Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer.

BACKGROUND: Unresectable locally advanced or metastatic triple-negative (hormone-receptor-negative and human epidermal growth factor receptor 2 [HER2]-negative) breast cancer is an aggressive disease with poor outcomes. Nanoparticle albumin-bound (nab)-paclitaxel may enhance the anticancer activity of atezolizumab. METHODS: In this phase 3 trial, we randomly assigned (in a 1:1 ratio) patients with untreated metastatic triple-negative breast cancer to receive atezolizumab plus nab-paclitaxel or placebo plus nab-paclitaxel; patients continued the intervention until disease progression or an unacceptable level of toxic effects occurred. Stratification factors were the receipt or nonreceipt of neoadjuvant or adjuvant taxane therapy, the presence or absence of liver metastases at baseline, and programmed death ligand 1 (PD-L1) expression at baseline (positive vs. negative). The two primary end points were progression-free survival (in the intention-to-treat population and PD-L1-positive subgroup) and overall survival (tested in the intention-to-treat population; if the finding was significant, then it would be tested in the PD-L1-positive subgroup). RESULTS: Each group included 451 patients (median follow-up, 12.9 months). In the intention-to-treat analysis, the median progression-free survival was 7.2 months with atezolizumab plus nab-paclitaxel, as compared with 5.5 months with placebo plus nab-paclitaxel (hazard ratio for progression or death, 0.80; 95% confidence interval [CI], 0.69 to 0.92; P=0.002); among patients with PD-L1-positive tumors, the median progression-free survival was 7.5 months and 5.0 months, respectively (hazard ratio, 0.62; 95% CI, 0.49 to 0.78; P<0.001). In the intention-to-treat analysis, the median overall survival was 21.3 months with atezolizumab plus nab-paclitaxel and 17.6 months with placebo plus nab-paclitaxel (hazard ratio for death, 0.84; 95% CI, 0.69 to 1.02; P=0.08); among patients with PD-L1-positive tumors, the median overall survival was 25.0 months and 15.5 months, respectively (hazard ratio, 0.62; 95% CI, 0.45 to 0.86). No new adverse effects were identified. Adverse events that led to the discontinuation of any agent occurred in 15.9% of the patients who received atezolizumab plus nab-paclitaxel and in 8.2% of those who received placebo plus nab-paclitaxel. CONCLUSIONS: Atezolizumab plus nab-paclitaxel prolonged progression-free survival among patients with metastatic triple-negative breast cancer in both the intention-to-treat population and the PD-L1-positive subgroup. Adverse events were consistent with the known safety profiles of each agent. (Funded by F. Hoffmann-La Roche/Genentech; IMpassion130 ClinicalTrials.gov number, NCT02425891 .).

Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Immunotherapy in combination with chemotherapy has shown promising efficacy across many different tumour types. We report the prespecified second interim overall survival analysis of the phase 3 IMpassion130 study assessing the efficacy and safety of atezolizumab plus nab-paclitaxel in patients with unresectable, locally advanced or metastatic triple-negative breast cancer. METHODS: In this randomised, placebo-controlled, double-blind, phase 3 trial, done in 246 academic centres and community oncology practices in 41 countries, patients aged 18 years or older, with previously untreated, histologically documented, locally advanced or metastatic triple-negative breast cancer, and Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) using a permuted block method (block size of four) and an interactive voice-web response system. Randomisation was stratified by previous taxane use, liver metastases, and PD-L1 expression on tumour-infiltrating immune cells. Patients received atezolizumab 840 mg or matching placebo intravenously on day 1 and day 15 of every 28-day cycle and nab-paclitaxel 100 mg/m2 of body surface area intravenously on days 1, 8, and 15 until progression or unacceptable toxicity. Investigators, patients, and the funder were masked to treatment assignment. Coprimary endpoints were investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1 and overall survival, assessed in the intention-to-treat population and in patients with PD-L1 immune cell-positive tumours (tumours with ≥1% PD-L1 expression). The final progression-free survival results were previously reported at the first interim overall survival analysis. The prespecified statistical testing hierarchy meant that overall survival in the subgroup of PD-L1 immune cell-positive patients could only be formally tested if overall survival was significantly different between the treatment groups in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02425891. FINDINGS: Between June 23, 2015, and May 24, 2017, 902 patients were enrolled, of whom 451 were randomly assigned to receive atezolizumab plus nab-paclitaxel and 451 were assigned to receive placebo plus nab-paclitaxel (the intention-to-treat population). Six patients from each group did not receive treatment. At the second interim analysis (data cutoff Jan 2, 2019), median follow-up was 18·5 months (IQR 9·6-22·8) in the atezolizumab group and 17·5 months (8·4-22·4) in the placebo group. Median overall survival in the intention-to-treat patients was 21·0 months (95% CI 19·0-22·6) with atezolizumab and 18·7 months (16·9-20·3) with placebo (stratified hazard ratio [HR] 0·86, 95% CI 0·72-1·02, p=0·078). In the exploratory overall survival analysis in patients with PD-L1 immune cell-positive tumours, median overall survival was 25·0 months (95% CI 19·6-30·7) with atezolizumab versus 18·0 months (13·6-20·1) with placebo (stratified HR 0·71, 0·54-0·94]). As of Sept 3, 2018 (the date up to which updated safety data were available), the most common grade 3-4 adverse events were neutropenia (38 [8%] of 453 patients in the atezolizumab group vs 36 [8%] of 437 patients in the placebo group), peripheral neuropathy (25 [6%] vs 12 [3%]), decreased neutrophil count (22 [5%] vs 16 [4%]), and fatigue (17 [4%] vs 15 [3%]). Treatment-related deaths occurred in two (<1%) patients in the atezolizumab group (autoimmune hepatitis related to atezolizumab [n=1] and septic shock related to nab-paclitaxel [n=1]) and one (<1%) patient in the placebo group (hepatic failure). No new treatment-related deaths have been reported since the primary clinical data cutoff date (April 17, 2018). INTERPRETATION: Consistent with the first interim analysis, this second interim overall survival analysis of IMpassion130 indicates no significant difference in overall survival between the treatment groups in the intention-to-treat population but suggests a clinically meaningful overall survival benefit with atezolizumab plus nab-paclitaxel in patients with PD-L1 immune cell-positive disease. However, this positive result could not be formally tested due to the prespecified statistical testing hierarchy. For patients with PD-L1 immune cell-positive metastatic triple-negative breast cancer, atezolizumab plus nab-paclitaxel is an important therapeutic option in a disease with high unmet need. FUNDING: F Hoffmann-La Roche and Genentech.

Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial.

BACKGROUND: Alectinib--a highly selective, CNS-active, ALK inhibitor-showed promising clinical activity in crizotinib-naive and crizotinib-resistant patients with ALK-rearranged (ALK-positive) non-small-cell lung cancer (NSCLC). We aimed to assess the safety and efficacy of alectinib in patients with ALK-positive NSCLC who progressed on previous crizotinib. METHODS: We did a phase 2 study at 27 centres in the USA and Canada. We enrolled patients aged 18 years or older with stage IIIB-IV, ALK-positive NSCLC who had progressed after crizotinib. Patients were treated with oral alectinib 600 mg twice daily until progression, death, or withdrawal. The primary endpoint was the proportion of patients achieving an objective response by an independent review committee using Response Evaluation Criteria in Solid Tumors, version 1.1. Response endpoints were assessed in the response-evaluable population (ie, patients with measurable disease at baseline who received at least one dose of study drug), and efficacy and safety analyses were done in the intention-to-treat population (all enrolled patients). This study is registered with ClinicalTrials.gov, number NCT01871805. The study is ongoing and patients are still receiving treatment. FINDINGS: Between Sept 4, 2013, and Aug 4, 2014, 87 patients were enrolled into the study (intention-to-treat population). At the time of the primary analysis (median follow-up 4·8 months [IQR 3·3-7·1]), 33 of 69 patients with measurable disease at baseline had a confirmed partial response; thus, the proportion of patients achieving an objective response by the independent review committee was 48% (95% CI 36-60). Adverse events were predominantly grade 1 or 2, most commonly constipation (31 [36%]), fatigue (29 [33%]), myalgia 21 [24%]), and peripheral oedema 20 [23%]). The most common grade 3 and 4 adverse events were changes in laboratory values, including increased blood creatine phosphokinase (seven [8%]), increased alanine aminotransferase (five [6%]), and increased aspartate aminotransferase (four [5%]). Two patients died: one had a haemorrhage (judged related to study treatment), and one had disease progression and a history of stroke (judged unrelated to treatment). INTERPRETATION: Alectinib showed clinical activity and was well tolerated in patients with ALK-positive NSCLC who had progressed on crizotinib. Therefore, alectinib could be a suitable treatment for patients with ALK-positive disease who have progressed on crizotinib. FUNDING: F Hoffmann-La Roche.

Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial.

BACKGROUND: The addition of bevacizumab to chemotherapy improves progression-free survival in metastatic breast cancer and pathological complete response rates in the neoadjuvant setting. Micrometastases are dependent on angiogenesis, suggesting that patients might benefit from anti-angiogenic strategies in the adjuvant setting. We therefore assessed the addition of bevacizumab to chemotherapy in the adjuvant setting for women with triple-negative breast cancer. METHODS: For this open-label, randomised phase 3 trial we recruited patients with centrally confirmed triple-negative operable primary invasive breast cancer from 360 sites in 37 countries. We randomly allocated patients aged 18 years or older (1:1 with block randomisation; stratified by nodal status, chemotherapy [with an anthracycline, taxane, or both], hormone receptor status [negative vs low], and type of surgery) to receive a minimum of four cycles of chemotherapy either alone or with bevacizumab (equivalent of 5 mg/kg every week for 1 year). The primary endpoint was invasive disease-free survival (IDFS). Efficacy analyses were based on the intention-to-treat population, safety analyses were done on all patients who received at least one dose of study drug, and plasma biomarker analyses were done on all treated patients consenting to biomarker analyses and providing a measurable baseline plasma sample. This trial is registered with ClinicalTrials.gov, number NCT00528567. FINDINGS: Between Dec 3, 2007, and March 8, 2010, we randomly assigned 1290 patients to receive chemotherapy alone and 1301 to receive bevacizumab plus chemotherapy. Most patients received anthracycline-containing therapy; 1638 (63%) of the 2591 patients had node-negative disease. At the time of analysis of IDFS, median follow-up was 31·5 months (IQR 25·6-36·8) in the chemotherapy-alone group and 32·0 months (27·5-36·9) in the bevacizumab group. At the time of the primary analysis, IDFS events had been reported in 205 patients (16%) in the chemotherapy-alone group and in 188 patients (14%) in the bevacizumab group (hazard ratio [HR] in stratified log-rank analysis 0·87, 95% CI 0·72-1·07; p=0·18). 3-year IDFS was 82·7% (95% CI 80·5-85·0) with chemotherapy alone and 83·7% (81·4-86·0) with bevacizumab and chemotherapy. After 200 deaths, no difference in overall survival was noted between the groups (HR 0·84, 95% CI 0·64-1·12; p=0·23). Exploratory biomarker assessment suggests that patients with high pre-treatment plasma VEGFR-2 might benefit from the addition of bevacizumab (Cox interaction test p=0·029). Use of bevacizumab versus chemotherapy alone was associated with increased incidences of grade 3 or worse hypertension (154 patients [12%] vs eight patients [1%]), severe cardiac events occurring at any point during the 18-month safety reporting period (19 [1%] vs two [<0·5%]), and treatment discontinuation (bevacizumab, chemotherapy, or both; 256 [20%] vs 30 [2%]); we recorded no increase in fatal adverse events with bevacizumab (four [<0·5%] vs three [<0·5%]). INTERPRETATION: Bevacizumab cannot be recommended as adjuvant treatment in unselected patients with triple-negative breast cancer. Further follow-up is needed to assess the potential effect of bevacizumab on overall survival.

Atezolizumab With Neoadjuvant Anti-Human Epidermal Growth Factor Receptor 2 Therapy and Chemotherapy in Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer: Primary Results of the Randomized Phase III IMpassion050 Trial.

PURPOSE: Combining standard of care (pertuzumab-trastuzumab [PH], chemotherapy) with cancer immunotherapy may potentiate antitumor immunity, cytotoxic activity, and patient outcomes in high-risk, human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. We report the phase III IMpassion050 primary analysis of neoadjuvant atezolizumab, PH, and chemotherapy in these patients. METHODS: Patients with a primary tumor of > 2 cm and histologically confirmed, positive lymph node status (T2-4, N1-3, M0) were randomly assigned 1:1 to atezolizumab/placebo with dose-dense doxorubicin/cyclophosphamide, followed by paclitaxel, and PH. After surgery, patients were to continue atezolizumab/placebo and PH (total: 1 year of HER2-targeted therapy); those with residual disease could switch to ado-trastuzumab emtansine with atezolizumab/placebo. Coprimary efficacy end points were pathologic complete response (pCR; ypT0/is ypN0) rates in intention-to-treat (ITT) and programmed cell death-ligand 1 (PD-L1)-positive populations. RESULTS: At clinical cutoff (February 5, 2021), pCR rates in the placebo and atezolizumab groups in the ITT populations were 62.7% (n = 143/228) and 62.4% (n = 141/226), respectively (difference -0.33%; 95% CI, -9.2 to 8.6; P = .9551). The pCR rates in the placebo and atezolizumab groups in patients with PD-L1-positive tumors were 72.5% (n = 79/109) and 64.2% (n = 70/109), respectively (difference -8.26%; 95% CI, -20.6 to 4.0; P = .1846). Grade 3-4 and serious adverse events were more frequent in the atezolizumab versus placebo group. Five grade 5 adverse events occurred (four neoadjuvant, one adjuvant; two assigned to study treatment), all with atezolizumab. Overall, the safety profile was consistent with that of atezolizumab in other combination studies. CONCLUSION: Atezolizumab with neoadjuvant dose-dense doxorubicin/cyclophosphamide-paclitaxel and PH for high-risk, HER2-positive early breast cancer did not increase pCR rates versus placebo in the ITT or PD-L1-positive populations. PH and chemotherapy remains standard of care; longer follow-up may help to inform the long-term impact of atezolizumab.

Diagnostic performance of the universal visual scoring system (UniViSS) on occlusal surfaces.

Aim of this investigation was to evaluate the validity and reproducibility of the universal visual scoring systems (UniViSS) on occlusal surfaces in vitro. The validity study included 65 third molars. Following to reach a UniViSS consensus diagnosis for each surface, all teeth were histologically prepared and evaluated according to the newly developed caries-extension-index (CE-index). The reproducibility study consisted of 149 molars. These teeth were examined by two dentists and four students without any calibration training. In result, the CE-index provided the exact caries depth for each UniViSS criterion, which could further be associated with a distinct preventive or treatment strategy. The mean intra-/inter-examiner weighted Kappa values amounted to 0.685/0.551 (UniViSS/severity) and 0.628/0.542 (UniViSS/discoloration). The cumulative Logit-model underlined that UniViSS/severity criteria were more frequently reproduced in comparison to the UniViSS/discoloration criteria. In conclusion, this study on the diagnostic performance of UniViSS showed encouraging results and give valuable hints for future studies.

A semiparametric Bayesian proportional hazards model for interval censored data with frailty effects.

BACKGROUND: Multivariate analysis of interval censored event data based on classical likelihood methods is notoriously cumbersome. Likelihood inference for models which additionally include random effects are not available at all. Developed algorithms bear problems for practical users like: matrix inversion, slow convergence, no assessment of statistical uncertainty. METHODS: MCMC procedures combined with imputation are used to implement hierarchical models for interval censored data within a Bayesian framework. RESULTS: Two examples from clinical practice demonstrate the handling of clustered interval censored event times as well as multilayer random effects for inter-institutional quality assessment. The software developed is called survBayes and is freely available at CRAN. CONCLUSION: The proposed software supports the solution of complex analyses in many fields of clinical epidemiology as well as health services research.

Serum concentrations of cortisol, interleukin 6, leptin and adiponectin predict stress induced insulin resistance in acute inflammatory reactions.

INTRODUCTION: Inflammatory stimuli are causative for insulin resistance in obesity as well as in acute inflammatory reactions. Ongoing research has identified a variety of secreted proteins that are released from immune cells and adipocytes as mediators of insulin resistance; however, knowledge about their relevance for acute inflammatory insulin resistance remains limited. In this study we aimed for a clarification of the relevance of different insulin resistance mediating factors in an acute inflammatory situation. METHODS: Insulin resistance was measured in a cohort of 37 non-diabetic patients undergoing cardiac surgery by assessment of insulin requirement to maintain euglycaemia and repeated measurements of an insulin glycaemic index. The kinetics of cortisol, interleukin 6 (IL6), tumour necrosis factor alpha (TNFalpha), resistin, leptin and adiponectin were assessed by repeated measurements in a period of 48 h. RESULTS: Insulin resistance increased during the observation period and peaked 22 h after the beginning of the operation. IL6 and TNFalpha displayed an early increase with peak concentrations at the 4-h time point. Serum levels of cortisol, resistin and leptin increased more slowly and peaked at the 22-h time point, while adiponectin declined, reaching a base at the 22-h time point. Model assessment identified cortisol as the best predictor of insulin resistance, followed by IL6, leptin and adiponectin. No additional information was gained by modelling for TNFalpha, resistin, catecholamine infusion rate, sex, age, body mass index (BMI), operation time or medication. CONCLUSIONS: Serum cortisol levels are the best predictor for inflammatory insulin resistance followed by IL6, leptin and adiponectin. TNFalpha, and resistin have minor relevance as predictors of stress dependent insulin resistance.

Validity of temporomandibular disorder examination procedures for assessment of temporomandibular joint status.

INTRODUCTION: This hypothesis-generating study was performed to determine which items in the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) and additional diagnostic tests have the best predictive accuracy for joint-related diagnoses. METHODS: One hundred forty-nine TMD patients and 43 symptom-free subjects were examined in clinical examinations and with magnetic resonance imaging (MRI). The importance of each variable of the clinical examination for correct joint-related diagnosis was assessed by using MRI diagnoses. For this purpose, "random forest" statistical software (based on classification trees) was used. RESULTS: Maximum unassisted jaw opening, maximum assisted jaw opening, history of locked jaw, joint sound with and without compression, joint pain, facial pain, pain on palpation of the lateral pterygoid area, and overjet proved suitable for distinguishing between subtypes of joint-related TMD. Measurement of excursion, protrusion, and midline deviation were less important. CONCLUSIONS: The validity of clinical TMD examination procedures can be enhanced by using the 16 variables of greatest importance identified in this study. In addition to other variables, maximum unassisted and assisted opening and a history of locked jaw were important when assessing the status of the TMJ.

In vitro leakage associated with three root-filling techniques in large and extremely large root canals.

This study assessed the apical leakage of ultrasonically condensed root fillings in extremely large canals, compared to cold lateral condensation and thermoplastic compaction. Ninety single-rooted teeth were used. In 45 teeth canals were enlarged to size 70 (large). The remaining 45 canals were enlarged to size 140 (extremely large). Each set of teeth was subdivided into three root-filling groups (n = 15): (1) cold lateral condensation (LC); (2) thermoplastic compaction (TC); and (3) ultrasonic lateral condensation (UC). Teeth in all six subgroups were subjected to drawing ink penetration, cleared, and evaluated for linear apical dye leakage. Significantly deeper dye penetration (p < 0.04, Wilcoxon rank-sum test) was observed for LC than for UC. TC did not differ significantly from LC and UC. Dye penetration was significantly deeper (p < 0.0001) in canals enlarged to size 140 than to size 70, independent of root-filling method. Apical leakage associated with ultrasonically condensed root fillings was less than that with cold lateral condensation. It was consistently greater in extremely large canals than that in large ones.

The vital threat of an upper gastrointestinal bleeding: Risk factor analysis of 121 consecutive patients.

AIM: To analyze the importance in predicting patients risk of mortality due to upper gastrointestinal (UGI) bleeding under today's therapeutic regimen. METHODS: From 1998 to 2001, 121 patients with the diagnosis of UGI bleeding were treated in our hospital. Based on the patients' data, a retrospective multivariate data analysis with initially more than 270 single factors was performed. Subsequently, the following potential risk factors underwent a logistic regression analysis: age, gender, initial hemoglobin, coumarines, liver cirrhosis, prothrombin time (PT), gastric ulcer (small curvature), duodenal ulcer (bulbus back wall), Forrest classification, vascular stump, variceal bleeding, Mallory-Weiss syndrome, RBC substitution, recurrent bleeding, conservative and surgical therapy. RESULTS: Seventy male (58%) and 51 female (42%) patients with a median age of 70 (range: 21-96) years were treated. Their in-hospital mortality was 14%. While 12% (11/91) of the patients died after conservative therapy, 20% (6/30) died after undergoing surgical therapy. UGI bleeding occurred due to duodenal ulcer (n = 36; 30%), gastric ulcer (n = 35; 29%), esophageal varicosis (n = 12; 10%), Mallory-Weiss syndrome (n = 8; 7%), erosive lesions of the mucosa (n = 20; 17%), cancer (n = 5; 4%), coagulopathy (n = 4; 3%), lymphoma (n = 2; 2%), benign tumor (n = 2; 2%) and unknown reason (n = 1; 1%). A logistic regression analysis of all aforementioned factors revealed that liver cirrhosis and duodenal ulcer (bulbus back wall) were associated risk factors for a fatal course after UGI bleeding. Prior to endoscopy, only liver cirrhosis was an assessable risk factor. Thereafter, liver cirrhosis, the location of a bleeding ulcer (bulbus back wall) and patients' gender (male) were of prognostic importance for the clinical outcome (mortality) of patients with a bleeding ulcer. CONCLUSION: Most prognostic parameters used in clinical routine today are not reliable enough in predicting a patient's vital threat posed by an UGI bleeding. Liver cirrhosis, on the other hand, is significantly more frequently associated with an increased risk to die after bleeding of an ulcer located at the posterior duodenal wall.

Impact of serum creatinine measurement error on dose adjustment in renal failure.

BACKGROUND: Doses of renally eliminated drugs should be adjusted according to kidney function to prevent adverse drug events and cost. Dose adjustment can be based on serum creatinine level, subsequent creatinine clearance estimation, and dosage calculation with consideration of the renal elimination properties of the respective compound. OBJECTIVE: Our objective was to quantify the impact and relevance of serum creatinine measurement error on dose adjustment in renal failure. METHODS: We analyzed 27914 measurements from external quality assessment surveys of 1878 German laboratories that used a kinetic alkaline picrate (69% of results) or an enzymatic method (25%) for creatinine determination. Linear models were fit for both methods combined and separately. On the basis of 95% confidence intervals (CIs) for creatinine values, 95% CIs for drug dosing were calculated. RESULTS: The 95% CI for a measured serum creatinine value was 0.80. Measured value < Reference method value < 1.28. Measured value for the kinetic alkaline picrate method and 0.87. Measured value < Reference method value < 1.21. Measured value for the enzymatic method. Applied to a data set of 6.5 million simulated patients with all possible combinations of characteristics relevant for drug dosing, the dosing error caused by serum creatinine measurement error did not exceed 25% in patients with creatinine clearance estimates lower than 50 mL/min according to the Cockcroft-Gault equation. For drugs completely eliminated by the kidneys in active form, the dosing error was up to 6-fold smaller than that which would occur if doses were not adjusted. CONCLUSION: The serum creatinine measurement error of current laboratory methods is small and is comparable to other errors influencing dose adjustment.

Safety and efficacy of SITAgliptin plus GRanulocyte-colony-stimulating factor in patients suffering from Acute Myocardial Infarction (SITAGRAMI-Trial)--rationale, design and first interim analysis.

AIMS: Our pre-clinical studies demonstrated that G-CSF based stem cell mobilization in combination with genetic or pharmaceutical CD26/DPP-IV inhibition after acute myocardial infarction leads to improved cardiac homing of stem cells, enhanced heart function and increased survival. Thereupon, we initiated a phase III, multi-centre, randomised, placebo-controlled efficacy and safety study (n=100) analyzing the effect of combined application of G-CSF and Sitagliptin, which is a clinically admitted, anti-diabetic DPP-IV-inhibitor, after acute myocardial infarction ("SITAGRAMI-Trial"; EudraCT Number: 2007-003941-34). METHODS: The primary objective of the study is to assess myocardial regeneration by improved myocardial homing of mobilized stem cells, as measured by cardiac function using MRI analysis. In this paper, we report on the study design and a planned first interim-analysis on safety issues without unblinding. RESULTS: During the first 6 weeks of follow-up, only two major adverse cardiac events occurred (one de novo stenosis and one instent-restenosis) in the first 36 patients. Presumably, they were not related to any study medication. No other side effects like headache, bone pain, hypoglycaemias etc. were observed. Furthermore, no myocardial infarction or death occurred in any patient. Thus, the rate of serious adverse events lay within the expected range. CONCLUSIONS: Our data demonstrate that the combined application of Sitagliptin and G-CSF seems to be safe on the short term and feasible after acute myocardial infarction and may represent a new therapeutic option in future.

G-CSF in patients suffering from late revascularised ST elevation myocardial infarction: final 1-year-results of the G-CSF-STEMI Trial.

AIMS: The aims of this trial were to investigate the effect of granulocyte colony-stimulating factor (G-CSF) on left-ventricular ejection fraction and event-free survival in patients suffering from sub-acute myocardial infarction (STEMI). METHODS: We enrolled 44 patients suffering from sub-acute STEMI with late revascularization achieved by percutaneous coronary intervention (PCI). Patients were randomized to receive either G-CSF (Filgrastim) at a dose of 10 µg/kg body weight/day subcutaneously or placebo. Changes of global and regional cardiac function from baseline (1 week after PCI) over 1 and 3 months to 12 months of follow-up were analyzed by magnetic resonance imaging. RESULTS: Ejection fraction improved in G-CSF treated patients from 41.1±11.9% to 47.1±11.9% (3 months) and decreased slightly to 45.7±15.1% after 1 year. Ejection fraction also improved in the placebo group from 43.8±9.0% to 49.5±11.8% (3 months) and decreased slightly to 42.9±15.4% after 1 year (1 year MRI follow-up was performed in 23 out initial 44 patients). There was no significant difference between the two groups at any time point. Other parameters such as infarct size, myocardial perfusion, left ventricular end-diastolic and end-systolic volumes were not different between the two groups. Event-free survival of such as death, (re) myocardial infarction or acute coronary syndromes, coronary artery bypass grafting and target lesion revascularization was not significantly different between both groups. CONCLUSIONS: G-CSF administration after sub-acute STEMI is feasible and safe but does not improve myocardial function or survival when used as a single substance.

Myofascial trigger points in children with tension-type headache: a new diagnostic and therapeutic option.

The goal of this pilot study was to evaluate the effect of a trigger point-specific physiotherapy on headache frequency, intensity, and duration in children with episodic or chronic tension-type headache. Patients were recruited from the special headache outpatient clinic. A total of 9 girls (mean age 13.1 years; range, 5-15 years) with the diagnosis of tension-type headache participated in the pilot study from May to September 2006 and received trigger point-specific physiotherapy twice a week by a trained physiotherapist. After an average number of 6.5 therapeutic sessions, the headache frequency had been reduced by 67.7%, intensity by 74.3%, and duration by 77.3%. No side effects were noted during the treatment. These preliminary findings suggest a role for active trigger points in children with tension-type headache. Trigger point-specific physiotherapy seems to be an effective therapy in these children. Further prospective and controlled studies in a larger cohort are warranted.

Abnormal motor cortex excitability in congenital stroke.

The aim of the present study was to investigate corticospinal and intracortical excitability in patients with congenital stroke. In adults, stroke sequelae reduce corticospinal excitability, as indicated by an elevated threshold for motor evoked potentials (MEP), and increase intracortical excitability, as indicated by reduced intracortical inhibition. Ten patients with pre- or perinatally acquired, unilateral cortico-subcortical infarctions in the middle cerebral artery territory were studied with single pulse transcranial magnetic stimulation (TMS) to measure motor threshold (MT) and with paired pulse TMS to study short interval intracortical inhibition (SICI) and intracortical facilitation (ICF). Eight healthy, age-matched subjects served as controls. MT over the affected hemisphere of patients compared with the dominant hemisphere of controls was significantly elevated, reflecting reduced corticospinal excitability, and SICI was significantly reduced, reflecting increased intracortical excitability. No such differences were found for ICF. Findings in patients with congenital stroke were comparable with adulthood stroke. Thus, similar assumptions can be made: reduced corticospinal excitability is probably a consequence of neuronal damage. Reduced intracortical inhibition might represent deficient inhibitory cortical properties or might reflect a compensational mechanism, dispositioning for use-dependent plasticity.

Short-term effects of treatment-induced hormonal changes on cognitive function in breast cancer patients: results of a multicenter, prospective, longitudinal study.

BACKGROUND: It is suspected that estrogen depletion resulting from treatment may contribute to cognitive compromise in patients with breast cancer. However, the evidence for estrogen effects on cognition is inconclusive, and the consequences of hormonal changes for cognitive function in patients with cancer rarely have been investigated. In this study, the authors investigated the effects of treatment-induced menopause and antiestrogen therapy with tamoxifen and aromatase inhibitors (AIs) on cognitive function. METHODS: Cognitive performance was assessed in 101 patients with breast cancer before the start of cancer therapy (T1), toward the end of neoadjuvant chemotherapy (T2), and 1 year after baseline (T3) using 12 cognitive tests. Menopause occurred in a subgroup of patients, and an overlapping subgroup started antiestrogen therapy with tamoxifen or AIs. Linear mixed-effects models that made it possible to determine effects at group levels and individual levels simultaneously were used for statistical analysis. RESULTS: At the group level, a significant favorable effect of induced menopause emerged in a test of executive function (P= .0035). Two additional group-level effects of induced menopause, both favorable, and 2 individual-level effects that were positive in some patients and negative in others were not significant when multiple testing was taken into account. No significant effects of tamoxifen or AIs on cognitive function were observed. CONCLUSIONS: Hormonal changes did not appear to contribute to cognitive compromise in patients with breast cancer during the first year after diagnosis. Antiestrogen treatment with tamoxifen or AIs did not affect cognition, and the effects of induced menopause were more likely to be favorable. However, the possibility that some cognitive decline occurs in individual patients could not be excluded.

Epidemiology and quality control of 245 000 outpatient colonoscopies.

INTRODUCTION: Screening colonoscopy is an effective means for early detection of colorectal carcinoma. Any exhaustive evaluation of the method must take further factors into account: epidemiology of colorectal adenomas and carcinomas in the target population, acceptance by the patients, structure, process, and outcome quality, and health economics. METHODS: The internet-based colonoscopy database of the Bavarian Association of Statutory Health Insurance Physicians (ASHIP) for the year 2006 includes data on 86.05% of all outpatient colonoscopies performed in Bavarian ASHIP patients, or a total of 245 263 documented examinations. RESULTS: The rate of participation in preventive colonoscopies was low (1.5%) and showed considerable geographical variation. The rate of detection of histologically confirmed colorectal neoplasia in symptom-free screened individuals was almost 26.0%. Some 1.3% of those screened had colorectal carcinoma. In 76.31% of the participants a completely clean gut was achieved. The incidence of bleeding, perforation, and cardiorespiratory complications was 0.22%, 0.03%, and 0.06%, respectively. DISCUSSION: The complication rate of outpatient colonoscopy is on the order of tenths of a percent, while the process quality is high. The rate of detection of colorectal adenoma and carcinoma is high and the projected benefits for public health are considerable, but the rate of participation is too low.

Reproducibility of DIAGNOdent 2095 and DIAGNOdent Pen measurements: results from an in vitro study on occlusal sites.

The aim of this in vitro study was to investigate the intra- and interdevice reproducibility of the DIAGNOdent 2095 (DD2095) and the new DIAGNOdent Pen (DDPen) on non-cavitated occlusal caries sites. Altogether, 241 sites on 90 molars were inspected twice with both devices and by four examiners. The intra/interdevice reproducibilities were assessed by means of the intraclass correlation coefficient (ICC) as well as by the range of the 95% limits of agreement of Bland & Altman. Additionally, a linear mixed-effects model was fitted with fixed effects for the visual scores and the devices used and random effects for occlusal sites and examiners within each measurement site. In result, the following values were determined for the intradevice reproducibility: DD2095: ICC 0.89, range 42.3; and DDPen: ICC 0.88, range 49.3. The interdevice reproducibility was found to be in the same order of magnitude (ICC 0.82, range 53.7). The comparison between both devices indicated significantly lower mean values for the DDPen. The estimates of the linear model show that there is a high variation between the sites that cannot be explained by the fixed effects. In conclusion, both devices showed an imperfect reproducibility, which indicate the usage as adjunct tool only in clinical practice.

Prediction of TMJ arthralgia according to clinical diagnosis and MRI findings.

PURPOSE: The aim of this study was to investigate the ability of clinical and magnetic resonance imaging (MRI) diagnoses to predict pain in the temporomandibular joint (TMJ). MATERIALS AND METHODS: One hundred forty-nine patients were examined by 2 calibrated examiners in strict accordance with the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). All patients who presented with a defined clinical RDC/TMD diagnosis were included and underwent bilateral coronal and sagittal MRI of the TMJ. Two raters blinded to the clinical diagnosis interpreted the MRI scans for TMJ pathology. The results were tested against the clinical diagnosis according to the RDC/TMD, including pain-related disability and psychosocial status, for associations to TMJ arthralgia using logistic regression analysis (GENMOD procedure, P < .05). RESULTS: MRI-depicted anatomic changes, such as joint effusions, disc displacement, and osteoarthrosis, were not significantly correlated with the presence of pain in the TMJ. However, a significant relationship between pain on palpation of the masseter muscle origin (P = .0050) and psychosocial factors (P = .0452) and pain in the TMJ was demonstrated. CONCLUSIONS: Pain in the TMJ caused by the anatomic proximity of the muscle masseter origin and the lateral TMJ pole and the possible existence of trigger points in the musculature may lead to a false-positive or a false-negative diagnosis of arthralgia. Additionally, clinicians must consider the psychosocial aspects of pain in ideal treatment planning.