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Background KRISTINE is an open-label, phase III study of trastuzumab emtansine + pertuzumab (T-DM1 + P) versus docetaxel + carboplatin + trastuzumab + pertuzumab (TCH + P) in patients with HER2-positive, stage II–III breast cancer. We investigated the association of biomarkers with clinical outcomes in KRISTINE. Methods Patients were randomized to receive neoadjuvant T-DM1 + P or TCH + P and assessed for pathologic complete response (pCR; ypT0/is, ypN0). HER2 status (per central assessment), hormone receptor status, PIK3CA mutation status, HER2/HER3 mRNA levels, tumor-infiltrating lymphocyte levels, PD-L1 status, and NanoString data were analyzed. pCR rates by treatment arm were compared across biomarker subgroups. Analyses were descriptive. Results Biomarker analyses included data from all 444 patients (T-DM1 + P, n  = 223; TCH + P, n  = 221) enrolled in KRISTINE. Biomarker distribution was balanced across treatment arms. All subgroups with higher HER2 amplification/expression and immune marker levels showed numerically higher pCR rates in both arms. Mutated versus non-mutated PIK3CA tumors were associated with numerically lower pCR rates in the T-DM1 + P arm but not in the TCH + P arm. In a multivariate analysis, Prediction Analysis of Microarray with the 50-gene classifier (PAM50) HER2-enriched subtype, HER2 gene ratio ≥ 4, and PD-L1-positive status positively influenced the pCR rate. Biomarkers associated with lower pCR rates (e.g., low HER2 levels, positive hormone receptor status, mutated PIK3CA ) were more likely to co-occur. Dynamic on-treatment biomarker changes were observed. Differences in the treatment effects for T-DM1 + P versus TCH + P were similar to those observed in the intent-to-treat population for the majority of the biomarker subgroups. Conclusions Although our biomarker analysis did not identify a subgroup of patients that benefited from neoadjuvant T-DM1 + P versus TCH + P, the data revealed that patients with higher HER2 amplification/expression and immune marker levels had improved response irrespective of treatment arm. These analyses confirm the role of HER2 tumor biology and the immune microenvironment in influencing pCR in the neoadjuvant setting and reaffirm the molecular diversity of HER2-positive breast cancer. Trial Registration : ClinicalTrials.gov NCT02131064. Registered 06 May 2014.

Following chemotherapy and human epidermal growth factor 2 (HER2)-targeted neoadjuvant therapy for HER2-positive early breast cancer, residual invasive breast cancer at surgery may be HER2-negative on retesting in some patients. We evaluated outcomes with T-DM1 and trastuzumab in patients randomized in the phase III KATHERINE trial based on HER2-positive central testing of the pre-treatment core biopsy with HER2-negative central testing on their corresponding surgical specimen after neoadjuvant treatment. In the 70/845 (8.3%) patients with HER2-negative residual disease on retesting at surgery, there were 11 IDFS events in the 42 trastuzumab-treated patients (26.2%) and none in the 28 T-DM1-treated patients, suggesting that T-DM1 should not be withheld in this patient population.

Traumatic brain injury (TBI) presents a variety of causes and symptoms, thus making the development of reliable diagnostic methods and therapeutic treatments challenging. Magnetic resonance elastography (MRE) is a technique that allows for a noninvasive assessment of the mechanical properties of soft biological tissue, such as tissue stiffness, storage modulus, and loss modulus. Importantly, by quantifying the changes in the stiffness of tissue that is often associated with disease, MRE is able to detect tissue pathologies at early stages. Recent improvements in instrumentation have allowed for the investigation of small samples with microscopic resolution (μMRE). We hypothesize that μMRE can sensitively detect variations in micromechanical properties in the brain caused by the compressive and shearing forces sustained during TBI. To test this hypothesis, we randomized 13 C57BL mice to receive a controlled cortical impact at a 0.5 mm or 0.75 mm depth, with both sham and naïve mice as controls. Our objective was to propagate mechanical shear waves throughout the brain for in vivo TBI μMRE imaging. The mechanical properties of the injured brain tissue were determined at days 0, 1, 7, and 28 post-injury. For both groups, we observed a significant drop in the stiffness of the impacted region immediately following the injury; the 0.75 mm animals experienced increased tissue softness that lasted longer than that for the 0.5 mm group. Although the shear stiffness, storage modulus, and loss modulus parameters all followed the same trend, the tissue stiffness yielded the most statistically significant results. Overall, this article introduces a transformative technique for mechanically mapping the brain and detecting brain diseases and injury.

Magnetic resonance elastography (MRE) is a potentially transformative imaging modality allowing local and non-invasive measurement of biological tissue mechanical properties. It uses a specific phase contrast MR pulse sequence to measure induced vibratory motion in soft material, from which material properties can be estimated. Compared to other imaging techniques, MRE is able to detect tissue pathology at early stages by quantifying the changes in tissue stiffness associated with diseases. In an effort to develop the technique and improve its capabilities, two inversion algorithms were written to evaluate viscoelastic properties from the measured displacements fields. The first one was based on a direct algebraic inversion of the differential equation of motion, which decouples under certain simplifying assumptions, and featured a spatio-temporal multi-directional filter. The second one relies on a finite element discretization of the governing equations to perform a direct inversion. Several applications of this technique have also been investigated, including the estimation of mechanical parameters in various gel phantoms and polymers, as well as the use of MRE as a diagnostic tools for brain disorders. In this respect, the particular interest was to investigate traumatic brain injury (TBI), a complex and diverse injury affecting 1.7 million Americans annually. The sensitivity of MRE to TBI was first assessed on excised rat brains subjected to a controlled cortical impact (CCI) injury, before execution of in vivo experiments in mice. MRE was also applied in vivo on mouse models of medulloblastoma tumors and multiple sclerosis. These studies showed the potential of MRE in mapping the brain mechanically and providing non-invasive in vivo imaging markers for neuropathology and pathogenesis of brain diseases. Furthermore, MRE can easily be translatable to clinical settings; thus, while this technique may not be used directly to diagnose different abnormalities in the brain at this time, it may be helpful to detect abnormalities, follow therapies, and trace macroscopic changes that are not seen by conventional methods with clinical relevance.

BackgroundInterleukin (IL)–2 increases CD4 T cell counts when combined with antiretroviral therapy (ART). Whether IL-2 alone can increase CD4 cell counts is unknown MethodsA total of 130 adults who had a CD4 cell count of 300–500 cells/μL (and, thus, were not eligible to receive ART) were randomized to receive either intermittent IL-2 therapy or no treatment. The primary end point was a drop in CD4 cell count to <300 cells/μL, initiation of ART, the occurrence of an AIDS-defining event, or death ResultsThrough week 96, 35% of the patients in the IL-2 arm and 59% in the control arm reached the primary end point (P=.008). Median changes from baseline in the IL-2 and control arms were +51 and −64 cells/μL, respectively, for CD4 cell count (P<.001) and were +0.02 and +0.04 log10 copies/mL, respectively, for plasma viral load (P=.93). Among patients with a baseline viral load <4.5 log10 copies/mL, 64% in the IL-2 arm and 10% in the control arm did not reach the primary end point through week 150 (P<.001), and the time to ART initiation was deferred by 92 weeks in the IL-2 arm. The incidences of an AIDS-defining event, death, and grade 3 or 4 adverse events were similar between study arms ConclusionIL-2 increased CD4 cell counts without affecting HIV replication and allowed the initiation of ART to be deferred Trial registrationClinicalTrials.gov identifier: NCT00120185

The assessment of asthma control is pivotal to the evaluation of treatment response in individuals and in clinical trials. Previously, asthma control, severity, and exacerbations were defined and assessed in many different ways. The Task Force was established to provide recommendations about standardization of outcomes relating to asthma control, severity, and exacerbations in clinical trials and clinical practice, for adults and children aged 6 years or older. A narrative literature review was conducted to evaluate the measurement properties and strengths/weaknesses of outcome measures relevant to asthma control and exacerbations. The review focused on diary variables, physiologic measurements, composite scores, biomarkers, quality of life questionnaires, and indirect measures. The Task Force developed new definitions for asthma control, severity, and exacerbations, based on current treatment principles and clinical and research relevance. In view of current knowledge about the multiple domains of asthma and asthma control, no single outcome measure can adequately assess asthma control. Its assessment in clinical trials and in clinical practice should include components relevant to both of the goals of asthma treatment, namely achievement of best possible clinical control and reduction of future risk of adverse outcomes. Recommendations are provided for the assessment of asthma control in clinical trials and clinical practice, both at baseline and in the assessment of treatment response. The Task Force recommendations provide a basis for a multicomponent assessment of asthma by clinicians, researchers, and other relevant groups in the design, conduct, and evaluation of clinical trials, and in clinical practice.

Cornelia de Lange Syndrome (CdLS) patients, who frequently carry a mutation in NIPBL, present an increased incidence of outflow tract (OFT)-related congenital heart defects (CHDs). Nipbl+/- mice recapitulate a number of phenotypic traits of CdLS patients, including a small body size and cardiac defects, but no study has specifically focused on the valves. Here, we show that adult Nipbl+/- mice present aortic valve thickening, a condition that has been associated with stenosis. During development, we observed that OFT septation and neural crest cell condensation was delayed in Nipbl+/- embryos. However, we did not observe defects in the deployment of the main lineages contributing to the semilunar valves. Indeed, endocardial endothelial-to-mesenchymal transition (EndMT), analysed via outflow tract explants, and neural crest migration, analysed via genetic lineage tracing, did not significantly differ in Nipbl+/- mice and their wild-type littermates. Our study provides the first direct evidence for valve formation defects in Nipbl+/- mice and points to specific developmental defects as an origin for valve disease in patients.

Purpose Desmoid tumors (DTs) are rare tumors that originate from myofibroblastic tissue. Recently, initial wait and see was recommended (ESMO guidelines Ann Oncol 2017) in the most frequent locations. This study investigates the outcome of breast desmoid tumor (BDT) according to the initial strategy. Method Data from all consecutive patients treated from a BDT in four referral centers were collected. Only intra-mammary desmoid tumors were included. A pathological review and a molecular analysis ( CTNNB1 gene mutation) were performed (National re-reading network of sarcomas-RRePS). Patients were grouped according to initial strategy: surgery group (SG) and active surveillance group (ASG). Results A total of 63 patients (61 women, 2 men) met the inclusion criteria. Median age was 50 years (16–86). CTNNB1 mutation was found in 61% ( n  = 36). SG included 46 patients (73%) (41 partial mastectomies, 2 mastectomies, and 3 mastectomies associated to parietectomies). Surgical margins were positive in 15 patients (33.3%). Median follow-up of SG was 24.9 (0.5–209) months; and 4 patients (8.7%) developed recurrence. ASG included 17 patients (27%). Their median follow-up was 42.2 (0–214) months, and 15 patients (88.2%) did not require any additional treatment. Six patients (35%) had a spontaneous regression, 9 patients (52%) were stable, and 2 patients presented a significant progression that was treated by partial mastectomy. Conclusion This study supports an initial nonsurgical approach to BDTs followed by surgery based on tumor growth in select cases, which is consistent with current ESMO recommendations.

Using adaptive radiotherapy (ART), to determine objective clinical criteria that identify extremity soft tissue sarcoma (ESTS) patients requiring adaptation of their preoperative radiotherapy (RT) plan. We included 17 patients with a lower extremity ESTS treated between 2019 and 2021 with preoperative RT, using helicoidal intensity-modulated RT (IMRT) tomotherapy, before surgical resection. We collected clinical, tumor parameters and treatment data. Repositioning was ascertained by daily Megavoltage computed tomography (MVCT) imaging. Using the PreciseART technology we retrospectively manually delineated at least one MVCT for each patient per week and recorded volume and dosimetric parameters. A greater than 5% change between target volume and planned target volume (PTV) dosimetric coverage from the initial planning CT scan to at least one MVCT was defined as clinically significant. All 17 patients experienced significant tumor volume changes during treatment; 7 tumors grew (41%) and 10 shrank (59%). Three patients (18%), all undifferentiated pleomorphic sarcomas (UPS) with increased volume changes, experienced significant reductions in tumor dose coverage. Seven patients required a plan adaptation, as determined by practical criteria applied in our departmental practice. Among these patients, only one ultimately experienced a significant change in PTV coverage. Three patients had a PTV decrease of coverage. Among them, 2 did not receive plan adaptation according our criteria. None of the patients with decreased tumor volumes had reduced target volume coverage. Monitoring volume variations by estimating gross tumor volume (GTV) on MVCT, in addition to axial and sagittal linear tumor dimensions, appeared to be most effective for detecting reductions in PTV coverage throughout treatment. Variations in ESTS volume are evident during preoperative RT, but significant dosimetric variations are rare. Specific attention should be paid to grade 2-3 UPSs during the first 2 weeks of treatment. In the absence of dedicated software in routine clinical practice, monitoring of tumor volume changes by estimating GTV may represent a useful strategy for identifying patients whose treatment needs to be replanned.

In sparkling wine cool-climate regions like Champagne, it is sometimes necessary to pick the healthy grape clusters that have a relatively low maturity level to avoid the deleterious effects of Botrytis cinerea. In such conditions, we know that classical oenological parameters (sugars, pH, total acidity) may change but there is little information concerning the impact of grape berry maturity on wine proteins and foaming properties. Therefore, healthy grapes (Chardonnay and Pinot meunier) in 2015 and 2016 were picked at different maturity levels within the range of common industrial maturity for potential alcohol content 8–11% v/v in the Champagne region. Base wine protein content and foamability, and oenological parameters in grape juice and their corresponding base wines, were investigated. The results showed that base wine protein contents (analyzed by the Bradford method and by electrophoresis) and foamability were higher when the grapes were riper. The Pearson’s correlation test found significant positive correlations (r = 0.890–0.997, p < 0.05) between Chardonnay grape berry maturity degree (MD) and base wine foamability in both vintages. Strong correlations between MD and most of the oenological parameters in grape juice and base wine were also found for the two cultivars. Under the premise of guaranteed grape health, delaying harvest date is an oenological decision capable of improving base wine protein content and foamability.