Immune-related adverse events and outcomes among pan-cancer patients receiving immune checkpoint inhibitors: A monocentric real-world observational study.

BACKGROUND: Real-world evidence on immune-related adverse events (irAEs) are relatively insufficient. Herein patterns and outcomes of irAEs after administration of anti-programmed cell death 1 (PD-1) and its legend 1 (PD-L1) antibodies were investigated. METHODS: Patients treated with anti-PD-1/PD-L1 drugs from January 2018 to September 2021 at Huadong Hospital, Fudan University were included. Common Terminology Criteria for Adverse Events (CTCAE) was used for irAEs evaluation. The primary endpoints were the clinical description of irAEs. RESULTS: Two hundred and forty-one solid tumor patients were included, with lung cancer as the most common tumor type (56%). 187 (77.6%) patients presented any kind of irAEs. The median time to any irAE onset was 28 (95% CI 24-32) days. Skin toxicities are the most common irAEs (46.1%) and the irAEs (36.5%) occurred earliest after immune-checkpoint inhibitors. The most frequently occurred all-grade irAEs were rash (23.7%), myelosuppression (20.7%), and hepatic injury (19.5%). 23 (9.5%) patients died of severe irAEs, which consists of 10 patients with pneumonitis, four colitis, four myocarditis, and one each for gastritis, pulmonary embolism, myelosuppression, hypophysitis, and encephalitis. Patients with any irAE onset had significantly longer progression-free survival (PFS) (p = 0.013) and overall survival (OS) (p = 0.007), respectively, than patients without irAEs. In addition, patients with skin toxicities (p = 0.012) or blood toxicities (p = 0.015) had achieved a longer PFS, than those without corresponding toxitities, respectively. CONCLUSION: Most irAEs are mild and manageable, while some irAEs can present at later time or can be life-threatening, especially pneumonitis as we observed. Patients with any irAE onset may achieve a better prognosis than those without irAEs, and presentation of skin or blood toxicities will indicate a better PFS.

A case of infection-induced thrombotic thrombocytopenic purpura.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) are a group of microvascular thrombohemorrhagic syndromes with low incidence and high mortality, which are characterized by thrombocytopenia, microangiopathic hemolytic anemia, fever, neuropsychiatric disorders, and renal involvement. In addition, TTP has a high rate of misdiagnosis and underdiagnosis due to the lack of specific clinical manifestations. CASE REPORT: A male patient aged 47 years was admitted to our hospital with complaints of dizziness and nausea for 2 days and soy-colored urine for 1 day. The patient had caught a cold and suffered from fever, dizziness, and nausea 2 days before admission. These symptoms were relieved by self-administration of berberine 1 day before admission. Later, the patient found that the urine was scanty and soy-colored. Physical examination on admission showed that the patient developed apathy, with occasional babbling, yellowing skin and sclera, and scattered bleeding spots on the anterior chest area. Based on auxiliary tests combined with clinical manifestations, the patient was diagnosed with TTP and administered plasma exchange, hemofiltration, hormone, and anti-platelet therapies. The patient recovered and was discharged after 3 weeks. The patient regularly took aspirin and was followed up one year later with no recurrence. CONCLUSION: TTP is an acute severe disease with complex etiology, abrupt onset, and dangerous conditions. In this patient with TTP, an important cause of the disease may have been an acute gastrointestinal infection. The plasma examination in another hospital revealed positive results for ADAMTS13 inhibitors, providing strong evidence for the diagnosis of this case. Multiple plasma exchanges and glucocorticoids yielded favorable treatment results and were critical measures of successful treatment of TTP.

[A Real-world Study on the Incidence and Outcome of Immune-related Adverse Events in Lung Cancer Patients].

BACKGROUND: Immune-related adverse events (irAEs) are commonly occurred in patients treated with immune checkpoint inhibitors. However, evidence of irAEs derived from the Chinese population is relatively lacking. The aim of this study was to investigate the incidence and outcomes of irAEs in Chinese patients with lung cancer after receiving immune checkpoint inhibitors (ICIs). METHODS: Clinical and follow-up data from lung cancer patients who received at least one time of ICIs from January 2018 to September 2021 at Huadong Hospital, Fudan University were included. Statistical descriptions and Kaplan-Meier method were used to analyze the overall incidence of irAEs, as well as the incidence and outcomes of each type of irAEs. RESULTS: 135 patients were included in the study. 106 patients (78.5%) presented at least one type of irAEs, and the median time to first irAEs onset was 28 d. Most irAEs occurred at early time after treatment, and most irAEs were mild-moderate and reversible. 57 patients (42.2%) died at the study cutoff. The mortality rate of severe irAEs was 12.6% (n=17), and among them 7 patients (41.2%) died of pneumonitis. The median progression-free survival (PFS) and overall survival (OS) time of the total population was 505 d (95%CI: 352-658) and 625 d (95%CI: 491-759), respectively. Patients who presented any irAEs achieved a longer PFS than those who did not (median PFS: 533 d vs 179 d, P=0.037, HR=0.57), while patients who presented skin toxicities achieved a longer OS than patients who did not (median OS: 797 d vs 469 d, P=0.006, HR=0.70). CONCLUSIONS: In real-world settings, irAEs in lung cancer patients were commonly observed, with pneumonitis as the most common fatal irAEs. In addition, patients who presented any irAEs may tend to achieve a longer PFS.

Intake of Sugar Substitute Gummy Candies Benefits the Glycemic Response in Healthy Adults: A Prospective Crossover Clinical Trial.

Sugar reduction in food has attracted great health concerns worldwide. Gummies have been one of the most popular and highly favored candies due to their chewable properties, simplicity to swallow, and delicious taste. The general perception is that gummies raise blood sugar levels, but the truth is that gummies with the right formula can control glycemic response. The purpose of this study is to investigate the effects of the gummy dosage form and sugar types on the glycemic response control. Maltitol and erythritol as sweetener alternatives were applied in gummy candies (total and partial sugar substitutes gummy, T-SG and P-SG), with sucrose-based gummies used as comparisons (CG). A prospective crossover study was then conducted on 17 healthy adults. The effects of different types of gummies on glycemic response in healthy adults were evaluated on the basis of the participants' glycemic index (GI) and glycemic load (GL) values. Every three-day interval, participants took CG, P-SG, T-SG, and glucose solution, respectively, and the theoretical glucose conversion content was kept the same in all groups for each trial. Each participant performed four tests with each sample and recorded the changes in blood glucose after food consumption. It was found that all three types of gummies slowed down subjects' glycemic response when not taken in excess, and the improvement effect was in the trend of T-SG > P-SG > CG. Both P-SG and T-SG were low-GI candies (54.1 and 49.9). CG that was not consumed in excess of 17.2 g had a high GI (81.9) but a low GL (<10). Texture analysis and in vitro digestion were used to explore the effect of gummy matrix on glucose release. T-SG and P-SG retained a higher hardness and were less hydrolyzed to release glucose during digestion compared with CG. Additionally, experiments have revealed that gummies can reverse the poor glucose tolerance in women. In conclusion, gummies are a good carrier for dietary supplements due to their sustained-release characteristic of available carbohydrates and provide healthier options for people in control of glucose homeostasis.

Long noncoding RNA LHFPL3-AS2 suppresses metastasis of non-small cell lung cancer by interacting with SFPQ to regulate TXNIP expression.

Lung cancer is the most common cancer and the leading cause of cancer deaths worldwide. In addition to coding genes, the contribution of long noncoding RNA (lncRNA) to non-small cell lung cancer (NSCLC) remains unclear. Here, we explored lncRNA expression profiles by Affymetrix Gene Chip Human Transcriptome Array 2.0 in 37 paired samples of tumorous NSCLC tissues and adjacent nontumorous tissues. We showed that LHFPL3-AS2 is a novel lncRNA, significantly decreased in NSCLC tissues. LHFPL3-AS2 was further validated in an additional 93 paired samples of NSCLC. Low levels of LHFPL3-AS2 expression were highly correlated with poor overall survival, TNM stage, and metastasis of NSCLC patients. Enhanced expression of LHFPL3-AS2 inhibited NSCLC invasion and metastasis in vitro and in vivo. Moreover, downregulation of LHFPL3-AS2 reduced its specific interaction with SFPQ, resulting in more SFPQ binding to the promoter of TXNIP and causing the transcriptional repression of TXNIP, thus finally promoting the migration and invasion of NSCLC cells. Furthermore, LHFPL3-AS2 was shown to be regulated by EGR1 under hypoxia.

A case report of rhabdomyolysis and osteofascial compartment syndrome in a patient with hypothyroidism and diabetes.

BACKGROUND: Hypothyroidism is frequent and has various forms of muscle involvement. We report the diagnosis and treatment of a case of rhabdomyolysis, bilateral osteofascial compartment syndrome (OCS) of the lower extremities, and peroneal nerve injury causing bilateral foot drop in a diabetic patient with hypothyroidism. CASE PRESENTATION: A 66-year-old man with diabetes for 22 years was admitted because of drowsiness, tiredness, facial swelling, and limb twitching for 2 months, and red and swollen lower limb skin for 3 days. Serum creatinine kinase (CK), CK-MB, myoglobin (Mb), blood glucose, and HbA1c were elevated. TSH, thyroid peroxidase antibodies, and antithyroglobulin antibodies were elevated. FT3 and FT4 were low. Urine was dark brown. He was diagnosed with hypothyroidism, rhabdomyolysis, and OCS. CK, CK-MB, and Mb returned to normal after treatment with thyroid hormone, insulin, albumin infusion, ceftriaxone, ulinastatin, and hemofiltration, and the redness and swelling of the lower limbs were relieved, but the patient developed dropping feet. The patient recovered well but had to undergo rehabilitation. CONCLUSION: Hypothyroidism may induce rhabdomyolysis, OCS, and other complications. This case reminds us of the importance of screening for hypothyroidism and strengthens the clinicians' understanding of the disease.

[Value of combined detection of biomarkers in early diagnosis and prognosis of patients with septic myocardial injury].

OBJECTIVE: To investigate the value of combined detection of biomarkers in early diagnosis and prognosis of patients with septic myocardial injury. METHODS: The clinical data of 103 patients with sepsis admitted to the intensive care unit (ICU) of the First Affiliated Hospital of Baotou Medical College of Inner Mongolia University of Science and Technology from October 2018 to January 2021 were enrolled. According to the cardiac troponin I (cTnI) at admission of ICU, they were divided into septic myocardial injury group (cTnI ≥ 0.15 µg/L) and non-septic myocardial injury group (cTnI < 0.15 µg/L). The serum levels of heart-type fatty acid-binding protein (H-FABP), procalcitonin (PCT), C-reactive protein (CRP), MB isoenzyme of creatine kinase (CK-MB), cTnI and N-terminal pro-brain natriuretic peptide (NT-proBNP) within 6 hours after ICU admission and the worst value of acute physiology and chronic health evaluation II (APACHE II) score within 24 hours after ICU admission in 103 patients was recorded as well as the 28-day prognosis of patient with septic myocardial injury. Spearman correlation analysis was used to analyze the correlation of each index; receiver operating characteristic curve (ROC curve) was drawn, and the area under ROC curve (AUC) was calculated to analyze the early diagnosis and prognostic value of each index and APACHE II score alone or combined detection in patients with septic myocardial injury. RESULTS: (1) Among 103 patients with sepsis, 58 patients were complicated with myocardial injury and 45 patients were not complicated with myocardial injury. The serum levels of PCT, CRP, NT-proBNP, CK-MB, cTnI, H-FABP and APACHE II score in patients with septic myocardial injury were significantly higher than those in patients without septic myocardial injury [PCT (µg/L): 3.46±1.35 vs. 1.89±0.43, CRP (mg/L): 81.1±26.8 vs. 65.3±19.1, NT-proBNP (U/L): 8 261.4±2 346.9 vs. 6 120.2±1 809.6, CK-MB (U/L): 15.89±6.25 vs. 12.14±4.24, cTnI (µg/L): 1.50 (0.91, 2.21) vs. 0.18 (0.16, 0.19), H-FABP (µg/L): 26.45±8.24 vs. 12.82±5.73, APACHE II score: 24.0 (18.0, 29.0) vs. 16.0 (14.0, 18.0), all P < 0.01]. Spearman correlation analysis showed that PCT, CRP and APACHE II scores were positively correlated with NT-proBNP, CK-MB, cTnI and H-FABP. ROC curve analysis showed that H-FABP in the diagnosis of septic myocardial injury (AUC = 0.916) was superior to NT-proBNP (AUC = 0.756) and CK-MB (AUC = 0.675); the AUC of NT-proBNP and CK-MB combined with H-FABP was 0.921, the sensitivity was 82.1%, and the specificity was 88.2%. (2) Twenty-three patients survived in 28 days, and 35 died. The levels of serum PCT, CRP, NT-proBNP, CK-MB, cTnI, H-FABP and APACHE II score in death group were significantly higher than those in survival group [PCT (µg/L): 3.86±1.27 vs. 2.84±1.24, CRP (mg/L): 92.3 (65.0, 101.7) vs. 74.3 (65.7, 79.8), NT-proBNP (ng/L): 9 106.4±2 013.9 vs. 6 975.5±2 266.7, CK-MB (U/L): 17.90±6.49 vs. 12.82±4.46, cTnI (µg/L): 2.11±0.86 vs. 1.12±0.44, H-FABP (µg/L): 30.08±7.90 vs. 20.93±5.14, APACHE II score: 25.0 (20.0, 30.0) vs. 19.0 (17.0, 24.0), all P < 0.01]. ROC curve analysis showed that H-FABP in evaluating 28-day death of patients with septic myocardial injury (AUC = 0.839) was superior to PCT (AUC = 0.707), CRP (AUC = 0.716), NT-proBNP (AUC = 0.761), CK-MB (AUC = 0.733), cTnI (AUC = 0.824) and APACHE II score (AUC = 0.724); the AUC of NT-proBNP and cTnI combined with H-FABP was 0.888, the sensitivity was 91.4%, and the specificity was 82.6%. CONCLUSIONS: H-FABP plays an important role in the early diagnosis and prognosis of septic myocardial injury. Early combined detection of NT-proBNP, CK-MB and H-FABP can significantly improve the diagnostic ability of septic myocardial injury, and NT-proBNP and cTnI combined with H-FABP can significantly improve the ability to predict the adverse prognosis of sepsis myocardial injury.

Novel strategy for enhancing the color intensity of ß-Carotene: Enriching onto the oil-water interface.

A novel strategy to enhance the color intensity of ß-carotene (BC), namely, "interfacial enriching", was developed in this work. As the sole emulsifier in W/O emulsion, BC particles were enriched onto the droplet surface through emulsifying process. By increasing the concentration of BC in oil phase from 1 mg/g to 5 mg/g, the average droplet size of the emulsion decreased from 92.2 ± 5.1 µm to 34.0 ± 5.4 µm. Too low (e.g. ≤ 1 mg/g) or too high (e.g. ≥25 mg/g) concentration of BC in the oil phase yielded an insufficient coverage or flocculation of the droplets. By enriching onto the interface, the color intensity of BC were enhanced apparently at the reflectance wavelength ranging from 500 nm to 700 nm, compared with that of the BC encapsulated within the emulsion droplets. This enhancement was due to the higher availability of incident light for the BC particles on the interface than that of the BC particles buried inside the droplets.

circFOXM1 promotes proliferation of non-small cell lung carcinoma cells by acting as a ceRNA to upregulate FAM83D.

BACKGROUND: Biological role and clinical significance of circular RNAs (circRNAs) remain largely unknown. Herein, we aimed to investigate biological function, molecular mechanism, and clinical significance of a circular RNA FOXM1 (circFOXM1) in non-small cell lung cancer (NSCLC). METHODS: Expression of circFOXM1 was measured in 48 paired samples of NSCLC by qRT-PCR. Functional roles of circFOXM1 on tumor cells were explored by in vitro and in vivo assays. Transcriptome sequencing was employed to screen the molecules involved in circFOXM1 regulatory network. RNA immunoprecipitation, luciferase analysis, RNA pull-down, and rescue assay were used to investigate potential mechanisms of circFOXM1. RESULTS: We found that circFOXM1 was significantly upregulated in NSCLC tissues, and its upregulation was positively correlated with advanced clinical stage and poor prognosis of NSCLC patients. Gain or loss-of-function assay showed that circFOXM1 promoted cell proliferation and cell cycle progression. In vivo assays showed that silencing circFOXM1 inhibited xenograft tumor growth. Mechanically, transcriptome sequencing data indicated that silencing circFOXM1 led to the downregulation of cell cycle-related mRNAs. RNA pull-down and dual-luciferase reporter assay suggested that circFOXM1 could bind to miR-614, and FAM83D was an essential gene involved in the circFOXM1/miR-614 regulatory network. CONCLUSIONS: circFOXM1promotes NSCLC progression by interacting with miR-614 and thus inactivating the function of miR-614, which will further release the suppression of FAM83D. circFOXM1/miR-614/FAM83D regulatory network may serve as a potential therapeutic target for NSCLC patients.

circTP63 functions as a ceRNA to promote lung squamous cell carcinoma progression by upregulating FOXM1.

Circular RNAs (circRNAs) are identified as vital regulators in a variety of cancers. However, the role of circRNA in lung squamous cell carcinoma (LUSC) remains largely unknown. Herein, we explore the expression profiles of circRNA and mRNA in 5 paired samples of LUSC. By analyzing the co-expression network of differentially expressed circRNAs and dysregulated mRNAs, we identify that a cell cycle-related circRNA, circTP63, is upregulated in LUSC tissues and its upregulation is correlated with larger tumor size and higher TNM stage in LUSC patients. Elevated circTP63 promotes cell proliferation both in vitro and in vivo. Mechanistically, circTP63 shares miRNA response elements with FOXM1. circTP63 competitively binds to miR-873-3p and prevents miR-873-3p to decrease the level of FOXM1, which upregulates CENPA and CENPB, and finally facilitates cell cycle progression.

Epidermal growth factor receptor-targeted immunomagnetic liposomes for circulating tumor cell enumeration in non-small cell lung cancer treated with epidermal growth factor receptor-tyrosine kinase inhibitors.

OBJECTIVES: To establish a circulating tumor cell (CTC) enrichment system for non-small cell lung cancer (NSCLC) patients who received first-line treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKI), using EGFR magnetic liposomes (EGFR-ML). MATERIALS AND METHODS: An inverted evaporation method was used to develop antibody modified EGFR-ML. Peripheral blood was collected from NSCLC patients who underwent first-line EGFR-TKI treatment for CTC enumeration. RESULTS: Protein electrophoresis, magnetic saturation curve, and ultraviolet absorption spectrum showed successful incorporation of the EGFR antibody on the surface of the magnetic microspheres, and the development of EGFR-ML was ascertained based on cell morphology and particle size. Using EGFR-ML, CTC were successfully enriched from blood samples and were identified in 77.3% (99/128) of the cohort. When compared to the 21L858R variant, EGFR-19del showed lower CTC counts by EGFR-ML (CTCEGFR). At one month after EGFR-TKI, a lower CTCEGFR was associated with partial response (PR) during treatment (CTCEGFR < 6 vs. ≥ 6/7.5 mL, 75% vs. 49%, P = 0.027). In addition, patients with a lower CTCEGFR at 3 months after EGFR-TKI achieved a longer progression-free survival (PFS) [CTCEGFR < 6 vs. ≥ 6/7.5 mL, 13 months vs. 10.4 months, HR = 2.4, P = 0.042]. CTCEGFR significantly increased at the time of RECIST-progressive disease (RECIST-PD). Representative cases showed that CTCEGFR might increase before and beyond RECIST-PD until no clinical benefit could be acquired from EGFR-TKI. CONCLUSION: We showed that establishing a CTC enrichment system by antibody modified EGFR-ML in NSCLC is feasible. CTC enumeration by EGFR-ML may have the potential to supplement RECIST in dynamically monitoring the response of NSCLC patients' to first-line EGFR-TKI.

Survival analysis for lung adenosquamous carcinoma patients with brain metastasis.

Purpose: We retrospectively collected consecutive survival data of lung adenosquamous cell carcinoma (ASC) patients with brain metastasis (BM) in our institute and discussed the factors related to prognosis of these patients. Patients and Methods: A total of 42 patients diagnosed as lung ASC with BM between July 1, 2008 and December 31, 2010 at the Department of Respiratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University were retrospectively reviewed. Time to BM (TTB) and overall survival (OS) data were analyzed. OS1 was calculated from the time ASC was diagnosed until the death of a patient. OS2 was defined as the duration from BM was first identified to the death of a patient. 1-year, 2-year and 3-year survival rates were also computed. Univariate and multivariate survival analysis was performed using Kaplan-Meier methods and Cox regression. Results: The median TTB for all patients was 5.7 months [95% confidence interval (CI): 0.8 - 10.6 months]. The median OS1 was 13.8 months (95%CI: 11.2 - 16.4 months). TTB longer than 12 months [adjusted HR: 0.15 (95%CI: 0.05 -0.48 vs. TTB≤ 6 months, P=0.001); 0.22 (95%CI: 0.07- 0.71, vs. TTB 6-12 months, P=0.010) and resection for BM lesions [adjusted hazard ratio (HR): 0.47 (95%CI: 0.24 - 0.94 vs. not resected, P=0.032)] were independent predictors for a longer OS1. The median OS2 was 7.9 months (95%CI: 4.5 - 11.3 months). Treatment cycles more than 3 [adjusted HR: 0.41 (95%CI: 0.20 - 0.83 vs. treatment cycles <3, P=0.013)] was an independent predictor for a longer OS2. Conclusions: This study shows that resection of BM if possible, and standard chemo-radiotherapy in patients with multiple BM lesions is associated with longer overall survival.

The Mobile Charging Vehicle Routing Problem with Time Windows and Recharging Services.

For the environmental friendliness of the technology on battery electric vehicles, there is growing attention on it. However, the market share of battery electric vehicles remains low due to the range anxiety. As a remedy, the mobile charging services could offer charging service at any time or locations requested. For profitability of the services, the operator should route the charging vehicles in a more efficient manner. For this consideration, we formulate the mobile charging vehicle routing problem as a mixed integer linear program based on the classical vehicle routing problem with time windows. To demonstrate the model, test instances are designed and computational results are presented. In order to examine the change of the number of mobile charging vehicles and travel distance, sensitivity analyses, such as battery capacity and recharging rate, are performed. The results show that larger battery capacity, quicker charging rate, or higher service efficiency could decrease the number of mobile charging vehicles and total traveled distances, respectively.

Mechanical Metamaterials Foams with Tunable Negative Poisson's Ratio for Enhanced Energy Absorption and Damage Resistance.

Systematic and deep understanding of mechanical properties of the negative Poisson's ratio convex-concave foams plays a very important role for their practical engineering applications. However, in the open literature, only a negative Poisson's ratio effect of the metamaterials convex-concave foams is simply mentioned. In this paper, through the experimental and finite element methods, effects of geometrical morphology on elastic moduli, energy absorption, and damage properties of the convex-concave foams are systematically studied. Results show that negative Poisson's ratio, energy absorption, and damage properties of the convex-concave foams could be tuned simultaneously through adjusting the chord height to span ratio of the sine-shaped cell edges. By the rational design of the negative Poisson's ratio, when compared to the conventional open-cell foams of equal mass, convex-concave foams could have the combined advantages of relative high stiffness and strength, enhanced energy absorption and damage resistance. The research of this paper provides theoretical foundations for optimization design of the mechanical properties of the convex-concave foams and thus could facilitate their practical applications in the engineering fields.

Feasibility of continuing crizotinib therapy after RECIST-PD in advanced non-small cell lung cancer patients with ALK/ROS-1 mutations.

Objectives: To study whether ongoing clinical benefits of continuing anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) inhibition are achieved by crizotinib treatment post progressive disease (PD) in advanced non-small cell lung cancer (NSCLC) patients harboring ALK/ROS1 mutations. Materials and methods: Demographic and clinicopathologic parameters were collected from 38 patients who continued crizotinib therapy beyond Response Evaluation Criteria in Solid Tumors (RECIST)-defined PD and analyzed. After adjusting for potential confounding factors, factors influencing the time from RECIST-PD to crizotinib discontinuation (progress-free survival 2, PFS2) were analyzed. Results: The median time from first dose treatment to RECIST-PD (PFS1) was 9.6 months (95% CI 5.6-13.6 months). The estimated median PFS2 was 5.9 months (95% CI 0.1-11.7 months). Six- and twelve-month crizotinib treatment probabilities after initial PD were 42.1% (95% CI 25.7-58.6%) and 21.1% (95% CI 7.5-34.6%), respectively. Patients who demonstrated RECIST-PD due to new lesions had a longer median PFS2 compared to patients who were attested to enlargement of original lesions (10.0 versus 2.4 months, p = 0.009). The median PFS2 was numerically longer among patients who received local therapy compared to those who did not receive local therapy, however the difference was not significant (9.9 versus 4.2 months, p = 0.094). Multivariable Cox regression analysis showed that only the progression pattern [new lesions versus enlargement of original lesions, HR = 0.329 (95% CI 0.138-0.782), p = 0.012] remained an independent prognostic factor of PFS2. Conclusion: Continuation of crizotinib therapy after RECIST-PD in Chinese NSCLC patients with positive ALK/ROS1 mutations is feasible in clinical practice.

Whole-genome sequencing reveals genomic signatures associated with the inflammatory microenvironments in Chinese NSCLC patients.

Chinese lung cancer patients have distinct epidemiologic and genomic features, highlighting the presence of specific etiologic mechanisms other than smoking. Here, we present a comprehensive genomic landscape of 149 non-small cell lung cancer (NSCLC) cases and identify 15 potential driver genes. We reveal that Chinese patients are specially characterized by not only highly clustered EGFR mutations but a mutational signature (MS3, 33.7%), that is associated with inflammatory tumor-infiltrating B lymphocytes (P = 0.001). The EGFR mutation rate is significantly increased with the proportion of the MS3 signature (P = 9.37 × 10-5). TCGA data confirm that the infiltrating B lymphocyte abundance is significantly higher in the EGFR-mutated patients (P = 0.007). Additionally, MS3-high patients carry a higher contribution of distant chromosomal rearrangements >1 Mb (P = 1.35 × 10-7), some of which result in fusions involving genes with important functions (i.e., ALK and RET). Thus, inflammatory infiltration may contribute to the accumulation of EGFR mutations, especially in never-smokers.

Exosomes as a liquid biopsy for lung cancer.

In lung cancer and other malignancies, the so-called "liquid biopsy" is quickly moving into clinical practice. Its full potential has not yet been fully identified, but the "liquid biopsy" is no longer a promise but has become a reality that allows for better treatment selection and monitoring of lung cancer. This emerging field has significant potential to make up for the limitations of the traditional tissue-derived biomaterials. Exosomes are spherical nano-sized vesicles with a diameter of 40-100 nm and a density of 1.13-1.19 g/ml. In both physiological and pathological conditions, exosomes can be released by different cell types, including immune cells, stem cells and tumor cells. These small molecules may serve as promising biomarkers in lung cancer "liquid biopsy" as they can be easily obtained from most body fluids. In addition, the lipid bilayer of exosomes allows for stable cargoes which are relatively hard to degrade. Furthermore, the composition of exosomes reflects that of their parental cells, suggesting that exosomes are potential surrogates of the original cells and, therefore, are useful for understanding cell biology. Previous studies have demonstrated that exosomes play important roles in cell-to-cell communication. Moreover, tumor-derived exosomes are evolved in tumor-specific biological process, including tumor proliferation and progression. Recently, a growing number of studies has focused on exosomal cargo and their use in lung cancer genesis and progression. In addition, their utility as lung cancer diagnostic, prognostic and predictive biomarkers have also been studied. The current review primarily summaries lung cancer-related exosomal biomarkers that have recently been identified and discusses their potential in clinical practice.

Use of SuperARMS EGFR Mutation Detection Kit to Detect EGFR in Plasma Cell-free DNA of Patients With Lung Adenocarcinoma.

BACKGROUND: The SuperARMS EGFR Mutation Detection Kit (SuperARMS) is highly selective and sensitive and able to detect 41 of the most common somatic mutations in exons 18 to 21 of the epidermal growth factor receptor gene (EGFR). It allows for the detection of 0.2% to 0.8% mutant DNA in a background of 99.8% to 99.2% normal DNA. The present study assessed the performance of SuperARMS in detecting EGFR mutations in cell-free DNA (cfDNA) samples derived from plasma in patients with advanced lung adenocarcinoma. MATERIALS AND METHODS: A total of 180 patients with advanced clinical stage lung adenocarcinoma were retrospectively registered. The concordance between the EGFR mutations detected by SuperARMS and ARMS (AmoyDx EGFR 29 Mutations Detection Kit) was analyzed. RESULTS: Of the 180 samples, 57 (31.7%) were positive for EGFR mutations using SuperARMS, with 38 (21.1%) positive using ARMS. For the entire cohort, the positive, negative, and overall concordance rates were 97.3% (95% confidence interval [CI], 86.2%-99.5%), 85.3% (95% CI, 78.6%-90.2%), and 87.8% (95% CI, 82.2%-91.8%), respectively. The kappa value was 0.69 (95% CI, 0.57-0.81). For the 61 treatment-naive patients and 119 previously treated patients, the kappa values were 0.59 (95% CI, 0.37-0.79) and 0.74 (95% CI, 0.60-0.87), respectively. SuperARMS identified 9 samples harboring the T790M mutation; of these, only 1 (11.1%) was detected using ARMS. CONCLUSION: SuperARMS is a promising plasma-based assay for EGFR mutations, including T790M. It might be useful in advanced-stage lung adenocarcinoma patients whose tissue biopsy samples are insufficient for a traditional diagnostic EGFR assay or for patients with a poor performance status.

Classifying Non-Small Cell Lung Cancer by Status of Programmed Cell Death Ligand 1 and Tumor-Infiltrating Lymphocytes on Tumor Cells.

Purpose: To explore the possible correlation between programmed death ligand 1 (PD-L1)/tumor-infiltrating lymphocytes (TIL) status and clinical factors in non-small cell lung (NSCLC). Materials and Methods: A total of 126 surgical NSCLC samples with stage I to IIIA were retrospectively collected and analyzed. Immunohistochemistry (IHC) assays were used to detect PD-L1 protein expression. PD-L1 positivity on tumor cells was defined by positive tumor cell (TC) percentage using 5% cutoff value. Results: Thirty-seven patients (29.4%), thirty patients (23.8%), six patients (4.8%) and fifty-three patients (42%) were classified as type I (PD-L1+, TIL+), type II (PD-L1-, TIL-), type III (PD-L1+, TIL-) and type IV (PD-L1-, TIL+) tumor environments according to PD-L1/TIL status, respectively. Statistical differences could be observed in factors including gender (P<0.001), smoking status (P<0.001), age (P=0.002), histological types (P<0.001), EGFR mutation (P=0.008) and KRAS mutation (P=0.003) across the four type tumors. Type I tumors were associated with ever smoking, non-adenocarcinoma histological types and KRAS mutation. Type II tumors were associated with female gender, never-smoking, adenocarcinoma histological types and EGFR mutation. Type III tumors were associated with ever smoking and type IV tumors were associated with female gender and EGFR mutation. Conclusion: Clinical factors associated with NSCLC microenvironment types based on PD-L1/TIL differed a lot across different types. The findings of this study may help to facilitate the understanding of the relationship between tumor microenvironment and clinical factors, and also the selecting of patients for combination immunotherapies.