The positivity rates and drug resistance patterns of Mycobacterium tuberculosis using nucleotide MALDI-TOF MS assay among suspected tuberculosis patients in Shandong, China: a multi-center prospective study.

Objective: To investigate the positivity rates and drug resistance characteristics of Mycobacterium tuberculosis (MTB) among suspected tuberculosis (TB) patients in Shandong Province, the second-largest population province in China. Methods: A prospective, multi-center study was conducted from April 2022 to June 2023. Pathogen and drug resistance were identified using nucleotide matrix-assisted laser desorption ionization time-of-flight mass spectrometry (nucleotide MALDI-TOF MS). Results: Of 940 suspected TB patients included in this study, 552 cases were found to be infected with MTB giving an overall positivity rate of 58.72%. Total of 346 cases were resistant to arbitrary anti-TB drug (62.68%), with Zibo (76.47%), Liaocheng and Weihai (both 69.23%) ranking top three and TB treatment history might be a related factor. Monoresistance was the most common pattern (33.53%), with isoniazid the highest at 12.43%, followed by rifampicin at 9.54%. Further analysis of gene mutations conferring resistance revealed diverse types with high heteroresistance rate found in multiple anti-TB drugs. Conclusion: A relatively high rate of MTB positivity and drug resistance was found in Shandong Province during and after the COVID-19 pandemic, indicating the need for strengthening rapid identification of species and drug resistance among suspected TB patients to guide better medication and minimize the occurrence of drug resistance.

Ginger volatile oil inhibits the growth of MDA-MB-231 in the bisphenol A environment by altering gut microbial diversity.

To examine the impact of ginger volatile oil (GVO) on the growth of MDA-MB-231 breast cancer cells in the presence of bisphenol A (BPA) by modulating the diversity of gut microbiota. METHODS: MDA-MB-231 breast cancer cells were injected subcutaneously into the right armpit of female BALB/c Nude (nu/nu) mice to create a triple negative breast cancer model. Thirty nude mice were randomly divided into 5 groups: control group (distilled water every day), BPA control group (distilled PEG-400+ DMSO + cyclodextrin every day), BPA + GVO (0.25 mL/kg) group, BPA + GVO (0.5 mL/kg) group, BPA + GVO (1 mL/kg) group, 6 mice in each group; The drug was given by gavage once a day for 4 weeks. At the end of the experiment, the changes of tumor mass and tumor volume were observed and compared in 5 groups of tumor-bearing mice. High-throughput sequencing (16S rRNA) was used to detect the changes of gut microflora in each group. RESULTS: The volume and weight of breast cancer decreased in the low, medium and high dose groups of GVO. Among them, the difference between the high-dose group and the BPA group reached a significant level (P < 0.05). The species and abundance of gut flora decreased following BPA treatment, but increased after combined treatment of BPA with GVO. In the tumor control group, the ratio of Firmicutes(F) and Bacteroidea(B) respectively was 0.10:0.79 at the phylum level, while the ratio of BPA group further decreased (0.04:0.88). After feeding GVO, the number of Firmicutes and Bacteroidea increased, the F/B ratio increased, and the level of Lactobacillus and alistipes increased. In the BPA and GVO treatment group, the predominant gut microflora functions are cell membrane biogenesis, carbohydrate transport and metabolism. This is followed by amino acid transport and metabolism, and transcription function. After GVO administration, the Gram-positive bacteria (G+) ratio had an increasing trend and the Gram-negative bacteria (G-)ratio had a decreasing trend. CONCLUSION: The species and abundance of gut flora decreased following BPA treatment, but increased after combined treatment of BPA with GVO.

Effects of Low-Intensity Pulsed Ultrasound in Tendon Injuries.

Tendon injuries are the most common soft tissue injuries, caused by tissue overuse and age-related degeneration. However, the tendon repair process is slow and inefficient due to the lack of cellular structure and blood vessels in the tendon. Low-intensity pulsed ultrasound (LIPUS) has received increasing attention as a non-invasive, simple, and safe way to promote tendon healing. This review summarizes the effects and underlying mechanisms of LIPUS on tendon injury by comprehensively examining the published literature, including in vitro, in vivo, and clinical studies. This review reviewed 24 studies, with 87.5% showing improvement. The application of LIPUS in tendon diseases is a promising field worthy of further study.

Corticosteroid treatment in severe patients with SARS-CoV-2 and chronic HBV co-infection: a retrospective multicenter study.

BACKGROUND: The impact of corticosteroids on patients with severe coronavirus disease 2019 (COVID-19)/chronic hepatitis B virus (HBV) co-infection is currently unknown. We aimed to investigate the association of corticosteroids on these patients. METHODS: This retrospective multicenter study screened 5447 confirmed COVID-19 patients hospitalized between Jan 1, 2020 to Apr 18, 2020 in seven centers in China, where the prevalence of chronic HBV infection is moderate to high. Severe patients who had chronic HBV and acute SARS-cov-2 infection were potentially eligible. The diagnosis of chronic HBV infection was based on positive testing for hepatitis B surface antigen (HBsAg) or HBV DNA during hospitalization and a medical history of chronic HBV infection. Severe patients (meeting one of following criteria: respiratory rate > 30 breaths/min; severe respiratory distress; or SpO2 ≤ 93% on room air; or oxygen index < 300 mmHg) with COVID-19/HBV co-infection were identified. The bias of confounding variables on corticosteroids effects was minimized using multivariable logistic regression model and inverse probability of treatment weighting (IPTW) based on propensity score. RESULTS: The prevalence of HBV co-infection in COVID-19 patients was 4.1%. There were 105 patients with severe COVID-19/HBV co-infections (median age 62 years, 57.1% male). Fifty-five patients received corticosteroid treatment and 50 patients did not. In the multivariable analysis, corticosteroid therapy (OR, 6.32, 95% CI 1.17-34.24, P = 0.033) was identified as an independent risk factor for 28-day mortality. With IPTW analysis, corticosteroid treatment was associated with delayed SARS-CoV-2 viral RNA clearance (OR, 2.95, 95% CI 1.63-5.32, P < 0.001), increased risk of 28-day and in-hospital mortality (OR, 4.90, 95% CI 1.68-14.28, P = 0.004; OR, 5.64, 95% CI 1.95-16.30, P = 0.001, respectively), and acute liver injury (OR, 4.50, 95% CI 2.57-7.85, P < 0.001). Methylprednisolone dose per day and cumulative dose in non-survivors were significantly higher than in survivors. CONCLUSIONS: In patients with severe COVID-19/HBV co-infection, corticosteroid treatment may be associated with increased risk of 28-day and in-hospital mortality.

An original deep learning model using limited data for COVID-19 discrimination: A multicenter study.

OBJECTIVES: Artificial intelligence (AI) has been proved to be a highly efficient tool for COVID-19 diagnosis, but the large data size and heavy label force required for algorithm development and the poor generalizability of AI algorithms, to some extent, limit the application of AI technology in clinical practice. The aim of this study is to develop an AI algorithm with high robustness using limited chest CT data for COVID-19 discrimination. METHODS: A three dimensional algorithm that combined multi-instance learning with the LSTM architecture (3DMTM) was developed for differentiating COVID-19 from community acquired pneumonia (CAP) while logistic regression (LR), k-nearest neighbor (KNN), support vector machine (SVM), and a three dimensional convolutional neural network set for comparison. Totally, 515 patients with or without COVID-19 between December 2019 and March 2020 from five different hospitals were recruited and divided into relatively large (150 COVID-19 and 183 CAP cases) and relatively small datasets (17 COVID-19 and 35 CAP cases) for either training or validation and another independent dataset (37 COVID-19 and 93 CAP cases) for external test. Area under the receiver operating characteristic curve (AUC), sensitivity, specificity, precision, accuracy, F1 score, and G-mean were utilized for performance evaluation. RESULTS: In the external test cohort, the relatively large data-based 3DMTM-LD achieved an AUC of 0.956 (95% confidence interval, 95% CI, 0.929∼0.982) with 86.2% and 98.0% for its sensitivity and specificity. 3DMTM-SD got an AUC of 0.937 (95% CI, 0.909∼0.965), while the AUC of 3DCM-SD decreased dramatically to 0.714 (95% CI, 0.649∼0.780) with training data reduction. KNN-MMSD, LR-MMSD, SVM-MMSD, and 3DCM-MMSD benefited significantly from the inclusion of clinical information while models trained with relatively large dataset got slight performance improvement in COVID-19 discrimination. 3DMTM, trained with either CT or multi-modal data, presented comparably excellent performance in COVID-19 discrimination. CONCLUSIONS: The 3DMTM algorithm presented excellent robustness for COVID-19 discrimination with limited CT data. 3DMTM based on CT data performed comparably in COVID-19 discrimination with that trained with multi-modal information. Clinical information could improve the performance of KNN, LR, SVM, and 3DCM in COVID-19 discrimination, especially in the scenario with limited data for training.

Sex Differences on Clinical Characteristics, Severity, and Mortality in Adult Patients With COVID-19: A Multicentre Retrospective Study.

Background: Coronavirus disease-2019 (COVID-19) epidemic is spreading globally. Sex differences in the severity and mortality of COVID-19 emerged. This study aims to describe the impact of sex on outcomes in COVOD-19 with a special focus on the effect of estrogen. Methods: We performed a retrospective cohort study which included 413 patients (230 males and 183 females) with COVID-19 from three designated hospitals in China with a follow up time from January 31, 2020, to April 17, 2020. Women over 55 were considered as postmenopausal patients according to the previous epidemiological data from China. The interaction between age and sex on in-hospital mortality was determined through Cox regression analysis. In addition, multivariate Cox regression models were performed to explore risk factors associated with in-hospital mortality of COVID-19. Results: Age and sex had significant interaction for the in-hospital mortality (P < 0.001). Multivariate Cox regression showed that age (HR 1.041, 95% CI 1.009-1.073, P = 0.012), male sex (HR 2.033, 95% CI 1.007-2.098, P = 0.010), the interaction between age and sex (HR 1.118, 95% CI 1.003-1.232, P = 0.018), and comorbidities (HR 9.845, 95% CI 2.280-42.520, P = 0.002) were independently associated with in-hospital mortality of COVID-19 patients. In this multicentre study, female experienced a lower fatality for COVID-19 than male (4.4 vs. 10.0%, P = 0.031). Interestingly, stratification by age group revealed no difference in-hospital mortality was noted in women under 55 compared with women over 55 (3.8 vs. 5.2%, P = 0.144), as well as in women under 55 compared with the same age men (3.8 vs. 4.0%, P = 0.918). However, there was significantly difference in women over 55 with men of the same age group (5.2 vs. 21.0%, P = 0.007). Compared with male patients, female patients had higher lymphocyte (P < 0.001) and high-density lipoprotein (P < 0.001), lower high sensitive c reaction protein level (P < 0.001), and lower incidence rate of acute cardiac injury (6.6 vs. 13.5%, P = 0.022). Conclusion: Male sex is an independent risk factor for COVID-19 in-hospital mortality. Although female mortality in COVID-19 is lower than male, it might not be directly related to the effect of estrogen. Further study is warranted to identify the sex difference in COVID-19 and mechanisms involved.

A deep learning integrated radiomics model for identification of coronavirus disease 2019 using computed tomography.

Since its first outbreak, Coronavirus Disease 2019 (COVID-19) has been rapidly spreading worldwide and caused a global pandemic. Rapid and early detection is essential to contain COVID-19. Here, we first developed a deep learning (DL) integrated radiomics model for end-to-end identification of COVID-19 using CT scans and then validated its clinical feasibility. We retrospectively collected CT images of 386 patients (129 with COVID-19 and 257 with other community-acquired pneumonia) from three medical centers to train and externally validate the developed models. A pre-trained DL algorithm was utilized to automatically segment infected lesions (ROIs) on CT images which were used for feature extraction. Five feature selection methods and four machine learning algorithms were utilized to develop radiomics models. Trained with features selected by L1 regularized logistic regression, classifier multi-layer perceptron (MLP) demonstrated the optimal performance with AUC of 0.922 (95% CI 0.856-0.988) and 0.959 (95% CI 0.910-1.000), the same sensitivity of 0.879, and specificity of 0.900 and 0.887 on internal and external testing datasets, which was equivalent to the senior radiologist in a reader study. Additionally, diagnostic time of DL-MLP was more efficient than radiologists (38 s vs 5.15 min). With an adequate performance for identifying COVID-19, DL-MLP may help in screening of suspected cases.

Risk factors for severe COVID-19 in middle-aged patients without comorbidities: a multicentre retrospective study.

BACKGROUND: Information regarding characteristics and risk factors of COVID-19 amongst middle-aged (40-59 years) patients without comorbidities is scarce. METHODS: We therefore conducted this multicentre retrospective study and collected data of middle-aged COVID-19 patients without comorbidities at admission from three designated hospitals in China. RESULTS: Among 119 middle-aged patients without comorbidities, 18 (15.1%) developed into severe illness and 5 (3.9%) died in hospital. ARDS (26, 21.8%) and elevated D-dimer (36, 31.3%) were the most common complications, while other organ complications were relatively rare. Multivariable regression showed increasing odds of severe illness associated with neutrophil to lymphocyte ratio (NLR, OR, 11.238; 95% CI 1.110-1.382; p < 0.001) and D-dimer greater than 1 µg/ml (OR, 16.079; 95% CI 3.162-81.775; p = 0.001) on admission. The AUCs for the NLR, D-dimer greater than 1 µg/ml and combined NLR and D-dimer index were 0.862 (95% CI, 0.751-0.973), 0.800 (95% CI 0.684-0.915) and 0.916 (95% CI, 0.855-0.977), respectively. SOFA yielded an AUC of 0.750 (95% CI 0.602-0.987). There was significant difference in the AUC between SOFA and combined index (z = 2.574, p = 0.010). CONCLUSIONS: More attention should be paid to the monitoring and early treatment of respiratory and coagulation abnormalities in middle-aged COVID-19 patients without comorbidities. In addition, the combined NLR and D-dimer higher than 1 µg/ml index might be a potential and reliable predictor for the incidence of severe illness in this specific patient with COVID-19, which could guide clinicians on early classification and management of patients, thereby relieving the shortage of medical resource. However, it is warranted to validate the reliability of the predictor in larger sample COVID-19 patients.

Irinotecan combined with oxaliplatin and S-1 in patients with metastatic pancreatic adenocarcinoma: a single-arm, three-centre, prospective study.

OBJECTIVE: To study the efficacy and toxicity of irinotecan combined with oxaliplatin and S-1 in patients with metastatic pancreatic adenocarcinoma. PATIENTS AND METHODS: Previously untreated patients with cytologically or histologically confirmed metastatic pancreatic adenocarcinoma underwent a treatment regimen consisting of an intravenous infusion of irinotecan 165 mg/m2 and oxaliplatin 85 mg/m2 on day 1, and oral S-1 40 mg/m2 twice daily on days 1-14, repeating the regimen every 21 days until one of the following occurred: disease progression, intolerable toxicity, or patient death. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), response rate, toxicity, and quality of life. This ongoing study had been registered on ClinicalTrials.gov, NCT03726021. RESULTS: A total of 41 patients were enrolled in this study, 18 men and 23 women. The median PFS was 4.33 months [95% confidence interval (CI): 2.83-5.88] and the median OS was 11.00 months (95% CI: 9.16-12.84). There were no instances of a complete response; the partial response, stable disease, and disease progression rates were 39.02% (16/41), 29.27% (12/41), and 31.71% (13/41), respectively.The most common adverse side effects were mild to moderate nausea, vomiting, neutropenia, and thrombocytopenia. Grade 3 or 4 neutropenia and thrombocytopenia were observed in 29.27% (12/41) and 12.20% (5/41) of the patients, respectively. No treatment-related death was observed. CONCLUSION: Irinotecan combined with oxaliplatin and S-1 is a safe and effective treatment for metastatic pancreatic adenocarcinoma, and any toxicities are mild to moderate and tolerable. A larger study population is needed for further evaluation.

Characteristics of asymptomatic patients with SARS-CoV-2 infection in Jinan, China.

Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) is continuously and rapidly circulating at present. Asymptomatic patients have been proven to be contagious and thus pose a significant infection control challenge. Here we describe the characteristics of asymptomatic patients with SARS-CoV-2 infection in Jinan, Shandong province, China. A total of 47 patients with confirmed COVID-19 were recruited. Among them, 11 patients were categorized as asymptomatic cases. We found that the asymptomatic patients in Jinan were relatively young and were mainly clustered cases. The laboratory indicators and lung lesion on chest CT were mild. No special factors were found accounting for the presence or absence of symptoms. The presence of asymptomatic patients increased the difficulty of screening. It is necessary to strengthen the identification of such patients in the future.

Clinical characteristics of COVID-19 in children compared with adults in Shandong Province, China.

AIMS AND BACKGROUND: The COVID-19 outbreak spread in China and is a threat to the world. We reported on the epidemiological, clinical, laboratory, and radiological characteristics of children cases to help health workers better understand and provide timely diagnosis and treatment. METHODS: Retrospectively, two research centers' case series of 67 consecutive hospitalized cases including 53 adult and 14 children cases with COVID-19 between 23 Jan 2020 and 15 Feb 2020 from Jinan and Rizhao were enrolled in this study. Epidemiological, clinical, laboratory, and radiological characteristics of children and adults were analyzed and compared. RESULTS: Most cases in children were mild (21.4%) and conventional cases (78.6%), with mild clinical signs and symptoms, and all cases were of family clusters. Fever (35.7%) and dry cough (21.4%) were described as clinical manifestations in children cases. Dry cough and phlegm were not the most common symptoms in children compared with adults (p = 0.03). In the early stages of the disease, lymphocyte counts did not significantly decline but neutrophils count did in children compared with adults (p = 0.02). There was a lower level of CRP (p = 0.00) in children compared with adults. There were 8 (57.1%) asymptomatic cases and 6 (42.9%) symptomatic cases among the 14 children cases. The age of asymptomatic patients was younger than that of symptomatic patients (p = 0.03). Even among asymptomatic patients, 5 (62.5%) cases had lung injuries including 3 (60%) cases with bilateral involvement, which was not different compared with that of symptomatic cases (p = 0.58, p = 0.74). CONCLUSIONS: The clinical symptoms of children are mild, there is substantial lung injury even among children, but that there is less clinical disease, perhaps because of a less pronounced inflammatory response, and that the occurrence of this pattern appears to inversely correlate with age.

Epidemic update of COVID-19 in Hubei Province compared with other regions in China.

AIMS & BACKGROUND: The COVID-19 outbreak spread in China and is a threat to the world. The aims of this study to help health workers better understand the epidemic of the COVID-19 and provide different control strategies toward Hubei Province and other regions in China. METHODS: A comprehensive search of the Chinese Center for Disease Control and Prevention official websites and announcements was performed between 20 Jan 2019 and 29 Feb 2020. The relevant data of the distribution of the infection on each reported day were obtained. RESULTS& FINDINGS: Up to 29 Feb 2020, 79,824 confirmed cases with the COVID-19 including 66,907 in Hubei Province and 12,377 in other administrative regions were reported. The SARS-COV-2 showed faster epidemic trends compared with the 2003-SARS-CoV. A total of 2,870 deaths have been reported nationwide among 79,824 confirmed cases, with a mortality of 3.6%. The mortality of the COVID-19 was significantly higher in Hubei Province than that in other regions(4.1% versus 0.84%). Since 1 Feb 2020 the number of discharged cases exceeded the number of the dead. By 29 Feb 2020, the number of discharged patients was 41,625, which exceeded the number of hospitalized patients, and the trend has further increased. CONCLUSIONS: The infection of the SARS-COV-2 is spreading and increasing nationwide, and Hubei Province is the main epidemic area, with higher mortality. The outbreak is now under initial control especially in other regions outside of Hubei Province. Due to the different epidemic characteristics between Hubei Province and other regions, we should focus on different prevention and control strategies.

Do children need a longer time to shed SARS-CoV-2 in stool than adults?

SARS-CoV-2 can be shed in the stool of patients in the recovery phase. Children show a longer shedding time than adults. We analyzed the possible causes of this finding and recommend that a negative stool sample be included in a patient's discharge criteria.

The different clinical characteristics of corona virus disease cases between children and their families in China - the character of children with COVID-19.

This study aims to analyze the different clinical characteristics between children and their families infected with severe acute respiratory syndrome coronavirus 2. Clinical data from nine children and their 14 families were collected, including general status, clinical, laboratory test, and imaging characteristics. All the children were detected positive result after their families onset. Three children had fever (22.2%) or cough (11.2%) symptoms and six (66.7%) children had no symptom. Among the 14 adult patients, the major symptoms included fever (57.1%), cough (35.7%), chest tightness/pain (21.4%), fatigue (21.4%) and sore throat (7.1%). Nearly 70% of the patients had normal (71.4%) or decreased (28.6%) white blood cell counts, and 50% (7/14) had lymphocytopenia. There were 10 adults (71.4%) showed abnormal imaging. The main manifestations were pulmonary consolidation (70%), nodular shadow (50%), and ground glass opacity (50%). Five discharged children were admitted again because their stool showed positive result in SARS-CoV-2 PCR. COVID-19 in children is mainly caused by family transmission, and their symptoms are mild and prognosis is better than adult. However, their PCR result in stool showed longer time than their families. Because of the mild or asymptomatic clinical process, it is difficult to recognize early for pediatrician and public health staff.

Treatment of Skin Reaction Induced by Nivolumab Combined with Radiotherapy in Non-small Cell Lung Cancer: A Case Report.

Skin reaction or dermatological toxicities induced by immunotherapy is common. It usually manifests skin rash or erythema and can be cured by skin lotion or steroid. Nivolumab, a human IgG4 programmed cell death protein 1 (PD-1) inhibitor, blocks T cells activation preventing signal and allows the immune system to clear cancer cells. Nivolumab was approved in the second-line therapy in squamous cell lung cancer by FDA, with less than 10% unusual skin reaction, like sensory neuropathy, peeling skin, erythema multiforme, vitiligo, and psoriasis. Radiotherapy could aggravate this skin reaction through inflammatory response and promotion of immunity. The combined treatment of anti-PD-1 and radiotherapy represented a new promising therapeutic approach in many studies, but the risk of side effects may be high. We reported a patient with advanced squamous cell lung cancer who suffered from serious skin immune-related adverse events when he was treated with nivolumab and radiotherapy. The immune overreaction of the treatment of anti-PD-1 treatment and radiotherapy might cause these serious skin adverse events. Our report warranted careful workup to reduce the risk of side effects by combinative therapy with anti-PD-1 and radiotherapy.

Osimertinib compared docetaxel-bevacizumab as third-line treatment in EGFR T790M mutated non-small-cell lung cancer.

OBJECTIVE: To compare the efficacy and toxicity of osimertinib versus docetaxel-bevacizumab as third-line treatment in EGFR T790M mutated NSCLC. METHODS: In this phase 3, open-label, three-center study, we randomly assigned (1:1) previously treated with TKI-chemotherapy or chemotherapy-TKI recurrent or metastatic advanced non-squamous lung cancer patients into two groups. These patients had acquired EGFR T790M resistance mutation confirmed by tumor tissues or serum. One group received oral osimertinib (80 mg/day) and the other group received intravenous infusion docetaxel (75 mg/m2) and bevacizumab (7.5 mg/kg) every 21 days until disease progression, unacceptable toxic effects or patient death. The primary endpoint of this study was progression-free survival (PFS) and the secondary endpoints were response rates, toxicities and overall survival (OS). This trial was registered with ClinicalTrials.gov, number NCT02959749. RESULTS: A total of 147 patients were treated. Among them, 74 were enrolled in the osimertinib group and 73 were in the docetaxel-bevacizumab group. The median progression-free survival was 10.20 months in the osimertinib group versus 2.95 months in the docetaxel-bevacizumab group (hazard ratio 0.23; 95% confidence interval [CI], 0.12-0.38; P < 0.001). The overall response rate in the osimertinib group was significantly better than in the docetaxel-bevacizumab group (61.6%; 95% CI, 55.5-67.7 versus 8.3%; 95% CI, 1.3-15.3; p < 0.001). Because all the progressed patients in the docetaxel-bevacizumab group crossed over to the osimertinib group, there was no significant difference in the median OS between two groups at the time of last follow-up (hazard ratio 0.79; 95% CI, 0.38-1.61; P = .551). The main grade 3 or 4 toxic effects were diarrhea (2.7%) and interstitial lung disease (1.4%) in the osimertinib group and alopecia (15.3%), anorexia (12.5%), neutropenia (9.7%) and nausea (8.3%) in the docetaxel-bevacizumab group. CONCLUSIONS: Osimertinib had higher response rate, longer PFS and milder side effects than docetaxel-bevacizumab in third-line therapy in patients with EGFR T790 M positive advanced NSCLC.

Mutational Profiling of Non-Small-Cell Lung Cancer Resistant to Osimertinib Using Next-Generation Sequencing in Chinese Patients.

PURPOSE: To identify the somatic mutated genes for optimal targets of non-small-cell lung cancer after resistance to osimertinib treatment. PATIENTS AND METHODS: Study patients all had advanced lung adenocarcinoma and acquired resistance to osimertinib as a second- or third-line treatment. These patients had harboring EGFR T790M mutation before osimertinib treatment, which was confirmed by Amplification Refractory Mutation System (ARMS) PCR or Next-Generation Sequencing (NGS). After resistance to osimertinib treatment, tumor tissue was collected by core needle biopsy. DNA was extracted from 15 × 5 um sliced section of formalin-fixed paraffin-embedded (FFPE) material and NGS was done. The genetic changes were analyzed. RESULTS: A total of 9 Chinese patients were studied, 5 females and 4 males, age 51-89 years. After progression with osimertinib treatment, core needle biopsy was performed and next-generation sequencing was performed. Nine patients had harboring 62 point mutations, 2 altered gene copies, 2 amplifications, and 1 EML4-ALK gene fusion. No MET or HER2 amplification was found in this cohort study. Nine patients still maintained initial EGFR 19 del or L858R activating mutations, while 7 of them kept EGFR T790M mutations. Among the 7 patients, 5 had secondary EGFR C797S and/or C797G mutations, which all happened in the same allele with T790M mutation. All patients were treated with targets therapies, chemotherapy, or best supportive care (BSC) in accordance with NGS genetic results and patients' performance status; 7 of them are still alive and 2 of them died of disease progression at last follow-up. CONCLUSIONS: EGFR C797S/G mutation and the same one presented on the same allele with EGFR T790M mutation were the most common mutation feature and played a key role in resistance to osimertinib in Chinese patients with NSCLC. Tumor cells losing T790M mutation and maintaining EGFR activating mutation might benefit from first-generation EGFR-TKI treatment.

[Heavy Metals in Sediments from the Haizhou Bay Marine Ranching Based on Geochemical Characteristics].

Marine ranching is a new sustainable production method, which plays an important role in the transformation of China's marine economy. In this paper, Haizhou Bay marine ranching was divided into 3 areas according to the intensity and delivery time of the submarine structures. Five geochemical indicators of temperature (T), pH, oxidation-reduction potential (Eh), grain size (D[3,2]) and total organic carbon (TOC) were determined on-site. A modified European Community Bureau of Reference(BCR)sequential extraction procedure was applied to determine the chemical speciation of different heavy metals (i.e. Cr, Cu, Ni, Zn, Pb, and Cd). The results showed a horizontal distribution of the Eh was influenced by the submarine structures. The TOC content ranged from 11.7 to 13.5 g·kg-1, which had a significant negative correlation with pH. Pb and Cd mainly present in the secondary phase of iron manganese oxide forms (F2), which were controlled by the Eh, however, Cu, Zn, Ni, and Cr were mainly present in the primary phase. A correlation and cluster analysis indicated that the Cr, Cu, Ni, and Zn present in sediments were from natural sources, while the Cd and Pb content obviously came from anthropogenic metal sources. The exchangeable and carbonate fractions (F1) of Cr, Ni, Cu, Zn, Pb, and Cd were significantly correlated with TOC. The residuals (F4) of Cr, Ni, Cu, Zn, Pb, Cd were significantly correlated with the grain size of sediments as well as the iron-manganese oxide forms (F2) of Cr, Ni, Cu, and Zn. A different speciation of Cd was controlled by multiple geochemical characteristics of the sediment. The heavy metal levels of the primary and secondary phases in the central and lateral areas were lower than the control and medial areas because of differences in the submarine structures and hydrodynamics. The enrichment and adsorption of Cr, Ni, Cu, and Zn in sediment was stronger than the release of particles that were resuspended. While the influence of fine particles and organic matter from the sediment in the central and outer areas was limited, an enrichment factor analysis suggested that Cd in sediment showed enrichment to some extent. This paper provides a scientific basis for the construction of marine ranching and ecological restoration in Haizhou Bay.

Clinical Observation of Bevacizumab Combined with S-1 in the Treatment of Pretreated Advanced Esophageal Carcinoma.

Objective To investigate the clinical effects and safety of bevacizumab combined with S-1 as the second-line treatment of recurrent and/or metastatic esophageal cancer after chemoradiation. Methods Patients with recurrent or metastatic esophageal cancer after chemoradiation were treated with bevacizumab and S-1. Bevacizumab was used by intravenous infusion, 7.5mg/kg body weight on day 1; S-1 was used by oral at 80mg/m2·d on day 1-14, 21 days as a cycle of treatment and repeated until either pro- gressive disease or intolerable toxicity occurred. Chest CT were performed and RECIST 1.1 was used for response evaluation. Kaplan-Meier method was used for survival analysis. Side effects were recorded and analyzed. Results Totally 78 patients were enrolled in the study, including 67 squamous cell carcinoma and 11 adenocarcinoma histologically. The overall response (CR+PR) rate was 22.4% (17/76) and disease control (CR+PR+SD) rate was 61.8% (47/76) respectively. The median follow-up time was 20 months (range from 9 to 44 months). The median progression-free survival (PFS) was 4.9 months (95% CI 4.4-5.5) and the median overall survival (OS) was 8.1 months (95% CI 7.6-9.2). The median PFS and OS of patients with metastasis diseases were 6.2 months (95% CI 3.3 to 6.3) and 8.5 months (95% CI 5.8 to 11.2), where PFS was longer than that of patients with local regional recurrence (median 5.0 months, 95% CI 3.0 to 5.5, P=0.017) and OS was longer than that of patients with regional disease and metastasis (median 8.0 months, 95% CI 4.6 to 9.5, P=0.010). The common adverse effects were mild to moderate neutropenia (84.2%), grade I-II hand and foot syndrome (51.3%), grade I-II nausea (48.7%), mild epistaxis (30.1%) and mild vomiting (14.5%). Esophageal bleeding occurred in 7.9% of patients. One patient (1.3%) died from massive bleeding which was caused by esophageal perforation. Conclusion Bevacizumab combined with S-1 was effective and safe for esophageal cancer patients who had recurrent or metastatic diseases after chemoradiation.