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Cancer peptide vaccination represents a promising therapeutic approach, but has been hampered by lack of suitable antigens and restricted applicability due to different HLA backgrounds of individual patients. We here introduce a novel warehouse-based concept for composition of personalized peptide vaccines and report on its successful application in a Phase II clinical trial in patients with chronic lymphocytic leukemia (CLL) after first-line therapy. 26 CLL patients in at least partial remission (PR) after 6 months of immuno-chemotherapy were vaccinated with a personalized vaccine compiled from a premanufactured peptide warehouse comprising immunopeptidome-defined CLL-associated peptides. Primary objective was evaluation of immunogenicity, secondary objectives were safety and minimal residual disease (MRD) response. Immunopeptidome-guided vaccine composition was throughout successful, proving the feasibility of warehouse-based vaccine design. Vaccination was well tolerated, with local injection site reactions being the most common adverse event. Only few patients showed vaccine-induced T cell responses, attributable to their inability to mount strong immune responses due to immune-chemotherapy and lack of potent adjuvant formulations. Both issues are addressed within a follow-up trial (NCT04688385), combining the immunopeptidome-guided warehouse-based vaccine design reported here with a potent novel adjuvant evaluating personalized multi- peptide vaccination in CLL patients under T cell supportive BTK inhibitor therapies.Clinical trial registrationwww.clinicaltrialsregister.eu, identifier NCT02802943.

IntroductionAcute myeloid leukemia (AML) has a dismal prognosis, mostly due to minimal residual disease-driven relapse, making an elimination of persisting therapy-resistant leukemia progenitor/stem cells (LPCs) the main goal for novel therapies. Peptide-based immunotherapy offers a low-side-effect approach aiming to induce T cell responses directed against human leukocyte antigen (HLA) presented tumor antigens on malignant cells by therapeutic vaccination. Mass spectrometry-based analysis of the naturally presented immunopeptidome of primary enriched LPC and AML samples enabled the selection of antigens exclusively expressed on LPC/AML cells, which showed de novo induction and spontaneous memory T cell responses in AML patients, and whose presentation and memory T cell recognition was associated with improved disease outcome.MethodsBased on these data the therapeutic vaccine AML-VAC-XS15 was designed, comprising two mutated HLA class I-restricted peptides from the common AML-specific mutation in NPM1 and seven HLA class II-restricted peptides (six non-mutated high-frequent AML/LPC-associated antigens and one mutated peptide from the AML-specific mutation R140Q in IDH2), adjuvanted with the toll like receptor 1/2 ligand XS15 and emulsified in Montanide ISA 51 VG. A phase I open label clinical trial investigating AML-VAC-XS15 was designed, recruiting AML patients in complete cytological remission (CR) or CR with incomplete blood count recovery. Patients are vaccinated twice with a six-week interval, with an optional booster vaccination four months after 2nd vaccination, and are then followed up for two years. The trial’s primary objectives are the assessment of the vaccine’s immunogenicity, safety and toxicity, secondary objectives include characterization of vaccine-induced T cell responses and assessment of preliminary clinical efficacy.Ethics and disseminationThe AML-VAC-XS15-01 study was approved by the Ethics Committee of the Bavarian State medical association and the Paul-Ehrlich Institut (P01392). Clinical trial results will be published in peer-reviewed journals.

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia among adults in Western countries. Despite the introduction of targeted therapies, including first-line Bruton’s tyrosine kinase inhibitor (BTKi) treatment, CLL remains largely incurable. Frequent disease relapses occur due to remaining treatment-resistant CLL cells, calling for novel therapies to eliminate minimal residual disease (MRD). Peptide-based vaccination targeting human leucocyte antigen (HLA)-presented CLL-associated antigens represents a promising, low-side-effect therapeutic option to optimize treatment responses and eliminate residual tumor cells by inducing an anti-leukemic immune response. The iVAC-XS15-CLL01 trial is an open-label, first-in-human (FIH) Phase I trial, evaluating the CLL-VAC-XS15 vaccine in CLL patients undergoing BTKi-based therapy. The vaccine was developed from HLA-presented CLL-associated antigen peptides, identified through comparative mass-spectrometry-based immunopeptidome analyses of CLL versus healthy samples in a previous study. To facilitate rapid and cost-effective deployment, vaccine peptides are selected for each patient from a pre-manufactured “peptide warehouse” based on the patient’s individual HLA allotype and CLL immunopeptidome. The trial enrolls 20 CLL patients, who receive up to three doses of the vaccine, adjuvanted with the toll-like-receptor (TLR) 1/2 ligand XS15 and emulsified in Montanide ISA 51 VG. The primary objective of the iVAC-XS15-CLL01 trial is to assess the safety and immunogenicity of the CLL-VAC-XS15 vaccine. Secondary objectives are to evaluate the vaccine impact on MRD, progression-free survival, and overall survival, as well as comprehensive immunophenotyping to characterize vaccine-induced T-cell responses. This Phase I trial aims to advance CLL treatment by enhancing immune-mediated disease clearance and guiding the design of subsequent Phase II/III trials to implement a new therapeutic strategy for CLL patients.

The DNAJB1-PRKACA fusion transcript was identified as the oncogenic driver of tumor pathogenesis in fibrolamellar hepatocellular carcinoma (FL-HCC), also known as fibrolamellar carcinoma (FLC), as well as in other tumor entities, thus representing a broad target for novel treatment in multiple cancer entities. FL-HCC is a rare primary liver tumor with a 5-year survival rate of only 45%, which typically affects young patients with no underlying primary liver disease. Surgical resection is the only curative treatment option if no metastases are present at diagnosis. There is no standard of care for systemic therapy. Peptide-based vaccines represent a low side-effect approach relying on specific immune recognition of tumor-associated human leucocyte antigen (HLA) presented peptides. The induction (priming) of tumor-specific T-cell responses against neoepitopes derived from gene fusion transcripts by peptide-vaccination combined with expansion of the immune response and optimization of immune function within the tumor microenvironment achieved by immune-checkpoint-inhibition (ICI) has the potential to improve response rates and durability of responses in malignant diseases. The phase I clinical trial FusionVAC22_01 will enroll patients with FL-HCC or other cancer entities carrying the DNAJB1-PRKACA fusion transcript that are locally advanced or metastatic. Two doses of the DNAJB1-PRKACA fusion-based neoepitope vaccine Fusion-VAC-XS15 will be applied subcutaneously (s.c.) with a 4-week interval in combination with the anti-programmed cell death-ligand 1 (PD-L1) antibody atezolizumab starting at day 15 after the first vaccination. Anti-PD-L1 will be applied every 4 weeks until end of the 54-week treatment phase or until disease progression or other reason for study termination. Thereafter, patients will enter a 6 months follow-up period. The clinical trial reported here was approved by the Ethics Committee II of the University of Heidelberg (Medical faculty of Mannheim) and the Paul-Ehrlich-Institute (P-00540). Clinical trial results will be published in peer-reviewed journals.Trial registration numbersEU CT Number: 2022-502869-17-01 and ClinicalTrials.gov Registry (NCT05937295).

Successful treatment for any type of carcinoma largely depends on understanding the patterns of invasion and migration. For oral squamous cell carcinoma (OSCC), these processes are not entirely understood as of now. Invadopodia and podosomes, called invadosomes, play an important role in cancer cell invasion and migration. Previous research has established that cortactin (CTTN) is a major inducer of invadosome formation. However, less is known about the expression patterns of CTTN and other genes related to it or invadopodia formation in OSCC during tumor progression in particular. In this study, gene expression patterns of CTTN and various genes (n = 36) associated with invadopodia formation were analyzed to reveal relevant expression patterns and give a comprehensive overview of them. The genes were analyzed from a whole genome dataset of 83 OSCC samples relating to tumor size, grading, lymph node status, and UICC (Union for Internatioanl Cancer Control). The data revealed significant overexpression of 18 genes, most notably CTTN, SRC (SRC proto-onocogene, non-receptor tyrosine kinase), EGFR (epidermal growth factor receptor), SYK (spleen associated tyrosine kinase), WASL (WASP like actin nucleation promotion factor), and ARPC2 (arrestin beta 1) due to their significant correlation with further tumor parameters. This study is one of the first to summarize the expression patterns of CTTN and related genes in a complex group of OSCC samples.

IntroductionColorectal cancer (CRC) is the third most common cancer worldwide in men and women. In the metastasized stage, treatment options and prognosis are limited. To address the high medical need of this patient population, we generated a CD276xCD3 bispecific antibody termed CC-3. CD276 is expressed on CRC cells and on tumor vessels, thereby allowing for a “dual” anticancer effect.Methods and analysisThis first-in-human clinical study is planned as a prospective multicenter trial, enrolling patients with metastatic CRC after three lines of therapy. During the dose-escalation part, initially, an accelerated titration design with single-patient cohorts is employed. Here, each patient will receive a fixed dose level (starting with 50 µg for the first patient); however, between patients, dose level may be increased by up to 100%, depending on the decision of a safety review committee. Upon occurrence of any adverse events (AEs) grade ≥2, dose-limiting toxicity (DLT), or reaching a dose level of ≥800 µg, the escalation will switch to a standard 3 + 3 dose design. After maximum tolerated dose (MTD) has been determined, defined as no more than one of the six patients experiencing DLT, an additional 14 patients receive CC-3 at the MTD level in the dose-expansion phase. Primary endpoints are incidence and severity of AEs, as well as the best objective response to the treatment according to response evaluation criteria in solid tumors (RECIST) 1.1. Secondary endpoints include overall safety, efficacy, survival, quality of life, and pharmacokinetic investigations.Ethics and disseminationThe CD276xCD3 study was approved by the Ethics Committee of the Medical Faculty of the Heinrich Heine University Düsseldorf and the Paul-Ehrlich-Institut (P00702). Clinical trial results will be published in peer-reviewed journals. Trial registration numbers: ClinicalTrials.cov Registry (NCT05999396) and EU ClinicalTrials Registry (EU trial number 2022-503084-15-00).

Abstract Aims Impairment of vascular function contributes to the progression of chronic heart failure (HF) by increasing the afterload. Treatment with selective sodium‐glucose cotransporter 2 (SGLT2) inhibitors improves the prognosis of HF, but the precise mechanisms remain unclear. The aim of this study was to analyse the effect of empagliflozin on vascular function in patients with HF. Methods and results In an investigator initiated, double‐blind, randomized, placebo‐controlled, parallel‐group, clinical study, patients with HF NYHA II‐III and an ejection fraction of 49% or less were randomized 2:1 to receive empagliflozin 10 mg once daily or placebo for 3 months. A total of 74 patients (15% female), aged 66 ± 9 years, with a mean ejection fraction of 39 ± 8% and a median NTproBNP of 558 pg/mL (IQR 219–1051 pg/mL), were included. Vascular parameters such as central systolic blood pressure (cSBP), central pulse pressure (cPP), forward (FPH), and reflected pressure pulse height (RPH) decreased under resting conditions after 1 and 3 months (1 month: cSBP −6.4 ± 8.3 mmHg, P

Abstract Background Type 2 diabetes causes cardio-renal complications and is treated with different combination therapies. The renal hemodynamics profile of such combination therapies has not been evaluated in detail. Methods Patients (N = 97) with type 2 diabetes were randomized to receive either empagliflozin and linagliptin (E+L group) or metformin and insulin glargine (M+I group) for 3 months. Renal hemodynamics were assessed with para-aminohippuric acid and inulin for renal plasma flow (RPF) and glomerular filtration rate (GFR). Intraglomerular hemodynamics were calculated according the Gomez´ model. Results Treatment with E+L reduced GFR (p = 0.003), but RPF remained unchanged (p = 0.536). In contrast, M+I not only reduced GFR (p = 0.001), but also resulted in a significant reduction of RPF (p

Abstract Aims Analysis of microvascular parameters in the retinal circulation—known to reflect those in the systemic circulation—allows us to differentiate between eutrophic and hypertrophic remodelling of small arteries. This study aimed to examine microvascular changes in patients with congestive heart failure (CHF) and reduced as well as mid‐range ejection fraction. Methods and results Forty subjects with CHF underwent measurement of retinal capillary flow (RCF), wall‐to‐lumen ratio (WLR), vessel and lumen diameter, wall thickness, and wall cross‐sectional area (WCSA) of retinal arterioles of the right eye by scanning laser Doppler flowmetry (SLDF). Applying a matched pair approach, we compared this group with reference values of age‐matched controls from a random sample in the population of Pilsen, Czech Republic. There was no significant difference in RCF and WLR between the groups (RCF: P = 0.513; WLR: P = 0.106). In contrast, wall thickness and WCSA, indicators of hypertrophic remodelling, were higher in CHF subjects (WT: 15.0 ± 4.2 vs. 12.7 ± 4.2 μm, P = 0.021; WCSA: 4437.6 ± 1314.5 vs. 3615.9 ± 1567.8 μm2, P = 0.014). Similarly, vessel (109.4 ± 11.1 vs. 100.5 ± 14.4 μm, P = 0.002) and lumen diameter (79.0 ± 7.9 vs. 75.2 ± 8.5 μm, P = 0.009) were increased in CHF. Conclusions In CHF subjects, we observed hypertrophic remodelling of retinal arterioles indicative of similar changes of small resistance arteries in the systemic circulation. Microvascular structure and function assessed by SLDF may thereby represent a useful, non‐invasive method for monitoring of microvascular damage in patients with CHF and may offer innovative treatment targets for new CHF therapies.

Abstract Background The aim of this study was to investigate the influence of clinical characteristics and dental restorative materials on oral health-related quality of life in patients with oral lichen planus. In particular, the influences of amalgam and metals were investigated. Methods A total of 112 patients with clinical and histological features of oral lichen planus from the Department of Cranio-Maxillofacial Surgery at the University Hospital of Münster participated in this prospective study. Clinical parameters of oral lichen planus and the dental restorative materials used were evaluated. Oral health-related quality of life was investigated by using the short form of the German version of the Oral Health Impact Profile (OHIP-14). In addition, physical pain was rated on a visual analogue scale. Results The average OHIP-14 score was 13.54. A high correlation was seen between OHIP and pain. Likewise, higher OHIP-values were seen for male patients, and such as for those patients with non-reticular forms of oral lichen planus (OLP). A local form of OLP is more often seen on female patients, such as with the presence of reticular lichen. In regard to the restorations, the presence of composite restorations is correlated with a local lichen, whereas the presence of gold restorations is often seen with a generalized lichen. Furthermore, the grading of strength of association between mucosal lesion and amalgam/metal was tested. No significant differences revealed the analysis of the relationship between gender, clinical form of OLP, age, and presentation form between the 4 gradings of Thornhill. Conclusions The oral health-related quality of life is significantly limited in patients with oral lichen planus. But these OHIP scores are not influenced by the restorative materials. Here, pain severity is the most important aspect. We found no statistical differences in the clinical parameters between patients with amalgam or metal restoration and patients without these restorations. It is not necessary to replace amalgam fillings that are not in direct contact with mucosal surfaces.

Background: Chronic mental stress is recognized as a modifiable risk factor for cardiovascular disease. The aim of this study was to demonstrate that noise annoyance-induced stress is associated with changes in renal hemodynamics. Methods: Renal hemodynamic parameters were measured using steady-state input clearance with infusion of para-aminohippuric acid and inulin in individuals with normal, high normal, and elevated blood pressure. All individuals ranked subjective annoyance due to noise in everyday life on a 7-grade Likert scale. The median of all rankings was used as a cutoff point to divide the group into noise-annoyed and non-noise-annoyed individuals. Different renal hemodynamic parameters were calculated based on the Gomez equation. Results: Noise-annoyed individuals (n = 58) showed lower renal plasma flow (599 ± 106 vs. 663 ± 124 mL/min, p = 0.009), lower renal blood flow (1,068 ± 203 vs. 1,172 ± 225 mL/min, p = 0.047), higher filtration fraction (22.7 ± 3.3 vs. 21.3 ± 3.0, p = 0.012), higher renal vascular resistance (88.9 ± 25.6 vs. 75.8 ± 22.9 mm Hg/[mL/min], p = 0.002), and higher resistance of afferent arteriole (2,439.5 ± 1,253.4 vs. 1,849.9 ± 1,242.0 dyn s−1 cm−5, p = 0.001) compared to non-noise-annoyed individuals (n = 55). There was no difference in measured glomerular filtration rate (133 ± 11.8 vs. 138 ± 15 mL/min, p = 0.181), resistance of efferent arteriole (2,419.4 ± 472.2 vs. 2,245.8 ± 370.3 dyn s−1 cm−5, p = 0.060), and intraglomerular pressure (64.0 ± 3.1 vs. 64.6 ± 3.5 mm Hg, p = 0.298) between the groups. After adjusting for age, renal plasma flow, renal blood flow, and renal vascular resistance remained significantly different between the groups, with a trend in increased afferent arteriolar resistance and filtration fraction. Conclusion: In this study, noise annoyance was associated with reduced renal perfusion attributed to increased renal vascular resistance predominantly at the afferent site. Long-term consequences of this renal hemodynamic pattern due to noise annoyance need to be investigated.

Abstract Aims Congestive heart failure (CHF) and impaired renal function are two often co‐existing medical conditions and associated with adverse cardiovascular outcome. The aim of the current study was to assess renal and intraglomerular haemodynamics by constant infusion input clearance technique in subjects with CHF. Methods and results The group of subjects with CHF consisted of 27 individuals with HFpEF and 27 individuals with HFrEF and were compared with 31 healthy controls. Subjects underwent renal clearance examination to measure glomerular filtration rate (GFR) and renal blood and plasma flow (RBF and RPF) and to calculate intraglomerular haemodynamics such as resistances of the afferent (RA) and efferent arterioles (RE) as well as intraglomerular pressure (Pglom). Measured GFR was lower in CHF subjects (68.1 ± 10.1 mL/min/1.73 m2) compared with controls (83.6 ± 13.4 mL/min/1.73 m2, Padj

The circulating low-density lipoprotein concentration in blood can be reduced by the administration of statins. Frequently simvastatin (SV) is prescribed. Due to the reported pleiotropic effects of SV the aim of this study was to evaluate mineralization effects on human adipose tissue-derived stromal cells upon administration of SV. After informed consent human adipose tissue-derived stromal cells were obtained from tissue surplus of regular treatments of 14 individuals. According to established protocols after adding various SV concentrations (0.01 µM, 0.1 µM, 1.0 µM, 2.0 µM), alkaline phosphate (osteoblastic marker), mineralization capability and viability were determined at day 18, 21 and 28. The Kruskal–Wallis test was performed for statistical analysis. After adding SV a dose-dependent significant decreased viability and levels of alkaline phosphatase (p < 0.01) and a significantly increased mineralization (p < 0.01) of the primary cultures was recognized during the late mineralization stage. Mineralization of the human adipose tissue-derived stromal cells was induced by SV, possibly originated from alternative pathways than the alkaline phosphatase pathway. Further investigations should be performed regarding switching into the osteoblastic differentiation and as a possible source of cells that can be used as the basis for a potential bone graft substitute, which may allow an extension of the field of application.

Abstract Background Frequently statins were administered to reduce the LDL-concentration in circulating blood. Especially simvastatin (SV) is an often prescribed statin. Pleiotropic effects of these drugs were reported. Thus, the aim of this study was to evaluate effects of SV on osteoblastic mineralization. Methods After informed consent primary osteoblasts were collected from tissue surplus after treatment of 14 individuals in the Department of Cranio-Maxillofacial Surgery, University Hospital Münster. The cells were passaged according to established protocols. Viability, mineralization capability and osteoblastic marker (alkaline phosphatase) were determined at day 9, 13 and 16 after adding various SV concentrations (0.05 μM, 0.1 μM, 0.5 μM, 1.0 μM). Statistical analysis was performed using the Kruskal-Wallis-test. Results The cell cultures showed a time and dose-dependent significantly decreased viability (p

Abstract Background The compound letermovir (LMV) has recently been approved for the prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV seropositive recipients of an allogeneic hematopoietic stem cell transplant. LMV inhibits CMV replication by binding to the viral terminase complex. However, first cases of clinical LMV resistance have been occurred. Here we report a fast breakthrough of resistant cytomegalovirus during secondary LMV prophylaxis in a hematopoietic-cell transplant recipient. Case presentation A 44-year-old male patient with acute myeloid leukemia (AML) experienced a CMV-reactivation within the first 4 weeks of allogeneic hematopoietic-cell transplantation. Administration of LMV was initiated at day + 34. Due to increasing viral loads, LMV treatment was discontinued after 8 days. The patient was then administered with valganciclovir (valGCV) until viral DNA was undetectable. Due to neutropenia, valGCV treatment was switched to LMV secondary prophylaxis. For 4 weeks, the patient maintain virologic suppression. Then, CMV viral loads increased with a fast kinetic. Genotypic testing of the viral polymerase UL54, the kinase UL97 as well as the viral terminase UL56 and UL89 revealed the mutation C325Y in UL56, which is associated with the high level LMV resistance. Conclusion It is known that Letermovir is approved for prophylactic purposes. However, it may be used for some patients with CMV infection who either have failed prior therapies or are unable to tolerate other anti-CMV compounds. Particularly, the administration of LMV should be avoided in patients with detectable viral loads. When this is not possible, viral load must be routinely monitored along with UL56 genotyping. Furthermore, LMV administration at high virus loads may foster the rapid selection of resistant CMV mutants.

Abstract Background Empagliflozin has been shown to reduce cardiovascular mortality, but the underlying pathogenetic mechanisms are poorly understood. It was previously demonstrated that empagliflozin improved arterial stiffness. Methods Our analysis comprising 58 patients with type 2 diabetes mellitus identifies factors triggering the improvement of arterial stiffness. All patients participated in an investigator-initiated, prospective, double-blind, randomized, placebo-controlled, interventional clinical trial (http://www.ClinicalTrials.gov: NCT02471963, registered 15th June 2015, retrospectively registered) and received either 6-weeks treatment with 25 mg empagliflozin orally once daily or placebo (crossover). Central systolic pressure and central pulse pressure were recorded by the SphygmoCor System (AtCor Medical). Now, we investigated the impact of parameters of glucose metabolism, volume status, sympathetic activation, lipids, uric acid, blood pressure and inflammation on vascular parameters of arterial stiffness using multivariate regression analysis. Results As previously reported, therapy with empagliflozin improved arterial stiffness as indicated by reduced central systolic blood pressure (113.6 ± 12.1 vs 118.6 ± 12.9 mmHg, p

Abstract Background The primary purpose of this study was to collect data on the oral health-related quality of life (OHRQoL) of individuals with x-linked hypophosphatemia (XLH). It was also designed to gather information on the period of diagnosis, oral symptoms, orthodontic therapy, and satisfaction with dental care and the healthcare system. Methods A questionnaire was developed to evaluate the OHRQoL consisting of open-ended questions and the standardised German version of the Oral Health Impact Profile-14 (OHIP-14). Results The questionnaires from 43 participants were analysed, including 32 females (74.41%) and 11 males (25.59%). The mean OHIP-14 total score for the combined genders was 10.30 points (range: 0–37 points). For the combined genders, the mean period of time that elapsed between the first signs of the illness and the diagnosis was 5.52 years (range: 0–49 years). In total, 77.50% of the participants described oral symptoms, such as tooth mineralisation defects (n = 26), abscess or fistula formation (n = 21), dysgnathia (n = 9) and temporomandibular dysfunction (n = 2). The correlation between the participants’ satisfaction with the healthcare system and the OHIP-14 values was weak (− 0.21), and it was not statistically significant (p = 0.199). Conclusions The majority of the study participants reported oral involvement in the context of XLH, especially dental hard tissue mineralisation disorders, abscess formation and fistula formation. Those individuals affected by XLH with oral manifestations exhibited a tendency toward a worse OHRQoL than those without oral symptoms. In Germany, the OHIP-14 scores for these XLH patients were worse than those values that were obtained from the general population.

Epithelioid rhabdomyosarcoma is a rare condition, which may be clinically misinterpreted as melanoma due to its morphological appearance. Careful morphological and immunohistochemical analysis play an important role in its diagnosis. This case report describes the clinicopathological features of an epithelioid RMS diagnosed at the high parietal area of the head. A 71-year-old male patient presented a red-brown pigmented ulcerative nodule in the high parietal region of the head. Previous biopsy and computer tomography imaging revealed a malignant melanoma in stage I (pT2, sN0, Mx). After tumor operation, histological and immunohistochemical analysis of the tumor were conducted. Histological analysis showed an erosive lesion with a monomorphic cell population containing small cells with prominent nucleoli. A positivity was confirmed for CD10, Vimentin, and Desmin. MyoD1 was detected, as well as a fluctuating signal for p53. Molecular analysis revealed a negativity for Sox-10, and a weak positivity for CK8/18 by absence of p40. Based on the morphological and immunohistochemical findings, the tumor was diagnosed as epithelioid RMS.

Abstract Background Diabetes converts from a metabolic disorder into a predominantly vascular disease, once its duration extends over several years or/and when additional cardiovascular risk factors such as hypertension coexist. In a cross-sectional analysis we analyzed various vascular parameters in the renal, retinal and systemic circulation, with the goal to identify which vascular parameter of early organ damage is the earliest that can be clinically detected. Methods In 111 patients with type 2 diabetes (T2DM) (off any anti-diabetic medication for at least 4 weeks) and 54 subjects without T2DM we compared various parameters of early vascular remodeling in the same patient: urinary albumin creatinine ratio ([UACR], early morning spot urine) and estimated glomerular filtration rate (eGFR), retinal capillary flow (RCF) and intercapillary distance (ICD) as parameters of capillary rarefaction, wall-to-lumen ratio (WLR) of the retinal arterioles [all assessed by Scanning Laser Doppler Flowmetry], and central systolic pressure (cSBP) and central pulse pressure (cPP) [measured by pulse wave analysis, Syphygmocor] both reflecting vascular stiffness of large arteries. Results Compared to subjects without T2DM, patients with T2DM (diabetes duration: median 48 months, interquartile range 24–88 months) were older (59.8 ± 7.3 vs 43.4 ± 12.9 years, p

Abstract Background Adult stem cells appear to be a promising subject for tissue engineering, representing an individual material for regeneration of aged and damaged cells. Especially adipose derived stromal cells (ADSC), which are easily to achieve, allow an encouraging perspective due to their capability of differentiating into miscellaneous cell types. Here we describe the in vitro formation of human subcutaneous, visceral and omental ADSC micromasses and compare their histological attributes while being cultivated on collagen membranes. Methods Subcutaneous, visceral and omental fat tissue derived cells were isolated and processed according to standard protocols. Positively stained cells for CD13, CD44 and CD90 were cultivated on agarose in order to study micromass formation using a special method of cell tracking. Stained paraffin-embedded micromasses were analysed morphologically before and after being plated on collagen membranes. Results The micromass formation process was similar in all three tissue types. Subcutaneous fat tissue derived micromasses turned out to develop a more homogeneous and compact shape than visceral and omental tissue. Nevertheless all micromasses adhered to collagen membranes with visible spreading of cells. The immune histochemical (IHC) staining of subcutaneous, visceral and omental ADSC micromasses shows a constant expression of CD13 and a decrease of CD44 and CD 90 expression within 28 days. After that period, omental fat cells don’t show any expression of CD44. Conclusion In conclusion micromass formation and cultivation of all analysed fat tissues can be achieved, subcutaneous cells appearing to be the best material for regenerative concepts.

Abstract Background Primary failure of eruption (PFE) is a rare disease defined as incomplete tooth eruption despite the presence of a clear eruption pathway. Orthodontic extrusion is not feasible in this case because it results in ankylosis of teeth. To the best of our knowledge, besides the study of Ahmad et al. (Eur J Orthod 28:535-540, 2006), no study has systematically analysed the clinical features of and factors associated with PFE. Therefore, the aim of this study was to systematically evaluate the current literature (from 2006 to 2017) for new insights and developments on the aetiology, diagnosis, genetics, and treatment options of PFE. Methods Following the PRISMA guidelines, a systematic search was performed using the PubMed/Medline database for studies reporting on PFE. The following terms were used: “primary failure of tooth eruption”, “primary failure of eruption”, “tooth eruption failure”, and “PFE”. Results Overall, 17 articles reporting clinical data of 314 patients were identified. In all patients, the molars were affected. In 81 reported cases, both the molars and the premolars were affected by PFE. Further, 38 patients’ primary teeth were also affected. In 27 patients, no family members were affected. Additional dental anomalies were observed in 39 patients. A total of 51 different variants of the PTH1R gene associated with PFE were recorded. Conclusions Infraocclusion of the posterior teeth, especially if both sides are affected, is the hallmark of PFE. If a patient is affected by PFE, all teeth distal to the most mesial tooth are also affected by PFE. Primary teeth can also be impacted; however, this may not necessarily occur. If a patient is suspected of having PFE, a genetic test for mutation in the PTH1R gene should be recommended prior to any orthodontic treatment to avoid ankylosis. Treatment options depend on the patient’s age and the clinical situation, and they must be evaluated individually.

Background: Combination of insulin with oral antidiabetic drugs is a valid option, but oral combination therapy emerged as an alternative treatment in type 2 diabetes (T2DM). However, the effects on blood pressure (BP) and vascular function of such combination therapies is less clear. Methods: In this study 101 patients with T2DM were randomized to receive either empagliflozin 10 mg and linagliptin 5 mg (E+L group) orally or metformin and insulin glargine (M+I group, with dose adjustments according to glucose levels), for 3 months. Patients underwent BP and vascular examination at baseline and after 12 weeks of treatment, including measurement of office and ambulatory BP and vascular function under clinical and ambulatory conditions by validated systems. Results: In comparison to baseline, office, 24-hour ambulatory BP and central blood and pulse pressure (PP) values decreased significantly after 12 weeks of treatment with E+L, whereas there was no significant change in vascular parameters in the M+I group (Table 1). Comparing the 2 groups, there were significant decreases in 24-h ambulatory peripheral systolic (mean difference between the 2 groups: −5.2 ± 1.5 mmHg, p = 0.004), diastolic BP (−1.9 ± 1.0 mmHg, p = 0.036) and PP (−3.3 ± 1.0 mmHg, p = 0.007) in favour of E+L. Central systolic BP (−5.56 ± 1.9 mmHg, p = 0.009), forward pressure pulse height (−2.0 ± 0.9 mmHg, p = 0.028) and 24-h ambulatory central systolic (−3.6 ± 1.4 mmHg, p = 0.045), diastolic BP (−1.95 ± 1.1 mmHg, p = 0.041) and 24-h pulse wave velocity (−0.14 ± 0.05 m/s, p = 0.043) were reduced to a greater extent in the E+L group than in the M+I group. Table 1 E + L M + I Baseline 12 weeks p-value Baseline 12 weeks p-value Peripheral (brachial) BP values 24-h ambulatory SBP [mmHg] 131 ± 10.9 127 ± 8.8

Background and Objective: The oral health-related quality of life (OHRQoL) of patients with achalasia has not been evaluated to date. Therefore, the aim of this study was to assess the OHRQoL of patients with achalasia and to get information about the time taken for diagnosis and oral symptoms. Materials and Methods: The study was conceived of as an anonymous epidemiological survey study in people with achalasia in order to assess their OHRQoL in each case. For this, a questionnaire was developed consisting of free-text questions and of the standardized German version of the OHIP-14 questionnaire. Results: In total, forty-four questionnaires were analyzed including 31 female and 13 male participants. Regardless of gender, the mean age was 50.57 years (range: 17–78). Of the surveyed individuals, seventy-nine-point-five-five percent had been diagnosed between 25 and 60 years of age. The period from the first signs of the disease to diagnosis was 6.15 years, irrespective of gender. The overall OHIP-14 score without gender differentiation was 8.72 points (range 0–48); the mean score of female participants was 11.13 (range: 0–48), and the OHIP score of male participants was 3.15 on average. Two participants reported oral symptoms. Conclusions: The already known problem of the delayed diagnosis of rare diseases was also confirmed in the case of achalasia. Females with achalasia seemed to be significantly affected by lower OHRQoL than males with achalasia and women of the general population. Demineralization of the tooth structure was described in two participants.

The aim of this study was to evaluate the effect of an epoxy resin-based (AH-Plus), a zinc oxide eugenol containing (Pulp-Canal-Sealer) and two calcium silicate containing (MTA-Fillapex and BioRoot-RCS) sealers on primary human osteoblasts (hOB) in freshly mixed and set state. All sealers were mixed strictly according to the manufacturers´ instructions and identically samples were produced. In a pretest cytotoxic sealer concentrations were determined. Thus, for the main cell culture study, dilutions of sealer extract 1:1, 1:2, and 1:10 were used. To simulate a clinical scenario, extracts from freshly mixed sealer were added to the cells on day one. Extracts form set sealers were used for subsequent culturing for 24h, 7d, 14d, and 21d. Cell viability was analyzed by living-cell-count, MTT-assay, and living/dead-staining, cytotoxicity by LDH-assay, and changes by Richardson-staining. All data were statistically evaluated by one way ANOVA and a posthoc analysis with Bonferroni-Holm testing (p

Background and Objectives: Salmonellosis is a major foodborne bacterial infection throughout the world. Epidemiological surveillance is one of the key factors to reduce the number of infections caused by this pathogen in both humans and animals. The first outcome measure was the prevalence of non-typhoid Salmonella (NTS) infections between 2000 and 2017 among the population of the predominantly agricultural and touristic Polish region of Warmia and Masuria (WaM). The second outcome measure was the comparison of the NTS hospitalization rate of all registered NTS cases, an investigation of the monthly reports of infections, and the exploration of the annual minimal and maximal NTS infection number in WaM in the above-mentioned time period. The last outcome was a comparison of the prevalence of NTS infections in the region and in its administrative districts by considering both rural and urban municipalities three years before and three years after the accession of Poland into the European Union (EU) in 2004. Materials and Methods: The total number of infections and hospitalizations in the 19 districts of the WaM voivodship in Poland was registered monthly between 2000–2017 by the Provincial Sanitary-Epidemiological Station in Olsztyn, Poland. Results: Between 2000 and 2017, the number of diagnosed salmonellosis cases decreased significantly in WaM; the decrease was higher in urban districts than in rural ones, and the ratio of hospitalizations and the total number of NTS cases increased significantly across all districts. The lowest number of cases was reported in the winter months and was stable from 2007, whereas the highest number was reported in the summer months with a higher tendency of outbreaks. Conclusion: The falling number of salmonellosis cases in 2000–2017 in WaM reflects the general trend in Poland and Europe. The decrease of NTS infections in WaM is related to the accession of Poland into the EU.