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Polyacrylonitrile (PAN)-based materials have been studied for decades as uranium (U(VI)) adsorbents, because the further products of abundant nitrile groups, amidoxime (AO) groups, show great affinity for U(VI) ions. However, excessive amidoximation could cause the shrinkage of PAN fibers, resulting in decreased adsorption performance. Hence, an amino-reinforced amidoxime (ARAO) swelling layer was constructed on the PAN fiber surface (PAN-NH2-AO) by modification of the strongly hydrophilic amino group to prevent shrinkage. The molecular chains in the ARAO swelling layer would be swelled due to the adsorption of a large amount of water. Simultaneously, U(Ⅵ) ions can penetrate into the ARAO swelling layer with water molecules and coordinate with amino or AO groups, leading to increased adsorption performance. PAN-NH2-AO exhibited maximum U(VI) and water adsorption capacities of 492.61 mg·g-1 and 20.32 g·g-1 at 25 ℃ with a swelling ratio of 20.73%, respectively. The adsorption capacity of PAN-NH2-AO was 0.312 mg·g-1 after a 91-day immersion in Yellow Sea, China. The study of the adsorption thermodynamics and kinetics of PAN-NH2-AO showed that the adsorption process was spontaneous homogeneous chemical adsorption. This paper proposes a novel method to obstruct amidoximation induced shrinkage and to maximize the potential application of PAN-based materials.

BACKGROUND The concurrence of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) is rare. Previous reports of such cases have focused mainly on clinical diagnosis and characteristics, so the mechanism remains unclear, and therapy options have been poorly explored. CASE SUMMARY Here, we report two cases of synchronous AML and CLL. Flow cytometry revealed two distinct abnormal cell populations (myeloblasts and lymphoid cells) according to scatter characteristics. CD5-positive B cell lymphoma with myeloid leukemia invasion was observed on lymph node biopsy. Chemotherapy regimens indicated for both AML and CLL were used in our patients, and our patients achieved complete response after chemotherapy. Next-generation sequencing of 88 genes was performed. CONCLUSION We conclude that early mutation and dysregulation at the hematopoietic stem cell stage and the accumulation of multiple rearrangements may cause the concurrence of CLL and AML. The treatment of infection and combination therapy aimed at the CLL component are significant in the management of patients with concurrent CLL and AML.

Background EGFR and ALK alternations often contribute to human malignancies, including lung cancer. EGFR and ALK mutations are usually sensitive to EGFR-tyrosine kinase inhibitors (TKIs) and ALK-TKIs. Although generally mutually exclusive, these mutations do co-exist in rare cases. This study investigated the frequencies, clinical characteristics, therapeutic efficacies, and genetic profiles of lung cancer patients with EGFR and ALK co-mutations. Methods Patients with concurrent EGFR and ALK mutations were included in this study, which analyzed mutation profiles and treatment histories. SPSS20.0 were used for survival analysis. Results Among 271 ALK-positive (ALK-pos) and 2975 EGFR-positive (EGFR-pos) patients in our database, nine (2.6% of ALK-pos and 0.2% of EGFR-pos) patients had concurrent EGFR and ALK mutations (including three exon19 Indel + EML4-ALK, two exon19 Indel + STRN-ALK, two L858R + L1152R, one L858R + EML4-ALK, and one G719C + S768I + STRN-ALK). Eight patients had at least one type of EGFR-TKIs treatment. The median progression free survival (PFS) of these patients on first-generation EGFR-TKIs was 14.5 months (95% CI: 11 - NR). Of these eight patients, one who progressed on Gefitinib and subsequently on Osimertinib had a T790M + C797G. The other seven EGFR-TKIs resistance patients had no known resistance mutations. No patients had ALK mutations before treatment, so ALK mutations may have developed as resistance mechanisms during EGFR-TKIs therapies. EGFR-TKIs-treated patients with EGFR/ALK L1152R mutations generally had a shorter PFS than patients with other mutation combinations. Conclusions ALK and EGFR mutations coincide at a relatively low frequency in lung cancer patients. ALK mutations developed either synchronously or heterochronously with EGFR mutations. Two ALK mutations (L1152R and STRN-ALK) may co-exist with EGFR mutations at a higher frequency than others. Most EGFR/ALK co-alteration patients (other than the EGFR/ALK L1152R type) can benefit from first line EGFR-TKIs.

BACKGROUND In recent years, targeted therapy and immunotherapy have become important treatment strategies for patients with non-small cell lung cancer (NSCLC). However, the clinical evidence for successful off-label use of targeted drugs for patients with NSCLC following progression on multiple lines of treatment is still lacking. CASE SUMMARY We describe a 62-year-old male patient with a right lung adenocarcinoma who harbored an EGFR exon 19 deletion mutation. He received gefitinib combined with six cycles of vinorelbine, cisplatin, and recombinant human endostatin as the first-line therapy. Then gefitinib was administered in combination with recombinant human endostatin as maintenance therapy, resulting in a progression-free survival (PFS) of 14 mo. Chemoradiotherapy was added following progression (enlarged brain metastases) on maintenance treatment. Unfortunately, the brain lesions were highly refractory and progressed again after 15 mo, at which time next-generation sequencing (NGS) of 1021 cancer-related genes was performed using peripheral blood to identify potential actionable mutations. NGS revealed that the patient harbored a BRCA2 germline mutation, the EGFR exon 19 deletion mutation disappeared, and no additional targetable genetic variant was detected. Therefore, the patient received olaparib combined with gefitinib and recombinant human endostatin, with a rapid and long-lasting clinical response (PFS = 13.5 mo). CONCLUSION This is a rare case of lung adenocarcinoma in a patient with a BRCA2 germline mutation who had long-term benefit from olaparib combination treatment, suggesting that NGS-based genetic testing may render the possibility of long-term survival in NSCLC patients after disease progression.

Anaplastic lymphocyte kinase (ALK) rearrangement, a key oncogenic driver promoting the expression of ALK protein in tumor cells, is found in 2%-7% of patients with nonsmall cell lung cancer (NSCLC). ALK fusion is routinely determined with immunohistochemistry (IHC) or RT-PCR in many laboratories. However, there were discordant cases. In this study, we employed a hybridization-based next-generation sequencing (NGS) of DNA and RNA to explore the underlying mechanisms. FFPE tissues of 302 NSCLC tumors, which had been ALK tested with IHC and RT-PCR, were retrospectively studied, of which 18 were IHC positive, and 14 were RT-PCR positive. This resulted in 4 discordant cases, which were further analyzed with NGS. One sample failed the RNA quality control due to extensive RNA degradation. Three non-EML4-ALK fusions were identified in the 4 cases with DNA sequencing, including a CLTC-ALK fusion (EX31:EX19), a WDPCP-ALK fusion (EX14:EX20), and a novel PLB1-ALK fusion (EX6:EX20). Interestingly, two additional fusions: STRN-ALK fusion (EX3:EX20) and DCTN1-ALK fusion (EX20:EX20), were identified with RNA sequencing. The discordance of IHC/RT-PCR was mainly due to limited coverage of non-EML4-ALK fusions in the RT-PCR assay. NGS-based DNA/RNA sequencing appears to be a promising rescue technique for nonclear-cut IHC/RT-PCR cases and also offers a unique opportunity to identify novel ALK fusions.

Background Fatal hemorrhagic pneumonia is one of the most severe manifestations of Stenotrophomonas maltophilia (SM) infections. Here, we aimed to investigate the clinical characteristics of SM bacteremia and to identify the risk factors of hemorrhagic pneumonia caused by SM in patients with hematologic diseases. Methods The clinical records of 55 patients diagnosed with hematologic diseases and SM bacteremia were retrospectively reviewed. We compared patients’ clinical characteristics and outcomes between the hemorrhagic pneumonia group and non-hemorrhagic pneumonia group. Results Twenty-seven (49.1%) patients developed hemorrhagic pneumonia. The overall mortality rate of SM bacteremia was 67.3%. Hemorrhagic pneumonia (adjusted HR 2.316, 95% CI 1.140–4.705; P = 0.020) was an independent risk factor of 30-day mortality in hematological patients with SM bacteremia. Compared with the non-hemorrhagic pneumonia group, patients in the hemorrhagic pneumonia group were older and showed clinical manifestations as higher proportions of isolated SM in sputum culture, neutropenia and elevated procalcitonin (PCT). Multivariate analysis showed that neutropenia, high levels of PCT, prior tigecycline therapy within 1 month were independent risk factors associated with hemorrhagic pneumonia. Conclusions Neutropenia, high level of PCT and prior tigecycline therapy within 1 month were significant independent predictors of hemorrhagic pneumonia in hematologic patients with SM bacteremia. Due to no effective antibiotics to prevent hemorrhagic pneumonia, prophylaxis of SM infection and its progression to hemorrhagic pneumonia is particularly important.

Chronic myeloid leukemia (CML) is triggered primarily by the t(9;22) (q34.13; q11.23) translocation. This reciprocal chromosomal translocation leads to the formation of the BCR-ABL fusion gene. Patients in the chronic phase (CP) experience a good curative effect with tyrosine kinase inhibitors. However, cases are treatment refractory, with a dismal prognosis, when the disease has progressed to the accelerated phase (AP) or blast phase (BP). Until now, few reports have provided a comprehensive description of the mechanisms involved at different molecular levels. Indeed, the underlying pathogenesis of CML evolution comprises genetic aberrations, chromosomal translocations (except for the Philadelphia chromosome), telomere biology, and epigenetic anomalies. Herein, we provide knowledge of the biology responsible for blast transformation of CML at several levels, such as genetics, telomere biology, and epigenetic anomalies. Because of the limited treatment options available and poor outcomes, only the therapeutic response is monitored regularly, which involves BCR-ABL transcript level assessment and immunologic surveillance, with the optimal treatment strategy for patients in CP adapted to evaluate disease recurrence or progression. Overall, selecting optimal treatment endpoints to predict survival and successful TFR improves the quality of life of patients. Thus, identifying risk factors and developing risk-adapted therapeutic options may contribute to a better outcome for advanced-phase patients.

Immune checkpoint inhibitors (ICI) monotherapy or combination therapies have become increasingly popular in patients with advanced non-small cell lung cancer (NSCLC). However, there are still many unknowns concerning the predictive bio-markers and resistance mechanisms to immunotherapy. Patients with primary tumor STK11 mutation reportedly to have a lower response rate than the STK11 wild-type and possibly a primary resistance mechanism to ICIs. However, there is presently no data regarding the contribution of STK11 to acquired resistance to ICIs. Herein we report on a patient who was diagnosed with advanced lung squamous cell carcinoma accompanied by Lynch syndrome. The patient developed an STK11 mutation after receiving pembrolizumab as a first-line treatment. Programmed death ligand 1 (PD-L1) was highly expressed (50%) in the biopsy. HRAS Q61L and TP53 R158L were mainly detected. Unexpectedly, the patient carried an MSH6 heterozygous germline mutation, and was classified as proficient mismatch repair (pMMR). The patient subsequently received pembrolizumab (200 mg, ivgtt, q3w) as first line therapy and achieved stable disease (SD) as the best response. After eight treatment cycles, the patient suffered disease progression (PD), and an STK11 frameshift mutation was newly identified in his plasma circulating tumor deoxyribonucleic acid (ctDNA). This case study suggests that STK11 could contribute to pembrolizumab acquired resistance. Furthermore, the patient was also diagnosed with Lynch syndrome, which rarely occurs in lung cancer.

Background Neutrophil-to-lymphocyte (NLR) ratio can predict survival outcome and assess response to chemotherapy in several tumors. However, the values of NLR in acute myeloid leukemia (AML) remains unknown. Methods A retrospective review of 181 patients with de novo AML excluding acute promyelocytic leukemia (M3) was conducted in our institute. We categorized the patients into two groups by defining NLR =2.0 as the cut-off point. NLR was calculated by the ratio of the number of neutrophils to lymphocytes in the peripheral blood (PB). The baseline clinicopathologic parameters were compared using Chi-squared test or Kruskal-Wallis H test. Kaplan-Meier analysis was used to assess survival, and overall survival (OS) and disease-free survival (DFS) were analyzed using the Cox regression with log-rank tests. Results We found AML patients with low NLR (

Purpose: Clonal architecture is fundamental for the understanding of cancer biology and therapy; however, multiregional sampling in advanced-stage cancers is not always applicable. This prospective clinical trial was to investigate whether paired tissue and circulating tumor DNA (ctDNA) could describe the clonal architecture of advanced non–small cell lung cancer (NSCLC) and its association with clinical outcome (NCT03059641). Patients and Methods: Paired tumor and plasma ctDNA samples were sequenced by target-capture deep sequencing of 1,021 genes. Clonal dominance analysis was performed on the basis of PyClone. Results: Overall, 300 treatment-naïve patients with stage IIIB–IV NSCLC were recruited from 14 centers. Of the 94 patients with available ctDNA data for EGFR clonal architecture analysis, 72 (76.6%) showed EGFR as the dominant clone. The median progression-free survival was longer for these patients than for the 22 patients whose EGFR was nondominant clone [11 vs. 10 months; HR, 0.46; 95% confidence interval (CI), 0.24–0.88; P = 0.02]. The difference was more significant if both tissue and ctDNA defined EGFR as dominant clone (n = 43) versus those not (n = 8; 11 vs. 6 months; HR, 0.13; 95% CI, 0.04–0.50; P = 0.003). Moreover, multivariate Cox proportional HR analysis demonstrated EGFR clonal architecture as an independent prognostic indicator of the efficacy of EGFR-tyrosine kinase inhibitors (TKIs). Conclusions: Paired tissue and ctDNA could be analyzed for clonal architecture in advanced cancer. EGFR mutations do not always make up a dominant clone in advanced NSCLC, which was associated with the efficacy of EGFR-TKIs in NSCLC.

Brain metastasis (BM) is a common malignant event in lung cancer. Here, we recruited 33 lung cancer patients with brain oligo-metastasis to explore the genomic features and tumor immune microenvironment (TIME) of the lung and BM independently. For genomic profiling, targeted sequencing was performed. We found that high-frequent ZFHX3 occurred in the lung (40%) and brain tumor (28%), which might relate to brain metastasis event; the vast majority of patients had lesions-shared mutations in primary tumor and BM, confirming the common clonal events; and EGFR was the most frequently clonal gene in both lung and BM, indicating its driver capability. To characterize TIME status, we also sequenced the T cell receptor (TCR) repertoires and performed immunohistochemistry (IHC) on CD8+ tumor-infiltrating lymphocytes (TILs) and PD-L1 expression in 28 patients who had paired samples. Through the comparison, the TCR clonality of BM was higher than lung tumor, indicating the distinct pattern of the stronger oligoclonal T cell expansion in BM; the primary tumor had a higher TMB than oligo-BM (13.9 vs 8.7 mutations, p = 0.019); CD8 + TILs of BM were significantly lower than lung tumor (10% vs 30%, p = 0.015), revealing the lower level of cytotoxic T cell infiltration; BM showed statistically equivalent level of PD-L1 compared with lung tumor (p = 0.722). We further investigated the potential biomarkers associated with overall survival (OS) after brain surgery. We found that higher TCR clonality was related to prolonged OS in EGFR-treated patients (HR 0.175, p p = 0.034). More CD8+ TILs were an independently positive indicator for OS, in EGFR-treated (HR 0.160, p = 0.001) and non-EGFR-treated patients (HR 0.308, p = 0.009). These findings provide a meaningful molecular and clinical understanding of lung carcinoma and brain oligo-metastasis.

Because depression is highly prevalent among Chinese undergraduates, it is crucial to develop an approach for early intervention and prevention. Cognitive bias modification of interpretation (CBM-I) has been shown to be an effective approach to alleviate anxiety. However, its utility in improving depression needs further verification. The current study sought to evaluate the efficacy of a four-session CBM-I program of depression prevention for Chinese undergraduates. Forty Chinese participants with depressive symptoms (Self-Rating Depression Scale, SDS ≥ 50) were randomly assigned to receive either a CBM-I training or a waitlist control condition. Test results of Ambiguous Scenarios Test for Depression-Related Bias and SDS indicate that the CBM-I training group have more positive interpretations and fewer symptoms of depression after the training compared to the control group. In addition, significant correlation was found between changes in depressive symptoms and changes in interpretation bias. The effect of the CBM-I on depressive symptoms was partially mediated by the change in interpretation bias. The study findings highlight the potential of CBM-I protocol as a brief, simple, and accessible approach for preventing depression.

Background Rearranged during transfection (RET) has been proven to be a tumorigenic target in non-small cell lung cancers (NSCLCs). In RET-rearranged NSCLCs, molecular features and their impact on prognosis were not well illustrated, and the activity of mainstay therapeutics has not currently been well compared. Methods Patients diagnosed with NSCLCs with RET rearrangements were analyzed for concomitant mutations, tumor mutation burden (TMB), PD-L1 expression, T cell receptor repertoire and clinical outcomes with chemotherapy, immune checkpoint inhibitors (ICIs), and multikinase inhibitors (MKIs). Results Among 129 patients with RET-rearranged NSCLC who were analyzed, 41.1% (53/129) had co-occurring genetic alterations by next-generation sequencing, and concomitant TP53 mutation appeared most frequently (20/53, 37.7%). Patients with concurrent TP53 mutation (n = 15) had shorter overall survival than those without (n = 30; median, 18.4 months [95% CI, 8.6–39.1] vs 24.8 months [95% CI, 11.7–52.8]; P < 0.05). Patients with lower peripheral blood TCR diversity (n = 5) had superior overall survival compared with those with higher diversity (n = 6; median, 18.4 months [95% CI, 16.9–19.9] vs 4.8 months [95% CI, 4.5–5.3]; P = 0.035). An association with overall survival was not observed for PD-L1 expression nor for tumor mutation burden level. Median progression-free survival was not significantly different across chemotherapy, ICIs, and MKIs (median, 3.5 vs 2.5 vs 3.8 months). For patients treated with ICIs, the disease control rate was 60% (6/10) and the objective response rate was 20% (2/10). Conclusions RET-rearranged lung cancers can be heterogeneous in terms of concomitant genetic alterations. Patients with concurrent TP53 mutation or high peripheral blood TCR repertoire diversity have relatively inferior overall survival in this series. Outcomes with traditional systemic therapies in general are suboptimal.

Objectives The 3rd generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR TKI) osimertinib has shown promising efficacy both in EGFR-mutant, T790M positive non-small cell lung cancer (NSCLC) patients who have become resistant to 1st or 2nd generation EGFR TKIs and patients with sensitizing EGFR mutations as the first line therapy. However, the degree and duration of response to osimertinib are heterogeneous. We hypothesized that the concurrent genomic landscape of these tumors could play a role in clinical outcomes and/or mechanisms of resistance. Materials and methods We conducted a retrospective multicenter study of lung cancer patients who had developed resistance to osimertinib. Genomic profiling was done for all the patients by using targeted next-generation sequencing encompassing 59–1021 cancer-related genes. Results and conclusion Known EGFR-dependent resistant mutations and activation of alternative pathways were identified in 44 % of all the patients with great heterogeneity. Gain-of-function mutations of CTNNB1 were highly enriched in our cohort. Some other putative resistance mechanisms to osimertinib, such as the recurrent EGFR V834 L mutation, were also identified. Moreover, pathogenic mutations of TP53 were negatively related to the efficacy of osimertinib. To sum up, heterogeneity of resistance to osimertinib was not only manifested by inter-individual differences, but also embodied in its intra-individual diversity.

Introduction Human c-ros oncogene 1 (ROS1) rearrangement is a distinctive molecular subtype identified in 1-2% of non-small-cell lung cancer (NSCLC) tumors. Since the first gene rearrangement involving the ROS1 gene was described in 2003, multiple ROS1 fusion partner genes have been reported. Crizotinib, a multi-targeted MET/ALK/ROS1 tyrosine kinase inhibitor approved by the FDA, shows efficacy in the treatment of NSCLC patients with common ROS1 fusions. However, its efficacy in patients with rare ROS1 fusions remains unknown. Case presentation Here, we report a 16-year-old boy diagnosed with advanced lung adenocarcinoma. Paired tumor-normal next-generation sequencing was performed on DNA derived from pericardial effusion and peripheral blood with simultaneous analyses of genetic alterations, microsatellite instability (MSI), and tumor mutation burden (TMB). A total of 34 somatic variations, including a novel RBPMS-ROS1 (Exon 1:Exon 32) fusion, were identified. In addition, the sample was found to exhibit MSI-H and TMB-H. The patient was administered crizotinib and showed a rapid, favorable response in both intracranial and primary lung lesions. Conclusion This case supports the use of crizotinib in NSCLC patients with RBPMS-ROS1 rearrangement. Broader molecular profiling is strongly recommended for patients with NSCLC to identify novel actionable fusions.

BackgroundEpidemiological surveys have suggested that lung cancer has inherited susceptibility and shows familial aggregation. However, the distribution and prevalence of epidermal growth factor receptor (EGFR) germline variants and their roles in lung cancer genetic predisposition in Chinese population remain to be elucidated.MethodsIn this study, EGFR germline and somatic variants were retrospectively reviewed from the next-generation sequencing results of 31,906 patients with lung cancer. Clinical information was also collected for patients with confirmed EGFR germline mutations.ResultsA total of 22 germline EGFR variants were identified in 64 patients with lung cancer, accounting for 0.2% of the total cases studied. Five patients were diagnosed as multiple primary carcinomas. Family history was documented in 31.3% (20/64) of patients, 55% of which were diagnosed as lung cancer. G863D was the most frequent EGFR germline mutation, followed by P848L, D1014N, and K757R. Somatic EGFR-sensitive mutations were identified in 51.6% of patients with germline EGFR mutations. The proportion of L858R mutation, exon 19 deletion, and rare sensitive mutation was 50%, 17.6%, and 32.4%, respectively. D1014N and T790M mutations were common in young patients. The family members of patients with P848L, R776H, V769M, and V774M mutations were more commonly diagnosed with cancers. A total of 19 patients were confirmed to have received EGFR tyrosine kinase inhibitors (TKIs), but the response to EGFR-TKIs differed among patients with different EGFR mutations.ConclusionChinese patients with lung cancer harbored unique and dispersive EGFR germline mutations and showed unique clinical and genetic characteristics, with varied response patterns to EGFR-TKI treatment.

ROS1 rearrangement, identified in ~2% of non-small cell lung cancer (NSCLC), has defined a distinctive molecular subtype. Patients with ROS1 fusion have been shown to be highly sensitive to treatment with crizotinib. However, the efficacy of crizotinib in NSCLC patients with double ROS1 fusions remains to be elucidated. Here, we report a 40-year-old male diagnosed with stage IIIA lung adenocarcinoma. Two ROS1 fusions [SDC4-ROS1 (EX2:EX32) and ROS1-GK (EX31:EX13)] were detected simultaneously in tumor tissue of this patient by next-generation sequencing. Crizotinib was administered, and the patient showed a partial response in lung lesions. Nevertheless, a brain lesion was found at 8 months after treatment. The slightly short duration of response may be related to the presence of ROS1-GK rearrangement. This case proved that patients with SDC4-ROS1 and ROS1-GK fusions may be sensitive to crizotinib, but short progression-free survival of this case showed that the presence of ROS1-GK rearrangement may affect the efficacy of crizotinib. A large-scale investigation on the efficacy of ROS1 inhibitors in patients with complex ROS1 fusions should be conducted in the future.

Objectives Anaplastic lymphoma kinase (ALK) fusion counts for 5% non-small cell lung cancer (NSCLC) and sensitive to ALK-TKIs. The most common fusion partner with ALK is echinoderm microtubule-associated protein-like4 (EML4), and a variety of other fusion partners have been found in recent years. In this study we report a intergenic fusion of ALK which involved exon 18 in a 52-year-old female lung adenocarcinoma. Materials and Methods CtDNA was used for genetic analysis by Next-generation sequencing (NGS). Immunohistochemistry (IHC) was performed on the tumor tissue to test ALK expression. Results NGS revealed a chr2 30297612-ALK fusion in ctDNA, which retained exon18-29 of ALK. And ALK protein was strongly expression in tumor by IHC. The patient received crizotinib (250mg, bid) and achieved long-term partial response. Conclusion Intergenic fusion of ALK which involved exon 18 can also benefit from crizotinib. NGS can detect and expose the detail of ALK fusion. This discovery extended the understanding of ALK fusion in NSCLC.

Objectives Previous studies have demonstrated EGFR L718Q as one of the resistant mechanisms to osimertinib. In vitro studies showed that EGFR L858R/L718Q mutant cancer cells were sensitive to second-generation EGFR-TKI. However, whether second-generation EGFR-TKI could offer equal therapeutic benefits clinically has not yet been reported. Materials and methods We performed capture-based sequencing on longitudinal plasma samples and pleural effusion samples obtained at various treatment milestones from an advanced lung adenocarcinoma patient undergoing targeted therapy. Results The EGFR-mutant patient underwent disease progression after 14 months of osimertinib administration. Targeted NGS sequencing identified a newly emerged EGFR L718Q mutation with remaining EGFR L858R and loss of T790M. Partial response was achieved one month after commencement of afatinib treatment; however, the patient experienced disease progression four months later with the emergence of a KRAS G12A mutation. Conclusions To the best of our knowledge, this is the first clinical evidence of afatinib’s efficacy targeting concomitant EGFR L858R and L718Q mutations after osimertinib resistance. We also demonstrate that EGFR L718Q might be a potential resistance mechanism.

Attentional control has an important role in attentional bias in social anxiety. This study aimed to investigate whether attentional bias in social anxiety was caused by attentional control deficit. Event-related potentials and behavioural attentional bias index (trial-level attentional bias variability) were recorded as participants completed the dot-probe task. The behaviour result showed that compared with the low socially anxious individuals, the high socially anxious individuals had a marginally higher score of attentional bias variability. For event-related potentials results, target-locked frontocentral N2 amplitude was significantly larger under the incongruent condition than the congruent condition in the low socially anxious group, whereas there was no significant difference between these two conditions in the high socially anxious group. The low socially anxious group also exhibited reduced target-locked P2 amplitude from the congruent condition to the incongruent condition. Our findings provide electrophysiological evidence of attentional control dysregulation in socially anxious individuals, which contributes to modifying social anxiety-related attentional bias.

Background There is currently no definite clinical implication for the subtypes of lung squamous cell carcinoma according to the 2015 WHO classification. This study aimed to investigate postoperative recurrence of the two major subtypes of lung squamous cell carcinoma: keratinizing squamous cell carcinoma (KSCC) and nonkeratinizing squamous cell carcinoma (NKSCC). Methods We identified the patients with KSCC and NKSCC who had undergone complete resection in Shanghai Chest Hospital between April 2015 and June 2016. Disease-free survival (DFS) was compared using Kaplan-Meier statistical analysis. Variables selected by univariate analysis were evaluated in multivariate analysis using the Cox proportional hazard model. Results A total of 334 patients included 231 (69.2%) cases with KSCC and 103 (30.8%) cases with NKSCC. There were more smokers in keratinizing than nonkeratinizing subtype (84.8% versus 72.8%, p = 0.009). The percentage of stage Ⅲ was higher in NKSCC than that in KSCC (35% versus 22.9%, p = 0.012). The 2-year DFS rates of stage Ⅰ, stage Ⅱ and stage Ⅲ were 90.1%, 66.4% and 37.7% in KSCC, 83.3%, 67.7% and 52.8% in NKSCC, respectively. There were no significant differences of 2-year DFS rates between KSCC and NKSCC. Furthermore, KSCC and NKSCC had no significant differences in recurrence patterns and metastatic sites. Conclusion There were no significant differences of postoperative recurrence between KSCC and NKSCC.

Background: During the COVID-19 pandemic, many patients admitted to hospital for treatment have recovered and been discharged; however, in some instances, these same patients are re-admitted due to a second fever or a positive COVID-19 PCR test result. To ascertain whether it is necessary to treat these patients in hospitals, especially in asymptomatic cases, we summarize and analyze the clinical and treatment characteristics of patients re-admitted to hospital with a second COVID-19 infection.Methods: Of the 141 COVID-19 cases admitted to the Wenzhou Central Hospital between January 17, 2020, to March 5, 2020, which were followed until March 30, 2020, 12 patients were re-admitted with a second COVID-19 infection. Data was collected and analyzed from their clinical records, lab indexes, commuted tomography (CT), and treatment strategies.Results: Most of the 141 patients had positive outcomes from treatment, with only 12 (8.5%) being re-admitted. In this sub-group: one (8.3%) had a fever, a high white blood cell count (WBC), and progressive CT changes; and one (8.3%) had increased transaminase. The PCR tests of these two patients returned negative results. Another 10 patients were admitted due to a positive PCR test result, seven of which were clinically asymptomatic. Compared to the CT imaging following their initial discharge, the CT imaging of all patients was significantly improved, and none required additional oxygen or mechanical ventilation during their second course of treatment.Conclusions: The prognoses of the re-admitted patients were good with no serious cases. We conclude that home treatment with concentrated medical observation is a safe and feasible course of treatment if the patient returns a positive PCR test result but does not display serious clinical symptoms. During medical observation, patients with underlying conditions should remain a primary focus, but most do not need to be re-admitted to the hospital.

Lung cancer is the leading cause of cancer-related deaths worldwide, and its occurrence is related to the accumulation of gene mutations and immune escape of the tumor. Sequencing of the T-cell receptor (TCR) repertoire can reveal the immunosurveillance status of the tumor microenvironment, which is related to tumor escape and immunotherapy. This study aimed to determine the characteristics and clinical significance of the TCR repertoire in lung cancer. To comprehensively profile the TCR repertoire, results from high-throughput sequencing of samples from 93 Chinese patients with lung cancer were analyzed. We found that the TCR clonality of tissues was related to smoking, with higher clonality in patients who had quit smoking for less than 1 year. As expected, TCR clonality was correlated with stages: patients with stage IV disease showed higher clonality than others. The correlation between TCR repertoire and epidermal growth factor receptor (EGFR) status was also investigated. Patients with EGFR non-L858R mutations showed higher clonality and a lower Shannon index than other groups, including patients with EGFR L858R mutation and wild-type EGFR. Furthermore, we analyzed the TCR similarity metrics—that is, the TCR shared between postoperative peripheral blood and tissue of patients with non-distant metastasis of lung cancer. A similar trend was found, in which patients with EGFR L858R mutations had lower overlap index (OLI) and Morisita index (MOI) scores. Moreover, the OLI showed a positive correlation with several clinical characteristics, including the tumor mutational burden of tissues and the maximum somatic allele frequency of blood; OLI showed a negative correlation with the ratio of CD4+CD28+ in CD4+ cells and the ratio of CD8+CD28+ in CD8+ cells. In conclusion, TCR clonality and TCR similarity metrics correlated with clinical characteristics of patients with lung cancer. Differences in TCR clonality, Shannon index, and OLI across EGFR subtypes provide information to improve understanding about varied responses to immunotherapy in patients with different EGFR mutations.

Tumor mutation burden (TMB) is an independent indicator used to select patients sensitive to immunotherapy. The present study aimed to investigate the clinicopathological and molecular characteristics of patients with hypermutant lung cancer to identify an economical, simple and complementary method for predicting TMB and immunotherapy responses. In total, 1,000 patients with lung cancer were randomly selected, and their samples were submitted to next-generation sequencing, with their TMB status reviewed. The threshold of hypermutation was set to 17.24 mutations (muts)/Mb. The proportion of smokers was higher in the hypermutant cohort (n=67) compared with in the non-hypermutant cohort (n=933; 85.1 vs. 46.6%; P

Background: GuiZhi-ShaoYao-ZhiMu decoction (GSZD), a traditional Chinese herbal medication, has been frequently used as an add-on medication to methotrexate (MTX) for rheumatoid arthritis (RA) treatment in China. This meta-analysis evaluated the efficacy and safety of adding GSZD to MTX for RA treatment. Methods: We performed a systematic search of PubMed, Web of Science, EMBASE, and the Cochrane Library (all databases) for English-language studies and WanFang, VIP, and CNKI for Chinese-language studies up to 28 July 2020. Data from selected studies, mainly the response rates and rate of adverse events (AEs), were extracted independently by two authors, and a random-effects model (Mantel–Haenszel method) was used for the meta-analysis. Results: A total of 14 randomized controlled trials and 1224 patients were included (623 patients in the GSZD + MTX group and 601 patients in the MTX group). For efficacy, the meta-analysis found that combining GSZD with MTX increased the effective rate [relative risk (RR) = 1.24, 95% confidence interval (CI): 1.18–1.30, based on 1069 patients], defined as >30% efficacy, American College of Rheumatology 20, or a decrease of disease activity score 28 >0.6. Adding GSZD reduced the swollen and tender joint counts, the duration of morning stiffness, the levels of C-reactive protein and rheumatoid factor, and erythrocyte sedimentation rate. The adjuvant therapeutic effect of GSZD was independent of the dose of MTX or the combined utilization of other drugs in both groups. For safety, adding GSZD was associated with a lower rate of total AEs (RR = 0.46, 95% CI: 0.26–0.83, based on 615 patients) and gastrointestinal tract AEs (RR = 0.46, 95% CI: 0.24–0.88, based on 537 patients). Conclusion: Combining GSZD with MTX may be a more efficacious and safer strategy for treating RA compared with MTX alone. Further large studies are warranted to investigate the long-term efficacy and safety of adding GSZD to MTX for RA treatment.

Breast cancer is one of the most commonly diagnosed malignancies. Although endocrine therapy improves the survival of patients with hormone receptor (HR)-positive breast cancer, the post-endocrine therapy strategy for metastatic breast cancer remains challenging. Herein, we report two patients who benefited from antiestrogen agents combined with an immunotherapy regimen to support the notion that an immunotherapy combination regimen may be a potential treatment for patients with HR-positive metastatic breast cancer post-endocrine therapy. Case 1 involved a patient with relapsed breast cancer with ovarian and brain metastases after endocrine therapy. After undergoing surgery for the ovarian lesions, she received three cycles of chemotherapy. Given that the lesions in the brain did not change, chemotherapy was discontinued. A high T cell receptor (TCR) repertoire (high Shannon index and clonality) was observed in the tumor. Considering the patient's preference and safety, and the efficacy of immunotherapy, she was administered with letrozole combined with pembrolizumab. The patient achieved a partial response, and the progression-free survival (PFS) was more than 21 months. Case 2 involved a patient with breast cancer with multiple bone metastases. After failure of combined radiotherapy and chemotherapy, the patient received tamoxifen combined with pembrolizumab based on the patient's preference and clinical biomarkers of a positive differentiation cluster of eight tumor-infiltrating lymphocytes and a high TCR repertoire (high Shannon index and clonality) in the tumor. The patient's bone pain and biomarkers were relieved after the treatment. The patients completed six cycles of pembrolizumab, and the PFS was more than 21 months. In conclusion, our study confirmed that antiestrogen agents combined with an immunotherapy regimen is a promising treatment for patients with HR-positive metastatic breast cancer.

Objective We aimed to analyse FGFR1 rare variants in a series of Chinese congenital hypogonadotropic hypogonadism (CHH) patients. In addition, we intended to understand the clinical characteristics and the response to treatment of CHH patients with FGFR1 rare variants. Patients and methods A total of 357 CHH patients were recruited at Peking Union Medical College Hospital. We used Sanger sequencing to analyse FGFR1 gene. In silico analysis was carried out to study the pathogenicity of novel missense variants. The clinical, endocrinological and therapeutic effects from patients carrying FGFR1 rare variants were analysed retrospectively. Results Thimissense mutations.rty patients in this series were found to harbour 29 FGFR1 rare variants, with 8 recurrent and 21 novel variants. After comprehensive analysis, 18 out of 21 novel variants were classified as likely pathogenic (LP) ones. These variants are widely spread throughout the FGFR1 gene and almost all FGFR1 functional domains, which exhibited no hot spot. Cryptorchidism, cleft palate and dental abnormality incidence in this CHH series that possessed FGFR1 LP variants were approximately 38.5%, 7.6% and 3.8%, respectively. Among patients who accepted the fertility-promoting treatment, 8 out of 10 patients succeeded in spermatogenesis. Conclusions Eighteen novel LP variants were found to expand the spectrum of FGFR1 rare variants. In CHH patients possessing FGFR1 variants, we found that the rate of spermatogenesis was high following fertility-promoting therapy and the existence of cryptorchidism may represent the underlying factors which affect spermatogenesis.

Immune checkpoint inhibitors have radically changed the landscape of antitumor therapies in several malignancies. Despite the long-term efficacy, severe immune-related adverse events (irAEs) were not uncommon. However, fatal simultaneous multiorgan failure was rare. Here, we described a patient who developed multiorgan failure, including fulminant myocarditis, myasthenia gravis crisis, hepatic dysfunction, and delayed pneumonitis after pembrolizumab therapy for lung large-cell neuroendocrine carcinoma. After failure of high-dose steroid treatment, implantation of cardiac pacemaker combined with high-dose steroids successfully controlled myocarditis caused by immune checkpoint inhibitors (ICIs). Delayed pneumonitis occurred unexpectedly, and it was treated successfully with steroids. With wild adoption of ICIs in clinical practice, investigations for predictive markers of irAEs are warranted, and more successful treatment strategies are worth sharing.

Treatment options for rare tumors are limited, and comprehensive genomic profiling may provide useful information for novel treatment strategies and improving outcomes. The aim of this study is to explore the treatment opportunities of patients with rare tumors using immune checkpoint inhibitors (ICIs) that have already been approved for routine treatment of common tumors. We collected immunotherapy-related indicators data from a total of 852 rare tumor patients from across China, including 136 programmed cell death ligand-1 (PD-L1) expression, 821 tumors mutational burden (TMB), 705 microsatellite instability (MSI) and 355 human leukocyte antigen class I (HLA-I) heterozygosity reports. We calculated the positive rates of these indicators and analyzed the consistency relationship between TMB and PD-L1, TMB and MSI, and HLA-I and PD-L1. The prevalence of PD-L1 positive, TMB-H, MSI-, and HLA-I -heterozygous was 47.8%, 15.5%, 7.4%, and 78.9%, respectively. The consistency ratio of TMB and PD-L1, TMB and MSI, and HLA-I and PD-L1 was 54.8% (78/135), 87.3% (598/685), and 47.4% (54/114), respectively. The prevalence of the four indicators varied widely across tumors systems and subtypes. The probability that neuroendocrine tumors (NETs) and biliary tumors may benefit from immunotherapy is high, since the proportion of TMB-H is as high as 50% and 25.4% respectively. The rates of PD-L1 positivity, TMB-H and MSI-H in carcinoma of unknown primary (CUP) were relatively high, while the rates of TMB-H and MSI-H in soft tissue tumors were both relatively low. Our study revealed the distribution of immunotherapeutic indicators in patients with rare tumors in China. Comprehensive genomic profiling may offer novel therapeutic modalities for patients with rare tumors to solve the dilemma of limited treatment options.

Mixed serous-endometrioid endometrial carcinoma is a type of endometrial cancer with relatively low incidence. The genetic factors contributing to the tumorigenesis of mixed carcinoma remains to be explored. Here, we report the first identification of two germline mutations in BRCA1 and MSH2 in a woman with mixed serous papillary adenocarcinoma and endometrioid carcinoma. Immunohistochemistry analysis showed loss of MSH2 and MSH6 protein expression in the endometrioid component. The patient showed partial response to tislelizumab treatment following progression on chemotherapy. Two germline mutations in BRCA1 and MSH2 may collectively promote the tumorigenesis of uterine endometrium with two distinct histological components.

Background: Lupus nephritis (LN) remains a predominant cause of morbidity and mortality in SLE. Here we performed a meta-analysis to evaluate the efficacy and safety of the induction treatment with mycophenolate mofetil (MMF) and cyclophosphamide (CYC) for LN. Methods: Relevant literature was searched by computer from the establishment of the database to November 2019. A meta-analysis was conducted to analysis the efficacy and safety between mycophenolate mofetil and cyclophosphamide as induction therapy in LN patients. The primary end-point was response to urine protein, serum creatinine (Scr) and serum complement C3, and the secondary end-points were complete remission and adverse reactions. Results: Eighteen articles were selected for the final meta-analysis, involving 1989 patients with LN, of which the renal biopsy result could be classified into class III–V according to the standards of WHO/ISN. The results revealed that MMF was superior to CYC in increasing the level of serum complement C3 [SMD = 0.475, 95%CI (0.230–0.719)] and complete remission [RR = 1.231, 95%CI (1.055–1.437)]. Furthermore, the subgroup analysis showed that it was in Asian patients, rather than in Caucasian patients, that CYC exerted a better effect on lowering the level of urine protein (UPRO) than MMF [SMD = 0.405, 95%CI (0.081–0.730)]. Besides, when the initial UPRO level was less than 4 g/day, the effect of CYC was better than MMF [SMD = 0.303, 95%CI (0.014–0.591)]. There was no significant difference between MMF and CYC in improving Scr [SMD = 0.090, 95%CI (−0.060–0.239)]. When it came to the comparison of safety between MMF and CYC, the meta-analysis showed that MMF was superior to CYC in decreasing infection in Caucasian patients [RR = 0.727, 95%CI (0.532–0.993)], reducing the risk of leukopenia and menstrual abnormalities in Asian patients and lowering the frequency of gastrointestinal symptoms [RR = 0.639, 95%CI (0.564–0.724)], independent of race. Conclusions: MMF precedes CYC in improving serum complement C3 and complete remission regardless of race, as well as shows fewer adverse drug reactions in the induction treatment of LN belonging to type III–V. But for Asian patients or those initial UPRO levels are less than 4 g/day, CYC may be superior to MMF.

Yi-fen Shi,1,* Na Wang,2,* Zi-yang Huang,1 Rong-rong Chen,1 Yi-sha Huang,1 Yi-yi Zhu,1 Chong-yun Xing,1 Bin Liang,1 Kang Yu,1 Jian-hua Feng1,3 1Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, People’s Republic of China; 2Health Care Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, People’s Republic of China; 3Department of Pediatric Hematology-Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jian-hua Feng; Kang Yu Department of HematologyThe First Affiliated Hospital of Wenzhou Medical University, Ouhai District, Wenzhou, Zhejiang 325000, People’s Republic of ChinaTel +86 577 55578999 extension 669889Fax +86 577 55578999Email wzfjh@126.com; yukang@wzhospital.cnBackground: Peripheral monocytes, a key cell type for innate immunity, have been shown to be associated with survival in various types of hematological malignancies. However, no previous studies regarding the prognostic impact of peripheral absolute monocyte count (AMC) in early relapsed B-lineage acute lymphoblastic leukemia (B-ALL) have been reported.Methods: Forty-nine cases of early relapsed adult B-ALL were reviewed. The upper (0.80 × 109/L) and lower limits (0.12 × 109/L) of the normal value for AMC were used as cut-off points. Kaplan–Meier curves and Log rank test were used for comparison of overall survival (OS). The univariate and multivariate Cox proportional hazards models were used for investigating the factors associated with OS.Results: More than half (59.2%) of all patients showed a normal AMC (0.12– 0.80 × 109/L). The median follow-up was 5.3 months from the start of first salvage therapy. Univariate analysis revealed that normal AMC (versus low/high AMC) at the time of relapse was a prognostic factor for improved OS (P = 0.021). On multivariate analysis, normal AMC (versus low/high AMC) at the time of relapse remained an independent prognostic factor for improved OS (hazard ratio = 0.43, P = 0.030).Conclusion: AMC at the time of relapse, which can be easily derived from routine clinical laboratory testing of complete blood count, might be used as a prognostic marker for survival outcomes in adult patients with early relapsed B-ALL.Keywords: B-lineage acute lymphoblastic leukemia, early relapse, absolute monocyte count, prognosis, survival

Background β3‐αC loop is a highly conserved structural domain across oncogene families, which is a switch for kinase activity. There have been numerous researches on mutations within β3‐αC loop in EGFR, but relatively less in ERBB2, BRAF, and MAP2K1. In addition, previous studies mainly focus on β3‐αC deletion in EGFR, which is the most common type affecting kinase activity and driving lung cancer. Other mutation types are not well studied. Methods Here we analyzed the profile of β3‐αC loop mutations in a total of 10,000 tumor biopsy and/or ctDNA patient samples using hybridization capture‐based next‐generation sequencing. Results We identified 1616 mutations within β3‐αC loop in this cohort. Most mutations were located in EGFR, with less percentage in ERBB2, BRAF, and MAP2K1. EGFR β3‐αC deletions occurred at a high percentage of 96.7% and were all drug‐relevant. We also detected rare EGFR β3‐αC insertions and point mutations, most of which were related to EGFR TKIs resistance. ERBB2 β3‐αC deletions were only found in breast cancers and sensitive to EGFR/ERBB2 inhibitor. Moreover, BRAF and MAP2K1 mutations within β3‐αC loop also demonstrated drugs relevance. Conclusion Our study showed that oncogenic mutations within the β3‐αC loop of ERBB2, MAP2K1, and BRAF are analogous to that of EGFR, which have profound effect on drug response. Understanding the mutation profile within the β3‐αC loop is critical for targeted therapies., Oncogenic alterations within the kinase domain β3‐αC loop, which is highly conserved across oncogene families, are very common in human cancers. Therefore, understanding the spectrum of β3‐αC loop mutations within these genes is critical for target therapies. Motivated by this, we analyzed tumor biopsy and/or ctDNA samples of a large cohort of patients (10,000) using hybridization capture‐based next‐generation sequencing and summarized different alterations in this region and the possible response to target therapy. Our findings provided a comprehensive instruction for target therapies for cancer patients.

Background Recently, multiple poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated excellent efficacy among patients with ovarian cancer with or without BRCA mutations. However, alternative therapeutic options are urgently required for patients who cannot benefit from conventional chemotherapy or PARP inhibitors. Case Presentation A patient with high-grade serous ovarian carcinoma presented to our clinic after developing resistance to chemotherapy. Paired tumor-normal next-generation sequencing (NGS) was performed using peripheral blood to identify potential actionable mutations. NGS revealed the patient harboring a GOPC-ROS1 fusion, which was subsequently verified using a reverse transcription polymerase chain reaction assay. No germline or somatic mutation in BRCA1/2 or mismatch repair genes was detected. Therefore, the patient received crizotinib treatment. A rapid, favorable clinical response (partial response at 1 month) was observed, with further pathological response monitored and evaluated in follow-up interrogation. Conclusion This study suggested that crizotinib was an off-the-shelf, practical, and ostensibly effective treatment option for patients with ovarian cancer with ROS1 rearrangement. NGS-based genetic testing may guide to plan therapeutic paradigms, and render precision medicine promising in ovarian cancer treatment. Implications for Practice Despite the previous report of ROS1 fusion in patients with ovarian cancer, it remains unknown whether patients can benefit from targeted therapeutic drugs. This study reports a GOPC-ROS1 fusion identified by next-generation sequencing in a patient with chemotherapy-resistant ovarian cancer. The patient was administered crizotinib and showed rapid, remarkable response. This study suggests that comprehensive sequencing should be offered for patients with ovarian cancer without effective therapeutic strategies, and crizotinib can be used to treat ROS1-rearranged ovarian carcinomas.