Technical know‐how in stereotactic ablative radiotherapy (SABR)

Should Estimated Glomerular Filtration Rate Be Adjusted for Race?

EL13 - Current status of stereotactic radiation therapy (SRT)

Chemotherapy continues to be a core component of cancer treatment, yet its success is frequently constrained by a "narrow therapeutic window"-some patients experience severe toxicity, while others show no tumor response. This dual challenge underscores the critical need for personalized medicine. Pharmacogenomics (PGx), the study of how genetic differences affect drug responses, presents a promising strategy for tailoring chemotherapy treatments. This Research Topic combines diverse studies that together push the field forward by comparing two main areas of PGx: toxicity prediction (reducing harm) and response prediction (increasing effectiveness). While current literature often concentrates on single-gene links, the contributions here highlight a shift toward polygenic risk models and real-world clinical factors that move the field beyond basic genotype-phenotype relationships.A notable highlight of this collection is the work by Cerpa et al., which developed multivariate models to predict the safety of 5-Fluorouracil (5-FU)-based chemotherapy in Chilean patients with advanced colorectal cancer. Using a nested case-control design, they examined 16 SNPs in key genes related to drug metabolism, detoxification, the folate cycle, DNA repair, and drug transport, such as DPYD, TYMS, TYMP, GSTP1, MTHFR, ERCC2, ABCB1, ABCC2, ABCC4, and ABCG2. Their findings revealed significant associations, including a higher risk of neuropathy with the DPYD (rs1801265) C allele, protection against hematological toxicity from the TYMS 3′UTR deletion (rs11280056), and a dual role of GSTP1 (rs1695)-reducing neuropathy risk but increasing mucositis risk. They also created multivariate models to predict anemia and pain, highlighting the potential to combine genetic and clinical data for better patient stratification regarding therapy benefits and toxicity risks. Importantly, by studying a non-European population, this research fills a vital gap in global pharmacogenomic data and emphasizes the need for population-specific tools to promote safer, fairer dosing of 5-FU.In this regard, the case report by Schmitt et al. provides a critical clinical "cautionary tale" regarding drug-induced inhibition of dihydropyrimidine dehydrogenase (DPD). It demonstrates that drugs like trifluridine/tipiracil (TAS-102), often used after 5-FU failure, can mimic genetic DPD deficiency. The case highlights the importance of careful differential diagnosis, recommending DPD phenotyping before TAS-102 or after proper washout, or using DPYD genotyping instead. Overall, the report stresses the need to understand drug-enzyme interactions to accurately assess and safely personalize fluoropyrimidine therapy.In pediatric settings, Wong et al. present a thorough systematic review of anthracycline-induced cardiotoxicity (ACT). Their meta-analysis confirms that combined clinical-genetic models (AUC 0.67-0.87) significantly outperform clinical variables alone (AUC 0.57-0.81). However, they appropriately urge caution, noting that the current evidence is rated as "very-low-certainty" due to publication bias and inconsistency. This suggests that identified markers need further prospective validation across different populations before they can be routinely used in clinical practice.While traditionally focused on toxicity, PGx research expands to treatment response in hepatocellular carcinoma (HCC), as Shilbayeh et al. demonstrate. Using a genome-wide association study (GWAS), they identified new hits in genes like AK3, TRPM3, and PCSK6 linked to doxorubicin response and tumor progression.While these results are encouraging, they should be interpreted with caution. The study's small sample size (n=78) restricts its power to identify rare variants and increases the likelihood of false positives. Furthermore, the authors highlight the necessity of independent replication-a common hurdle in HCC research-since reproducibility across various ethno-geographic groups is often challenging. The clinical application of these markers remains distant, requiring larger validation studies to confirm their ability to accurately predict outcomes at different disease stages.The economic impact of PGx is crucial for its integration into healthcare. Wong et al. highlighted a pediatric study indicating that PGx-guided care for ACT could be "Incremental Cost-Effectiveness Ratio (ICER)-negative," reducing costs by 5.7% and mortality by 17%. It is essential to differentiate these pediatric results-where long-term survival and the prevention of lifelong heart failure offer significant economic benefits-from adult oncology, where different cost factors and clinical considerations influence outcomes.This collection shows that the field is approaching the point of implementation. To increase impact, future research should focus on:• Priority Biomarkers: Shifting from individual SNPs to high-impact polygenic risk scores, specifically incorporating DPYD, TYMS, and GSTP1 for fluoropyrimidines. • Preferred Study Designs: Transitioning from retrospective case-control studies to prospective, randomized trials that focus on clinical utility as the main endpoint.• Clinical Decision Support (CDS): Developing practical strategies for integrating PGx results directly into electronic health records to help oncologists make real-time dose adjustments.The studies presented here do not merely identify markers; they highlight the need for an integrative approach that considers genetics, clinical factors, and the patient's socioeconomic landscape (Figure 1).

Suramin is an anticancer agent with a narrow therapeutic window and a terminal half-life of 45 to 55 days. These characteristics make it necessary to control accurately the serum concentrations of the drug. Therefore, the aim of the present study was to develop a rapid loading regimen, followed by weekly administration of suramin to maintain serum concentrations of between 150 and 300 micrograms/mL for 8 weeks. Eligible patients were treated with five different loading regimens. Initially, weekly maintenance doses were estimated manually by the treating physician. Subsequently, computer-assisted dosing that used Bayesian pharmacokinetic modeling was used. Thirty-eight courses of suramin that were administered to 35 patients were studied. The optimal loading regimen consisted of a continuous infusion of 600 mg/m2 during a 24-hour period, which resulted in a mean serum concentration of 319 micrograms/mL. Potentially toxic concentrations that were observed with shorter infusions were avoided. Maintenance treatment, which used the weekly administration of suramin during a 6-hour period, seemed to be able to maintain mean suramin serum trough concentrations of 150 micrograms/mL, while preventing mean peak concentrations of more than 300 micrograms/mL. The use of Bayesian pharmacokinetics was superior to manual estimation in tailoring the optimal dose to the therapeutic window. Continuous infusion is the optimal way of delivering suramin during the loading phase. To maintain trough levels and peak levels within a narrower therapeutic window, suramin will have to be administered more frequently than once a week. Bayesian modeling based on individual serum levels and population pharmacokinetics allows accurate dosing to maintain suramin levels within the therapeutic window.

Proton minibeam radiation therapy (pMBRT) is a new radiotherapy approach that has shown a significant increase in the therapeutic window in glioma-bearing rats compared to conventional proton therapy. Such preclinical results encourage the preparation of clinical trials. In this study, the potential of pMBRT for treating clinical indications candidates for the first clinical trials (i.e., brain, lung, and liver metastases) was evaluated. Four clinical cases, initially treated with stereotactic radiotherapy (SRT), were selected for this study. pMBRT, SRT, and conventional proton therapy (PT) dose distributions were compared by using three main criteria: (i) the tumor coverage, (ii) the mean dose to organs-at-risk, and (iii) the possible adverse effects in normal tissues by considering valley doses as the responsible for tissue sparing. pMBRT plans consisted of one fraction and one-two fields. Dose calculations were computed by means of Monte Carlo simulations. pMBRT treatments provide a similar or superior target coverage than SRT, even using fewer fields. pMBRT also significantly reduces the biologically effective dose (BED) to organs-at-risk. In addition, valley and mean doses to normal tissues remain below tolerance limits when treatments are delivered in a single fraction, contrary to PT treatments. This work provides a first insight into the possibility of treating metastases with pMBRT. More favorable dose distributions and treatment delivery regimes may be expected from this new approach than SRT. The advantages of pMBRT would need to be confirmed by means of Phase I clinical trials.

Recombinant tissue plasminogen activator (rt-PA) is a safe and effective treatment for acute brain ischemia stroke, albeit with a narrow therapeutic window. We aimed to assess the effect of epigallocatechin gallate (EGCG) in extending the rt-PA treatment window in this clinical trial among stroke patients. Patients were randomly assigned according to their onset-to-treatment time (OTT) and were then treated with rt-PA simultaneously with EGCG or placebo. Treatment outcome was assessed by the National Institutes of Health stroke scale (NIHSS) and plasma levels of matrix metalloproteinases (MMP)-2 and 9. Administration of EGCG significantly improved treatment outcomes of patients in the delayed OTT strata, as evidenced by improved NIHSS scores. This improved treatment outcome was likely attributed to reduction in plasma levels of both MMP-2 and 9, as indicated by strong linear correlations between both MMPs and NIHSS scores in all patients. Epigallocatechin gallate could potentially be used as a supplement of traditional rt-PA treatment among stroke patients, particularly those with delayed OTT, to extend the otherwise narrow therapeutic window and improve the outcome in late stroke treatment.

d-cycloserine, N-methyl-d-aspartate/glutamate (NMDA) receptor co-agonist (GluN2A/GluN2B partial and GluN2C super-agonist), improves negative symptom of schizophrenia with narrow therapeutic window, but the mechanisms remains unclear. Effects of chronic d-cycloserine administration (2-5mg·kg-1) on sucrose preference of adult male rats were determined. Dose/concentration-dependent effects of acute/chronic administrations of d-cycloserine (25-300 μM and 2-25 mg·kg-1) on expression of GluN2 subunits and associated transmission of l-glutamate/d-serine/GABA were determined using microdialysis in adult male rats, primary cultured astrocytes (male/female neonatal rats) and capillary immunoblotting. d-cycloserine dose-dependently increased release of astroglial l-glutamate/d-serine and neuronal GABA in the thalamus and medial prefrontal cortex (mPFC) (d-serine > GABA > l-glutamate), according to intrinsic activities (GluN2C > GluN2A [but unaffected GluN2B]). Chronic d-cycloserine dose-dependently down-regulated GluN2C > GluN2B > GluN2A (according to affinity) and attenuated d-cycloserine-induced astroglial release of l-glutamate/d-serine, dose dependently (GluN2C > GluN2A). Chronic exposure (25 μM) d-cycloserine down-regulated GluN2C but increased GluN2C-related astroglial l-glutamate/d-serine release. Chronic exposure to >60μM d-cycloserine diminished GluN2C-related astroglial release but activated GluN2A-related release. Chronic administration of 2but not 5-mg·kg-1 d-cycloserine restored MK-801-induced decrease sucrose preference. Chronic d-cycloserine (25 μM and 2mg·kg-1) down-regulated GluN2C without affecting GluN2A/GluN2B but increased GluN2-related astroglial l-glutamate/d-serine release. Higher d-cycloserine dose (>60 μM; >5mg·kg-1) inactivated GluN2C, but increased GluN2A related astroglial release. These results indicate that dose-dependent activation and inactivation of GluN2C by d-cycloserine is possibly involved in its efficacy on negative symptom of schizophrenia, but with a narrow therapeutic window.

CYP2C9 is a member of the cytochrome P450 (CYP) superfamily responsible for the metabolism of 16% of drugs that undergo oxidative metabolism. The activity of CYP2C9 exhibits marked inter-individual variability, which translates into prominent differences in the pharmacokinetics of CYP2C9 substrates, some of which are characterized by a narrow therapeutic window. Genetic polymorphisms in the gene encoding for CYP2C9 account for a fraction of the variability in CYP2C9 activity. The phenytoin metabolic ratio (PMR) is a marker of CYP2C9 activity in vivo, which correlates with CYP2C9 genetic polymorphisms. The purpose of the current study was to evaluate the ability of the PMR to predict the oral clearance of (S)-warfarin (SWOCL) and its formation clearance towards its CYP2C9-mediated metabolites (SWCLf) [i.e., 6- and 7-hydroxy-(S)-warfarin]. The study was conducted in 150 healthy non-smoker subjects (segment 1) and 60 patients treated with warfarin (segment 2). In the first segment, the participants received on two separate occasions a single 300-mg dose of phenytoin and at least 7 days later a single dose of warfarin (5 or 10 mg). The same PMR procedure was performed in the second segment, except that it was performed either before warfarin initiation or after the patients had reached stable anticoagulation. The PMR was derived from the ratio of 5-(4-hydroxyphenyl)-5-phenyl-hydantoin content in a 24-hour urine collection to plasma phenytoin concentration 12- (PMR24/12) or 24- (PMR24/24) post-dosing. In segment 1, SWOCL was calculated from the ratio of (S)-warfarin dose to the warfarin area under the plasma concentration-time curve extrapolated to infinity and the SWCLf from the ratio of urine content of 6- and 7-hydroxy-(S)-warfarin to (S)-warfarin area under the (S)-warfarin plasma concentration-time curve until the last measured timepoint. In segment 2, estimated SWOCL was derived from the ratio of (S)-warfarin dose to the mid-interval plasma concentration of (S)-warfarin. The PMR, SWOCL, and SWCLf varied significantly between carriers of different CYP2C9 genotypes in both healthy subjects (p < 0.001) and patients (p < 0.005). However, PMR and SWOCL values exhibited substantial intra-genotypic variability. PMR24/12 and PMR24/24 were significantly correlated with SWOCL both in healthy subjects (r = 0.62 and r = 0.67, respectively, p < 0.001) and in patients (r = 0.57 and r = 0.61, respectively, p < 0.001). In a multiple regression model that included all variables that correlated with SWOCL, PMR was the strongest predictor, explaining 44% and 38% of the variability in SWOCL among healthy subjects and patients, respectively, and accounting for 95.7% (44%/46%) and 90.5% (38%/42%) of the total explained variability in SWOCL among healthy subjects and patients, respectively. The PMR is the strongest predictor of SWOCL, and as such, it exhibits a significant advantage over the CYP2C9 genotype. The inclusion of PMR in future dosing algorithms of CYP2C9 substrates characterized by a narrow therapeutic window should be encouraged and further investigated.

Background: Pharmacotherapy of chronic heart failure (CHF) with a reduced ejection fraction includes a combination of drugs. Often, different groups of drugs are added together for the treatment of concomitant conditions, such as statins, anticoagulants, antiplatelet agents, and cardiac glycosides, which have a narrow therapeutic window. Increased medication intake is a prerequisite for the increased risk of potential adverse drug-drug interactions (DDI), especially those occurring at the pharmacokinetic level. The main objectives of this study are to identify the most common potential pharmacokinetic drug-drug interactions (pPKDDIs), to explore more complex cases, and to simulate and analyze them with appropriate software. Methods: The data selected for the simulations were collected over a two-year period from January 2014 to December 2015. Identification of the pPKDDIs was carried out using Lexicomp Drug interaction, while simulations were performed with Simcyp software (V20, R1). Results: The most common pharmacokinetic mechanisms responsible for the occurrence of drug-drug interactions in the selected drugs with narrow therapeutic windows are those featuring the cytochrome isoforms CYP3A4 and 2C9 and the efflux pump-P-glycoprotein (P-gp). Simulations with the available data in Simcyp software showed possibilities to analyze and evaluate pPKDDIs, which would be difficult to assess without appropriate software, as well as ways to manage them. Conclusions: The frequency and complexity of pPKDDIs in patients with cardiovascular disease are high. Therefore, such patients require a specific approach to reduce these risks as well as to optimize the therapy. An appropriate PBPK software with the necessary database would be suitable in these cases.

COLCHICINE TOXICITY IN A PATIENT WITH CHRONIC URTICARIA MASQUERADING WITH FEATURES OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS

On Warfarin Use in Kidney Disease: A Therapeutic Window of Opportunity?

Infections often occur while treating patients with long-term medications for chronic illnesses. Treating these infections with systemic antibiotics often leads to pharmacokinetic and pharmacodynamic interactions between the antimicrobials and one or more of the maintenance medications. Previously optimized long-term regimens may become either subtherapeutic or super-therapeutic, with deleterious consequences. This article discusses some of the most significant and commonly encountered antibiotic drug interactions that may occur with medications with "narrow therapeutic windows" including warfarin, phenytoin, carbamazepine, theophylline, and the two calcineurin inhibitors. Given the logistics of many consultant pharmacists' practices, it may not always be possible for them to react prospectively when these combinations are prescribed at their facilities. Therefore, there are several things the pharmacist can do: provide regular and comprehensive inservice raining on this topic, be available as needed to answer patient-specific questions, and provide readily available charts and other educational materials that help identify and characterize these important interactions. A Medline search of the English literature was performed in October/November 2003, going back to 1980 for the commonly used antibiotics and drug interactions stated in this text. In some cases, cross referencing of articles reviewed also led to older publications. Textbooks dealing with drug interactions also were used as initial sources. However, whenever possible, any data quoted within the text were verified from the original research paper. Pharmacokinetic studies, case reports, and general review articles published in the English medical literature were all selected for review. In cases where review articles were cited that summarize groups of data from previous original research papers, the authors made the best possible effort to verify the accuracy by referring to the original research papers. Because of the breadth of the topic in terms of all the antibiotics discussed, the interacting medications that pertained to each antibiotic, and the lack of homogeneity among the various types of papers (most of which were case reports), most analyses include broad-based summaries based on the aggregate findings of the authors. The addition of antibiotics to a stabilized medical regimen can result in either potentiation or antagonism of the clinical effects of narrow-therapeutic-window medications such as warfarin, phenytoin, theophylline, calcineurin inhibitors, carbamazepine, and numerous other agents. As usual in the clinical arena, awareness is the first step in appropriate management of these encounters.

Background: Ischemic stroke (IS) is one of the leading causes of death and disability worldwide. The narrow therapeutic window (within 4.5 h) and severe hemorrhagic potential limits therapeutic efficacy of recombinant tissue type plasminogen activator (rt-PA) intravenous thrombolysis for patients. Xingnao Kaiqiao (XNKQ) acupuncture is an integral part of traditional Chinese medicine, specifically designed to address acute ischemic stroke by targeting key acupoints such as Shuigou (GV26) and Neiguan (PC6). In this study, we explored the therapeutic potential of XNKQ acupuncture in extending the time window for thrombolysis and interrogated the molecular mechanisms responsible for this effect. Methods: The effect of extending the thrombolysis window by acupuncture was evaluated via TTC staining, neuronal score evaluation, hemorrhagic transformation assay, and H&E staining. RNA sequencing (RNA-seq) technology was performed to identify the therapeutic targets and intervention mechanisms of acupuncture. Evans blue staining and transmission electron microscopy were used to assess blood–brain barrier (BBB) integrity. Immunofluorescence staining and co-immunoprecipitation were performed to evaluate the level of autophagy and apoptosis and validate their interactions with BBB endothelial cells. Results: Acupuncture alleviated infarction and neurological deficits and extended the thrombolysis window to 6 h. The RNA-seq revealed 16 potential therapeutic predictors for acupuncture intervention, which related to suppressing inflammation and restoring the function of BBB and blood vessels. Furthermore, acupuncture suppressed BBB leakage and preserved tight junction protein expression. The protective effect was associated with regulation of the autophagy–apoptosis balance in BBB endothelial cells. Acupuncture intervention dissociated the Beclin1/Bcl-2 complex, thereby promoting autophagy and reducing apoptosis. Conclusion: XNKQ acupuncture could serve as an adjunctive therapy for rt-PA thrombolysis, aiming to extend the therapeutic time window and mitigate ischemia–reperfusion injury. Acupuncture suppressed BBB disruption by regulating the autophagy–apoptosis balance, which in turn extended the therapeutic window of rt-PA in IS. These findings provide a rationale for further exploration of acupuncture as a complementary candidate co-administered with rt-PA.

Exploring potential anticoagulant drug formulations using thrombin generation test

CD33 (Siglec-3) is a cell surface receptor expressed in approximately 90% of acute myeloid leukemia (AML) blasts, making it an attractive target for therapy of AML. Although previous CD33-targeting antibody-drug conjugates (ADC) like gemtuzumab ozogamicin (GO, Mylotarg) have shown efficacy in AML treatment, they have suffered from toxicity and narrow therapeutic window. This study aimed to develop a novelADCwith improved tolerability and a wider therapeutic window. GLK-33 consists of the anti-CD33 antibody lintuzumab and eight mavg-MMAU auristatin linkerpayloads per antibody. The experimental methods included testing in cell cultures, patient-derived samples, mouse xenograft models, and rat toxicology studies. GLK-33 exhibited remarkable efficacy in reducing cell viability within CD33-positive leukemia cell lines and primary AML samples. Notably, GLK-33 demonstrated antitumor activity at single dose as low as 300 mg/kg in mice, while maintaining tolerability at single dose of 20 to 30 mg/kg in rats. In contrast with both GO and lintuzumab vedotin, GLK-33 exhibited a wide therapeutic window and activity against multidrug-resistant cells. The development of GLK-33 addresses the limitations of previous ADCs, offering a wider therapeutic window, improved tolerability, and activity against drug-resistant leukemia cells. These findings encourage further exploration of GLK-33 in AML through clinical trials.