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.     

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.     

The Impact of IMRT and Proton Radiotherapy on Secondary Cancer Incidence

BACKGROUND AND PURPOSE: There is concern about the increase of radiation-induced malignancies with the application of modern radiation treatment techniques such as intensity-modulated radiotherapy (IMRT) and proton radiotherapy. Therefore, X-ray scatter and neutron radiation as well as the impact of the primary dose distribution on secondary cancer incidence are analyzed. MATERIAL AND METHODS: The organ equivalent dose (OED) concept with a linear-exponential and a plateau dose-response curve was applied to dose distributions of 30 patients who received radiation therapy of prostate cancer. Three-dimensional conformal radiotherapy was used in eleven patients, another eleven patients received IMRT with 6-MV photons, and eight patients were treated with spot-scanned protons. The treatment plans were recalculated with 15-MV and 18-MV photons. Secondary cancer risk was estimated based on the OED for the different treatment techniques. RESULTS: A modest increase of 15% radiation-induced cancer results from IMRT using low energies (6 MV), compared to conventional four-field planning with 15-MV photons (plateau dose-response: 1%). The probability to develop a secondary cancer increases with IMRT of higher energies by 20% and 60% for 15 MV and 18 MV, respectively (plateau dose-response: 2% and 30%). The use of spot-scanned protons can reduce secondary cancer incidence as much as 50% (independent of dose-response). CONCLUSION: By including the primary dose distribution into the analysis of radiation-induced cancer incidence, the resulting increase in risk for secondary cancer using modern treatment techniques such as IMRT is not as dramatic as expected from earlier studies. By using 6-MV photons, only a moderate risk increase is expected. Spot-scanned protons are the treatment of choice in regard to secondary cancer incidence.     

Continuously moving table 3D MRI with lateral frequency-encoding direction.

A method is presented for 3D MRI in an extended field of view (FOV) based on continuous motion of the patient table and an efficient acquisition scheme. A gradient-echo MR pulse sequence is applied with lateral (left-right (L/R)) frequency-encoding direction and slab selection along the direction of motion. Compensation for the table motion is achieved by a combination of slab tracking and data alignment in hybrid space. The method allows fast k-space coverage to be achieved, especially when a short sampling FOV is chosen along the direction of table motion, as is desirable for good image quality. The method can be incorporated into different acquisitions schemes, including segmented k-space scanning, which allows for contrast variation with the use of magnetization preparation. Head-to-toe images of volunteers were obtained with good quality using 3D spoiled gradient-echo sequences. As an example of magnetization-prepared imaging, fat/water separated images were acquired using chemical shift selective (CHESS) presaturation pulses.     

Incidence and Prognosis of Organ Failure in Severely Injured Children and Adult Patients

Abstract Background: Does there exist a difference in the outcome of severely injured children and severely injured healthy adults? Methods: The data of 1,566 severely injured patients, treated between May 1998 and December 2002 in our emergency department of the University Essen/Germany, were analyzed. Patients with an injury severity score (ISS) > 24 were included in the present study. Patients younger as 18 (17) years were located to the children group c. Patients aged 18 and up to the age of 54 were included in the adult group a. Results: Fifty-four children and 252 adults met the selection criteria. ISS and the Glasgow coma scale (GCS) before intubation were not statistically different in both groups. Seriously injured children stayed significantly shorter on the intensive care unit, required significantly less ventilator days. Furthermore, the incidence of single organ failure (SOF) and multiple organ failure (MOF) was significantly lower in the children group. Mortality in the children group (29.6%) was lower than that in the adult group (33.7%). There was no death due to MOF in the children group as compared to 2.4% (n = 6) in the adults. Conclusion: The incidence of SOF and MOF was significantly lower in the children group although there was no difference in ISS, GCS and injury patterns. The prognosis of severely injured children was found to be better than those of adults. Moreover, there was no death due to MOF in the children group.