Inflammation at diagnosis and cognitive impairment two years later in breast cancer patients from the Canto-Cog study.

BACKGROUND: Inflammation could be related to cancer-related cognitive impairment (CRCI) and might be used as a predictive marker of long-term CRCI. We evaluated associations between inflammatory markers assessed at diagnosis of breast cancer and CRCI two years afterwards. METHODS: Newly diagnosed stage I-III patients with breast cancer from the French CANTO-Cog (Cognitive sub-study of CANTO, NCT01993498) were included at diagnosis (baseline). Serum inflammatory markers (IL-2, IL-4, IL-6, IL-8, IL-10, TNFα, CRP) were assessed at baseline. Outcomes at year 2 post-baseline included overall cognitive impairment (≥ 2 impaired domains) and the following domains: episodic memory, working memory, attention, processing speed, and executive functions. Multivariable logistic regression models evaluated associations between markers and outcomes, controlling for age, education, and baseline cognitive impairment. RESULTS: Among 200 patients, the mean age was 54 ± 11 years, with 127 (64%) receiving chemotherapy. Fifty-three (27%) patients had overall cognitive impairment at both timepoints. Overall cognitive impairment at year 2 was associated with high (> 3 mg/L) baseline CRP (OR = 2.84, 95%CI: 1.06-7.64, p = 0.037). In addition, associations were found between high CRP and processing speed impairment (OR = 2.47, 95%CI:1.05-5.87, p = 0.039), and between high IL-6 and episodic memory impairment (OR = 5.50, 95%CI:1.43-36.6, p = 0.010). CONCLUSIONS: In this cohort, high levels of CRP and IL-6 assessed at diagnosis were associated with overall CRCI, processing speed and episodic memory impairments two years later. These findings suggest a potential inflammatory basis for long-term CRCI. CRP may represent an easily measurable marker in clinical settings and be potentially used to screen patients at greater risk of persistent CRCI.

Phase 1 first-in-human dose-escalation study of ANV419 in patients with relapsed/refractory advanced solid tumors.

Patients with advanced cancer, previously treated with immune checkpoint blockade therapy, may retain residual treatment when undergoing the initial infusion of experimental monotherapy in phase 1 clinical trials. ANV419, an antibody-cytokine fusion protein, combines interleukin-2 (IL-2) with an anti-IL-2 monoclonal antibody, aiming to stimulate the expansion of CD8 T and natural killer lymphocytes while restricting regulatory T lymphocytes. In the recent publication of the phase 1 dose escalation study of ANV419, a notable gap exists in detailed information regarding patients' prior antitumoral treatments, specifically programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) targeted monoclonal antibodies. Some patients likely retained residual anti-PD-1/PD-L1 monoclonal antibodies, potentially influencing the outcomes of ANV419. In a separate clinical cohort, we retrospectively measured the residual concentration of nivolumab and pembrolizumab, revealing persistent serum concentrations of anti-PD-1/PD-L1 antibodies even months after treatment cessation. This underscores the importance of comprehensively documenting prior immunotherapy details in clinical trials. Such information is crucial for understanding potential interactions that may impact both immunological and clinical effects.

A Score to Predict the Clinical Usefulness of Therapeutic Drug Monitoring: Application to Oral Molecular Targeted Therapies in Cancer.

Therapeutic drug monitoring (TDM) involves measuring and interpreting drug concentrations in biological fluids to adjust drug dosages. In onco-hematology, TDM guidelines for oral molecular targeted therapies (oMTTs) are varied. This study evaluates a quantitative approach with a score to predict the clinical usefulness of TDM for oMTTs. We identified key parameters for an oMTT's suitability for TDM from standard TDM recommendations. We gathered oMTT pharmacological data, which covered exposure variability (considering pharmacokinetic (PK) impact of food and proton pump inhibitors), technical intricacy (PK linearity and active metabolites), efficacy (exposure-response relationship), and safety (maximum tolerated dose, and exposure-safety relationship). To assess the validity and the relevance of the score and define relevant thresholds, we evaluated molecules with prospective validation or strong recommendations for TDM, both in oncology and in other fields. By September 1, 2021, the US Food and Drug Administration (FDA) approved 67 oMTTs for onco-hematological indications. Scores ranged from 15 (acalabrutinib) to 80 (sunitinib) with an average of 48.3 and a standard deviation of 15.6. Top scorers included sunitinib, sorafenib, cabozantinib, nilotinib, and abemaciclib. Based on scores, drugs were categorized into low (< 40), intermediate (≥ 40 and < 60), and high (≥ 60) relevance for TDM. Notably, negative controls generally scored around or under 40, whereas positive controls had a high score across different indications. In this work, we propose a quantitative and reproducible score to compare the potential usefulness of TDM for oMTTs. Future guidelines should prioritize the TDM for molecules with the highest score.

Management of Pain Medication in Patients With a History of Bariatric Surgery: A Systematic Review.

CONTEXT: Obesity prevalence is persistently increasing worldwide. Among surgical therapeutic procedures, bypass surgery and sleeve gastrectomy have shown the best results regarding weight loss, prevention, and treatment of secondary complications. However, these surgeries are associated with an increased risk of malabsorption and metabolic changes that could further affect the pharmacokinetics of drugs. On the other hand, patients with a history of such surgeries are more likely to experience pain and request analgesic initiation or adaptation. The question of how to manage pain medication in these patients is challenging due to their narrow therapeutic indexes. OBJECTIVES: To summarize the current literature on the impact of bariatric surgery on the subsequent pharmacokinetics of analgesics and propose a multidisciplinary therapeutic attitude to optimize pain management in these patients. METHODS: We conducted a systematic review that included all pharmacological studies published after 2000. RESULTS: Unexpectedly, these surgeries seem to increase the bioavailability of drugs by long-term improvement of hepatic function. Yet, the medical community drastically lacks robust guidelines for pain management in those patients. This systematic review aims to bring together pharmacological studies related to the use of pain treatments in patients who underwent bypass surgery or sleeve gastrectomy. CONCLUSIONS: Caution should be exercised regarding the risk of overdose in every circumstance: treatment initiation, change of doses, or change of molecule. More prospective trials comparing the pharmacokinetics of medications in obese patients with and without prior bariatric surgery are needed.

Quantitative impact of pre-analytical process on plasma uracil when testing for dihydropyrimidine dehydrogenase deficiency.

AIMS: Determining dihydropyrimidine dehydrogenase (DPD) activity by measuring patient's uracil (U) plasma concentration is mandatory before fluoropyrimidine (FP) administration in France. In this study, we aimed to refine the pre-analytical recommendations for determining U and dihydrouracil (UH2 ) concentrations, as they are essential in reliable DPD-deficiency testing. METHODS: U and UH2 concentrations were collected from 14 hospital laboratories. Stability in whole blood and plasma after centrifugation, the type of anticoagulant and long-term plasma storage were evaluated. The variation induced by time and temperature was calculated and compared to an acceptability range of ±20%. Inter-occasion variability (IOV) of U and UH2 was assessed in 573 patients double sampled for DPD-deficiency testing. RESULTS: Storage of blood samples before centrifugation at room temperature (RT) should not exceed 1 h, whereas cold (+4°C) storage maintains the stability of uracil after 5 hours. For patients correctly double sampled, IOV of U reached 22.4% for U (SD = 17.9%, range = 0-99%). Notably, 17% of them were assigned with a different phenotype (normal or DPD-deficient) based on the analysis of their two samples. For those having at least one non-compliant sample, this percentage increased up to 33.8%. The moment of blood collection did not affect the DPD phenotyping result. CONCLUSION: Caution should be taken when interpreting U concentrations if the time before centrifugation exceeds 1 hour at RT, since it rises significantly afterwards. Not respecting the pre-analytical conditions for DPD phenotyping increases the risk of DPD status misclassification.

Succinate: A Serum Biomarker of SDHB-Mutated Paragangliomas and Pheochromocytomas.

CONTEXT: Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors that are frequently associated with succinate dehydrogenase (SDH) germline mutations. When mutated, SDH losses its function, thus leading to succinate accumulation. OBJECTIVE: In this study, we evaluated serum succinate levels as a new metabolic biomarker in SDHx-related carriers. METHODS: Retrospective monocentric study of 88 PPGL patients (43 sporadic, 35 SDHB, 10 SDHA/C/D), 17 tumor-free familial asymptomatic carriers (13 SDHB, 4 SDHC/D), and 60 healthy controls. Clinical, biological, and imaging data were reviewed. Serum succinate levels (n = 280) were quantified by an ultra-performance liquid chromatography coupled to a tandem mass spectrometry method and correlated to SDHx mutational status, disease extension, and other biological biomarkers. RESULTS: Serum succinate levels > 7 µM allowed identification of tumor-free asymptomatic SDHB-mutated cases compared to a healthy control group (100% specificity; 85% sensitivity). At PPGL diagnosis, SDHB-mutated patients had a significantly increased median succinate level (14 µM) compared to sporadic patients (8 µM) (P < 0.01). Metastatic disease extension was correlated to serum succinate levels (r = 0.81). In the SDHB group, patients displaying highest tumor burdens showed significant increased succinate levels compared to the sporadic group (P < 0.0001). CONCLUSIONS: In this pilot study, we showed that serum succinate level is an oncometabolic biomarker that should be useful to identify SDHB-related carriers. Succinate levels are also a marker of metabolic tumor burden in patients with a metastatic PPGL and a potential marker of treatment response and follow-up.

Quantification of succinic acid levels, linked to succinate dehydrogenase (SDH) dysfunctions, by an automated and fully validated liquid chromatography tandem mass spectrometry method suitable for multi-matrix applications.

The hallmarks of cancer include metabolism with deregulating cellular energetics. Dysfunctions in succinate dehydrogenase (SDH) metabolic enzyme activity, leading to an abnormal accumulation of succinic acid has been described in solid tumors but also in inflammation and ischemia reperfusion injury. Succinic acid is a potential biomarker of SDH related pathologies for diagnostic, evaluation of treatment response and follow-up of the disease. We developed a liquid chromatography tandem mass spectrometry (LC-MS/MS) method allowing a rapid, accurate and precise quantification of succinic acid levels in clinical (serum, urine) and preclinical (cellular pellets, supernatants) samples. 13C4 succinic acid disodium salt was used as internal standard and added to samples before a solid phase extraction (SPE) on Phenomenex STRATATM XL-A (200 mg - 3 mL) 33 µm cartridges. This method is automated by a Freedom EVO® platform from TECAN and succinic acid is separated on a C18 column combined to a Xevo® TQ-S micro Waters mass spectrometer with electrospray ionization (ESI) source. This biomedical analysis allows standard curves to be linear over the range 1.0-135.5 µM with r2 values > 0.999 and low matrix effects (<9.1 %). This method, which is validated according updated European Medicine Agency (EMA) guidelines, is accurate between-run (<11.0 %) and within-run (<7.8 %), precise between-run (<14.4 CV %) and within-run (<3.7 CV %), and is suitable for clinical and preclinical applications.

Immune checkpoint-targeted antibodies: a room for dose and schedule optimization?

Anti-CTLA-4 and anti-PD-1/PD-L1 immune checkpoint inhibitors are therapeutic monoclonal antibodies that do not target cancer cells but are designed to reactivate or promote antitumor immunity. Dosing and scheduling of these biologics were established according to conventional drug development models, even though the determination of a maximum tolerated dose in the clinic could only be defined for anti-CTLA-4. Given the pharmacology of these monoclonal antibodies, their high interpatient pharmacokinetic variability, the actual clinical benefit as monotherapy that is observed only in a specific subset of patients, and the substantial cost of these treatments, a number of questions arise regarding the selected dose and the dosing interval. This review aims to outline the development of these immunotherapies and considers optimization options that could be used in clinical practice.

New dosing nomogram and population pharmacokinetic model for young and very young children receiving busulfan for hematopoietic stem cell transplantation conditioning.

BACKGROUND: Busulfan (Bu) is the cornerstone of conditioning regimens prior to hematopoietic stem cell transplantation, widely used in both adults and children for the treatment of malignant and nonmalignant diseases. Despite an intravenous formulation, interindividual variability (IIV) remains high and optimal exposure difficult to achieve, especially in neonates and infants. PROCEDURE: To ensure both efficacy and safety, we set up in 2005 an observational study designed for children not fully assessed during the drug registration procedure. From a large cohort of 540 patients, we developed a Bu population pharmacokinetic model based on body weight (BW) and maturation concepts to reduce IIV and optimize exposure. A new dosing nomogram was evaluated to better fit the population pharmacokinetic model. RESULTS: Bu clearance IIV was significantly decreased from 61.3% (covariate-free model) to 28.6% when combining BW and maturation function. Median Bu area under the curve (AUC) was 1179 µmol/L × min compared to 1025 with the EMA dosing nomogram for children <9 kg. The target AUC was reached for each BW strata, significantly increasing the percentages of patients achieving reaching the targeted AUC as compared to FDA schedule. CONCLUSION: This new model made it possible to propose a novel dosing nomogram that better considered children below 16 kg of BW and allowed better initial exposure as compared to existing dosing schedules. This nomogram, which would be easy to use to determine an optimal dosing schedule in daily practice, will need to be validated in clinical routine. Therapeutic drug monitoring remains strongly advisable for small children and those with specific diseases.

Pharmacokinetics/Pharmacodynamic (PK/PD) relationship of therapeutic monoclonal antibodies used in oncology: what's new?

Monoclonal antibodies in oncology, used as targeted molecular therapy, linked to cytotoxic compound or directed against immune checkpoints, feature complex PKs essentially determined by their physicochemical characteristics. The increasing number of studies shows the existence of Pharmacokinetics/Pharmacodynamic (PK/PD) relationships for many of them. Although more studies, especially conducted in early clinical phases, are needed, existing studies highlight the need to integrate PK data for monoclonal antibodies in all phases of their development and the therapeutic management of patients with cancer. The current challenge is to identify non-responders as soon as possible. The use of monoclonal antibody dosage to determine the patient's PK profile and, as a result, the disease activity profile could therefore be an early predictive marker to help physicians optimise the strategy to be pursued, including dose adjustment, prolongation of the dose interval or even discontinuation of treatment.

Pharmacokinetic/pharmacodynamic relationship of therapeutic monoclonal antibodies used in oncology: Part 1, monoclonal antibodies, antibody-drug conjugates and bispecific T-cell engagers.

More than 25 therapeutic monoclonal antibodies (mAbs) used in oncology have been approved since 1997. Their nature has been largely modified through the last 20 years, from the chimeric IgG1 rituximab with pharmacokinetic parameters specific of murin or chimeric mAbs to humanized or human mAbs. Doses and administration frequency have been chosen based on this nature. More recently, the developed and registered mAbs are mostly IgG1, IgG2, IgG3 or IgG4 humanized or 100% human. Therefore, their behavior is different from the first mAbs authorized leading to lower systemic clearance and shorter half-life due to higher cellular uptake balanced by FcRn recognition with recirculation. The complexity of the pharmacokinetics and the pharmacokinetics/pharmacodynamics relation are increased for antibody-drug conjugates or bispecific T-cell engagers. However, significant number of studies reported pharmacokinetics/pharmacodynamics relations, with positive exposure-response link justifying the exploration of the pharmacokinetics in routine clinical practice of these therapeutic mAbs to prevent treatment failures and to limit their toxicities.

Pharmacokinetic/pharmacodynamic relationship of therapeutic monoclonal antibodies used in oncology: Part 2, immune checkpoint inhibitor antibodies.

Immune checkpoint inhibitors are monoclonal antibodies (mAbs) directed against negative immunologic regulators that are used to restore the immune response against cancer. Approved drugs include anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4), anti-programmed cell death 1 (PD-1) and anti-programmed cell death-ligand 1 (PD-L1) antibodies exhibiting pharmacokinetic (PK) characteristics typical of mAbs. Most factors such as age, sex, ethnicity, tumour burden, performance status and immunogenicity, but not body weight, do not seem to affect drug clearance clinically. However, an exposure-response relation has been described for both the efficacy and toxicity of anti-CTLA-4 and anti-PD-1 agents. The change in clearance over time is associated with overall response at least for nivolumab and pembrolizumab. Few PK/pharmacodynamic (PD) data are available for anti-PD-L1 mAbs, but time-varying clearance has been described for these drugs, and the high immunogenicity rate observed with atezolizumab may affect PK parameters and should be further studied. These data suggest the need for additional PK/PD studies. In this review, we summarise studies of the PKs of immune checkpoint inhibitors, exploring possible interactions with PD considerations.

Crizotinib-induced immunogenic cell death in non-small cell lung cancer.

Immunogenic cell death (ICD) converts dying cancer cells into a therapeutic vaccine and stimulates antitumor immune responses. Here we unravel the results of an unbiased screen identifying high-dose (10 µM) crizotinib as an ICD-inducing tyrosine kinase inhibitor that has exceptional antineoplastic activity when combined with non-ICD inducing chemotherapeutics like cisplatin. The combination of cisplatin and high-dose crizotinib induces ICD in non-small cell lung carcinoma (NSCLC) cells and effectively controls the growth of distinct (transplantable, carcinogen- or oncogene induced) orthotopic NSCLC models. These anticancer effects are linked to increased T lymphocyte infiltration and are abolished by T cell depletion or interferon-γ neutralization. Crizotinib plus cisplatin leads to an increase in the expression of PD-1 and PD-L1 in tumors, coupled to a strong sensitization of NSCLC to immunotherapy with PD-1 antibodies. Hence, a sequential combination treatment consisting in conventional chemotherapy together with crizotinib, followed by immune checkpoint blockade may be active against NSCLC.

Author Correction: Crizotinib-induced immunogenic cell death in non-small cell lung cancer.

The original version of this Article contained an error in the spelling of the author Lin Xia, which was incorrectly given as Xia Lin. This has now been corrected in both the PDF and HTML versions of the Article.

What sample preparation should be chosen for targeted MS monoclonal antibody quantification in human serum?

AIM: Monoclonal antibody-based treatment of cancer has been established as one of the most successful therapeutic strategies. MATERIALS & METHODS: In this work, we developed a workflow based on an automated protein-A capture and LC-MS/MS analysis to quantify bevacizumab on patient serum during treatment. This analytical approach was fully validated and compared with a commercially available Monoclonal antibody-based treatment preparation (nanosurface and molecular-orientation limited kit). RESULTS: The analytical comparison of the two preparative workflows based on protein-A capture gave similar results with a better lower limit of quantification for the nanosurface and molecular-orientation limited kit (0.26986 vs 1.9565 µg/ml). CONCLUSION: LC-MS/MS has clear advantages compared with ELISA when considering method development time, multiplexing capacities and absolute quantification with internal standardization.

[Renal toxicity of high-dose methotrexate]. / Toxicité rénale du méthotrexate à haute dose.

INTRODUCTION: High-dose methotrexate (at least 1g/m2) is used to treat haematologic malignancies and osteosarcomas. Acute kidney injury is a well-known adverse-event after high-dose methotrexate and may lead to delayed drug elimination. Besides usual therapeutics (hyperhydration, urine alkalinisation, leucovorin rescue, renal replacement therapy), a costly specific enzymatic treatment (glucarpidase) is now available but its clinical impact remains elusive. PATIENTS AND METHODS: We analysed high-dose methotrexate prescription charts in 11 clinical centres during the last 15 years to identify and describe adult patients who developed acute kidney injury (according to KDIGO classification). Glucarpidase use was recorded (French temporary regulatory approval criteria: methotrexate at least 10µmol/L at 48h or at least 3µmol/L at 48h associated with acute kidney injury). RESULTS: Seventy-six acute kidney injury cases have been studied. Mean peak creatinine was 206µmol/L after a mean delay of 5.6 days, with 19 cases of stage 1 acute kidney injury (25%), 29 cases of stage 2 (38%) and 27 cases of stage 3 (36%). Anuria (one case) and need for renal replacement therapy (four cases) were unusual whereas fluid overload was often observed (29%). Three months after high-dose methotrexate treatment, mortality-rate was 17%, and 12% of surviving patients developed renal sequelae. CONCLUSION: Sixty-one percent of patients received a glucarpidase perfusion during acute kidney injury. Despite a dramatic decrease of methotrexate serum levels, glucarpidase as compared with conservative treatment did not modify acute kidney injury stage, recovery delay, need for renal replacement therapy or the incidence of extrarenal toxicities. Net clinical benefit was not observed even after stratification according to eligibility criteria for glucarpidase use. Glucarpidase has probably no or little effects on methotrexate localized into tubular lumen or proximal tubular cells and that may account for the absence of nephroprotective effect for enzymatic treatment.

Circulating oncometabolite D-2-hydroxyglutarate enantiomer is a surrogate marker of isocitrate dehydrogenase-mutated intrahepatic cholangiocarcinomas.

Therapeutic resources are limited for advanced biliary tract cancers and prognosis remains poor. Somatic mutations in isocitrate dehydrogenase (IDH)1/2 gene are found in 5-36% of patients with intrahepatic cholangiocarcinoma (ICC). The mutant forms of IDH1/2 catalyse the non-reversible accumulation of 2-hydroxyglutarate (2HG). Increasing numbers of indirect or direct-targeted therapies are developed to IDH1/2 mutations and could be assisted by a routinely feasible, rapid and inexpensive serum 2HG measurement by liquid chromatography coupled to tandem mass spectrometry. By comparing eight patients with an IDH1/2-mutated ICC to nine patients with wild-type IDH1/2 ICC, we found significantly higher levels of 2HG in patients with IDH1/2 mutations versus the wild-type group (median, 10.9 vs. 0.8 µmol/L, p = 0.0037). D and L-2HG enantiomer levels significantly differed between the two groups with a higher level of D-2HG (p < 0.0001) in patients with IDH1/2 mutations. Accordingly, the D/L ratio was markedly higher in the patients with IDH1/2 mutations compared with the wild-type group (38.0 vs. 0.9 µmol/L, p < 0.0001). D-2HG measurement ensured 100% sensitivity and specificity at a cut-off of 0.6 µmol/L. D-2HG levels were correlated with tumour burden and tumour response to treatment with IDH-targeted therapies or indirect therapies. D-2HG serum level measurement by liquid chromatography coupled to tandem mass spectrometry is a sensitive, specific, precise (a coefficient of variation <10% and an accuracy >95%), fast (9 min run per sample) and inexpensive surrogate marker of IDH1/2 somatic mutation in ICC. Systematic measurement in patients with ICC may facilitate access to, and monitoring of, IDH-driven therapies.

Therapeutic Drug Monitoring of Carboplatin in High-Dose Protocol (TI-CE) for Advanced Germ Cell Tumors: Pharmacokinetic Results of a Phase II Multicenter Study.

Purpose: We aimed to evaluate the performance of therapeutic drug monitoring (TDM) approach in controlling interpatient variability of carboplatin exposure (AUC) in patients treated with TI-CE high-dose chemotherapy for advanced germ cell tumors and to assess the possibility of using a formula-based dosing method as a possible alternative.Experimental Design: Eighty-nine patients receiving carboplatin for 3 consecutive days during 3 cycles were evaluable for pharmacokinetic study. Blood samples were taken on day 1 to determine the carboplatin clearance using a Bayesian approach (NONMEM 7.2) and to adjust the dose on day 3 to reach the target AUC of 24 mg.min/mL over 3 days. On days 2 and 3, samples were taken for retrospective assessment of the actual AUC. A population pharmacokinetic analysis was also performed on 58 patients using NONMEM to develop a covariate equation for carboplatin clearance prediction adapted for future TI-CE patients, and its performance was prospectively evaluated on the other 29 patients along with different methods of carboplatin clearance prediction.Results: The mean actual AUC was 24.4 mg.min/mL per cycle (22.4 and 26.8 for 10th and 90th percentiles, respectively). The new covariate equation [CL (mL/min) = 130.7 × (Scr/83)-0.826 × (BW/76)+0.907 × (Age/36)-0.223 with Scr in µmol/L, BW in kilograms, age in years] allows unbiased and more accurate prediction of carboplatin clearance compared with other equations.Conclusions: TDM allows controlling and reaching the target AUC. Alternatively, the new equation of carboplatin clearance prediction, better adapted to these young male patients, could be used if TDM cannot be implemented. Clin Cancer Res; 23(23); 7171-9. ©2017 AACR.