Inhibitory Effect of Ursodeoxycholic Acid on Clostridium difficile Germination Is Insufficient to Prevent Colitis: A Study in Hamsters and Humans

Introduction: Bile acids (BA) influence germination and growth of Clostridium difficile. Ursodeoxycholic acid (UDCA), a BA minor in human, used for cholestatic liver diseases, inhibits germination and growth of C. difficile in vitro, but was never tested in vivo with an infectious challenge versus control. We hypothesized that UDCA could prevent CDI. We evaluated the effects of UDCA on C. difficile in vitro and in hamsters, with pharmacokinetics study and with an infectious challenge. Then, we studied CDI incidence in UDCA–treated patients.Methods: We evaluated germination and growth of C. difficile, with 0.01, 0.05, and 0.1% UDCA. We analyzed fecal BA of hamsters receiving antibiotics and UDCA (50 mg/kg/day), antibiotics, or UDCA alone. Then, we challenged with spores of C. difficile at D6 hamsters treated with UDCA (50 mg/kg/day) from D1 to D13, versus control. In human, we analyzed the database of a cohort on CDI in acute flares of inflammatory bowel disease (IBD). As PSC-IBD patients were under UDCA treatment, we compared PSC-IBD patients to IBD patients without PSC.Results:In vitro, UDCA inhibited germination and growth of C. difficile at 0.05 and 0.1%, competing with 0.1% TCA (with 0.1%: 0.05% ± 0.05% colony forming unit versus 100% ± 0%, P < 0.0001). In hamsters, UDCA reached high levels only when administered with antibiotics (43.5% UDCA at D5). Without antibiotics, UDCA was in small amount in feces (max. 4.28%), probably because of UDCA transformation into LCA by gut microbiota. During infectious challenge, mortality was similar in animals treated or not with UDCA (62.5%, n = 5/8, P = 0.78). UDCA percentage was high, similar and with the same kinetics in dead and surviving hamsters. However, dead hamsters had a higher ratio of primary over secondary BA compared to surviving hamsters. 9% (n = 41/404) of IBD patients without PSC had a CDI, versus 25% (n = 4/12) of PSC-IBD patients treated with UDCA.Conclusion: We confirmed the inhibitory effect of UDCA on growth and germination of C. difficile in vitro, with 0.05 or 0.1% UDCA. However, in our hamster model, UDCA was inefficient to prevent CDI, despite high levels of UDCA in feces. Patients with PSC-IBD treated with UDCA did not have less CDI than IBD patients

Saccharomyces boulardii CNCM I-745 Modulates the Fecal Bile Acids Metabolism During Antimicrobial Therapy in Healthy Volunteers

Saccharomyces boulardii CNCM I-745 (SB) is a probiotic yeast used to lower the incidence of antibiotic-associated Clostridium difficile (C. difficile) infection, though its mechanism of action remains unclear. Cholic acid is a primary bile acid, which triggers the germination and promotes the growth of C. difficile. The intestinal microbiota transforms primary into secondary bile acids. This study examined (1) the antimicrobial-induced alteration of fecal bile acid content, and (2) whether the concomitant administration of SB influences this transformation. This is an ancillary work from a randomized study, which revealed that SB modulates fecal microbiota dysbiosis during antibiotic treatment. Healthy subjects were randomly assigned to (1) SB only, (2) amoxicillin-clavulanate (AC), (3) SB plus AC, or (4) no treatment. We analyzed fecal concentrations of BA by high performance liquid chromatography/tandem mass spectrometry. Compared to the untreated or the SB-treated groups, AC decreased the percentage of fecal secondary BA significantly (days 3 and 7). When SB and AC were administered concomitantly, this decrease in secondary BA was no longer significant. Following treatment with AC, a significant peak of fecal CA was measured on days 3 and 7, which was prevented by the concomitant administration of SB. AC administered to healthy volunteers altered the microbial transformation of primary BA, decreased secondary BA, and increased CA. The latter was prevented by the concomitant administration of SB and AC, suggesting a potent mechanism protection conferred by SB against post-antimicrobial C. difficile infection.Clinical Trial Registration:www.ClinicalTrials.gov, identifier NCT01473368

Major pitfalls of protein kinase inhibitors prescription: a review of their clinical pharmacology for daily use

International audienceProtein kinase inhibitors (PKI) are a growing class of anticancer agents. They are prescribed with flat doses, and their oral administration is associated with interindividual variability in exposure. Patients can be over- or underexposed, due to numerous factors. We reviewed key pharmacokinetic concepts and mechanisms by which PKIs prescription could be altered. Challenging situations that could lead to increased toxicity or to therapeutic failure are described and recommendation for clinicians are proposed. Finally, the interest of therapeutic drug monitoring and indications for its use in daily practice is discussed

Medical Treatment of Advanced Pancreatic Neuroendocrine Neoplasms

Pancreatic neuroendocrine neoplasms (panNENs) are relatively rare but their incidence has increased almost sevenfold over the last four decades. Neuroendocrine neoplasms are classified according to their histologic differentiation and their grade. Their grade is based on their Ki-67 proliferation index and mitotic index. Their prognosis is highly variable according to these elements and treatments also vary according to their classification. Surgery is the only curative treatment for localized and advanced panNENs and offers a better prognosis than non-surgical treatments. In the case of an advanced panNEN without the possibility of resection and/or ablation, medical treatment remains the cornerstone for improving survival and preserving quality-of-life. PanNENs are considered as chemosensitive tumors, unlike midgut neuroendocrine tumors. Thus, panNENs can be treated with chemotherapy, but targeted therapies and somatostatin analogs are also treatment options. The scarcity and heterogeneity of NENs make their management difficult. The present review aims to clarify the medical treatments currently available for advanced panNENs, based on their characteristics, and to propose a treatment algorithm

Impact of Delaying the Addition of Anti-EGFR in First Line of RAS Wild-Type Metastatic Colorectal Cancer: A Propensity-Weighted Pooled Data Analysis

The first-line therapy of patients with RAS wild-type (WT) non-resectable metastatic colorectal cancer (mCRC) is usually 5-fluorouracil-based chemotherapy with either bevacizumab or an anti-epidermal growth factor receptor (EGFR). The addition of anti-EGFR antibodies is commonly delayed in clinical practice because of late RAS testing results. Our objective was to evaluate the impact on overall survival (OS) of a delayed anti-EGFR introduction strategy. This study pooled the data of two large retrospective studies. Patients with RAS WT non-resectable mCRC, treated in first line by a doublet chemotherapy with an anti-EGFR introduced with a delay of 2 to 4 cycles, were compared to an anti-EGFR and to an anti-VEGF that was introduced immediately. Patients numbering 305 in the delayed anti-EGFR group, 401 in the immediate anti-EGFR group, and 129 in the immediate anti-VEGF group were analyzed. After propensity scoring, there was no difference between the characteristics of the three groups. Median OS was 28.6 months (95% CI: 23.5–34.1) in the immediate anti-EGFR group, 35.1 (95% CI: 29.9–43.5) in the delayed anti-EGFR group, and 32.4 (95% CI: 25.4–44.8) in the immediate anti-VEGF group. There was no significant difference concerning median OS (p = 0.24) or progression-free survival (p = 0.56). This study suggests that delaying the introduction of an anti-EGFR has no deleterious impact on survival compared to the immediate introduction of an anti-VEGF or of an anti-EGFR

Circulating H3K27me3 modified nucleosomes as a biomarker to monitor anti EZH2-based treatment in advanced solid tumour patients: Translational analyses from CAIRE trial

CAIRE is a phase 2 umbrella study which assessed activity of combined anti-EZH2 tazemetostat and anti-PDL1 durvalumab (T+D) in advanced pretreated pancreatic, colorectal and sarcoma cancer patients. The are currently no plasma biomarkers for anti-EZH2 treatment monitoring or outcome. EZH2 catalyzes tri-methylation of Lysine 27 (K27me3) on nucleosomal histone 3 (H3, H3K27me3). Circulating, cell free H3K27me3 modified nucleosomes are thus a potential biomarker for tazemetostat activity. We evaluated the concentration of circulating H3K27me3 modified nucleosomes normalized to H3.1 nucleosomes (the most common isoform of H3) in T+D treated patients, irrespective of the tumor primary site, to determine target engagement during anti-EZH2 treatment. Plasma from patients receiving T+D was collected before the first cycle administration (C1D1), on the following two cycles administration (C2D1, C3D1) and at end of treatment (EOT). H3.1 and H3K27me3 containing nucleosomes were quantified by Nu.Q®-H3.1 and Nu.Q®-H3K27me3 Chemiluminescent Immunoassays. Concentrations are reported as ng/ml and the comparison of their median values at the different timepoints were tested with Kruskal-Wallis and Mann Whitney (independent samples) or Wilcoxon tests (paired samples), with SciPy.stat package (1.6.2). Bonferroni correction was applied to multiple comparisons. Of 197 total samples, 191 were evaluable for both biomarkers (6 higher than top standard after 5x dilution): 69 at C1D1, 63 at C2D1, 50 at C3D1 and 9 at EOT. For 58 patients paired C1D1 and C1D2 levels were available, 46 from C1D1 to C3D1 and 8 from C1D1 to EOT. The normalized Nu.Q®-H3K27me3 C1D1 median value (0.56) was significantly higher than C2D1 (0.31, p: e-12), C3D1 (0.31, p: e-12) and EOT ones (0.28, p: 0.001). Conversely, Nu.Q®-H3.1 levels were similar from C1D1 to C3D1 (range of the medians: 122.16-133.25 ng/ml) and increased at EOT (290.09 ng/ml), but with no significant difference between pairwise timepoints. Regarding paired-samples comparison, the normalized Nu.Q®-H3K27me3 was significantly higher at C1D1 than at C2D1 (p: e-8) and C3D1 (p: e-9) and at EOT (p: 0.02). Conversely, H3.1 concentration was significantly higher at EOT than at C1D1 (p: 0.02), at C2D1 (p: 0.02) and C3D1 (p: 0.05).In conclusion, we described for the first time that normalized circulating nucleosomal H3K27me3 values significantly decrease during T-based treatment in metastatic solid tumor patients, irrespective of the primary disease site, supporting its potential role as a pharmacodynamic biomarker for EZH2 inhibition. Moreover, total nucleosomal H3.1 seems to represent a surrogate of disease burden in metastatic pancreatic, colorectal and sarcoma cancers, as suggested previously in other hematological malignancies

Tumor-size responses to first-line is a predictor of overall survival in metastatic colorectal cancer

International audienceOBJECTIVES: Early tumor shrinkage (ETS) has been reported to be associated with survival of metastatic colorectal cancer (mCRC) patients. Our aim was to analyze long-term tumor-size evolution, according to early mCRC best responses during the first-line therapy, to evaluate first best response-survival links.METHODS: Sixty-five patients with unresectable mCRCs, treated between 2010 and 2015, were included retrospectively in this descriptive monocenter study and grouped according to their RECIST 1.1 first-line best responses: progressive disease (PDfl), stable disease with tumor-size evolution between 0 and + 19% (SDfl+) or 0 and - 29% (SDfl-), and partial responders (PRs), who were classed PR with ETS (ETSfl) or without (PRfl). Tumor-size evolution and best tumor responses to each chemotherapy line were analyzed.RESULTS: Tumor loads of ETSfl or PRfl mCRCs tended to remain inferior to their initial values: 60% of patients died with target lesion sums below baseline. For first-line SDfl+ or PDfl mCRCs, rapid tumor load increases continued during successive lines: > 80% died with target lesion sums above baseline. ETSfl mCRCs responded better to subsequent lines (37.5% second-line PR), whereas PDfl mCRCs remained refractory to other therapies (0% second- and third-line PR). Overall survival rates were significantly (p = 0.03) longer for the ETSfl group (29.9 [95% CI: 12.6-47.1] months) and shorter for the PDfl group (17.1 [95% CI: 1.5-37.5] months).CONCLUSION:Tumors responding to first-line chemotherapy also responded better to subsequent lines, whereas PDfl mCRCs remained refractory, which may explain the better survival associated with ETSfl

Echoendoscopic ultrasound pancreatic adenocarcinoma diagnosis and theranostic approach: should mutation research be recommended in everyday practice?

Background: The impact of KRAS mutation testing on pancreatic ductal adenocarcinoma (PDAC) samples by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) for reducing the need to repeat EUS-FNA has been demonstrated. Such testing however is not part of standard practice for endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB). Objectives: We aim to analyse the proportion of non-contributive samples by EUS-FNB and to evaluate the impact of KRAS mutation testing on the diagnosis, theranostics and survival. Design: In this retrospective study, the impact on diagnosis and survival of KRAS testing for contributive and non-contributive samples by EUS-FNB was analysed. Methods: The EUS-FNB samples, combined with KRAS testing using the Idylla ® technique on liquid-based cytology from patients with PDAC between February 2019 and May 2023, were retrospectively reviewed. The cytology results were classified according to the guidelines of the World Health Organization System for Reporting Pancreaticobiliary Cytopathology (WHOSRPC). Results: A total of 85 EUS-FNB specimens were reviewed. In all, 25 EUS-FNB samples did not lead to a formal diagnosis of PDAC according to the WHOSRPC (30.2%). Out of these 25, 11 (44%) could have been considered positive for a PDAC diagnosis thanks to the KRAS mutation test without carrying out further diagnosis procedures. The sensitivity of KRAS mutation testing using the Idylla technique was 98.6%. According to the available data, survival rates were not statistically different depending on the type of mutation. Conclusion: KRAS mutation testing on liquid-based cytology using the Idylla or equivalent technique, combined with the PDAC EUS-FNB sample, should become a standard for diagnosis to avoid delaying treatment by doing another biopsy. Furthermore, knowledge of the KRAS status from treatment initiation could be used to isolate mutations requiring targeted treatments or inclusion in clinical research trials, especially for wild-type KRAS PDAC

The Role of Interventional Radiology for the Treatment of Hepatic Metastases from Neuroendocrine Tumor: An Updated Review

Interventional radiology plays an important role in the management of patients with neuroendocrine tumor liver metastasis (NELM). Transarterial embolization (TAE), transarterial chemoembolization (TACE), and selective internal radiation therapy (SIRT) are intra-arterial therapies available for these patients in order to improve symptoms and overall survival. These treatment options are proposed in patients with NELM not responding to systemic therapies and without extrahepatic progression. Currently, available data suggest that TAE should be preferred to TACE in patients with NELM from extrapancreatic origin because of similar efficacy and better patient tolerance. TACE is more effective in patients with pancreatic NELM and SIRT has shown promising results along with good tolerance. However, large randomized controlled trials are still lacking in this setting. Available literature mainly consists in small sample size and retrospective studies with important technical heterogeneity. The purpose of this review is to provide an updated overview of the currently reported endovascular interventional radiology procedures that are used for the treatment of NELM

Patterns of ICU admissions and outcomes in patients with solid malignancies over the revolution of cancer treatment

International audienceBackground: Major therapeutic advances including immunotherapy and targeted therapies have been changing the face of oncology and resulted in improved prognosis as well as in new toxic complications. The aim of this study is to appraise the trends in intensive care unit (ICU) admissions and outcomes of critically ill patients with solid malignancies. We performed a retrospective single-centre study over a 12-year period (2007–2018) including adult patients with solid malignancies requiring unplanned ICU admission. Admission patterns were classified as: (i) specific if directly related to the underlying cancer; (ii) non-specific; (iii) drug-related or procedural adverse events. Results: 1525 patients were analysed. Lung and gastro-intestinal tract accounted for the two main tumour sites. The proportion of patients with metastatic diseases increased from 48.6% in 2007–2008 to 60.2% in 2017–2018 (p = 0.004). Critical conditions were increasingly related to drug- or procedure-related adverse events, from 8.8% of ICU admissions in 2007–2008 to 16% in 2017–2018 (p = 0.01). The crude severity of critical illness at ICU admission did not change over time. The ICU survival rate was 77.4%, without any significant changes over the study period. Among the 1279 patients with complete follow-up, the 1-year survival rate was 33.2%. Independent determinants of ICU mortality were metastatic disease, cancer in progression under treatment, admission for specific complications and the extent of organ failures (invasive and non-invasive ventilation, inotropes/vasopressors, renal replacement therapy and SOFA score). One-year mortality in ICU-survivors was independently associated with lung cancer, metastatic disease, cancer in progression under treatment, admission for specific complications and decision to forgo life-sustaining therapies. Conclusion: Advances in the management and the prognosis of solid malignancies substantially modified the ICU admission patterns of cancer patients. Despite underlying advanced and often metastatic malignancies, encouraging short-term and long-term outcomes should help changing the dismal perception of critically ill cancer patients