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Budigalimab is a humanized, recombinant, Fc mutated IgG1 monoclonal antibody targeting programmed cell death 1 (PD‐1) receptor, currently in phase I clinical trials. The safety, efficacy, pharmacokinetics (PKs), pharmacodynamics (PDs), and budigalimab dose selection from monotherapy dose escalation and multihistology expansion cohorts were evaluated in patients with previously treated advanced solid tumors who received budigalimab at 1, 3, or 10 mg/kg intravenously every 2 weeks (Q2W) in dose escalation, including Japanese patients that received 3 and 10 mg/kg Q2W. PK modeling and PK/PD assessments informed the dosing regimen in expansion phase using data from body‐weight‐based dosing in the escalation phase, based on which patients in the multihistology expansion cohort received flat doses of 250 mg Q2W or 500 mg every four weeks (Q4W). Immune‐related adverse events (AEs) were reported in 11 of 59 patients (18.6%), of which 1 of 59 (1.7%) was considered grade ≥ 3 and the safety profile of budigalimab was consistent with other PD‐1 targeting agents. No treatment‐related grade 5 AEs were reported. Four responses per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were reported in the dose escalation cohort and none in the multihistology expansion cohort. PK of budigalimab was approximately dose proportional and sustained > 99% peripheral PD‐1 receptor saturation was observed by 2 hours postdosing, across doses. PK/PD and safety profiles were comparable between Japanese and Western patients, and exposure‐safety analyses did not indicate any trends. Observed PK and PD‐1 receptor saturation were consistent with model predictions for flat doses and less frequent regimens, validating the early application of PK modeling and PK/PD assessments to inform the recommended dose and regimen, following dose escalation.

–Coronavirus disease 2019 (COVID-19) outbreak has rapidly evolved into a global pandemic. The impact of COVID-19 on patient journeys in oncology represents a new risk to interpretation of trial results and its broad applicability for future clinical practice. We identify key intercurrent events (ICEs) that may occur due to COVID-19 in oncology clinical trials with a focus on time-to-event endpoints and discuss considerations pertaining to the other estimand attributes introduced in the ICH E9 addendum. We propose strategies to handle COVID-19 related ICEs, depending on their relationship with malignancy and treatment and the interpretability of data after them. We argue that the clinical trial objective from a world without COVID-19 pandemic remains valid. The estimand framework provides a common language to discuss the impact of COVID-19 in a structured and transparent manner. This demonstrates that the applicability of the framework may even go beyond what it was initially intended for.

The COVID-19 pandemic has had and continues to have major impacts on planned and ongoing clinical trials. Its effects on trial data create multiple potential statistical issues. The scale of impact is unprecedented, but when viewed individually, many of the issues are well defined and feasible to address. A number of strategies and recommendations are put forward to assess and address issues related to estimands, missing data, validity and modifications of statistical analysis methods, need for additional analyses, ability to meet objectives and overall trial interpretability., Comment: Accepted for publication in Statistics in Biopharmaceutical Research. 40 pages

Background: Agents targeting programmed cell death protein 1 (PD-1) have been approved as monotherapy for patients with small cell lung cancer (SCLC). In preclinical models, the combined targeting of PD-1 and delta-like protein 3 resulted in enhanced antitumor activity. Herein, we report results from the expansion arm of study NCT03000257 evaluating the combination of the anti-PD-1 antibody budigalimab and the targeted antibody-drug conjugate rovalpituzumab tesirine (Rova-T) in patients with previously treated SCLC. Materials and methods: This expansion arm of a multicenter, open-label, multi-arm, first-in-human phase 1 clinical trial enrolled adult patients with progressive SCLC. The primary objective was to assess safety and tolerability. Patients received budigalimab 375 mg via intravenous infusion every 3 weeks, and Rova-T was administered as a dose of 0.3 mg/kg intravenously, on day 1 of the first and third 3-week cycle. Results: As of October 2019, 31 patients with SCLC were enrolled and treated with budigalimab plus Rova-T. The combination was tolerated, with the most common treatment-emergent adverse events (in >30%) being pleural effusion, fatigue, and cough. The overall response rate was 24.1%, with one confirmed complete response and six confirmed partial responses. The overall response rate in patients with high delta-like protein 3 expression was similar (21.1%). The median progression-free survival was 3.48 months. Conclusion: Combination therapy with budigalimab and Rova-T had promising efficacy and appeared to be tolerated in patients with SCLC. Although Rova-T development has been discontinued, development of budigalimab combined with other anticancer agents is ongoing. Clinical trial registration number: NCT03000257 Statement on originality of the work The manuscript represents original work and has not been submitted for publication elsewhere nor previously published. Statement of prior presentation Data from this study were previously presented at the European Society for Medical Oncology (ESMO) Congress 2019. Keywords: Antibody-drug conjugate; Clinical trial; Immunotherapy; Lung cancer; Small-molecule agent.

Budigalimab, a novel anti-PD-1 monoclonal antibody, demonstrated efficacy and biomarker pharmacodynamics in patients with head and neck squamous cell carcinoma (HNSCC) or non-small cell lung cancer (NSCLC) consistent with those reported by other PD-1 inhibitors. Herein are presented additional outcomes of biomarker analyses from the phase 1 study of budigalimab monotherapy in patients with HNSCC and NSCLC (NCT03000257). PD-1 inhibitor naive patients with advanced HNSCC (n=41) or NSCLC (n=40) received budigalimab intravenously at 250 mg every 2 weeks (Q2W) or 500 mg Q4W until progression. Archival tumor specimens were evaluated by immunohistochemistry for CD8 and tumor PD-1 ligand 1 (PD-L1) expression, RNA, and whole-exome sequencing. Serum and whole blood samples were acquired at baseline and at select on-treatment time points. As of October 2019, best overall response of 15% in HNSCC and 18% in NSCLC was observed in all treated patients; both cohorts reported responses in PD-L1+ and PD-L1- tumors. Treatment with budigalimab was associated with increases in multiple soluble biomarkers including interferon gamma-induced chemokines. Expanded overall T-cell counts, total CD8 T-cell counts, and percentages of CD8+CD45RA-CD62L- effector memory T cells were observed at cycle 1, day 15 in responders. Univariate analysis demonstrated an association between prolonged progression-free survival and higher tumor mutational burden/neoantigen load, smaller tumor size, lower platelet-lymphocyte ratios, lower CCL23, lower colony-stimulating factor 1, and lower interleukin-6 levels at baseline. The biomarker analysis presented herein identified additional early pharmacodynamic biomarkers associated with anti-PD-1 activity and improved clinical responses to budigalimab in patients with advanced HNSCC and NSCLC.

Wir standen vor der Aufgabe ein motivierendes, aktivierendes und gleichzeitig zeiteffektives Training in der Programmiersprache R fur die Datenanalysten und Statistiker unserer Firma zu entwickeln. Dabei waren wir mit einem sehr gemischten Zielpublikum konfrontiert, sowohl hinsichtlich ihres beruflichen Hintergrunds als auch ihrer Vorerfahrung mit R. Uns war besonders wichtig, dass jeder Teilnehmende aktiv eingebunden ist und in jeder Lerneinheit etwas Neues lernt, was direkt verwendet werden kann. Mittlerweile haben wir dieses Training zwei Mal durchgefuhrt. Basierend auf unseren Erfahrungen des ersten Durchlaufs haben wir das Training grundlegend uberarbeitet und weiter optimiert. Diese Erfahrungen mochten wir hier teilen und die (didaktischen) Methoden vorstellen, die wir eingesetzt haben, um unser Training fur alle Teilnehmenden interessant und gewinnbringend zu gestalten. Unser Werkzeugkasten an Methoden ist dabei universell anwendbar und keinesfalls auf unseren konkreten Anwendungsfall beschrankt.

Background: Match or mismatch of objective physiological and subjectively perceived fall risk may have serious consequences in patients with dementia (PwD) while research is lacking.Objective: To analyze mismatch of objective and subjective fall risk and associated factors in PwD.Method: Cohort study in a geriatric rehabilitation center. Objective and subjective risk of falling were operationalized by Tinetti's Performance Oriented Mobility Assessment and the Falls Efficacy Scale-International. Four sub-groups according to objective and subjective fall risk were classified. Subgroups were compared for differences in clinical, cognitive, psychological, and behavioral variables.Results: In geriatric rehab patients with mild to moderate dementia (n=173), two-thirds showed a mismatch of subjective versus objective risk of falling, independently associated with previous falls. Underestimation of objective fall risk (37.6%) was determined by lower activity avoidance (OR 0.39), less concerns about falling due to previous falls (OR 0.25), and higher quality of life (OR 1.10), while overestimation (28.9%) was determined by higher rate of support seeking strategies (OR 50.3), activity avoidance (OR 15.2), better executive (OR 21.0) and memory functions (OR 21.5), and lower quality of life (OR.75) in multivariate logistic regression.Conclusion: The majority of patients showed a mismatch between objective and subjective falls risk. Underestimation as well as overestimation of fall risk was associated with specific profiles based on cognitive- and psychological status, falls and fall-related behavioral consequences which should be included in the comprehensive assessment of fall risk, and planning of individualized fall prevention programs for this population.

3015 Background: Mirzotamab clezutoclax (ABBV-155) is a first-in-class antibody drug conjugate comprised of a BCL-XL (B-cell lymphoma - extra long) inhibitor, solubilizing linker, and a monoclonal anti-B7H3 antibody. Methods: Patients (pts) with relapsed and/or refractory (R/R) solid tumors were administered mirzotamab clezutoclax with or without paclitaxel. Dose escalation of mirzotamab clezutoclax was guided by Bayesian continual reassessment. Primary outcomes were to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D). Secondary outcomes: safety, pharmacokinetics, and overall response rate per RECIST v1.1. Results: As of November 6, 2020, 31 pts received mirzotamab clezutoclax monotherapy (monoTx) and 28 pts received combination therapy with paclitaxel (comboTx). Overall demographics: median age 62 years (range 25–79); 61% female; 86% white; 24% ECOG 0, 76% ECOG 1; 51% had > 3 prior systemic therapies. The median duration of mirzotamab clezutoclax exposure was 3 cycles (range 1–14) for monoTx and 5 cycles (range 1–14) for comboTx. There were no dose limiting toxicities (DLT) reported with monoTx. In comboTx, 2 pts experienced a DLT: Grade 4 neutrophil count decreased and Grade 3 lymphocyte count decreased considered related to paclitaxel. 97% of all pts had adverse events (AEs). The most common AEs (in ≥20% of pts) overall were fatigue (39%), nausea (25%), diarrhea and arthralgia (22% each), vomiting and hypokalemia (20% each). AEs in ≥5 pts related to mirzotamab cleuzutoclax were fatigue (27%), diarrhea (12%), and nausea (9%). Related Grade 3/4 AEs overall (in > 1 patient) included anemia, lymphocyte count decreased, fatigue, and diarrhea (3% each). One patient on monoTx experienced a fatal cardiac arrest. No fatal AEs occurred on comboTx. Responses were observed with comboTx as shown in the Table. Conclusions: Mirzotamab clezutoclax as monotherapy and with paclitaxel demonstrates a tolerable safety profile (MTD not reached) with anti-tumor activity in R/R solid tumors. Further investigation in prospectively-selected B7H3 positive tumors as monoTx in pts with R/R small cell lung cancer and with paclitaxel in pts with R/R breast cancer and docetaxel in pts with R/R non-small cell lung cancer in the dose expansion phase is ongoing. Clinical trial information: NCT03595059. [Table: see text]

In clinical trials, the choice of an adequate primary endpoint is often difficult. Besides its clinical relevance, the endpoint must be measurable within reasonable time and must allow differentiating between the treatments. Often, the most relevant endpoint is ‘’time-to-death,” but if the overall survival prognosis is good, only a few deaths are observed during the study duration. A possible solution is to use surrogate endpoints instead. However, various examples from the literature demonstrate that surrogates do not always perform as intended. Sometimes, the surrogate effect is smaller than for the original endpoint, or the latter shows a higher effect than anticipated so using the surrogate is not reasonable. In this work, different adaptive design strategies for two candidate endpoints are proposed to solve these problems. The idea is to base the efficacy proof on the significance of at least one endpoint. At an interim analysis, both candidates are evaluated. If it is not possible to stop th...

Disseminated tumor cells (DTC) in the bone marrow (BM) of primary breast cancer (BC) patients are a promising surrogate marker of micrometastatic spread and an independent predictor of poor prognosis for disease-free survival (DFS) and overall survival (OS). The present study aims to analyze DTCs as an independent prognostic factor for DFS/OS in tumor biology and bisphosphonate treatment. A total of 504 patients with operable primary BC and a median observation time of 72.3 months [lower quartile (LQ) 58.1; upper quartile (UQ) 82.8] have been included. DTCs were detected via immunohistochemistry as MUC-1 positive cells in the BM of 59.13 % (298 of 504) of the patients. The immunophenotyping of cancer cells was achieved immunohistochemically as well. For luminal A/B carcinoma patients, we observed a significant benefit of BM DTC negativity with respect to DFS (luminal A, P = 0.0498; luminal B, P = 0.0224). In triple-negative patients, DTC-negative BM was associated with a longer OS (P = 0.0326). In a multivariate Cox survival analysis relating to DFS and OS, the DTC status was identified as an independent prognostic factor for DFS in luminal A/B BC (P = 0.0071). A multivariate Cox survival analysis among DTC-positive patients with luminal immunophenotype showed bisphosphonate application (P = 0.0326) to be an independent prognostic factor for DFS. The findings of our multivariate analyses reveal BM DTC positivity as an independent risk factor for DFS particularly in luminal A/B BC patients. This might be a novel criterion for the identification of candidates most likely to benefit from additional adjuvant therapy possibly including bisphosphonates.

Background: Programmed cell death 1 (PD-1) is a receptor upregulated on activated lymphocytes that mediates a dominant-negative checkpoint signal limiting antigen receptor-driven cellular activation. PD-1 immune checkpoint inhibitors have shown durable clinical responses in patients with non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC). Budigalimab (formerly ABBV-181) is a blocking humanized recombinant anti-PD-1 monoclonal antibody, currently under evaluation in multiple studies such as phase 1 clinical trial (NCT03000257) in patients with solid tumors including HNSCC and NSCLC. Multiple clinical biomarker assessments have been incorporated into this study to accommodate pharmacodynamic (PD) and predictive analyses. Methods: Patients with previously treated, advanced HNSCC (n=41) or NSCLC (n=40) that were PD-1 inhibitor naïve received budigalimab IV at 250 mg every two weeks or 500 mg every four weeks to progression, with responses assessed every 8 weeks. Archival tumor FFPE specimens from patients with HNSCC (n=37) and NSCLC (N=33) were evaluated for CD8 infiltration and tumor PD-L1 expression by Dako 28-8 IHC assay, with remaining samples processed for RNA sequencing and whole-exome sequencing. Serum (for soluble biomarkers) and whole blood (for flow cytometric analysis of T cell biomarkers) were taken at baseline and selected on-treatment time points. Univariate analysis of biomarkers associated with the best overall response (BOR) and progression-free survival was conducted. Results: As of July 2019, responses per response evaluation criteria in solid tumors (RECIST) v1.1 or iRECIST were observed at the expected rates for a PD-1 inhibitor (BOR of partial or complete response of 15% in HNSCC and 19% in NSCLC), with responses in PD-L1+ and PD-L1- tumors in both groups. Budigalimab dosing was associated with rapid complete PD-1 receptor saturation, transient decreases in circulating lymphocytes, upregulation of proliferation (Ki67) biomarkers in T cells, and upregulation of multiple soluble biomarkers, including IFNγ-induced chemokines. Differential neoantigen burden and lymphocyte-associated gene expression in tumors were observed in responders versus non-responders. Preliminary univariate analysis of biomarkers found that baseline tumor size, serum IL-6, and T cell counts were significantly associated with outcomes. Conclusions: Our biomarker analysis of budigalimab-treated HNSCC and NSCLC patients has identified early PD biomarkers consistent with PD-1 inhibitor activity as well as pre-treatment tumor and peripheral biomarkers associated with observed clinical responses. These findings confirm that budigalimab is a biologically active PD-1 inhibitor. Citation Format: Stacie Lambert, Chun Zhang, Stefan Englert, Claire Guo, Tolga Turan, Catherine Tribouley, David Masica, Robert T. McLaughlin, Gregory S. Vosganian, Daniel E. Afar. Pharmacodynamic and predictive biomarkers of clinical responses to PD-1 inhibitor budigalimab from the first-in-human clinical trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4464.

Background & Aims It is well known that inflammation increases liver stiffness (LS) in patients with chronic hepatitis C (HCV) and alcoholic liver disease (ALD) independent of fibrosis stage, but no inflammation-adapted cut-off values have been settled so far. An early identification of rapid fibrosers, however, is essential to decide whom to treat first with the novel but expensive antiviral drugs. Methods Liver stiffness, biopsy-proven fibrosis stages F0–F4 (METAVIR or Kleiner score) and routine laboratory parameters were studied in 2068 patients with HCV (n = 1391) and ALD (n = 677). Results Among the routine parameters for liver damage, AST correlated best with LS (HCV: r = 0.54, P

The role of Phase II trials in oncology drug development Traditionally, Phase II in oncology drug development acts as a screening tool by identifying treatments with sufficient activ ity that warrant further investigation in large and costly Phase III studies. However, Phase II has also another more prominent role in cancer research as there is a significant number of drugs that were approved based on data of Phase II trials only. For example, according to the registration information for US FDA oncology drug approvals for solid tumours, for 17% of approvals between

Phase II studies in oncology are frequently conducted as two-stage single-arm trials with a binary endpoint indicating tumor response. As a common feature of these designs, the sample sizes of the two stages and the decision rules for the interim and the final analysis have to be pre-specified and adhered to strictly during the course of the trial in order to assure control of the type I error rate. In practice, however, the attained sample sizes often deviate from the planned ones leading to the situation of overrunning or underrunning. The currently available approaches to deal with this problem are either based on assumptions that are rarely met in practice or do not guarantee that the significance level is kept. However, strict control of the type I error rate plays an important role also for single-arm cancer trials, as they are frequently a fundamental part of the registration information. We propose a general methodology that allows handling both unintentional and intentional overrunning and underrunning while strictly controlling the type I error rate. Application of the proposed procedure and some of its characteristics are illustrated with a real phase II oncology trial.

Wenn ein Bild mehr als tausend Worte sagen kann, so bieten dynamische interaktive Grafiken ein noch groseres Potenzial. In der Lehre eignen sich diese insbesondere als einfaches und effektives Mittel zur Visualisierung und damit zur Vermittlung komplexer Sachverhalte.

In clinical phase II studies, the efficacy of a promising therapy is tested in patients for the first time. Based on the results, it is decided whether the development programme should be stopped or whether the benefit-risk profile is promising enough to justify the initiation of large phase III studies. In oncology, phase II trials are commonly conducted as single-arm trials with planned interim analyses to allow for an early stopping for futility. The specification of an adequate study design that guarantees control of the type I and II error rates is a key task in the planning stage of such a trial. A variety of statistical methods exists which can be used to optimise the planning and analysis of such studies. However, there are currently neither commercial nor non-commercial software tools available that support the practical application of these methods comprehensively. The R package OneArmPhaseTwoStudy was implemented to fill this gap. The package allows determining an adequate study design for the particular situation at hand as well as monitoring the progress of the study and evaluating the results with valid and efficient analyses methods. This article describes the features of the R package and its application.

When planning a single-armed clinical trial with binary endpoint, the sample size is determined such that the desired power is achieved for a single value of the target rate. However, there is usually some uncertainty with respect to the true treatment effect. It is therefore more realistic to specify an interval for the possible true rate to accommodate this uncertainty. For this situation, we examine comprehensively the overall performance of various Phase II oncology designs and sample size recalculation strategies. The methods and results of our investigations can be used to identify the most appropriate approach for a specific clinical trial situation at hand. Application is illustrated with a clinical trial in rectal cancer.

Background: There is a need for simple clinical tools that can objectively assess the fall risk in people with dementia. Wearable sensors seem to have the potential for fall prediction; however, there has been limited work performed in this important area. Objective: To explore the validity of sensor-derived physical activity (PA) parameters for predicting future falls in people with dementia. To compare sensor-based fall risk assessment with conventional fall risk measures. Methods: This was a cohort study of people with confirmed dementia discharged from a geriatric rehabilitation ward. PA was quantified using 24-hour motion-sensor monitoring at the beginning of the study. PA parameters (percentage of walking, standing, sitting, and lying; duration of single walking, standing, and sitting bouts) were extracted using specific algorithms. Conventional assessment included performance-based tests (Timed Up and Go Test, Performance-Oriented Mobility Assessment, 5-chair stand) and questionnaires (cognition, ADL status, fear of falling, depression, previous faller). Outcome measures were fallers (at least one fall in the 3-month follow-up period) versus non-fallers. Results: 77 people were included in the study (age 81.8 ± 6.3; community-dwelling 88%, institutionalized 12%). Surprisingly, fallers and non-fallers did not differ on any conventional assessment (p = 0.069-0.991), except for ‘previous faller' (p = 0.006). Interestingly, several PA parameters discriminated between the groups. The ‘walking bout average duration', ‘longest walking bout duration' and ‘walking bout duration variability' were lower in fallers, compared to non-fallers (p = 0.008-0.027). The ‘standing bout average duration' was higher in fallers (p = 0.050). Two variables, ‘walking bout average duration' [odds ratio (OR) 0.79, p = 0.012] and ‘previous faller' (OR 4.44, p = 0.007) were identified as independent predictors for falls. The OR for a ‘walking bout average duration' Discussion: Results demonstrate that sensor-derived PA parameters are independent predictors of the fall risk and may have higher diagnostic accuracy in persons with dementia compared to conventional fall risk measures. Our findings highlight the potential of telemonitoring technology for estimating the fall risk. Results should be confirmed in a larger study and by measuring PA over a longer period of time.

In oncology, single-arm two-stage designs with binary endpoint are widely applied in phase II for the development of cytotoxic cancer therapies. Simon's optimal design with prefixed sample sizes in both stages minimizes the expected sample size under the null hypothesis and is one of the most popular designs. The search algorithms that are currently used to identify phase II designs showing prespecified characteristics are computationally intensive. For this reason, most authors impose restrictions on their search procedure. However, it remains unclear to what extent this approach influences the optimality of the resulting designs. This article describes an extension to fixed sample size phase II designs by allowing the sample size of stage two to depend on the number of responses observed in the first stage. Furthermore, we present a more efficient numerical algorithm that allows for an exhaustive search of designs. Comparisons between designs presented in the literature and the proposed optimal adaptive designs show that while the improvements are generally moderate, notable reductions in the average sample size can be achieved for specific parameter constellations when applying the new method and search strategy.

Phase II trials in oncology are usually conducted as single-arm two-stage designs with binary endpoints. Currently available adaptive design methods are tailored to comparative studies with continuous test statistics. Direct transfer of these methods to discrete test statistics results in conservative procedures and, therefore, in a loss in power. We propose a method based on the conditional error function principle that directly accounts for the discreteness of the outcome. It is shown how application of the method can be used to construct new phase II designs that are more efficient as compared to currently applied designs and that allow flexible mid-course design modifications. The proposed method is illustrated with a variety of frequently used phase II designs.

Background Endothelial progenitor cells (EPC) are bone marrow-derived cells which can undergo differentiation into endothelial cells and participate in endothelial repair and angiogenesis. Insulin facilitates this in vitro mediated by the IGF-1 receptor. Clinical trials showed that the number of circulating EPCs is influenced by glucose control and EPC are a predictor of cardiovascular death. To study direct effects of insulin treatment on EPCs in type 2 diabetes patients, add-on basal insulin treatment was compared to an escalation of oral medication aiming at similar glucose control between the groups. Methods 55 patients with type 2 diabetes (61.6±5.9 years) on oral diabetes medication were randomized in a 2:2:1 ratio in 3 groups. Patients were treated additionally with insulin glargine (n=20), NPH insulin (n=22) or escalated with oral medication (n=13). Number of circulating EPC, EPC-outgrowth, intima media thickness, skin microvascular function and HbA1c were documented at baseline and/or after 4 weeks and 4 months. Results HbA1c at baseline was, 7.3+/−0.7% in the oral group, 7.3+/−0.9% and 7.5+/−0.7% in the glargine and NPH insulin respectively (p=0.713). HbA1c after 4 months decreased to 6.8+/−0.8%, 6.6+/−0.7% and 6.7+/−0.6%, in the oral, glargine and NPH insulin group respectively (p=0.61). FACS analysis showed no difference in number of circulating EPC between the groups after 4 weeks and 4 months. However, the outgrowth of EPCs as detected by colony forming assay was increased in the NPH insulin and glargine groups (29.2+/−6.4 and 29.4+/− 6.7 units respectively) compared to the group on oral medication (23.2+/−6.3, p=0.013) after 4 months of treatment. A significant decrease of IMT from 0.80mm (+/−0.14) at baseline to 0.76mm (+/−0.12) after 4 months could be observed in all patients only (p=0.03) with a trend towards a reduction of IMT after 4 months when all patients on insulin treatment were compared to the oral treatment group (p=0.06). Skin microvascular function revealed no differences between the groups (p=0.74). Conclusion The study shows that a 4-month treatment with add-on insulin significantly increases the outgrowth of EPC in patients with type 2 diabetes mellitus. Trial registration (Clinical Trials Identifier: NCT00523393).

Introduction: Clinical trials have shown that the number of circulating endothelial progenitor cells (EPCs) correlates with cardiovascular risk factors and is an independent predictor of cardiovascular death. We were previously able to show that insulin stimulates the in vitro outgrowth of EPCs. Therefore we studied whether treating type 2 diabetic patients with insulin affects circulating EPCs or vascular function. Study design: 55 patients with type 2 diabetes mellitus on oral antidiabetics were randomized in 3 groups. For the following 4 months patients were treated additionally with insulin glargine (n = 20), NPH insulin (n = 22) or with a combination of oral antidiabetics (n = 13). Data for EPC- mobilization, EPC-differentiation, intima-media thickness (IMT) and HbA1c were documented/performed at the entry visit (visit 1); after 4 weeks (visit 2) and after 4 months (visit 3). Results: HbA1c levels were similarly high in all 3 groups at baseline (p = 0.71). HbA1c was equally decreased after 4 months in all 3 arm groups independently from the form of treatment without showing any statistical significance between the groups (p = 0.61). FACS analysis showed no significant difference between the 3 groups concerning the mobilization of EPCs 4 weeks (p = 0.96) and 4 months (p = 0.55) after treatment. However the number of EPCs as detected by ex-vivo outgrowth was in both insulin groups at visit 3 significantly higher than the oral group (p = 0.013). A statistically significant decrease of IMT from 0.80 mm (± 0.14) at visit 1 to 0.76 mm (± 0.12) at visit 3 could be observed in all patients (p = 0.03). Summary: The study shows that a 4-month treatment with insulin glargine or NPH insulin significantly increases the differentiation of EPCs on patients with type 2 diabetes mellitus, compared to those treated only with oral antidiabetics. Besides it could be shown that all groups achieved a significant decrease of HbA1c as well as a significant reduction of the intima-media thickness.

Background: Preventing and rehabilitating gait disorders in people with dementia during early disease stage is of high importance for staying independent and ambulating safely. However, the evidence gathered in randomized controlled trials (RCTs) on the effectiveness of exercise training for improving spatio-temporal gait parameters in people with dementia is scarce. The aim of the present study was to determine whether a specific, standardized training regimen can improve gait characteristics in people with dementia.Methods: Sixty-one individuals (mean age: 81.9 years) with confirmed mild to moderate stage dementia took part in a 3-month double-blinded outpatient RCT. Subjects in the intervention group (IG) received supervised, progressive resistance and functional group training for 3 months (2 times per week for two hours) specifically developed for people with dementia. Subjects in the control group (CG) conducted a low-intensity motor placebo activity program. Gait characteristics were measured before and after the intervention period using a computerized gait analysis system (GAITRite®).Results: Adherence to the intervention was excellent, averaging 91.9% in the IG and 94.4% in the CG. The exercise training significantly improved gait speed (P < 0.001), cadence (P = 0.002), stride length (P = 0.008), stride time (P = 0.001), and double support (P = 0.001) in the IG compared to the CG. Effect sizes were large for all gait parameters that improved significantly (Cohen’s d: 0.80-1.27). No improvements were found for step width (P = 0.999), step time variability (P = 0.425) and Walk-Ratio (P = 0.554). Interestingly, low baseline motor status, but not cognitive status, predicted positive training response (relative change in gait speed from baseline).Conclusion: The intensive, dementia-adjusted training was feasible and improved clinically meaningful gait variables in people with dementia. The exercise program may represent a model for preventing and rehabilitating gait deficits in the target group. Further research is required for improving specific gait characteristics such as gait variability in people with dementia.Trial registration: ISRCTN49243245 published

Background: Translation of intensive exercise programs developed specifically for patients with dementia into clinical settings is lacking. Objective: To determine if a progressive resistance and functional training program, previously evaluated in dementia outpatients, can be implemented in a geriatric inpatient setting in order to improve motor performances in patients with dementia. Methods: Eligible patients in one ward of a German geriatric hospital were assigned to the intervention group (IG, n = 74) and received intensive exercise training specifically designed for patients with dementia. Patients in the second ward were observed as a control group (CG, n = 74). All patients received usual care treatment. Primary endpoints were maximal lower extremity strength measured by a leg-press device and duration of the 5-chair-stand test for functional performance. Secondary outcomes included a number of parameters for strength and function. Results: The rehabilitation period averaged 18.1 ± 6.8 days. The IG significantly improved in both primary endpoints (change: maximal strength, IG: +51.9 ± 42.3% versus CG: +13.5 ± 51.8%, p < 0.001; functional performance, IG: −19.2 ± 22.3% versus CG: −3.8 ± 32.2% s, p = 0.037). Secondary outcomes confirmed effects for strength and some, but not all, functional parameters. Interestingly, low baseline motor status, but not cognitive status, predicted positive training response. Conclusion: An intensive exercise program can be implemented in a geriatric rehabilitation setting to improve motor performances in patients with dementia. Results suggest that an intensification of training is feasible in the target group and substantially increases the benefits in comparison to receiving usual care exercise only.

Background Post-stroke immune depression contributes to the development of infections which are major complications after stroke. Previous experimental and clinical studies suggested that humoral stress mediators induce immune dysfunction. However, prospective clinical studies testing this concept are missing and no data exists for other cerebrovascular diseases including intracerebral hemorrhage (ICH) and TIA. Methods We performed a prospective clinical study investigating 166 patients with TIA, ischemic and hemorrhagic stroke. We measured a broad panel of stress mediators, leukocyte subpopulations, cytokines and infection markers from hospital admission to day 7 and on follow-up after 2–3 months. Multivariate regression analyses detected independent predictors of immune dysfunction and bacterial infections. ROC curves were used to test the diagnostic value of these parameters. Results Only severe ischemic strokes and ICH increased some catecholamine metabolites, ACTH and cortisol levels. Immunodysfunction was eminent already on hospital admission after large brain lesions with lymphocytopenia as a key feature. None of the stress mediators was an independent predictor of lymphocytopenia or infections. However, lymphocytopenia on hospital admission was detected as an independent explanatory variable of later infections. NIHSSS and lymphocytopenia on admission were excellent predictors of infection. Conclusions Our results question the present pathophysiological concept of stress-hormone mediated immunodysfunction after stroke. Early lymphocytopenia was identified as an early independent predictor of post-stroke infections. Absence of lymphocytopenia may serve as a negative predictive marker for stratification for early antibiotic treatment.

Purpose: Chemokine receptors and their ligands are involved in a number of cell processes, including normal cell trafficking as well as metastasis in cancer. During metastasis, they are thought to play a role in determining cancer cell distribution and target organs. The aim of this study was to examine the expression of the chemokine receptors CXCR4, CCR7 and CCR10 as well as their respective chemokine ligands (CXCL12, CCL19, CCL27) in human uveal melanomas. Methods: Seventy formalin-fixed paraffin-embedded uveal melanoma specimens from patients treated in 1996–1997 were examined using immunohistochemistry and evaluated using an immune reactive score (IRS). Results: The chemokine receptors CXCR4, CCR7 and CCR10 were primarily expressed in the cytoplasm of uveal melanoma cells, with CXCR4 (average IRS 8.2) and CCR7 (average IRS 5.7) showing the strongest expression, respectively. The chemokine ligand CCL19 demonstrated a moderate expression (average IRS 5.3), whereas the expression of receptor CCR10 (average IRS of 3.4), ligand CCL27 (average IRS 2.5) and ligand CXCL12 (average IRS 0.6) by uveal melanoma cells was low. A significant association between liver metastases and chemokine expression was found for CCR7 expression (p = 0.037) only. Comparison of liver metastasis and choroid uveal melanoma (35.3%, n = 12 of 34) versus ciliary body involvement (72.7%, n = 8 of 11) was significant (p = 0.030). Conclusion: Chemokine receptors are more strongly expressed on uveal melanoma cells than their ligands. Our results show new aspects of the metastatic process in uveal melanoma.

A majority of geriatric patients experience difficulty in performing sit-to-stand (SiSt) transitions. A detailed assessment of SiSt ability is a prerequisite for successful rehabilitation. Body fixed sensors (BFSs) are increasingly used to assess functional performances. As to date there is no system which analyzes clinically relevant phases of SiSt, the aim of this study was to determine the reliability of an automated approach for quantifying durations and angular velocities of trunk flexion and extension during repeated SiSt transitions using one BFS (DynaPort® Hybrid). Forty multimorbid geriatric patients aged 84.1 ± 6.6 years were included. Each patient participated in two test sessions with a 5 min rest period in between. Intra- and interrater reliability was assessed. Intraclass correlation coefficients (ICCs), absolute and relative standard measurement errors (SEMs, SEMs%) and minimal detectable changes (MDCs(95), MDCs(95)%) were calculated. ICCs were good to excellent for all variables in the total sample (0.80-0.94). The intraobserver group (50%) showed a higher number of excellent ICCs (≥.9) compared to the interobserver subgroup (10%). SEM% was low for all variables (6.9-12.7%). MDC(95)% ranged 19.2-34.4% and more variables ≤30% were found in the intra- (80%) compared to the inter-observer group (60%). Study results demonstrate that the BFS system provides a reliable analysis of SiSt phases in geriatric patients, and is a substantial improvement over the stopwatch approach used in clinical practice today.

In oncology, single-arm two-stage designs with binary endpoint are widely applied in phase II for the development of cytotoxic cancer therapies. Simon's optimal design with prefixed sample sizes in both stages minimizes the expected sample size under the null hypothesis and is one of the most popular designs. The search algorithms that are currently used to identify phase II designs showing prespecified characteristics are computationally intensive. For this reason, most authors impose restrictions on their search procedure. However, it remains unclear to what extent this approach influences the optimality of the resulting designs. This article describes an extension to fixed sample size phase II designs by allowing the sample size of stage two to depend on the number of responses observed in the first stage. Furthermore, we present a more efficient numerical algorithm that allows for an exhaustive search of designs. Comparisons between designs presented in the literature and the proposed optimal adaptive designs show that while the improvements are generally moderate, notable reductions in the average sample size can be achieved for specific parameter constellations when applying the new method and search strategy.

A high-fat, low-fiber diet resulting in increased excretion of fecal secondary bile acids is regarded as a major risk factor for colon cancer. Incubation of human colonic biopsies with the secondary bile acid deoxycholic acid (DCA) leads to hyperproliferation with expansion of the proliferative zone, ie, a biomarker of increased cancer risk. Antiproliferative effects on various colon cancer cell lines, however, were reported for butyrate (BUT), a fermentation product of dietary fiber.In the following in vitro study we incubated biopsies from the normal sigmoid colon of 12 patients (age 55.8 +/- 3.6 years) with 5 microM DCA or a combination of 5 microM DCA plus 10 mM BUT (DCA/BUT) and determined epithelial proliferation by bromodeoxyuridine immunohistochemistry. As a possible mediator for the DCA effects on colonic cell proliferation, mucosal prostaglandin E2 (PGE2) release into the incubation medium was measured by 125I-PGE2 radioimmunoassay.Incubation with DCA alone revealed a significantly higher labeling index for the whole crypt (.17 vs .11, p.01) and for the upper 40% of the crypt (.05 vs .01, p.01) compared with DCA/BUT. Mucosal PGE2 release during DCA/BUT incubation showed a trend toward lower values compared with DCA incubation (357.07 vs 434.29 pg/mg per hour; p = .07).The results indicate a normalization of DCA-induced hyperproliferation of colonic epithelium by butyrate that is not clearly mediated by PGE2. Considering that nutrition affects the luminal concentrations of DCA and butyrate, our findings may have implications for colonic carcinogenesis.

Background Currently, it remains unclear, if patients with colon cancer and synchronous unresectable metastases who present without severe symptoms should undergo resection of the primary tumour prior to systemic chemotherapy. Resection of the primary tumour may be associated with significant morbidity and delays the beginning of chemotherapy. However, it may prevent local symptoms and may, moreover, prolong survival as has been demonstrated in patients with metastatic renal cell carcinoma. It is the aim of the present randomised controlled trial to evaluate the efficacy of primary tumour resection prior to systemic chemotherapy to prolong survival in patients with newly diagnosed colon cancer who are not amenable to curative therapy. Methods/design The SYNCHRONOUS trial is a multicentre, randomised, controlled, superiority trial with a two-group parallel design. Colon cancer patients with synchronous unresectable metastases are eligible for inclusion. Exclusion criteria are primary tumour-related symptoms, inability to tolerate surgery and/or systemic chemotherapy and history of another primary cancer. Resection of the primary tumour as well as systemic chemotherapy is provided according to the standards of the participating institution. The primary endpoint is overall survival that is assessed with a minimum follow-up of 36 months. Furthermore, it is the objective of the trial to assess the safety of both treatment strategies as well as quality of life. Discussion The SYNCHRONOUS trial is a multicentre, randomised, controlled trial to assess the efficacy and safety of primary tumour resection before beginning of systemic chemotherapy in patients with metastatic colon cancer not amenable to curative therapy. Trial registration ISRCTN30964555

Clinical phase II trials in oncology are conducted to determine whether the activity of a new anticancer treatment is promising enough to merit further investigation. Two-stage designs are commonly used for this situation to allow for early termination. Designs proposed in the literature so far have the common drawback that the sample sizes for the two stages have to be specified in the protocol and have to be adhered to strictly during the course of the trial. As a consequence, designs that allow a higher extent of flexibility are desirable. In this article, we propose a new adaptive method that allows an arbitrary modification of the sample size of the second stage using the results of the interim analysis or external information while controlling the type I error rate. If the sample size is not changed during the trial, the proposed design shows very similar characteristics to the optimal two-stage design proposed by Chang et al. (Biometrics 1987; 43:865-874). However, the new design allows the use of mid-course information for the planning of the second stage, thus meeting practical requirements when performing clinical phase II trials in oncology.