[Research on the establishment of standard limits for perfluorooctanoic acid and perfluorooctane sulfonate in the "Standards for Drinking Water Quality（GB5749-2022）"in China].

Perfluorinated compounds, especially Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), are widely detected in water environments in China. Considering the potential health risks of drinking water exposure routes, PFOA and PFOS have been added to the water quality reference index of the newly issued "Standards for Drinking Water Quality (GB5749-2022)", with limit values of 40 and 80 ng/L, respectively. This study analyzed and discussed the relevant technical contents for determining the limits of the hygiene standard, including the environmental existence level and exposure status of PFOA and PFOS, health effects, derivation of safety reference values, and determination of hygiene standard limits. It also proposed prospects for the future direction of formulating drinking water standards.

[Research on the standard limits for vinyl chloride and trichloroethylene in the "Standards for Drinking Water Quality（GB5749-2022）" in China].

The usage of vinyl chloride and trichloroethylene in China has been increasing year by year, and they have been detected in both drinking water and environmental water, making them important environmental pollutants. Based on the latest research results on the health effects of vinyl chloride and trichloroethylene, the newly issued, "Standards for Drinking Water Quality (GB5749-2022)" in China has adjusted the standard limit of vinyl chloride from 0.005 mg/L to 0.001 mg/L and the standard limit of trichloroethylene from 0.07 mg/L to 0.02 mg/L. This article analyzed and discussed the relevant technical contents for determining the above standard limits, including the levels and exposure conditions of vinyl chloride and trichloroethylene in the water environment, health effects, derivation of safety reference values, and determination of hygiene standard limits. Suggestions were also made for the implementation of this standard.

[Methodological study on the establishment of limit values in the Standards of Drinking Water Quality].

The establishment of limit values for standards of drinking water quality is an important and complex process. This study systematically introduced the methodology of the establishment of standard limit values for drinking water quality and elaborated on the workflow of setting limit values of water quality indicators, principles and methods of selecting water quality indicators, derivation of safety reference values, and establishment of limit values. It also aimed to provide reference and support for the future revision of relevant standards.

A phase II open-label trial of avelumab plus axitinib in previously treated non-small-cell lung cancer or treatment-naïve, cisplatin-ineligible urothelial cancer.

BACKGROUND: We hypothesized that avelumab plus axitinib could improve clinical outcomes in patients with advanced non-small-cell lung cancer (NSCLC) or urothelial carcinoma (UC). PATIENTS AND METHODS: We enrolled previously treated patients with advanced or metastatic NSCLC, or untreated, cisplatin-ineligible patients with advanced or metastatic UC. Patients received avelumab 800 mg every 2 weeks (Q2W) and axitinib 5 mg orally two times daily. The primary endpoint was objective response rate (ORR). Immunohistochemistry was used to assess programmed death-ligand 1 (PD-L1) expression (SP263 assay) and the presence of CD8+ T cells (clone C8/144B). Tumor mutational burden (TMB) was assessed by whole-exome sequencing. RESULTS: A total of 61 patients were enrolled and treated (NSCLC, n = 41; UC, n = 20); 5 remained on treatment at data cut-off (26 February 2021). The confirmed ORR was 31.7% in the NSCLC cohort and 10.0% in the UC cohort (all partial responses). Antitumor activity was observed irrespective of PD-L1 expression. In exploratory subgroups, ORRs were higher in patients with higher (≥median) CD8+ T cells in the tumor. ORRs were higher in patients with lower TMB (

[The role of fluorescent cholangiography in preventing biliary tract injury and finding bile leakage].

The study investigated the clinical value of fluorescence cholangiography using indocyanine green (ICG) in laparoscopic cholecystectomy (LC) and laparoscopic common bile duct exploration (LCBDE) in preventing bile duct injury (BDI) and detecting bile leakage. A total of 300 patients who underwent fluorescent navigation LC and LCBDE in the Second Department of General Surgery, Shengjing Hospital Affiliated to China Medical University from June 2020 to September 2022 were selected as the research objects for observation and analysis. There were 114 males and 186 females, and aged (50.7±14.0) years with the body mass index (BMI) of (23.6±1.6) kg/m². All 300 cases of fluorescence navigation surgery were successfully completed, of which 5 patients received fluorescence-guided LCBDE and primary suture. The results showed that the application of fluorescence cholangiography with ICG can effectively avoid and detect the occurrence of BDI and bile leakage. Meanwhile, it is reasonable to hypothesize that ICG can be used for rapid localization and the final check to prevent the recurrence of bile leakage when bile leakage is suspected in the second operation.

[Status of fungal sepsis among preterm infants in 25 neonatal intensive care units of tertiary hospitals in China].

Objective: To analyze the prevalence and the risk factors of fungal sepsis in 25 neonatal intensive care units (NICU) among preterm infants in China, and to provide a basis for preventive strategies of fungal sepsis. Methods: This was a second-analysis of the data from the "reduction of infection in neonatal intensive care units using the evidence-based practice for improving quality" study. The current status of fungal sepsis of the 24 731 preterm infants with the gestational age of <34+0 weeks, who were admitted to 25 participating NICU within 7 days of birth between May 2015 and April 2018 were retrospectively analyzed. These preterm infants were divided into the fungal sepsis group and the without fungal sepsis group according to whether they developed fungal sepsis to analyze the incidences and the microbiology of fungal sepsis. Chi-square test was used to compare the incidences of fungal sepsis in preterm infants with different gestational ages and birth weights and in different NICU. Multivariate Logistic regression analysis was used to study the outcomes of preterm infants with fungal sepsis, which were further compared with those of preterm infants without fungal sepsis. The 144 preterm infants in the fungal sepsis group were matched with 288 preterm infants in the non-fungal sepsis group by propensity score-matched method. Univariate and multivariate Logistic regression analysis were used to analyze the risk factors of fungal sepsis. Results: In all, 166 (0.7%) of the 24 731 preterm infants developed fungal sepsis, with the gestational age of (29.7±2.0) weeks and the birth weight of (1 300±293) g. The incidence of fungal sepsis increased with decreasing gestational age and birth weight (both P<0.001). The preterm infants with gestational age of <32 weeks accounted for 87.3% (145/166). The incidence of fungal sepsis was 1.0% (117/11 438) in very preterm infants and 2.0% (28/1 401) in extremely preterm infants, and was 1.3% (103/8 060) in very low birth weight infants and 1.7% (21/1 211) in extremely low birth weight infants, respectively. There was no fungal sepsis in 3 NICU, and the incidences in the other 22 NICU ranged from 0.7% (10/1 397) to 2.9% (21/724), with significant statistical difference (P<0.001). The pathogens were mainly Candida (150/166, 90.4%), including 59 cases of Candida albicans and 91 cases of non-Candida albicans, of which Candida parapsilosis was the most common (41 cases). Fungal sepsis was independently associated with increased risk of moderate to severe bronchopulmonary dysplasia (BPD) (adjusted OR 1.52, 95%CI 1.04-2.22, P=0.030) and severe retinopathy of prematurity (ROP) (adjusted OR 2.55, 95%CI 1.12-5.80, P=0.025). Previous broad spectrum antibiotics exposure (adjusted OR=2.50, 95%CI 1.50-4.17, P<0.001), prolonged use of central line (adjusted OR=1.05, 95%CI 1.03-1.08, P<0.001) and previous total parenteral nutrition (TPN) duration (adjusted OR=1.04, 95%CI 1.02-1.06, P<0.001) were all independently associated with increasing risk of fungal sepsis. Conclusions: Candida albicans and Candida parapsilosis are the main pathogens of fungal sepsis among preterm infants in Chinese NICU. Preterm infants with fungal sepsis are at increased risk of moderate to severe BPD and severe ROP. Previous broad spectrum antibiotics exposure, prolonged use of central line and prolonged duration of TPN will increase the risk of fungal sepsis. Ongoing initiatives are needed to reduce fungal sepsis based on these risk factors.

[Influencing factors of Legionella reproduction in secondary water supply operation and management].

Objective: To analyze the pollution status and influencing factors of Legionella pneumophila in a secondary water supply facility in a city. Methods: From June to August 2020, a survey on the level of Legionella pneumophila in secondary water supply unit was carried out in a city in northern China, and 304 sets of secondary water supply facilities were included in the study. A total of 760 water samples were collected from the inlet and outlet water of the secondary water supply facilities and some water samples in the water tank were collected for the detection of Legionella pneumophila, standard plate-count bacteria and related physical and chemical indicators. Through questionnaire survey, the basic information of secondary water supply facilities and daily management of water quality were collected. Multivariate logistic regression model was used to analyze the influencing factors of Legionella pneumophila contamination. Results: Among 304 sets of secondary water supply facilities, most of them were located in residential buildings [57.24% (174/304)]. High and low water tank water supply, low water tank variable frequency conversion water supply and non-negative pressure water supply accounted for 26.6% (81/304), 36.8% (112/304) and 36.5% (111/304), respectively. About 25.7% of facilities (78/304) were positive for Legionella pneumophila. Among them, the positive rates of Legionella pneumophila in high and low water tank water supply, low water tank variable frequency conversion water supply and non-negative pressure water supply facilities were 38.3% (31/81), 29.5% (33/112) and 12.6% (14/111), respectively. The results of multivariate logistic regression model analysis showed that the disinfectant residue could reduce the risk of Legionella pneumophila contamination in water samples, and the OR (95%CI) value was 0.083 (0.022-0.317). The increase of the standard plate-count bacteria and conductivity might increase the risk of Legionella pneumophila contamination in water samples. The OR (95%CI) values were 3.160 (1.667-5.99) and 1.004 (1.001-1.006), respectively. Compared with the non-negative pressure water supply, the risk of Legionella pneumophila contamination of secondary water supply facilities was increased by water supply from high and low water tanks and variable frequency conversion water supply from low water tanks, with OR (95%CI) values of 4.296 (2.096-8.803) and 2.894 (1.449-5.782), respectively. Conclusion: The positive rate of Legionella pneumophila in secondary water supply in the study city is high. Disinfectant residue, conductivity and method of water supply are associated with the positive rate of Legionella pneumophila.

Impact of smoking status on the relative efficacy of the EGFR TKI/angiogenesis inhibitor combination therapy in advanced NSCLC-a systematic review and meta-analysis.

BACKGROUND: The ETOP 10-16 BOOSTER trial failed to demonstrate a progression-free survival (PFS) benefit for adding bevacizumab to osimertinib in second line. An exploratory subgroup analysis, however, suggested a PFS benefit of the combination in patients with a smoking history and prompted us to do this study. METHODS: A systematic review and meta-analysis to evaluate the differential effect of smoking status on the benefit of adding an angiogenesis inhibitor to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor therapy was carried out. All relevant randomized controlled trials appearing in main oncology congresses or in PubMed as of 1 November 2021 were used according to the Preferred Reporting Items for Systematic Review and Meta-Analyses statement. Primarily PFS according to smoking status, and secondarily overall survival (OS) were of interest. Pooled and interaction hazard ratios (HRs) were estimated by fixed or random effects models, depending on the detected degree of heterogeneity. Bias was assessed using the revised Cochrane tool for randomized controlled trials (RoB 2). RESULTS: Information by smoking was available for 1291 patients for PFS (seven studies) and 678 patients for OS (four studies). The risk of bias was low for all studies. Combination treatment significantly prolonged PFS for smokers [n = 502, HR = 0.55, 95% confidence interval (CI): 0.44-0.69] but not for nonsmokers (n = 789, HR = 0.92, 95% CI: 0.66-1.27; treatment-by-smoking interaction P = 0.02). Similarly, a significant OS benefit was found for smokers (n = 271, HR = 0.66, 95% CI: 0.47-0.93) but not for nonsmokers (n = 407, HR = 1.07, 95% CI: 0.82-1.42; treatment-by-smoking interaction P = 0.03). CONCLUSION: In advanced EGFR-non-small-cell lung cancer patients, the addition of an angiogenesis inhibitor to EGFR-tyrosine kinase inhibitor therapy provides a statistically significant PFS and OS benefit in smokers, but not in non-smokers. The biological basis for this observation should be pursued and could determine whether this might be due to a specific co-mutational pattern produced by tobacco exposure.

A randomised phase II study of osimertinib and bevacizumab versus osimertinib alone as second-line targeted treatment in advanced NSCLC with confirmed EGFR and acquired T790M mutations: the European Thoracic Oncology Platform (ETOP 10-16) BOOSTER trial.

BACKGROUND: While osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is the standard treatment in patients with advanced non-small-cell lung cancer (NSCLC) with sensitising EGFR and acquired T790M mutations, progression inevitably occurs. The angiogenic pathway is implicated in EGFR TKI resistance. PATIENTS AND METHODS: BOOSTER is an open-label randomised phase II trial investigating the efficacy and safety of combined osimertinib 80 mg daily and bevacizumab 15 mg/kg every 3 weeks, versus osimertinib alone, in patients with EGFR-mutant advanced NSCLC and acquired T790M mutations after failure on previous EGFR TKI therapy. Primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR) and adverse events (AEs). RESULTS: Between May 2017 and February 2019, 155 patients were randomised (combination: 78; osimertinib: 77). At data cut-off of 22 February 2021, median follow-up was 33.8 months [interquartile range (IQR): 26.5-37.6 months] and 129 (83.2%) PFS events were reported in the intention-to-treat population. There was no difference in median PFS between the combination [15.4 months; 95% confidence interval (CI) 9.2-18.0 months] and osimertinib arm (12.3 months; 95% CI 6.2-17.2 months; stratified log-rank P = 0.83), [hazard ratio (HR) = 0.96; 95% CI 0.68-1.37]. Median OS was 24.0 months (95% CI 17.8-32.1 months) in the combination arm and 24.3 months (95% CI 16.9-37.0 months) in the osimertinib arm (stratified log-rank P = 0.91), (HR = 1.03; 95% CI 0.67-1.56). Exploratory analysis revealed a significant interaction of smoking history with treatment for PFS (adjusted P = 0.0052) with a HR of 0.52 (95% CI 0.30-0.90) for smokers, and 1.47 (95% CI 0.92-2.33) for never smokers. ORR was 55% in both arms and the median time to treatment failure was significantly shorter in the combination than in the osimertinib arm, 8.2 months versus 10.8 months, respectively (P = 0.0074). Safety of osimertinib and bevacizumab was consistent with previous reports with grade ≥3 treatment-related AEs (TRAEs) reported in 47% and 18% of patients on combination and osimertinib alone, respectively. CONCLUSIONS: No difference in PFS was observed between osimertinib plus bevacizumab and osimertinib alone. Grade ≥3 TRAEs were more common in patients on combination.

[Feasibility of radiofrequency ablation for cancer patients with atrial fibrillation].

Objective: To analyze the impact of cancer on the recurrence rate of atrial fibrillation (AF) after AF radiofrequency ablation and further evaluate the feasibility of radiofrequency ablation therapy in cancer patients with AF. Methods: This study was a single-center, retrospective study. Cancer patients with AF undergoing radiofrequency ablation for the first time in the First Affiliated Hospital of Dalian Medical University from May 30, 2008 to September 30, 2018 were included (cancer group). AF patients without cancer undergoing radiofrequency ablation for the first time during the same period served as non-cancer group. Clinical data including age, gender, past history, cancer and AF-related parameters, etc. were analyzed. Patients were followed up after radiofrequency ablation. The primary endpoints were AF recurrence or all-cause death. Kaplan-Meier survival analysis was used to analyze the effect of cancers on the recurrence after AF ablation. The multivariate cox regression analysis was further applied to correct for other confounding factors to analyze whether the impact of cancers on the recurrence of atrial fibrillation was statistically significant. Results: A total of 90 patients were enrolled, there were 30 patients in the cancer group (mean age (64.8±6.6) years, 16 (53.3%) males) and 60 patients in the non-cancer group (mean age (63.6±6.2) years, 32 (53.3%) males). Clinical data, such as age, gender, and cancer treatment, were similar between the two groups. During an average follow-up period of (328.7±110.2) days, there were 6 AF recurrences (recurrence rate 20.0%) in the cancer group, and 17 AF recurrences (recurrence rate 28.3%) in the control group. AF recurrence rate was similar between the two groups (P>0.05). During the follow-up period, there was no all-cause death in the two groups. Kaplan-Meier survival analysis showed that cancer was not related to AF recurrence after radiofrequency ablation (P = 0.383). After adjusting for other confounding factors, the multivariate Cox regression analysis showed that cancer was not an independent predictor of AF recurrence after radiofrequency ablation (HR=0.508, 95%CI: 0.192-1.342, P = 0.172). Conclusions: The combination of cancer has no impact on the recurrence of AF after radiofrequency ablation. For cancer patients with AF, radiofrequency ablation therapy can be considered as a feasible heart rhythm control treatment strategy.

One-step lateral window approach for removal of benign minor sinus pathologies combined with transcrestal sinus floor elevation without bone grafts: a retrospective study.

The aim of this study was to evaluate the clinical and radiographic outcomes of a lateral window approach for removal of benign minor sinus pathologies combined with transcrestal sinus floor elevation. From 2014 to 2018, all patients who received sinus pathology removal via a lateral window approach combined with transcrestal sinus floor elevation were screened. The serous exudate or minor sinus pathology was drained or removed via lateral window approach. Subsequently, transcrestal sinus floor elevation without grafting and simultaneous implant placement were performed. Panoramic radiographs and cone-beam computed tomography were taken preoperatively, immediately after surgery, and after prosthesis delivery. Twelve patients were included in this study. The decrease in Schneiderian membrane thickness was statistically significant (P<0.001). Endo-sinus bone formation was observed on the buccal (1.35±2.31mm) and palatal (1.61±2.65mm) sites of the implant. The implant survival rate was 100%. All implants survived for an average of 21.83±11.11 months. Within the limitations of this study, we suggest that the lateral window approach for minor sinus pathology removal combined with transcrestal sinus floor elevation has several advantages including endo-sinus bone gain without bone graft, minimal patient discomfort, reduced postoperative complications and shorter treatment period.

[Analysis on clinical factors affecting transrectal natural orifice specimen extraction in rectal cancer surgery].

Objective: To identify the factors associated with successful transrectal specimen extraction after laparoscopic rectal cancer resection. Methods: A retrospective case-control study was conducted. Clinical data of rectal cancer patients who did or did not successfully undergo transrectal specimen extraction in Shanghai East Hospital between January 2017 and December 2017 were retrieved through the rectal cancer database of Shanghai East Hospital. Case inclusion criteria: (1) tumor size ≤7 cm by pelvic MRI; (2) body mass index (BMI)≤ 30 kg/m(2); (3) no history of neoadjuvant chemoradiotherapy; (4) no anal stenosis. Clinical data including age, gender, BMI, tumor obstruction, distance from tumor to anal verge, history of abdominal operation, maximal diameter of tumor and width of mesorectum in the anteroposterior dimension measured by pelvic MRI, etc. were collected. The χ(2) test was used to perform univariate analysis. Multivariate logistic regression was used to identify factors affecting transrectal specimen extraction. Results: A total of 208 patients were included in the analysis. Of 208 patients, 132 were men and 76 were women; mean age was (63±11) years old and median tumor size was 3.8 (IQR, 3.0 to 5.0) cm. Sixty-six (31.7%) patients completed transrectal specimen extraction successfully. Univariate analysis showed that patients who completed transrectal specimen extraction were more likely to have a lower BMI (χ(2)=7.420, P=0.006), be free from malignant obstruction (χ(2)=8.972, P=0.003), have a shorter distance from tumor to the anal verge (<5.0 cm) (χ(2)=14.960, P<0.001), a smaller tumor size (≤5.0 cm) (χ(2)=18.495, P<0.001) and a thinner mesorectum in the anteroposterior dimension (≤6.0 cm) (χ(2)=34.612, P<0.001) than those who failed to perform transrectal specimen extraction. Gender, age or history of abdominal operation were not associated with the successful extraction (all P>0.05). Multivariate analysis revealed that BMI ≤25.0 kg/m(2) (OR=2.32, 95% CI: 1.06 to 5.06, P=0.034), free from malignant obstruction (OR=3.01, 95% CI: 1.82 to 6.69, P<0.001), the distance from tumor to the anal verge <5.0 cm (OR=3.73, 95% CI: 1.22 to 11.43, P=0.021), tumor size ≤ 5.0 cm (OR=4.43, 95% CI: 1.39 to 14.09, P=0.012), and the anteroposterior width of mesorectum ≤ 6.0 cm (OR=4.30, 95% CI: 2.02 to 9.18, P<0.001) were independent protective factors for successful transrectal specimen extraction. Conclusion: Preoperative assessment of BMI, malignant obstruction, distance from tumor to the anal verge, tumor size and anteroposterior width of mesorectum is beneficial to choose appropriate patients with rectal cancer to undergo transrectal specimen extraction.

Osimertinib versus platinum-pemetrexed for patients with EGFR T790M advanced NSCLC and progression on a prior EGFR-tyrosine kinase inhibitor: AURA3 overall survival analysis.

BACKGROUND: In AURA3 (NCT02151981), osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), significantly prolonged progression-free survival and improved response in patients with EGFR T790M advanced non-small-cell lung cancer (NSCLC) and progression on prior EGFR-TKI treatment. We report the final AURA3 overall survival (OS) analysis. PATIENTS AND METHODS: Adult patients were randomized 2 : 1 to osimertinib (80 mg orally, once daily) or pemetrexed plus carboplatin/cisplatin (platinum-pemetrexed) intravenously, every 3 weeks (≤6 cycles). Patients could crossover to osimertinib on progression confirmed by blinded independent central review. OS and safety were secondary end points. RESULTS: A total of 279 patients were randomly assigned to receive osimertinib and 140 to platinum-pemetrexed (136 received treatment). At data cut-off (DCO; 15 March 2019), 188 patients (67%) receiving osimertinib versus 93 (66%) receiving platinum-pemetrexed had died. The hazard ratio (HR) for OS was 0.87 [95% confidence interval (CI) 0.67-1.12; P = 0.277]; the median OS was 26.8 months (95% CI 23.5-31.5) versus 22.5 months (95% CI 20.2-28.8) for osimertinib and platinum-pemetrexed, respectively. The estimated 24- and 36-month survival was 55% versus 43% and 37% versus 30%, respectively. After crossover adjustment, there was an HR of 0.54 (95% CI 0.18-1.6). Time to first subsequent therapy or death showed a clinically meaningful advantage toward osimertinib (HR 0.21, 95% CI 0.16-0.28; P < 0.001). At DCO, 99/136 (73%) patients in the platinum-pemetrexed arm had crossed over to osimertinib, 66/99 (67%) of whom had died. The most common adverse events possibly related to study treatment were diarrhea (32%; grade ≥3, 1%) and rash (grouped term; 32%; grade ≥3, <1%) in the osimertinib arm, versus nausea (47%; grade ≥3, 3%) in the platinum-pemetrexed arm. CONCLUSIONS: In patients with T790M advanced NSCLC, no statistically significant benefit in OS was observed for osimertinib versus platinum-pemetrexed, which possibly reflects the high crossover rate of patients from platinum-pemetrexed to osimertinib. CLINICAL TRIALS NUMBER: ClinicalTrials.gov NCT02151981; https://clinicaltrials.gov/ct2/show/NCT02151981.

[The Function of CD40/CD40L Pathway in Silicosis Fibrosis].

Objective: To investigate the role of CD40/CD40L Pathway in the formation of silicosis fibrosis. Methods: Totally 64 inpatients were recruited and assigned to the silicosis group and the control group, 23 in each group. The alveolar lavage fluid was collected from all patients and isolated. The expression of CD40L protein was detected by Flow Cytometry. The level of IL-8、The IL-6、INF-γ and MCP-1 was detected by ELISA. Two groups of BALF were co-cultured with HFL-1 cells, the expression of Collagen I and α-SMA was detected by Immunohistochemistry. Results: Compared with the control group, CD40L was highly expressed on T lymphocyte cells in silicosis group (P<0.05) , and the contents of IL-8、The IL-6、INF-γand MCP-1 in Silicosis group were significantly higher than those in control group (P<0.05) . After co-culture of BALF and HFL-1 cells, the expression levels of Collagen I and α-SMA in Silicosis group were significantly higher than those in control group (P<0.05) . Conclusion: CD40-CD40L cross-linking system can promote the activation of T cells, release inflammatory factors, promote the synthesis of collagen I and α-SMA by fibroblasts, make the lung fibrous tissue proliferate, and lead to the formation of silicosis fibrosis.

Molecular correlates of response to capmatinib in advanced non-small-cell lung cancer: clinical and biomarker results from a phase I trial.

BACKGROUND: Dysregulation of receptor tyrosine kinase MET by various mechanisms occurs in 3%-4% of non-small-cell lung cancer (NSCLC) and is associated with unfavorable prognosis. While MET is a validated drug target in lung cancer, the best biomarker strategy for the enrichment of a susceptible patient population still remains to be defined. Towards this end we analyze here primary data from a phase I dose expansion study of the MET inhibitor capmatinib in patients with advanced MET-dysregulated NSCLC. PATIENTS AND METHODS: Eligible patients [≥18 years; Eastern Cooperative Oncology Group (ECOG) performance status ≤2] with MET-dysregulated advanced NSCLC, defined as either (i) MET status by immunohistochemistry (MET IHC) 2+ or 3+ or H-score ≥150, or MET/centromere ratio ≥2.0 or gene copy number (GCN) ≥5, or (ii) epidermal growth factor receptor wild-type (EGFRwt) and centrally assessed MET IHC 3+, received capmatinib at the recommended dose of 400 mg (tablets) or 600 mg (capsules) b.i.d. The primary objective was to determine safety and tolerability; the key secondary objective was to explore antitumor activity. The exploratory end point was the correlation of clinical activity with different biomarker formats. RESULTS: Of 55 patients with advanced MET-dysregulated NSCLC, 40/55 (73%) had received two or more prior systemic therapies. All patients discontinued treatment, primarily due to disease progression (69.1%). The median treatment duration was 10.4 weeks. The overall response rate per RECIST was 20% (95% confidence interval, 10.4-33.0). In patients with MET GCN ≥6 (n = 15), the overall response rate by both the investigator and central assessments was 47%. The median progression-free survival per investigator for patients with MET GCN ≥6 was 9.3 months (95% confidence interval, 3.8-11.9). Tumor responses were observed in all four patients with METex14. The most common toxicities were nausea (42%), peripheral edema (33%), and vomiting (31%). CONCLUSIONS: MET GCN ≥6 and/or METex14 are suited to predict clinical activity of capmatinib in patients with NSCLC (NCT01324479).

Enhanced sample filling and discretization in thermoplastic 2D microwell arrays using asymmetric contact angles.

Sample filling and discretization within thermoplastic 2D microwell arrays is investigated toward the development of low cost disposable microfluidics for passive sample discretization. By using a high level of contact angle asymmetry between the filling channel and microwell surfaces, a significant increase in the range of well geometries that can be successfully filled is revealed. The performance of various array designs is characterized numerically and experimentally to assess the impact of contact angle asymmetry and device geometry on sample filling and discretization, resulting in guidelines to ensure robust microwell filling and sample isolation over a wide range of well dimensions. Using the developed design rules, reliable and bubble-free sample filling and discretization is achieved in designs with critical dimensions ranging from 20 µm to 800 µm. The resulting devices are demonstrated for discretized nucleic acid amplification by performing loop-mediated isothermal amplification for the detection of the mecA gene associated with methicillin-resistant Staphylococcus aureus.

Usefulness of the Delay Alternating with Nutation for Tailored Excitation Pulse with T1-Weighted Sampling Perfection with Application-Optimized Contrasts Using Different Flip Angle Evolution in the Detection of Cerebral Metastases: Comparison with MPRAGE Imaging.

BACKGROUND AND PURPOSE: Contrast-enhanced T1-weighted sampling perfection with application-optimized contrasts by using different flip angle evolution (SPACE) with the delay alternating with nutation for tailored excitation (DANTE) pulse could suppress the blood flow signal and provide a higher contrast-to-noise ratio of enhancing lesion-to-brain parenchyma than the MPRAGE sequence. The purpose of our study was to evaluate the usefulness of SPACE with DANTE compared with MPRAGE for detecting brain metastases. MATERIALS AND METHODS: Seventy-one patients who underwent contrast-enhanced SPACE with DANTE and MPRAGE sequences and who were suspected of having metastatic lesions were included. Two neuroradiologists determined the number of enhancing lesions, and diagnostic performance was evaluated using figure of merit, sensitivity, positive predictive value, interobserver agreement, and reading time. Contrast-to-noise ratiolesion/parenchyma and contrast-to-noise ratiowhite matter/gray matter were also assessed. RESULTS: SPACE with DANTE (observer one, 328; observer two, 324) revealed significantly more small (<5 mm) enhancing lesions than MPRAGE (observer one, 175; observer two, 150) (P < 0.001 for observer 1, P ≤ .0001 for observer 2). Furthermore, SPACE with DANTE showed significantly higher figure of merit and sensitivity and shorter reading time than MPRAGE for both observers. The mean contrast-to-noise ratiolesion/parenchyma of SPACE with DANTE (52.3 ± 43.1) was significantly higher than that of MPRAGE (17.5 ± 19.3) (P ≤ .0001), but the mean contrast-to-noise ratiowhite matter/gray matter of SPACE with DANTE (-0.65 ± 1.39) was significantly lower than that of MPRAGE (3.08 ± 1.39) (P ≤ .0001). CONCLUSIONS: Compared with MPRAGE, SPACE with DANTE significantly improves the detection of brain metastases.

ALK-positive anaplastic large cell lymphoma with a monomorphic small-cell pattern masquerading as inflammatory gastric lesions.

INTRODUCTION: Anaplastic lymphoma kinase-positive (ALK+) anaplastic large cell lymphoma (ALCL) with a non-common pattern can be diagnostic challenging. Pathologists can be unavoidably and unintentionally blind to non-descript tumor cells in a lymphohistiocytic- (LH) or small-cell (SC)-pattern. We report a case of primary systemic ALK+ ALCL with a SC pattern that presented as secondary gastric lesions with a mixed LH and SC pattern that was masqueraded as inflammatory lesions. CASE REPORT: A 34-year-old woman with intractable epigastric pain was referred to have repeated endoscopy with biopsy. She was found to multiple gastric erosions and nodules that were diagnosed as inflammatory lesions both endoscopically and histologically. Meanwhile, she developed an acute onset of severe back pain associated with a pathologic compression fracture in the T3 thoracic vertebral body. Imaging studies disclosed a disseminated systemic disease involving abdominopelvic lymph nodes and cervical and thoracic vertebral bodies. The needle biopsy of the pelvic lymph node disclosed diffuse proliferation of monomorphic small round cells that were diffusely positive for CD30 and ALK. A diagnosis of ALK+ ALCL with a monomorphic SC pattern was rendered. DISCUSSION: A retrospective review of the gastric biopsies with the aid of immunohistochemistry enabled us to recognise the presence of lymphomatous infiltrates with a mixed LH and SC pattern in every piece of gastric biopsies that were repeatedly misdiagnosed as inflammatory lesions. This case illustrates a significant diagnostic pitfall of the LH- and SC-patterns in ALK+ ALCL, in which the tumour cells featuring lymphoid, plasmacytoid or histiocytoid appearance can be masqueraded as inflammatory cells.

Influence of exposure to summer environments on skin properties.

BACKGROUND: Although cosmetic companies have launched products to combat extreme environments (hot or cold) and various pollutants, research into the effects of these conditions on skin properties is lacking. We aimed to investigate the influence of exposure to outdoor environments during summer on skin properties. METHODS: We enrolled 20 women in their 20s and 40s. They were exposed to outdoor and indoor environments for 90 min each in July 2016. Skin evaluations were performed on the face (forehead and cheek) and forearm. Skin hydration level, sebum secretion, trans-epidermal water loss (TEWL), pH and greasiness were evaluated. RESULTS: Skin hydration levels, sebum secretion, TEWL and greasiness in all examined regions were higher after outdoor exposure than after indoor exposure; however, skin pH decreased after outdoor exposure. Hydration levels on the forearm and sebum secretion on the face increased, whereas hydration levels and TEWL on the cheek, greasiness in all regions except the cheek, and pH in all regions decreased during the 90-min outdoor exposure. The hydration levels in all regions except the cheek, sebum secretion and greasiness on the face increased, but the TEWL and the pH declined after being indoors. CONCLUSION: Hot environments cause the production of more sweat, increasing hydration levels, sebum secretion, TEWL, and greasiness and reducing skin pH. After acclimatization, skin hydration on the cheek decreases because of sweat evaporation. Cosmetics that are marketed for use in summer should control sweat and sebum secretion, solve related inconveniences, and provide moisture, especially on the cheeks.

Optimization of broth recovery for repair of heat-injured Salmonella enterica serovar Typhimurium and Escherichia coli O157:H7.

AIMS: The purpose of this research was to determine optimum conditions for broth recovery of heat-injured Salmonella Typhimurium and Escherichia coli O157:H7. METHODS AND RESULTS: Exposure to 55°C for 15 and 25 min, respectively, induced cellular injury to those pathogens. Comparison was made with the commonly used overlay method using selective medium for recovering sublethally injured cells of S. Typhimurium. For E. coli O157:H7, phenol red agar base with 1% sorbitol was used. After cell suspensions were heated at 55°C for selected time intervals, microbes were 10-fold diluted with brain heart infusion (BHI), tryptic soy broth (TSB) and TSB with 0·6% yeast extract (TSBYE) and incubated at 37°C for up to 3 h. At hourly intervals, diluents were plated onto selective medium for recovery. Simultaneously, diluents were plated onto tryptic soy agar (TSA) for recovery of sublethally injured cells. For overlays, diluents were plated onto TSA and overlaid with selective agar after a resuscitation interval. Broth recovery conditions for S. Typhimurium and E. coli O157:H7 were determined to be 1 h in any of the following broth media: BHI, TSB or TSBYE. When liquid resuscitation was applied to sublethally injured cells in food samples (milk), 1 h was also sufficient time for recovery. CONCLUSIONS: The broth recovery method is a convenient alternative to conventional recovery methods. SIGNIFICANCE AND IMPACT OF THE STUDY: Cells sublethally injured by control interventions might not grow on selective medium because they have no resistance to several selective compounds. However, injured cells can recuperate and multiply under conditions sufficient for recovery. To repair and detect heat-injured cells, the overlay method is commonly used but this method has some limitations. This study confirms the effectiveness of liquid resuscitation method on recovery of injured cells. The broth recovery can replace the overlay method due to greater convenience and timesaving.