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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.

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

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.

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 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.

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.

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.

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.

Die Revision einer gelockerten und migrierten Pfannenkomponente mit Knochenverlust im Rahmen der Huftendoprothetik stellt eine grose chirurgische Herausforderung dar. Ziel sollte eine funktionell gunstige Rekonstruktion des Rotationszentrums bei suffizienter, mechanischer Belastbarkeit des Acetabulums sein. Die diesbezuglich in Europa am haufigsten eingesetzten Revisionsimplantate sind die Muller-Abstutzschale, die Hakendachschale nach Ganz, sowie der Burch-Schneider-Ring. Wir berichten uber unsere Erfahrungen mit diesen Implantaten bei 298 Patienten (298 Huften) und einer medianen Nachuntersuchungszeit von 4 (0–17) Jahren im Rahmen einer retrospektiven Studie. Von 224 Patienten (75%) konnten Nachuntersuchungsdaten erhoben werden. Hierbei wurde bei 176 Patienten (59%) eine radiologische Untersuchung durchgefuhrt. Weiterhin waren 54 Patienten (18%) verstorben, von 3 Patienten (1%) konnten keine Daten erhoben werden. Bei 18 Patienten (6%) wurde im Nachbeobachtungszeitraum eine erneute Revision durchgefuhrt, davon war in 9 Fallen die Ursache eine aseptische Lockerung, bei den ubrigen 9 Fallen eine septische Lockerung. In 7 weiteren Fallen (2%) wurde im Rahmen der Nachuntersuchung ein radiologisches und klinisches Versagen des Implantats diagnostiziert. Die Uberlebensrate nach 5 Jahren betrug 94% bzw. 89% nach 8 Jahren. Die Revision mit Abstutzschalen fuhrt zu akzeptablen, mittelfristigen Ergebnissen. Hauptsorgenpunkte bilden die septischen Komplikationen sowie das lytische Versagen des Spongiosatransplantats mit konsekutiver Lockerung des Abstutzrings.

Recent retrospective studies have challenged the current TNM classification of 7.0 cm to distinguish between T1 and T2 tumors. We reevaluated the optimal tumor size cutoff point that independently differentiates patient prognosis beyond the other accepted prognostic features.From 1990 to October 2006, 398 patients who underwent radical nephrectomy for localized renal cell carcinoma (T1-T2, N0, M0) were followed prospectively. Median followup was 5.3 years and 37 patients died of tumor related causes. The optimal tumor cutoff point was calculated and multivariate Cox proportional hazards models were used to adjust for the effects of Fuhrman grade, tumor type, sex, age and Karnofsky performance status on cancer specific survival. Sensitivity analysis included all 66 patients with elective nephron sparing surgery.Univariate analysis supported 7 cm as the optimal cutoff point for prognostic stratification (p = 0.002). The 4 cm cutoff point that is used to distinguish between stage T1a and T1b could not be confirmed with analogous statistical significance (p = 0.20). On multivariate analysis tumor size dichotomized at 7 cm was an independent prognostic factor (HR 2.89, 95% CI 1.46-5.73, p = 0.002), as was Fuhrman grade 3 (HR 3.68, 95% CI 1.37-9.83, p = 0.010) and age older than 60 years (HR 3.64, 95% CI 1.63-8.14, p = 0.002). The inclusion of patients with elective nephron sparing surgery confirmed these results.Univariate and multivariate analyses of our patient cohort undergoing radical nephrectomy for localized renal cell carcinoma showed no cutoff point other than 7 cm to be more suitable for distinguishing between T1 and T2 tumors, supporting the current TNM classification. In T1 tumors the analysis did not allow a clear dichotomization of tumor size in this group.

In revision hip arthroplasty, cages are commonly used for acetabular reconstruction in cases with loss of bone stock. It is important to follow this patient group closely, in order to better understand failure mechanisms and the chance of long-term success.We followed our first 164 acetabular revisions with the Mueller reinforcement ring (ARR) in 164 patients, with an average follow-up period of 6 (2-17) years. Mean age at surgery was 69 (29-92) years. 39 patients died (39 hips) during follow-up, but only 3 patients (3 hips) were lost to follow-up.In the observation period, 13 of the hips had to undergo acetabular re-revision for aseptic and septic loosening. Overall survival at 5 years was 95% (CI: 89%-98%) and 90% (CI: 76%-95%) at 8 years using acetabular re-revision or implant removal for all reasons as endpoint. In addition, mechanical and clinical failure was seen in 2 cases. The mean Harris hip score was 70 points, whilst the Merle d'Aubigné score averaged 7 points. Radiolucent lines according to DeLee and Charnley were observed twice in zone I, 6 times in zone II and 14 times in zone III.We found that mid- to long-term survival of the ARR is acceptable. However, failure of the implant due to allograft collapse/resorption or deep infection, and also poor clinical outcome, remain major concerns in acetabular revision arthroplasty. This should be recognized when advising patients.

Background Growth factors such as platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) appear to play a key role in immunologic reactions in the long-term course after heart transplant. Their expression in the early phase after transplant has been recently described. The aim of the present study was, therefore, to examine the growth factor expression in the early and later periods, up to three years after transplant in the same patient cohort. Methods Right ventricular endomyocardial biopsies were obtained from 29 heart transplant recipients before implantation, after one and two weeks, and after one, two, and three years after heart transplant, and immediately frozen in liquid nitrogen. The growth factor expression was examined immunohistochemically. Results The PDGFs were mainly expressed in vascular structures and they were less pronounced in cardiomyocytes. Especially after the first week, a significant increase was found in the expression of PDGF A and B as well as PDGF-receptors α and β. In the yearly biopsies, PDGF expression was rarely found. The bFGF expression was merely weak in the later period three years after transplant and the aFGF was only expressed in the early phase. A comparison of recipients with short and long ischemic time did not reveal any significant differences in the intensity of expression. Conclusions The increased expression of PDGF and FGF in the first postoperative week can be interpreted as an unspecific reaction to peritransplant injury. This might be related to important reparative, angioprotective, and wound-healing processes shortly after the heart transplant had taken place. The weak expression in the later period appears to be linked to a stable transplant function and a direct influence by the immunosuppressive therapy.

This study was undertaken to investigate whether there might be differences in the distribution of extracellular matrix (ECM) proteins and matrix metalloproteinases (MMPs), depending on their specific sites within the heart. We investigated 33 explanted human hearts, 15 with dilated cardiomyopathy (DCM) and 18 with ischemic cardiomyopathy (ICM). Transmural samples from the right ventricle, the interventricular septum and the left ventricle, either from near the apex or from near the base were taken from every heart. Frozen sections were processed for connective tissue staining and immunohistochemistry for collagens type I, III, IV, laminin and fibronectin, as well as MMP-1, -2 and -9. Volume densities of laminin in ICM as well as of fibronectin and collagen types I and IV in DCM showed significant differences between right and left ventricular sites. The volume densities of matrix proteins usually did not reveal significant differences among the three left ventricular sites tested in both DCM and ICM. MMPs partly showed differences between the right and the left ventricular myocardium. These results suggest that the distributions of ECM proteins and MMPs differ between the two ventricles in both end-stage DCM and ICM. This gives rise to the hypothesis that a specific pattern of ECM degradation exists in the right and left ventricular myocardium.

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.

Few studies have been published on the influence of psychotherapy on the physical and psychosocial course of Crohn's disease (CD).The present study, a prospective, randomized multicenter investigation conducted with 108 of 488 consecutive CD patients, was designed to investigate the influence of short-term psychodynamic therapy and relaxation in addition to a standardized glucocorticoid therapy on the somatic course of the disease as well as on patient psychosocial status. Based on the same standardized somatic treatment, the psychotherapy and control groups were compared after a 1-year treatment period and a follow-up of another year with regard to somatic course and psychosocial situation.A total of 81 (75%) of 108 randomized patients completed the psychosocial follow-up. The comparison between the therapy groups after 1 year showed no significant differences in the four main target criteria of psychosocial status (depression, anxiety, psychosocial-communicative status and health-related quality of life). The mean Beck's Depression Inventory (BDI) score at admission was 12.3 in the psychotherapy group and 8.7 in the control group. At the 1-year follow-up, the scores for depression have been 7.8 (psychotherapy group) and 7.8 (control group). In the 2-year follow-up, 84 patients were classified into four groups on the basis of somatic course; 23% of the control group and 30% of the psychotherapy group showed episode-free courses, 29% and 17% respectively underwent surgery due to failure of immunosuppressive or medical therapy, and a further subranking showed no significant differences between the two groups (P=.125). At the 1-year follow-up, the scores for depression of patients with an active episode respective remission were 14.6 vs. 5.8. From the patient's point of view, at the end of the 2-year follow-up, the overall subjective evaluation of the effectiveness of psychotherapy was positive.The patients included showed no psychosocial disturbances of clinical relevance. Although a tendency toward fewer surgical interventions, fewer relapses and reduction of depression was noted, the analysis was unable to demonstrate any benefit from psychosocial intervention on hypothesized parameters of psychosocial status and somatic course. Further studies should be performed to identify patient subgroups that may benefit from psychosocial intervention.

Summary Background Osteoporosis and related fractures are a major complication after organ transplantation. The aim of this study was to find out the frequency and predictors of osteoporotic fractures after cardiac or liver transplantation. Methods 235 consecutive patients who had a cardiac transplant (n=105; 88 men, 17 women) or a liver transplant (130; 75 men, 55 women) were followed. Vertebral fractures were assessed by a standardised analysis of spinal radiographs before and annually after transplantation. Clinical and non-vertebral fracture data were noted from hospital records. Findings In the first and second years after transplantation, the proportion of patients (Kaplan-Meier estimates) who had at least one vertebral fracture was slightly higher in the cardiac group (first year 21%, second year 27%) than in the liver group (first year 14%, second year 21%). In the third and fourth years, one third of patients from both groups had had one or more vertebral fractures. Non-vertebral fractures occurred in nine patients (7%) after liver transplantation and avascular necrosis of the hip head in three patients (3%) after cardiac transplantation. In both groups, no dose dependent effect of immunosuppressive therapy on fracture development could be identified. Independent predictors assessed by multivariate analysis were age (hazard ratio [95% CI] increase of 5 years, 1·71 [1·1–2·7]) and lumbar bone-mineral density (decrease of 1 SD t score, 1·97 [1·2–3·2]) in cardiac transplantation patients, and vertebral fractures before transplantation (6·07 [1·7–21·7]) in the liver group. Interpretation The high frequency of osteoporotic fractures in the 2 years after transplantation and the limitations of reliable fracture-risk predictions, show the need to investigate preventive therapies.

PURPOSE In patients with stage IV melanoma, durable responses have been reported with treatment regimens that involve high-dose interleukin-2 (IL-2). We analyze long-term results of 631 melanoma patients from 12 institutions who had received IL-2 alone, in combination with interferon alfa 2a or 2b (IFNalpha), or with cytotoxic drugs. METHODS Case records that contained pretreatment parameters, response data, and updated survival information were collected. After univariate analysis, the multivariate evaluation of the impact of pretreatment parameters on response and survival was performed by logistic regression and Cox's regression, respectively. RESULTS Patients were divided into four groups according to treatment: IL-2 alone (n=117), IL-2 and chemotherapy (n=49), IL-2 and IFNalpha (n=153), and IL-2, chemotherapy, and IFNalpha (n=312). The median survival of all patients was 10.5 months and the 2- and 5-year survival rates were 19.9% and 10.4%, respectively. Independent prognostic factors for response and survival were entirely different, treatment group being the only significant factor for response, and serum lactate dehydrogenase (LDH), metastatic site, and performance predicting survival. The addition of IFNalpha to IL-2 was associated with prolonged survival, but the effect of additional chemotherapy was less obvious. CONCLUSION Serum LDH, metastatic site, and performance status are useful stratification factors for randomized trials in metastatic melanoma. The improved long-term survival rates observed in melanoma patients treated with IL-2/IFNalpha-containing regimens are notable in contrast to the reported 5-year survival rates of 2% to 6% achieved with chemotherapy, but because selection bias cannot be ruled out, the impact of IL-2, as well as all other components of the treatment regimens, on survival needs to be confirmed in prospective randomized trials.

Background. Small cell lung cancer (SCLC) is distinguished from other histologic types of lung cancer by possessing a variety of neuroendocrine properties. Neuron-specific enolase (NSE) is the most frequently elevated tumor marker for patients with SCLC at diagnosis. To assess the value of neural cell adhesion molecules (NCAM), another possible tumor marker for small cell lung cancer, NCAM was evaluated in the sera of patients with histologically confirmed SCLC in two prospective multicenter trials. Methods. The study includes 221 patients with SCLC, normal human blood donors (n = 34), patients with benign lung disease (n = 53), and patients with non-small cell lung cancer (n = 28). NCAM was determined by means of an enzyme immunoassay, NSE by a radioimmunoassay. Results. The data show the following: (1) 51% (113 of 221) of all patients with SCLC had NCAM levels higher than 20 U/ml, 34% (75 of 221) had NSE levels higher than 25 ng/ml; (2) levels of both markers significantly differ between limited and extensive disease patients; (3) patients with pathologic NCAM and NSE levels have significantly shorter survival times; (4) a positive correlation between pretreatment NSE and NCAM levels was found (n = 221, r = 0.60); and (5) a correlation between serum marker levels and clinical status was found in follow-up studies of 19 patients. Conclusions. From these data, it is concluded that NCAM is, along with NSE, a potential tumor marker for SCLC.

To test if inflammation also interferes with liver stiffness (LS) assessment in alcoholic liver disease (ALD) and to provide a clinical algorithm for reliable fibrosis assessment in ALD by FibroScan (FS).We first performed sequential LS analysis before and after normalization of serum transaminases in a learning cohort of 50 patients with ALD admitted for alcohol detoxification. LS decreased in almost all patients within a mean observation interval of 5.3 d. Six patients (12%) would have been misdiagnosed with F3 and F4 fibrosis but LS decreased below critical cut-off values of 8 and 12.5 kPa after normalization of transaminases.Of the serum transaminases, the decrease in LS correlated best with the decrease in glutamic oxaloacetic transaminase (GOT). No significant changes in LS were observed below GOT levels of 100 U/L. After establishing the association between LS and GOT levels, we applied the rule of GOT100 U/L for reliable LS assessment in a second validation cohort of 101 patients with histologically confirmed ALD. By excluding those patients with GOT100 U/L at the time of LS assessment from this cohort, the area under the receiver operating characteristic (AUROC) for cirrhosis detection by FS improved from 0.921 to 0.945 while specificity increased from 80% to 90% at a sensitivity of 96%. A similar AUROC could be obtained for lower F3 fibrosis stage if LS measurements were restricted to patients with GOT50 U/L. Histological grading of inflammation did not further improve the diagnostic accuracy of LS.Coexisting steatohepatitis markedly increases LS in patients with ALD independent of fibrosis stage. Postponing cirrhosis assessment by FS during alcohol withdrawal until GOT decreases to100 U/mL significantly improves the diagnostic accuracy.

Background The enhancer of zeste homolog 2 (EZH2) gene exerts oncogene-like activities and its (over)expression has been linked to several human malignancies. Here, we studied a possible association between EZH2 expression and prognosis in patients with renal cell carcinoma (RCC). Methods EZH2 protein expression in RCC specimens was analyzed by immunohistochemistry using a tissue microarray (TMA) containing RCC tumor tissue and corresponding normal tissue samples of 520 patients. For immunohistochemical assessment of EZH2 expression, nuclear staining quantity was evaluated using a semiquantitative score. The effect of EZH2 expression on cancer specific survival (CSS) was assessed by univariate and multivariate Cox regression analyses. Results During follow-up, 147 patients (28%) had died of their disease, median follow-up of patients still alive was 6.0 years (range 0-16.1 years). EZH2 nuclear staining was present in tumor cores of 411 (79%) patients. A multivariate Cox regression analysis revealed that high nuclear EZH2 expression was an independent predictor of poor CSS (> 25-50% vs. 0%: HR 2.72, p = 0.025) in patients suffering from non-metastatic RCC. Apart from high nuclear EZH2 expression, tumor stage and Fuhrman's grading emerged as significant prognostic markers. In metastatic disease, nuclear EZH2 expression and histopathological subtype were independent predictive parameters of poor CSS (EZH2: 1-5%: HR 2.63, p = 0.043, >5-25%: HR 3.35, p = 0.013, >25%-50%: HR 4.92, p = 0.003, all compared to 0%: HR 0.36, p = 0.025, respectively). Conclusions This study defines EZH2 as a powerful independent unfavourable prognostic marker of CSS in patients with metastatic and non-metastatic RCC.