<p>MSC mitochondria modify the usage of metabolites by GCSs in response to TMZ CTRL Mito TMZ CTRL Mito Mito TMZ (A) Metabolic substrate consumption of GSCs expressed as metabolite initial consumption rates (Biolog MitoPlates). Mean values ± SEM (4 independent experiments). (B) Production of cis-aconitate, succinate and L-malate expressed as a percentage of all TCA metabolites produced in each experimental condition. Tukey boxplots with one-way ANOVA, *p < 0.05, ***p < 0.001.</p>
Abstract Background Brain metastases (BM) are common among HER2+ breast cancer (BC) and prognostic stratification is crucial for optimal management. BC-GPA score and subsequent refinements (modified-GPA, updated-GPA) recapitulate prognostic factors. Since none of these indexes includes extracranial disease control, we evaluated its prognostic value in HER2+ BCBM. Methods Patients diagnosed with HER2+ BCBM at Istituto Oncologico Veneto-Padova (2002–2021) and Montpellier Cancer Institute (2001–2015) were included as exploratory and validation cohorts, respectively. Extracranial disease control at BM diagnosis (no disease/stable disease/response vs. progressive disease) was evaluated. Results In the exploratory cohort of 113 patients (median OS 12.2 months), extracranial control ( n = 65, 57.5%) was significantly associated with better OS at univariate (median OS 17.7 vs. 8.7 months, p = 0.005) and multivariate analysis after adjustment for BC-GPA (HR 0.61, 95% CI 0.39–0.94), modified-GPA (HR 0.64, 95% CI 0.42–0.98) and updated-GPA (HR 0.63, 95% CI 0.41–0.98). The prognostic impact of extracranial disease control ( n = 66, 56.4%) was then confirmed in the validation cohort ( n = 117) at univariate (median OS 20.2 vs. 9.1 months, p < 0.001) and multivariate analysis adjusting for BC-GPA (HR 0.41, 95% CI 0.27–0.61), modified-GPA (HR 0.44, 95% CI 0.29–0.67) and updated-GPA (HR 0.42, 95% CI 0.28–0.63). Conclusions Extracranial disease control provides independent prognostic information in HER2+ BCBM beyond commonly used prognostic scores.
Abstract Background Breast cancer (BC) is the most frequent cause of leptomeningeal metastases (LM). LM diagnosis is confirmed by the detection of tumor cells in the cerebrospinal fluid (CSF) using conventional cytology (gold standard). However, even with optimal CSF sample volume and time to the analysis, the sensitivity of this technique is low, demanding repeated samples. Here, we aimed to evaluate the value of circulating tumor cell (CTC) detection in CSF using the CellSearch® system for LM diagnosis. Materials and Methods This prospective, monocentric study included adult BC patients with suspected LM (clinical and/or radiological signs). CSF samples from 1-3 lumbar puncture(s) were analyzed: protein level, conventional cytology (60 drops), and CTC detection with the CellSearch® system (60 drops, first lumbar puncture only). Sensitivity (Se) and specificity (Sp) were calculated, using the results of the conventional cytology as the gold-standard. Results Forty-nine eligible patients were included (Jan 2017-Jan 2020): median age 51.8, 95.9% women, 20.4% HER2+ BC, 93.8% previously diagnosed with metastatic BC, 89.8% with clinical symptoms. Among them, 40 were evaluable (CTC detection failure: n=8, eligibility criteria failure: n=1). Median sample volume was 3.0 mL for conventional cytology samples (median time to analysis: 22min) and 3.3 mL for CTC samples. Of the 40 evaluable patients, 18 had a positive cytology (on CSF sample n=°1/n°2: n=16/n=2) and were therefore diagnosed with LM using the gold-standard method. Protein level was elevated in 88.2% of these patients, compared with 45.1% of patients with negative CSF cytology (p=0.005). CTCs were detected in these 18 patients (median 5824 CTCs, range 93-45052). CTCs were also detected in 5/22 patients with a negative cytology (median 2 CTCs, range 1-44). Among them, one patient (44 CTCs) was diagnosed with a cytologically-proven LM 9 months later, while there was no further argument for LM in the other 4 patients’ history (1-3 CTC), who died of the extra-cerebral disease after a median time of 5.2 months (range 0.9-25.9). The detection of at least one CTC in CSF was associated with a Se of 100.0% (IC95% 82.4-100) and a Spe of 77.3% (IC95% 64.3-90.3) for the diagnosis of LM. Considering the number of CTC as a quantitative value, we determined the cut-off maximizing the Youden index using the ROC analysis (93 CTC). The detection of at least 93 CTC in CSF was associated with a Se and a Spe of 100.0% for the diagnosis of LM (area under the curve [AUC]: 1.0). Conclusion CTCs were detected with the CellSearch® system in all patients diagnosed with a cytologically-proven LM, as well as in a few patients without a cytological confirmation of LM. The prognosis of these patients with CSF cytology-/CTCs+ needs to be further investigated in a larger cohort. Citation Format: Amélie Darlix, Stéphane Pouderoux, Simon Thezenas, Alexis Bievelez, William Jacot, Laure Cayrefourcq, Nicolas Menjot-de-Champfleur, Cristina Leaha, Catherine Alix-Panabières. Detection of circulating tumor cells in cerebrospinal fluid for patients with suspected breast cancer leptomeningeal metastases: A prospective study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-01-12.
Abstract Diffuse low-grade glioma form a rare entity affecting young people. Despite advances in surgery, chemotherapy, and radiation therapy, diffuse low-grade glioma are still incurable. According to current guidelines, maximum safe resection, when feasible, is the first line of treatment. Apart from surgery, all other treatment modalities (temozolomide, procarbazine-CCNU-vincristine regimen, and radiation therapy) are handled very differently among different teams, and this in spite of recent results of several phase 3 studies. Based on a European survey, this paper aimed to get a picture of this heterogeneity in diffuse low-grade glioma management, to identify clinically relevant questions raised by this heterogeneity of practice, and to propose new methodological frameworks to address these questions.
Diffuse low-grade gliomas (DLGG) are brain tumors of young adults. They affect the quality of life of the inflicted patients and, if untreated, they evolve into higher grade tumors where the patient's life is at risk. Therapeutic management of DLGGs includes chemotherapy, and tumor diameter is particularly important for the follow-up of DLGG evolution. In fact, the main clinical basis for deciding whether to continue chemotherapy is tumor diameter growth rate. In order to reliably assist the doctors in selecting the most appropriate time to stop treatment, we propose a novel clinical decision support system. Based on two mathematical models, one linear and one exponential, we are able to predict the evolution of tumor diameter under Temozolomide chemotherapy as a first treatment and thus offer a prognosis on when to end it. We present the results of an implementation of these models on a database of 42 patients from Nancy and Montpellier University Hospitals. In this database, 38 patients followed the linear model and four patients followed the exponential model. From a training data set of a minimal size of five, we are able to predict the next tumor diameter with high accuracy. Thanks to the corresponding prediction interval, it is possible to check if the new observation corresponds to the predicted diameter. If the observed diameter is within the prediction interval, the clinician is notified that the trend is within a normal range. Otherwise, the practitioner is alerted of a significant change in tumor diameter.
<p>Exchange of mitochondria between MSCs with GSCs enhances GSC energy metabolism and proliferation. <b>A</b> and <b>B,</b> Mitochondria exchange during coculture of MSCs and GSCs, respectively prelabeled with red MitoTracker and green CellTracker. <b>A,</b> Imaging by confocal microscopy (24 hours). Scale bars: left, 20 μm; right, 5 μm. Arrows: MSC mitochondria. <b>B,</b> Quantification of mitochondria transfer to GSCs by flow cytometry analysis (48 hours coculture) Representative experiment and quantification with MSC from 3 donors. <b>C</b>–<b>I</b>, MSC mitochondria (three concentrations with 2-fold incremental increases) were transferred to GSCs by Mitoception and their effects on GSC functions were analyzed at 48 hours. <b>C,</b> Time line. <b>D–H,</b> Dose–response effects of MSC mitochondria on GSCs OCRs (D, E) and ECARs (F, G). All values were normalized to GSC cell numbers. <b>D,</b> Representative plot of GSC OCR in basal conditions and after sequential addition of oligomycin, Carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP), and rotenone/antimycin. Mean values and SEM are indicated (<i>n</i> = 4). <b>E,</b> Tukey boxplots showing basal respiration, respiration linked to ATP production and maximal respiration. <i>n</i> = 18 from four independent experiments. One-way ANOVA; *, <i>P</i> < 0.05; ***, <i>P</i> < 0.001. <b>F,</b> Representative plot of GSC ECAR in basal conditions and after sequential addition of glucose, oligomycin, oxamate, and 2-deoxyglucose. Mean values and SEM are indicated (<i>n</i> = 6). <b>G,</b> Tukey boxplots showing basal glycolysis, glycolytic capacity, and lactate acidification. <i>n</i> = 13 from three independent experiments. One-way ANOVA; *, <i>P</i> < 0.05; **, <i>P</i> < 0.01; ***, <i>P</i> < 0.001. <b>H,</b> OCR versus ECAR of GSCs with MSC mitochondria. Mean and SEM. <b>I,</b> Tukey boxplots showing GSCs proliferation. One-way ANOVA; ***, <i>P</i> < 0.001. Data from B to I were obtained with MSCs from 3 donors.</p>
