Arsthinol nanosuspensions: pharmacokinetics and anti‐leukaemic activity on NB4 promyelocytic leukaemia cells

Objectives The organoarsenical arsthinol was used in the 1950s in the treatment of amoebiasis and yaws and was considered as ‘highly tolerated’. The aim of this work was to study its anti‐leukaemic activity and to develop nanosuspensions of the drug, thereby limiting brain concentrations and the risk of encephalopathy. Methods Arsthinol nanosuspensions were produced by high‐pressure homogenization. The anti‐leukaemic activity was assessed on NB4 acute promyelocytic leukaemia cells (vs solutions of arsthinol, As₂O₃ and melarsoprol). In addition, a pharmacokinetics study was performed to compare the nanosuspensions and the solution of arsthinol. Key findings Arsthinol induced growth inhibition of NB4 cells at lower concentration (IC50 (concentration inhibiting growth by 50%) = 0.78 ± 0.08 μmol/l after 24 h) than As₂O₃ (IC50 = 1.60 ± 0.23 μmol/l after 24 h) or melarsoprol (IC50 = 1.44 ± 0.08 μmol/l after 24 h). When formulated as nanosuspension, arsthinol remained cytotoxic (IC50 = 1.33 ± 0.30 μmol/l after 24 h). This formulation also reduced the drug's access to the brain (C_max = 0.03 μmol/g) whereas bone marrow concentrations remained very high (C_max = 2 μmol/g). Conclusions Nanosuspensions of arsthinol could be proposed for further studies in the treatment of acute promyelocytic leukaemia.     

A case-control study of lung cancer in Casablanca,Morocco

Objective: To evaluate etiologic risk factors for lung cancer in Casablanca, Morocco. Methods: We conducted a hospital-based case–control study that included 118 incident lung cancer cases and 235 age-, sex- and residence-matched controls. We analyzed the data using matched univariate and matched and unmatched multivariate logistic regression analyses. Results: Active tobacco smoking and history of chronic bronchitis were the strongest risk factors for lung cancer in the matched logistic regression model. Multivariate odds ratio (OR) and 95% confidence intervals varied from 1.79 (0.47–6.79) for former light smokers to 26.07 (6.58–103.27) for current heavy tobacco smokers at the time of disease occurrence. Combined use of hashish/kiff and snuff had an OR of 6.67 (1.65–26.90), whereas the OR for hashish/kiff (without snuff) was 1.93 (0.57–6.58). History of chronic bronchitis had an OR of 4.16 (1.76–9.85). Other slightly increased risks of lung cancer were found for exposure to passive smoking (1.36; 0.71–2.62), occupational exposures (1.75; 0.84–3.63), use of candles for lighting (1.44; 0.42–5.01), and poor ventilation of the kitchen (1.22; 0.57–2.58). Conclusions: This study confirms known risk factors for lung cancer and uncovers potential new etiologic ones such as the role of hashish/kiff.     

Analytical evaluation of the Tosoh HLC-723 G8 automated HPLC analyzer for hemoglobin analysis in beta-thalassemia mode

ObjectivesThe analytical performances of a new kit conceived for Hb variants separation and measurement procedures on an HPLC instrument (Tosoh HLC-723 G8) were studied.ResultsBetween-run and within-run precision tests were satisfactory for both HbA2 and HbF measurements. HbA2 and HbF values measured using the TOSOH HLC-723 G8 were correlated to those obtained using the Bio-Rad Variant II HPLC system (r = 0.974 and 0.997 respectively) and to those given by the Sebia Capillary's system (r = 0.980 and 0.996 respectively). Linearity was observed for HbA2 from 2.24% to 6.56% and for HbF from 0.5 to 6%.ConclusionThe new analyzer Tosoh HLC-723 G8 was found to have a wide analytical range for both HbA2 and HbF. The G8 Mode beta-thal is suitable for a first-level laboratory screening for Hb analysis but also for a second-level test for the characterization of Hb variants after a first-line screening.     

Association of PALB2 Messenger RNA Expression with Platinum-Docetaxel Efficacy in Advanced Non–Small Cell Lung Cancer

Introduction

Partner and localizer of BRCA2 (PALB2) is essential for homologous recombination repair. We examined mRNA levels of DNA repair genes, including partner and localizer of BRCA2 gene (PALB2), ring finger protein 8 gene (RNF8), replication timing regulatory factor 1 gene (RIF1), ATM serine/threonine kinase gene (ATM), and tumor protein p53 binding protein 1 gene (53BP1) as predictive biomarkers for cisplatin-docetaxel in the European phase III BRCA1, DNA repair associated (BRCA1)–receptor-associated protein 80 (RAP80) expression customization (BREC) phase III clinical trial (ClinicalTrials.gov identifier NCT00617656).

Survival Impact of Aggressive Treatment and PD-L1 Expression in Oligometastatic NSCLC

Background: Studies have shown that aggressive treatment of non-small cell lung cancer (NSCLC) with oligometastatic disease improves the overall survival (OS) compared to a palliative approach and some immunotherapy checkpoint inhibitors, such as anti-programmed cell death ligand 1 (PD-L1), anti-programmed cell death protein 1 (PD-1), and T-Lymphocyte-associated antigen 4 (CTLA-4) inhibitors are now part of the standard of care for advanced NSCLC. However, the prognostic impact of PD-L1 expression in the oligometastatic setting remains unknown. Methods: Patients with oligometastatic NSCLC were identified from the patient database of the Centre hospitalier de l’Université de Montréal (CHUM). “Oligometastatic disease” definition chosen is one synchronous metastasis based on the M1b staging of the eight IASLC (The International Association for the Study of Lung Cancer) Classification (within sixth months of diagnosis) or up to three cerebral metastasis based on the methodology of the previous major phase II randomized study of Gomez et al. We compared the OS between patients receiving aggressive treatment at both metastatic and primary sites (Group A) and patients receiving non-aggressive treatment (Group B). Subgroup analysis was performed using tumor PD-L1 expression. Results: Among 643 metastatic NSCLC patients, we identified 67 patients with oligometastasis (10%). Median follow-up was 13.3 months. Twenty-nine patients (43%) received radical treatment at metastatic and primary sites (Group A), and 38 patients (57%) received non-aggressive treatment (Group B). The median OS (mOS) of Group A was significantly longer than for Group B (26 months vs. 5 months, p = 0.0001). Median progression-free survival (mPFS) of Group A was superior than Group B (17.5 months vs. 3.4 months, p = 0.0001). This difference was still significant when controlled for primary tumor staging: stage I (p = 0.316), stage II (p = 0.024), and stage III (p = 0.001). In the cohort of patients who were not treated with PD-L1 inhibitors, PD-L1 expression negatively correlated with mOS. Conclusions: Aggressive treatments of oligometastatic NSCLC significantly improve mOS and mPFS compared to a more palliative approach. PD-L1 expression is a negative prognostic factor which suggests a possible role for immunotherapy in this setting.     

Current and future therapies for targeting HER2 mutations in gastrointestinal cancer

Introduction: Gastrointestinal (GI) cancers altogether represent the most common cancer type. HER2 is found to be present in nearly all histologic types of GI cancers in variable degrees of expression. Over the last decade, substantial advances have been made in targeting HER2-positive cancers.

Areas covered: The present review summarizes the current progress and future directions for HER2 targeted therapies in GI cancers, including esophagogastric, pancreaticobiliary, and colon cancers. To date trastuzumab is the only anti-HER2 therapy approved for metastatic esophagogastric adenocarcinoma. Efforts are ongoing to expand the therapeutic role of HER2 to other GI cancers and overcome mechanisms of drug resistance. Novel agents and combinations are being tested in most HER2 positive GI cancers including early stage disease. These are of recent interest in colorectal cancer with studies indicating that HER2 overexpression might increase resistance to anti-EGFR therapy and may be potentially targeted.

Expert commentary: With the current ability to sequence tumors and detect genetic alterations, emphasis should be put on genomically-selected pan-tumor targeted therapies. HER2 is a perfect example of a promising drug target in GI cancers.     

Biomarker-Driven and Molecular Targeted Therapies for Hepatobiliary Cancers

The recent accumulation of molecular profiling data for primary hepatobiliary malignancies, including hepatocellular carcinoma and biliary tract cancers, has led to a proliferation of promising therapeutic investigations in recent years. Treatment with pathway-specific targeted inhibitors and immunotherapeutic agents have demonstrated promising early clinical results. Key molecular alterations in common hepatobiliary cancers and ongoing interventional clinical trials of molecularly targeted systemic agents focusing on hepatocellular carcinoma and biliary tract cancer are reviewed.