Long‐term analysis of phase II studies of single‐agent lenalidomide in relapsed/refractory mantle cell lymphoma

Mantle cell lymphoma (MCL) is a type of non‐Hodgkin lymphoma (NHL) with aggressive disease characteristics resulting in multiple relapses after initial treatment. Lenalidomide is an immunomodulatory agent approved in the US for patients with relapsed/refractory MCL following bortezomib based on results from 3 multicenter phase II studies (2 including relapsed/refractory aggressive NHL and 1 focusing on MCL post‐bortezomib). The purpose of this report is to provide longer follow‐up on the MCL‐001 study (follow‐ups were 6.8 [NHL‐002], 7.6 [NHL‐003], and 52.2 [MCL‐001] months). The 206 relapsed MCL patients treated with single‐agent lenalidomide (25 mg/day PO, days 1 to 21 every 28‐days) had a median age of 67 years (63% ≥65 years), 91% with stage III/IV disease, and 50% with ≥4 previous treatment regimens. With a median follow‐up of X, the combined best overall response rate (ORR) was 33% (including 11% with complete remission [CR]/CR unconfirmed CRu). Lenalidomide produced rapid and durable responses with a median time to response of 2.2 months and median duration of response (DOR) of 16.6 months (95% CI: 11.1%‐29.8%). The safety profile was consistent and manageable; myelosuppression was the most common adverse event (AE). Overall, single‐agent lenalidomide showed consistent efficacy and safety in multiple phase II studies of heavily pretreated patients with relapsed/refractory MCL, including those previously treated with bortezomib.     

Protein Content and Methyl Donors in Maternal Diet Interact to Influence the Proliferation Rate and Cell Fate of Neural Stem Cells in Rat Hippocampus

Maternal diet during pregnancy and early postnatal life influences the setting up of normal physiological functions in the offspring. Epigenetic mechanisms regulate cell differentiation during embryonic development and may mediate gene/environment interactions. We showed here that high methyl donors associated with normal protein content in maternal diet increased the in vitro proliferation rate of neural stem/progenitor cells isolated from rat E19 fetuses. Gene expression on whole hippocampi at weaning confirmed this effect as evidenced by the higher expression of the Nestin and Igf2 genes, suggesting a higher amount of undifferentiated precursor cells. Additionally, protein restriction reduced the expression of the insulin receptor gene, which is essential to the action of IGFII. Inhibition of DNA methylation in neural stem/progenitor cells in vitro increased the expression of the astrocyte-specific Gfap gene and decreased the expression of the neuron-specific Dcx gene, suggesting an impact on cell differentiation. Our data suggest a complex interaction between methyl donors and protein content in maternal diet that influence the expression of major growth factors and their receptors and therefore impact the proliferation and differentiation capacities of neural stem cells, either through external hormone signals or internal genomic regulation.     

Frequent expression of PD‐L1 on circulating breast cancer cells

Immune checkpoint regulators such as PD‐L1 have become exciting new therapeutic targets leading to long lasting remissions in patients with advanced malignancies. However, in view of the remarkable costs and the toxicity profiles of these therapies, predictive biomarkers able to discriminate responders from non‐responders are urgently needed. In the present paper, we provide evidence that PD‐L1 is frequently expressed on metastatic cells circulating in the blood of hormone receptor‐positive, HER2‐negative breast cancer patients. We performed western blot, flow cytometry and immunocytochemical analyses to demonstrate the specificity of the PDL1 antibody used in our study and established immunoscores for PDL1 expression on single tumor cells. We then selected sixteen patients with circulating tumor cells (CTCs) using the CellSearch® system and found PD‐L1(+) CTCs in 11 patients (68.8%). The fraction of PD‐L1(+) CTCs varied from 0.2 to 100% in individual patients. This is the first report demonstrating the expression of PD‐L1 on CTCs. The established CTC/PD‐L1 assay can be used for liquid biopsy in future clinical trials for stratification and monitoring of cancer patients undergoing immune checkpoint blockade.     

Electro‐optic probe for real‐time assessments of RF electric field produced in an MRI scanner: Feasibility tests at 3 and 4.7 T

During magnetic resonance imaging (MRI) examinations, the average specific absorption rate (SAR) of the whole body is calculated as an index of global energy deposition in biological tissue without taking into account the presence of metallic implants or conductive materials. However, this global SAR calculation is not sufficient to ensure patient safety and a local SAR measurement should be carried out. Several measurement techniques have already been used to evaluate the local SAR, in particular electric field (E‐field) probes, but the accuracy of the measurements and the resolutions (spatial and temporal) depend strongly on the measurement method/probe. This work presents an MR‐compatible, subcentimeter probe based on an electro‐optic (EO) principle enabling a real‐time measurement of the local E‐field during MRI scans. The experiments using these probes were performed on two different MR systems (preclinical and clinical) having different static magnetic field strengths and with different volume coil geometries. The E‐field was measured with unloaded (in air) and loaded volume coils in order to assess the sensing characteristics of the optical probe. The results show an excellent linearity between the measured E‐field and the radiofrequency (RF) magnetic field in both experimental conditions. Moreover, the distribution of the E‐field throughout the volume coil was experimentally determined and was in good agreement with numerical simulations. Finally, we demonstrate through our measurements that the E‐field depends strongly on the dielectric properties of the medium.     

Resistance of the sheep skull after a monocortical cranial graft harvest

IntroductionCranial bone grafts are commonly used for preimplant or facial reconstructive surgery. However, removing bone may weaken the parietal bone and lead to a loss of strength. This loss has never been quantified. Bone harvest site reconstruction is being carried out more frequently than in the past, but its effect on the strength of the donor site is unknown.The aim of our study is to quantify the loss of strength due to a monocortical cranial bone graft harvest in sheep.Materials and methodsThirty-four fresh sheep cadaver heads were used for the study. We performed a monocortical bone graft harvest on the posterior part of the right frontal bone. We used a surgical navigation system with optoelectronic tracking to measure bone thickness.To evaluate the resistance of the skull to an impact we developed a pendulum Charpy impact testing machine. The impact force hit a defined target frontal area.ResultsThe total thickness on both sides ranged from 3 mm to 10 mm with a mean of 6 mm (SD = 1.4 mm).The loss of strength between the intact left side and the harvested right side varied with a mean of 49% (SD = 17%) and was significant (p = 6.10^?10).ConclusionThis study has demonstrated that there is a loss of strength in the skull on the side where a bone graft has been harvested.Reconstruction of the harvested site using biomaterials reduces the poor aesthetic outcome due to depression at the site, but we do not know its effects on strength. This kind of study cannot be performed in humans for ethical reasons.Data obtained from this study will allow us to carry out a study in sheep to evaluate strength of the frontal area of a skull with a harvest site reconstructed with hydroxyapatite cement.