Do proton pump inhibitors alter the response to immune checkpoint inhibitors in cancer patients? A meta-analysis.

Introduction: Gut microbiota can significantly affect the effectiveness of immune checkpoint inhibitors (ICIs) in cancer patients. Recently, antibiotics were shown to decrease survival rate of patients treated by ICIs. Proton pump inhibitors (PPIs) can indeed modulate microbiota's diversity, therefore altering ICIs response. A meta-analysis was performed based on published data to verify this hypothesis. Methods: In this study, over 41 publications, exploring the impact of concomitant PPI treatment on outcomes of ICI-treated patients, were analyzed. Evaluated endpoints were overall survival (OS) and progression-free survival (PFS). Pooled hazard ratios (HRs) with a 95% confidence interval (CI) were reported in ICIs in PPI users versus non-PPI users. Subgroup analyses were performed to minimize the impact of study heterogeneity and to investigate the influence of PPI on the different groups of interest. There was no evidence of publication bias for OS and PFS analysis in subgroup analysis. Results: Forty-one studies were included in the meta-analysis, including a total of 20,042 patients. OS of patients receiving ICIs was negatively correlated in patients concomitantly treated with PPI (HR=1.37; 95%CI, 1.23-1.52). PFS of cancer patients receiving ICIs was also negatively correlated with PPI treatment (HR=1.28; 95%CI, 1.15-1.42). PPI and ICI use was associated with worst OS and PFS not only for non-small-cell lung cancer (NSCLC) or urothelial cancer patients but also for patients treated with anti PD-1 (OS) and anti PD-L1 (OS and PFS) immunotherapies when administered in non-first line and when PPI was received as baseline treatment or in 60 days before ICI initiation. PPI and ICI use also showed the worst OS and PFS for patients from Europe and Asia. Conclusion: This meta-analysis suggests that PPI treatment leads to significantly worse outcomes in advanced cancer patients treated by ICIs in terms of PFS and OS.

Efficacy and Safety of 0.1% Cyclosporine versus 2% Cyclosporine in the Treatment of Severe Vernal Keratoconjunctivitis in Children.

Introduction: Vernal keratoconjunctivitis (VKC) is an inflammatory condition in children that can cause severe eye complications. Treatment is based on corticosteroid therapy during flare-ups, then antihistamines and cyclosporine in calmer periods. The dosage and posology of cyclosporine are subject to debate. Methods: The aim of the study is to compare the evolution in symptomatic and clinical scores, and need for topical corticosteroid treatment in a population of children with severe VKC treated with two dosages of cyclosporine treatment (0.1% and 2%). Data were compiled on inclusion then every three months from March, with a total follow-up duration of 12 months. Data concerning patient evolutions and complications were collected for the two treatment groups. Results: The mean age of the 46 children was 8.8 ±2.4 years with age at onset of symptoms of 5.1 ± 0.9 years. The cohort was predominantly (65%) male. Corticosteroid dependence on inclusion was present in 52% of the children included. A significant improvement in the various symptomatic and clinical scores was observed following treatment with cyclosporine (0.1% and 2%). Use of topical corticosteroid treatment reduced from 19 drops per month on inclusion to 4 drops per month at 12 months. Safety was comparable for the two groups. Conclusion: Treatments with cyclosporine 0.1% and 2% lead to a favourable evolution in clinical and symptomatic scores and reduced corticosteroid use. Cyclosporine 0.1% is an interesting alternative to the 2% dosage, particularly due to its availability and ease of handling.

Improving patient pathways for systemic lupus erythematosus: a multistakeholder pathway optimisation study.

OBJECTIVE: Among the most significant challenges in SLE are the excessive diagnosis delay and the lack of coordinated care. The aim of the study was to investigate patient pathways in SLE in order to improve clinical and organisational challenges in the management of those with suspected and confirmed SLE. METHODS: We conducted a cross-sectional study of patients with SLE, healthcare providers and other representative stakeholders. Focus groups were conducted, and based on the collected data the most impactful disruption points in SLE patient pathways were identified. A novel framework to improve individual patient pathways in SLE was developed, discussed and validated during a consensus meeting with representative stakeholders. RESULTS: Six thematic clusters regarding disruption in optimal patient pathways in SLE were identified: appropriate and timely referral strategy for SLE diagnosis; the need for a dedicated consultation during which the diagnosis of SLE would be announced, and following which clarifications and psychological support offered; individualised patient pathways with coordinated care based on organ involvement, disease severity and patient preference; improved therapeutic patient education; prevention of complications such as infections, osteoporosis and cancer; and additional patient support. During the consensus meeting, the broader panel of stakeholders achieved consensus on these attributes and a framework for optimising SLE patient pathways was developed. CONCLUSIONS: We have identified significant disruption points and developed a novel conceptual framework to improve individual patient pathways in SLE. These data may be of valuable interest to patients with SLE, their physicians, health organisations as well as policy makers.

Association between proton pump inhibitors and severe hematological toxicity in patients receiving pemetrexed-based anticancer treatment: The prospective IPPEM study.

OBJECTIVE: Pemetrexed is associated with hematological toxicity. Drug-drug interactions (DDIs) between methotrexate and proton pump inhibitors (PPIs) induce a higher risk of hematological toxicity due to the inhibition of methotrexate excretion by PPIs. As pemetrexed and methotrexate are both excreted by human organic anion transporter 3 (hOAT3), this study investigates the hypothetical DDI between pemetrexed and PPIs in lung cancer patients. The primary objective was the occurrence of severe (grade ≥ 3) hematological toxicity. The secondary objectives were to describe the type of hematological toxicity and associated clinical consequences (NCT03537833). MATERIALS AND METHODS: PPI consumption was collected for each patient receiving pemetrexed-based anticancer chemotherapy from May 2018 to October 2020 in a prospective multicentric observational and nonrandomized study. Multivariate Cox regression and propensity score (PS) adjustment, PS matching and inverse weighting on PS (IPTW) methods were used. RESULTS: PPI consumption (55 among 156 included patients) was associated with a significantly higher risk of severe hematological toxicity in the multivariable Cox regression model (hazard ratio HR = 2.51, 95% confidence interval [1.47-4.26]; p = 0.005). Similar results were found with PS adjustment (HR = 1.91 CI95% [1.14-3.20]; p = 0.002), PS-matching (HR = 1.93 CI95% [1.08-3.45]; p = 0.02) and IPTW method (HR = 2.06 CI95% [1.27-3.35]; p = 0.004). Severe neutropenia and anemia occurred in 32.7% and 14.1% of patients, respectively. This resulted in 48 anticancer chemotherapy postponements and 24 dose adjustments, 26 growth factor prescriptions, 24 red blood cell transfusions, and 20 hospitalizations. CONCLUSIONS: The results strongly suggest an association between PPI consumption and pemetrexed-related severe hematological toxicity. Deprescription of PPIs when feasible should be considered to prevent this DDI.

Evaluation of a collaborative care program for pulmonary hypertension patients: a multicenter randomized trial.

Background Pulmonary hypertension is a rare, chronic and life-threatening group of diseases. Recent advances in pulmonary hypertension management prolong survival and improve quality-of-life. However, highly complex drug therapy enhances the risk of drug-related problems. Objective To assess the impact of involving clinical pharmacists in the collaborative care of pulmonary hypertension patients. Setting Ten French University Hospital Pneumology departments, all members of the French Network for Pulmonary Hypertension. Methods This prospective multicenter randomized controlled trial included incident pulmonary hypertension patients who were followed-up for 18 months. Randomization using an adapted Zelen method allocated patients to collaborative care (n = 41) or usual care groups (n = 51). A collaborative care program involving clinical pharmacists was developed through a close partnership between with physicians, nurses and pharmacists. Besides usual care, the program includes regular one-to-one interviews between the pharmacist and the patient. These interviews had following objectives: to perform an exhaustive medication history review; to identify the patient' needs, knowledge and skills; to define educational objectives and to provide patients with relevant information when needed. Following each interview, a standardized report form containing the pharmacist's recommendations was provided to physicians and nurses and discussed collaboratively. An ancillary economic analysis was performed. Main outcome measure Number of drug-related problems and their outcomes. Results The number of drug-related problems was not significantly different between groups (1.6 ± 1.5 vs. 1.9 ± 2.4; p = 0.41). More problems were resolved in the collaborative care group than in the usual care group (86.5% vs. 66.7%, p = 0.01). Time to clinical worsening, therapeutic adherence, satisfaction or quality-of-life were not statistically different between groups. Collaborative care decreased costs of drug-related hospitalizations. Conclusion Including clinical pharmacists in the multidisciplinary care of hospitalized patients with pulmonary hypertension improved the outcome of drug-related problems and reduced the costs of related hospitalization. However, we observed no efficacy on medication errors, clinical outcomes or medication adherence. Clinical Trial Registration ClinicalTrials.gov Identifier NCT01038284.

In Vitro Amoebicidal Activity of Titanium Dioxide/UV-A Combination Against Acanthamoeba.

Purpose: To assess the amoebicidal effect of titanium dioxide (TiO2)/UV-A combination against Acanthamoeba sp trophozoites and cysts. Methods: The amoebicidal effect of the TiO2/UV-A combination was tested on trophozoites and cysts of clinical isolates of Acanthamoeba hatchetti and Acanthamoeba sp genotype T4, obtained from two severe cases of ulcerative keratitis. Samples of cultured Acanthamoeba were transferred to a 96-well plate. We tested the effect of sterile water (blank control), TiO2 alone, UV-A alone, TiO2 and additional UV-A exposure, chlorhexidine 0.02% alone, chlorhexidine 0.02% and TiO2, chlorhexidine and UV-A, chlorhexidine 0.02% and TiO2, and additional UV-A exposure. Cell viability assessment was done using the trypan blue dye exclusion method. Results: The combination of TiO2 with UV-A demonstrated antitrophozoite and anticyst activity (P < 0.05). This in vitro study showed a synergistic effect of the association of chlorhexidine with TiO2 and UV-A on cysts (P < 0.001). Conclusions: Given the in vitro synergistic effectiveness of the association of chlorhexidine with TiO2 and UV-A against cysts, the treatment of Acanthamoeba keratitis could be improved by this new therapeutic approach.

[Evaluation of educational interventions with dialysis patient]. / Évaluation d'interventions éducatives auprès du patient dialysé.

The treatment of end-stage renal disease requires a significant number of drug treatments. At patient level, daily management is somewhat difficult: Number of prescribed pills, medication side effects, treatment of asymptomatic diseases… The objective of the study was to investigate the effect of guidance tailored to each patient receiving hemodialysis, performed by the pharmacist (educational interventions). Adult haemodialysis patients with hyperphosphatemia despite phosphate binders were eligible for study entry. The study was controlled with a retrospective group. The primary end point was a change in serum phosphate levels. The secondary end points were therapy adherence, knowledge regarding phosphate management and patient satisfaction with the programme. Sixteen patients in each group participated in the study. The mean serum phosphate level at endpoint was decreased by 0.25 mmol/L in the intervention group (0.41 mmol/L for patients with expectancy for this reduction) and by 0.11 mmol/L in the control group. Five patients normalized their serum phosphate level in the intervention group against three patients in the control group. The mean score of adherence decreased from 1.75 to 1.50. The main factors affecting adherence were forgetfulness or carelessness in taking medications and number of daily doses. This study showed the feasibility of an improvement in serum phosphate level and adherence driven by therapeutic education, though effect was highly amplified by the motivation induced by pharmaceutical guidance. Patients emphasize the importance of the involvement of pharmacist in their care.

Gastrointestinal perforations in patients treated with erlotinib: A report of two cases with fatal outcome and literature review.

Erlotinib has been approved as second-line treatment in patients with non-small cell lung cancer (NSCLC) experiencing relapse after first-line platinum-based chemotherapy. Herein, we report two occurrences of erlotinib-associated gastrointestinal perforation (GIP) in NSCLC patients. Two patients aged 60 and 79 years received erlotinib as third- and second-line NSCLC treatment, respectively. GIP occurred following 3 weeks and 6 months of erlotinib treatment, leading to death a few days later in both patients, neither of whom had any intestinal metastasis. Risk factors related to erlotinib-induced GIP were concomitant oral corticosteroid therapy and ciprofloxacin administration, which may result in erlotinib overexposure. GIP is a severe adverse drug reaction of erlotinib, infrequently described in the literature, compared to other targeted therapies. The lethal risk of erlotinib-associated GIP should be taken into account when evaluating the benefit-risk balance of erlotinib in patients without epidermal growth factor receptor activating mutations.

A UV-Raman spectrometry method for quality control of anticancer preparations: Results after 18 months of implementation in hospital pharmacy.

In France, chemotherapy preparation units of hospital pharmacy compound cytotoxic infusion bags adapted to each patient. The narrow therapeutic index of these preparations led us to implement qualitative and quantitative control for patients' safety. To this aim, we calibrated an equipment combining UV-vis spectrometry and Raman spectroscopy (QC Prep+) and monitored 14 different molecule-solvent combinations over a 18 months period. This rapid and specific method allowed the qualitative and quantitative analysis of 1 mL sample tests in less than 2 min. On 5742 anticancer preparations, we obtained accepted results with more than 99.4% solvent identification, 99.6% drug identification and only 1.52% of preparations not matching quantitative specifications (±15% of theoretical concentration). This quantitative control enabled us to pinpoint some critical points of production for two of the most common preparations. We thus updated the procedures of reconstitution and preparation, increasing the quality of final product. UV-Raman spectrometry is thus an effective tool to control chemotherapy infusions and to improve good practices of preparation.

[Mecanisms of pharmacokinetic interactions involving oral anticancer agents]. / Mécanismes des interactions pharmacocinétiques impliquant les agents anticancéreux oraux.

Oral anticancer agents and particularly kinase inhibitors are subject to pharmacokinetic drug interactions in relation to absorption and elimination phases. Interacting factors are food, fruit juices, cigarette smoke, acid-reducing agents and inducers/inhibitors. Some anticancer agents are inducers and/or inhibitors and can also perpetrate drug interactions. This review emphasizes the mechanisms of pharmacokinetic drug interactions involving oral anticancer agents.

Erlotinib: another candidate for the therapeutic drug monitoring of targeted therapy of cancer? A pharmacokinetic and pharmacodynamic systematic review of literature.

Erlotinib is currently marketed at fixed standard dosage against pancreatic cancer and non-small-cell lung carcinoma. However, erlotinib pharmacokinetics (PK) is characterized by significant variability that may affect efficacy and tolerability. The aim of this review is to assess evidence that would justify therapeutic drug monitoring (TDM) and provide key information for the interpretation of erlotinib plasma concentrations. Literature was systematically reviewed to evaluate the standard criteria defining the potential clinical usefulness of TDM. Assessment was focused on the existence of unpredictable and wide PK variability and of consistent PK-pharmacodynamic relationships. PK parameters actually show marked variability (apparent clearance estimated to 4.85 ± 4.71 L/h, elimination half-life to 21.86 ± 28.35 hours, and apparent volume of distribution to 208 ± 133 L). Many covariates influence these parameters (CYP3A4 inducers or inhibitors, food, age, liver impairment), but most sources of variability still have to be identified. Some studies have demonstrated a relationship between exposure to erlotinib and clinical outcomes or skin toxicity. Erlotinib activity and target concentrations furthermore depend on tumor characteristics (eg, mutations on epidermal growth factor receptor and on K-ras). These results are in favor of TDM in addition to treatment adjustment for tumor biomarkers, but prospective clinical trials validating its clinical benefits are lacking. This review provides all the relevant information available to assist clinical interpretation of erlotinib plasma measurements. PK percentile curves and consideration to covariates yield information on whether a concentration measured is expected, whereas half maximal inhibitory concentration values determined in vitro provide preliminary insights on target concentration values to reach. Eventually, dosage adaptation might be considered in patients with intolerable toxicity because of excessive plasma levels or conversely nonresponse imputable to insufficient exposure.

Ocular penetration of topically applied linezolid in a rabbit model.

PURPOSE: To evaluate ocular penetration of topically applied linezolid, a new antibiotic agent targeted against gram-positive organisms. SETTING: Laboratory of Pharmacology, University Hospital of Strasbourg, Strasbourg, France. METHODS: New Zealand White rabbits were divided into 3 equal groups. One drop of 50 microL (2 mg/mL) linezolid was administrated in Group 1. In Group 2, eyes were dosed in accordance with a keratitis protocol (1 drop of 2 mg/mL every 15 minutes for 1 hour). Aqueous humor was sampled 6 times from immediately after to 3 hours after drop delivery. In Group 3, a keratitis protocol was implemented before the animals were humanely killed. Conjunctiva, cornea, vitreous, and blood samples were collected 1 hour and 2 hours after the last drop. Linezolid concentrations were measured by high-performance liquid chromatography. RESULTS: Each group comprised 8 rabbits. In Group 1 and Group 2, the peak linezolid concentration in the aqueous humor (mean 0.87 mg/L +/- 0.16 [SD] and 2.17 +/- 0.4 mg/L, respectively) was 45 minutes after the last drop delivery. In Group 3, the concentrations 1 hour and 2 hours after the last drop were higher than 3 microg/g in the conjunctiva samples and higher than 4 microg/g in the cornea samples. The linezolid concentration in the vitreous and serum was negligible. CONCLUSIONS: Linezolid levels in the aqueous humor, conjunctiva, and cornea exceeded the minimum inhibitory concentration of most gram-positive organisms that cause bacterial keratitis and endophthalmitis. Linezolid could be a valuable alternative in cases of increased resistance to vancomycin.