Mammazentrum Hamburg

<bold>RATIONALE:</bold> Daily FeNO may reflect airway T2 inflammation better than singular clinic data. <bold>Objectives:</bold> To compare longitudinal mean FeNO and variability (CV) in relation to asthma control; to compare sensitivity to detect T2_FeNO inflammation at diagnostic (≥40 ppb in GINA 1) and on-treatment (≥25 ppb in GINA 2-5) cutoffs vs. single clinic values. <bold>Methods:</bold> Observational study with daily home-based FeNO (Vivatmo <italic>me</italic>) and symptom diary in asthmatics of different GINA steps over 3 months. Clinic FeNO, FEV₁, and ACQ were also collected at 2 visits (enrollment/study end). <bold>Results:</bold> We enrolled n=85 patients (n=23 Step 1, n=37 Step 2-3, and n=25 Step 4-5). Mean daily FeNO over 3 months was highest in uncontrolled Step 4-5 (p=0.031), and FeNO variability in Step 2-3 (p=0.045). Overall, subjects with (+) sustained control (ACQ<0.75 both visits) had comparable mean FeNO values, but fewer proportion of patients with variability above the median CV vs. (-)sustained control patients (39.1 vs. 54.1%; p=0.03). Mean FeNO was elevated on symptomatic asthma days, particularly in Step 1 (p=0.001), with similar trends during loss of control phases. Home FeNO increased sensitivity to detect T2_FeNO inflammation at diagnostic cutoff (Step 1) from 8.7% (clinic FeNO) to 47.8% of subjects. In GINA 2-3 and 4-5, sensitivity for on-treatment T2_FeNO inflammation by home vs. clinic FeNO increased from 58.3% to 83.3%, and 64% to 96%, respectively. <bold>Conclusions:</bold> Daily FeNO provides important information about airway inflammation, complimentary to symptom control. Further, detection of T2 inflammation in asthmatics is improved at all GINA steps at both diagnostic and predictive/prognostic cutoffs, with important implications for management and diagnosis.

Background/Objectives: The treatment of cartilage damage is an ongoing challenge. Several techniques have been developed to address this problem. Matrix-Induced Autologous Chondrocyte Implantation (MACI) is often referred to as the "gold standard" for cartilage treatment. Numerous long-term outcome studies also have reported favorable results with Autologous Matrix-Induced Chondrogenesis (AMIC). Minced Cartilage Implantation (MCI) is a recently developed arthroscopic method. This technique has demonstrated promising outcomes, with the prospect of longer-term results still under investigation. This study aims to directly compare the patient-reported outcomes of these three techniques over a 2-year follow-up period. Methods: A total of N = 48 patients were included in the retrospective matched pair analysis (n = 16 MACI, n = 16 AMIC, n = 16 MCI). VAS, KOOS-Pain, and KOOS-Symptoms scores served as primary outcomes; the KOOS-ADL and -QOL and the Tegner Activity Scale (TAS) served as secondary outcomes. Results: All three groups did not differ from each other in the primary or secondary outcomes. Pain and function significantly improved from pre-surgery to two years after (VAS: p < 0.000; ES: η2 = 0.27; KOOS-Pain: p < 0.000; ES: η2 = 0.30; KOOS-Symptoms: p = 0.000; ES: η2 = 0.26; KOOS-ADL: p > 0.000; ES: η2 = 0.20; KOOS-QOL: p > 0.000; ES: η2 = 0.30). There was no significant effect of time on the activity level. Conclusions: All three procedures show good patient-reported outcomes, low complication rates, and long graft longevity in the 2-year follow-up. Therefore, all three methods seem to be equally recommendable for the treatment of cartilage lesions.

The randomized GeparOLA trial reported comparable pathologic complete response (pCR) rates with neoadjuvant treatment containing olaparib versus carboplatin. In this study, we evaluate the association between functional homologous recombination deficiency (HRD) by RAD51 foci and pCR and the potential of improving patient selection by combining RAD51 and stromal tumor-infiltrating lymphocytes. This is a post hoc blinded biomarker analysis from the randomized GeparOLA trial. Patients with early-stage HER2-negative breast cancer and HRD assessed by Myriad MyChoice or BRCA1/BRCA2 mutations were randomized 1:1 to receive (i) paclitaxel plus olaparib or (ii) paclitaxel plus carboplatin, both followed by epirubicin/cyclophosphamide. Functional HRD was predefined as a RAD51 score ≤10% (RAD51-low). Overall, 90 of 97 (92.8%) samples were evaluable for RAD51 testing, and 72 of 90 (80.0%) were RAD51-low. The pCR rate in patients with RAD51-low tumors was 66.7% (48/72), whereas it decreased to 22.2% (4/18) in those with RAD51-high. In the multivariable model including clinicopathologic factors and treatment, the RAD51 score remained significantly associated with pCR (OR = 12.03; 95% confidence interval, 2.60-55.73; P = 0.002). Patients with RAD51-low and high stromal tumor-infiltrating lymphocytes in their tumors achieved a pCR rate of 75.0% (27/36). Similar results were observed for olaparib or carboplatin. In the exploratory disease-free survival analysis, no differences were observed between RAD51 groups (high vs. low: HR = 0.85; 95% confidence interval, 0.25-2.97). In a preselected population with HRD, according to a genetic test, RAD51 testing identifies patients with different pCR rates under PARP inhibitor-based or platinum-based therapies. Future biomarker-driven studies should consider this information to refine stratification factors and to improve patient selection.

Background:Symptomatic cartilage defects of the knee joint are frequently diagnosed and can be treated with different available surgical methods. Nevertheless, there is currently no gold standard treatment for all indications. Minced cartilage implantation is increasingly coming into focus as a refined surgical technique.Purpose:To investigate the 2-year clinical and radiological outcomes of arthroscopic autologous minced cartilage repair with the standardized commercial implantation system AutoCart.Study Design:Case series; Level of evidence, 4.Methods:A total of 62 consecutive patients were included and prospectively evaluated preoperatively and at 3, 6, 12, and 24 months postoperatively. Outcomes were assessed using the Knee injury and Osteoarthritis Outcome Score (KOOS), visual analog scale (VAS) for pain, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Single Assessment Numeric Evaluation (SANE), and Tegner activity scale at all follow-up time points. The examination of preoperative magnetic resonance imaging (MRI) was performed using the Area Measurement and Depth and Underlying Structures (AMADEUS) score, and the examination of MRI at 24 months was performed using the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) 2.0 score.Results:There were 34 male and 28 female patients (mean age, 38.79 ± 10.78 years) with symptomatic cartilage lesions with a mean defect size of 2.53 ± 1.24 cm2. Lesions were predominantly International Cartilage Repair Society grade 3 located in the region of the femoral condyles. Concomitant surgery was performed in 40.3% of patients. The total KOOS score significantly improved from 62.4 ± 13.1 at baseline to 74.4 ± 15.9 at 24 months (P < .001). The secondary outcome measures of the VAS, WOMAC, and SANE showed a similar pattern, with score improvements in the follow-up period compared to baseline. The mean AMADEUS score was 64.75 ± 13.87, while the mean MOCART 2.0 score was 62.88 ± 9.86, among 20 available patients. The revision surgery rate was 8.1% mainly because of hypertrophy (6.5%).Conclusion:Among this cohort of patients, minced cartilage implantation demonstrated satisfying 2-year outcomes with increased patient-reported outcome measure scores from 3 to 24 months postoperatively. Regenerated tissue quality on MRI was comparable to that using other cartilage repair methods and showed no associations with patient characteristics or patient-reported outcome measures. Larger cohorts, longer postoperative intervals, and comparable trials are needed to further evaluate the role of this technique in treating cartilage defects.

Therapy-induced molecular adaptation of triple-negative breast cancer is crucial for immunotherapy response and resistance. We analyze tumor biopsies from three different time points in the randomized neoadjuvant GeparNuevo trial (NCT02685059), evaluating the combination of durvalumab with chemotherapy, for longitudinal alterations of gene expression. Durvalumab induces an activation of immune and stromal gene expression as well as a reduction of proliferation-related gene expression. Immune genes are positive prognostic factors irrespective of treatment, while proliferation genes are positive prognostic factors only in the durvalumab arm. We identify stromal-related gene expression as a contributor to immunotherapy resistance and poor therapy response. The results provide evidence from clinical trial cohorts suggesting a role for stromal reorganization in therapy resistance to immunotherapy and in the generation of an immune-suppressive microenvironment, which might be relevant for future therapy approaches targeting the tumor stroma parallel to immunotherapy, such as combinations of immunotherapy with anti-angiogenic therapy.

Cachexia is a body wasting syndrome that significantly affects well-being and prognosis of cancer patients, without effective treatment. Serum metabolites take part in pathophysiological processes of cancer cachexia, but apart from altered levels of select serum metabolites, little is known on the global changes of the overall serum metabolome, which represents a functional readout of the whole-body metabolic state. Here, we aimed to comprehensively characterize serum metabolite alterations and analyze associated pathways in cachectic cancer patients to gain new insights that could help instruct strategies for novel interventions of greater clinical benefit. Serum was sampled from 120 metastatic cancer patients (stage UICC IV). Patients were grouped as cachectic or non-cachectic according to the criteria for cancer cachexia agreed upon international consensus (main criterium: weight loss adjusted to body mass index). Samples were pooled by cachexia phenotype and assayed using non-targeted gas chromatography-mass spectrometry (GC-MS). Normalized metabolite levels were compared using t-test (p < 0.05, adjusted for false discovery rate) and partial least squares discriminant analysis (PLS-DA). Machine-learning models were applied to identify metabolite signatures for separating cachexia states. Significant metabolites underwent MetaboAnalyst 5.0 pathway analysis. Comparative analyses included 78 cachectic and 42 non-cachectic patients. Cachectic patients exhibited 19 annotable, significantly elevated (including glucose and fructose) or decreased (mostly amino acids) metabolites associating with aminoacyl-tRNA, glutathione and amino acid metabolism pathways. PLS-DA showed distinct clusters (accuracy: 85.6%), and machine-learning models identified metabolic signatures for separating cachectic states (accuracy: 83.2%; area under ROC: 88.0%). We newly identified altered blood levels of erythronic acid and glucuronic acid in human cancer cachexia, potentially linked to pentose-phosphate and detoxification pathways. We found both known and yet unknown serum metabolite and metabolic pathway alterations in cachectic cancer patients that collectively support a whole-body metabolic state with impaired detoxification capability, altered glucose and fructose metabolism, and substrate supply for increased and/or distinct metabolic needs of cachexia-associated tumors. These findings together imply vulnerabilities, dependencies and targets for novel interventions that have potential to make a significant impact on future research in an important field of cancer patient care.