the results between the two processes, the risk associated with each poly-therapy was classified as low, moderate, or high.

RESULTS: The number of baseline poly-therapies classified in low-, moderate- or high-risk did not change significantly between manual system or Drug-PIN system. As the counselling process, also the Drug-PIN system produces a significant decrease in the predicted treatment-associated risk.

CONCLUSION: Drug-PIN substantially replicates the output of the counselling process, allowing a substantial reduction in the time needed for therapy evaluation. Availability of an effective bioinformatic tool for proper drug selection is expected to exponentially increase the actuation of targeted therapy strategies.

PMID:34385834 | PMC:PMC8352633 | DOI:10.2147/PGPM.S316556

J Am Coll Cardiol. 2021 Aug 17;78(7):710-712. doi: 10.1016/j.jacc.2021.05.050.

NO ABSTRACT

PMID:34384553 | DOI:10.1016/j.jacc.2021.05.050

Pediatr Blood Cancer. 2021 Aug 12:e29282. doi: 10.1002/pbc.29282. Online ahead of print.

ABSTRACT

BACKGROUND: Sorafenib,an orally bioavailable, multitarget tyrosine kinase inhibitor, and irinotecan, a topoisomerase I inhibitor, have demonstrated activity in pediatric and adult malignancies. We evaluated the toxicity, pharmacokinetic (PK), and pharmacogenomic (PGX) profile of sorafenib with irinotecan in children with relapsed or refractory solid tumors and assessed the feasibility of incorporating patient-reported outcome (PRO) measures as an adjunct to traditional endpoints.

METHODS: Sorafenib, continuous oral twice daily dosing, was administered with irinotecan, orally, once daily days 1-5, repeated every 21 days (NCT01518413). Based on tolerability, escalation of sorafenib followed by escalation of irinotecan was planned. Three patients were initially enrolled at each dose level. Sorafenib and irinotecan PK analyses were performed during cycle 1. PRO measurements were collected during cycles 1 and 2.

RESULTS: Fifteen patients were evaluable. Two of three patients at dose level 2 experienced dose-limiting toxicity (DLT), grade 3 diarrhea, and grade 3 hyponatremia. Therefore, dose level 1 was expanded to 12 patients and two patients had DLT, grade 4 thrombocytopenia, grade 3 elevated lipase. Nine of 15 (60%) patients had a best response of stable disease with four patients receiving ≥6 cycles.

CONCLUSIONS: The recommended dose for pediatric patients was sorafenib 150 mg/m2 /dose twice daily with irinotecan 70 mg/m2 /dose daily × 5 days every 21 days. This oral outpatient regimen was well tolerated and resulted in prolonged disease stabilization. There were no significant alterations in the PK profile of either agent when administered in combination. Patients were willing and able to report their subjective experiences with this regimen.

PMID:34383370 | DOI:10.1002/pbc.29282

J Thromb Haemost. 2021 Aug 12. doi: 10.1111/jth.15494. Online ahead of print.

ABSTRACT

BACKGROUND: Warfarin dose variability observed in patients is attributed to variation in genes involved in the warfarin metabolic pathway. Genetic variation in CYP2C9 and VKORC1 has been the traditional focus in evaluating warfarin dose variability, with little focus on other genes.

OBJECTIVE: We set out to evaluate 27 single nucleotide polymorphisms (SNPs) in the CYP2C cluster loci and 8 genes (VKORC1, ABCB1, CYP2C9, CYP2C19, CYP2C8, CYP1A2, CYP3A4, and CYP3A5) involved in pharmacokinetics of warfarin.

PATIENTS/METHODS: 503 participants were recruited among black Africans and Mixed Ancestry population groups, from South Africa and Zimbabwe, and a blood sample taken for DNA. Clinical parameters were obtained from patient medical records, and these were correlated with genetic variation.

RESULTS: Among black Africans, the SNPs CYP2C rs12777823G>A, CYP2C9 c.449G>A (*8), CYP2C9 c.1003C>T (*11) and CYP2C8 c.805A>T (*2) were significantly associated with warfarin maintenance dose. Conversely, CYP2C9 c.430C>T (*2), CYP2C8 c.792C>G (*4) and VKORC1 g.-1639G>A were significantly associated with maintenance dose among the Mixed Ancestry. The presence of CYP2C8*2 and CYP3A5*6 alleles was associated with increased mean warfarin maintenance dose, whereas CYP2C9*8 allele was associated with reduced warfarin maintenance dose.

CONCLUSION: African populations present with a diversity of variants that are important in predicting pharmacogenetics-based warfarin dosing in addition to those reported in CYP2C9 and VKORC1. It is therefore important, to include African populations in pharmacogenomics studies to be able to identify all possible biomarkers that are potential predictors for drug response.

PMID:34382722 | DOI:10.1111/jth.15494

Cancer Med. 2021 Aug 12. doi: 10.1002/cam4.4196. Online ahead of print.

ABSTRACT

INTRODUCTION: We evaluated the arginine-depleting enzyme pegargiminase (ADI-PEG20; ADI) with pemetrexed (Pem) and cisplatin (Cis) (ADIPemCis) in ASS1-deficient non-squamous non-small cell lung cancer (NSCLC) via a phase 1 dose-expansion trial with exploratory biomarker analysis.

METHODS: Sixty-seven chemonaïve patients with advanced non-squamous NSCLC were screened, enrolling 21 ASS1-deficient subjects from March 2015 to July 2017 onto weekly pegargiminase (36 mg/m2 ) with Pem (500 mg/m2 ) and Cis (75 mg/m2 ), every 3 weeks (four cycles maximum), with maintenance Pem or pegargiminase. Safety, pharmacodynamics, immunogenicity, and efficacy were determined; molecular biomarkers were annotated by next-generation sequencing and PD-L1 immunohistochemistry.

RESULTS: ADIPemCis was well-tolerated. Plasma arginine and citrulline were differentially modulated; pegargiminase antibodies plateaued by week 10. The disease control rate was 85.7% (n = 18/21; 95% CI 63.7%-97%), with a partial response rate of 47.6% (n = 10/21; 95% CI 25.7%-70.2%). The median progression-free and overall survivals were 4.2 (95% CI 2.9-4.8) and 7.2 (95% CI 5.1-18.4) months, respectively. Two PD-L1-expressing (≥1%) patients are alive following subsequent pembrolizumab immunotherapy (9.5%). Tumoral ASS1 deficiency enriched for p53 (64.7%) mutations, and numerically worse median overall survival as compared to ASS1-proficient disease (10.2 months; n = 29). There was no apparent increase in KRAS mutations (35.3%) and PD-L1 (<1%) expression (55.6%). Re-expression of tumoral ASS1 was detected in one patient at progression (n = 1/3).

CONCLUSIONS: ADIPemCis was safe and highly active in patients with ASS1-deficient non-squamous NSCLC, however, survival was poor overall. ASS1 loss was co-associated with p53 mutations. Therapies incorporating pegargiminase merit further evaluation in ASS1-deficient and treatment-refractory NSCLC.

PMID:34382365 | DOI:10.1002/cam4.4196