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Modified FOLFIRINOX (mFOLFIRINOX) and gemcitabine + nab-paclitaxel (GemNab) regimens represent a standard treatment in advanced pancreatic cancer (aPC). DPYD and UGT1A1 variants are relevant predictors of fluoropyrimidine and irinotecan-associated adverse events (AEs). Furthermore, data about the associations between polymorphisms in ABCB and CDA genes and GemNab-related toxicities are still controversial. The present study analyzes the association between DPYD, UGT, ABCB1, CDA variants, and AEs in aPC patients (pts) treated with mFOLFIRINOX or GemNab. Blood samples collected from 104 aPC pts treated with mFOLFIRINOX and 63 with GemNab were tested for DPYD c.1679T>G, IVS14+1G>A, c.2194G>A, c.2846A>T, UGT1A1*28, CDA c.79A>C, and ABCB1 c.1236C>T, c.2677G>T/A, c.3435C>T by real-time PCR and automatic sequencing. In mFOLFIRINOX cohort, DPYD IVS14+1GA genotype was associated with G4 hematological AEs, while the UGT1A1*28 significantly correlated with the risk of thrombocytopenia (p = 0.006). In the GemNab cohort, a significant association between CDA c.79CC and high-grade nausea was observed (p = 0.002). Moreover, the presence of at least a mutant allele in ABCB1 increased the risk of overall hematological AEs (p = 0.01), both further strengthened by the presence of CDA c.79CC (p = 0.0002). DPYD IVS14+1A allele is confirmed to be associated with fluoropyrimidine life-threatening toxicities, and UGT1A1*28 is related with a higher risk of hematologic AEs following irinotecan treatment. CDA c.79C and ABCB1 c.1236T, c.2677T/A, and c.3435T mutant alleles are predictive biomarkers of GemNab-related AEs. All these variants should be considered in aPC pts candidate to mFOLFIRINOX or GemNab treatments.

Background Despite the increasing number of treatment options, reliable prognostic/predictive biomarkers are still missing for patients affected by metastatic clear cell renal cell carcinoma (mccRCC). Methods Patients with mccRCC undergoing standard first line treatment were enrolled. Blood (12 ml) was drawn at treatment baseline and circulating free DNA (cfDNA) was extracted from plasma. Next-generation sequencing (NGS) was performed on cfDNA using the Oncomine Pan-Cancer Cell-Free Assay and clinical outcomes were correlated with liquid biopsy findings. Results A total of 48 patients were enrolled, 12 received immunotherapy and 36 received a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI). A cfDNA cut-off of 0.883 ng/μl stratified patients based on progression-free survival (PFS) and overall survival (OS) (p = 0.001 and p = 0.008, respectively). cfDNA amount was also correlated with best response (p = 0.006). Additional cfDNA cut-points divided patients into short, intermediate and long responders, with PFS of 4.87 vs 9.13 vs 23.1 months, respectively (p < 0.001). PFS resulted to be significantly shorter in carriers of mutant TP53 compared to not carriers (p = 0.04). Patients with high cfDNA levels and mutant TP53 have the worst PFS, while patients with low cfDNA amounts and no mutations in TP53 displayed the longest PFS (p = 0.004). Conclusions The present study demonstrates that cfDNA and TP53 are potential predictive biomarkers of response in mccRCC to be further explored in larger and/or prospective studies.

SummaryThe aim of this study was to investigate possible synergistic effects in vitro of trifluridine/tipiracil (TAS-102) and 5-fluoruracil (5-FU) on fluoropyrimidine-sensitive colon cancer cell lines of different mutational status in order to build a rational basis for the future use of this combination therapy in adjuvant settings or as a first-line treatment for metastatic disease. Proliferation assays were performed on HT-29 (B-raf mutated), SW-620 (ras mutated), and Caco-2 (wild type) colon cancer cell lines exposed to 120-h treatments of 5-FU, TAS-102 and their different combination schedules (simultaneous, sequential and reverse) at equimolar and non-equimolar ratios. The synergistic, additive and antagonistic effects of 5-FU and TAS-102 were determined by the combination index (CI) and dose reduction index (DRI). Our preclinical in vitro results may suggest an apparently counterintuitive but strongly synergistic combination of 5-FU and TAS-102 in fluoropyrimidine-sensitive colon cancer cells allowing a marked theoretical reduction in the administered doses of both drugs. In particular, this association seems to be highly effective in wild-type colon cancer cells, both in sequential and simultaneous schedules. Together, these data may build a rational basis for the future use of TAS-102 combined with 5-FU in adjuvant settings, or as a first-line treatment for metastatic disease.

Mitotane (DDD) is prescribed in adrenocortical renal carcinoma. Its principal metabolite, dichlorodiphenylethene (DDE), can accumulate in fat tissues and from a toxicological point of view, is probably more interesting than the other metabolite dichlorodiphenylacetate (DDA). Therapeutic Drug Monitoring (TDM) of DDD plasma concentrations is required to combine therapeutic efficacy with acceptable toxicity. Therefore, we developed a simple and fast HPLC-UV method to monitor plasma concentrations after a liquid–liquid extraction of plasma calibration samples, quality controls, and anonymous plasma samples with unknown DDD and DDE concentrations. Samples were injected into an HPLC instrument and peaks of mitotane (DDD), DDE and aldrin (internal standard, IS) were resolved by a stationary phase C18 column (250 mm × 4.6 mm, 5 μm), maintained at 35 °C. Mobile phase, made by water/acetonitrile (10/90, v/v), was pumped at a flow of 1.0 mL/min, and absorbance was monitored at a wavelength of 226 nm. Average recovery was 95% for all analytes, and the method was linear for both DDD (r2 = 0.9988, range 1–50 mg/L) and DDE (r2 = 0.9964, range 1–40 mg/L). The values of limit of detection and quantitation were 0.102 and 0.310 mg/L for DDD and 0.036 and 0.108 mg/L for DDE, respectively. The retention time values of DDD, DDE and IS were 7.06, 9.42 and 12.60 min, respectively. The method was successfully validated according to FDA guidelines and finally adopted for routine TDM.

BackgroundIt is still unclear how to combine biomarkers to identify patients who will truly benefit from anti-PD-1 agents in NSCLC. This study investigates exosomal mRNA expression of PD-L1 and IFN-γ, PD-L1 polymorphisms, tumor mutational load (TML) in circulating cell-free DNA (cfDNA) and radiomic features as possible predictive markers of response to nivolumab and pembrolizumab in metastatic NSCLC patients.MethodsPatients were enrolled and blood (12 ml) was collected at baseline before receiving anti-PD-1 therapy. Exosome-derived mRNA and cfDNA were extracted to analyse PD-L1 and IFN-γ expression and tumor mutational load (TML) by digital droplet PCR (ddPCR) and next-generation sequencing (NGS), respectively. The PD-L1 single nucleotide polymorphisms (SNPs) c.-14-368 T > C and c.*395G > C, were analysed on genomic DNA by Real-Time PCR. A radiomic analysis was performed on the QUIBIM Precision® V3.0 platform.ResultsThirty-eight patients were enrolled. High baseline IFN-γ was independently associated with shorter median PFS (5.6 months vs. not reached p = 0.0057), and levels of PD-L1 showed an increase at 3 months vs. baseline in patients who progressed (p = 0.01). PD-L1 baseline levels showed significant direct and inverse relationships with radiomic features. Radiomic features also inversely correlated with PD-L1 expression in tumor tissue. In subjects receiving nivolumab, median PFS was shorter in carriers of c.*395GG vs. c.*395GC/CC genotype (2.3 months vs. not reached, p = 0.041). Lastly, responders had higher non-synonymous mutations and more links between co-occurring genetic somatic mutations and ARID1A alterations as well.ConclusionsA combined multiparametric approach may provide a better understanding of the molecular determinants of response to immunotherapy.

Abstract Study Objectives Recently, a role for gain-of-function (GoF) mutations of the astrocytic potassium channel Kir4.1 (KCNJ10 gene) has been proposed in subjects with Autism–Epilepsy phenotype (AEP). Epilepsy and autism spectrum disorder (ASD) are common and complexly related to sleep disorders. We tested whether well characterized mutations in KCNJ10 could result in specific sleep electrophysiological features, paving the way to the discovery of a potentially relevant biomarker for Kir4.1-related disorders. Methods For this case–control study, we recruited seven children with ASD either comorbid or not with epilepsy and/or EEG paroxysmal abnormalities (AEP) carrying GoF mutations of KCNJ10 and seven children with similar phenotypes but wild-type for the same gene, comparing period-amplitude features of slow waves detected by fronto-central bipolar EEG derivations (F3-C3, F4-C4, and Fz-Cz) during daytime naps. Results Children with Kir4.1 mutations displayed longer slow waves periods than controls, in Fz-Cz (mean period = 112,617 ms ± SE = 0.465 in mutated versus mean period = 105,249 ms ± SE = 0.375 in controls, p < 0.001). An analog result was found in F3-C3 (mean period = 125,706 ms ± SE = 0.397 in mutated versus mean period = 120,872 ms ± SE = 0.472 in controls, p < 0.001) and F4-C4 (mean period = 127,914 ms ± SE = 0.557 in mutated versus mean period = 118,174 ms ± SE = 0.442 in controls, p < 0.001). Conclusion This preliminary finding suggests that period-amplitude slow wave features are modified in subjects carrying Kir4.1 GoF mutations. Potential clinical applications of this finding are discussed.

Non-expandable lung (NEL) occurs when the lung fails to fully re-expand after pleural fluid drainage, complicating management and limiting therapeutic options. Diagnosis, based on clinical symptoms, pleural manometry, and traditional imaging, is often delayed to the peri- or post-procedural stages, leading to improper management, complications, and higher healthcare costs. Therefore, early, pre-procedural diagnostic methods are needed. Thoracic ultrasound (TUS) has emerged as a non-invasive tool with the potential to enhance diagnostic accuracy and guide clinical decisions, yet, it remains inadequately studied within the context of NEL. We conducted a non-systematic narrative review using a structured methodology, including a comprehensive database search, predefined inclusion criteria, and QUADAS-2 quality assessment. This approach ensured a rigorous synthesis of evidence on TUS in NEL, with the aim of identifying knowledge gaps and guiding future studies. Non-invasive, real-time, bedside M-mode TUS has demonstrated efficacy in predicting NEL prior to thoracentesis by detecting an absent sinusoidal sign and reduced atelectatic lung movement. Emerging experimental techniques, including 2D shear wave elastography (SWE), speckle tracking imaging (STI) strain analysis, the lung/liver echogenicity (LLE) ratio, TUS assessment of dynamic air bronchograms, and pleural thickening evaluation, show additional potential to enhance pre-procedural NEL detection. However, all these methods have significant limitations that require further comprehensive investigation. Despite their significant promise, TUS modalities for early NEL detection still require rigorous validation and standardization before broad clinical use. A multimodal diagnostic approach, combining clinical manifestations, pleural manometry, radiologic and ultrasonographic findings, along with emerging techniques (once fully validated), may provide the most extensive framework for NEL. Regardless of advancements, patient-centered care and shared decision-making remain essential. Further research is needed to improve outcomes, reduce healthcare costs, and enhance long-term treatment strategies.

ABSTRACT Background The molecular landscape of thymic epithelial tumors has been partially elucidated. GTF2I mutation drives the pathogenesis in approximately 50% of tumors; however, the key molecular aberrations in the other cases remain unclear. Methods We designed a panel including the most frequently mutated genes in thymic epithelial tumors and sequenced tumor and normal DNA from 70 patients prospectively accrued at a single institution in the Thymogene trial. Moreover, 19 neoplastic samples were dissociated to isolate tumor cells using flow cytometry. Results GTF2I mutations were the most common, being present in 41% of patients. GTF2I mutations were prevalent in type A and AB thymomas, in Stage I–II tumors, and in patients without myasthenia gravis. The unique pattern of mutually exclusive and co‐occurring mutations suggests a distinct pathogenesis for thymomas with and without GTF2I mutation. In 39% of patients, no mutations were found in the 77 genes evaluated. The absence of epithelial cells in some dissociated tumors highlights the challenge of identifying mutations in a subset of thymic epithelial tumors that lack the GTF2I mutation. Mutational signatures, including COSMIC 1, 19, and 25, were enriched, possibly linked to 5′‐methylcytosine deamination and the effects of chemotherapy. Conclusions GTF2I mutations drive the growth of a significant portion of thymic epithelial tumors, often in conjunction with other gene mutations. Somatic mutations are not commonly found in many GTF2I wild‐type tumors, where the underlying genomic abnormalities remain elusive, even when using a dedicated tool for sequencing thymic epithelial tumors.

Pancreatic ductal adenocarcinoma (PDAC) is a non-immunogenic tumor poorly responsive to immune checkpoint inhibitors. This study investigates the effect of 5-fluorouracil (5-FU), irinotecan, and oxaliplatin (FOLFIRINOX), and gemcitabine plus nab-paclitaxel (GEMnPAC) regimens on PD-L1 mRNA expression in plasma-derived microvesicles (MVs) in 50 PDAC patients. Plasma was collected before starting chemotherapy and after 3 months of treatment. mRNA was extracted from MVs, and PD-L1 expression was measured by digital droplet PCR. Twenty-eight patients were PD-L1 positive in MVs at baseline, of which 18 were in the GEMnPAC cohort and 10 in the FOLFIRINOX one. The amount of PD-L1 expression in MVs increased from baseline to 3 months of treatment in patients receiving GEMnPAC (median value 0.002 vs. 0.005; p = 0.01) compared to those treated with FOLFIRINOX (median 0.003 vs. 0.004; p = 0.97). The increase in PD-L1 mRNA expression in MVs was not related to tumor response (PR + SD: p = 0.08; PD: p = 0.28). Our findings demonstrate that GEMnPAC can increase PD-L1 mRNA expression in patient-derived circulating MVs, providing a rationale for testing the efficacy of this regimen in sequential or simultaneous combinations with immunotherapy in PDAC patients.