The 12-item Oxford Knee Score: cross-cultural adaptation into German and assessment of its psychometric properties in patients with osteoarthritis of the knee

SummaryObjectiveTo cross-culturally adapt and validate the Oxford Knee Score (OKS) for use in German-speaking patients with osteoarthritis of the knee.MethodsAfter the cross-cultural adaptation (OKS-D), the following metric properties of the questionnaire were assessed in 100 consecutive patients (mean age 66.5 years, 61 women) undergoing total knee replacement: feasibility (percentage of fully completed questionnaires), reliability (Intraclass Correlation Coefficients [ICC] and Bland and Altman's limits of agreement), and construct validity (correlation with the Western Ontario and McMaster Universities Index [WOMAC], Knee Society Score [KSS], Activities of Daily Living Scale [ADLS], and Short Form 12 [SF-12]), floor and ceiling effects, and internal consistency (Cronbach's Alpha, CA).ResultsWe received 91.9% fully completed questionnaires. Reliability of the OKS-D was excellent (ICC 0.91). Bland and Altman's limits of agreement revealed no significant bias (−0.2) and a random error of 6.2. Correlation coefficients with the other questionnaires ranged from −0.22 (SF-12 Mental Component Scale [MCS]) to −0.77 (ADLS). We observed no floor or ceiling effects. The CA was 0.83.ConclusionsThe German version of the OKS is a reliable and valid measure for the self-assessment of pain and function in German-speaking patients with osteoarthritis of the knee

Towards global volcano monitoring using multisensor sentinel missions and artificial intelligence: The MOUNTS monitoring system

Most of the world’s 1500 active volcanoes are not instrumentally monitored, resulting in deadly eruptions which can occur without observation of precursory activity. The new Sentinel missions are now providing freely available imagery with unprecedented spatial and temporal resolutions, with payloads allowing for a comprehensive monitoring of volcanic hazards. We here present the volcano monitoring platform MOUNTS (Monitoring Unrest from Space), which aims for global monitoring, using multisensor satellite-based imagery (Sentinel-1 Synthetic Aperture Radar SAR, Sentinel-2 Short-Wave InfraRed SWIR, Sentinel-5P TROPOMI), ground-based seismic data (GEOFON and USGS global earthquake catalogues), and artificial intelligence (AI) to assist monitoring tasks. It provides near-real-time access to surface deformation, heat anomalies, SO2 gas emissions, and local seismicity at a number of volcanoes around the globe, providing support to both scientific and operational communities for volcanic risk assessment. Results are visualized on an open-access website where both geocoded images and time series of relevant parameters are provided, allowing for a comprehensive understanding of the temporal evolution of volcanic activity and eruptive products. We further demonstrate that AI can play a key role in such monitoring frameworks. Here we design and train a Convolutional Neural Network (CNN) on synthetically generated interferograms, to operationally detect strong deformation (e.g., related to dyke intrusions), in the real interferograms produced by MOUNTS. The utility of this interdisciplinary approach is illustrated through a number of recent eruptions (Erta Ale 2017, Fuego 2018, Kilauea 2018, Anak Krakatau 2018, Ambrym 2018, and Piton de la Fournaise 2018–2019). We show how exploiting multiple sensors allows for assessment of a variety of volcanic processes in various climatic settings, ranging from subsurface magma intrusion, to surface eruptive deposit emplacement, pre/syn-eruptive morphological changes, and gas propagation into the atmosphere. The data processed by MOUNTS is providing insights into eruptive precursors and eruptive dynamics of these volcanoes, and is sharpening our understanding of how the integration of multiparametric datasets can help better monitor volcanic hazards

α-chloralose poisoning in a cat

A five-year-old domestic cat with acute unexplainable neurological signs was presented for postmortem examination. Clinically, the cat showed an acute onset of ataxia, depressed mentation and continuous twitching/ seizure activity in the morning after having been outside overnight. Despite immediate treatment, the cat# progressed within 24 hours to a comatose state, opisthotonus and severe miosis unresponsive to light. Given a poor prognosis, euthanasia was elected. Gross findings were disappointing and consisted of a nonspecific lung oedema and congested lungs and spleen. Surprisingly, within the stomach and intestines, fragments of cockshafers were found. Histological examination confirmed the gross findings and additionally showed evidence of mild brain oedema, but failed to identify a cause for the severe clinical signs. In a final attempt to solve the case, a urine sample was tested for toxic substances and it was found to contain a significant amount of α-chloralose. This finding was unexpected

Circulating Tumor DNA Markers for Early Progression on Fulvestrant With or Without Palbociclib in ER+ Advanced Breast Cancer.

Background There are no established molecular biomarkers for patients with breast cancer receiving combination endocrine and CDK4/6 inhibitor (CDK4/6i). We aimed to determine whether genomic markers in circulating tumor DNA (ctDNA) can identify patients at higher risk of early progression on fulvestrant therapy with or without palbociclib, a CDK4/6i.Methods PALOMA-3 was a phase III, multicenter, double-blind randomized controlled trial of palbociclib plus fulvestrant (n = 347) vs placebo plus fulvestrant (n = 174) in patients with endocrine-pretreated estrogen receptor-positive (ER+) breast cancer. Pretreatment plasma samples from 459 patients were analyzed for mutations in 17 genes, copy number in 14 genes, and circulating tumor fraction. Progression-free survival (PFS) was compared in patients with circulating tumor fraction above or below a prespecified cutoff of 10% and with or without a specific genomic alteration. All statistical tests were 2-sided.Results Patients with high ctDNA fraction had worse PFS on both palbociclib plus fulvestrant (hazard ratio [HR] = 1.62, 95% confidence interval [CI] = 1.17 to 2.24; P = .004) and placebo plus fulvestrant (HR = 1.77, 95% CI = 1.21 to 2.59; P = .004). In multivariable analysis, high-circulating tumor fraction was associated with worse PFS (HR = 1.20 per 10% increase in tumor fraction, 95% CI = 1.09 to 1.32; P < .001), as was TP53 mutation (HR = 1.84, 95% CI = 1.27 to 2.65; P = .001) and FGFR1 amplification (HR = 2.91, 95% CI = 1.61 to 5.25; P < .001). No interaction with treatment randomization was observed.Conclusions Pretreatment ctDNA identified a group of high-risk patients with poor clinical outcome despite the addition of CDK4/6 inhibition. These patients might benefit from inclusion in future trials of escalating treatment, with therapies that may be active in these genomic contexts

Time course and management of key adverse events during the randomized phase III SOLAR-1 study of PI3K inhibitor alpelisib plus fulvestrant in patients with HR-positive advanced breast cancer.

Background Alpelisib (α-selective phosphatidylinositol 3-kinase inhibitor) plus fulvestrant is approved in multiple countries for men and postmenopausal women with PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer following progression on or after endocrine therapy. A detailed understanding of alpelisib's safety profile should inform adverse event (AE) management and enhance patient care. Patients and methods AEs in the phase III SOLAR-1 trial were assessed in patients with and without PIK3CA mutations. The impact of protocol-specified AE-management recommendations was evaluated, including an amendment to optimize hyperglycemia and rash management. Results Patients were randomly assigned to receive fulvestrant plus alpelisib (n = 284) or placebo (n = 287). The most common grade 3/4 AEs with alpelisib were hyperglycemia (grade 3, 32.7%; grade 4, 3.9%), rash (grade 3, 9.9%), and diarrhea (grade 3, 6.7%). Median time to onset of grade ≥3 toxicity was 15 days (hyperglycemia, based on fasting plasma glucose), 13 days (rash), and 139 days (diarrhea). Metformin alone or in combination with other antidiabetic agents was used by most patients (87.1%) with hyperglycemia. Preventive anti-rash medication resulted in lower incidence (any grade, 26.7% versus 64.1%) and severity of rash (grade 3, 11.6% versus 22.7%) versus no preventative medication. Discontinuations due to grade ≥3 AEs were lower following more-detailed AE management guidelines (7.9% versus 18.1% previously). Patients with PIK3CA mutations had a median alpelisib dose intensity of 248 mg/day. Median progression-free survival with alpelisib was 12.5 and 9.6 months for alpelisib dose intensities of ≥248 mg/day and Conclusions Hyperglycemia and rash occurred early during alpelisib treatment, while diarrhea occurred at a later time point. Early identification, prevention, and intervention, including concomitant medications and alpelisib dose modifications, resulted in less severe toxicities. Reductions in treatment discontinuations and improved progression-free survival at higher alpelisib dose intensities support the need for optimal AE management. ClinicalTrials.gov Id NCT02437318

Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer

BACKGROUND The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor palbociclib, in combination with fulvestrant therapy, prolongs progression-free survival among patients with hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer. We report the results of a prespecified analysis of overall survival. METHODS We randomly assigned patients with hormone-receptor–positive, HER2-negative advanced breast cancer who had progression or relapse during previous endocrine therapy to receive palbociclib plus fulvestrant or placebo plus fulvestrant. We analyzed overall survival; the effect of palbociclib according to the prespecified stratification factors of presence or absence of sensitivity to endocrine therapy, presence or absence of visceral metastatic disease, and menopausal status; the efficacy of subsequent therapies after disease progression; and safety. RESULTS Among 521 patients who underwent randomization, the median overall survival was 34.9 months (95% confidence interval [CI], 28.8 to 40.0) in the palbociclib– fulvestrant group and 28.0 months (95% CI, 23.6 to 34.6) in the placebo–fulvestrant group (hazard ratio for death, 0.81; 95% CI, 0.64 to 1.03; P=0.09; absolute difference, 6.9 months). CDK4/6 inhibitor treatment after the completion of the trial regimen occurred in 16% of the patients in the placebo–fulvestrant group. Among 410 patients with sensitivity to previous endocrine therapy, the median overall survival was 39.7 months (95% CI, 34.8 to 45.7) in the palbociclib–fulvestrant group and 29.7 months (95% CI, 23.8 to 37.9) in the placebo–fulvestrant group (hazard ratio, 0.72; 95% CI, 0.55 to 0.94; absolute difference, 10.0 months). The median duration of subsequent therapy was similar in the two groups, and the median time to the receipt of chemotherapy was 17.6 months in the palbociclib– fulvestrant group, as compared with 8.8 months in the placebo–fulvestrant group (hazard ratio, 0.58; 95% CI, 0.47 to 0.73; P<0.001). No new safety signals were observed with 44.8 months of follow-up. CONCLUSIONS Among patients with hormone-receptor–positive, HER2-negative advanced breast cancer who had sensitivity to previous endocrine therapy, treatment with palbociclib–fulvestrant resulted in longer overall survival than treatment with placebo– fulvestrant. The differences in overall survival in the entire trial group were not significant. (Funded by Pfizer; PALOMA-3 ClinicalTrials.gov number, NCT01942135.

Comparative biomarker analysis of PALOMA-2/3 trials for palbociclib.

While cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, including palbociclib, combined with endocrine therapy (ET), are becoming the standard-of-care for hormone receptor-positive/human epidermal growth factor receptor 2‒negative metastatic breast cancer, further mechanistic insights are needed to maximize benefit from the treatment regimen. Herein, we conducted a systematic comparative analysis of gene expression/progression-free survival relationship from two phase 3 trials (PALOMA-2 [first-line] and PALOMA-3 [≥second-line]). In the ET-only arm, there was no inter-therapy line correlation. However, adding palbociclib resulted in concordant biomarkers independent of initial ET responsiveness, with shared sensitivity genes enriched in estrogen response and resistance genes over-represented by mTORC1 signaling and G2/M checkpoint. Biomarker patterns from the combination arm resembled patterns observed in ET in advanced treatment-naive patients, especially patients likely to be endocrine-responsive. Our findings suggest palbociclib may recondition endocrine-resistant tumors to ET, and may guide optimal therapeutic sequencing by partnering CDK4/6 inhibitors with different ETs. Pfizer (NCT01740427; NCT01942135)

LBA3_PRAlpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): Results of the phase III SOLAR-1 trial

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