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Regulatory CD4+ T cells (Treg) prevent tumor clearance by conventional T cells (Tconv) comprising a major obstacle of cancer immune-surveillance. Hitherto, the mechanisms of Treg repertoire formation in human cancers remain largely unclear. Here, we analyze Treg clonal origin in breast cancer patients using T-Cell Receptor and single-cell transcriptome sequencing. While Treg in peripheral blood and breast tumors are clonally distinct, Tconv clones, including tumor-antigen reactive effectors (Teff), are detected in both compartments. Tumor-infiltrating CD4+ cells accumulate into distinct transcriptome clusters, including early activated Tconv, uncommitted Teff, Th1 Teff, suppressive Treg and pro-tumorigenic Treg. Trajectory analysis suggests early activated Tconv differentiation either into Th1 Teff or into suppressive and pro-tumorigenic Treg. Importantly, Tconv, activated Tconv and Treg share highly-expanded clones contributing up to 65% of intratumoral Treg. Here we show that Treg in human breast cancer may considerably stem from antigen-experienced Tconv converting into secondary induced Treg through intratumoral activation., The mechanisms that shape the regulatory T cell repertoire in patients with cancer are not completely understood. Here, the authors observe that, in breast cancer patients, tumor-resident regulatory T cells do not show clonal relationship with their circulating counterpart, but share a common origin with intratumoral antigen-experienced conventional T cells.

The widespread use of high‐dose therapy and autologous stem cell transplantation (ASCT) as well as the introduction of novel agents have significantly improved outcomes in multiple myeloma (MM) enabling long‐term survival. We here analyze factors influencing survival in 865 newly diagnosed MM patients who underwent first‐line ASCT at our center between 1993 and 2014. Relative survival and conditional survival were assessed to further characterize long‐term survivors. Achievement of complete response (CR) post‐ASCT was associated with prolonged progression‐free survival (PFS) in the whole cohort and with significantly superior overall survival (OS) in the subgroup of patients receiving novel agent‐based induction therapy. Landmark analyses performed at 1, 3, and 5 years post‐ASCT revealed that sustainment of any response had a highly significant influence on survival with no significant differences between sustained CR and sustained inferior responses. Furthermore, outcome was independently improved by administration of maintenance therapy. A subset of patients did experience long‐term survival >15 years. However, conditional survival demonstrated a persistent risk of myeloma‐associated death and cumulative relative survival curves did not show development of a clear plateau, even in prognostically advantageous groups. In conclusion, in this large retrospective study, sustained response after first‐line ASCT was found to be a major prognostic factor for OS independent of depth of sustained response. Administration of maintenance therapy further improved outcome, supporting the hypothesis that interventions to prolong responses achieved post‐ASCT may be essential to reach long‐term survival, especially in the setting of persisting residual disease.

// Anna-Lena Krause 1 , Florian Schuetz 2 , Marc Boudewijns 2 , Maria Pritsch 1 , Markus Wallwiener 2 , Michael Golatta 2 , Joachim Rom 2 , Joerg Heil 2 , Christof Sohn 2 , Andreas Schneeweiss 2 , Philipp Beckhove 1, 3, * and Christoph Domschke 2, * 1 Translational Immunology Division, German Cancer Research Center (DKFZ), Heidelberg, Germany 2 Department of Gynecology and Obstetrics, Heidelberg University Hospital, National Center for Tumor Diseases (NCT), Heidelberg, Germany 3 Regensburg Center for Interventional Immunology (RCI) and University Medical Center of Regensburg, Regensburg, Germany * Equal contributions Correspondence to: Philipp Beckhove, email: beckhove@rcii.de Christoph Domschke, email: christoph.domschke@med.uni-heidelberg.de Keywords: pregnancy; breast cancer; anti-tumor T cells; regulatory T cells; tumor-associated antigens Received: July 08, 2017 Accepted: August 04, 2017 Published: September 08, 2017 ABSTRACT Compared to nulliparous women, parous women have an up to 50% lower lifetime risk of developing breast cancer. An endogenous mechanism to prevent the development of cancer is the destruction of tumor cells by T cells that recognize tumor-associated antigens (TAA). Since a number of TAA are also highly present in the breast and placenta of pregnant women, we investigated the induction and characteristics of spontaneous T cell responses against TAA during pregnancy. To this end, we collected peripheral blood from healthy nulliparous, primigravid and parous women, as well as from breast cancer patients. IFN-γ ELISpot assays were performed to measure the intensity and specificity of T cell responses against 11 different TAA. The impact of TAA-specific Treg cells on anti-TAA responses was assessed by performing the assay before and after depletion of CD4 + CD25 + T cells. The antigenic specificities of these Treg cells were analyzed by the Treg specificity assay. Furthermore, we conducted flow cytometric analyses to determine the memory phenotype and cytokine secretion profile of TAA-specific T cells. Our results demonstrate that pregnancy induces functional and long-lived memory and effector T cells that react against multiple TAA. These persist for many decades in parous females, but are not found in age-matched females without children. We also detected TAA-specific Treg cells, which suppressed strong effector T cell responses after delivery. Nulliparous breast cancer patients displayed median TAA-specific effector T cell responses to be decreased threefold compared to parous patients, which could be restored in vitro after depletion of Treg cells.

Endogenous tumor-specific T cells are detectable in patients with different tumor types including malignant melanoma (MM). They can control tumor growth, have impact on patient survival and correlate with improved clinical response to immune checkpoint therapy. Thus, they may represent a potent biomarker for respective treatment decisions. So far, major target antigens of endogenous MM-reactive T cells have not been determined systematically. Instead, autoantibodies are discussed as surrogate parameter for MM-specific T cells. Throughout a period of more than 60 days after tumor resection, we therefore determined in 38 non-metastasized primary MM patients and in healthy individuals by IFNγ ELISpot and bead-based fluorescent multiplex assay major target antigens of spontaneous T cell and humoral responses using a broad panel of MM antigens and assessed the presence and suppressive impact of MM-reactive regulatory T cells (Tregs). We show that MM-reactive T cells are frequent in MM patients, transiently increase after tumor removal and are mostly directed against Melan-A/MART-1, Tyrosinase, NA17-A and p53. MM-specific Tregs were only detected in few patients and inhibited MM-reactive T cells particularly early after tumor resection. Tumor-specific autoantibodies occurred in most patients, but did not correlate with T cell responses. Thus, endogenous antibodies may not be reliable surrogate parameters of MM-reactive T cells.

Circulating tumor cells as a biomarker for response to therapy in multiple myeloma patients treated within the GMMG-MM5 trial

Regulatory T cells (Tregs) play a key role in cancer immune escape. We identified target antigens of spontaneous tumor-specific T cell responses in urothelial carcinoma (UC) and evaluated their modulation by treatment and Treg. We determined Treg target antigens in UC. Fifty-six UC and 13 control patients were prospectively enrolled. Blood was drawn before and after routine treatment. Changes in Treg frequency were measured by fluorescence cytometry and the T effector cell (Teff) response against a set of nine tumor-associated antigens (TAAs) was monitored with an interferon-gamma ELISpot. Antigen specificity of Treg was determined by their increased capacity to inhibit after TAA-specific activation the proliferation of an autologous T cell population. The highest difference in the overall response rate for the total T cell population was observed for epidermal growth factor receptor (EGFR) (UC: 23% and controls: 0%). After depleting Treg, also new york esophageal (NYES)O1 (19 and 0%) and MUC20 (27 and 0%) were more frequently recognized in UC patients. In metastasized patients, the TAA-directed T cell response was augmented by Treg depletion. Tumor resection seemed to diminish Treg suppression of TAA-specific immunity, whereas chemotherapy had no effect. We demonstrated the existence of TAA-specific Treg in UC, which share antigen specificities with Teff. The coexistence of TAA-specific Treg and Teff was very rare. Treg frequencies in the peripheral blood were not changed by therapy. In summary, we identified potentially immunologically relevant TAA in UC. TAA-specific T cell responses against these antigens are suppressed by Treg. We identified TAA-specific Treg in UC patients, which do not cooccur with TAA-specific Teff.

The aim of this study was to evaluate the prognostic relevance of melanoma-associated antigen (MAGE) A9 in renal cell carcinoma (RCC).Immunohistochemical staining for MAGE A9 was evaluated in a tissue microarray containing 587 RCC tumour tissue samples. Nuclear MAGE A9 expression was reviewed using a semiquantitative score. Follow-up has been surveyed since 1990 in a prospectively conducted tumour database. The effect of MAGE A9 expression on cancer-specific survival (CSS) was assessed by univariate and multivariate Cox regression analyses. Subgroup analyses were performed for non-metastatic and metastatic disease.Median age in all patients was 63.2 years, 354 patients were male and 233 female, and 108 patients had metastatic disease. Median follow-up was 5.6 years for all patients and 9.0 years for patients still alive (range 0-19.9 years). High nuclear MAGE A9 expression was present in 326 tumour specimens (55.5%). In multivariate analyses high nuclear MAGE A9 expression was associated with poor CSS (p = 0.0027). Furthermore, tumour stage, lymph-node and distant metastasis, Fuhrman grade G3/4, Karnofsky index80% and male gender were associated with poor CSS. In subgroup analyses, results were concordant for patients with non-metastatic disease. In patients with metastatic disease, only Karnofsky index80% was a significant predictor for CSS; MAGE A9 expression could not be shown to be associated with CSS (p = 0.161).High nuclear MAGE A9 expression is independently associated with poor CSS in patients with non-metastatic RCC. The assessment of MAGE A9 expression can provide additional prognostic information and should be used in decision-making regarding adjuvant therapy in patients with non-metastatic disease.

Purpose The use of dental implants may be limited by lack of sufficient bone. The effectiveness of the alveolar ridge bone-spreading technique in the maxilla was compared with the standard technique. Bone spreading is a technique in which hand osteotomes are used to progressively enlarge the remaining deficient edentulous ridge to enable placement of dental implants. Materials and Methods In the test group (bone spreading), 72 patients received 126 implants. Thirty-six patients with 63 implants placed with conventional implant preparation served as a control group. Measurements of outcome were implant failure and complications after therapy. Kaplan-Meier curves were used to depict time from implant placement to implant failure or complication. Results Six complications were observed after placement of the implants (3 implant failures, peri-implant inflammation in 2 implants, and 1 exposure of rough implant surface). There was a trend toward more implant failures in the control group. Conclusions Results of the ridge-spreading technique seem to be similar to those of the standard technique. However, these results should be regarded with caution because of the small number of complications.

The purpose of this study is to compare success rates of dual-viscosity impressions for two types of mixing techniques of the polyether elastomeric impression material. Additionally, influencing parameters on the success rates should be evaluated. The expectation was that there would be no difference between the success rates for the two mixing techniques. Two centres enrolled 290 subjects (727 teeth) into the trial. Patients were randomized for the two types of mixing techniques. One step, dual-viscosity impressions were made with either statically mixed Impregum Soft tray material (SAM) or dynamically mixed Impregum Penta H DuoSoft (DMM). Low viscosity Impregum Garant L DuoSoft was used for both groups. Gingival displacement involved the use of two braided cords. Full-arch trays were used exclusively. Both critical defects and operator errors were assessed for the first impression taken by trained dentists. The primary outcome was impression success. For comparison of the two mixing techniques, the odds ratio for success and the corresponding one-sided 95% confidence interval was calculated by a logistic regression model. To account for the dependence between several teeth within one patient, the method of general estimating equations was used. The overall impression success rate was 35.4%. Both mixing techniques showed equal success rates indicated by an OR of 1.0 and a lower limit of the one-sided 95% confidence interval of 0.71. Using this result to develop the corresponding interval for the difference, it could be shown that the success rate using SAM was at most 8.2% lower than that when using DMM with a probability of 95%. Multivariate logistic regression analysis of other potential influencing factors showed position of finish line (p = 0.008, supra compared to mixed), blood coagulation disorder (p = 0.021) and the level of training of the clinician (student vs dentist, p=0.008) to have an independent influence on the success rate. Dynamic mechanical mixing and the new static mixing of polyether tray material showed nearly equal success rates in the study even though success rates were comparatively low (DMM, 35.3%; SAM, 35.4%).

Objectives Irregular tooth shape and position in the anterior maxilla and mandible are major aesthetic problems for patients. In recent years such conditions have increasingly been treated minimally or even non-invasively by recontouring teeth with direct composite resin buildups. Although clinical experience with this treatment option is promising, evidence-based data about longevity are limited. Methods The authors evaluated survival and quality of 327 composite buildups that were placed in 101 patients in the Department of Conservative Dentistry, University of Heidelberg, between 2002 and 2008. Follow-up intervals and failures were recorded. Quality was assessed by grading restorations (modified USPHS/Ryge critera) still in situ without adverse event during the follow-up period. Results After a mean follow-up interval of 27.8 months, 284 restorations were in situ and had no event. Forty-two restorations were in situ but had events that were mostly minor fractures of the composite resin. One restoration had been lost. Analysis of the time from insertion to any event or end of follow-up yielded an estimated 5-year survival rate of 79.2% (95% CI, 70.5–87.9). Quality was assessed by grading in situ restorations without event. More than 90% of graded restorations were categorized as “clinically excellent” (1) or “clinically good” (2). A correlation between those rated “clinically sufficient” or worse (≥3) and the follow-up period was observed. Conclusions Direct composite buildups are aesthetic, functional, and biologically sound treatment options for recontouring teeth and closing diastemas with clinically promising survival rates. Therefore, tooth shape correction can be recommended in cases in which minimally invasive or non-invasive procedures on healthy teeth are indicated.

In a cohort study, bone mineral density (BMD) around uncemented femoral components after total hip arthroplasty (THA) was evaluated. The results suggest that there are no clinically relevant changes in overall periprosthetic BMD in the second decade. However, continuous remodeling with limited proximal bone loss (stress-shielding) occurs, predominantly in female patients.Progressive periprosthetic bone loss and stress-shielding are a major concern in THA. Little is known about the extent and pattern of periprosthetic bone remodeling around uncemented stems in the second decade.In a cohort study, periprosthetic BMD was measured in 131 patients with 146 uncemented CLS stems using dual-energy X-ray absorptiometry (DXA) at a mean of 12 years postoperatively (t1). Patients were followed clinically and radiographically, and a second DXA was performed at a mean of 17 years postoperatively (t2) using the identical protocol.We obtained a complete set of two consecutive DXA measurements for 88 hips (78 patients, 35 male, 43 female). On radiographic evaluation at t1 and t2, regular bone ongrowth was present in all cases and no signs of radiographic loosening, severe bone loss or diaphyseal cortical hypertrophy were detected. There was no clinically relevant change in overall periprosthetic BMD (netavg) between t1 and t2 for both male and female patients. We analyzed the differences in BMD in the periprosthetic regions of interest (ROIs) according to Gruen and found a slight decrease in periprosthetic BMD in ROI 7 in male patients and in ROIs 1, 4, 6 and 7 in female patients.The study suggests that there are no clinically relevant changes in overall periprosthetic BMD around stable, straight uncemented stems between 12 and 17 years postoperatively. However, continuous remodeling with limited proximal bone loss occurs, predominantly in female patients. After secondary osteointegration of this implant, stress-shielding remains minimal in the second decade.

This study determined the mechanical properties of 19 dental floss holders. Eight single-use holders and 11 reusable ones were tested. An in vitro model with dental proximal contact strength of 8 N was created. Every device had to pass the proximal contact 30 times. We measured (1) the displacement of the floss [mm], (2) the force [N] necessary to pass the proximal contact after the 30th passage, (3) the loosening of the floss (offset [mm]), and (4) the change in the distance between the branches [mm]. Each measurement was repeated seven times. The results are displacement of the floss after 30 passages, 2.0 to 9.2 mm; passage force, 2.6 to 11 N; increases in branch distance, 0–2.9 mm; offset of the floss, 0–1.8 mm (all numbers are medians). Based on cleaning a full dentition (30 passages), we suggest introducing minimal requirements of

Statement of problem The wear behavior of newly developed denture teeth with nanofillers may be different from teeth with other chemical formulations. Purpose The purpose of this study was to examine the 3-body wear resistance of 11 different commercially available resin denture teeth. Material and methods The materials tested were conventional (SR Orthotyp PE, Orthognath) and cross-linked acrylic resin teeth without inorganic fillers (Premium 8, SR Postaris DCL, Trubyte Portrait, Artiplus), composite resin teeth with inorganic fillers (SR Orthosit PE, Vitapan), and composite resin teeth (experimental materials) with inorganic nanofillers (NC Veracia Posterior, e-Ha, Mondial). Human enamel and a ceramic denture tooth (Lumin Vacuum) were used as reference materials. The 3-body wear test was performed in a wear machine developed by the Academic Center for Dentistry Amsterdam (ACTA), with millet suspension acting as an abrasive medium (n=10, test load: 15 N, slip rate: 20%, number of cycles: 100,000). Wear was determined with the aid of a profilometer. Data were analyzed with the Kruskal-Wallis test and Mann-Whitney U test using the closed testing approach (significance level for familywise error rate, α=.05). Results None of the acrylic and composite resin materials tested in this study demonstrated the 3-body wear resistance of ceramic teeth or human enamel. Teeth with inorganic fillers demonstrated significantly lower wear values than conventional or cross-linked acrylic resin teeth without fillers. Composite resin teeth with traditional fillers showed significantly lower wear than composite resin teeth with nanofillers. Conclusions Denture teeth with and without inorganic fillers differed significantly with regard to the degree of wear generated in the ACTA wear simulator. The incorporation of nanofillers did not improve the wear resistance compared to teeth with traditional fillers.

Background: Total hip arthroplasty without cement is frequently performed in young active patients, but only limited outcomes data are available after durations of follow-up of more than fifteen years. Methods: We retrospectively evaluated the clinical and radiographic results of a consecutive series of 154 total hip arthroplasties (in 141 patients) performed with an uncemented grit-blasted straight tapered titanium femoral stem combined with a threaded socket in patients under the age of fifty-five years. The median duration of follow-up was seventeen years. Clinical results were evaluated with use of the Harris hip score. The canal fill index was used as the criterion to determine the adequacy of stem sizing. Kaplan-Meier survivorship analysis was performed to predict long-term outcomes. Results: The stem was undersized, with a canal fill index of ≤80%, in forty-one hips (27%). Late aseptic loosening of the stem occurred in four femora, and the femoral component was undersized in all four. These four stems were stable for ten years and then underwent progressive subsidence, which was associated with pain. Five stems were revised because of a late postoperative periprosthetic fracture following trauma. Localized proximal femoral osteolysis was seen in seven hips without signs of loosening. Survivorship of the stem with revision for any reason as the end point was estimated to be 90% (95% confidence interval, 87% to 97%) at twenty years. Survivorship with aseptic loosening as the end point was estimated to be 95% (95% confidence interval, 91% to 99%) at twenty years. Sixty-seven (44%) of the threaded uncemented acetabular components were revised during the follow-up period. Conclusions: After a minimum duration of follow-up of fifteen years, the survival of this type of femoral component is excellent in individuals younger than fifty-five years. The main mode of stem failure was a periprosthetic fracture due to trauma, or late aseptic loosening in a small percentage of the hips in which the femoral implant was undersized. The high rate of failure of the acetabular components was attributable to a poor design that is no longer in use. Level of Evidence: Therapeutic Level IV. See Instructions to Authors for a complete description of levels of evidence.

OBJECTIVE To evaluate the influence of perinephric (PN) and renal sinus (RS) fat infiltration on cancer-specific survival beyond other prognostic factors, as the Tumour-Node-Metastasis (TNM) classification system defines stage T3a renal cell carcinoma (RCC) as infiltration of perirenal fat and/or direct infiltration of the adrenal gland. Perirenal fat invasion is differentiated into RS and PN fat infiltration, but not further classified for the prognosis. PATIENTS AND METHODS From 1990 to October 2007 106 patients with advanced RCC (T3a) were followed prospectively at one academic centre; all had a radical nephrectomy. To identify prognostic effects of PN, RS or RS + PN fat infiltration, univariable and multivariable Cox proportional hazard regression models were applied, including lymph node status, metastases, presence of sarcomatoid features and tumour necrosis, Fuhrman’s grade, Karnofsky performance status, and tumour size. RESULTS PN fat invasion alone was present in 58, RS in 21, and PN + RS in 27 patients. The median follow-up was 2.9 years; 49 patients died from RCC. In univariable and multivariable analyses RS fat infiltration was an unfavourable prognostic factor (adjusted hazard ratio, HR, 2.24, P = 0.019). Univariable analysis of RS + PN fat infiltration showed the worst prognostic effect (HR 3.25, P

OBJECTIVE: The newly developed conjugate 5-aminofluorescein (AFL)-human serum albumin (HSA) was investigated in a clinical trial for fluorescence-guided surgery of malignant brain tumors to assess its efficacy and tolerability. METHODS: AFL, covalently linked to human serum albumin at a molar ratio of 1:1, was administered intravenously 0.5 to 4 days before surgery at 0.5 or 1.0 mg/kg of body weight to 13 patients aged 38 to 71 years who were suspected of having malignant gliomas. Fluorescence guidance using a 488-nm argon laser was performed during surgery at will. The extent of tumor resection was verified by early postoperative magnetic resonance imaging. Fluorescent and nonfluorescent samples were collected for neuropathology. Blood samples for laboratory and pharmacokinetic analyses were taken over the course of 4 weeks. RESULTS: Fluorescence staining of tumor tissue was bright in 11 patients (84%), resulting in complete resection of fluorescent tumor tissue in 9 patients (69%). In 2 patients, residual fluorescent tumor tissue was also confirmed by magnetic resonance imaging. Neither bleaching nor penetration of AFL-HSA into the surrounding brain edema or into necrotic tissue was seen. The agreement between fluorescence and histopathology in tumor samples and samples of the tumor border was 83.3%. There were no toxic side effects. The quality of fluorescence was independent of the dose administered. The optimal time for surgery is between 1 and 4 days after AFL-HSA administration. CONCLUSION: Tumor fluorescence using AFL-HSA made fluorescence-guided brain tumor resection possible, demonstrating that albumin is a suitable carrier system for selective targeting of aminofluorescein into malignant gliomas.

The aim of this study was to provide detailed information concerning clinically relevant occlusal traits and the prevalence of occlusal anomalies in an orthodontically relevant period of dental development. Four hundred and ninety-four German schoolchildren (237 males and 257 females), median age 9 years, were orthodontically examined. Overjet and overbite were measured to the nearest 0.5 mm, and sagittal molar relationships were registered clinically to the nearest quarter unit. In addition, crossbites, scissor bites, and midline displacements were evaluated. Descriptive statistics was complemented by testing gender differences and differences between groups with Class I and Class II anomalies (Mann-Whitney U-test) as well as a statistical evaluation of differences between the three dental stages (Kruskal-Wallis test). Overjet exhibited an extreme range between -2 and 12 mm (median values 3-3.5 mm). An increased overjet was more prevalent than a reduced or reverse overjet, and a severely increased overjet greater than 6 mm was a common finding affecting around 5-10 per cent of the children. Similarly, overbite showed considerable variations of between -1 and 9 mm (medians 3-3.5 mm) and males exhibited a significantly larger overbite than females. In Class II malocclusion subjects, overbite was significantly enlarged (on average between 0.5 and 1 mm) when compared with those with a Class I malocclusion. Traumatic contact of the gingiva affected every 14th child. A Class II molar relationship of three-quarter units or more was a frequent finding affecting more than one child in five. In addition, at 9 years of age, 3 per cent of the children exhibited a Class III molar relationship of at least a half unit. The wide range of orthodontically relevant occlusal traits found in the present study underlines the need for orthodontic screening at 9 years of age (or earlier).

OBJECTIVES To assess the protein expression of Livin, an apoptosis inhibitor, in renal cell carcinoma (RCC) and to determine its prognostic relevance. PATIENTS AND METHODS Immunohistochemical staining for Livin was performed in tissue microarrays (TMAs), including tumour tissue cores, from patients with RCC who had undergone renal surgery. In 682 TMAs cytoplasmatic staining intensity and nuclear staining quantity were evaluated, and the association of Livin expression with progression-free survival (PFS) and cancer-specific survival (CSS) was analysed with a multivariate Cox regression model. RESULTS Over a median (range) follow-up of 5.2 (0–16.1) years, 204 patients (28%) had died from their disease. The CSS rates at 1 and 5 years for the entire cohort was 88% and 71%. Cytoplasmatic Livin staining was absent in 516 (76%) specimens; staining was positive in 166 (24%) specimens. Weak nuclear Livin staining (≤25%) was present in 571 (84%) specimens, strong nuclear staining (26–100%) in 111 (16%). In multivariate analysis, high (>25%) nuclear Livin expression was a favourable independent predictor of PFS and CSS even after adjusting for tumour stage, Fuhrman grade, age, sex and Karnofsky severity rating. Cytoplasmatic Livin expression did not offer additional prognostic information. CONCLUSION High nuclear Livin expression is a favourable independent predictor of PFS and CSS in patients with RCC.

OBJECTIVE To compare the safety and outcome of potassium-titanyl-phosphate (KTP) GreenlightTM (Laserscope, AMS, Minnetonka, MN, USA) vaporization for treating benign prostatic hyperplasia (BPH) in prostates of ≥80 vs

OBJECTIVE To assess whether under- or overweight at the time of surgery has any effect on the survival of the patients with renal cell carcinoma (RCC), as obesity increases the risk of developing RCC. PATIENTS AND METHODS We prospectively evaluated 780 patients who had nephrectomy for RCC between 1990 and 2005. We used uni- and multivariate Cox proportional hazards models to assess the effect of body mass index (BMI), tumour stage, Fuhrman grade, age, sex, histological type and performance status on cancer-specific survival (CSS). Patients were grouped according to BMI (in kg/m2), as underweight (

To give detailed insight into the space conditions and prevalence of spacing and crowding in schoolchildren at nine years of age. The reliability and validity of screening methods was also assessed.Epidemiological survey.South-western part of Germany (Rhein-Neckar-Kreis); elementary schools in a region with a low orthodontic care rate.494 nine-year-old German schoolchildren (237 males, 257 females, median age 9 years) were examined orthodontically in cooperation with the local community dentistry service. A special measurement ruler was developed to enhance validity and reliability of space measurements on location in the schools.Concerning space conditions in the incisor segments: in the maxilla the variety encountered comprised both space excess and moderate to severe crowding. This was considerably larger in the maxilla than in the mandible. Severe crowding (5 mm) was found more often in the maxilla than in the mandible and affected around 2-3% of the maxillary dentitions. Also severe contact point displacements (IOTN Grade 4) were mainly restricted to the maxilla (prevalence approximately 3%). In the canine-premolar segments, the arch segments in males were in general around 0.5 mm larger than among the females, also within each dental stage. In general, the maxilla was more often affected by posterior crowding than the mandible. Anterior crowding seemed to be more prevalent than posterior crowding. With respect to the screening methods used in the present study, reliable and valid measurements were also found to be possible in schools. This may open up further opportunities for orthodontic screening by community dentistry services or similar organizations.

We prospectively evaluated long-term survival in patients with renal cell carcinoma extending to the inferior vena cava.From 1993 and thereafter we followed 86 men and 48 women with a median age of 64 years (range 28 to 86) with renal cell carcinoma and tumor thrombus involvement of the inferior vena cava. Cancer specific survival was analyzed based on clinical therapy, tumor extent, thrombus level and grading.Median followup was 16.4 months (range 0 to 178.9). At the time of this report 97 cancer specific deaths had occurred. Of the 134 patients 111 underwent radical nephrectomy, cavotomy and thrombus extraction, of whom 30 had distant metastases at surgery, and 23 were treated with embolization and immunotherapy. These nonsurgical patients who refused surgery had a high tumor load or a low Karnofsky performance status that may have affected survival. They died at a median of 6.9 months (range 0.1 to 23.6). Patients treated surgically, including those with metastases, had a significantly higher median survival of 19.8 months (range 0 to 178.9). Surgical patients with localized tumor (N0M0) had significantly higher median survival than those with metastatic (NxM1) disease (51.7 months, range 0 to 178.9 vs 6.9, range 0.6 to 149.7). Surgical patients with metastatic disease who underwent interferon and interleukin based immunotherapy had significantly higher median survival than those who did not (13.5 months, range 2.5 to 149.7 vs 5.1, range 0.6 to 24.0). On multivariate analysis localized tumor stage (N0M0) vs advanced tumor stage (N+M0 and NxM1), Fuhrman grade groups 1 and 2 vs 3 and 4, and tumor thrombus levels I and II vs III and IV were independent prognostic factors.Currently radical surgery represents the only chance of long-term survival for patients with renal cell carcinoma and tumor thrombus extension in the inferior vena cava. Median cancer specific survival is significantly higher with localized tumor. However, even with metastatic disease radical surgery can prolong survival, especially when immunotherapy is added. Fuhrman grade and tumor thrombus level are also prognostic factors.

Aims: To investigate whether or not there are differences in the distribution of extracellular matrix (ECM) proteins and matrix metalloproteinases (MMPs) in end-stage heart failure underlying different cardiomyopathies. Methods and results: Thirty-nine explanted human hearts were investigated: 15 with dilated cardiomyopathy (DCM), 17 with ischaemic cardiomyopathy (ICM) and seven with valvular cardiomyopathy (VCM). Transmural samples from four different sites were investigated. Frozen sections were processed for immunohistochemistry for collagens type I, III, IV, laminin and fibronectin, as well as MMP-1, -2 and -9. Volume densities were determined. All ECM components were expressed more frequently in DCM than in ICM. Comparing ICM with VCM, all proteins were found more frequently in VCM than in ICM except for type III collagen, which was significantly more frequent in ICM. Comparing DCM and VCM, VCM showed significantly higher volume densities for type III collagen and laminin. MMPs showed only slight variations between the cardiomyopathies. Conclusion: The distribution of ECM proteins differs between DCM, ICM and VCM, which suggests that they can be morphologically discriminated by interstitial fibrosis, especially by their expression of matrix proteins.

Purpose: We describe a new clinical sign for subscapularis lesions that we call the belly-off sign and compare its diagnostic value with standard subscapularis tests (the lift-off test, internal rotation lag sign, and belly-press test/Napoleon sign) in cases of different types of subscapularis lesions. The belly-off sign represents the inability of the patient to maintain the palm of the hand attached to the abdomen with the arm passively brought into flexion and internal rotation. Type of Study: Case series. Methods: This descriptive and explorative study included 60 patients (mean age, 55.3 years) with clinical, surgical, and/or magnetic resonance imaging–confirmed evidence of isolated or combined lesions of the subscapularis musculotendinous unit. In all patients, a complete physical shoulder examination was performed and the results were compared with the intraoperative and magnetic resonance imaging findings. Results: The belly-off sign appeared to be more reliable than any other diagnostic test or sign in detecting isolated partial tears of the subscapularis tendon (group I), combined partial subscapularis and complete supraspinatus tendon tears (group II), and postoperative subscapularis insufficiency with mild atrophy of the upper aspect of the subscapularis muscle (group VII). In cases of complete/near complete subscapularis tears with or without supraspinatus and infraspinatus tendon tears (groups IV, V, and VI), the belly-off sign appeared to be as reliable as the belly-press test, internal rotation lag sign, and lift-off test. For assessing partial subscapularis tendon tears and insufficient external rotators (group III), the belly-off sign was less reliable than any other diagnostic test or sign. Conclusions: The belly-off sign represents a promising new clinical diagnostic sign for subscapularis lesions. In particular, subtle lesions of the upper subscapularis tendon and postoperative subscapularis insufficiencies can be detected by the belly-off sign in cases of intact external rotators. In cases of an advanced lack of external rotators, the belly-off sign becomes negative and loses its diagnostic value. We therefore conclude that the belly-off sign is attributable to an unbalanced transverse force couple with overwhelming of the external rotators of the shoulder. Level of Evidence: Level IV, case series with no, or historical, control group.

Purpose Early restenosis is one of the major complications after successful percutaneous transluminal angioplasty (PTA), in main, as well as peripheral, arteries. The effectiveness of hypofractionated external beam radiotherapy (EBRT) as a prophylaxis for restenosis was examined in a prospective, randomized, double-blind, clinical trial. Methods and materials Forty-eight patients underwent sham RT and 47 were treated with daily RT in 3-Gy fractions, to a total dose of 21 Gy. The follow-up lasted for 12 months, and the examinations included pressure measurements and calculations of the ankle-brachial index or duplex sonography ("peak velocity ratio"). If restenosis was suspected, additional angiography was performed. Results No statistically significant difference was found between the treatment groups: sham RT 16 failures (33.3%) and EBRT group 21 failures (45.7%; p = 0.292). EBRT also showed no substantial effects on subgroups classified by the specific length of the lesion or in diabetic patients. Conclusion External beam radiotherapy does not prevent restenosis. A reduction in the failure rate >8% using fractionated EBRT with doses aimed at keloid prevention can be ruled out with a probability of 97.5%. Endovascular brachytherapy remains the preferred therapeutic method for achieving restenosis prophylaxis through RT.

Lesions of the biceps pulley and the rotator cuff have been reported to be associated with an internal anterosuperior impingement (ASI) of the shoulder. The purpose of this study was to determine the factors influencing the development of an ASI. Eighty-nine patients with an arthroscopically diagnosed pulley lesion were prospectively included in this study. Four patterns of intraarticular lesions could be identified. Twenty-six patients (group 1) showed an isolated lesion of the superior glenohumeral ligament (SGHL). In 21 patients (group 2) an SGHL lesion and a partial articular-side supraspinatus tendon tear were found. Twenty-two patients (group 3) had an SGHL lesion and a deep surface tear of the subscapularis tendon, and in twenty patients (group 4) a lesion of the SGHL combined with a partial articular-side supraspinatus and subscapularis tendon tear was diagnosed. Of the patients, 80 (89.9%) showed involvement of the long head of the biceps tendon including synovitis, subluxation, dislocation, and partial or complete tearing. In 43.8% of all patients, ASI was observed. Whereas ASI was seen in 26.6% and 19.1% of patients in groups 1 and 2, respectively, 59.1% of patients in group 3 and 75% of patients in group 4 were found to have an ASI. ASI was significantly more often seen in patients with additional partial articular-side subscapularis tendon tears (P

Bone resorption in the proximal femur is commonly seen after total hip arthroplasty (THA). With dual energy X-ray absorptiometry (DXA), the amount of bone mass (BMD) after implantation of a total hip stem can be precisely determined. However, prospective evaluation of the change of bone mass around the stem is only available for selected stems and short-term follow-up (up to 36 months). We analyzed BMD in patients who had undergone uncemented THA by DXA. Only patients with good clinical outcome (Merle d' Aubigné score12) were included to obtain normative data for regular bone response. Two separate studies were performed: a prospective longitudinal study over 84 months with baseline values acquired within the first postoperative week (group A) (n = 26 patients) and a separate cross-sectional study, median follow-up 156 (124-178) months (group B) (n = 35 patients). Regions of interest were defined according to Gruen (ROI 1-7) and as net average ROI (net avg) for the periprosthetic femoral bone. After the initial remodeling process (12 months), BMD was compared to the 84-month (longitudinal) and the 156-month (cross-sectional) follow-up values to determine long-term periprosthetic changes of bone mineral density. The longitudinal study (group A), after the initial bone remodeling, showed no relevant further bone loss for women and men with BMD values 1.19 +/- 0.15 and 1.40 +/- 0.19, respectively, 12 months (women 89.8%, men 93.6%), and 1.19 +/- 0.13 and 1.36 +/- 0.18, respectively, after 84 months (women 90.0%, men 91.3%) (P = 0.98, P = 0.08,) respectively. The distribution of the BMD around the stem changed during the first 12 months. The ROIs around the proximal stem (ROI 1 and 7) showed the lowest absolute values at the 12-month follow-up and BMD in ROI 7 decreased most during the further follow-up until 84 months. The cross-sectional study (group B) showed no significant difference in BMD (net avg) values at a median of 156 months follow-up compared to the 12-month values (group A) (women: P = 0.77, men: P = 0.44). Initial BMD, implant diameter, and body mass index did not influence BMD loss (net avg) in this study, whereas age showed a weak correlation with BMD loss. The results show that after the initial remodeling process, no relevant further bone loss (net avg) occurs up to 84 months postsurgery, and values after a median of 156 months are similar. Normative long-term changes in the periprosthetic bone can be demonstrated in defined ROIs after implantation of a tapered corundum-blasted titanium stem with a good clinical result.

Contemporary cementing techniques in total hip arthroplasty include the use of a cement restrictor to occlude the intramedullary canal. As there are many different designs currently available it was the aim of our study to compare the stability of eight different systems. We investigated the displacement and the ability to occlude the femur of these cement restrictors during standardised cementing of artificial and fresh frozen femora. The maximal intramedullary pressures and the displacement of the plugs were continuously recorded and statistically evaluated. The results revealed significant differences between the tested cement restrictors. The expandable REX Cement Stop and the Exeter Plug achieved the highest stability and the least cement leakage. The more rigid designs (Palacos Plug, BUCK, Universal) in contrast showed inferior performance. Our biomechanical study emphasises the importance of cement restrictor selection, which can have a crucial influence on the fixation of a cemented total hip replacement.

In a cadaver study, we prepared 20 matched pairs of human femora using chipped-tooth broaches and robotic milling with the same geometry. For robotic bone preparation the CASPAR robotic system with a rotating milling head was used. Cancel-lous bone was irrigated with 1 liter of pulsed lavage and the specimens were embedded in specially-designed pots. After vacuum mixing, bone cement was introduced in a retrograde manner and subjected to a standard pressure protocol with a constant force of 3,000 N. Radiographs were taken and horizontal sections were obtained at predefined levels, using a diamond saw. Microradiographs of the bone slices were taken, digitized and analyzed to assess cement penetration into cancellous bone. No femoral fractures or fissures occurred with either preparation technique. The microradiographic evaluation showed no morphometric differences between chipped-tooth broaches and robotic milling as regards cement penetration into cancellous bone. Therefore, in the presence of pulsed lavag...

In a cadaver study, we prepared 20 matched pairs of human femora using chipped-tooth broaches and robotic milling with the same geometry. For robotic bone preparation the CASPAR robotic system with a rotating milling head was used. Cancellous bone was irrigated with 1 liter of pulsed lavage and the specimens were embedded in specially-designed pots. After vacuum mixing, bone cement was introduced in a retrograde manner and subjected to a standard pressure protocol with a constant force of 3,000 N. Radiographs were taken and horizontal sections were obtained at predefined levels, using a diamond saw. Microradiographs of the bone slices were taken, digitized and analyzed to assess cement penetration into cancellous bone. No femoral fractures or fissures occurred with either preparation technique. The microradiographic evaluation showed no morphometric differences between chipped-tooth broaches and robotic milling as regards cement penetration into cancellous bone. Therefore, in the presence of pulsed lavage, we conclude that robotic bone preparation does not increase cement penetration into cancellous bone of the proximal end of the femur.

The aim of this randomized, controlled, double-blind study was to examine how the activation pattern of the masseter muscle changes during natural function when experimental pain is induced in a discrete anterior area of the muscle. In 20 subjects, three bipolar surface electrodes and three intramuscular fine-wire electrodes (antero-posterior mapping) were simultaneously attached above and in the right masseter muscle to record the electromyographic (EMG) activity during unilateral chewing before and after infusion of a 0.9% isotonic and 5% hypertonic saline bolus in the anterior area of the muscle. The activity of the contralateral masseter muscle was registered by surface electrodes. In addition, the development of pain intensity was quantitatively measured with a numerical rating scale (NRS). While both saline concentrations caused pain, the hypertonic solution evoked stronger pain. The experiments also provided evidence of a significant although differential activity reduction of the ipsilateral masseter muscle in the antero-posterior direction. The activity reduction decreased with increasing distance from the location of the infusion. The results support the idea that the strategy of differential activation protects the injured muscle while simultaneously maintaining optimal function.

CD4+ regulatory T cells (Treg) have a detrimental effect in cancer-immunity, as they suppress tumor-specific effector T cells (Teff) hindering tumor eradication. Indeed, increased Treg numbers in various cancer types, including breast cancer, correlate with poor patient prognosis. Based on animal studies, Treg enrichment may result from the expansion of thymic natural Treg but also through the conversion of conventional T cells (Tconv) into induced Treg (iTreg) under tumor-suppressive conditions. However, little is known about tumor-specific iTreg generation in humans and its impact on the TCR repertoire of peripheral Treg. Therefore, we compared the TCRβ repertoire of total Treg and tumor-reactive Teff or total Tconv from peripheral blood of breast cancer patients or healthy individuals, as negative control, for the identification of overlapping TCRs, representing iTreg. In addition, using high-throughput single-cell transcriptome sequencing combined with TCRαβ characterization we analyze the functional profile of individual Treg and Tconv clones, in order to elucidate their specific role in anti-tumor immunity in humans. No major TCR overlap was observed between Treg and tumor-reactive Teff or total Tconv in peripheral blood of patients and healthy individuals, arguing against the existence of tumor-specific iTreg in the circulation. Nevertheless, within the tumor Treg and Tconv shared dominant highly-expanded clones, representing 10–65% of the tumor-infiltrating Treg population but with no effect in peripheral blood. Taken together, our data suggest that intratumoral secondary Treg conversion from dominant Tconv clones may have a major impact on the tumor-infiltrating but not on the circulating Treg population.

Background: In the last decade, the introduction of novel agents into multiple myeloma (MM) therapy has significantly improved response rates and enabled long-term survival in a subset of patients. Yet, clinical characteristics of these long-term survivors as well as the exact impact of depth and sustainment of response still remain a matter of debate. Methods: MM patients treated at our center with high-dose melphalan supported by autologous stem cell transplantation (ASCT) as part of their first-line therapy between June 1992 and July 2014 were retrospectively analyzed. Response assessment was performed 100 days after ASCT according to EBMT criteria, since 2008 response according to IMWG criteria was also available. Overall survival (OS) and progression-free survival (PFS) were calculated from day of first ASCT. Additionally, landmark analyses regarding OS were performed at 1, 2, 3, and 5 years after ASCT. Impact of variables on PFS and OS were analyzed using multivariate Cox regression models. Furthermore, in order to assess evolution of prognosis over time, the conditional survival CS(t|s), which expresses the conditional probability of surviving further t years, was calculated as the ratio of two Kaplan-Meier estimates Ŝ(t) with . Results: 865 patients were included in this analysis, median age was 57.0 years (range 24-74), 509 were male. New agents based induction therapy was administered in 358 patients, 258 patients underwent tandem ASCT. Following ASCT, 386 patients received maintenance therapy, mainly with interferon or thalidomide. 75 patients proceeded to allogeneic transplantation and were censored at that time. Median PFS was 2.1 years, median OS was 6.4 years. Analysis of clinical influence factors revealed novel agent based induction therapy (p To assess the importance of duration of response, landmark analyses were performed at 1, 2, 3, and 5 years after ASCT evaluating OS of patients with sustained CR, sustained inferior responses (non-CR), lost CR and lost non-CR at these respective time points. Remarkably, sustainment of any response showed a highly significant impact on survival at each of these time points (p Conditional survival regarding the probability to survive further three years CS(3|s) was calculated starting from the time of first ASCT stratified for the different response cohorts (see Figure 2). No significant differences could be found between patients with complete and partial response. In contrast, patients with progressive disease (PD) at day 100 after ASCT had a much lower probability of surviving the following three years after ASCT compared to patients responding to ASCT. However, those patients with PD that did survive the first year after ASCT, achieved a similar conditional three-year survival to that of patients responding initially. Conclusions: In this large retrospective study, sustainment of response after first-line ASCT was revealed as a major impact factor for OS independent of the depth of response. Administration of maintenance therapy further improved outcome, supporting the hypothesis that interventions prolonging responses achieved after ASCT are essential to reach long-term survival. Figure 1 OS of patients with sustained vs not-sustained responses at 1-year landmark analysis. Figure 1. OS of patients with sustained vs not-sustained responses at 1-year landmark analysis. Figure 2 3-year-conditional survival CS(3|s) after ASCT stratified for responses achieved. Figure 2. 3-year-conditional survival CS(3|s) after ASCT stratified for responses achieved. Figure 3 Figure 3. Disclosures Hillengass: Amgen: Consultancy, Honoraria; Celgene: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Novartis: Research Funding; Sanofi: Research Funding. Goldschmidt:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Raab:Amgen: Consultancy, Research Funding; BMS: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Research Funding.

□ Eine der wichtigsten Aufgaben der medizinischen Forschung besteht in der Evaluation der Wirksamkeit therapeutischer Masnahmen. In den letzten Jahrzehnten sind hierfur detaillierte Standards entwickelt worden. □ Grundlage einer jeden Wirksamkeitsaussage ist der Vergleich mit einer Kontrollgruppe. Wichtigste Anforderungen zur Gewahrleistung der internen Validitat der Vergleiche sind: Die Gruppen mussen zu Beginn, im Verlauf und am Ende der Studie auch tatsachlich vergleichbar sein. Die Vergleichbarkeit zu Beginn ist nur durch eine zufallige Zuteilung der Patienten zu der jeweiligen Therapiegruppe, die sogenannte Randomisation, zu erreichen. Zur Gewahrleistung der Vergleichbarkeit im Verlauf der Studie sollten Patient und Arzt moglichst bezuglich der Therapiegruppenzugehorigkeit verblindet sein, um subjektive Einflusse auf das Therapieergebnis ausschliesen zu konnen. Bei der Auswertung mus die Vergleichbarkeit der Gruppen gewahrleistet bleiben, d.h., es sollte entsprechend der bei der Randomisation zugewiesenen Gruppenzugehorigkeit ausgewertet werden (Intention-to-treat-Prinzip). □ Diese unverzichtbaren Grundprinzipien fur Planung, Durchfuhrung und Auswertung klinischer Studien sind allgemein anerkannt und tragen zu aussagefahigen Studien und glaubwurdigen Ergebnissen bei.

OBJECTIVE: This prospective randomized clinical trial investigated the impact of different tooth brushing strategies and sealant application on patients with fixed appliances: plaque, gingival, caries index scores, periodontal parameters, microbial, and molecular biological parameters were assessed. MATERIALS AND METHODS: Fifty-five male and 63 female patients aged 11–15 years were enrolled in this 12-week, four-arm parallel-group trial. Patients of group 1 used a Sonicare® FlexCare electric brush, patients of group 2 used a manual (elmex® interX short head) plus interdental (Curaprox® CPS 15) brush, and patients of group 3 and 4 used a manual brush only. The teeth of patients in groups 1, 2, and 3 were sealed with a filled resin (ProSeal®). Patients were advised to brush twice daily and measured time spent brushing mornings and evenings [tooth brushing duration (TBD)]. Plaque (PIB, TQHI, MAPI) and gingival index (PBI) as well as caries index (DMFT/DMFS) scores were assessed at baseline and after 4, 8, and 12 weeks. RESULTS AND CONCLUSIONS: TBD did not differ significantly between patients using the electric or manual brush only (between 197 and 209 seconds) but was longer when using the combination of two manual brushes. TBD was slightly longer in the evenings. There was no gender difference. Although TBD was longer for the combination group, we failed to demonstrate any beneficial effect on outcome parameters for this group. No differences between sealed or unsealed tooth surfaces or for use of a manual or electric brush were observed.

Regulatory T cells (Tregs) play a key role in cancer immune escape. We identified target antigens of spontaneous tumor-specific T cell responses in urothelial carcinoma (UC) and evaluated their modulation by treatment and Treg. We determined Treg target antigens in UC. Fifty-six UC and 13 control patients were prospectively enrolled. Blood was drawn before and after routine treatment. Changes in Treg frequency were measured by fluorescence cytometry and the T effector cell (Teff) response against a set of nine tumor-associated antigens (TAAs) was monitored with an interferon-gamma ELISpot. Antigen specificity of Treg was determined by their increased capacity to inhibit after TAA-specific activation the proliferation of an autologous T cell population. The highest difference in the overall response rate for the total T cell population was observed for epidermal growth factor receptor (EGFR) (UC: 23% and controls: 0%). After depleting Treg, also new york esophageal (NYES)O1 (19 and 0%) and MUC20 (27 and 0%) were more frequently recognized in UC patients. In metastasized patients, the TAA-directed T cell response was augmented by Treg depletion. Tumor resection seemed to diminish Treg suppression of TAA-specific immunity, whereas chemotherapy had no effect. We demonstrated the existence of TAA-specific Treg in UC, which share antigen specificities with Teff. The coexistence of TAA-specific Treg and Teff was very rare. Treg frequencies in the peripheral blood were not changed by therapy. In summary, we identified potentially immunologically relevant TAA in UC. TAA-specific T cell responses against these antigens are suppressed by Treg. We identified TAA-specific Treg in UC patients, which do not cooccur with TAA-specific Teff.

OBJECTIVES Aim of the study was to evaluate the predictive value of the modified periodontal risk assessment (PRA) in patients with aggressive periodontitis (AgP) for the first time. MATERIAL AND METHODS A total of 86 Patients with AgP were re-examined 5-17 years after active periodontal treatment. Risk profile according to the modified PRA was assigned and regularity of maintenance monitored. Tooth loss, bone loss and recurrence of periodontitis were analysed in association with gender, diagnosis, compliance and risk profile using uni- and multivariate parametric regression and Cox proportional hazards models. RESULTS A total of 14 patients showed a localized AgP, 60 a high-risk-profile and 19 were compliant with the proposed maintenance-interval. Of 2202 teeth 98 were lost. Multivariate analysis could not assign a statistically significant impact to risk-profile. By excluding Interleukin-1 composite genotype from the modified PRA a significant influence (p = 0.003, HR 2.74) was detected. The impact of compliance was shown to be nearly significant (p = 0.059, HR 2.0). In patients with generalized AgP a tendency for increased tooth loss was found. CONCLUSION The prognostic value of the modified PRA could not be confirmed in patients with AgP. However, exclusion of Interleukin-1 composite genotype led to a model with significant influence on tooth loss.

Infantile haemangiomas are benign vascular neoplasms that occur frequently in premature infants. The authors hypothesised that in addition to gestational age and birth weight, erythropoietin therapy may influence the incidence of these soft tissue tumours in preterm infants.2563 infants born prematurely and admitted to the Division of Neonatology, University of Heidelberg Medical School were investigated in a retrospective analysis. Hospital charts for all infants were reviewed for clinical data. The primary endpoint was the percentage of infants who had received erythropoietin treatment and were diagnosed with a haemangioma.Haemangiomas were diagnosed in 4.3% (n=110) of the 2563 preterm infants. These 110 infants had a median gestational age of 29 weeks (IQR 27-33 weeks) and the female:male ratio was 1.8:1. A higher incidence of haemangiomas (12-15%) was detected in premature infants with a lower gestational age (31 weeks). Erythropoietin therapy was shown to be an independent risk factor after adjusting for all other known factors and oxygen therapy in multivariable analysis (HR 2.82, 95% CI 1.55 to 5.12). Subgroup analysis revealed that the effect was more pronounced in male than female infants (HR 3.61, 95% CI 1.52 to 8.57).This retrospective study demonstrates that erythropoietin treatment is associated with an increase in the incidence of these benign vascular tumours after adjusting for all other factors.

The objectives of this preliminary, longitudinal, and explorative cohort study were to assess changes in and the onset of osteoarthrosis (OA)-related pain in the temporomandibular joint (TMJ) and to address factors that might impact the development or reduction of associated pain symptoms.In this sex-matched study, 60 women were recruited (30 asymptomatic with a magnetic resonance imaging [MRI] diagnosis of OA-related TMJ changes, 30 symptomatic with accompanying MRI evidence of OA of the TMJ). All subjects underwent a baseline clinical examination and MRI assessment and were subsequently referred to a dental practitioner, who was informed of the diagnosis and further treatment where required. Not all subjects underwent dental treatment interventions. Following a mean 4-year period, subjects were reexamined clinically. Spearman rank correlation and Mann-Whitney U tests were used to evaluate possible correlations in reported pain level changes with the number of posterior occlusal contacts and new dental restorations placed between baseline and recall appointments.The dropout rate was 28% (6.7% for symptomatic, 50% for asymptomatic). OA-related TMJ pain in symptomatic subjects decreased with time (pain reduction: ?3.6 ± 3.4 on a 0 to 10 numeric rating scale); asymptomatic patients rarely developed pain.These preliminary results suggest that factors other than dental occlusion might play a role in the reduction of pain.

To obtain survival data on 32 fiber-reinforced fixed dental prostheses which were inserted in our department and to rate the quality of these restorations on the basis of esthetic, biological, and functional parameters.Thirty-two patients with fiber-reinforced fixed dental prostheses were included in the study. The fiber frameworks were made of a polymer-monomer-preimpregnated continuous unidirectional glass fiber material. The survival times, failure events, and clinical parameters were recorded. Restorations in function without previous failure were classified as "Overall Survival". The classification "Functional Survival" was assigned in the event of minor failure and subsequent repair. Loss of the restoration was regarded as "Failure". The quality rating was performed using modified USHPS/Ryge criteria.The follow-up interval ranged from 2 to 64 months with a median follow-up time of 18.2 months. Twenty-four restorations were classified as "Overall Survival", seven were classified as "Functional Survival", and one was classified as "Failure". The overall survival at the median follow-up time was 74.4%. For the majority, the quality rating (USHPS/Ryge criteria) yielded clinically excellent results in all categories. No restoration was rated as insufficient or poor.Fiber-reinforced composite fixed dental prostheses provide sufficient stability and very good esthetic, biological, and functional performance in the case of specific clinical indications.

In a prospective clinical study, 59 patients with anteromedial osteoarthritis of the knee (61 knee joints) underwent minimally invasive medial Oxford unicompartmental arthroplasty phase 3. Clinical and radiographic examinations of 56 knees were carried out at five (4–7) years. American Knee Society (AKS) scores improved from mean 45.5 (20–80) points (knee score) and 55 (15–100) points (function score) before surgery to 90 (30–100) points in both scores after surgery. The position of each implant was determined on screened radiographs using an image intensifier. The implant position was analysed according to the Oxford X-ray rating system. We evaluated nine measures, and there was no detectable correlation between implant position and clinical result. However, long-term studies are needed before it is possible to elaborate an evidence-based guideline on positioning.

We assessed the effect of T stage, Fuhrman’s grade, multifocality, bilaterality, positive surgical margins, and synchronism of bilateral tumors on cancer-specific survival of patients with nonmetastatic renal-cell carcinoma (RCC) undergoing nephron-sparing surgery for imperative indications. We retrospectively analyzed 168 patients who underwent nephron-sparing surgery for imperative RCC indications between 1974 and 2002. A total of 85 patients had bilateral RCCs; in 27 patients, the tumors were multifocal. Multivariate Cox proportional hazards models were fitted to assess the features associated with cancer-specific survival. The median follow-up was 99 months (range, 2–326 months). Patients were followed until January 2008. A total of 52 patients died of their cancer during follow-up. Multivariate analyses of the total group only revealed Fuhrman’s grade 3 (hazard ratio [HR] 2.94) and bilateral occurrence of RCC (HR 1.82) as independent prognostic factors. In a subgroup analysis of patients with bilateral occurrence of RCC, we observed a tendency toward positive surgical margins (HR 2.89, P = 0.08) being another negative prognostic factor. There was no difference in cancer-specific survival between patients with synchronous and metachronous bilateral RCC presence (HR 1.08). Fuhrman’s grade 3 and bilateral occurrence of RCC were the only statistically significant prognostic factors for cancer-specific survival in patients undergoing nephron-sparing surgery for imperative indications for nonmetastatic RCC. The presence of sporadic multifocal tumors and the synchronous occurrence of bilateral tumors have no influence on cancer-specific survival, while positive surgical margins may have an impact in the subset of patients with bilateral RCC.

Since introduction and widespread use of the Ponseti method in the last decade, the need for surgical treatment of clubfeet is nowadays limited to resistant cases. In the time before, surgery via dorsomedial release was a very common treatment option.Very few long-term follow-up studies cover the outcome of surgical methods, which is particularly interesting, as clinical results rather worsen with time. In the present study, 98 children (131 clubfeet), who underwent surgical correction using the Imhauser method at the age of 4.5 months were included. Follow-up time was 8.2 years (0-11.8 years) at average.Data could be retrieved from 46 patients (71 feet), only 5 patients (7 feet) were lost to follow-up. The rate of relapses was high, as 47 patients (53 feet) needed surgical revision for recurrence, while clinical scores showed a good result in the Laaveg and Ponseti Score and the Foot-Function-Index. Isokinetic testing and clinical data indicated a significant weakness of the treated foot, when compared to the healthy side in 12 patients with unilateral deformity. The presented study supports like others the issue that the clinical outcome of a surgical, posteromedial release in terms of relapses is disappointing. This fact is apparently not sufficiently reflected in the current clinical scores, which showed rather good results.As the question of evaluation methods for results of clubfoot treatment remains controversial, isokinetic testing is an easy to use alternative that provides detailed information about functional limitations and may help in reducing the need for repeated radiographic examinations.

The purpose of this study was to evaluate, for both genders and two elderly age groups, differences in lightness, chroma, and hue of pairs of natural anterior teeth, so that more accurate information on color would be available for the production of dentures with a natural appearance. The subjects in the younger group (YG) were 54 to 56 years of age, those in the older group 73 to 75 (N = 195, 48% women). Tooth color was measured using a spectrophotometer. Mixed models were calculated for each pair of teeth, with gender as a fixed factor. Gender did not have a significant effect in either age group. In both groups, differences in chroma between upper canines and lateral incisors and in lightness and hue between upper and lower canines were observed. In the YG, additional differences were found, with the only exception of the comparison between upper central and lateral incisors. The nongender-specific color differences observed should be considered when producing denture teeth for these groups of patients, in order to come as close as possible to the natural color ideal.

OBJECTIVES To evaluate the effect of body mass index (BMI) on the histopathological and clinical outcome in prostate cancer. PATIENTS AND METHODS In a prospective urological cancer database, 620 patients with prostate cancer had a radical prostatectomy (RP) as a curative treatment. The patients were categorized into three groups of BMI (kg/m2); ≤25.0 (190, ‘normal weight’), >25.0–30.0 (343, ‘overweight’) and >30.0 (87, ‘obese’). We evaluated the histopathological features and the clinical follow-up after RP. The median (range) age of the men was 64.4 (41.1–80.1) years and the median follow-up 5.5 (0.1–15.1) years. The preoperative median prostate-specific antigen (PSA) levels for normal, overweight and obese patients were 9.0 (0.3–133.0), 8.9 (0.4–230.0) and 9.2 (0.5–194.0) ng/mL, respectively. RESULTS Serum PSA levels were no different among the three groups (P = 0.92). The normal, overweight and obese patients had organ-confined prostate cancer in 53.7%, 57.1% and 58.6%, respectively (P = 0.34) and had lymph node metastases in 7.9%, 7.6% and 4.6% (P = 0.58). Tumour grading was no different for the three groups (P = 0.25). The PSA recurrence-free, prostate cancer-specific and overall survival for the three BMI groups did not differ significantly (each P > 0.05). CONCLUSION The BMI cannot be shown to be a predictor of adverse prognosis either for histopathological features or for the clinical outcome, e.g. PSA-free, prostate cancer-specific and overall survival, in a mid-European study population after RP.

Background The treatment of Herpes-simplex-virus-encephalitis (HSVE) remains a major unsolved problem in Neurology. Current gold standard for therapy is acyclovir, a drug that inhibits viral replication. Despite antiviral treatment, mortality remains up to 15%, less than 20% of patients are able to go back to work, and the majority of patients suffer from severe disability. This is a discouraging, unsatisfactory situation for treating physicians, the disabled patients and their families, and constitutes an enormous burden to the public health services. The information obtained from experimental animal research and from recent retrospective clinical observations, indicates that a substantial benefit in outcome can be expected in patients with HSVE who are treated with adjuvant dexamethasone. But currently there is no available evidence to support the routine use of adjuvant corticosteroid treatment in HSVE. A randomized multicenter trial is the only useful instrument to address this question. Design GACHE is a multicenter, randomized, double-blind, placebo-controlled, parallel group clinical trial of treatment with acyclovir and adjuvant dexamethasone, as compared with acyclovir and placebo in adults with HSVE. The statistical design will be that of a 3-stage-group sequential trial with potential sample size adaptation in the last stage. Conclusion 372 patients with proven HSVE (positive HSV-DNA-PCR), aged 18 up to 85 years; with focal neurological signs no longer than 5 days prior to admission, and who give informed consent will be recruited from Departments of Neurology of academic medical centers in Germany, Austria and The Netherlands. Sample size will potentially be extended after the second interim analysis up to a maximum of 450 patients. Trial Registration Current Controlled Trials ISRCTN45122933

A prospective multicenter phase-II trial (12 centers) was performed by the German larynx organ preservation group (DeLOS) to evaluate the effect of induction chemotherapy (ICHT) with paclitaxel/cisplatin (TP), followed by accelerated-hyperfractionated (concomitant boost) radiotherapy (RT) in responders. The trial was focused on larynx preservation, tumor control, survival, salvage surgery and late toxicity in patients with advanced larynx/hypopharynx carcinoma eligible for total laryngectomy (LE). Seventy-one patients (40 larynx, 87.5% St. III, IV; 31 hypopharynx, 93.4% St. III, IV) were enrolled into the study and treated with ICHT (200 mg/m(2) paclitaxel, 100 mg/m(2) cisplatin; day 1, 22) according to the DeLOS protocol. Patients with complete or partial tumor response proceeded to RT (69.9 Gy in 5.5 weeks). Non-responders received a LE followed by postoperative RT (56-70 Gy in 5.5-7 weeks). The response rate to ICHT for larynx cancer was 69.6% (7.1% complete, 62.5% partial response) and for hypopharyngeal cancer was 84.3% (6.9% complete, 77.4% partial response). Overall survival after 36 months was 60.3% (95% CI, 48.4-72.2%), after 42 months was 56.5% (95% CI, 44.2-68.8%). Laryngectomy-free survival was as follows: after 36 months, 43.0% (95% CI, 30.9-55.0%); after 42 months, 41.3% (95% CI, 29.3-53.3%). Both parameters did not show different outcomes after distinguishing larynx from hypopharynx. LE was indicated in 15 non-responders after ICHT. Five of the 15 non-responders refused the laryngectomy. Two of the five received RT instead and had no evidence of disease 42 months after RT. Late toxicity (dysphagia III, IV LENT SOMA score in laryngectomy-free survivors: after 6 months, 1.8%; 12 months, 11.4%; 18 months, 14.5%; 24 months, 8.1%; 36 months, 16%) and salvage surgery (4 pharyngocutaneous fistulas in 27 operations) were tolerable. In a large portion of patients eligible for LE, the larynx could be preserved with satisfying functional outcome. Good responders after ICHT had also a good general outcome with relatively rare severe late toxicities. Due to a slight increase of relevant late dysphagia, functional outcome regarding swallowing and tracheotomy free breathing should be more focused in future larynx organ preservation trials.