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Nowadays 80% of scandium in China is obtained from titanium pigments production waste through a complex purification process. The study mainly focused on the purification of Sc from its concentrate generated from titanium pigments production waste by solvent extraction. Several extractants have been tried and 10% D2EHPA - 5% TBP - 85% sulfonated kerosene exhibited the best extraction performance towards Sc in 7 mol/L H2SO4 solution, so it was selected as the oil phase. 0.5% of H2O2 was added into the concentrated solution which can effectively inhibit the extraction of Ti. Both the extraction and back extraction parameters are optimized. The preferred extraction conditions were obtained, i.e., acidity: 7 mol/L H2SO4, the phase ratio A/O: 10, room temperature, mixed contact time: 30 min, Sc concentrate: 10 g/L, that the extraction rate of Sc in the above conditions was nearly 100%. NaOH was used for back extraction with the stripping rate 99% on the following conditions: 5 mol/L NaOH stripping for 30 min at a phase ratio A/O: 1 at 90 °C. Finally, H2C2O4 was used to further purify the back extraction product and Sc2(C2O4)3 precipitant formed. The final product Sc2O3 with a purity over 99.5% was obtained by calcining Sc2(C2O4)3 at 1000 °C for 2 h. A conceptual process for Sc purification was put forward and proved. The total recovery yield of Sc in the whole process is 95%.

Tumor response T cells, which have specific T cell receptor (TCR) rearrangements in tumor-infiltrating lymphocytes, determine their ability to interact with the mutation-derived neoantigens presented by antigen-presenting cells. Little is known about the genetic alterations related to specific TCR clones in non-small cell lung cancer (NSCLC) patients who have an epidermal growth factor receptor (EGFR) mutation. In this study, tumor tissues were collected from 101 patients with stage II/III resectable NSCLC with an EGFR mutation (57 patients were treated with gefitinib and 44 were treated with chemotherapy) in the ADJUVANT-CTONG1104 trial for high-throughput TCRβ V region and exome sequencing. Ten clonal TCRs were associated with EGFR exon 19 deletion (del), EGFR exon 21 mutation (L858R), RB1 alteration, TP53 exon 4/5 missense mutation, TP53 nonsense mutation, or copy number gains in NKX2-1 and CDK4. Among the TCRs, there was frequent use of Vβ20-1Jβ2-3 specifically for EGFR exon 19 del or Vβ9Jβ2-1 specifically for EGFR exon 21 mutation (L858R), and these were significantly associated with favorable overall survival (OS) for NSCLC patients harboring EGFR exon 19 del or exon 21 L858R, particularly in the adjuvant gefitinib setting. Moreover, in comparison with the chemotherapy-preferable (CP) group, higher frequencies of Vβ20-1Jβ2-3 and Vβ9Jβ2-1 were found in the highly TKI-preferable (HTP) or TKI-preferable (TP) groups. Altogether, we identified ten TCR rearrangements specific for genetic alterations in NSCLC. Importantly, high abundance Vβ20-1Jβ2-3 or Vβ9Jβ2-1 may be an immune biomarker for guiding adjuvant gefitinib decisions for NSCLC patients harboring EGFR exon 19 del or EGFR exon 21 L858R.

The ADJUVANT study reported the comparative superiority of adjuvant gefitinib over chemotherapy in disease-free survival of resected EGFR-mutant stage II–IIIA non-small cell lung cancer (NSCLC). However, not all patients experienced favorable clinical outcomes with tyrosine kinase inhibitors (TKI), raising the necessity for further biomarker assessment. In this work, by comprehensive genomic profiling of 171 tumor tissues from the ADJUVANT trial, five predictive biomarkers are identified (TP53 exon4/5 mutations, RB1 alterations, and copy number gains of NKX2-1, CDK4, and MYC). Then we integrate them into the Multiple-gene INdex to Evaluate the Relative benefit of Various Adjuvant therapies (MINERVA) score, which categorizes patients into three subgroups with relative disease-free survival and overall survival benefits from either adjuvant gefitinib or chemotherapy (Highly TKI-Preferable, TKI-Preferable, and Chemotherapy-Preferable groups). This study demonstrates that predictive genomic signatures could potentially stratify resected EGFR-mutant NSCLC patients and provide precise guidance towards future personalized adjuvant therapy., Adjuvant gefitinib improves outcomes in non-small cell lung cancer (NSCLC) patients compared to chemotherapy, but not in all cases. Here, the authors find genomic biomarkers of response to gefitinib in NSCLC patients from the ADJUVANT trial, and propose a score to stratify them by potential benefit from the treatment.

The third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib has demonstrated significant clinical benefit in EGFR T790M-mutated non-small-cell lung cancer (NSCLC) patients, with extensive research focusing on the mechanisms of acquired resistance. However, there are limited studies on second-line treatment options for EGFR T790M-negative patients and their clinical outcomes. We aimed to provide better understanding of the resistance mechanisms to osimertinib treatment as well as the therapeutic options for T790M-negative NSCLC patients. In this case study, a patient was admitted and diagnosed with stage IV lung adenocarcinoma. Tissue specimen and blood samples collected from baseline and during the course of treatment were subjected to genomic profiling of 416 cancer-related genes using hybridization capture-based targeted next-generation sequencing. Following progression on initial chemoradiotherapy, the patient received EGFR TKI treatment with icotinib upon the confirmation of carrying an EGFR L858R mutation. However, the patient was negative for the EGFR T790M mutation when he became resistant to icotinib. The patient received subsequent osimertinib treatment and achieved a progression-free survival (PFS) of 10.4 months. Upon disease progression, an acquired L718V mutation within the EGFR kinase domain was found, which may interfere with the binding of osimertinib to the kinase domain and confer resistance regardless of T790M status. This is the first clinical evidence of EGFR L718V giving rise to osimertinib resistance in a T790M-negative context, which provides valuable information for the discovery of resistance mechanisms to osimertinib and guidance for personalized NSCLC treatment in such patients.

Background: Reversion mutations of BRCA1/2 are associated with decreased response to platinum-based chemotherapies and PARP inhibitors. While patient with homologous recombination repair (HRR) genes have proven efficacy to PARP inhibitors, reversion mutations in these genes have not been widely studied. Here, we performed pan-cancer analysis to reveal the characteristics of HRR reversion mutations. Methods: We assessed 1,992 patients with at least one loss of function mutation in BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54L, ERCC3, RAD51, WRN, FANCI, MRE11A, ATR, FANCD2, FANCA, FANCC, BLM and NBN. Somatic reversion mutations were indel or missense mutations that restore the open reading frame and potentially protein function fully or partially. Definitive reversion mutations are confirmed secondary mutations in patients with known pathogenic germline HRR gene mutations, or in a subsequent sample of previously detected somatic pathogenic mutants. Other reversion mutations are putative due to lack of matched samples. Results: Overall, we found 31/1,992 (1.6%) tumors with definitive or putative HRR reversion mutations, including 17 with germline and 14 with somatic predisposed pathogenic HRR mutations. Of these, we identified 9 BRCA1 (29%, 2 sBRCA1 and 7 gBRCA1) and 12 BRCA2 (39%, 4 sBRCA2 and 8 gBRCA2). We also found pathogenic germline PALB2 (1, 3%) and RAD41D (1, 3%), and somatic mutations in CDK12 (3, 9%), ATM (2, 6%), WRN (1, 3%), FANCD2 (1, 3%), and ATR (1, 3%). Overall, 43 reversion mutations were detected (37 definitive and 6 putative), with eight patients carrying multiple reversion mutations. Importantly, 40/43 reversion mutations were found within 2bp upstream to the start site of original deleterious variants, and all were unique to currently known database. Missense-induced reversions were found in 74% primary stop-gain mutations, while indel-induced reversions were associated with 59% primary frameshift mutations. These HRR reversion mutations were primarily found in breast cancer (9%, 10/107) and ovarian cancer (6%, 3/54), and also in cases of prostate (1/25, 4%), pancreatic (1/29, 3%), colorectal (2%, 9/418), and non-small cell lung cancer (1%, 6/703). Of note, the incidence of multiple HRR reversion mutations was higher in breast cancer (75%, 6/8). Lastly, reversion mutations were detectable in plasma, pleural and ascites fluid samples, suggesting great clinical utility of ctDNA to monitor reversion mutations. Conclusions: This study analyzed clinical and mutational characteristics of reversion mutations in HRR genes, which could occur as single or multiple variants to restore the function of predisposed pathogenic HRR mutations, resulting in resistance to platinum-based chemotherapies or PARP inhibitors. Monitoring these mutations with tissue or liquid biopsy samples are crucial for treatment guidance. Citation Format: Jing Li, Xiaoying Wu, Yan Shi, Di Wang, Yedan Chen, Yang Shao. Pan-cancer analysis revealed characteristics of reversion mutations in homologous recombination repair genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5766.

Background: Classic sensitizing mutations of epidermal growth factor receptor (cEGFR) (i.e., exon 19 deletions and exon 21 L858R) have shown positive responses to first-generation TKIs in non-small cell lung cancer (NSCLC). For patients with uncommon EGFR mutations (uEGFR), such as G719X, S768I, L861Q and exon 20 insertions, first-generation TKIs might still be one of the mainstay choices in clinic. However, they exhibited heterogeneity in treatment responses. Here, we aimed to elucidate different genomic profiles of tumors carrying uncommon EGFR activating mutations to explain differential treatment responses. Method: We screened 6669 NSCLC patients that underwent targeted NGS of 416 cancer-related genes. Total 2280 EGFR-positive NSCLCs were selected for analysis. We compared somatic mutations, tumor mutation burden (TMB), mutational signature and canonical oncogenic pathways between cEGFR and uEGFR. A validation set of 159 NSCLCs from the Cancer Genome Atlas (TCGA) was used. Adjusted p value less than 0.1 were considered statistically significant. Results: Only patients carrying known EGFR activating mutations and without complex mutations were included. The final cohort comprised 1022 patients with L858R (44.8%), 973 with exon 19 deletion (42.7%), 139 with exon 20 insertion (6.1%), 59 with G719X (2.6%), 51 with L861Q (2.2%), and 36 with S768I (1.6%). In general, clinical features were equally distributed except for higher prevalence of G719X and S768I in male. Most frequently co-mutated genes were similar between cEGFR and uEGFR subgroups, including TP53 (56% vs 60%), PIK3CA (8% vs 11%), and RB1 (8% vs 9%). Despite these, we found enrichment of EPHA3 and MED12 with S768I(both 5/36, 14%)as compared to with cEGFR (2% vs 3%, padj Conclusion: This comprehensive analysis of EGFR-positive mutational landscape revealed specific genomic characteristics associated with uncommon EGFR mutations that might explain their poor response to first-generation TKIs. Citation Format: Xue Wu, Junli Zhang, Jingwen Liu, Yedan Chen, Yang Shao. Genomic characteristics of classic and uncommon EGFR activating mutations explains different responses to first-generation EGFR-TKIs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5768.

BackgroundMolecular characteristics are essential for the classification and grading of gliomas. However, diagnostic classification of midline glioma is still debatable and substantial molecular and clinical heterogeneity within each subgroup suggested that they should be further stratified. Here, we studied the mutation landscape of Chinese midline glioma patients in hope to provide new insights for glioma prognosis and treatment.MethodsTissue samples from 112 midline glioma patients underwent next-generation sequencing targeting 425 cancer-relevant genes. Gene mutations and copy number variations were investigated for their somatic interactions and prognostic effect using overall survival data. Pathway-based survival analysis was performed for ten canonical oncogenic pathways.ResultsWe identified several currently established diagnostic and prognostic biomarkers of glioma, including TP53 (33%), EGFR (26%), TERT (24%), PTEN (21%), PIK3CA (14%), ATRX (14%), BRAF (13%), and IDH1/2 (6%). Among all genetic aberrations with more than 5% occurrence rate, six mutations and three copy number gains were greatly associated with poor overall survival (univariate, P < 0.1). Of these, TERT mutations (hazard ratio [HR], 3.00; 95% confidence interval [CI], 1.37–6.61; P = 0.01) and PIK3CA mutations (HR, 2.04; 95% CI, 1.08–3.84; P = 0.02) remained significant in multivariate analyses. Additionally, we have also identified a novel MCL1 amplification (found in 31% patients) as a potential independent biomarker for glioma (multivariate HR, 2.78; 95% CI, 1.53–5.08; P < 0.001), which was seldom reported in public databases. Pathway analyses revealed significantly worse prognosis with abnormal PI3K (HR, 1.81; 95% CI, 1.12–2.95; P = 0.01) and cell cycle pathways (HR, 1.97; 95% CI, 1.15–3.37; P = 0.01), both of which stayed meaningful after multivariate adjustment.ConclusionsIn this study, we discovered shorter survival in midline glioma patients with PIK3CA and TERT mutations and with abnormal PI3K and cell cycle pathways. We also revealed a novel prognostic marker, MCL1 amplification that collectively provided new insights and opportunities in understanding and treating midline gliomas.

Background: The ADJUVANT study reported the comparative superiority of adjuvant gefitinib over chemotherapy in disease-free survival (DFS) of resected EGFR-mutated stage II-IIIA non-small cell lung cancer (NSCLC). However, inconsistent clinical benefits have necessitated precise genetic categorization to reevaluate the benefit and risk assessment. Methods: Total 171 baseline surgical specimens from the ADJUVANT trial (n=95, gefitinib arm; n=76, VP arm) underwent targeted sequencing of 422 cancer-related genes. Predictive biomarkers of DFS were identified by Cox proportional hazard regression with gene-by-treatment interactions. A multi-gene composite score, MINERVA (Multiple-gene INdex to Evaluate the Relative benefit of Various Adjuvant therapies), that incorporates the predictive value of selected biomarkers, was developed for survival stratification based on the ratio of 2-year DFS rate and the difference in median DFS. The model was internally validated using ten-fold and leave-one-out cross-validation methods. Findings: TP53 exon4/5 mutations, RB1 alterations, and copy number gains of NKX2-1, CDK4, and MYC were identified as significant predictors for DFS and integrated into MINERVA score. Although updated overall OS presented no difference between adjuvant TKI and chemotherapy, MINERVA categorized patients into three subgroups. In Highly TKI-Preferable group (n=60, 35%), gefitinib achieved significantly longer median DFS than chemotherapy (34.5 vs 9.1 months; hazard ratio (HR) 0.21; p

The waste sulfuric acid solution generated from titanium dioxide production is called titanium dioxide waste acid (TWWA), which is an important resource for scandium production. A way including enrichment and purification stages for recovery and purification of Sc from TWWA with 10% P204 - 5% TBP synergistic extraction system was studied. In the enrichment stage, the preferred experimental conditions were obtained, i.e., the A/O ratio: 30, 25 °C, contact time: 30 min. In the following purification stage, the above-obtained enrichment products by stripping with 5 M NaOH were dissolved with 3 M HCl with 1% H2O2 added. The added H2O2 can lead to Ti form peroxy complex ([TiO(H2O2)]2+) that can effectively inhibit its co-extraction into the oil phase. The optimized purification conditions were the A/O ratio of 5, 30 min and 11 mmol/L Sc concentration. The stripping products obtained from the purification stage were dissolved with 2 M HCl, and then 0.5 M H2C2O4 was added to precipitate scandium. After washing and calcining, a product of 99.28% Sc2O3 was obtained. The recovery rate of scandium in the whole process was 90.34%.

Recovery of scandium (Sc) from various wastes is generally one strategy to solve potential supply shortage problems of Sc. This work proposes a synergistic process for co-recovery of Sc by using the acid titanium white waste acid (TWWA) to leach the basic red mud, to which the acidity was adjusted with concentrated sulfuric acid when necessary. First, the effect of adjusted acidity of TWWA on Sc leaching from red mud was studied when the acidity of TWWA was adjusted to 5 mol/L H2SO4, which inhibited the formation of silica gel in the leachate with a Sc recovery of 70%. Then, the volume fraction of 10% P204 (di-(2-ethylhexyl) phosphate)-5% TBP (tributyl phosphate)-85% sulfonated kerosene was used to extract Sc from the leachate under the most suitable conditions. Specifically, at an A/O (volumetric liquid phase over oil phase) ratio of 10 for 30 min at room temperature, over 99% Sc was extracted and almost no Fe and Al were co-extracted. The selective scrubbing of 99% Ti was achieved via 5 mol/L H2SO4–1% H2O2 at 60 °C with almost no scrubbing towards Sc. A solution of 3 mol/L NaOH was then used as the stripping agent, which resulted in solid Sc enrichment with a high stripping efficiency of 99%. The process generated a final Sc-enrichment product with a purity of 17.4% and a total recovery yield of 68.6%.

Scandium (Sc), a rare earth element, generally lacks independent large-scale deposits and is mainly recovered as a by-product in mineral processing. Herein, we systematically investigated the extraction of Sc by trialkyl phosphine oxide (TRPO) from both a scandium sulfate solution and leaching solution of Sc concentrate generated from titanium white waste acid in the sulfuric medium. The results showed that the optimum extraction conditions of Sc from scandium sulfate by TRPO were as follows: 10% TRPO, 5 mol/L H2SO4, and an A/O ratio of 1 for 20 min. The equation of scandium extraction by TRPO was calculated based on the log[c(TRPO)] - log[D] fitting results coupled with Fourier transform infrared spectroscopy (FT-IR) analysis, to which the extracted complex was deduced to be HSc(SO4)2•2TRPO. Furthermore, for Sc extraction from leaching solution of its concentrate from titanium white waste acid, a relatively high extraction rate of up to 95.5% was obtained on the conditions of 20% TRPO, 7 mol/L H2SO4, 0.5% of H2O2, and at an A/O ratio of 10. Stripping with H2C2O4 produced a high stripping rate of 99.9%, and the extraction and stripping system still presented excellent extraction performances even after five treatment cycles. Through the subsequent calcination of the stripped Sc2(C2O4)3 at 1000 °C for 2 h, we obtained the final product of Sc2O3 with a high purity of over 99.34% with a total recovery yield of Sc as high as 95% in the whole process. Our findings contribute novel insights into the extraction and purification of Sc for its recovery from the secondary wastes.

e13528 Background: As an extremely rare variant of lung adenocarcinoma, the diagnosis of pulmonary enteric adenocarcinoma (PEAC) remains challenging in the clinic due to shared morphological and immunohistochemical features with lung metastatic colorectal cancer (mCRC). Current differentiation of PEAC and mCRC mainly relies on clinical history and pathological examination while which still remain risks of misdiagnosis. Due to their distinct treatment regimens, effective molecular markers are essential for accurate diagnosis. However, comprehensive molecular features of PEAC is still poorly understood. Methods: We performed whole-exome sequencing and targeted bisulfite sequencing of 23 PEAC and 20 mCRC and matched normal tissue to improve molecular characterization. For DNA methylation profiling, differentially methylated regions (DMR) were analyzed by comparing PEAC with normal lung tissue and with mCRC. We also trained machine learning methods to distinguish PEAC from mCRC and validated the classifier in an independent cohort with 10 PEAC and 10 mCRC. Results: Mutations of KRAS, APC, and EGFR, alterations of chromosome arms 13q, 14q and 18p were found to be the major differential genetic alterations between PEAC and mCRC (P < 0.05), yet not enough to aid clinical diagnosis. For epigenomic profile, we identified 524 DMRs (false discovery rate ≤0.05) which were further reduced to 30 DMRs according to importance rank by the random forest algorithm. Based on these DMR features, we developed a diagnostic classifier that correctly classified 95.1% of patients in this discovery cohort. We further validated this predictive model in the validation cohort, with a prediction accuracy of 90.0%. We demonstrated its clinical application in two cases with difficulties to diagnosis by traditional methods. Conclusions: We have illustrated the unique genetic and methylation profiles of PEAC and mCRC. Our approach for disease classification may have a substantial impact on diagnostic precision and therapeutic decision for PEAC.

2507 Background: Brain metastases occur in approximately 20% of tumor patients and is often associated with terminal events and poor prognosis. Cerebrospinal fluid (CSF) can be a promising source for detecting circulating tumor DNA (ctDNA) specific to the central nervous system (CNS) instead of peripheral blood due to the blood-brain barrier. However, CSF’s suboptimal ctDNA detection rate might limit its clinical application. Precise screening of suitable patients is needed to maximize clinical benefit. Methods: We sequenced 425 cancer-relevant genes in CSF and matched extracranial tissue or blood samples obtained from 67 lung cancer patients with brain metastases. The impact of clinical factors, including age, gender, tumor size, number of lesions, and distance of lesions to the ventricle on CSF ctDNA detection was then evaluated by univariate logistic regression. To predict the probability of successful CSF ctDNA detection, best subsets regression was employed for feature selection and cross validation was used for performance assessment to determine the final model. Results: We detected somatic alterations in 39/67 (58%) CSF ctDNA, 57/66 (86%) plasma ctDNA and 45/49 (92%) tissue samples. Mutation detection rate of CSF ctDNA was significantly lower than that from extracranial tissue and plasma (P < 0.001). Univariate analysis revealed significant association (P < 0.05) of high CSF ctDNA detection rate with the following features: (1) intracranial lesion size ( T), (2) shortest distance between the largest lesion and the ventricle ( Dtop), and (3) shortest distance between all intracranial lesion and the ventricle ( Dall). We also revealed a trend of higher detection rate in patients with CNS symptoms ( SCNS). Subsequent best subsets analysis and cross validation suggested best prediction power with lesion size and largest lesion-ventriclar distance (area under curve [AUC], 0.76 [95% CI, 0.71 to 0.85]; accuracy, 0.75 [95% CI, 0.70 to 0.81]). Final probability can then be derived from Logit P = 0.11×T−0.16×Dall (AUC, 0.82; sensitivity, 0.91; specificity, 0.74). The detection of CSF ctDNA was significantly improved from 58% to 83% (P = 0.03) based on the model. Conclusions: This study established a regression model to predict the probability of CSF ctDNA that can be useful to facilitate clinical decisions and avoid excessive practice when monitoring tumor evolution in the brain.

e14538 Background: Molecular charactersitcs are essential for the classification and grading of gliomas. However, majority of current understanding is based on public databases that might not accurately reflect the Asian population. Here, we studied the mutation landscape of Chinese glioma patients in hope to provide new insights for glioma prognosis and treatment. Methods: Tissue samples from 112 glioma patients underwent next-generation sequencing targeting 425 cancer-relevant genes. Gene mutations and copy number variations were investigated for their prognostic effect using overall survival data. Pathway-based survival analysis was peformed using top ten predefined oncogenic pathways. Results: We identified similar prevalence of currently established molecular diagnostic markers of glioma, including TP53 (33%), EGFR(26%), TERT (24%), PTEN (21%), ATRX (14%), BRAF (13%) and IDH1/2 (6%). Among all genetic abberations with more than 5% occurrence rate, four mutations and four copy number gains were significantly associated with poor overall survival (univariate, P < 0.05). Of these, TERT mutations (hazard ratio [HR], 3.14; 95% confidence interval [CI], 1.31 to 7.49; P = 0.01) and EGFR amplification (HR, 2.67; 95% CI, 1.20 to 5.95; P = 0.02) remained significant after adjusting for clinical parameters. Similarly, PIK3CA mutations, which was also frequently mutated in glioma but not used for clinical classification, were found to correlate with poor prognosis (HR, 2.61; 95% CI, 1.19 to 5.74; P = 0.02). Additionally, we have also identified MCL1 amplification as a potential novel biomarker for glioma (HR, 2.73; 95% CI, 1.47 to 5.07; P < 0.001), which was seldom reported in the TCGA database and might possibly be ancestral specific giving its high prevelance in our cohort (found in 32% patients). Pathway analyses revealed significantly worse prognosis with abnormal PI3K (HR, 1.81; 95% CI, 1.12 to 2.95; P = 0.02) and cell cycle pathways (HR, 2.04; 95% CI, 1.2 to 3.47; P < 0.001), both of which stayed meaningful after adjusting for clinical factors. Conclusions: In this study, we discovered PIK3CA mutations and MCL1 amplification as novel prognostic markers of glioma. We also demonstrated shorter survival with abnormal PI3K and cell cycle pathways that provided an intergrative understanding of glioma.