High Local Concentrations of Intradermal MSCs Restore Skin Integrity and Facilitate Wound Healing in Dystrophic Epidermolysis Bullosa

Dystrophic epidermolysis bullosa (DEB) is an incurable skin fragility disorder caused by mutations in the COL7A1 gene, coding for the anchoring fibril protein collagen VII (C7). Life-long mechanosensitivity of skin and mucosal surfaces is associated with large body surface erosions, chronic wounds, and secondary fibrosis that severely impede functionality. Here, we present the first systematic long-term evaluation of the therapeutic potential of a mesenchymal stromal cell (MSC)-based therapy for DEB. Intradermal administration of MSCs in a DEB mouse model resulted in production and deposition of C7 at the dermal-epidermal junction, the physiological site of function. The effect was dose-dependent with MSCs being up to 10-fold more potent than dermal fibroblasts. MSCs promoted regeneration of DEB wounds via normalization of dermal and epidermal healing and improved skin integrity through de novo formation of functional immature anchoring fibrils. Additional benefits were gained by MSCs'' anti-inflammatory effects, which led to decreased immune cell infiltration into injured DEB skin. In our setting, the clinical benefit of MSC injections lasted for more than 3 months. We conclude that MSCs are viable options for localized DEB therapy. Importantly, however, the cell number needed to achieve therapeutic efficacy excludes the use of systemic administration.     

Association of Oversized Tracheal Tubes and Cuff Overinsufflation With Postintubation Tracheal Ruptures

Objectives

Postintubation tracheal ruptures (PTR) are rare but cause severe complications. Our objective was to investigate the tracheal pattern of injury resulting from cuff inflation of the tracheal tube, to study the two main factors responsible for PTR (cuff overinsufflation and inapplicable tube sizes), and to explain the context, why small women are particularly susceptible to PTR.

Methods

Experimental study performed on 28 fresh human laryngotracheal specimens (16 males, 12 females) within 24 hours post autopsy. Artificial ventilation was simulated by using an underwater construction and a standard tracheal tube. Tube sizes were selected according to our previously published nomogram. Tracheal lesions were detected visually and tracheal diameters measured. The influence of body size, sex difference and appropriate tube size were investigated according to patient height.

Results

In all 28 cases, the typical tracheal lesion pattern was a longitudinal median rupture of the posterior trachea. Appropriate tube sizes according to body size caused PTR with significantly higher cuff pressure when compared with oversized tubes. An increased risk of PTR was found in shorter patients, when oversized tubes were used. Sex difference did not have any significant influence.

Conclusion

This experimental model provides information about tracheal patterns in PTR for the first time. The model confirms by experiment the observations of case series in PTR patients, and therefore emphasizes the importance of correct tube size selection according to patient height. This minimizes the risk of PTR, especially in shorter patients, who have an increased risk of PTR when oversized tubes are used.     

Histomorphometric Assessment of Cancellous and Cortical Bone Material Distribution in the Proximal Humerus of Normal and Osteoporotic Individuals: Significantly Reduced Bone Stock in the Metaphyseal and Subcapital Regions of Osteoporotic Individuals

Osteoporosis is a systemic disorder predominantly affecting postmenopausal women but also men at an advanced age. Both genders may suffer from low-energy fractures of, for example, the proximal humerus when reduction of the bone stock or/and quality has occurred.The aim of the current study was to compare the amount of bone in typical fracture zones of the proximal humerus in osteoporotic and non-osteoporotic individuals.The amount of bone in the proximal humerus was determined histomorphometrically in frontal plane sections. The donor bones were allocated to normal and osteoporotic groups using the T-score from distal radius DXA measurements of the same extremities. The T-score evaluation was done according to WHO criteria. Regional thickness of the subchondral plate and the metaphyseal cortical bone were measured using interactive image analysis.At all measured locations the amount of cancellous bone was significantly lower in individuals from the osteoporotic group compared to the non-osteoporotic one. The osteoporotic group showed more significant differences between regions of the same bone than the non-osteoporotic group. In both groups the subchondral cancellous bone and the subchondral plate were least affected by bone loss. In contrast, the medial metaphyseal region in the osteoporotic group exhibited higher bone loss in comparison to the lateral side.This observation may explain prevailing fracture patterns, which frequently involve compression fractures and certainly has an influence on the stability of implants placed in this medial region. It should be considered when planning the anchoring of osteosynthesis materials in osteoporotic patients with fractures of the proximal humerus.     

Dopamine D2 receptor agonists inhibit lung cancer progression by reducing angiogenesis and tumor infiltrating myeloid derived suppressor cells

We sought to determine whether Dopamine D2 Receptor (D2R) agonists inhibit lung tumor progression and identify subpopulations of lung cancer patients that benefit most from D2R agonist therapy. We demonstrate D2R agonists abrogate lung tumor progression in syngeneic (LLC1) and human xenograft (A549) orthotopic murine models through inhibition of tumor angiogenesis and reduction of tumor infiltrating myeloid derived suppressor cells. Pathological examination of human lung cancer tissue revealed a positive correlation between endothelial D2R expression and tumor stage. Lung cancer patients with a smoking history exhibited greater levels of D2R in lung endothelium. Our results suggest D2R agonists may represent a promising individualized therapy for lung cancer patients with high levels of endothelial D2R expression and a smoking history.     

Primary Synovial Cell Sarcoma of the Kidney: Case Report and Review of the Literature

Synovial cell sarcoma (SCS) of the kidney is a rare tumor entity with a poor prognosis. Morphologic and immunohistochemical characteristics may overlap with other more common neoplasms of the kidney. Therefore, the diagnosis of primary renal SCS not only requires the exclusion of similar tumor types, but also a confirmation of SYT-SSX gene fusion using molecular techniques. The treatment comprises radical surgery, and, depending on age and health status, adjuvant chemotherapy in selected patients. Here, we present an elderly SCS patient in whom straightforward radical surgical treatment resulted in a sustained complete remission; it allowed us to perform a literature survey focusing on current diagnostic tools for SCS.Key Words: Renal synovial cell sarcoma, Renal spindle cell tumor, SYT-SSX gene fusion, SYT gene rearrangement, Transducin-like enhancer of split 1     

The metastatic infiltration at the metastasis/brain parenchyma-interface is very heterogeneous and has a significant impact on survival in a prospective study

The current approach to brain metastases resection is macroscopic removal of metastasis until reaching the glial pseudo-capsule (gross total resection (GTR)). However, autopsy studies demonstrated infiltrating metastatic cells into the parenchyma at the metastasis/brain parenchyma (M/BP)-interface. Aims/Methods: To analyze the astrocyte reaction and metastatic infiltration pattern at the M/BP-interface with an organotypic brain slice coculture system. Secondly, to evaluate the significance of infiltrating metastatic tumor cells in a prospective biopsy study. Therefore, after GTR, biopsies were obtained from the brain parenchyma beyond the glial pseudo-capsule and analyzed histomorphologically. Results: The coculture revealed three types of cancer cell infiltration. Interestingly, the astrocyte reaction was significantly different in the coculture with a benign, neuroectodermal-derived cell line. In the prospective biopsy study 58/167 (34.7%) samples revealed infiltrating metastatic cells. Altogether, 25/39 patients (64.1%) had proven to exhibit infiltration in at least one biopsy specimen with significant impact on survival (OS) (3.4 HR; p = 0.009; 2-year OS was 6.6% versus 43.5%). Exceptionally, in the non-infiltrating cohort three patients were long-term survivors. Conclusions: Metastatic infiltration has a significant impact on prognosis. Secondly, the astrocyte reaction at the M/BP-interface is heterogeneous and supports our previous concept of the organ-specific defense against metastatic (organ-foreign) cells.     

SA2RAGE: a new sequence for fast B1+ -mapping

At high magnetic field strengths (≥ 3T), the radiofrequency wavelength used in MRI is of the same order of magnitude of (or smaller than) the typical sample size, making transmit magnetic field (B1+) inhomogeneities more prominent. Methods such as radiofrequency-shimming and transmit SENSE have been proposed to mitigate these undesirable effects. A prerequisite for such approaches is an accurate and rapid characterization of the B1+ field in the organ of interest. In this work, a new phase-sensitive three-dimensional B1+-mapping technique is introduced that allows the acquisition of a 64 × 64 × 8 B1+-map in ≈ 20 s, yielding an accurate mapping of the relative B1+ with a 10-fold dynamic range (0.2-2 times the nominal B1+). Moreover, the predominant use of low flip angle excitations in the presented sequence minimizes specific absorption rate, which is an important asset for in vivo B1+-shimming procedures at high magnetic fields. The proposed methodology was validated in phantom experiments and demonstrated good results in phantom and human B1+-shimming using an 8-channel transmit-receive array.     

Synthesis and evaluation of a C-6 alkylated pyrimidine derivative for the in vivo imaging of HSV1-TK gene expression

IntroductionWe report on the synthesis, radiolabeling, in vitro and in vivo characterization of N-Me-[¹⁸F]FHBT (6-(3-[¹⁸F]fluoro-2-(hydroxymethyl)propyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione), a C-6-substituted N-1-methylated pyrimidine derivative as a reporter probe for imaging herpes simplex virus type 1 thymidine kinase (HSV1-TK) expression.MethodsN-Me-[¹⁸F]FHBT was synthesized via a standard nucleophilic substitution reaction followed by acidic cleavage of the methoxytrityl protecting group. Cell uptake was studied in vitro with control HEK293 (human embryonic kidney cells) and HEK293 cells stably transfected with nonmutant HSV1-tk (HEK293TK+ cells). Positron emission tomography (PET) imaging and biodistribution studies of N-Me-[¹⁸F]FHBT or [¹⁸F]FHBG were performed in nude mice bearing xenografts of HEK293 control and TK+ cells.ResultsN-Me-[¹⁸F]FHBT was obtained in a two-step reaction in an overall maximal radiochemical yield (decay-corrected) of 5% and a radiochemical purity >96%. The tracer uptake in HSV1-TK containing HEK293TK+ cells was 14.5 times (at 30 min) and 55.4 times (at 240 min) higher than in control HEK293 cells. In mice, N-Me-[¹⁸F]FHBT and [¹⁸F]FHBG accumulated significantly and exhibited similar radioactivity levels in the HEK293TK+ xenografts; however, standardized uptake values ratios between HEK293TK+ and HEK293 control xenografts were higher for [¹⁸F]FHBG than for N-Me-[¹⁸F]FHBT. Both tracers showed high gall bladder and abdominal activity.ConclusionThe biological evaluations demonstrated the feasibility of using N-methylated C-6-substituted pyrimidine derivative N-Me-[¹⁸F]FHBT as a PET radiotracer for monitoring HSV1-TK expression in vivo.     

Publication rate of abstracts presented at the Annual Congress of the German Society of Orthopaedics and Trauma Surgery

Introduction  

The quality of abstracts presented at medical conferences reflects the scientific activity in the organisations involved. The aims of this study were to evaluate the publication rate of studies presented at the annual congress of the German Society of Orthopaedics and Trauma Surgery and to investigate predictive factors for publication. The results were to be compared with other international meetings.