A large qubit capacity and an individual readout capability are two crucial requirements for large-scale quantum computing and simulation1. As one of the leading physical platforms for quantum information processing, the ion trap has achieved a quantum simulation of tens of ions with site-resolved readout in a one-dimensional Paul trap2-4 and of hundreds of ions with global observables in a two-dimensional (2D) Penning trap5,6. However, integrating these two features into a single system is still very challenging. Here we report the stable trapping of 512 ions in a 2D Wigner crystal and the sideband cooling of their transverse motion. We demonstrate the quantum simulation of long-range quantum Ising models with tunable coupling strengths and patterns, with or without frustration, using 300 ions. Enabled by the site resolution in the single-shot measurement, we observe rich spatial correlation patterns in the quasi-adiabatically prepared ground states, which allows us to verify quantum simulation results by comparing the measured two-spin correlations with the calculated collective phonon modes and with classical simulated annealing. We further probe the quench dynamics of the Ising model in a transverse field to demonstrate quantum sampling tasks. Our work paves the way for simulating classically intractable quantum dynamics and for running noisy intermediate-scale quantum algorithms7,8 using 2D ion trap quantum simulators.

Two-dimensional (2D) ion crystals may represent a promising path to scale up qubit numbers for ion trap quantum information processing. However, to realize universal quantum computing in this system, individually addressed high-fidelity two-qubit entangling gates still remain challenging due to the inevitable micromotion of ions in a 2D crystal as well as the technical difficulty in 2D addressing. Here we demonstrate two-qubit entangling gates between any ion pairs in a 2D crystal of four ions. We use symmetrically placed crossed acousto-optic deflectors (AODs) to drive Raman transitions and achieve an addressing crosstalk error below 0.1%. We design and demonstrate a gate sequence by alternatingly addressing two target ions, making it compatible with any single-ion addressing techniques without crosstalk from multiple addressing beams. We further examine the gate performance versus the micromotion amplitude of the ions and show that its effect can be compensated by a recalibration of the laser intensity without degrading the gate fidelity. Our work paves the way for ion trap quantum computing with hundreds to thousands of qubits on a 2D ion crystal. Quantum gates in 2D ion crystals are more challenging than in 1D. Here, the authors use their 2D ion trap platform and acousto-optical deflectors to demonstrate a 2-qubit gate that can stand the ion micromotion in such configuration.

A large qubit capacity and an individual readout capability are two crucial requirements for large-scale quantum computing and simulation. As one of the leading physical platforms for quantum information processing, the ion trap has achieved quantum simulation of tens of ions with site-resolved readout in 1D Paul trap, and that of hundreds of ions with global observables in 2D Penning trap. However, integrating these two features into a single system is still very challenging. Here we report the stable trapping of 512 ions in a 2D Wigner crystal and the sideband cooling of their transverse motion. We demonstrate the quantum simulation of long-range quantum Ising models with tunable coupling strengths and patterns, with or without frustration, using 300 ions. Enabled by the site resolution in the single-shot measurement, we observe rich spatial correlation patterns in the quasi-adiabatically prepared ground states, which allows us to verify quantum simulation results by comparing with the calculated collective phonon modes and with classical simulated annealing. We further probe the quench dynamics of the Ising model in a transverse field to demonstrate quantum sampling tasks. Our work paves the way for simulating classically intractable quantum dynamics and for running NISQ algorithms using 2D ion trap quantum simulators.

Cross-bounding system is the most commonly used method to reduce sheath current. The sheath currents of cables are induced by currents in the cable cores, and sheath currents also increase when the loads increase gradually. The current carrying capacity of the cable is limited by sheath currents further, owing to their thermal effect, which is not favourable to the heat dissipation and operation of the cable. The sheath currents of single cable and the sheath currents of single loop cables in the case of cross-bounding interconnection are calculate by FEM including configurations of three phase cables in square triangle, horizontal and right angled triangle with the same distance between the cable cores. The results show that the right triangle arrangement should be preferred in order to minimize the sheath circulation.

There are limited studies about the molecular characteristics and clinical response to EGFR TKIs in NSCLC patients harboring EGFR E709-T710delinsX mutation, a rare mutation type in exon 18 of EGFR. In this study, we aimed to explore the molecular distribution and clinical outcome of EGFR TKIs in EGFR E709-T710delinsX mutated patients.

EGFR exon 18 G724S mutation has been described to be associated with cancer progression and mediating resistance to first- and third-generation EGFR tyrosine kinase inhibitors(TKIs). In vitro experiments have provided compelling evidence that EGFR G724S retains its sensitivity for second-generation inhibitors, including afatinib. However, limited data has reported the clinical efficacy of afatinib in Non-small cell lung cancer (NSCLC) patients harboring EGFR G724S mutation. In our study, we aimed to investigate the treatment response and survival outcome of advanced lung adenocarcinoma patients with EGFR G724S mutation who were treated with afatinib.

ERBB2 mutations, mostly affecting the kinase domain (KD), were later found in the transmembrane domain (TMD), most frequently seen in residues V659, G660, but with a much lower prevalence. Comparing to other solid tumors, ERBB2-mutant NSCLC shows a lower response rate to HER2 inhibitors (HER2i). ERBB2 V659E has been reported to respond to lapatinib in combination with carpecitabine, afatinib, or ado-trastuzumab emtansine (TDM-1). However, since the prevalence of ERBB2 V659E is low, no study has reported the subsequent clinical management after developing resistance to HER2i.

Genetic alterations in TP53 gene occurs between 5-80% of cancers. Numerous studies have reported the prognostic implications of certain TP53 mutations at specific sites, mutation types and functional effects. We aimed to explore the potential of TP53 mutations as prognostic markers in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). We retrieved the genomic and clinical data from publicly-available pan lung cancer dataset from The Cancer Genome Atlas. The dataset was comprised of 1,053 patients, including 566 LUAD and 487 LUSC. We analyzed the disease-free (DFS) and overall (OS) survival outcomes of TP53-mutant and TP53 wild-type (WT) NSCLC. TP53 mutations were detected from 52% (264/566) of the LUAD and 86% (401/487) of the LUSC patients. Among the LUAD patients, TP53-mutants have significantly more co-occurring mutations than TP53-WT patients. Consistently, TP53-mutant LUAD patients have significantly higher tumor mutation burden (TMB) than TP53-WT patients (P<0.01). Significant mutual exclusive relationship was found between TP53 and KRAS mutations in TP53-mutant LUAD patients (P=0.002). Among the LUSC patients, TMB were similar between TP53-mutant and TP53-WT patients. However, among the TP53-mutant LUSC patients, those who harbored mutations in exons 5-8 had significantly higher TMB than those whose mutations are located in other regions (P=0.002). Survival analysis among TP53-mutant LUSC patients revealed a shorter DFS for those with LOF mutations than those with non-LOF mutations (P=0.04). Moreover, OS was significantly shorter for TP53-mutant LUAD patients than TP53-WT (41.6 vs. 53.3 mo; P=0.03); while OS was significantly longer for TP53-mutant LUSC patients than TP53-WT (61.6 vs. 29.0 mo; P=0.01). Our study demonstrates a significantly higher TMB for TP53-mutant LUAD patients, suggesting a possibility of exploring TP53 mutations as additional markers for immunotherapy response. In addition, we also revealed a histology-specific difference in overall survival outcomes for TP53-mutants, suggesting distinct prognostic implications of TP53 mutations in various histology or even other tumor types. These promising results warrant further investigation.

e21521 Background: ERBB2 mutations, mostly affecting the kinase domain (KD), were later found in the transmembrane domain (TMD), most frequently seen in residues V659, G660, but with a much lower prevalence. Comparing to other solid tumors, ERBB2-mutant NSCLC shows a lower response rate to HER2 inhibitors (HER2i). ERBB2 V659E has been reported to respond to lapatinib in combination with carpecitabine, afatinib, or ado-trastuzumab emtansine (TDM-1). However, since the prevalence of ERBB2 V659E is low, no study has reported the subsequent clinical management after developing resistance to HER2i. Methods: We retrospectively screened genomic profiles of 7,812 lung adenocarcinoma (LADC) patients. Molecular docking of lapatinib, afatinib and pyrotinib with the HER2 KD was simulated with AutoDock 4.2 and the binding affinity was predicted by MMPBSA.py program in AmberTools18. Results: We analyzed NGS data of 7812 LADC patients and identified 14 patients (0.18%) with HER2 TMD mutation, mostly V659E mutation (11/7812, 0.14%); other mutations included V664F, T652M, V664F; each occurred in 1 patient. In this cohort, all adenocarcinomas harbor a dinucleotide missense mutation, including 10 TT→AA and 6 TT→AG (c.1976_1977). T P53 was the most frequently co-mutated gene (n = 4) followed by HER2 (n = 2), NSD1 (n = 2) and RARA (n = 2). Treatment history of 9 advanced LADC patients were collected and analyzed. 3 of them had chemotherapy as first-line therapy. 5 patients were treated with HERi as first-line therapy, achieving a median PFS of 192 days (ranged from 60-515days), comparing to patients treated with chemotherapy (71.7±53.3days). 1 patient who was treated with different HERi sequentially in the order of lapatinib, afatinib, TDM-1, achieving an overall PFS of 515 days. Subsequently, she was treated with pyrotinib and had a PFS of 92 days. Molecular docking simulation showed the covalent inhibitors Afatinib and Pyrotinib are more favorable for blocking HER2 KD than non-covalent inhibitor Lapatinib. Between the two covalent inhibitors, Pyrotinib (∆GPyrotinib = -65.92kcal/mol) shows stronger non-covalent binding ability than Afatinib (∆GAfatinib = -59.71 kcal/mol) (p < 0.001). Conclusions: To the best of our knowledge, this is the largest-reported HER2 V659E mutation cohort. We revealed the prevalence of ERBB2 V659E in Chinese LUAD patients and elucidated the genomic profile of ERBB2 V659E mutant. This study paves avenue for the utilization of the novel HER2 inhibitors pyrotinib in ERBB2 V659E mutant LUAD patients.

The pulmonary nodule especially small solid nodule (<2cm) represents a common diagnostic challenge for clinicians, which are sometimes very difficult to diagnose by radiographic techniques. In addition, complications of invasive diagnostic procedures of lung cancer are common in clinical practice. Bronchoalveolar lavage fluid (BALF), flushed into a small part of the lung and then recollected for examination, is routinely performed for the diagnosis of lung infections, interstitial lung diseases and sarcoidosis. However, limited evidences support the use of BALF for lung cancer diagnosis. The aim of this study is to investigate the potential value of BALF as liquid biopsy for differential diagnosis of pulmonary nodule characteristics. A total of 36 patients with solid pulmonary nodule (<2 cm) at department of respiratory medicine of the first affiliated hospital of soochow university were enrolled. BALF supernatant cfDNA and matched tissue samples were profiled using 168-cancer-related gene panel, with median sequencing depths of 45259× and 2007×, respectively. Patients were eventually diagnosed by surgery, tracheoscopy, transthoracic needle aspiration or follow-up. The consistency of diagnoses based on genomic profiling of BALF and pathological examination were evaluated. Of the 36 patients with solid pulmonary nodule (<2 cm), 15 cases were finally diagnosed as malignant nodules (11 by surgery, 4 by tracheoscopy), 16 with benign nodules (5 by surgery, 10 by tracheoscopy and fellow-up ,1 by TTNA), and 5 with uncertain nodules for the present. Using BALF mutation spectrum for diagnosis of pulmonary nodule characteristics, the sensitivities of 168 genes and 10 key genes (EGFR, ERBB2, ROS1, BRAF, RET, ALK, KRAS, MET, TP53 and RB1) from NGS panel were 80% and 73%, the specificities were as high as 75% and 100%, positive predictive values were 75% and 100%, and negative predictive values were 80% and 80%, respectively. NGS detection consistency between BALFs and tissues was analyzed in paired BALF and tissue samples from 14 malignant patients. Alterations were detected in 11 (78.6%, 11/14) BALF supernatant samples and all the 14 (100%, 14/14) tissues. In total, 45 mutations were detected in paired BALF and tissue samples, of which 27 were detected in BALF samples and 40 in tissue samples,the consistency between tissue and BALF supernatant was 48.9%. BALF supernatant cfDNA could reveal the genetic profiles of patients with lung cancer and distinguish benign or malignant solitary pulmonary nodule (<2cm) with high specificity. It should be considered as liquid biopsy medium for identification the solitary pulmonary nodule in clinical practice.

Brain metastases (BM), with a dismal prognosis, are a common and lethal complication of non-small cell lung cancer. Approximately, 10% patients present with BM at their initial diagnosis. Although, surgery and/or radiation therapy remain to be the mainstay treatment, targeted therapies are finding increasing application in treating BM. However, due to the very limited accessibility of brain lesions, its genomic and epigenomic landscape remain elusive. Capture-based targeted sequencing for somatic mutation profiling was performed on 27 treatment-naïve advanced NSCLC patients with paired lung primary and BM lesions using a pane consisting of 520 cancer related genes. DNA methylation analyses was performed on same samples using a DNA methylation panel consisting of 100,000 CpG sites. Collectively, we identified 370 (291 SNVs+Indels, 78 CNVs and 1 rearrangement) and 574 (245 SNVs+Indels, 327 CNVs and 2 rearrangements) mutations from lung primary lesions and BM, respectively. Among them, 242 mutations were shared; 128 were lung primary-specific and 332 were BM-specific. Among the BM specific mutations, a majority of them (82%, 272/332) were copy number variations (CNVs). Only 16% of CNVs were shared by lung lesions and BM. The concordance for SNVs and indels were much higher-54% between the two sources of tissues. Furthermore, we observed a much higher concordance rate (79%) in TP53 and classic lung cancer driver genes than other genes (p<0.001), indicating that they might be stem mutations. Next, we performed pathway analysis of genes that were only mutated in BM and revealed an enrichment of genes participating in PI3K-AKT and focal adhesion pathways. We also compared tumor mutation burden (TMB) between them and revealed comparable TMB (p=0.1). Our DNA methylation analysis revealed distinct methylation patterns with 268 blocks that are significantly differentially methylated between primary lung lesions and BM. Among them, 211 blocks were hypermethylated in BM and the remaining 57 blocks were hypermethylated in lung lesions. These blocks were enrichment in genes participating in cell adhesion, Rap1 signaling and calcium signaling pathways. We revealed diverse somatic mutation and DNA methylation profiles between lung primary lesions and BM. BM had significantly more unique CNVs. A great concordance was observed for classic lung cancer driver genes and TP53. Our study provided a comprehensive view of genomic and DNA methylation profiling for lung primary lesions and BM, paving the avenue for the development of targeted therapies for treating BM.

To investigate the impact of targeted-drugs on therapeutic models, expenditure patterns and disease burden of cancer patients with the purpose of providing reference for price negotiation and payment policy-making of National Reimbursement Drug List (NRDL). A retrospective observational study was conducted based on China Health Insurance Research Association (CHIRA) database in 2016. The year-round treatment data (including in-patient-department and out-patient-department) of sample cancer patients (with C00-C97 codes defined by ICD 10) were extracted, and their medical resource utilization, expenditure patterns and drug use mode were analyzed and described. Medical expense of cancer patients is much higher than average level: with 0.71% distribution of total visits, their medical constitutes 6.71%, figures of visits and hospitalization days of each cancer patient (OPD 16.44, IPD 2.90, 32.70d) are higher than average (6.04, 1.54, 16.11d), their annual medical cost is 27,331 RMB. The medical cost of top 5 cancer diseases constitutes 54.02% of total: the cost difference expenditure and treatment patterns among cancers is obvious, the proportion paid by fund remains similar. Among prescribed drugs, the share of directly treating drugs takes less than 25%. The medical cost of patients treated by targeted-drugs brings sharp stressing impact on Basic Medical Insurance: the number of patient treating by targeted-drugs is not large yet but with rapid growth rate. Listing targeted-drugs into NRDL by price negotiation will impact patient behavior, fund safety and market development, increase drug accessibility and better satisfy clinical demands. With consideration of improving price negotiation and payment management, we suggest:

Cerebrospinal fluid (CSF) has been proven as good media for genetic profiling of central nervous system (CNS) metastases. However, the association of genetic alterations in CSF and clinical outcomes remains elusive. A total of 94 lung cancer patients with CNS metastases underwent lumbar puncture. Circulating tumor DNA were extracted from CSF and profiled by next-generation sequencing. The effect of genetic alterations in CSF on survival and treatment outcomes were evaluated. The most common genes seen in CSF were EGFR, TP53, MET, CDKN2A, MYC, NTRK1 and CDK6. Kaplan-Meier survival analysis indicated that CDK4, CDK6, FGFR1, MET and MYC alterations, which were also characterized by more copy number changes, were associated with poor survival. Multivariate analysis found only MET (HR, 2.01; 95% CI, 1.15 to 3.52) and MYC alterations (HR, 2.31; 95% CI, 1.27 to 4.21) were correlated to poor OS. Forty-two patients harbored high n-CNVs (defined as the number of genes with copy number variations >2) while 50 patients carried low n-CNVs (defined as the number of genes with copy number variations ≤2). Median overall survival (OS) of patients with high n-CNVs in CSF was 14.9 months (95% CI, 9.2 to 25.8 months), significantly shorter than those with low n-CNVs (21.6 months, 95% CI, 17.9 months to not reached (NR); HR, 1.9; 95% CI, 1.11 to 3.24; P=0.016). Patients with high n-CNVs and MET and MYC CNVs (copy number variations) were associated with the poorest OS. Osimertinib significantly prolonged OS only among patients with high n-CNVs (with vs. without osimertinib, 25.8 vs. 9.2 months; P=0.004). Among T790M negative patients, high n-CNVs seemed to positively associate with better response to osimertinib (OS with vs. without osimertinib, 23 vs. 7.8 months; P=0.058). Further analysis indicated that EGFR and FGFR1 CNV were the most significant factors associated with OS benefit from osimertinib among the high n-CNVs group (P=0.014; P=0.02). TP53_LOH and Wnt pathway alterations were significantly more prevalent in the high n-CNVs group than in the low n-CNVs group (P=0.016, P=0.006). With regard to clinical characteristics, higher performance status score (HR, 2.06; 95% CI, 1.38 to 3.07; P=0.0004) and occurrence of extracranial metastases (HR, 3.21; 95% CI, 1.25 to 8.24; P=0.015) suggested poor OS. While genetic profiles in CSF, like high n-CNVs as well as MET and MYC CNV were related to poor prognosis, patients with high n-CNVs, especially those with EGFR or FGFR1 CNV might benefit more from osimertinib, further supporting CSF as liquid biopsy of CNS metastases in lung cancer.

To explore the treatment pattern and to estimate direct medical costs in lung cancer patients. A retrospective observational study was carried out on the basis of China Health Insurance Research Association (CHIRA) database in 2016. Patients with ≥1 diagnosis of lung cancer during the first season were identified. If the patient met one of the following criteria: 1) with other cancer diagnosis; 2) complicated with schizophrenia; 3) receiving hemodialysis or peritoneal dialysis treatment, he (she) would be excluded. Eligible patients were classified into one of the subgroups by the treatment methods: 1) chemotherapy group; 2) radiotherapy group; 3) radiotherapy combined with chemotherapy group; 4) surgical treatment group; 5) targeted agent group; 6) palliative treatment group. The age, sex, proportion and annual direct medical costs of those subgroups were described and calculated. 3,365 lung cancer patients met the inclusion criteria. The mean age was 65.2±11.0 years. 65.1% of the total participants were male. The proportion of the chemotherapy group, radiotherapy group, radiotherapy combined with chemotherapy group, surgical treatment group, targeted agent group and palliative treatment group was 20.5% (n=691), 6.2% (n=210), 10.4% (n=350), 4.7% (n=157), 2.9% (n=96) and 55.3% (n=1,861), respectively. The annual mean all-cause direct medical cost per capita was CNY 53,143.8±60,771.3. The ratio of the cost covered by medical insurance reimbursement was 71.8%. Medication cost made up 55.6% of the total cost. The annual mean all-cause direct medical cost per capita of the subgroups above was CNY 61,253.0±58,682.3, CNY 63,266.5±51,248. 7, CNY 113,001.5±66,705.1, CNY 100,338.3±4,8949.3, CNY 161,089.4±90,240.3 and CNY 28,183.2±39,141.9, respectively. The percentage of the medication cost was the highest in the targeted agent group (CNY 104,534.5±67,592.3, 64.9%). In this database analysis, more than half of the lung cancer patients received palliative treatment. The total annual direct medical cost was the highest in patients who received targeted agent treatment.

The controversial classification of lung neuroendocrine tumor has been amended a few times since recognised as a separate entity. LCNEC shares clinical features with small cell lung carcinoma (SCLC) and they were both classified as lung neuroendocrine carcinoma according to the 2015 WHO lung primary pathology classification, numerous studies have revealed barely satisfactory outcomes when it was treated as SCLC. However the underlying molecular basis for such commonalities and discrepancies are poorly understood. In this study, we interrogated the genomic landscape of LCNEC and SCLC along with their histologically related subtypes: carcinoids and atypical carcinoids to define the molecular pattern of LCNEC. We performed targeted sequencing in 35 tissue samples using a panel covering 520 cancer related genes, spanning 1.6MB of human genome, with an average sequencing depth of 1,418x. Among them, 15 were diagnosed with SCLC, 9 with LCNEC, 6 with carcinoid and 5 with atypical carcinoid. On average, LCNEC exhibited 13.5 mutations per million base pairs (Mb) and a C:G>A:T transversion rate of 34%, which is indicative of tobacco exposure. LCNEC had SCLC (16.7 Mb) had comparable TMB (p=0.18), which is significantly higher than carcinoids (1.2/Mb, p<0.001) and atypical carcinoids (2.4/Mb, p<0.001). The most frequently mutated gene in LCNEC is TP53 (89%, 8/9), followed by NOTCH1 (33%), KEAP1 (22%), RB1 (22%) and a few chromatin modifiers, including KMT2D (33%), KMT2C (33%). Co-mutation in TP53 and RB1, a hallmark of SCLC, was found in 22% (2/9) of LCNEC patients; in contrast, 80% of SCLC patients harbored concurrent mutation. 67% carcinoid (4/6) and 20% (1/5) atypical carcinoid patients had no mutation identified from this panel. No classic lung adenocarcinoma driver mutations were found in any subtype. Copy number analyses revealed significantly higher copy number variation (CNV) in SCLC and LCNEC comparing with carcinoids and atypical carcinoids, which yield virtually no CNV. Our analysis revealed a comparable CNV status of SCLC and LCNEC (p=0.158), with an enrichment in amplification of chromatin modifiers. Our study, comprehensively characterized 4 subtypes of neuroendocrine tumors, revealed a high TMB and CG:AT transversion rate in LCNEC patients as well as a distinctive mutation landscape, with an enrichment of mutations occurring at chromatin remodelers. Furthermore, LCNEC has comparable TMB and CNV status as SCLC, which are significantly higher than carcinoid and atypical carcinoids.