J Geriatr Oncol. 2023 Jul 22:101595. doi: 10.1016/j.jgo.2023.101595. Online ahead of print.

NO ABSTRACT

PMID:37487857 | DOI:10.1016/j.jgo.2023.101595

Clin Lung Cancer. 2023 Jul 19:S1525-7304(23)00142-0. doi: 10.1016/j.cllc.2023.07.003. Online ahead of print.

NO ABSTRACT

PMID:37487787 | DOI:10.1016/j.cllc.2023.07.003

Front Med (Lausanne). 2023 Jul 6;10:1198088. doi: 10.3389/fmed.2023.1198088. eCollection 2023.

ABSTRACT

Randomized controlled trials are considered the 'gold standard' to reduce bias by randomizing patients to an experimental intervention, versus placebo or standard of care cohort. There are inherent challenges to enrolling a standard of care or cohorts: costs, site engagement logistics, socioeconomic variability, patient willingness, ethics of placebo interventions, cannibalizing the treatment arm population, and extending study duration. The COVID-19 pandemic has magnified aspects of constraints in trial recruitment and logistics, spurring innovative approaches to reducing trial sizes, accelerating trial accrual while preserving statistical rigor. Using data from medical records and databases allows for construction of external control arms that reduce the costs of an external control arm (ECA) randomized to standard of care. Simultaneously examining covariates of the clinical outcomes in ECAs that are being measured in the interventional arm can be particularly useful in phase 2 trials to better understand social and genetic determinants of clinical outcomes that might inform pivotal trial design. The FDA and EMA have promulgated a number of publicly available guidance documents and qualification reports that inform the use of this regulatory science tool to streamline clinical development, of phase 4 surveillance, and policy aspects of clinical outcomes research. Availability and quality of real-world data (RWD) are a prevalent impediment to the use of ECAs given such data is not collected with the rigor and deliberateness that characterizes prospective interventional control arm data. Conversely, in the case of contemporary control arms, a clinical trial outcome can be compared to a contemporary standard of care in cases where the standard of care is evolving at a fast pace, such as the use of checkpoint inhibitors in cancer care. Innovative statistical methods are an essential aspect of an ECA strategy and regulatory paths for these innovative approaches have been navigated, qualified, and in some cases published.

PMID:37484840 | PMC:PMC10359981 | DOI:10.3389/fmed.2023.1198088

Heliyon. 2023 Jul 4;9(7):e17712. doi: 10.1016/j.heliyon.2023.e17712. eCollection 2023 Jul.

ABSTRACT

BACKGROUND: Cervical cancer (CC) is the second most common type of female malignancy in Bangladesh. Polymorphisms in the CYP1A1 gene have been reported to be associated with CC in different populations. This case-control study with meta-analysis was undertaken to assess the relation of CYP1A1 rs4646903 and rs1048943 polymorphisms with the susceptibility of CC.

METHODS: A total of 185 CC patients and 220 controls were recruited, and the PCR-RFLP (Polymerase chain reaction-restriction fragment length polymorphism) technique was applied for genotyping. Again, 42 eligible studies (24 with rs4646903 and 18 with rs1048943) were included for meta-analysis, and RevMan 5.3 and the MetaGenyo web-based tool were used.

RESULTS: The rs4646903 polymorphism was significantly linked with CC in all association models, namely, additive 1, additive 2, dominant, recessive, overdominant, and allele models (OR = 2.41, 4.75, 2.67, 3.61, 2.13, and 2.44 with corresponding 95% CI = 1.55-3.76, 1.81-12.45, 1.75-4.07, 1.39-9.35, 1.38-3.30, and 1.71-3.48, respectively). On the contrary, rs1048943 showed no association (p > 0.05) with CC. Haplotype analysis revealed AT and AC haplotypes significantly decreased (OR = 0.45) and increased (OR = 4.86) CC risk, respectively, and SNPs are in strong linkage disequilibrium (D' = 0.912, r2 = 0.448). Again, rs4646903 carriers with a contraception history and >5 years of taking contraceptives showed an enhanced risk of CC (OR = 2.39, OR = 3.05). Besides, rs1048943 carriers aged >40 years (OR = 0.44), conceived first child aged ≤18 years (OR = 3.45), and history of contraceptives (OR = 2.18) were significantly linked with CC. Our meta-analysis found that for CYP1A1 rs4646903 codominant 1 (COD 1), codominant 2 (COD 2), codominant 3 (COD 3), dominant model (DM), recessive model (RM), and allele model (AM) in Caucasians and overdominant model (OD) in the overall population are associated with an elevated risk of CC, whereas rs1048943 is also associated with CC in overall, Caucasians and Asians in some genetic models.

CONCLUSION: Our case-control study and meta-analysis summarize that CYP1A1 rs4646903 and rs1048943 polymorphisms may be correlated with cervical cancer.

PMID:37483787 | PMC:PMC10359826 | DOI:10.1016/j.heliyon.2023.e17712

Clin Microbiol Infect. 2023 Jul 21:S1198-743X(23)00339-7. doi: 10.1016/j.cmi.2023.07.013. Online ahead of print.

ABSTRACT

BACKGROUND: Tuberculosis is a global health challenge and one of the leading causes of death worldwide. In the last decade, the tuberculosis treatment landscape has dramatically changed. After long years of stagnation, new compounds entered the market (bedaquiline, delamanid and pretomanid) and phase III clinical trials have shown promising results towards shortening duration of treatment for both drug-susceptible (Study 31/A5349, TRUNCATE-TB, SHINE) and drug-resistant tuberculosis (STREAM, NiX-TB, ZeNix, TB-PRACTECAL). Dose optimization of rifamycins and repurposed drugs have also brought hopes of further development of safe and effective regimens. Consequently, international and World Health Organization clinical guidelines have been updated multiple times in the last years to keep pace with these advances.

OBJECTIVES: This narrative review aims to summarize the state-of-the-art on treatment of drug-susceptible and drug-resistant tuberculosis, as well as recent trials results and an overview of ongoing clinical trials.

SOURCES: A non-systematic literature review was conducted in PubMed and MEDLINE, focusing on the treatment of tuberculosis. Ongoing clinical trials were listed according to the authors' knowledge, and completed consulting clinicaltrials.gov and other publicly available websites (www.resisttb.org/clinical-trials-progress-report, www.newtbdrugs.org/pipeline/trials).

CONTENT: This review summarizes the recent, major changes in the landscape for drug-susceptible and drug-resistant treatment, with a specific focus on their potential impact on patient outcomes and programmatic TB management. Moreover, insights in host-directed therapies, and advances in pharmacokinetic and pharmacogenomics are discussed. A thorough outline of ongoing therapeutic clinical trials is presented, highlighting different approaches and goals in current TB clinical research.

IMPLICATIONS: Future research should be directed to individualize regimens and protect these recent breakthroughs by preventing and identifying the selection of drug resistance and providing widespread, affordable, patient-centered access to new treatment options for all people affected by tuberculosis.

PMID:37482332 | DOI:10.1016/j.cmi.2023.07.013

Eur J Med Chem. 2023 Jul 20;259:115666. doi: 10.1016/j.ejmech.2023.115666. Online ahead of print.

ABSTRACT

ATP-binding cassette subfamily G member 2 (ABCG2), an efflux transporter, is involved in multiple pathological processes. Ko143 is a potent ABCG2 inhibitor; however, it is quickly metabolized through carboxylesterase 1-mediated hydrolysis of its t-butyl ester moiety. The current work aimed to develop more metabolically stable ABCG2 inhibitors. Novel Ko143 analogs were designed and synthesized by replacing the unstable t-butyl ester moiety in Ko143 with an amide group. The synthesized Ko143 analogs were evaluated for their ABCG2 inhibitory activity, binding mode with ABCG2, cytotoxicity, and metabolic stability. We found that the amide modification of Ko143 led to metabolically stable ABCG2 inhibitors. Among these Ko143 analogs, K2 and K34 are promising candidates with favorable oral pharmacokinetic profiles in mice. In summary, we synthesized novel Ko143 analogs with improved metabolic stability, which can potentially be used as lead compounds for the future development of ABCG2 inhibitors.

PMID:37482017 | DOI:10.1016/j.ejmech.2023.115666

Eur J Med Res. 2023 Jul 22;28(1):248. doi: 10.1186/s40001-023-01221-4.

ABSTRACT

OBJECTIVE: The latest research proposed a novel copper-dependent programmed cell death named cuproptosis. We aimed to elucidate the influence of cuproptosis in clear cell renal cell carcinoma (ccRCC) from a multi-omic perspective.

METHODS: This study systematically assessed mRNA expression, methylation, and genetic alterations of cuproptosis genes in TCGA ccRCC samples. Through unsupervised clustering analysis, the samples were classified as different cuproptosis subtypes, which were verified through NTP method in the E-MTAB-1980 dataset. Next, the cuproptosis score (Cuscore) was computed based on cuproptosis-related genes via PCA. We also evaluated clinical and immunogenomic features, drug sensitivity, immunotherapeutic response, and post-transcriptional regulation.

RESULTS: Cuproptosis genes presented multi-layer alterations in ccRCC, and were linked with patients' survival and immune microenvironment. We defined three cuproptosis subtypes [C1 (moderate cuproptosis), C2 (low cuproptosis), and C3 (high cuproptosis)], and the robustness and reproducibility of this classification was further proven. Overall survival was best in C3, moderate in C1, and worst in C2. C1 had the highest sensitivity to pazopanib, and sorafenib, while C2 was most sensitive to sunitinib. Furthermore, C1 patients benefited more from anti-PD-1 immunotherapy. Patients with high Cuscore presented the notable survival advantage. Cuscore was highly linked with immunogenomic features, and post-transcriptional events that contributed to ccRCC development. Finally, several potential compounds and druggable targets (NMU, RARRES1) were selected for low Cuscore group.

CONCLUSION: Overall, our study revealed the non-negligible role of cuproptosis in ccRCC development. Evaluation of the cuproptosis subtypes improves our cognition of immunogenomic features and better guides personalized prognostication and precision therapy.

PMID:37481601 | DOI:10.1186/s40001-023-01221-4

J Mol Diagn. 2023 Jul 20:S1525-1578(23)00154-X. doi: 10.1016/j.jmoldx.2023.07.001. Online ahead of print.

NO ABSTRACT

PMID:37481236 | DOI:10.1016/j.jmoldx.2023.07.001

Acta Neurol Belg. 2023 Jul 22. doi: 10.1007/s13760-023-02340-9. Online ahead of print.

NO ABSTRACT

PMID:37480479 | DOI:10.1007/s13760-023-02340-9

Clin Exp Med. 2023 Jul 22. doi: 10.1007/s10238-023-01142-w. Online ahead of print.

ABSTRACT

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a wide range of clinical manifestations and multifactorial etiologies ranging from environmental to genetic. SLE is associated with dysregulated immunological reactions, with increased immune complex formation leading to end-organ damages such as lupus nephritis, cutaneous lupus, and musculoskeletal disorders. Lupus treatment aims to reduce disease activity, prevent organ damage, and improve long-term patient survival and quality of life. Antimalarial, hydroxychloroquine (HCQ) is used as a first-line systemic treatment for lupus. It has shown profound efficacy in lupus and its associated conditions. However, wide variation in terms of clinical response to this drug has been observed among this group of patients. This variability has limited the potential of HCQ to achieve absolute clinical benefits. Several factors, including genetic polymorphisms of cytochrome P450 enzymes, have been stipulated as key entities leading to this inter-individual variation. Thus, there is a need for more studies to understand the role of genetic polymorphisms in CYP450 enzymes in the clinical response to HCQ. Focusing on the role of genetic polymorphism on whole blood HCQ in lupus disorder, this review aims to highlight up-to-date pathophysiology of SLE, the mechanism of action of HCQ, and finally the role of genetic polymorphism of CYP450 enzymes on whole blood HCQ level as well as clinical response in lupus.

PMID:37480404 | DOI:10.1007/s10238-023-01142-w

Nat Commun. 2023 Jul 21;14(1):4418. doi: 10.1038/s41467-023-39996-z.

ABSTRACT

Obesity is associated with an increased risk of developing breast cancer (BC) and worse prognosis in BC patients, yet its impact on BC biology remains understudied in humans. This study investigates how the biology of untreated primary BC differs according to patients' body mass index (BMI) using data from >2,000 patients. We identify several genomic alterations that are differentially prevalent in overweight or obese patients compared to lean patients. We report evidence supporting an ageing accelerating effect of obesity at the genetic level. We show that BMI-associated differences in bulk transcriptomic profile are subtle, while single cell profiling allows detection of more pronounced changes in different cell compartments. These analyses further reveal an elevated and unresolved inflammation of the BC tumor microenvironment associated with obesity, with distinct characteristics contingent on the estrogen receptor status. Collectively, our analyses imply that obesity is associated with an inflammaging-like phenotype. We conclude that patient adiposity may play a significant role in the heterogeneity of BC and should be considered for BC treatment tailoring.

PMID:37479706 | DOI:10.1038/s41467-023-39996-z

Talanta. 2023 Jul 11;266(Pt 1):124936. doi: 10.1016/j.talanta.2023.124936. Online ahead of print.

ABSTRACT

DNA is an indispensable part of metabolism, which affects many important processes in the body, including gene expression, protein synthesis, and drug delivery. Surface-enhanced Raman spectroscopy (SERS) is one of the most important methods used to study the structure and function of DNA and can obtain rich DNA molecular fingerprints. However, it is still a great challenge to use SERS to directly analyze the characteristic Raman signals of the DNA molecule and achieve rapid and simple detection. Hence, a detection platform based on gold bipyramidal nanoparticles (AuNBs) self-assembly that can be directly used for the detection of DNA molecules without the need for additional aggregators and cleaning agents was designed in this study. The original hexadecyltrimethylammonium bromide (CTAB) of AuNBs can be used as the internal standard for DNA quantification without an additional standard. This is the first time that the Raman signals of the analyte molecule can be obtained directly without labels by using the interaction between the molecule and the enhanced substrate. We used this method to capture the original DNA molecules in methylated DNA, serum, and cell metabolites and obtained spectral data processing results using linear discriminant analysis (LDA). This provides new ideas for the digitization of disease treatment and the study of the metabolic processes of life.

PMID:37478765 | DOI:10.1016/j.talanta.2023.124936

Am J Health Syst Pharm. 2023 Jul 21:zxad159. doi: 10.1093/ajhp/zxad159. Online ahead of print.

ABSTRACT

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.

PURPOSE: To develop a pharmacist-driven, exploratory pharmacogenomics implementation model with the goal of creating a process for pharmacists to interpret pharmacogenomics results from RIGHT 10K Study samples and provide electronic consults to providers.

SUMMARY: A train-the-trainer model program was initiated whereby pharmacogenomics pharmacists developed a documentation template and a quick reference guide as a standard guide to train other pharmacists. Pharmacists completed electronic consults (e-consults) reviewing pharmacogenomics results, with reference to drug-gene interactions, for patients with "semi-urgent" and "clinically actionable" results, defined as those indicating a potential for gene-drug interactions to cause major harm and those indicating a potential for an adverse drug reaction or reduced efficacy, respectively. Outcomes measured included the number of consults over time, number and role of pharmacists involved, average time to complete e-consults over time, and gene-drug pairs for semi-urgent consults per month. A total of 395 pharmacists were trained. The total number of e-consults completed was 2,843: 61 semi-urgent and 2,782 clinically actionable consults. The average time spent per consult was 24 minutes, and the average number of e-consults per pharmacist was 7. CYP2C19-clopidogrel was the most common gene-drug pair targeted in semi-urgent consults.

CONCLUSION: Pharmacy leaders planning to implement similar pharmacogenomics programs can utilize this data to estimate hiring needs for future pharmacogenomics implementation, while also considering the potential additional cost of developing resources.

PMID:37478473 | DOI:10.1093/ajhp/zxad159

CourseSource. 2023;10. doi: 10.24918/cs.2023.10.

ABSTRACT

Cytochrome P450 (CYP) enzymes are important regulators of drug efficacy and toxicity. Genetic variation in CYP isoforms can impact how well patients respond to medications or experience unwanted toxicities. PharmGKB is an online pharmacogenomics resource that collates the latest data and clinical guidelines on genetic variation and drug responses. The purpose of this lesson was to develop an interactive, case-based activity that demonstrated how pharmacogenetics can be used to influence the prescribing of medications. This lesson was provided to 71 students during a two-hour online interactive session. The lesson consisted of 1) a didactic lecture on pharmacogenetic principles, 2) an overview of the PharmGKB website by the instructor, and 3) patient cases that used the PharmGKB website to answer questions and make recommendations about drug therapy. Patient cases explored the impact of genetic variation in CYP enzymes on patients prescribed medications for different diseases including depression (citalopram, CYP2C19), pain (codeine, CYP2D6), organ transplantation (tacrolimus, CYP3A5), and viral infection (efavirenz, CYP2B6). Four additional cases are included in this lesson. Students reviewed the patient cases in small groups, used PharmGKB to answer questions and design treatment plans, and presented their recommendations to instructors and other students. Based on pre-/post-lesson assessment questions and student feedback, we conclude that an interactive, group-based activity can be used to teach basic principles of pharmacogenetics and connect students to online resources for drug dosing.

PMID:37476533 | PMC:PMC10357923 | DOI:10.24918/cs.2023.10

Front Endocrinol (Lausanne). 2023 Jul 4;14:1184024. doi: 10.3389/fendo.2023.1184024. eCollection 2023.

ABSTRACT

Gender dysphoria is the imparity between a person's experienced gender and their birth-assigned gender. Gender transition is the process of adapting a person's sexual characteristics to match their experienced gender. The number of adults receiving sex hormone therapy for gender dysphoria is increasingly and these pharmacotherapies are increasing being prescribed in a general practice setting. The role of hormone therapy is to reverse or reduce physical sexual characteristics of the birth-assigned gender and enhance and build characteristics aligning to the expressed gender and these therapies apply to both transgender and gender nonconforming patients. Recognizing the options and interpreting the effects of gender transition therapies are fundamental to the discussion and treatment of gender dysphoria. This review summarizes pharmacodynamics, comparative dosing, adverse effects, monitoring, and potential pharmacogenetic influence of current pharmacotherapy. These include the use of 17-beta-estradiol, spironolactone, testosterone, GnRH agonists as well as adjunctive phosphodiesterase-5 inhibitors. The article also addresses gaps within the published literature including optimal routes of administration for individual patients, risks of malignancy and dosing reductions as transgender patients age.

PMID:37476490 | PMC:PMC10355117 | DOI:10.3389/fendo.2023.1184024

Cancer Res Commun. 2023 Jul 19;3(7):1286-1311. doi: 10.1158/2767-9764.CRC-22-0427. eCollection 2023 Jul.

ABSTRACT

Prostate cancer is the second leading cause of noncutaneous cancer-related deaths in American men. Androgen deprivation therapy (ADT), radical prostatectomy, and radiotherapy remain the primary treatment for patients with early-stage prostate cancer (castration-sensitive prostate cancer). Following ADT, many patients ultimately develop metastatic castration-resistant prostate cancer (mCRPC). Standard chemotherapy options for CRPC are docetaxel (DTX) and cabazitaxel, which increase median survival, although the development of resistance is common. Cancer stem-like cells possess mesenchymal phenotypes [epithelial-to-mesenchymal transition (EMT)] and play crucial roles in tumor initiation and progression of mCRPC. We have shown that low-dose continuous administration of topotecan (METRO-TOPO) inhibits prostate cancer growth by interfering with key cancer pathway genes. This study utilized bulk and single-cell or whole-transcriptome analysis [(RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq)], and we observed greater expression of several EMT markers, including Vimentin, hyaluronan synthase-3, S100 calcium binding protein A6, TGFB1, CD44, CD55, and CD109 in European American and African American aggressive variant prostate cancer (AVPC) subtypes-mCRPC, neuroendocrine variant (NEPC), and taxane-resistant. The taxane-resistant gene FSCN1 was also expressed highly in single-cell subclonal populations in mCRPC. Furthermore, metronomic-topotecan single agent and combinations with DTX downregulated these EMT markers as well as CD44+ and CD44+/CD133+ "stem-like" cell populations. A microfluidic chip-based cell invasion assay revealed that METRO-TOPO treatment as a single agent or in combination with DTX was potentially effective against invasive prostate cancer spread. Our RNA-seq and scRNA-seq analysis were supported by in silico and in vitro studies, suggesting METRO-TOPO combined with DTX may inhibit oncogenic progression by reducing cancer stemness in AVPC through the inhibition of EMT markers and multiple oncogenic factors/pathways.

SIGNIFICANCE: The utilization of metronomic-like dosing regimens of topotecan alone and in combination with DTX resulted in the suppression of makers associated with EMT and stem-like cell populations in AVPC models. The identification of molecular signatures and their potential to serve as novel biomarkers for monitoring treatment efficacy and disease progression response to treatment efficacy and disease progression were achieved using bulk RNA-seq and single-cell-omics methodologies.

PMID:37476073 | PMC:PMC10355222 | DOI:10.1158/2767-9764.CRC-22-0427

Toxicol Appl Pharmacol. 2023 Jul 18:116630. doi: 10.1016/j.taap.2023.116630. Online ahead of print.

ABSTRACT

Gastric cancer (GC) is among the most-diagnosed and deadly malignancies worldwide. Deregulation in cellular bioenergetics is a hallmark of cancer. Based on the importance of metabolic reprogramming for the development and cancer progression, inhibitors of cell metabolism have been studied as potential candidates for chemotherapy in oncology. Mebendazole (MBZ), an antihelminthic approved by FDA, has shown antitumoral activity against cancer cell lines. However, its potential in the modulation of tumoral metabolism remains unclear. Results evidenced that the antitumoral and cytotoxic mechanism of MBZ in GC cells is related to the modulation of the mRNA expression of glycolic targets SLC2A1, HK1, GAPDH, and LDHA. Moreover, in silico analysis has shown that these genes are overexpressed in GC samples, and this increase in expression is related to decreased overall survival rates. Molecular docking revealed that MBZ modifies the protein structure of these targets, which may lead to changes in their protein function. In vitro studies also showed that MBZ induces alterations in glucose uptake, LDH's enzymatic activity, and ATP production. Furthermore, MBZ induced morphologic and intracellular alterations typical of the apoptotic cell death pathway. Thus, this data indicated that the cytotoxic mechanism of MBZ is related to an initial modulation of the tumoral metabolism in the GC cell line. Altogether, our results provide more evidence about the antitumoral mechanism of action of MBZ towards GC cells and reveal metabolic reprogramming as a potential area in the discovery of new pharmacological targets for GC chemotherapy.

PMID:37473966 | DOI:10.1016/j.taap.2023.116630

Pharmacol Res. 2023 Jul 18:106859. doi: 10.1016/j.phrs.2023.106859. Online ahead of print.

ABSTRACT

Few genetic polymorphisms predict early response to anti-TNF drugs in inflammatory bowel disease (IBD), and even fewer have been identified in the pediatric population. However, it would be of considerable clinical interest to identify and validate genetic biomarkers of long-term response. Therefore, the aim of the study was to analyze the usefulness of biomarkers of response to anti-TNFs in pediatric IBD (pIBD) as long-term biomarkers and to find differences by type of IBD and type of anti-TNF drug. The study population comprised 340 children diagnosed with IBD who were treated with infliximab or adalimumab. Genotyping of 9 selected SNPs for their association with early response and/or immunogenicity to anti-TNFs was performed using real-time PCR. Variants C rs10508884 (CXCL12), A rs2241880 (ATG16L1), and T rs6100556 (PHACTR3) (p value 0.049; p value 0.03; p value 0.031) were associated with worse long-term response to anti-TNFs in pIBD. DNA variants specific to disease type and anti-TNF type were identified in the pediatric population. Genotyping of these genetic variants before initiation of anti-TNFs would enable, if validated in a prospective cohort, the identification of pediatric patients who are long-term responders to this therapy.

PMID:37473877 | DOI:10.1016/j.phrs.2023.106859

Am J Cardiol. 2023 Jul 18;202:218-222. doi: 10.1016/j.amjcard.2023.06.090. Online ahead of print.

ABSTRACT

Current evidence increasingly supports CYP2C19 genotype-guided P2Y12 inhibitor selection. Clopidogrel remains the most prescribed P2Y12 inhibitor despite higher readmission rates than those of more efficacious third-generation P2Y12 inhibitors. It remains unclear whether pharmacogenetically (PGx)-guided antiplatelet therapy directly reduces readmissions after percutaneous coronary intervention (PCI). A single-center retrospective observational cohort study at a tertiary academic medical center was conducted. Patients receiving CYP2C19 genotyping after PCI were included and stratified into 2 groups (PGx-optimal vs PGx-suboptimal P2Y12 inhibitor prescribed) on the basis of CPIC (Clinical Pharmacogenetics Implementation Consortium) recommendations. Primary outcomes included 30-day and 90-day readmissions after index PCI. Most patients (78%) were of non-European ancestry. Among patients receiving PGx-optimal therapy, 50% had acute coronary syndromes whereas 61% receiving PGx-suboptimal therapy had stable coronary artery disease. Comparable 30-day (12% vs 10%, p = 0.481) and 90-day readmission rates (24% vs 28%, p = 0.323) were observed between patients receiving PGx-optimal or PGx-suboptimal therapies. PGx-optimal therapy was associated with fewer emergency department visits (3.4% vs 4.0%, p = 0.021) within 30 days, and patients initially prescribed PGx-suboptimal therapy were switched more often to PGx-optimal therapy during a readmission than were patients prescribed PGx-suboptimal antiplatelet therapy (p <0.001). In conclusion, CYP2C19 genotype-guided P2Y12 inhibitor therapy did not improve 30- and 90-day all-cause readmission rates in a predominantly non-European population. However, P2Y12 inhibitor therapy became concordant with CYP2C19 genotype in approximately half of patients during the first readmission after PCI, which may present further opportunities to revisit and optimize dual antiplatelet therapy in patients who undergo PCI.

PMID:37473671 | DOI:10.1016/j.amjcard.2023.06.090

Lung Cancer. 2023 Jul 16;183:107308. doi: 10.1016/j.lungcan.2023.107308. Online ahead of print.

ABSTRACT

OBJECTIVES: Predictive biomarkers of response to immune checkpoint inhibitors (ICIs) have been extensively studied in non-small cell lung cancer (NSCLC) with controversial results. Recently, gene-network analysis emerged as a new tool to address tumor biology and behavior, representing a potential tool to evaluate response to therapies.

METHODS: Clinical data and genetic profiles of 644 advanced NSCLCs were retrieved from cBioPortal and the Cancer Genome Atlas (TCGA); 243 ICI-treated NSCLCs were used to identify an immunotherapy response signatures via mutated gene network analysis and K-means unsupervised clustering. Signatures predictive values were tested in an external dataset of 242 cases and assessed versus a control group of 159 NSCLCs treated with standard chemotherapy.

RESULTS: At least two mutations in the coding sequence of genes belonging to the chromatin remodelling pathway (A signature), and/or at least two mutations of genes involved in cell-to-cell signalling pathways (B signature), showed positive prediction in ICI-treated advanced NSCLC. Signatures performed best when combined for patients undergoing first-line immunotherapy, and for those receiving combined ICIs.

CONCLUSIONS: Alterations in genes related to chromatin remodelling complexes and cell-to-cell crosstalk may force dysfunctional immune evasion, explaining susceptibility to immunotherapy. Therefore, exploring mutated gene networks could be valuable for determining essential biological interactions, contributing to treatment personalization.

PMID:37473500 | DOI:10.1016/j.lungcan.2023.107308