A perivascular niche in the bone marrow hosts quiescent and proliferating tumorigenic colorectal cancer cells

Disseminated tumor cells (dTCs) can frequently be detected in the bone marrow (BM) of colorectal cancer (CRC) patients, raising the possibility that the BM serves as a reservoir for metastatic tumor cells. Identification of dTCs in BM aspirates harbors the potential of assessing therapeutic outcome and directing therapy intensity with limited risk and effort. Still, the functional and prognostic relevance of dTCs is not fully established. We have previously shown that CRC cell clones can be traced to the BM of mice carrying patient-derived xenografts. However, cellular interactions, proliferative state and tumorigenicity of dTCs remain largely unknown. Here, we applied a coculture system modeling the microvascular niche and used immunofluorescence imaging of the murine BM to show that primary CRC cells migrate toward endothelial tubes. dTCs in the BM were rare, but detectable in mice with xenografts from most patient samples (8/10) predominantly at perivascular sites. Comparable to primary tumors, a substantial fraction of proliferating dTCs was detected in the BM. However, most dTCs were found as isolated cells, indicating that dividing dTCs rather separate than aggregate to metastatic clones—a phenomenon frequently observed in the microvascular niche model. Clonal tracking identified subsets of self-renewing tumor-initiating cells in the BM that formed tumors out of BM transplants, including one subset that did not drive primary tumor growth. Our results indicate an important role of the perivascular BM niche for CRC cell dissemination and show that dTCs can be a potential source for tumor relapse and tumor heterogeneity.     

Clinical and haematological risk factors for cerebral macrovasculopathy in a sickle cell disease newborn cohort: a prospective study

Children with sickle cell disease (SCD) have a significant vascular morbidity, especially cerebral macrovasculopathy (CV), detectable by transcranial Doppler. This study aimed to identify risk factors for CV using longitudinal biological and clinical data in a SCD newborn cohort followed at the Robert Debre Reference centre (n = 375 SS/Sβ⁰). Median follow‐up was 6·8 years (2677 patient‐years). Among the 59 children presenting with CV, seven had a stroke. Overall, the incidence of CV was 2·20/100 patient‐years [95% confidence interval (_95%CI): 1·64–2·76] and the incidence of stroke was 0·26/100 patient‐years (_95%CI: 0·07–0·46). The cumulative risk of CV by age 14 years was 26·0% (_95%CI: 20·0‐33·3%). Risk factors for CV were assessed by a Cox model encompassing linear multivariate modelling of longitudinal quantitative variables. Years per upper‐airway obstruction [Hazard ratio (HR) = 1·47; _95%CI: 1·05–2·06] or bronchial obstruction (HR = 1·76; 95% CI: 1·49–2·08) and reticulocyte count (HR = 1·82 per 50 × 10⁹/l increase; _95%CI: 1·10–3·01) were independent risk factors whereas fetal haemoglobin level (HR = 0·68 per 5% increase; _95%CI: 0·48–0·96) was protective. Alpha‐thalassaemia was not protective in multivariate analysis (ancillary analysis n = 209). Specific treatment for upper or lower‐airway obstruction and indirect targeting of fetal haemoglobin and reticulocyte count by hydroxycarbamide could potentially reduce the risk of CV.     

Assessment of implant stability following sinus lift procedures with different grafting materials

Objective

The objective of this research was to evaluate implant stability following sinus lift with two grafting materials, and to compare it with the results obtained for the implants placed in a pristine posterior maxilla.

Materials and methods

The study included 44 healthy patients with an existing indication for sinus lift procedure (test group). 46 implants were placed following sinus lift with a pure-phase beta-tricalcium phosphate, while 39 implants were placed following augmentation with 60% hydroxyapatite with 40% beta-tricalcium phosphate material. The control group consisted of 48 healthy patients who were treated with 85 implants but without bone augmentation in posterior maxilla. Astra Tech OsseoSpeed implants were placed in all subjects. Resonance frequency analysis was used in both groups for determining implant stability 4 months after insertion. A mean implant stability quotient (ISQ) was calculated on the basis of 3 measurements.

Results

No statistical difference was observed in ISQ values of implants placed with and without augmentation procedure (p=0,789). Statistically significant difference was not found when ISQ values of implants placed following particular grafting material were compared with ISQ values of corresponding implants in a pristine bone (p=0.697 and p=0.402).

Conclusions

This study demonstrated that the implant stability is comparable among implants placed in the posterior maxilla regardless of sinus lift and grafting procedure. Implants placed in the grafted posterior maxilla can be predictably loaded as the implants placed in a non-grafted, pristine maxilla.Key words: Dental Implants, Sinus Floor Augmentation, Resonance Frequency Analysis, Beta-tricalcium Phosphate, Hydroxyapatite     

Cellular uptake and efflux of azithromycin, erythromycin, clarithromycin, telithromycin, and cethromycin

Macrolide antibiotics have an outstanding ability to concentrate within host cells, particularly phagocytes. In the study described in this paper five different macrolide antibiotics were compared regarding the uptake and release kinetics in human peripheral blood polymorphonuclear neutrophils (PMNs) and three different cell lines, two phagocytic cell lines (RAW 264.7 and THP-1) and an epithelial cell line (MDCK). Based on the results obtained, the substances tested could be clustered into different groups. Azithromycin constituted the first group, characterized by rapid and nonsaturable uptake into phagocytic cells and a high degree of retention in the preloaded cells. The second group included erythromycin and clarithromycin. These two substances do not exhibit cell specificity; consequently, they are taken up to a similar extent and are released by all cell types studied. Ketolides constituted the last group. Their uptake was saturable in cells of monocytic lineage as well as in nondifferentiated cells of myeloid lineage, and they were rapidly released from all the cell lines studied. However, in PMNs, ketolide uptake was not saturable; and unlike telithromycin, cethromycin rapidly egressed from the loaded cells.     

Prolonged mean reaction time in posterior cerebral artery during visual stimulation in patients with severe carotid stenosis

While the mean increase in flow velocities in posterior cerebral artery (PCA) as a response to visual stimuli is well documented, the data on the reaction time as a measurement of the vasomotor response of the posterior part of the circle of Willis are still sparse. The aim was to assess the visual evoked response in PCA during white light stimulation by means of functional transcranial doppler in patients with severe internal carotid artery (ICA) stenosis, to introduce a real‐time haemodynamic changes as a measurement of the effect of severe carotid disease on the posterior circulation. The measurements were taken in 49 right‐handed patients with severe ICA stenosis or occlusion and 30 healthy volunteers, simultaneously in left and right PCA using 2‐MHz probes, successively in the dark and during the white light stimulation, during three consecutive repetitive periods of 1 min each. Mean values of mean blood flow velocities (MBFV) and mean reaction time (MRT) with and without visual stimuli were analysed. Linear regression analysis showed no statistically significant correlation between the age, MBFV and a degree of left and right carotid stenosis, and MRT in left and right PCA either in the group of healthy subjects or in the group of patients with severe carotid stenosis, in both test conditions. MRT could be an indicator of compromised cerebral circulation in the presence of haemodynamic significant carotid stenosis as well as an additional and independent haemodynamic parameter of the cerebral visual evoked response.     

High dose chemotherapy and autologous stem cell transplantation in nodular lymphocyte‐predominant Hodgkin lymphoma: A retrospective study by the European society for blood and marrow transplantation‐lymphoma working party

Whilst autologous stem cell transplantation (auto‐SCT) is considered standard of care for relapsed/refractory classical Hodgkin lymphoma, the role of auto‐SCT in nodular lymphocyte‐predominant Hodgkin lymphoma (NLPHL) is not well defined due to limited data. We report the first study on auto‐SCT for NLPHL with a larger cohort. Eligible for this retrospective registry study were patients reported to the EBMT between 2003 and 2013, aged 18 or older with relapsed/refractory NLPHL who underwent first auto‐SCT with disease chemosensitive to salvage therapy. NLPHL transformed to diffuse large B cell lymphoma were excluded. Sixty patients (83% male; median age 40 years) met the eligibility criteria. The median time between diagnosis and transplant was 21 months (IQR 13–58), and the median number of prior treatment lines was 2 (range 1–5), including rituximab in 63% of the patients. At auto‐SCT, 62% of the patients were in complete remission (CR) and 38% in partial remission. Seventy‐two percent of the patients received BEAM as high‐dose therapy. With a median follow‐up of 56 months (range 3–105), 5‐year progression‐free and overall survival (OS) were 66% and 87%, respectively. Univariate comparisons considering age, time from diagnosis to transplant, prior chemotherapy lines, and prior rituximab use failed to identify significant predictors for any survival endpoint except for being in CR at the time of auto‐SCT (vs PR, P = .049) for OS. Auto‐SCT in patients with relapsed/refractory NLPHL who are sensitive to salvage therapy gives excellent disease control and long‐term survival independent of the time interval between diagnosis and transplant.