Common clonal origin of conventional T cells and induced regulatory T cells in breast cancer patients.

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.

Analysis of long-term survival in multiple myeloma after first-line autologous stem cell transplantation: impact of clinical risk factors and sustained response.

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.

Parity improves anti-tumor immunity in breast cancer patients.

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.

Mucin 1-specific B cell immune responses and their impact on overall survival in breast cancer patients.

Considering the diverse functions of B cells, responses to tumor-associated antigens (TAA) have been thought to be the main source of B cell-mediated antitumor immunity. Polymorphic epithelial mucin (MUC1) is considered one of the most specific TAA in patients with breast cancer. The present study aims to dissect the level and subclasses of naturally occurring anti-MUC1 antibodies in regard to tumor biologic parameters, clinical characteristics and overall survival. In 288 primary, non-metastatic breast cancer patients, pretreatment serum levels of anti-MUC1 immunoglobulin G (IgG) and its subclasses G1-4 as well as immunoglobulin M (IgM) were analyzed via ELISA. With respect to overall survival (Kaplan-Meier analysis), tumor biologic parameters as hormone receptor status, human epidermal growth factor receptor 2 (Her2), Ki-67 expression and tumor grading have been correlated as well as clinical characteristics as nodal involvement, tumor stage and patients' age at the time of diagnosis. Median follow-up time was 148 mo (IQR: 73.1-158.5 mo). A significant increase in IgG antibody titers was correlated highly significantly with an improved overall survival of patients. In multivariate analysis, total IgG proved to be an independent prognostic marker for overall survival (p = 0.002). IgG subclass analysis did not reveal any correlation of IgG1, IgG3 and IgG4 levels with overall survival, while increased immunoglobulin G2 (IgG2) values, although statistically not significant, tended to correlate with prolonged patient survival. MUC1-specific IgM antibodies were shown not to be predictive of overall survival. Altogether, humoral immune responses appear to play a crucial part in the tumor immunity of breast cancer patients. The present data confirms the positive impact of tumor-specific IgG on prolonged overall survival in breast cancer patients. MUC1-antibody testing might be a useful tool to identify high-risk patients who may need adjuvant therapy and potentially might benefit from MUC1-directed immunotherapy.

T cell responses in early-stage melanoma patients occur frequently and are not associated with humoral response.

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.

A randomized clinical trial comparing the impact of different oral hygiene protocols and sealant applications on plaque, gingival, and caries index scores.

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.

Antitumor T cell responses in bladder cancer are directed against a limited set of antigens and are modulated by regulatory T cells and routine treatment approaches.

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.

Prognostic value of melanoma-associated antigen A9 in renal cell carcinoma.

OBJECTIVE: The aim of this study was to evaluate the prognostic relevance of melanoma-associated antigen (MAGE) A9 in renal cell carcinoma (RCC). MATERIAL AND METHODS: 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. RESULTS: 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 index < 80% 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 index > 80% was a significant predictor for CSS; MAGE A9 expression could not be shown to be associated with CSS (p = 0.161). CONCLUSIONS: 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.

Prognostic value of the periodontal risk assessment in patients with aggressive periodontitis.

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.

Clinical success rates for polyether crown impressions when mixed dynamically and statically.

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%).

An association between infantile haemangiomas and erythropoietin treatment in preterm infants.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Effect of the osteotome technique in cases of deficient edentulous ridge.

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.

Fiber-reinforced composite fixed dental prostheses: a retrospective clinical examination.

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: Fiber-reinforced composite fixed dental prostheses provide sufficient stability and very good esthetic, biological, and functional performance in the case of specific clinical indications.

Experimental study determining the mechanical properties of dental floss holders.

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 <4 mm for the displacement of the floss, ≥11 N for the force, and <0.1 mm for the difference in branch distance and the offset. Only two products fulfilled our criteria. The tests show that dental floss holders vary extremely in their mechanical properties. Their effective use seems often impossible due to limited mechanical properties.

Enhancer of zeste homolog 2 (EZH2) expression is an independent prognostic factor in renal cell carcinoma.

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.

Recontouring teeth and closing diastemas with direct composite buildups: a clinical evaluation of survival and quality parameters.

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.

Three-body wear of resin denture teeth with and without nanofillers.

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, alpha=.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.

Increased liver stiffness in alcoholic liver disease: differentiating fibrosis from steatohepatitis.

AIM: 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). METHODS: 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. RESULTS: 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 GOT < 100 U/L for reliable LS assessment in a second validation cohort of 101 patients with histologically confirmed ALD. By excluding those patients with GOT > 100 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 GOT < 50 U/L. Histological grading of inflammation did not further improve the diagnostic accuracy of LS. CONCLUSION: Coexisting steatohepatitis markedly increases LS in patients with ALD independent of fibrosis stage. Postponing cirrhosis assessment by FS during alcohol withdrawal until GOT decreases to < 100 U/mL significantly improves the diagnostic accuracy.

Preliminary longitudinal report on symptom outcomes in symptomatic and asymptomatic women with imaging evidence of temporomandibular joint arthritic changes.

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: These preliminary results suggest that factors other than dental occlusion might play a role in the reduction of pain.