Reflection of neuroblastoma intratumor heterogeneity in the new OHC-NB1 disease model

Accurate modeling of intratumor heterogeneity presents a bottleneck against drug testing. Flexibility in a preclinical platform is also desirable to support assessment of different endpoints. We established the model system, OHC-NB1, from a bone marrow metastasis from a patient diagnosed with MYCN-amplified neuroblastoma and performed whole-exome sequencing on the source metastasis and the different models and passages during model development (monolayer cell line, 3D spheroid culture and subcutaneous xenograft tumors propagated in mice). OHC-NB1 harbors a MYCN amplification in double minutes, 1p deletion, 17q gain and diploid karyotype, which persisted in all models. A total of 80–540 single-nucleotide variants (SNVs) was detected in each sample, and comparisons between the source metastasis and models identified 34 of 80 somatic SNVs to be propagated in the models. Clonal reconstruction using the combined copy number and SNV data revealed marked clonal heterogeneity in the originating metastasis, with four clones being reflected in the model systems. The set of OHC-NB1 models represents 43% of somatic SNVs and 23% of the cellularity in the originating metastasis with varying clonal compositions, indicating that heterogeneity is partially preserved in our model system.     

Phase I and pharmacokinetic study of veliparib,a PARP inhibitor,and pegylated liposomal doxorubicin (PLD) in recurrent gynecologic cancer and triple negative breast cancer with long-term follow-up

Poly(ADP-ribosyl) polymerases (PARPs) are nuclear enzymes with roles in DNA damage recognition and repair. PARP1 inhibition enhances the effects of DNA-damaging agents like doxorubicin. We sought to determine the recommended phase two dose (RP2D) of veliparib with pegylated liposomal doxorubicin (PLD) in breast and recurrent gynecologic cancer patients. Veliparib and PLD were administered in a standard phase 1, 3 + 3 dose-escalation design starting at 50 mg veliparib BID on days 1–14 with PLD 40 mg/mg2 on day 1 of a 28-day cycle. Dose escalation proceeded in two strata: A (prior PLD exposure) and B (no prior PLD exposure). Patients underwent limited pharmacokinetic (PK) sampling; an expansion PK cohort was added. 44 patients with recurrent ovarian or triple negative breast cancer were enrolled. Median age 56 years; 23 patients BRCA mutation carriers; median prior regimens four. Patients received a median of four cycles of veliparib/PLD. Grade 3/4 toxicities were observed in 10% of patients. Antitumor activity was observed in both sporadic and BRCA-deficient cancers. Two BRCA mutation carriers had complete responses. Two BRCA patients developed oral squamous cell cancers after completing this regimen. PLD exposure was observed to be higher when veliparib doses were > 200 mg BID. The RP2D is 200 mg veliparib BID on days 1–14 with 40 mg/m2 PLD on day 1 of a 28-day cycle. Anti-tumor activity was seen in both strata. However, given development of long-term squamous cell cancers and the PK interaction observed, efforts should focus on other targeted combinations to improve efficacy.     

Rosmarinus plants: Key farm concepts towards food applications

Rosmarinus species are aromatic plants that mainly grow in the Mediterranean region. They are widely used in folk medicine, food, and flavor industries and represent a valuable source of biologically active compounds (e.g., terpenoids, flavonoids, and phenolic acids). The extraction of rosemary essential oil is being done using three main methods: carbon dioxide supercritical extraction, steam distillation, and hydrodistillation. Furthermore, interesting antioxidant, antibacterial, antifungal, antileishmanial, anthelmintic, anticancer, anti‐inflammatory, antidepressant, and antiamnesic effects have also been broadly recognized for rosemary plant extracts. Thus the present review summarized data on economically important Rosmarinus officinalis species, including isolation, extraction techniques, chemical composition, pharmaceutical, and food applications.     

One Week of Hospitalization Following Elective Hip Surgery Induces Substantial Muscle Atrophy in Older Patients

Objectives

Short successive periods of skeletal muscle disuse have been suggested to substantially contribute to the observed loss of skeletal muscle mass over the life span. Hospitalization of older individuals due to acute illness, injury, or major surgery generally results in a mean hospital stay of 5 to 7 days, during which the level of physical activity is strongly reduced. We hypothesized that hospitalization following elective total hip arthroplasty is accompanied by substantial leg muscle atrophy in older men and women.

A prospective,double-blind,randomized, placebo-controlled study on the efficacy and safety of influenza vaccination in myasthenia gravis

Objective

To investigate the efficacy and safety of an influenza vaccination in patients with myasthenia gravis with acetylcholine receptor antibodies (AChR MG).

Radiothérapie en conditions stéréotaxiques : étude prospective évaluant la fatigue et la qualité de vie

PurposeTo evaluate prospectively asthenia and the quality of life in patients treated by stereotactic body irradiation and to determine their predictive factors.Methods and materialsQuality of life was assessed by the EORTC QLQ-C30 and asthenia was evaluated with the Brief Fatigue Inventory (BFI), on the first day (T1), last day (T2) and 1–3 weeks after the end of treatment (T3).ResultsSixty-three patients were treated with stereotactic body irradiation from February 2017 to May 2017 and 41 were included in the analysis (22 patients excluded for lack of understanding, organization, psychologic disorders or refusal). The mean number of fractions was 5 (± 2). The compliance to quality of life assessment was 98%, 95% was 81% at T1, T2 and T3, respectively. An increase of asthenia and a worsened quality of life were found in 12 (29%) and 14 (34%) patients between T1 and T2. Univariate analysis demonstrated a correlation between asthenia and quality of life were correlated with performans status (P = 0.03 and 0.05 respectively), hemoglobin level (p = 0.01 and 0.004), albumin level (P = 0.01 and 0.06), distance between home and radiotherapy department (P = 0.05 and 0.02). Multivariate analysis demonstrated a correlation between female gender (P = 0.012), albumin level (P < 0.001), distance over 25 km (P < 0.001) with asthenia, and albumin level (P = 0.003), hemoglobin level (P = 0.004) and previous chemotherapy (P = 0.003) with quality of life. No influence of stereotactic body ratiotherapy parameters was seen.ConclusionDespite hypofractionation, stereotactic body radiotherapy induced asthenia and deterioration of quality of life.