Time-Dependent Prediction Models for Individual Prognosis of Chronic Postsurgical Pain following Knee Replacement Based on an Extensive Multivariable Data Set.

(1) Background: Clinically useful prediction models for chronic postsurgical pain (CPSP) in knee replacement (TKA) are lacking. (2) Methods: In our prospective, multicenter study, a wide-ranging set of 91 variables was collected from 933 TKA patients at eight time points up to one year after surgery. Based on this extensive data pool, simple and complex prediction models were calculated for the preoperative time point and for 6 months after surgery, using least absolute shrinkage and selection operator (LASSO) 1se and LASSO min, respectively. (3) Results: Using preoperative data only, LASSO 1se selected age, the Revised Life Orientation Test on pessimism, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)-subscore pain and the Timed "Up and Go" Test for prediction, resulting in an area under the curve (AUC) of 0.617 and a Brier score of 0.201, expressing low predictive power only. Using data up to 6 months after surgery, LASSO 1se included preoperative Patient Health Questionnaire-4, Knee Injury and Osteoarthritis Outcome Score (KOOS)-subscore pain (pain) 3 months after surgery (month), WOMAC pain 3 and 6 months, KOOS subscore symptoms 6 months, KOOS subscore sport 6 months and KOOS subscore Quality of Life 6 months. This improved the predictive power to an intermediate one (AUC 0.755, Brier score 0.168). More complex models computed using LASSO min did little to further improve the strength of prediction. (4) Conclusions: Even using multiple variables and complex calculation methods, the possibility of individual prediction of CPSP after TKA remains limited.

Phase II study of metronomic treatment with daily oral vinorelbine as first-line chemotherapy in patients with advanced/metastatic HR+/HER2- breast cancer resistant to endocrine therapy: VinoMetro-AGO-B-046.

PURPOSE: Metronomic chemotherapy (MCT) is an increasingly used treatment option in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced/metastatic breast cancer (MBC) after failure of endocrine-based therapies. METHODS: VinoMetro was a multicentre, open-label, single-arm, phase II study of metronomic oral vinorelbine (VRL; 30 mg/day) as a first-line chemotherapy (CT) in patients with HR+/HER2- MBC after endocrine failure. The primary endpoint was the clinical benefit rate (CBR) at 24 weeks. RESULTS: Between January 2017 and April 2019, nine patients were enrolled. The CBR was 22.2% (90% confidence interval [CI] 4.1-55.0), p = 0.211. The median progression-free survival (PFS) was 12.0 weeks (95% CI 11.3-12.7). Grade 3-4 adverse events (AEs) occurred in 22.2% of patients. One patient died of febrile neutropenia. CONCLUSION: VinoMetro (AGO-B-046) was closed early after nine patients and occurrence of one grade 5 toxicity in agreement with the lead institutional review board (IRB). Metronomic dosing of oral VRL in HR+/HER2- MBC as first-line CT after failure of endocrine therapies showed only limited benefit in this population. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: ClinicalTrials.gov Identifier: NCT03007992; December 15, 2016.

The PROMISE study protocol: a multicenter prospective study of process optimization with interdisciplinary and cross-sectoral care for German patients receiving hip and knee endoprostheses.

Background and purpose - Knee and hip replacement are common and increasing procedures, and an optimized care process that could be implemented in different settings would be useful. The PROMISE trial investigates whether a new care process works equally in different German settings and how the results compare with current non-standardized care.Patients and methods - This multi-center prospective mixed-method study includes 2,000 German patients receiving arthritis-related hip or knee endoprostheses. An interdisciplinary and cross-sectoral care process was developed and implemented in 3 German hospitals with different levels of care, and corresponding rehabilitation centers were included to bridge the gap after acute care.Duration and outcome - The PROMISE trial recruited patients between May 2018 and March 2020. Follow-up will end in February 2021. Assessments are performed at: examination on clinical indication, 1 week before surgery, on the day of surgery, at the end of hospitalization, end of the rehabilitation program, and 3 months, 6 months, and 12 months after surgery. Outcomes include patient-reported outcomes, medical examination findings, and routinely collected data regarding the surgery and complications. Guideline-based interviews are conducted with selected patients and care partners. The primary endpoint is the presence of chronic pain at 12 months after surgery. Secondary endpoints are the number of recognized pre-existing conditions, physical activity at 12 months after surgery, use of medical services, quality of life, and interactions between care partners.Trial registration - The trial is registered with the German Clinical Trials Register (https://www.drks.de; DRKS00013972; March 23, 2018).

Sunitinib added to FOLFIRI versus FOLFIRI in patients with chemorefractory advanced adenocarcinoma of the stomach or lower esophagus: a randomized, placebo-controlled phase II AIO trial with serum biomarker program.

BACKGROUND: As a multi-targeted anti-angiogenic receptor tyrosine kinase (RTK) inhibitor sunitinib (SUN) has been established for renal cancer and gastrointestinal stromal tumors. In advanced refractory esophagogastric cancer patients, monotherapy with SUN was associated with good tolerability but limited tumor response. METHODS: This double-blind, placebo-controlled, multicenter, phase II clinical trial was conducted to evaluate the efficacy, safety and tolerability of SUN as an adjunct to second and third-line FOLFIRI (NCT01020630). Patients were randomized to receive 6-week cycles including FOLFIRI plus sodium folinate (Na-FOLFIRI) once every two weeks and SUN or placebo (PL) continuously for four weeks followed by a 2-week rest period. The primary study endpoint was progression-free survival (PFS). Preplanned serum analyses of VEGF-A, VEGF-D, VEGFR2 and SDF-1α were performed retrospectively. RESULTS: Overall, 91 patients were randomized, 45 in each group (one patient withdrew). The main grade ≥3 AEs were neutropenia and leucopenia, observed in 56 %/20 % and 27 %/16 % for FOLFIRI + SUN/FOLFIRI + PL, respectively. Median PFS was similar, 3.5 vs. 3.3 months (hazard ratio (HR) 1.11, 95 % CI 0.70-1.74, P = 0.66) for FOLFIRI + SUN vs. FOLFIRI + PL, respectively. For FOLFIRI + SUN, a trend towards longer median overall survival (OS) compared with placebo was observed (10.4 vs. 8.9 months, HR 0.82, 95 % CI 0.50-1.34, one-sided P = 0.21). In subgroup serum analyses, significant changes in VEGF-A (P = 0.017), VEGFR2 (P = 0.012) and VEGF-D (P < 0.001) serum levels were observed. CONCLUSIONS: Although sunitinib combined with FOLFIRI did not improve PFS and response in chemotherapy-resistant gastric cancer, a trend towards better OS was observed. Further biomarker-driven studies with other anti-angiogenic RTK inhibitors are warranted. TRIAL REGISTRATION: This study was registered prospectively in the NCT Clinical Trials Registry (ClinicalTrials.gov) under NCT01020630 on November 23, 2009 after approval by the leading ethics committee of the Medical Association of Rhineland-Palatinate, Mainz, in coordination with the participating ethics committees (see Additional file 2) on September 16, 2009.

RhoA regulates peroxisome association to microtubules and the actin cytoskeleton.

The current view of peroxisome inheritance provides for the formation of new peroxisomes by both budding from the endoplasmic reticulum and autonomous division. Here we investigate peroxisome-cytoskeleton interactions and show by proteomics, biochemical and immunofluorescence analyses that actin, non-muscle myosin IIA (NMM IIA), RhoA, Rho kinase II (ROCKII) and Rab8 associate with peroxisomes. Our data provide evidence that (i) RhoA in its inactive state, maintained for example by C. botulinum toxin exoenzyme C3, dissociates from peroxisomes enabling microtubule-based peroxisomal movements and (ii) dominant-active RhoA targets to peroxisomes, uncouples the organelles from microtubules and favors Rho kinase recruitment to peroxisomes. We suggest that ROCKII activates NMM IIA mediating local peroxisomal constrictions. Although our understanding of peroxisome-cytoskeleton interactions is still incomplete, a picture is emerging demonstrating alternate RhoA-dependent association of peroxisomes to the microtubular and actin cytoskeleton. Whereas association of peroxisomes to microtubules clearly serves bidirectional, long-range saltatory movements, peroxisome-acto-myosin interactions may support biogenetic functions balancing peroxisome size, shape, number, and clustering.