Scientists working with cancer registry data are often confronted with large proportions of missing values in ordinal variables, such as tumor stage, grading or the general health status (ECOG-PS scored 0 to 5). Despite the long-standing issue, research on handling missing ordinal cancer registry data remains sparse. A simulation study was conducted using complete lung cancer cases (2019–2022) from the North Rhine-Westphalia Cancer Registry. Missing values in ECOG-PS were generated with varying missingness mechanisms (MCAR, MAR, MNAR), missingness proportions (10

BACKGROUND AND OBJECTIVE:We established prognostic nomograms incorporating prostate-specific membrane antigen (PSMA) positron emission tomography (PET) parameters standardised by Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE; PPP1). Here, we develop an updated PPP2 risk score from a large international multicentre registry study. METHODS:We included 6128 prostate cancer patients who underwent PSMA-PET at 20 hospitals in Europe, USA, and Australia between 2013 and 2022. Investigator sites were split 2:1 into the development (4044 patients) and validation (2084 patients) cohorts. We created nomograms of version 2 (PPP2) based on Cox regression models with the least absolute shrinkage and selection operator penalty for overall survival (development cohort). Performance of both nomograms was measured using Harrell's C-index and calibration plots and a head-to-head comparison with the National Comprehensive Cancer Network (NCCN) risk score by receiver operating characteristic curves (validation cohort). KEY FINDINGS AND LIMITATIONS:Predictors were distant metastases (extrapelvic nodal metastases [M1a], bone metastases [M1b], and visceral metastases [M1c]), PSMA expression score, and total lesion count (visual PPP2) or total tumour volume (quantitative PPP2). C-indices (95% confidence interval) in the validation cohort were 0.80 (0.78-0.82; visual) and 0.80 (0.79-0.82; quantitative), respectively. Accuracy of both the PPP2 nomograms was superior to the NCCN risk score (n = 1034, area under the curve 0.84 vs 0.76; p < 0.001). The retrospective design represents a limitation of the study. CONCLUSIONS AND CLINICAL IMPLICATIONS:PPP nomograms were improved in an international multicentre study to predict accurately the 3- and 5-yr overall survival probabilities of prostate cancer. PPP2 yielded superior accuracy to the NCCN risk score. A free software tool has been created for PROMISE and PPP2 assessments (promise-pet.org).

INTRODUCTION:There is no organized prostate cancer screening in Germany. The aim of this study was to investigate the development of incidence and survival in patients with primary malignant tumors of the prostate in relation to changing recommendations of prostate-specific antigen (PSA) screening in guidelines. METHODS:Age-standardized incidence rates and 5-year relative survival (RS) (period approach) were calculated using data from the cancer registry North Rhine-Westphalia with the subset of the administrative district Münster respectively for the years 1992-2019. Analyses were stratified according to TNM classification. RESULTS:Until 2008 overall prostate cancer incidence increased, followed by a decrease up to 2017 and another increase thereafter. The same trend was observed in nonmetastatic but not in metastatic prostate cancer. Overall 5-year RS showed an increase of 10 percentage points up to period 2005-2009, followed by a constant RS. 5-year RS of patients with distant metastases remained constant from period 2000-2004 to 2015-2019, while 5-year RS with nonmetastatic prostate cancer and lymph node metastases increased slightly. DISCUSSION:Overall and nonmetastatic incidence rates reflect changes of recommendation in PSA screening guidelines from the United States. Accordingly, the increase in 5-year RS might be influenced by lead time bias. Incidence and survival of metastatic prostate cancer barely suggest any association with changing PSA screening recommendations. CONCLUSION:Structured early detection of metastases with additionally applied diagnostic methods might improve 5-year RS rates of metastatic prostate cancer patients.

BACKGROUND:The crude mortality rate and the lifetime mortality risk from prostate cancer in Germany are above international average. However age-standardised mortality and years of life lost per capita from prostate cancer are declining. This study analyses the mortality-related measures for the federal state of North Rhine-Westphalia (NRW) in Germany. METHODS:Based on the cause of death statistics and data from the NRW State Cancer Registry on 45,300 deaths in the years 2007-2021, mortality rates, the lifetime mortality risk from prostate cancer, median age at death and years of life lost are presented. Additionally, the 15 most frequent causes of death of 95,013 patients diagnosed with prostate cancer are reported. RESULTS:With a stable lifetime mortality risk from prostate cancer, age-standardised mortality and years of life lost per capita are decreasing while crude mortality and median age at death are increasing in NRW. Less than half of the patients die from their prostate cancer. Cancers of the urinary bladder and other urinary organs also occur more frequently as a cause of death than it would be expected based on the age-specific risk in the total population. CONCLUSIONS:More people in North Rhine-Westphalia are dying of prostate cancer over time due to demographic ageing alone. At the same time, the age-specific mortality risk has not increased and when patients die of prostate cancer, it is at an increasingly older age. However, there is a statistical association with deaths from cancers of the lower urinary tract in patients diagnosed with prostate cancer, which demands further evaluation.

Supplementary Figure 1. MMSE assessment at study entry, during treatment, and at follow-up

Supplementary Tables 1-7. Supplementary Table 1. Safety and tolerability. Supplementary Table 2. Outcome by MGMT promoter methylation status and treatment arm. Supplementary Table 3. Outcome by interval from last TMZ administration and MGMT promoter methylation status. Supplementary Table 4. Adherence to Mini Mental Status data collection over the course of the study. Supplementary Table 5. Treatment effect (Arm B versus Arm A) on EORTC-QLQ-C30 and -BN20 scales evaluated at timepoint 90 days Supplementary Table 6. Absolute changes of (0-100) score points of quality of life (as assessed by the EORTC-QLQ-C30 and -BN20 scales) within one treatment cycle of 28 days in Arms A and B, along with local p-values for difference in slopes. Supplementary Table 7. Adherence to EORTC-QLQ-BN20 and -C30 data collection over the course of the study.

A vaccine remains a priority in the global fight against malaria. Here, we report on a single-center, randomized, double-blind, placebo and adjuvant-controlled, dose escalation phase 1a safety and immunogenicity clinical trial of full-length Plasmodium falciparum merozoite surface protein 1 (MSP1) in combination with GLA-SE adjuvant. Thirty-two healthy volunteers were vaccinated at least three times with MSP1 plus adjuvant, adjuvant alone, or placebo (24:4:4) to evaluate the safety and immunogenicity. MSP1 was safe, well tolerated and immunogenic, with all vaccinees sero-converting independent of the dose. The MSP1-specific IgG and IgM titers persisted above levels found in malaria semi-immune humans for at least 6 months after the last immunization. The antibodies were variant- and strain-transcending and stimulated respiratory activity in granulocytes. Furthermore, full-length MSP1 induced memory T-cells. Our findings encourage challenge studies as the next step to evaluate the efficacy of full-length MSP1 as a vaccine candidate against falciparum malaria (EudraCT 2016-002463-33).

Apoptotic intestinal crypt cells are pathognomonic of acute intestinal graft versus host disease (GVHD). Serum levels of the apoptotic degradation product cytokeratin-18 fragments (CK18F) were associated with acute hepato-intestinal GVHD. Here we present a prospective clinical observational trial (NCT00935324) investigating serum levels of total CK18 (tCK18) and apoptotic CK18F to predict imminent acute hepato-intestinal GVHD and response to treatment. Total (t)CK18 and CK18F kinetics were measured before transplantation and in weekly intervals thereafter. In total 109 patients were enrolled. Acute hepato-intestinal GVHD grade I–IV was suspected in 36 patients (33%) at a median of 56 days post-transplant, 12 of these patients developed steroid-refractory GVHD. Both tCK18 and apoptotic CK18F increased at GVHD onset, and distinguished patients with suspected acute hepato-intestinal GVHD who were negative in intestinal histology. In patients with clinical acute hepato-intestinal GVHD, tCK18 significantly raised already 7–14 days before symptom onset. In receiver operator characteristics, areas under the curve at GVHD onset were 0.927 (p < 0.001) for tCK18 and 0.875 (p < 0.001) for apoptotic CK18F for patients with proven hepato-intestinal acute GVHD. This prospective study validates CK18F and highlights tCK18 as specific biomarkers suitable for improving prediction and diagnosis of suspected imminent and clinically manifest acute hepato-intestinal GVHD.

Introduction/Hypothesis: Despite effective reperfusion therapies, outcome following ischemic stroke (IS) often remains poor. Shortly after IS onset, the already necrotic area is surrounded by the severely hypoperfused but still viable penumbra. Sustaining the latter may widen treatment time windows and improve outcomes. As tissue damage in IS is primarily mediated by hypoxia, increasing penumbral oxygen (O2) supply seems a logical approach. Normobaric hyperoxygenation (NBHO) increased penumbral O2 and attenuated brain injury when initiated early in animal models of transient vessel occlusion. The few clinical trials conducted so far did not adapt these insights: NBHO initiation was late (treatment windows of more than 9 hours) and patients eligible for intravenous thrombolysis and endovascular treatment were excluded. Methods: Multi-center, randomized phase-II proof-of-concept trial studying NBHO adjunct to standard IS treatment; adaptive patient sample size of 180 to 460 depending on interim analysis. Eligibility: Patients with an acute large vessel occlusion in the anterior circulation (terminal ICA plus M1, proximal M1, or distal M1) and an Alberta Stroke Program Early CT Score of 7 or higher. Study treatment must be initiated prior to recanalization therapy and within 3 hours after IS onset. NBHO is achieved by administration of high-flow O2 (40 L/min) via non-rebreather face mask with reservoir or FiO2 of 1.0 during mechanical ventilation. NBHO will be stopped after endovascular treatment or applied for a maximum of four hours in case of not-attempted endovascular treatment. Controls will receive standard O2 supplementation whenever required. Primary Endpoint: Infarct growth from baseline to 24 hours; key secondary endpoint: Δ24h-NIHSS. Conclusion: PROOF is the first clinical trial to incorporate two cornerstones of effective experimental NBHO: early initiation and fast reperfusion. If proven beneficial, phase-III trials may be undertaken. Considering its low cost, NBHO may impact stroke care worldwide.

Although a device is needed to continuously measure blood glucose levels within an intensive care setting, and several large-scale prospective studies have shown that patients might benefit from intensive insulin, potassium, or glucose therapy during intensive care, no devices are currently available to continuously assess blood glucose levels in critically ill patients. We conceived the study described here to evaluate the clinical use of the Continuous Glucose Monitor (CGM) performed via a central vein, and to determine the impact of phenomena, such as drift and shift, on the agreement between the CGM and a RAPIDLab® 1265 blood gas analyser (BGA).

BACKGROUND:Radiation therapy is an essential modality in the treatment of breast cancer. Addition of radiotherapy to surgery has significantly increased local control and survival rates of the disease. However, radiotherapy is also associated with side effects, such as tissue fibrosis or enhanced vascular morbidity. Modern radiotherapy strategies, such as intensity modulated radiotherapy (IMRT), can shorten the overall treatment time by integration of the additional tumor bed boost significantly. To what extent this might be possible without impairing treatment outcome and cosmetic results remains to be clarified.METHODS/DESIGN:The IMRT-MC2 study is a prospective, two armed, multicenter, randomized phase-III-trial comparing intensity modulated radiotherapy with integrated boost to conventional radiotherapy with consecutive boost in patients with breast cancer after breast conserving surgery. 502 patients will be recruited and randomized into two arms: patients in arm A will receive IMRT in 28 fractions delivering 50.4 Gy to the breast and 64.4 Gy to the tumor bed by integrated boost, while patients in arm B will receive conventional radiotherapy of the breast in 28 fractions to a dose of 50.4 Gy and consecutive boost in 8 fractions to a total dose of 66.4 Gy.DISCUSSION:Primary objectives of the study are the evaluation of the cosmetic results 6 weeks and 2 years post treatment and the 2- and 5-year local recurrence rates for the two different radiotherapy strategies. Secondary objectives are long term overall survival, disease free survival and quality of life.TRIAL REGISTRATION:ClinicalTrials.gov Protocol ID: NCT01322854.

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.

Background: The development of suture hole bleeding at peripheral arterial bypass anastomoses using PTFE graft prostheses is a common problem in peripheral vascular surgery. Traditionally the problem is managed by compression with surgical swabs and reversal heparin or by using several haemostatic device e. g. different forms of collagen, oxidized cellulose, gelatine sponge, ethylcyanoacrylate glue or fibrin) with various success. Preclinical data suggest that the haemostatic effect of collagen is stronger than that of oxidized cellulose, but no direct clinical comparison of their hemostatic performance has been published so far.Design: This randomized, controlled, prospective trial evaluates the haemostatic effect of Lyostypt versus Surgicel in arterial bypass anastomosis. 28 patients undergoing an elective peripheral vascular reconstruction due to peripheral vascular disease will be included. Suture hole bleeding occurring at the arterial bypass anastomosis using a PTFE prostheses will be stopped by the application of Lyostypt and/or Surgicel. The proximal anastomoses will be randomized intraoperatively. The patients will be allocated into 4 different treatment groups. Group1 Lyostypt distal/Surgicel proximal; Group 2: Lyostypt proximal/Surgicel distal; Group 3: Surgicel distal and proximal; Group 4: Lyostypt distal and proximal. Primary endpoint of the study is time to haemostasis. Secondary endpoints are the number of intraoperatively used haemostatic devices, postoperative mortality within 30 days as well as the intraoperative efficacy rating of the two devices evaluated by the surgeon. As a safety secondary parameter, the local and general complication occurring till 30 +/- 10 days postoperatively will also be analysed. After hospital discharge the investigator will examine the enrolled patients again at 30 days after surgery.Discussion: The COBBANA trial aims to assess, whether the haemostatic effect of Lyostypt is superior to Surgicel in suture hole bleedings of arterial bypass anastomoses.

Even though the primary success rate of Punction of the Vena Subclavia (PVS) for an implantation of a Totally Implantable Access Port (TIAP) is described as significantly higher than the surgical technique of classical Venae Sectio (cVS) the latter has the advantage of not causing pneumothorax. Therefore, the surgical technique must be improved. We conducted a randomized controlled trial to evaluate the primary success rate of the cVS in comparison to a modified Venae Sectio (cVS + Seldinger technique). 206 patients were screened between March 2006 and January 2007. 164 patients could be randomized and the primary success rate was determined. There was no significant difference between the primary success rate of cVS (81 %) and mVS (84 %) employing the Chi2 test. But performing either cVS or mVS lead to a overall success rate of 94 % of the two surgical techniques. Only 6 % of the patients needed to receive a PSV for implantation of a TIAP.

Abstract Background Several randomized controlled trials have compared different suture materials and techniques for abdominal wall closure with respect to the incidence of incisional hernias after midline laparotomy and shown that it remains, irrespective of the methods used, considerably high, ranging from 9% to 20%. The development of improved suture materials which would reduce postoperative complications may help to lower its frequency. Design This is a historically controlled, single-arm, multi-centre, prospective trial to evaluate the safety of MonoMax® suture material for abdominal wall closure in 150 patients with primary elective midline incisions. INSECT patients who underwent abdominal closure using Monoplus® and PDS® will serve as historical control group. The incidences of wound infections and of burst abdomen are defined as composite primary endpoints. Secondary endpoints are the frequency of incisional hernias within one year after operation and safety. To ensure adequate comparability in surgical performance and recruitment, the 4 largest centres of the INSECT-Trial will participate. After hospital discharge, the investigators will examine the enrolled patients again at 30 days and at 12 ± 1 months after surgery. Conclusion This historically controlled, single-arm, multi-centre, prospective ISSAAC trial aims to assess whether the use of an ultra-long-lasting absorbable monofilament suture material is safe and efficient. Trial registration NCT005725079

Summaryobjective Diabetes is associated with coronary microvasculature abnormalities and impaired coronary flow reserve (CFR). CFR is the ratio of coronary flow under maximal vasodilation to basal flow and is a measure for coronary vasoreactivity. Insulin resistance is the central defect in the development of type 2 diabetes, preceding its onset by 10–20 years. Thus, the relationship between insulin sensitivity and CFR in nondiabetic subjects is particularly interesting. The aim of the study was to investigate this relationship.design Cross‐sectional study.patients The study population consisted of 18 nondiabetic subjects without coronary artery stenosis on coronary angiography. We excluded patients with structural heart disease or with conditions affecting CFR or insulin sensitivity such as low density lipoprotein (LDL)‐cholesterol ≥ 4·14 mmol/l, smoking, hypertension or obesity with a body mass index (BMI) > 28 kg/m2.measurements and results CFR was 3·1 ± 0·8 (range 1·7–4·8), as assessed by intracoronary Doppler measurements in the left anterior descending coronary arteries after adenosine stimulation. Intravascular ultrasound revealed zero to moderate coronary atherosclerotic changes. Whole‐body insulin sensitivity (M‐value) was 7·5 ± 2·9 mg/kg/min (range 2·2–12·6), as assessed by the hyperinsulinaemic–euglycaemic clamp test. Subjects with low CFR (< 3·0) had a significantly lower M‐value than subjects with normal CFR (> 3·0) (6·0 ± 2·5 vs. 9·0 ± 2·5 mg/kg/min, P = 0·021). Univariate linear regression demonstrated a strong correlation between CFR and M‐value (r = 0·76, P < 0·001). In multiple regression analysis, the significant association of CFR with M‐value was independent of potential confounders (sex, age, BMI, LDL‐cholesterol and plaque burden on intravascular ultrasound). Bootstrap analysis corroborated this finding.conclusions Whole‐body insulin sensitivity relates to coronary vasoreactivity. Across a wide range of both insulin sensitivity and coronary flow reserve from markedly abnormal to normal values, an increase in insulin sensitivity appears to be associated with an increase in coronary flow reserve. Insulin resistance is therefore associated with coronary microvasculature abnormalities in nondiabetics.

Biometrical JournalVolume 46, Issue S1 p. 153-153 Poster Sessions Abstracts P2.64: Effects of the probeset expression measure computation of gene expression data derived from Affymetrix-Chips Tanja Boes, Tanja Boes tanja.boes@medizin.uni-essen.de Search for more papers by this authorElisabeth Kruse, Elisabeth KruseSearch for more papers by this authorJohannes Hüsing, Johannes HüsingSearch for more papers by this authorKarl-Heinz Jöckel, Karl-Heinz JöckelSearch for more papers by this author Tanja Boes, Tanja Boes tanja.boes@medizin.uni-essen.de Search for more papers by this authorElisabeth Kruse, Elisabeth KruseSearch for more papers by this authorJohannes Hüsing, Johannes HüsingSearch for more papers by this authorKarl-Heinz Jöckel, Karl-Heinz JöckelSearch for more papers by this author First published: 17 March 2004 https://doi.org/10.1002/bimj.200490061Citations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume46, IssueS1Supplement: Abstracts of the Joint Meeting of the IBS-DR and the DAEMarch 2004Pages 153-153 RelatedInformation

Although uniparental disomy often results from the postzygotic rescue of a meiotic non-disjunction event, mosaicism is usually confined to the placenta. We describe a girl with Prader-Willi syndrome (PWS) who is mosaic for normal cells and cells with maternal uniparental disomy 15 [upd(15)mat] in blood and skin. Somatic mosaicism was confirmed by cloning and genotyping of skin fibroblasts. X inactivation studies indicated that upd occurred prior to X inactivation. RNA samples from the cloned cells were used in DNA microarray experiments to study the effect of upd(15)mat on the gene expression pattern of fibroblasts. Proof of principle was obtained by detecting several chromosome 15 genes known to be imprinted. We did not obtain any evidence for novel 15q genes showing imprinted expression in fibroblasts. Differentially expressed genes on other chromosomes are candidates for downstream genes regulated by an imprinted gene and may play a role in the pathogenesis of PWS. The finding of strongly reduced mRNA levels in upd(15)mat cells of the gene encoding secretogranin II (SCG2), which is a precursor of the dopamine releasing factor secretoneurin, raises the question whether hyperphagia in patients with PWS might be due to a defect in dopamine-modulated food reward circuits.

Microarray technology enables researchers to investigate the expression of several thousand genes simultaneously. The whole transcriptional response of these genes in normal cells or tissue, in disease condition, as an response to biological, genetical or chemical stimuli or during normal biological processes such as cell cycle or embryonic development can be investigated. This leads to a huge amount of data, from which the relevant information has to be extracted by statistical and computational methods. Several software packages for the analysis of gene expression data are available, both commercially and freely. They differ particularly with regard to the implemented analytical methods, the graphical display and the manageability. In this paper the commercial software packages arraySCOUT, GeneSpring and Spotfire DecisionSite for Functional Genomics are compared and their applicability for analysis of gene expression data is studied. Small artificial and application test datasets are used to compare the computational results of the software packages. As far as possible results are verified with standard statistical software package SAS.