Discovery and validation of a transcriptional signature identifying homologous recombination-deficient breast, endometrial and ovarian cancers.

BACKGROUND: Molecular alterations leading to homologous recombination deficiency (HRD) are heterogeneous. We aimed to identify a transcriptional profile shared by endometrial (UCEC), breast (BRCA) and ovarian (OV) cancers with HRD. METHODS: Genes differentially expressed with HRD genomic score (continuous gHRD score) in UCEC/BRCA/OV were identified using edgeR, and used to train a RNAseq score (ridge-regression model) predictive of the gHRD score (PanCanAtlas, N = 1684 samples). The RNAseq score was applied in independent gynaecological datasets (CARPEM/CPTAC/SCAN/TCGA, N = 4038 samples). Validations used ROC curves, linear regressions and Pearson correlations. Overall survival (OS) analyses used Kaplan-Meier curves and Cox models. RESULTS: In total, 656 genes were commonly up/downregulated with gHRD score in UCEC/BRCA/OV. Upregulated genes were enriched for nuclear/chromatin/DNA-repair processes, while downregulated genes for cytoskeleton (gene ontologies). The RNAseq score correlated with gHRD score in independent gynaecological cancers (R² = 0.4-0.7, Pearson correlation = 0.64-0.86, all P < 10-11), and was predictive of gHRD score >42 (RNAseq HRD profile; AUC = 0.95/0.92/0.78 in UCEC/BRCA/OV). RNAseq HRD profile was associated (i) with better OS in platinum-treated advanced TP53-mutated-UCEC (P < 0.001) and OV (P = 0.013), and (ii) with poorer OS (P < 0.001) and higher benefit of adjuvant chemotherapy in Stage I-III BRCA (interaction test, P < 0.001). CONCLUSIONS: UCEC/BRCA/OV with HRD-associated genomic scars share a common transcriptional profile. RNAseq signatures might be relevant for identifying HRD-gynaecological cancers, for prognostication and for therapeutic decision.

Potential competing risk of death in older high-risk endometrial carcinoma patients: Results from a multicentric retrospective cohort.

INTRODUCTION: Adjuvant therapeutic decisions in older endometrial carcinoma (EC) patients are challenged by a balance between more frequent aggressive EC and comorbidities. We assessed whether EC and comorbidities are competing or cumulative risks in older EC patients. METHODS: All consecutive patients treated for FIGO stage I-IV EC in two University Hospitals in Paris between 2010 and 2017 were retrospectively included. Patients were categorized as: <70 years (y), >70y without comorbidity (fit), and > 70y with a Charlson comorbidity index>3 (comorbid). Association between high-risk EC (2021-ESGO-ETRO-ESP) or comorbidity, and disease-specific-survival (DSS), was evaluated using Cox model (estimation of cause-specific hazard ratio (CSHR), and Fine-Gray model (subdistribution HR) to account for competing events (death unrelated with EC). RESULTS: Overall, 253 patients were included (median age = 67y, IQR[59-77], median follow-up = 61.5 months, [44.4-76.8]). Among them, 109 (43%) were categorized at high-risk (proportion independent of age), including 67 (26%) who had TP53-mutated tumors. Comorbidity and high-risk group were both associated with all-cause mortality (HR = 4.09, 95%CI[2.29; 7.32] and HR = 3.21, 95%CI [1.69; 6.09], respectively). By multivariate analysis, patients with high-risk EC exhibited poorer DSS, regardless of age/comorbidity (Adjusted-CSHR = 6.62, 95%CI[2.53;17.3]; adjusted-SHR = 6.62 95%CI[2.50;17.5]). Patients>70y-comorbid with high-risk EC had 5-years cumulative incidences of EC-related and EC-unrelated death of 29% and 19%, respectively. In patients <70y, 5-years cumulative incidence of EC-related and EC-unrelated death were 25% and < 1% (one event), respectively. CONCLUSION: High-risk EC patients are exposed to poorer DSS regardless of age/comorbidities, comorbidities and cancer being two cumulative rather than competing risks. Our results suggest that age/comorbidity alone should not lead to underestimate EC-specific survival.

Development and validation of a RNAseq signature for prognostic stratification in endometrial cancer.

BACKGROUND: Despite recent advances in endometrial carcinoma (EC) molecular characterization, its prognostication remains challenging. We aimed to assess whether RNAseq could stratify EC patient prognosis beyond current classification systems. METHODS: A prognostic signature was identified using a LASSO-penalized Cox model trained on TCGA (N = 543 patients). A clinically applicable polyA-RNAseq-based work-flow was developed for validation of the signature in a cohort of stage I-IV patients treated in two Hospitals [2010-2017]. Model performances were evaluated using time-dependent ROC curves (prediction of disease-specific-survival (DSS)). The additional value of the RNAseq signature was evaluated by multivariable Cox model, adjusted on high-risk prognostic group (2021 ESGO-ESTRO-ESP guidelines: non-endometrioid histology or stage III-IVA orTP53-mutated molecular subgroup). RESULTS: Among 209 patients included in the external validation cohort, 61 (30%), 10 (5%), 52 (25%), and 82 (40%), had mismatch repair-deficient, POLE-mutated, TP53-mutated tumors, and tumors with no specific molecular profile, respectively. The 38-genes signature accurately predicted DSS (AUC = 0.80). Most disease-related deaths occurred in high-risk patients (5-years DSS = 78% (95% CI = [68%-89%]) versus 99% [97%-100%] in patients without high-risk). A composite classifier accounting for the TP53-mutated subgroup and the RNAseq signature identified three classes independently associated with DSS: RNAseq-good prognosis (reference, 5-years DSS = 99%), non-TP53 tumors but with RNAseq-poor prognosis (adjusted-hazard ratio (aHR) = 5.75, 95% CI[1.14-29.0]), and TP53-mutated subgroup (aHR = 5.64 [1.12-28.3]). The model accounting for the high-risk group and the composite classifier predicted DSS with AUC = 0.84, versus AUC = 0.76 without (p = 0.01). CONCLUSION: RNA-seq profiling can provide an additional prognostic information to established classification systems, and warrants validation for potential RNAseq-based therapeutic strategies in EC.

The tumor inflammation signature (TIS) is associated with anti-PD-1 treatment benefit in the CERTIM pan-cancer cohort.

BACKGROUND: The 18-gene tumor inflammation signature (TIS) is a clinical research assay that enriches for clinical benefit to immune checkpoint blockade. We evaluated its ability to predict clinical benefit of immunotherapy in cancer patients treated with PD-1 checkpoint inhibitors in routine clinical care. METHODS: The CERTIM cohort is a prospective cohort which includes patients receiving immune checkpoint inhibitors in Cochin University hospital. RNA extracted from 58 archival formalin fixed paraffin embedded tumor blocks (including 38 lung cancers, 5 melanomas, 10 renal carcinomas, 4 urothelial carcinomas and 1 colon carcinoma) was hybridized to a beta version of the NanoString® PanCancer IO360™ CodeSet using nCounter® technology. Gene expression signatures were correlated with tumor responses (by RECIST criteria) and overall survival. PD-L1 immunostaining on tumor cells was assessed in 37 non-small cell lung cancer (NSCLC) samples and tumor mutational burden (TMB) measured by whole exome sequencing in 19 of these. RESULTS: TIS scores were significantly associated with complete or partial response to anti-PD-1 treatment in the whole cohort (odds ratio = 2.64, 95% CI [1.4; 6.0], p = 0.008), as well as in the NSCLC population (odds ratio = 3.27, 95% CI [1.2; 11.6], p = 0.03). Patients whose tumor had a high TIS score (upper tertile) showed prolonged overall survival compared to patients whose tumor had lower TIS scores, both in the whole cohort (hazard ratio = 0.37, 95% CI [0.18, 0.76], p = 0.005) and in the NSCLC population (hazard ratio = 0.36, 95% CI [0.14, 0.90], p = 0.02). In the latter, the TIS score was independent from either PD-L1 staining on tumor cells (spearman coefficient 0.2) and TMB (spearman coefficient - 0.2). CONCLUSIONS: These results indicate that validated gene expression assay measuring the level of tumor microenvironment inflammation such as TIS, are accurate and independent predictive biomarkers and can be easily implemented in the clinical practice.

Paleo-inspired Systems: Durability, Sustainability, and Remarkable Properties.

The process of mimicking properties of specific interest (such as mechanical, optical, and structural) observed in ancient and historical systems is designated here as paleo-inspiration. For instance, recovery in archaeology or paleontology identifies materials that are a posteriori extremely resilient to alteration. All the more encouraging is that many ancient materials were synthesized in soft chemical ways, often using low-energy resources and sometimes rudimentary manufacturing equipment. In this Minireview, ancient systems are presented as a source of inspiration for innovative material design in the Anthropocene.

X-ray Photochemistry of Prussian Blue Cellulosic Materials: Evidence for a Substrate-Mediated Redox Process.

Beside its promising applications in the design of multifunctional materials, batteries and biosensors, the pigment Prussian blue is still studied in heritage science because of its capricious fading behavior due to a complex light-induced redox mechanism. We studied model heritage materials composed of Prussian blue embedded into a cellulosic fiber substrate by means of X-ray absorption near-edge spectroscopy. Significant X-ray radiation damage was observed and characterized. X-ray radiation induced first a reduction of Prussian blue, in a similar way to what visible light does, followed by a complete degradation of the pigment and the formation of iron(III) oxyhydroxide. We took advantage of this X-ray photochemistry to investigate in depth the redox behavior of Prussian blue. We could particularly demonstrate that the rate, extent, and quality of Prussian blue photoreduction can be tuned by modifying the pH and alkali cation content of the cellulosic substrate. The present study represents a step further in the understanding of Prussian blue heritage materials from an electrochemical viewpoint and provides evidence of substrate-mediated photochemistry applicable to a wider class of Prussian blue composite materials.

[Collecting duct carcinoma and renal medullary carcinoma in the age of new therapies]. / Tumeurs de Bellini et carcinomes médullaires rénaux à l'ère des nouvelles thérapies.

Collecting duct carcinoma (also known as Bellini tumour) and renal medullary carcinoma are two extremely rare and aggressive renal cancers. They are both less responsive to conventional treatments used in clear cell renal carcinoma. There are very few studies evaluating their optimal management and currently, at the metastatic stage, polychemotherapy based on platinum salts remains the most widely used. The emergence of new treatments such as anti-angiogenic TKIs, immunotherapy or treatments targeting specific genetic abnormalities, opens up a new field of possibilities in the management of these cancers. The evaluation of the response to these treatments is therefore essential. In this article, we will review the status of their management and the various studies that have evaluated recent treatments in these two cancers.

Future treatment options in metastatic clear cell renal cell carcinoma.

The field of clear cell renal cell carcinoma (ccRCC) has undergone major changes in the last decade, both in terms of the understanding of the mechanisms of oncogenesis and the role of the tumor microenvironment in anti-tumor immunity, as well as in therapeutic developments. After the era of tyrosine kinase inhibitors (TKIs) targeting VEGFR and then the era of immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 pathway, we are now entering the era of combination therapy for first-line metastatic cancer (m-ccRCC), such as combinations including a TKI and a PD-1 inhibitor or combinations of PD-1 and CTLA-4 blockers. In this extremely dynamic environment, new molecules with various mechanisms of action will appear in the very near future: immune response modulators (other ICIs, pro-inflammatory cytokines, gut microbiota modulators), new anti-angiogenic agents (new TKIs, anti-HIF-1α antibodies), agents affecting cell metabolism (glutaminase inhibitors, tryptophan regulators or adenosine A2A receptor antagonists) or epigenetic regulators (HDAC inhibitors). In parallel, new strategies are being evaluated that could rapidly change the standards of management of advanced disease, including therapeutic intensification with triple combinations or, conversely, adaptive and/or alternative de-escalation regimens (SURF trial), and biomarker-driven treatments (BIONIKK trial). The main new molecules and strategies currently being evaluated are reviewed in this article.

Association between Olaparib Exposure and Early Toxicity in BRCA-Mutated Ovarian Cancer Patients: Results from a Retrospective Multicenter Study.

Factors associated with olaparib toxicity remain unknown in ovarian cancer patients. The large inter-individual variability in olaparib pharmacokinetics could contribute to the onset of early significant adverse events (SAE). We aimed to retrospectively analyze the pharmacokinetic/pharmacodynamic relationship for toxicity in ovarian cancer patients from "real life" data. The clinical endpoint was the onset of SAE (grade III/IV toxicity or dose reduction/discontinuation). Plasma olaparib concentration was assayed using liquid chromatography at any time over the dosing interval. Trough concentrations (CminPred) were estimated using a population pharmacokinetic model. The association between toxicity and clinical characteristics or CminPred was assessed by logistic regression and non-parametric statistical tests. Twenty-seven patients were included, among whom 13 (48%) experienced SAE during the first six months of treatment. Olaparib CminPred was the only covariate significantly associated with increased risk of SAE onset (odds ratio = 1.31, 95%CI = [1.10; 1.57], for each additional 1000 ng/mL). The ROC curve identified a threshold of CminPred = 2500 ng/mL for prediction of SAE onset (sensitivity/specificity 0.62 and 1.00, respectively). This study highlights a significant association between olaparib plasma exposure and SAE onset and identified the threshold of 2500 ng/mL trough concentration as potentially useful to guide dose adjustment in ovarian cancer patients.

CAR T-cell Entry into Tumor Islets Is a Two-Step Process Dependent on IFNγ and ICAM-1.

Adoptive transfer of T cells expressing chimeric antigen receptors (CAR) has shown remarkable clinical efficacy against advanced B-cell malignancies but not yet against solid tumors. Here, we used fluorescent imaging microscopy and ex vivo assays to compare the early functional responses (migration, Ca2+, and cytotoxicity) of CD20 and EGFR CAR T cells upon contact with malignant B cells and carcinoma cells. Our results indicated that CD20 CAR T cells rapidly form productive ICAM-1-dependent conjugates with their targets. By comparison, EGFR CAR T cells only initially interacted with a subset of carcinoma cells located at the periphery of tumor islets. After this initial peripheral activation, EGFR CAR T cells progressively relocated to the center of tumor cell regions. The analysis of this two-step entry process showed that activated CAR T cells triggered the upregulation of ICAM-1 on tumor cells in an IFNγ-dependent pathway. The ICAM-1/LFA-1 interaction interference, through antibody or shRNA blockade, prevented CAR T-cell enrichment in tumor islets. The requirement for IFNγ and ICAM-1 to enable CAR T-cell entry into tumor islets is of significance for improving CAR T-cell therapy in solid tumors.

Development and validation of a host-dependent, PDL1-independent, biomarker to predict 6-month progression-free survival in metastatic non-small cell lung cancer (mNSCLC) patients treated with anti-PD1 immune checkpoint inhibitors (ICI) in the CERTIM Cohort: The ELY study.

BACKGROUND: Immune checkpoint inhibitors (ICI) are dramatically active in a minority of non-small cell lung cancer (NSCLC) patients. We studied here the relationship between patients's metabolism and outcome under ICI. METHODS: Metastatic NSCLC patients underwent a nutritional assessment prior to initiating immunotherapy. Resting energy expenditure (REE) was measured (mREE) using ambulatory indirect calorimetry and compared with the theoretical value (tREE) provided by the Harris and Benedict formula. The primary endpoint was 6-month progression-free survival (PFS). Secondary endpoints included objective response rate (ORR) and disease control rate (DCR) based on investigator review per RECIST v1.1. and overall survival (OS). The association of patient's metabolism with 6-month PFS was first explored in a single-center training cohort to estimate the effect size. The relationship between patient's metabolism and 6-month PFS was then tested in an independent non interventional observational prospective cohort (ELY) of 100 patients recruited in two tertiary university centers. FINDINGS: In the entire cohort, the ORR was 14% for the hypermetabolic group (n = 10/74) vs 38% for the normometabolic group (n = 26/68), respectively (estimated difference 25%, 95CI 9-40%, p = 0.001). The DCR was 28% for the hypermetabolic group (n = 21/74) vs 53% for the normometabolic group (n = 36/68), respectively (estimated difference 25%, 95CI 7-42%, p = 0.005). In the validation cohort (100 patients, 2 centers), normometabolic patients (defined as mREE/tREE < 110%) had increased 6-month PFS (57% versus 22%; odds ratio: 4.76; IC95 [1.87 - 12.89]; p<0.001) and improved overall survival (HR 2.20; IC95: 1.41-3.44; p<0.001). The positive and negative predictive values of normometabolism to identify non-progressive patients at 6 months, were 57% and 78% respectively, sensitivity was 72% and specificity was 66%. In multivariate analysis including PD-L1 tumor status, basal metabolism was an independent predictive factor for 6-month PFS. INTERPRETATION: Normometabolism is a new independent parameter to identify mNSCLC patients who will benefit from ICI, with both improved tumor response, 6-month PFS, and survival. FUNDING: This work was supported by Baxter (04012016).

The impact of body composition parameters on severe toxicity of nivolumab.

BACKGROUND: The occurrence of severe, acute limiting toxicity in patients receiving anti-programmed cell death receptor-1 monoclonal antibodies, such as nivolumab, is largely unpredictable. Sarcopenia was found to be associated with anti-cytotoxic T-lymphocyte-associated protein 4 acute toxicity. We explore the clinical and pharmacological parameters influencing nivolumab toxicity, including body composition. METHODS: From June 2015 to January 2017, all consecutive patients treated with nivolumab in our institution were prospectively included. We studied the relationship between muscle mass assessed by computed tomography, nivolumab trough level (Cmin) at day 14 assessed using the enzyme-linked immunosorbent assay method, and the occurrence of immune grade III or IV toxicity or any toxicity leading to treatment discontinuation (immune-related acute limiting toxicity [irALT]). RESULTS: In our population (n = 92) with a majority of lung cancer (72%), forty-five (51.7%) patients were sarcopenic. The median plasma nivolumab Cmin at day 14 was 15.4 µg/mL (interquartile range = 11.8-21.0). In multivariate analysis, hypoalbuminaemia (<35 g/L) was independently associated with low nivolumab Cmin on day 14 (odds ratio [OR] = 0.09; 95% confidence interval [CI] = 0.01-0.59, p = 0.01) and overweight/obesity with high nivolumab Cmin on day 14 (OR = 5.94; 95% CI = 1.25-28.29, p = 0.03). We observed 22 irALTs in 19 patients (21%). The most frequent irALT was respiratory (6.5%) disorders and gastrointestinal (4.3%) disorders. Patients with sarcopenia were at significantly increased risk of experiencing an irALT (OR = 3.84; 95% CI = 1.02-14.46, p = 0.047). No association was found between toxicity and nivolumab plasma Cmin at day 14. CONCLUSIONS: Our results highlight the importance of assessing body composition and suggest that sarcopenia could predict severe immune-related toxicity of nivolumab in real life.

Application of the Wang-Landau algorithm to the dimerization of glycophorin A.

A two-step Monte Carlo procedure is developed to investigate the dimerization process of the homodimer glycophorin A. In the first step, the energy density of states of the system is estimated by the Wang-Landau algorithm. In the second step, a production run is performed during which various energetical and structural observables are sampled to provide insight into the thermodynamics of the system. All seven residues LIxxGVxxGVxxT constituting the contact interface play a dominating role in the dimerization, however at different stages of the process. The leucine motif and to some extent the GxxxG motif are involved at the very beginning of the dimerization when the two helices come into contact, ensuring an interface already similar to the native one. At a lower temperature, the threonine motif stabilizes by hydrogen bonding the dimer, which finally converges toward its native state at around 300 K. The power and flexibility of the procedure employed here makes it an interesting alternative to other Monte Carlo methods for the study of similar protein systems.

Multi-modal tomography to assess dechlorination treatments of iron-based archaeological artifacts.

Chloride ions are an important actor in the corrosion of iron-based archaeological artifact. To stop this degradation, excavated objects are subjected to dechlorination treatment. However, there is no guarantee that this will remove all chloride from the object, as some can be found deep inside the object. To assess the ability of dechlorination treatment to remove chloride, we propose to use both neutron and X-ray tomography. Indeed, these tomographic techniques have sensitivities to different elements and are thus complementary. Neutron tomography in particular is highly sensitive to the presence of chloride. This study demonstrate that this methodology allows to detect local and global changes caused by the dechlorination treatment, an useful tool to assess the effectiveness of a treatment and potentially improve it.

Factors affecting the health-related quality of life of patients with cervical dystonia and the impact of botulinum toxin type A injections.

The purpose of this study was to analyze the health-related quality of life (HRQL) of patients with cervical dystonia (CD) and the impact of botulinum toxin A (BTX-A) therapy in these patients. The authors recruited 101 patients with CD, all previously treated with BTX-A. Both before and 4 weeks after injection of BTX-A the patients were assessed using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), a Visual Analogue Scale for pain (VAS: 0-100%), the Short Form 36 health survey questionnaire (SF-36), and the Montgomery-Asberg Depression Rating Scale (MADRS). A control group of 84 healthy volunteers was also evaluated. The patients? baseline SF-36 scores were worse in all the domains when compared with those of the controls. Depression was found in 47.5% of the patients. Improvements were noticed 4 weeks after the single BTX-A injections in all the SF-36 domains, and in the VAS, TWSTRS and MADRS scores. The TWSTRS results did not correlate with any of the SF-36 subscores. Stepwise backward regression analysis revealed depression as the main predictor of poor HRQL, as well as female sex, poor financial situation, and living alone. On contrary, longer treatment with BTX-A was associated with better scores. Cervical dystonia has a marked impact on HRQL and treatment with BTX-A injections has a beneficial effect, seen both in objective and in subjective measures. Depression in CD patients is a main predictor of worse HRQL.

[Constipation and cancer: Current strategies]. / Constipation et cancer : stratégies actuelles.

Digestive disorders, in particular constipation, are symptoms very often reported by cancer patients as having a major impact on their quality of life. An accurate diagnosis of bowel delayed transit and defecation disorders is required to best adapt therapeutic management. Constipation associated with cancer may be related to several causes, which can be placed in three nosological categories that sometimes overlap: chronic constipation prior to cancer and having its own evolution; constipation related to the cancer condition, in particular the occlusive syndrome, and constipation induced by cancer therapies. The stricter application of diet and lifestyle measures is often necessary and sometimes sufficient. Laxative drug treatments come under various galenic forms and administration routes and must be selected according to the clinical features of constipation. Surgical management can be indicated in case of ileus or pelvic static disorders. In the case of refractory constipation induced by opioids and within the framework of palliative care to treat an advanced pathology, a peripheral morphinic antagonist can offer fast symptom relief. A way forward to improve the patients' quality of life could be to identify the contributing factors (in particular, genetic factors) to determine which patients are the more at risk and anticipate their management.

Insertion of dipolar molecules in channels of a centrosymmetric organic zeolite: molecular modeling and experimental investigations on diffusion and polarity formation.

The mechanism of insertion of p-nitroaniline (PNA) and its diffusion behavior in channels of the hexagonal host structure of tris(o-phenylenedioxy)cyclotriphosphazene (TPP) was investigated by means of molecular modeling tools. Strong preferential sites in the bulk were found to be due to pi-pi and NH-pi interactions between PNA and channel walls of TPP. MD simulations showed that diffusion can be characterized by jumps from one site to the next, occurring mainly because of the dynamic flexibility of the host structure. Calculations of host-guest interactions between the TPP surface and PNA approaching the entrance of channels with its terminal H2N-first or O2N-first revealed that the H2N-first insertion is clearly preferred. Preferential insertion of PNA is found to be the reason for polar effects, observed experimentally. Because of a distinct guest-host recognition at the surface, guest-guest interactions were found to have a minor influence on polarity.

Simple model designed to generate new crystal structures derived from a mother phase; application to molecular compounds.

The basic principles of a model predicting new lattices from a known crystal structure are described. The first of the two-step procedure consists of extracting one- or two-dimensional periodic fragments (PF) from the mother structure. In the second step, symmetry operators are added to the PFs in order to generate one or several new three-dimensional lattices consistent with the 230 space groups. Most of the examples are related to polymorphism, but relationships between racemic compounds and enantiomers, twinning and lamellar epitaxy phenomena are also exemplified.

Prediction of solid solution formation in a family of diastereomeric salts. A molecular modeling study.

The possibility of solid solution behavior of diastereomeric salts, containing multiple resolving agents of the same family (Dutch Resolution), is predicted by molecular modeling. Super-cells containing different ratios of resolving agents in the diastereomeric salt are constructed and optimized, and their lattice energy is computed. The energy difference between these "simulated solid solutions" and the native structures is related in an understandable fashion to the probability of solid solution formation. This procedure is applied to a family of diastereomeric salts of ephedrine and cyclic phosphoric acids, for which the ternary diagrams have been determined experimentally at 25 degrees C in ethanol. Good agreement between experimental and computational results indicates that this relatively simple and fast method could predict the stable character of solid solution behavior in binary systems.