Immune responses and reinfection of SARS-CoV-2 Omicron variant in patients with lung cancer.

A significant Omicron wave emerged in China in December 2022. To explore the duration of humoral and cellular response postinfection and the efficacy of hybrid immunity in preventing Omicron reinfection in patients with lung cancer, a total of 447 patients were included in the longitudinal study after the Omicron wave from March 2023 to August 2023. Humoral responses were measured at pre-Omicron wave, 3 months and 7 months postinfection. The detected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) specific antibodies including total antibodies, anti-receptor binding domain (RBD) specific IgG, and neutralizing antibodies against SARS-CoV-2 wild type (WT) and BA.4/5 variant. T cell responses against SARS-CoV-2 WT and Omicron variant were evaluated in 101 patients by ELISpot at 3 months postinfection. The results showed that Omicron-infected symptoms were mild, while fatigue (30.2%), shortness of breath (34.0%) and persistent cough (23.6%) were long-lasting, and vaccines showed efficacy against fever in lung cancer patients. Humoral responses were higher in full or booster vaccinated patients than those unvaccinated (p < .05 for all four antibodies), and the enhanced response persisted for at least 7 months. T cell response to Omicron was higher than WT peptides (21.3 vs. 16.0 SFUs/106 PBMCs, p = .0093). Moreover, 38 (9.74%) patients were reinfected, which had lower antibody responses than non-reinfected patients (all p < .05), and those patients of unvaccinated at late stage receiving anti-cancer immunotherapy alone were at high risk of reinfection. Collectively, these data demonstrate the Omicron infection induces a high and durable immune response in vaccinated patients with lung cancer, which protects vaccinated patients from reinfection.

Bronchoalveolar lavage fluid analysis in patients with checkpoint inhibitor pneumonitis.

BACKGROUND: Checkpoint inhibitor pneumonitis (CIP) is a relatively uncommon but potentially life-threatening immune-related adverse event (irAE). Lung biopsies have not been commonly performed for CIP patients. Bronchoalveolar lavage fluid (BALF) analysis is a useful diagnostic approach for interstitial lung disease. However, BALF features were inconsistent across different studies. METHODS: We retrospectively reviewed the medical records of 154 patients with pathologically confirmed malignancies and suffering from CIPs between July 2018 and December 2022. Patients who had bronchoalveolar lavage (BAL) data available were enrolled in our study. Patient clinical, laboratory, radiological and follow-up data were reviewed and analyzed. RESULTS: The BALF differential cell count and lymphocyte subset analysis were performed for 42 CIP patients. There were 32 males (76.2%). The mean age at diagnosis of CIP was 62.0 ± 10.4 (range: 31-78) years. The median time to onset of CIP was 98.5 days after the start of immunotherapy. There were 18 patients (42.9%) with low-grade CIPs and 24 patients (57.1%) with high-grade CIPs. The mean lymphocyte percentage was 36.7 ± 22.5%. There were 34 (81%) CIP patients with a lymphocytic cellular pattern. The median ratio of CD3+CD4+/CD3+CD8+ lymphocytes was 0.5 (0.3, 1.0). The ratio was less than 1.0 for 31 CIP patients (73.8%). However, there was no significant difference in the BALF features between patients with low-grade CIPs and those with high-grade CIPs. CONCLUSIONS: The CD3+CD8+ lymphocytosis pattern was the main inflammatory profile in the BALF of CIP patients in this cohort. Targeting CD3+CD8+ lymphocytes might be a treatment option for CIPs.

Current clinical practice and physicians' insights on Chinese patients with advanced non-small cell lung cancer habouring epidermal growth factor receptor 20 insertion mutation.

BACKGROUND: The present study aimed to investigate physicians' perspectives on the diagnosis and treatment decisions for patients with non-small cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) exon 20 insertion (exon20ins) mutations in a real-world setting in China using an online questionnaire. METHODS: This study was performed via the CAPTRA-Lung collaboration between December 9, 2022 and March 6, 2023. The questionnaire was distributed digitally to physicians around China and was comprised of three sections: basic characteristics of surveyed physicians, diagnosis and treatment status of NSCLC patients with the EGFR exon20ins-mutation, and physicians' perspectives on treatment options. Physicians who treat more than 10 patients with advanced NSCLC every month and who have treated patients with advanced EGFR exon20ins-mutant NSCLC in the past six months were involved in this study. RESULTS: A total of 53,729 questionnaires were distributed and 390 valid ones were collected. The EGFR mutation test was performed in 80.9% and 59.9% of patients receiving first-line or second-line therapy and beyond (hereinafter "second-line")therapy, respectively. In terms of treatment options, chemotherapy plus antiangiogenic therapy was the most common treatment option (30.0% of patients in first-line settings; 25.0% of patients in second-line settings), and a certain proportion of patients received novel EGFR exon20ins-targeted agents (including tyrosine kinase inhibitors [TKIs] and bispecific antibodies) in first- or second-line settings, which accounted for 11.9% and 15.7% of all treated patients, respectively. Additionally, physicians reported the highest satisfaction score for the efficacy and safety of targeted agents. Most physicians believed that EGFR exon20ins-targeted TKIs represented the most promising treatment option (80.2% in first-line treatment and 73.3% in second-line treatment). Among several novel agents under study, sunvozertinib has received the highest recognition for efficacy and safety. CONCLUSIONS: This study investigated the current diagnosis and treatment status and physicians' perspective, of patients with EGFR exon20ins-mutant NSCLC. The results highlight significant unmet clinical needs in this subgroup of patients. EGFR exon20ins-targeted TKIs were recognized as the most promising treatment regimen and may benefit more patients considering their awareness and acceptance of targeted therapy.

Efficacy and safety of iruplinalkib (WX-0593) in ALK-positive crizotinib-resistant advanced non-small cell lung cancer patients: a single-arm, multicenter phase II study (INTELLECT).

BACKGROUND: Iruplinalkib (WX-0593) is an anaplastic lymphoma kinase (ALK)/c-ros oncogene 1 (ROS1) tyrosine kinase inhibitor. Here we reported the single-arm, phase II study (INTELLECT) results of the efficacy and safety of iruplinalkib for ALK-positive crizotinib-resistant advanced non-small cell lung cancer (NSCLC) patients. METHODS: ALK-positive crizotinib-resistant advanced NSCLC patients aged ≥18 years, with Eastern Cooperative Oncology Group performance status of 0-2 were eligible. Patients received iruplinalkib 180 mg orally once daily for a 21-day cycle with a 7-day lead-in phase at 60 mg orally once daily. The primary endpoint was the independent review committee (IRC)-assessed objective response rate (ORR). RESULTS: From August 7, 2019, to October 30, 2020, 146 patients were included. As of the data cut-off date on November 30, 2021, the median follow-up time was 18.2 months (95% confidence interval [CI] 16.8-18.8). IRC-assessed ORR and disease control rate (DCR) were 69.9% (95% CI 61.7-77.2%) and 96.6% (95% CI 92.2-98.9%), respectively. Investigator-assessed ORR and DCR were 63.0% (95% CI 54.6-70.8%) and 94.5% (95% CI 89.5-97.6%), respectively. Investigator-assessed median duration of response and progression-free survival (the same as median time to progression) were 13.2 months (95% CI 10.4-17.7) and 14.5 months (95% CI 11.7-20.0), respectively. Corresponding IRC-assessed results were 14.4 months (95% CI 13.1-not evaluable [NE]), 19.8 months (95% CI 14.5-NE), and NE (95% CI 14.5-NE), respectively. Investigator-assessed intracranial ORRs were 46% (41/90, 95% CI 35-56%) in patients with central nervous system metastases and 64% (27/42, 95% CI 48-78%) in patients with measurable intracranial lesions. Overall survival data were immature. Treatment-related adverse events (TRAEs) occurred in 136/146 (93.2%) patients. The most common TRAEs were aspartate aminotransferase increased (63 [43.2%]), alanine aminotransferase increased (54 [37.0%]), and blood creatine phosphokinase increased (51 [34.9%]). Dose interruption, reduction, and discontinuation due to TRAEs occurred in 21 (14.4%), 16 (11.0%), and four (2.7%) patients, respectively. CONCLUSIONS: In this study, iruplinalkib (WX-0593) demonstrated favorable efficacy and manageable safety profiles in patients with ALK-positive crizotinib-resistant advanced NSCLC. Iruplinalkib could be a new treatment option for this patient population. TRIAL REGISTRATION: Center for Drug Evaluation of National Medical Products Administration of China: CTR20190789, registered on April 28, 2019; ClinicalTrials.gov: NCT04641754, registered on November 24, 2020.

Risk factors associated with COVID-19 pneumonia in Chinese patients with pre-existing interstitial lung disease during the SARS-CoV-2 pandemic.

In China, the emergence of a nationally widespread epidemic infection of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) has appeared within a month since December 7, 2022. To evaluate the risk factors for suffering from coronavirus disease 2019 (COVID-19) pneumonia due to infection with SARS-CoV-2 in different kinds of interstitial lung disease (ILD) patients with diverse immunizations, we conducted this retrospective study on 525 patients with ILDs who underwent regular follow-up in our ILD clinic. Among them, 128 ILD patients (24.4%) suffered from COVID-19 pneumonia after SARS-CoV-2 infection. Patients were older with a male predominance in the pneumonia group than in the nonpneumonia group (65.0 ± 10.0 years vs. 56.4 ± 11.7 years, p < 0.001, 55.5% vs. 39.5%, p = 0.002, respectively). Connective tissue disease-associated ILD (CTD-ILD) (25%), idiopathic pulmonary fibrosis (23.4%), and interstitial pneumonia with autoimmune features (21.1%) were the main pre-existing ILDs in the pneumonia group. In Cox multivariable analysis, only male sex and corticosteroid use were risk factors for COVID-19 pneumonia after infection. Two or three doses of vaccination were a protective factor for pre-existing ILD patients suffering from COVID-19 pneumonia. More than two doses of vaccination were strongly recommended for pre-existing ILD patients, particularly for males who were administered corticosteroids.

The Presence of Lung Cancer Affects SARS-CoV-2 Vaccine Uptake and Attitude in Chinese Patients: A Clinical Cross-Sectional Investigation.

With the SARS-CoV-2 mutations evolving and prompt of SARS-CoV-2 vaccines, no information is available on SARS-CoV-2 vaccination status in Chinese patients with lung cancer. An electronic questionnaire including sociodemographic characteristics, vaccine status, side effect post-vaccination, and attitude towards a fourth dose of vaccine was conducted within 1018 Chinese patients with lung cancer from October 18th, 2022, to November 25th, 2022. Among 1018 patients, a total of 75 (13.7%) patients reported acceptable systemic adverse events in those had received the SARS-CoV-2 vaccine (549, 54%), the most common of which was fever (39, 7%). Factors including females (OR, 1.512; 95% CI, 1.076-2.124), residents in the municipality (OR, 2.048; 95% CI, 1.238-3.389), undergoing therapy (OR, 2.897; 95% CI, 1.348-6.226), disagree to vaccines is safe for patients with lung cancer (OR, 3.816; 95% CI, 2.198-6.626) contributed to hesitancy. Among 373 patients had received three doses, half respondents (206, 55.2%) were hesitant to receive a fourth dose due to the safety concern and efficacy towards the variants. In conclusion, low vaccine uptake rates in patients with lung cancer could be improved by increasing confidence in vaccine safety, particularly for those with negative beliefs. Appropriate guidance and individualized vaccination plans that meet the healthcare needs of patients with lung cancer were needed during the constantly evolving pandemic.

A pre-treatment CT-based weighted radiomic approach combined with clinical characteristics to predict durable clinical benefits of immunotherapy in advanced lung cancer.

OBJECTIVES: To develop a pre-treatment CT-based predictive model to anticipate inoperable lung cancer patients' progression-free survival (PFS) to immunotherapy. METHODS: This single-center retrospective study developed and cross-validated a radiomic model in 185 patients and tested it in 48 patients. The binary endpoint is the durable clinical benefit (DCB, PFS ≥ 6 months) and non-DCB (NDCB, PFS < 6 months). Radiomic features were extracted from multiple intrapulmonary lesions and weighted by an attention-based multiple-instance learning model. Aggregated features were then selected through L2-regularized ridge regression. Five machine-learning classifiers were conducted to build predictive models using radiomic and clinical features alone and then together. Lastly, the predictive value of the model with the best performance was validated by Kaplan-Meier survival analysis. RESULTS: The predictive models based on the weighted radiomic approach showed superior performance across all classifiers (AUCs: 0.75-0.82) compared with the largest lesion approach (AUCs: 0.70-0.78) and the average sum approach (AUCs: 0.64-0.80). Among them, the logistic regression model yielded the most balanced performance (AUC = 0.87 [95%CI 0.84-0.89], 0.75 [0.68-0.82], 0.80 [0.68-0.92] in the training, validation, and test cohort respectively). The addition of five clinical characteristics significantly enhanced the performance of radiomic-only model (train: AUC 0.91 [0.89-0.93], p = .042; validation: AUC 0.86 [0.80-0.91], p = .011; test: AUC 0.86 [0.76-0.96], p = .026). Kaplan-Meier analysis of the radiomic-based predictive models showed a clear stratification between classifier-predicted DCB versus NDCB for PFS (HR = 2.40-2.95, p < 0.05). CONCLUSIONS: The adoption of weighted radiomic features from multiple intrapulmonary lesions has the potential to predict long-term PFS benefits for patients who are candidates for PD-1/PD-L1 immunotherapies. KEY POINTS: • Weighted radiomic-based model derived from multiple intrapulmonary lesions on pre-treatment CT images has the potential to predict durable clinical benefits of immunotherapy in lung cancer. • Early line immunotherapy is associated with longer progression-free survival in advanced lung cancer.

Influence of polyvinyl chloride microplastic on chromium uptake and toxicity in sweet potato.

The extensive use of plastic products and rapid industrialization have created a universal concern about microplastics (MPs). MPs can pose serious environmental risks when combined with heavy metals. However, current research on the combined effects of MPs and hexavalent chromium [Cr(VI)] on plants is insufficient. Herein, a 14-day hydroponic experiment was conducted to investigate the impact of PVC MPs (100 and 200 mg/L) and Cr(VI) (5, 10, and 20 µM) alone and in combination on sweet potato. Results showed that combined Cr(VI) and PVC MPs affected plant growth parameters significantly, but PVC MPs alone did not. The combined application of PVC MPs and Cr(VI) resulted in a decrease in plant height (24-65%), fresh biomass per plant (36-71%), and chlorophyll content (16-34%). Cr(VI) bioaccumulation increased with the increase in its doses, with the highest concentration of Cr(VI) in the leaves (16.45 mg/kg), stems (13.81 mg/kg), and roots (236.65 mg/kg). Cr(VI) and PVC MPs-induced inhibition varied with Cr(VI) and PVC MPs doses. Osmolytes and antioxidants, lipid peroxidation, and H2O2 contents were significantly increased, while antioxidant enzymes except CAT were decreased with increasing Cr(VI) concentration alone and mixed treatments. The presence of PVC MPs promoted Cr(VI) accumulation in sweet potato plants, which clearly showed severe toxic effects on their physio-biochemical characteristics, as indicated by a negative correlation between Cr(VI) concentration and these parameters. PVC MPs alone did not significantly inhibit these parameters. The findings of this study provide valuable implications for the proper management of PVC MPs and Cr(VI) in sweet potato plants.

Phase Ia/Ib Study of the Selective MET Inhibitor, Savolitinib, in Patients with Advanced Solid Tumors: Safety, Efficacy, and Biomarkers.

BACKGROUND: Savolitinib has shown good tolerability and preliminary efficacy, but efficacy biomarkers require investigation. The main purpose of this study was to confirm in Chinese patients the recommended phase II dose (RP2D) of savolitinib and to explore overall benefit in tumors bearing c-Met aberration. METHODS: This was an open-label, multi-center, 2-part phase I study. A starting dose of 600 mg QD was initiated in the escalation phase, utilizing a 3+3 design with repeated QD and BID dosing. In the dose expansion phase, we enrolled patients with gastric cancer and non-small cell lung cancer (NSCLC) with documented c-met aberration into 5 cohorts to further explore biomarkers. c-Met overexpression and amplification were assessed by immunohistochemistry and FISH, respectively. RESULTS: The safety analysis set included 85 patients. Only one dose-limiting toxicity (grade 3 fatigue) was reported in the 600 mg BID dosing group. The most frequent treatment-related adverse events were nausea (29.4%), vomiting (27.1%), and peripheral edema (21.2%). Notably, in gastric cancer, response was only observed in patients with MET amplification (copy number 9.7-18.4), with an objective response rate of 35.7% and a disease control rate of 64.3%. For patients with NSCLC bearing a MET exon 14 skipping mutation, obvious target lesion shrinkage was observed in 2 of 4 patients, although PR was not achieved. CONCLUSION: The RP2D of savolitinib was established as 600 mg QD or 500 mg BID in Chinese patients. The promising response observed in patients with gastric cancer with c-met amplification and NSCLC with MET exon 14 skipping mutation warrants further investigation. CLINICALTRIALS.GOV IDENTIFIER: NCT0198555.

The association between ROS1 rearrangement and risk of thromboembolic events in patients with advanced non-small cell lung cancer: a multicenter study in China.

BACKGROUND: According to several studies, ROS1 rearrangement is associated with thrombotic risk in non-small cell lung cancer (NSCLC). However, there is no clear understanding of the predictors and prognostic impact of thromboembolic events (TEEs) in patients with advanced ROS1 rearrangement NSCLC. METHODS: A total of 47 newly diagnosed advanced NSCLC patients with ROS1 rearrangement from four Chinese hospitals were retrospectively included and were evaluated for TEEs incidence, characteristics, predictors, as well as response to therapies and overall survival (OS). RESULTS: Of the 47 enrolled patients, 23.4% (n = 11) patients developed TEEs. Among them, 7 of 11 patients (64%) developed pulmonary embolism (PE), and 5 patients (45%) experienced recurrent TEEs. In multivariate analysis, D-dimer was associated with the occurrence of TEEs in ROS1 rearranged NSCLC (HR 1.16, 95% CI 1.08-1.23, P < 0.001). Median progression-free survival (PFS) after first-line ROS1 tyrosine kinase inhibitors (TKIs) therapy was significantly longer in patients without TEEs than in those developing TEEs (26 months vs. 12 months, P = 0.0383). Furthermore, patients with TEEs had a shorter OS period than those without TEEs (29.8 months vs. not estimable, P = 0.0647). CONCLUSION: The results of this multicenter study indicated that advanced NSCLC patients with ROS1 rearrangement were more likely to experience PE and TEEs recurrence. And patients with TEEs tended to have a worse prognosis. Furthermore, an elevated D-dimer level suggested a hypercoagulable state in NSCLC patients with ROS1 rearrangement.

Chromium Induces Toxicity at Different Phenotypic, Physiological, Biochemical, and Ultrastructural Levels in Sweet Potato (Ipomoea batatas L.) Plants.

Crop productivity is enormously exposed to different environmental stresses, among which chromium (Cr) stress raises considerable concerns and causes a serious threat to plant growth. This study explored the toxic effect of Cr on sweet potato plants. Plants were hydroponically grown, and treatments of 0, 25, 50, 100, and 200 µM Cr were applied for seven days. This study exhibited that a low level of Cr treatment (25 µM) enhanced the growth, biomass, photosynthesis, osmolytes, antioxidants, and enzyme activities. However, significant deleterious effects in growth, biomass, photosynthetic attributes, antioxidants, and enzymes were observed at higher levels of Cr treatment. The remarkable reduction in plant growth traits was associated with the over-accumulation of H2O2 and MDA contents (410% and 577%, respectively) under the highest rate of Cr (200 µM). Under 200 µM Cr, the uptake in the roots were 27.4 mg kg-1 DW, while in shoots were 11 mg kg-1 DW with the highest translocation rate from root to shoot was 0.40. The results showed that the higher accumulation of Cr negatively correlated with the phenotypic and physiological parameters. It may be proposed that Cr toxicity causes oxidative damage as sustained by augmented lipid peroxidation, reactive oxygen species, and reduced photosynthetic rate, chlorophyll, and stomatal traits. The chloroplastic ultrastructure was damaged, and more apparent damage and size reduction were observed at higher Cr levels. Furthermore, aggregated Cr concentration positively correlates with the increase of osmolytes and superoxide dismutase (SOD) activity in the leaves of sweet potato. Moreover, improved osmolytes and SOD do not help protect sweet potato against high Cr stress. Overall, these findings will improve the understanding of the defense mechanisms of sweet potato to Cr stress.

Risk and prognosis factors for systemic sclerosis with lung cancer: A single-centre case-control study in China.

OBJECTIVE: To analyse clinical characteristics, risk and prognosis factors for systemic sclerosis (SSc) patients with lung cancer. METHODS: SSc patients with lung cancer admitted to Peking Union Medical College Hospital from February 1992 to December 2018 were included. Age and sex-matched controls were selected from a pool of SSc patients without lung cancer during the same period. Conditional logistic regression and Cox proportional-hazard regression were used to identify risk factors and prognosis factors. The Kaplan-Meier method was used to draw the survival curve and calculate median survival. RESULTS: Nineteen SSc patients with lung cancer and 76 controls were included. The mean age at lung cancer diagnosis was 54.4 ± 10.2 years. In all 19 cases the lung cancer had been diagnosed after SSc and the median interval between SSc onset and lung cancer onset was 10.5 years (range 2.0-36.2 years). Among SSc patients with lung cancer, the median follow-up time and median survival were 2.6 years and 1.4 years, respectively. In the sex and age-matched conditional logistic multivariable regression analysis, family history of malignancy (OR 4.930, 95%CI 1.926-12.619, P = .001), ILD (OR 7.701, 95%CI 1.009-58.767, P = .049) were independent risk factors for lung cancer among SSc patients, and considering sex and age of SSc onset, SSc patients with more advanced staging of lung cancer (HR 3.190, 95%CI 1.127-6.126, P = .06) had poorer prognosis. CONCLUSION: Lung cancer is not uncommon in SSc patients, especially those with family histories of malignancy or ILD. Early detection of lung cancer is of vital importance for better prognosis.

Lighting Direction Affects Leaf Morphology, Stomatal Characteristics, and Physiology of Head Lettuce (Lactuca sativa L.).

Plants are exposed to numerous biotic and abiotic stresses, and light is one of the most important factors that influences the plant morphology. This study was carried out to examine how the lighting direction affected the plant morphology by investigating the growth parameters, epidermal cell elongation, stomatal properties, and physiological changes. Seedlings of two head lettuce (Lactuca sativa L.) cultivars, Caesar Green and Polla, were subjected to a 12 h photoperiod with a 300 µmol·m-2·s-1 photosynthetic photon flux density (PPFD) provided by light emitting diodes (LEDs) from three directions: the top, side, and bottom, relative to the plants. Compared with the top and side lighting, the bottom lighting increased the leaf angle and canopy by stimulating the epidermal cell elongation in leaf midrib, reduced the leaf number and root biomass, and induced large stomata with a low density, which is associated with reduced stomatal conductance and carbohydrate contents. However, the proline content and quantum yield exhibited no significant differences with the different lighting directions in both cultivars, which implies that the plants were under normal physiological conditions. In a conclusion, the lighting direction had a profound effect on the morphological characteristics of lettuce, where the plants adapted to the changing lighting environments.

BAG3-Related Myofibrillar Myopathy Presenting as Hypercapnia: A Case Report and Literature Review.

Objective BAG3-related myopathy is a rare condition so far reported in twenty patients worldwide. The purpose of this study was to draw attention to this rare disease and to the fact that BAG3-related myopathy should be considered as a rare differential diagnosis of hypercapnia. Methods We report a sporadic case of a 14-year-old Chinese girl with a de novo p.Pro209Leu mutation in BAG3 and reviewed the literatures for reported cases related to this mutation. Results We described a 14-year-old Chinese girl who presented with gradually appearing symptoms of hypercapnia that required assisted ventilation. The muscle biopsy and the blood whole-exome sequencing results confirmed the diagnosis of myofibrillar myopathy with a de novo p.Pro209Leu mutation in BAG3. Totally twenty-one patients from twenty families with a confirmed diagnosis of BAG3-related myopathy were reported to date, including this patient and literature review. The male to female ratio was 11:10 and most showed initial symptoms in the first decade of life. Most patients presented toe/clumsy walking or running as the onset symptom, followed by muscle weakness or atrophy. Creatine kinase levels were elevated in fourteen patients and were normal in three. Eighteen patients developed respiratory insufficiency during the disease course and thirteen (one could not tolerate non-invasive assisted ventilation) required non-invasive assisted ventilation for treatment. Except for one not reported, heart involvement was found in seventeen patients during the disease course and seven underwent heart transplantation. Z-disk streaming and aggregation could be observed in most of the patients' muscle histology. In the long-term follow-up, five patients died of cardiac or respiratory failure. Conclusion BAG3-associated myopathy is a rare type of myofibrillar myopathy. It should be considered as a rare differential diagnosis of hypercapnia.

Rational design of a far-red fluorescent probe for endogenous biothiol imbalance induced by hydrogen peroxide in living cells and mice.

Intracellular biothiols are correlated with many diseases such as nerve disorder and Parkinson's disease likely due to a redox imbalance. In this work, we designed an ultrafast fluorescent probe (Cou-DNBS) for biothiols with a large Stokes shift (131 nm). The probe was constructed through linking the 2,4-dinitrobenzenesulfonyl moiety as the specially recognizing biothiols site to an iminocoumarin fluorophore Cou-NH obtained by fusing an additional benzene ring. The presence of biothiols could ultrafast perform a significant fluorescence emission at 617 nm upon the excitation of 480 with the low limits of detection (2.5 nM for Cys, 1.7 nM for Hcy and 0.84 nM for GSH). HRMS spectra as well as theoretical calculations further evidenced the rationale of recognition mechanism. Furthermore, the probe can successfully visualize endogenous biothiol recovery in living cells damaged by H2O2.

Circulating tumor cells in patients with lung cancer: developments and applications for precision medicine.

Lung cancer is the most common cause of cancer-related deaths, with most patients dying with distant metastases. Circulating tumor cells (CTCs) are cancer cells that have disseminated into the peripheral blood from primary or metastatic sites and present great potentials as prognostic biomarkers for guiding individualized treatment in lung cancer. To date, various methods have been developed to capture CTCs in peripheral blood, and some approaches for the detection of CTC in lung cancer have shown both high sensitivity and specificity. The CTC analyses offer much promise as a real-time 'liquid biopsy' for prognosis evaluation and therapy intervention in lung cancer. In this Review, we present and discuss the current status of CTC detection and applications in lung cancer.

IgG4-related disease can present as recurrent spontaneous hemothorax: a case report.

BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) encompasses a group of immune-mediated disorders that are gaining increasing recognition. Pulmonary presentations are common, with four types of patterns been described on radiography, including solid nodular, bronchovascular, ground glass opacities, and alveolar interstitial. Pleural thickening and pleural effusion have also been reported. However, there have been no reports of IgG4-RD that presents as spontaneous hemothorax. CASE PRESENTATION: A 61-year-old Chinese woman experienced recurrent right-sided chest pain and transient syncope. A significant decrease in her hemoglobin level and thick bloody pleural fluid demonstrated spontaneous hemothorax. The elevated serum IgG4 and histopathological analysis of the right pleura and intercostal lymph node specimens all supported the diagnosis of IgG4-RD in this patient. Further diagnostic evaluation did not reveal other causes for spontaneous hemothorax. She received steroids and no recurrent bleeding event occurred during a follow-up period of more than 1 year. CONCLUSION: Recurrent spontaneous hemothorax can be a rare manifestation of IgG4-RD, with pleural involvement as the most probable mechanism.

Impact of crizotinib on long-term survival of ALK-positive advanced non-small-cell lung cancer: A Chinese multicenter cohort study.

OBJECTIVE: Crizotinib has demonstrated promising efficacy in patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) in clinical trials. We conducted this retrospective multicenter study to assess the outcomes of crizotinib therapy in, to our knowledge, a large sample cohort of patients with ALK-positive advanced NSCLC. METHODS: We reviewed the medical records of 484 unselected ALK-positive NSCLC patients treated with crizotinib at 5 cancer centers in China from January 2013 to November 2017. Clinical data were collected from the initiation of crizotinib therapy to Response Evaluation Criteria in Solid Tumors (RECIST)-defined progressive disease (PD). RESULTS: A total of 428 eligible ALK-positive NSCLC patients were enrolled, 273 (63.8%) of whom received crizotinib as first-line treatment. The median progression-free survival (PFS) and overall survival (OS) from the initiation of crizotinib treatment were 14.4 [95% confidence interval (95% CI), 12.4-16.4] months and 53.4 (95% CI, 33.7-73.1) months, respectively. In subgroup analyses, patients who received crizotinib as first-line treatment showed a higher disease control rate (DCR) and a longer median OS compared with second-/later-line crizotinib treatment (94.8% and OS not reachedvs. 89.0% and 40.5 months, respectively). For 261 patients with RECIST-defined PD, multivariate Cox analysis revealed that in patients who received first-line crizotinib therapy, continued crizotinib beyond progressive disease (CBPD) and next-generation ALK inhibitors after crizotinib failure were associated with improved survival. CONCLUSIONS: This study has demonstrated the clinically meaningful benefit of crizotinib treatment in a large cohort of Chinese ALK-positive NSCLC patients. CBPD and next-generation ALK inhibitor treatment may provide improved survival after RECIST-defined progression on crizotinib.

CD47 is a novel potent immunotherapy target in human malignancies: current studies and future promises.

Recently, many immunosuppressive checkpoints such as PD-L1, CTLA-4 and CD47, were identified in succession and serve as potential immunotherapy targets in human cancers. Among them, CD47, a 'marker-of-self' protein that is overexpressed broadly across tumor types, is emerging as a novel potent macrophage immune checkpoint for cancer immunotherapy. In this review, we highlight the prominent role of CD47 as a 'don't-eat-me' signal that inhibits macrophage phagocytosis for immune evasion of a tumor and presents the opportunities and challenges for CD47 inhibitors both as monotherapy and in combination treatments for hematological cancers and solid tumors; some of these agents are currently in clinical trials.

PI3K in cancer: its structure, activation modes and role in shaping tumor microenvironment.

The role of PI3K in cancer has been well established, and mutations of PIK3CA, the gene coding for catalytic subunit p110α of PI3K, are found in approximately 30% human cancers. The hyperactivated PI3K pathway plays a central role in the tumor cell activities such as proliferation, differentiation, chemotaxis, survival, trafficking and metabolism. Besides, PI3K pathway is involved in the regulation of angiogenesis and the host immune response against cancer. Therefore, the inhibition of PI3K pathway can yield multifaceted tumor cell-extrinsic effects that may synergize with chemotherapy, and more importantly, with the newly revived immunotherapy. Here, we review the structures and activation modes of PI3Ks and its implications in angiogenesis, extracellular matrix remodeling and tumor immunity.