Clinical Benefits and Utility of Pretherapeutic DPYD and UGT1A1 Testing in Gastrointestinal Cancer: A Secondary Analysis of the PREPARE Randomized Clinical Trial.

Importance: To date, the clinical benefit and utility of implementing a DPYD/UGT1A1 pharmacogenetic-informed therapy with fluoropyrimidines and/or irinotecan have not been prospectively investigated.

Objective: To examine clinically relevant toxic effects, hospitalizations, and related costs while preserving treatment intensity and efficacy outcomes in patients with gastrointestinal cancer.

Design, Setting, And Participants: This nonprespecified secondary analysis stems from Pre-Emptive Pharmacogenomic Testing for Preventing Adverse Drug Reactions (PREPARE), a multicenter, controlled, open, block-randomized, crossover implementation trial conducted from March 7, 2017, to June 30, 2020, and includes data from Italy according to a sequential study design.

Increased plasma imatinib exposure and toxicity in chronically treated GIST patients with SARS-CoV-2 infection: a case series.

Introduction: Inflammatory factors released during severe coronavirus disease-19 (COVID-19) caused by acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are known to influence drug exposure, but data on the effect of mild infection are few. Here we describe for the first time an increase in plasma imatinib and norimatinib concentrations observed in a series of 5 patients treated with imatinib for gastrointestinal stromal tumor (GIST) after mild COVID-19.

Methods: The patients were undergoing routine therapeutic drug monitoring (TDM) and pharmacogenetic (PGx) analyses of polymorphisms in genes involved in imatinib metabolism and transport (, , , and ) when SARS-CoV-2 infection occurred.

Liquid biopsy in colorectal cancer: Onward and upward.

Colorectal cancer (CRC) remains a leading cause of cancer-related deaths worldwide. In recent years, liquid biopsy has emerged as one of the most interesting areas of research in oncology, leading to innovative trials and practical changes in all aspects of CRC management. RNAs and cell free DNA (cfDNA) methylation are emerging as promising biomarkers for early diagnosis.

Therapeutic drug monitoring and pharmacogenetics to tune imatinib exposure in gastrointestinal stromal tumor patients: hurdles and perspectives for clinical implementation.

Tweetable abstract Present evidence supports the use of intensified pharmacologic monitoring of #imatinib including #TherapeuticDrugMonitoring and #PGx to improve outcomes in patients with GI stromal tumor. Future studies need to address emerging questions to facilitate implementation in clinics.

Predicting survival in patients with 'non-high-risk' acute variceal bleeding receiving β-blockers+ligation to prevent re-bleeding.

Background & Aims: Pre-emptive transjugular intrahepatic portosystemic shunt (TIPS) is the treatment of choice for high-risk acute variceal bleeding (AVB; i.e., Child-Turcotte-Pugh [CTP] B8-9+active bleeding/C10-13).

Second-line treatment strategies for RAS wild-type colorectal cancer: A systematic review and Network Meta-analysis (NMA).

Background: The optimal strategy for second-line (IIL) treatment in KRAS wt metastatic colorectal cancer (mCRC) is not determined yet.

Methods: A random-effect NMA of phase II/III RCTs was conducted to evaluate IIL treatment for all-RAS wt mCRC, comparing anti-EGFR or anti-VEGF, and chemotherapy (CT).

Results: Overall, 11 RCTs (3613 patients) were included.

The use of therapeutic drug monitoring to highlight an over-looked drug-drug interaction leading to imatinib treatment failure.

Background: Chronic oral anticancer therapies, are increasingly prescribed and present new challenges including the enhanced risk of overlooked drug-drug interactions (DDIs). Lengthy treatments and patients' management by different professionals can lead to serious prescribing errors that therapeutic drug monitoring (TDM) can help identifying thus allowing a more effective and safer treatment of patients with polypharmacy.

Objectives: This report aims to exemplify how an intensified pharmacological approach could help in the clinical monitoring of patients on chronic treatments.

Alcohol-related liver disease phenotype impacts survival after an acute variceal bleeding episode.

Background & Aims: Alcohol-related hepatitis (AH) encompasses a high mortality. AH might be a concomitant event in patients with acute variceal bleeding (AVB). The current study aimed to assess the prevalence of AH in patients with AVB and to compare the clinical outcomes of AH patients to other alcohol-related liver disease (ALD) phenotypes and viral cirrhosis.

Preoperative treatments in borderline resectable and locally advanced pancreatic cancer: Current evidence and new perspectives.

Surgery is the only curative treatment for non-metastatic pancreatic adenocarcinoma, but less than 20 % of patients present a resectable disease at diagnosis. Treatment strategies and disease definition for borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC) vary in the different cancer centres. Preoperative chemotherapy (CT) is the standard of care for both BRPC and LAPC patients, however literature data are still controversial concerning the type, dose and duration of the different CT regimens, as well as regarding the integration of radiotherapy (RT) or chemoradiation (CRT) in the therapeutic algorithm.

Impact of and Polymorphisms on Imatinib Plasmatic Exposure: An Original Work and Meta-Analysis.

Adequate imatinib plasma levels are necessary to guarantee an efficacious and safe treatment in gastrointestinal stromal tumor (GIST) and chronic myeloid leukemia (CML) patients. Imatinib is a substrate of the drug transporters ATP-binding cassette subfamily B member 1 (ABCB1) and ATP-binding cassette subfamily G member 2 (ABCG2) that can affect its plasma concentration. In the present study, the association between three genetic polymorphisms in (rs1045642, rs2032582, rs1128503) and one in (rs2231142) and the imatinib plasma trough concentration (C) was investigated in 33 GIST patients enrolled in a prospective clinical trial.

A fast and validated LC-MS/MS method to quantify lenvatinib in dried blood spot.

A new LC-MS/MS method for the quantification of lenvatinib (LENVA) in venous Dried Blood Spot (DBS) samples has been presented. This method is characterized by a short run time (4 min), requires a volumetric sampling of 10 µL and extraction of the entire spot to avoid hematocrit (Hct) and spot volume effects. The quantification method was successfully validated in the range of 5.

Hepatic encephalopathy is not a contraindication to pre-emptive TIPS in high-risk patients with cirrhosis with variceal bleeding.

Background: A pre-emptive transjugular intrahepatic portosystemic shunt (pTIPS) reduces mortality in high-risk patients with cirrhosis (Child-Pugh C/B+active bleeding) with acute variceal bleeding (AVB). Real-life studies point out that <15% of patients eligible for pTIPS ultimately undergo transjugular intrahepatic portosystemic shunt (TIPS) due to concerns about hepatic encephalopathy (HE). The outcome of patients undergoing pTIPS with HE is unknown.

CYP2D6 and CYP2C8 pharmacogenetics and pharmacological interactions to predict imatinib plasmatic exposure in GIST patients.

Aims: Patients on treatment with oral fixed dose imatinib are frequently under- or overexposed to the drug. We investigated the association between the gene activity score (GAS) of imatinib-metabolizing cytochromes (CYP3A4, CYP3A5, CYP2D6, CYP2C9, CYP2C19, CYP2C8) and imatinib and nor-imatinib exposure. We also investigated the impact of concurrent drug-drug-interactions (DDIs) on the association between GAS and imatinib exposure.

A new dried blood spot LC-MS/MS method for therapeutic drug monitoring of palbociclib, ribociclib, and letrozole in patients with cancer.

Therapeutic drug monitoring (TDM) is strongly suggested to define the proper drug dosage to overcome inter- and intra-patient variability in drug exposure, which is typically observed with oral anticancer agents, such as palbociclib (PALBO), ribociclib (RIBO) and letrozole (LETRO), all approved for the treatment of HR+, HER2- locally advanced or metastatic breast cancer (BC). Optimal TDM implementation requires a blood sampling organization that can be hampered by limited availability of health and laboratory personnel. Dried Blood Spot (DBS) sampling is proposed to overcome such limitations.

A rapid, simple and sensitive LC-MS/MS method for lenvatinib quantification in human plasma for therapeutic drug monitoring.

Lenvatinib (LENVA) is an oral antineoplastic drug used for the treatment of hepatocellular carcinoma and thyroid carcinoma. LENVA therapeutic drug monitoring (TDM) should be mandatory for a precision medicine to optimize the drug dosage. To this end, the development of a sensitive and robust quantification method to be applied in the clinical setting is essential.

NAFLD-Related Hepatocarcinoma: The Malignant Side of Metabolic Syndrome.

Hepatocellular carcinoma (HCC) is the seventh most common cancer worldwide and the second leading cause of cancer-related mortality. HCC typically arises within a cirrhotic liver, but in about 20% of cases occurs in absence of cirrhosis. Among non-cirrhotic risk factors, non-alcoholic fatty liver disease (NAFLD) currently represents the most important emerging cause of HCC in developed countries.

Dried Blood Spot Technique Applied in Therapeutic Drug Monitoring of Anticancer Drugs: a Review on Conversion Methods to Correlate Plasma and Dried Blood Spot Concentrations.

Background: Anticancer drugs are notoriously characterized by a low therapeutic index, the introduction of therapeutic drug monitoring (TDM) in oncologic clinical practice could therefore be fundamental to improve treatment efficacy. In this context, an attractive technique to overcome the conventional venous sampling limits and simplify TDM application is represented by dried blood spot (DBS). Despite the significant progress made in bioanalysis exploiting DBS, there is still the need to tackle some challenges that limit the application of this technology: one of the main issues is the comparison of drug concentrations obtained from DBS with those obtained from reference matrix (e.

Pharmacological strategies to prevent SARS-CoV-2 infection and treat the early phases of COVID-19.

A novel coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is the cause of coronavirus disease 2019 (COVID-19). It emerged in China in 2019 and has since spread worldwide. COVID-19 has a wide spectrum of clinical scenarios, ranging from totally asymptomatic to death.

Immune Checkpoint Inhibitors as Monotherapy or Within a Combinatorial Strategy in Advanced Hepatocellular Carcinoma.

In advanced-stage hepatocellular carcinoma (HCC), systemic treatment represents the standard therapy. Target therapy has marked a new era based on a greater knowledge of molecular disease signaling. Nonetheless, survival outcomes and long-term response remain unsatisfactory, mostly because of the onset of primary or acquired resistance.

A LC-MS/MS method for therapeutic drug monitoring of sorafenib, regorafenib and their active metabolites in patients with hepatocellular carcinoma.

A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous quantification of sorafenib (SORA), its N-oxide active metabolite and of regorafenib (REGO) and its two active metabolites regorafenib N-oxide and N-desmethyl regorafenib N-oxide in hepatocellular carcinoma patients' plasma. A proper analytes' separation was obtained with Synergi Fusion RP column (4 μm, 80 Å, 50 × 2.0 mm) using a gradient elution of 10 mM ammonium acetate with 0.

Rebleeding and mortality risk are increased by ACLF but reduced by pre-emptive TIPS.

Background & Aims: The relationship between acute-on-chronic liver failure (ACLF) and acute variceal bleeding (AVB) is poorly understood. Specifically, the prevalence and prognosis of ACLF in the context of AVB is unclear, while the role of transjugular intrahepatic portosystemic shunt (TIPS) in the management in patients with ACLF has not been described to date.

Methods: A multicenter, international, observational study was conducted in 2,138 patients from 34 centers between 2011 and 2015.

Clonal Selection of a Novel Deleterious TP53 Somatic Mutation Discovered in ctDNA of a KIT/PDGFRA Wild-Type Gastrointestinal Stromal Tumor Resistant to Imatinib.

The standard of care for the first-line treatment of advanced gastrointestinal stromal tumor (GIST) is represented by imatinib, which is given daily at a standard dosage until tumor progression. Resistance to imatinib commonly occurs through the clonal selection of genetic mutations in the tumor DNA, and an increase in imatinib dosage was demonstrated to be efficacious to overcome imatinib resistance. Wild-type GISTs, which do not display KIT or platelet-derived growth factor receptor alpha (PDGFRA) mutations, are usually primarily insensitive to imatinib and tend to rapidly relapse in course of treatment.

Simultaneous quantification of palbociclib, ribociclib and letrozole in human plasma by a new LC-MS/MS method for clinical application.

A novel LC-MS/MS method was developed for the quantification of the new cyclin dependent kinase inhibitors (CDKIs) palbociclib and ribociclib and the aromatase inhibitor letrozole used in combinatory regimen. The proposed method is appropriate to be applied in clinical practice due to the simple and fast sample preparation based on protein precipitation, the low amount of patient sample necessary for the analysis (10 μL) and the total run time of 6.5 min.