The PerPAIN trial: a pilot randomized controlled trial of personalized treatment allocation for chronic musculoskeletal pain-a protocol.

BACKGROUND: The therapy of chronic musculoskeletal pain (CMSP) is complex and the treatment results are often insufficient despite numerous therapeutic options. While individual patients respond very well to specific interventions, other patients show no improvement. Personalized treatment assignment offers a promising approach to improve response rates; however, there are no validated cross-disease allocation algorithms available for the treatment of chronic pain in validated personalized pain interventions. This trial aims to test the feasibility and safety of a personalized pain psychotherapy allocation with three different treatment modules and estimate initial signals of efficacy and utility of such an approach compared to non-personalized allocation. METHODS: This is a randomized, controlled assessor-blinded pilot trial with a multifactorial parallel arm design. CMSP patients (n = 105) will be randomly assigned 1:1 to personalized or non-personalized treatment based on a cluster assignment of the West Haven-Yale Multidimensional Pain Inventory (MPI). In the personalized assignment condition, patients with high levels of distress receive an emotional distress-tailored intervention, patients with pain-related interference receive an exposure/extinction-tailored treatment intervention and patients who adapt relatively well to the pain receive a low-level smartphone-based activity diary intervention. In the control arm, patients receive one of the two non-matching interventions. Effect sizes will be calculated for change in core pain outcome domains (pain intensity, physical and emotional functioning, stress experience, participant ratings of improvement and satisfaction) after intervention and at follow-up. Feasibility and safety outcomes will assess rates of recruitment, retention, adherence and adverse events. Additional data on neurobiological and psychological characteristics of the patients are collected to improve treatment allocation in future studies. CONCLUSION: Although the call for personalized treatment approaches is widely discussed, randomized controlled trials are lacking. As the personalization of treatment approaches is challenging, both allocation and intervention need to be dynamically coordinated. This study will test the feasibility and safety of a novel study design in order to provide a methodological framework for future multicentre RCTs for personalized pain psychotherapy. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00022792 ( https://www.drks.de ). Prospectively registered on 04/06/2021.

Epidemiology and reporting of osteoporotic vertebral fractures in patients with long-term hospital records based on routine clinical CT imaging.

Osteoporotic vertebral fractures signify an increased risk of future fractures and mortality and can manifest the diagnosis of osteoporosis. We investigated the prevalence of vertebral fractures in routine CT of patients with long-term hospital records. Three out of ten patients showed osteoporotic vertebral fractures (VFs) corresponding to the highest rates reported in European population-based studies. INTRODUCTION: VFs are a common manifestation of osteoporosis, which influences future fracture risk. Their epidemiology has been investigated in population-based studies. However, few studies report the prevalence of osteoporotic VF in patients seen in clinical routine and include all common fracture levels of the thoracolumbar spine. The purpose of this study was to investigate the prevalence of osteoporotic VF in patients with CT scans and long-term hospital records and identify clinical factors associated with prevalent VFs. METHODS: All patients aged 45 years and older with a CT scan and prior hospital record of at least 5 years that were seen in the study period between September 2008 and May 2017 were reviewed. Imaging requirements were a CT scan with sagittal reformations including at least T6-L4. Patients with multiple myeloma were excluded. Fracture reading was performed using the Genant semi-quantitative method. Medical notes were reviewed for established diagnoses of osteoporosis and clinical information. Clinical factors (e.g. drug intake, chemotherapy, and mobility level) associated with prevalent VF were identified in logistic regression. RESULTS: The study population consisted of 718 patients (228 women and 490 men; mean age 69.3 ± 10.1 years) with mainly cancer staging and angiography CT imaging. The overall prevalence of VFs was 30.5%, with non-significantly more men showing a fracture (32.5%) compared to women (26.3%; p > 0.05). Intake of metamizole for ≥ 3 months was significantly associated with a prevalent VF. Medical records did not include information about bone health in 90% of all patients. CT reports did mention a VF in only 24.7% of patients with a prevalent VF on CT review. CONCLUSION: Approximately 30% of elderly patients with CT imaging and long-term hospital records showed VFs. Only one-quarter of these patients had VFs mentioned in CT reports. Osteoporosis management could be improved by consequent reporting of VFs in CT, opportunistic bone density measurements, and early involvement of fracture liaison services.

[Tumor vaccines-therapeutic vaccination against cancer]. / Tumorvakzinierung ­ therapeutische Vakzinierung gegen Krebs.

Tumor cells always exhibit differences to normal cells. These differences can be recognized by the immune system, enabling the destruction of tumor cells by T cells, as was impressively demonstrated by the success of immune checkpoint inhibition, e.g., in malignant melanoma. Many cancers, however, do not respond to this kind of therapy. In these cases, vaccination against tumor antigens could be very helpful. Nevertheless, all of the efforts made in this respect during the past 30 years have been virtually futile. With current knowledge and technology there is new hope.

Prevalence and risk factors of smell dysfunction - a comparison between five German population-based studies.

BACKGROUND: The prevalence of olfactory impairment increases with age and is known to be an early sign of different neurodegenerative diseases. Only few population-based studies examined the prevalence of olfactory impairment and comparisons across studies are scarce. Aim of this analysis was to compare the prevalence and determinants of normosmia across five population based studies in Germany. METHODOLOGY: Data from five population-based, cross-sectional studies were included. They were independently conducted and used the same test system (Sniffin' Sticks Screening 12) to measure olfactory function. This system consists of 12 odor-dispensing felt-tip pens; the task is a forced-choice selection among four alternative odors per pen. Sociodemographic information and comorbidities were assessed in face-to-face interviews. Univariate, descriptive statistics and multivariable logistic regression models stratified by study, were performed to determine risks, i.e. prevalence odds ratios, associated with olfactory function. RESULTS: The prevalence of normosmic participants varied considerably across studies. Olfactory function was lower in men, decreased with age, and increased with higher education. Several individual comorbidities and a comorbidity index were associated with olfactory dysfunction. Recognition performance for three of the 12 pens was especially low in all studies. CONCLUSION: Four factors, well known to describe population composition, contribute to explain differences in the prevalence of olfactory function between studies when the same test system is used. Our results indicate that comorbidities and educational level should always be considered when test systems based on smell recognition are used in population-based studies.

X-ray-based quantitative osteoporosis imaging at the spine.

Osteoporosis is a metabolic bone disease with a high prevalence that affects the population worldwide, particularly the elderly. It is often due to fractures associated with bone fragility that the diagnosis of osteoporosis becomes clinically evident. However, early diagnosis would be necessary to initiate therapy and to prevent occurrence of further fractures, thus reducing morbidity and mortality. X-ray-based imaging plays a key role for fracture risk assessment and monitoring of osteoporosis. Whereas over decades dual-energy X-ray absorptiometry (DXA) has been the main method used and still reflects the reference standard, another modality reemerges with quantitative computed tomography (QCT) because of its three-dimensional advantages and the opportunistic exploitation of routine CT scans. Against this background, this article intends to review and evaluate recent advances in the field of X-ray-based quantitative imaging of osteoporosis at the spine. First, standard DXA with the recent addition of trabecular bone score (TBS) is presented. Secondly, standard QCT, dual-energy BMD quantification, and opportunistic BMD screening in non-dedicated CT exams are discussed. Lastly, finite element analysis and microstructural parameter analysis are reviewed.

The evaluation and brain representation of pleasant touch in chronic and subacute back pain.

If touch is perceived as pleasant, it can counteract the experience of pain. However, its pain-inhibitory function might be disturbed in chronic pain and this could contribute to pain-related interference. We investigated the perception of pleasant touch and its brain correlates in chronic back pain patients (CBP) compared to subacute back pain patients (SABP) and healthy controls (HC) using soft brush strokes. CBP showed less positive evaluations of touch. We found the highest activation in somatosensory and insular cortices in CBP, ventral striatum (VS) in SABP, and the orbitofrontal cortex in HC. Brain responses were significantly positively correlated with pleasantness ratings in HC and SABP, but not CBP. Further, the insula responses in CBP were positively correlated with pain-related interference and the VS activation in SABP correlated negatively with affective distress. Brain and behavioral changes in the processing of touch and its pleasantness may be a marker of pain chronicity and raise questions about the therapeutic value of pleasant touch in pain prevention and treatment.

Opportunistic osteoporosis screening in multi-detector CT images via local classification of textures.

Our study proposed an automatic pipeline for opportunistic osteoporosis screening using 3D texture features and regional vBMD using multi-detector CT images. A combination of different local and global texture features outperformed the global vBMD and showed high discriminative power to identify patients with vertebral fractures. INTRODUCTION: Many patients at risk for osteoporosis undergo computed tomography (CT) scans, usable for opportunistic (non-dedicated) screening. We compared the performance of global volumetric bone mineral density (vBMD) with a random forest classifier based on regional vBMD and 3D texture features to separate patients with and without osteoporotic fractures. METHODS: In total, 154 patients (mean age 64 ± 8.5, male; n = 103) were included in this retrospective single-center analysis, who underwent contrast-enhanced CT for other reasons than osteoporosis screening. Patients were dichotomized regarding prevalent vertebral osteoporotic fractures (noFX, n = 101; FX, n = 53). Vertebral bodies were automatically segmented, and trabecular vBMD was calculated with a dedicated phantom. For 3D texture analysis, we extracted gray-level co-occurrence matrix Haralick features (HAR), histogram of gradients (HoG), local binary patterns (LBP), and wavelets (WL). Fractured vertebrae were excluded for texture-feature and vBMD data extraction. The performance to identify patients with prevalent osteoporotic vertebral fractures was evaluated in a fourfold cross-validation. RESULTS: The random forest classifier showed a high discriminatory power (AUC = 0.88). Parameters of all vertebral levels significantly contributed to this classification. Importantly, the AUC of the proposed algorithm was significantly higher than that of volumetric global BMD alone (AUC = 0.64). CONCLUSION: The presented classifier combining 3D texture features and regional vBMD including the complete thoracolumbar spine showed high discriminatory power to identify patients with vertebral fractures and had a better diagnostic performance than vBMD alone.

Quantitative analysis of backscattered electron (BSE) contrast using low voltage scanning electron microscopy (LVSEM) and its application to Al0.22Ga0.78N/GaN layers.

A novel method to quantify and predict the material contrast using Backscattered Electron (BSE) imaging in Scanning Electron Microscopy (SEM) is presented while using low primary electron beam energies (Ep). In this study, the parameters for BSE imaging in Low Voltage Scanning Electron Microscopy (LVSEM) are optimized for the layer system Al0.22Ga0.78N/GaN, which is typically used in High Electron Mobility Transistors (HEMTs). The layers are imaged at high resolution and the compounds are identified based on the quantitative BSE material contrast between Al0.22Ga0.78N and GaN. The quantification process described in this study is based on an analytical description that predicts the material contrast using a function that correlates the effective backscattering coefficient (η) with the atomic number Z.

New perspectives on the roles of pyrimidines in the central nervous system.

Since 1956, when exogenous uridine and cytidine were found to be necessary for the maintenance of perfused rat brain function, the co-existence of de novo synthesis, salvage pathways and removal of pyrimidine bases in the CNS has been a controversial subject. Here, we review studies on metabolites and enzymes of pyrimidine metabolism through more than 60 years. In view of known and newly-described inherited pyrimidine and purine disorders - some with complex clinical profiles of neurological impairments - we underline the necessity to investigate how the different pathways work together in the developing brain and then sustain plasticity, regeneration and neuro-transmission in the adult CNS. Experimentally, early incorporation studies in animal brain slices and homogenates with radio-labelled nucleosides or precursors demonstrated salvage activity or de novo synthesis. Later, the nucleoside transporters and organic anionic transporters underlying uptake of metabolites and anti-pyrimidine drugs in the CNS were identified. Recently, the expression of de novo enzymes in glial cells and neurons was verified using (immuno) histochemical and in-situ-hybridization techniques. Adult brain was shown to take up or produce all pyrimidine (deoxy) ribonucleosides or, after uptake and phosphorolysis of nucleosides, to make use of ribose for different purposes, including energy. More recently, non-canonical pyrimidine bases (5mC, 5hmC) have been found most notably in brain, pointing to considerable postreplicative DNA metabolism, with the need for pyrimidine-specific enzymes. Even more perspectives are emerging, with advances in genome analysis and in the manipulation of expression from the gene.

Orotate (orotic acid): An essential and versatile molecule.

Orotate (OA) is well-known as a precursor in biosynthesis of pyrimidines; in mammals it is released from the mitochondrial dihydroorotate dehydrogenase (DHODH) for conversion to UMP by the cytoplasmic UMP synthase enzyme. OA is also a normal part of the diet, being found in milk and dairy products, and it is converted to uridine for use in the pyrimidine salvage pathway predominantly in liver, kidney and erythrocytes. Early research into nutrition identified orotate as "vitamin B13," and its use as a complex with organic cations or metal ions was promulgated in body-building, and in assisting therapies of metabolic syndromes. It has recently been established that the amelioration of gout by dairy products arises from the competition of orotate and urate at the hURAT1 transporter. The orotic aciduria that arises in children with defective UMP synthase can be rescued by oral uridine therapy, since UMP is the end-product and also a feedback inhibitor of the de novo pathway. In contrast, Miller (dysmorphology) syndrome is connected with defects in DHODH, and hence in the supply of OA, and cannot be helped by uridine. Other models of dysmorphisms are connected with enzymes early in the pyrimidine de novo pathway. We conclude that the OA molecule is itself required for the regulation of genes that are important in the development of cells, tissues and organisms.

Clinical, pathological and genetic features of follicular lymphoma grade 3A: a joint analysis of the German low-grade and high-grade lymphoma study groups GLSG and DSHNHL.

BACKGROUND: Histologically, follicular lymphoma (FL) grades 1, 2 and 3A are composed of two distinct cell types, centroblasts and centrocytes. FL grade 3B is composed only of centroblasts and has been shown to differ in immunophenotype and genetics from FL that contain centrocytes. We aimed to understand the pathogenetic and clinical relation between FL grade 3A to FL grade 1/2 on the one hand and FL grade 3B on the other hand. PATIENTS AND METHODS: Trial patients with long-term follow-up and diagnosis of FL grade 3 were selected and samples underwent a second central pathological review using a multiple-observer approach to assess grading. RESULTS: Interobserver variability for diagnosing FL grade 3 was high. FL grade 3A frequently harbored areas of FL grade 1/2 within the same tissue specimen. FL grade 3B rarely coexisted with grade 1/2 or 3A, suggesting divergent pathogenesis. There was no statistically significant difference in outcome between 47 cases of FL grade 3A and 14 cases of grade 3B. Compared with grade 1/2 FL, both groups showed longer progression-free survival without late events, especially after immunochemotherapy; this outcome difference was retained after adjustment for clinical prognostic factors. The subgroup of FL grade 3A with an additional FL grade 1/2 component or a translocation t(14;18) showed a poorer outcome. In contrast, the FL grade 3A lacking t(14;18) and of localized stage resembled the pediatric type of FL and showed a very good outcome. FL3 with MYC breaks showed a poor outcome. CONCLUSIONS: The results suggest that first-line immunochemotherapy might allow long-lasting remissions in a subgroup of FL grade 3A similar to diffuse large B-cell lymphoma. Within FL3A, prognostic subgroups can be identified by analyzing for coexisting FL1/2 and MYC breaks.

Suffering as an independent component of the experience of pain.

BACKGROUND: Pain has consistently been viewed as containing two dimensions, a sensory (intensity) and an emotional (unpleasantness). It has been suggested that pain involves higher order cognitive processes that go beyond unpleasantness. We therefore aimed at extending the assessment of pain by introducing an additional dimension of pain-related suffering and identifying noxious stimulation protocols that are most adequate for its psychophysical and psychophysiological characterization. METHODS: Twenty-four healthy volunteers received separate series of tonic and phasic noxious mechanical stimuli. Visual analogue scales were used to rate intensity, unpleasantness and suffering and psychophysiological measurements such as heart rate, skin conductance and corrugator electromyography were recorded. Acoustically evoked startle responses were measured in part of the assessments to obtain additional indicators of pain aversiveness. RESULTS: Spearman's correlation coefficients and partial correlations analyses as well as principal component analyses confirmed that suffering constitutes an integral component of pain processing that is distinct from intensity and unpleasantness. Tonic, rather than phasic, stimulation method was more effective in eliciting pain and suffering and under this condition startle responses where higher during long compared to short stimuli. CONCLUSIONS: These results suggest that in acute pain, suffering is a constitutive dimension that might even be more crucial in clinical states of pain.

Enteral nutrition is associated with improved outcome in patients with severe sepsis. A secondary analysis of the VISEP trial.

INTRODUCTION: The optimal nutritional strategy remains controversial, particularly in severely septic patients. Our aim was to analyze the effect of three nutritional strategies--enteral (EN), parenteral (PN), and combined nutrition (EN+PN)--on the outcome of patients with severe sepsis or septic shock. PATIENTS AND METHODS: This secondary analysis of the prospective, randomized-controlled, multicenter "Intensive Insulin Therapy and Pentastarch Resuscitation in Severe Sepsis (VISEP)" trial only included patients with a length of stay in the intensive care unit (ICU) of more than 7 days. Besides patient characteristics, data on nutrition therapy were collected daily for up to 21 days. Morbidity as measured by the mean Sequential Organ Failure Assessment (SOFA) score, incidence of secondary infections, renal replacement therapy, ventilator-free days and severe hypoglycemia, length of ICU stay, and mortality at 90 days were compared between the three nutritional strategies. RESULTS: In all, 353 patients were included in the analysis with the majority (68.5 %) receiving EN+PN, 24.4 % receiving EN, and only 7.1 % receiving PN. Median caloric intake was 918 kcal/day (EN), 1,210 kcal/day (PN), and 1,343 kcal/day (EN+PN; p < 0.001). In the latter group, calories were predominantly administered via the parenteral route within the first week. The rate of death at 90 days was lower with EN than with EN+PN (26.7 % vs. 41.3 %, p = 0.048), as was the rate of secondary infections, renal replacement therapy, and duration of mechanical ventilation. In the adjusted Cox regression analysis, the effect on mortality [hazard ratio (HR)= 1.86, 95 % confidence interval (CI): 1.16-2.98, p = 0.010] and the rate of secondary infections (HR= 1.89, 95 % CI: 1.27-2.81, p = 0.002) remained different between EN and EN+PN. CONCLUSION: In patients with severe sepsis or septic shock and prolonged ICU stay, EN alone was associated with improved clinical outcome compared to EN+PN. This hypothesis-generating result has to be confirmed by a randomized-controlled trial in this specific patient population.

[Enrolment of intensive care patients in clinical studies. Ethical, legal and organizational problems from an interdisciplinary point of view]. / Der Einschluss von Intensivpatienten in klinische Studien. Ethische, rechtliche und organisatorische Probleme aus interdisziplinärer Sicht.

Nowadays, most patients in hospital die in the intensive care unit from sepsis and multiple organ failure. Clinical research in this critically ill and vulnerable patient population bears a lot of ethical and legal problems; however, it remains a must in order to develop evidence-based diagnostic and therapeutic strategies for life-threatening diseases with special respect to limited health care resources. With regard to the Declaration of Helsinki, good clinical practice guidelines (GCP) from the European Medicines Agency (EMA) and the German medical drug law (AMG) this article discusses ethical and legal aspects of patient inclusion for clinical trials as well as incentives for appropriate patient recruitment from an interdisciplinary point of view.

Rapamycin-induced impaired wound healing is associated with compromised tissue lactate accumulation and extracellular matrix remodeling.

INTRODUCTION: Extracellular matrix (ECM) remodeling involving matrix metalloproteinases (MMPs) and wound lactate accumulation are essential elements of tissue repair. The aim of this study was to investigate whether rapamycin-induced impaired healing is associated with compromised wound fluid lactate accumulation and altered ECM remodeling. METHODS: Polyvinyl alcohol sponges were subcutaneously implanted in male C57/BL6 mice. Animals were randomized to daily intraperitoneal treatment with either vehicle or 1.5 mg/kg rapamycin. After 7 or 14 days, sponges were harvested to collect wound fluid for subsequent analyses. Wounds were excised for assessment of tensile strength. RESULTS: After 7 days, wound hydroxyproline content was significantly decreased due to rapamycin therapy, whereas the observed difference in tensile strength marginally failed to show statistical significance. In addition, rapamycin reduced wound lactate accumulation and enhanced MMP-2 protein expression, and both MMP-2 and MMP-9 activity. At day 14, wound tensile strength and hydroxyproline content were significantly lower along with an increase in MMP-2 and MMP-9 activity in rapamycin-treated mice. Similarly, wound fluid lactate concentration and MMP-2 protein expression were found to be persistently decreased and increased, respectively. CONCLUSIONS: Rapamycin affects tissue repair by interfering with fundamental mechanisms involved in healing, namely lactate accumulation and ECM remodeling.

Wound fluid lactate concentration: a helpful marker for diagnosing soft-tissue infection in diabetic foot ulcers? Preliminary findings.

AIMS: To investigate the impact of wound fluid lactate concentration on diagnosing soft-tissue infection in diabetic foot ulcers. METHODS: Lactate concentration in wound fluid obtained from diabetic foot ulcers was determined using a lactate analyser and compared with clinical examination findings. RESULTS: Overall median wound fluid lactate concentration was 21.03 mm (5.58-80.40 mm). Wound lactate levels were significantly higher in infected compared with non-infected diabetic foot ulcers (P=0.001). Non-infected diabetic foot ulcers that healed within 6 months of treatment showed a significantly lower wound fluid lactate concentration at baseline as opposed to those that did not heal (P=0.007). CONCLUSIONS: Non-healing diabetic foot ulcers are characterized by high wound fluid lactate levels. Assessment of wound fluid lactate concentration might be helpful for confirming the suspicion of soft tissue infection, particularly when clinical signs are atypical.

Robust determination of Young's modulus of individual carbon nanotubes by quasi-static interaction with Lorentz forces.

Young's modulus of an individual multi-wall carbon nanotube has been determined by the method of quasi-static transverse bending due to a Lorentz force observed in situ in a transmission electron microscope. The deflection of the nanotube allows the determination of Young's modulus using Euler-Bernoulli's beam equation. Because we determine the specific dependence of the deflection on the position along the nanotube axis, it is possible to gain insight into the type of mountings and furthermore allows for an estimation of the homogeneity of the nanotube. Both properties have been found to be of importance to determine Young's modulus. It was found to be higher by up to a factor of 1.6 compared to the value obtained by assuming rigid mountings.

Complementary therapy use in patients with glioma: an observational study.

OBJECTIVE: Despite novel multimodal therapeutic approaches, the vast majority of glial tumors are not curable. Patients may search for complementary therapies in order to contribute to the fight against their disease or to relieve symptoms induced by their brain tumor. The extent of the use of complementary or alternative therapies, the patients' rationale behind it, and the cost of complementary therapy for gliomas are not known. We used a questionnaire and the database of the German Glioma Network to evaluate these questions. METHODS: A total of 621 questionnaires were available for evaluation from patients with glial tumors of WHO grades II to grade IV. The patients were recruited from 6 neuro-oncologic centers in Germany. Complementary therapy was defined as methods or compounds not used in routine clinical practice and not scientifically evaluated. RESULTS: Forty percent of the responding patients reported the use of complementary therapies. Significant differences between the group of complementary therapy users and nonusers were seen with respect to age (younger > older), gender (female > male), and education (high education level > low education level). The motivation for complementary therapy use was not driven by unsatisfactory clinical care by the neuro-oncologists, but by the wish to add something beneficial to the standard of care. CONCLUSIONS: In clinical practice, patients' use of complementary therapies may be largely overseen and underestimated. The major motivation is not distrust in conventional therapies. Neuro-oncologists should be aware of this phenomenon and encourage an open but critical dialogue with their patients.

Mesenchymal stem cells in cartilage repair: state of the art and methods to monitor cell growth, differentiation and cartilage regeneration.

Degenerative joint diseases caused by rheumatism, joint dysplasia or traumata are particularly widespread in countries with high life expectation. Although there is no absolutely convincing cure available so far, hyaline cartilage and bone defects resulting from joint destruction can be treated today by appropriate transplantations. Recently, procedures were developed based on autologous chondrocytes from intact joint areas. The chondrocytes are expanded in cell culture and subsequently transplanted into the defect areas of the affected joints. However, these autologous chondrocytes are characterized by low expansion capacity and the synthesis of extracellular matrix of poor functionality and quality. An alternative approach is the use of adult mesenchymal stem cells (MSCs). These cells effectively expand in 2D culture and have the potential to differentiate into various cell types, including chondrocytes. Furthermore, they have the ability to synthesize extracellular matrix with properties mimicking closely the healthy hyaline joint cartilage. Beside a more general survey of the architecture of hyaline cartilage, its composition and the pathological processes of joint diseases, we will describe here which advances were achieved recently regarding the development of closed, aseptic bioreactors for the production of autologous grafts for cartilage regeneration based on MSCs. Additionally, a novel mathematical model will be presented that supports the understanding of the growth and differentiation of MSCs. It will be particularly emphasized that such models are helpful to explain the well-known fact that MSCs exhibit improved growth properties under reduced oxygen pressure and limited supply with nutrients. Finally, it will be comprehensively shown how different analytical methods can be used to characterize MSCs on different levels. Besides discussing methods for non-invasive monitoring and tracking of the cells and the determination of their elastic properties, mass spectrometric methods to evaluate the lipid compositions of cells will be highlighted.

Are patients with Hodgkin lymphoma and high-grade non-Hodgkin lymphoma in clinical therapy optimization protocols representative of these groups of patients in Germany?

BACKGROUND: Improvement of lymphoma therapy is largely driven by clinical therapy optimization protocols (TOPs). It is unclear, however, whether the patients treated in clinical TOP are representative for all patients. PATIENTS AND METHODS: TOP participants were compared with nonstudy patients in a population-based approach. The study included patients with Hodgkin lymphoma (HL) and high-grade non-Hodgkin lymphoma (hgNHL). Incident cases (N = 743) were ascertained in a large population-based epidemiologic survey. Each patient's status with respect to exclusion criteria of the pertinent TOP was abstracted from primary data sources. TOP participants were identified on the basis of the trial databases. Baseline characteristics and risk factor prevalence were compared between nonstudy and TOP patients. RESULTS: Eligible for the respective TOPs were 64.1% of all incident HL patients and 29.6% of all hgNHL patients in the population. Main exclusion criterion was age (HL: 15.2%; hgNHL: 27.4%). Only 71 HL patients (23.0%) and 11 hgNHL patients (3.4%) had actually been enrolled in the respective TOPs. CONCLUSIONS: TOP participants do not represent all patients with hgNHL and HL in the population. TOP inclusion criteria caused considerable selection among the participants. Further investigation is required to clarify possible limitations for the application of the outcomes observed in TOP patients for all patients with these diseases.