Search

Background: APG-1387 is a novel second mitochondrial-derived activator of caspases mimetic, small-molecule inhibitor targeting inhibitor of apoptosis proteins. We report results from two phase I trials evaluating the tolerability, safety, and antitumor activity of APG-1387 monotherapy and APG-1387 plus toripalimab [a programmed cell death 1 (PD-1) inhibitor] for advanced solid tumors., Patients and Methods: Participants aged ≥18 years who had histologically confirmed advanced solid tumors with no appropriate standard of care (or refractory to standard care) were eligible. Patients received escalating intravenous doses of APG-1387 alone or combined with fixed-dose toripalimab (240 mg every 3 weeks) in a '3 + 3' design. Primary endpoints were dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) in the monotherapy trial, and recommended phase II dose (RP2D) in the combination therapy trial. Secondary endpoints included the pharmacokinetic and pharmacodynamic profiles and preliminary efficacy in both trials., Results: In the monotherapy trial, 28 subjects were enrolled and received ≥1 treatment cycle. No DLT was reported among the 28 subjects, and the MTD was not reached. One participant (3.6%) had a grade ≥3 treatment-related adverse event (TRAE) of alanine aminotransferase elevation. In efficacy analysis of 23 participants, none achieved an objective response, and the disease control rate was 21.7%. In the combination trial, 22 subjects were enrolled and included in all analyses. There was one DLT of grade 3 lipase elevation. The MTD was not reached. Four grade ≥3 TRAEs occurred in three participants (13.6%), with the most common being lipase elevation (n = 2). The RP2D was 45 mg weekly. The objective response rate was 13.6%, with complete response achieved in one subject, and the disease control rate was 54.5%., Conclusions: APG-1387 45 mg weekly plus toripalimab was well tolerated and is recommended for further study, with preliminary clinical activity observed in study participants with advanced solid tumors., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

As immunotherapy makes its way into the perioperative setting, a growing number of clinical trials are expanding the evidence base for resectable non-small cell lung cancer (NSCLC) management. Identifying the optimal treatment pattern-whether it's neoadjuvant, adjuvant, or a combination of both-is a crucial next step, particularly in pinpointing which patients benefit the most. This decision-making process requires a multi-disciplinary treatment team capable of utilizing tissue and plasma genomic testing to inform therapeutic choices. Leveraging the perioperative treatment platform, it remains pivotal to integrate circulating tumor DNA (ctDNA) monitoring into clinical trial design efficiently and provide clear guidance on treatment., Competing Interests: Declaration of interests Y.-L.W reports grants and personal fees from AstraZeneca, BMS, and Pfizer and personal fees from Boehringer Ingelheim, Eli Lilly, Hengrui, MSD, Sanofi, and Roche., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Circulating tumor cells (CTCs) are prognostic biomarker in non-small-cell lung cancer (NSCLC). CTCs could also be used as predictor of efficacy of systemic treatments in advanced NSCLC., Objectives: We described the dynamic changes of CTCs during first-line platinum-based chemotherapy in advanced NSCLC and clarified the correlation between CTC counts and efficacy of chemotherapy., Design: Chemotherapy is administered and blood specimens are collected at four time points from baseline to disease progression for CTC detection., Methods: This multicenter prospective study enrolled patients with previously untreated stage III or IV NSCLC fit for standard platinum-based chemotherapy. Bloods were sampled as per standard operating procedures at baseline, cycle 1 and cycle 4 of chemotherapy, and at disease progression for CTC analysis using the CellSearch system., Results: Among 150 patients enrolled, median overall survival (OS) was 13.8, 8.4, and 7.9 months in patients with CTC - , KIT - CTC, and KIT + CTC at baseline ( p  = 0.002). Patients with persistent negative CTC (46.0%) had longer progression-free survival [5.7 months, 95% confidence interval (CI): 5.0-6.5 versus 3.0 months, 0.6-5.4; hazard ratio (HR): 0.34, 95% CI: 0.18-0.67) and OS (13.1 months, 10.9-15.3 versus 5.6 months, 4.1-7.1; HR: 0.17, 0.08-0.36) compared with patients with persistent positive CTC (10.7%), which was not impacted by chemotherapy. Chemotherapy decreased CTC from 36.0% (54/150) to 13.7% (13/95)., Conclusions: CTC persistent presence during treatment represents poor prognosis and resistance to chemotherapy in advanced NSCLC. Chemotherapy could effectively eliminate CTCs. Molecular characterization and the functionalization of CTC will be warranted for further intensive investigation., Trial Registration: NCT01740804., Competing Interests: Yi-Long Wu reports receiving speaker bureau fees from AstraZeneca, Bristol-Myers Squibb, Pfizer Inc., Roche AG, Boehringer Ingelheim, Eli Lilly & Co., Merck Sharp & Dohme, and Sanofi and research grants from AstraZeneca, Bristol-Myers Squibb, Pfizer Inc., and Roche AG. Other authors declare that there is no conflict of interest., (© The Author(s), 2023.)

Background: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is still under investigation as adjuvant treatment for early-stage disease. Here, we performed a meta-analysis to evaluate the efficacy of adjuvant EGFR-TKI versus non-EGFR-TKI treatment in patients with completely resected non-small cell lung cancer (NSCLC) harboring EGFR mutation., Methods: Two investigators independently extracted data from databases. A meta-analysis was performed following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The protocol was registered in PROSPERO (ID: CRD42022316481). The primary outcome was disease-free survival (DFS) in patients with EGFR mutation, measured as the hazard ratio (HR). Other outcomes (of subgroup analyses) included overall survival (OS) and DFS., Results: After the systematic screening, eight studies with a total of 3098 patients with stage IB-IIIA NSCLC were included. The results show that in patients with EGFR mutation, the DFS in the adjuvant EGFR-TKI group was significantly superior to that in the control group, with a HR of 0.47 (95% confidence interval [CI]: 0.30-0.74; P = 0.001). In subgroup analyses of DFS, the benefit was observed in the EGFR-TKI group versus the chemotherapy group (HR 0.50, 95% CI 0.30-0.84; P = 0.009), the EGFR-TKI combined with chemotherapy group versus the chemotherapy group (HR 0.37, 95% CI 0.16-0.85; P = 0.02), and in stage IIA-IIIA NSCLC (HR 0.45, 95% CI 0.27-0.74; P = 0.002). However, the benefit of DFS did not translate into improved OS in the whole population (HR 0.79, 95% CI 0.54-1.14; P = 0.20)., Conclusion: EGFR-TKIs prolonged DFS but not OS in patients with completely resected stage II-IIIA NSCLC harboring EGFR mutation. Longer follow-ups and new clinical trials that can result in changes in clinical practice are needed., (© 2023. The Author(s).)

The adsorption and desorption of electrolyte ions strongly modulates the carrier density or carrier type on the surface of monolayer-MoS 2 catalyst during the hydrogen evolution reaction (HER). The buildup of electrolyte ions onto the surface of monolayer MoS 2 during the HER may also result in the formation of excitons and trions, similar to those observed in gate-controlled field-effect transistor devices. Using the distinct carrier relaxation dynamics of excitons and trions of monolayer MoS 2 as sensitive descriptors, an in situ microcell-based scanning time-resolved liquid cell microscope is set up to simultaneously measure the bias-dependent exciton/trion dynamics and spatially map the catalytic activity of monolayer MoS 2 during the HER. This operando probing technique used to monitor the interplay between exciton/trion dynamics and electrocatalytic activity for two-dimensional transition metal dichalcogenides provides an excellent platform to investigate the local carrier behaviors at the atomic layer/liquid electrolyte interfaces during electrocatalytic reaction.

Objective: This study aimed to investigate the impact of tumor mutational burden (TMB) and DNA damage repair (DDR) gene alteration on overall survival (OS) in advanced non-small cell lung cancer (NSCLC) patients., Patients and Methods: A DNA library of cancer cells from 67 NSCLC patients in stages III-IV was constructed for next-generation sequencing (NGS). Geneseeq422 probes were used for hybridization enrichment. The target-enriched library was sequenced on HiSeqNGS platforms, and we analyzed the relevant signaling pathways. Then, we correlated the OS of the patients with TMB and DDR mutations., Results: Many significant alterations were found, including in the EGFR, p53, KRAS, RB1, ERBB2, NF1, DNMT3A, ALK, MYC, PIK3CA, ROS1, BRAF, ARID1A, PTEN, CDKN2A, and FGF19 genes. We also identified many mutations in the genes relevant to the DDR pathway. Interestingly, we found that the TMB of patients with DDR gene mutations was dramatically higher than that in the DDR wild-type (WT). Univariable analysis showed that DNMT3A, RB1, DDR pathway-related gene mutations, and TMB were critical factors for the effects on OS. Multivariable analysis confirmed that DNMT3A and mutations in the DDR pathway-related genes were important for predicting OS., Conclusions: Multiple mutations in the genes of the DDR pathway caused higher TMB levels, which resulted in longer OS. By contrast, OS was significantly longer in patients with non-DNMT3A mutations than in those with DNMT3A variants. DNMT3A alteration in NSCLC patients led to poor outcomes.

The effect of blood pump flow rate on the cardiac functions of hemodialysis patients with arteriovenous fistula (AVF) is largely unknown. This study aimed to investigate if blood pump flow rate (Qb) and AVF access flow rate (Qa) can affect the cardiac function of Chinese hemodialysis patients. A total of 72 patients undergoing AVF hemodialysis were included from March 2010 to June 2014 and dichotomized into the high- and low-flow groups using the medians of Qb (220 mL/min) and Qa (1000 mL/min) as the cutoffs. The cardiac function parameters were measured by ultrasound dilution technique within the first (t + 30) and the last (t - 30) 30 min of dialysis. At t + 30, Qb-high group had significantly higher systolic blood pressure (SBP) and mean arterial pressure (MAP) than Qb-low group. At t - 30, Qb-high group had higher SBP, diastolic blood pressure (DBP), and MAP than Qb-low group. Qa-high group had higher SBP, MAP, cardiac output (CO), cardiac index (CI), central blood volume (CBV), and lower peripheral resistance than Qa-low group. Multiple linear regression showed that at t - 30, Qb was positively correlated with SBP and MAP. Qa was positively correlated with CO, CI, CBV, and PR but negatively correlated with heart rate. Although Qb > 220 mL/min and Qa >1000 mL/min would elevate some parameters, the means of SBP, DBP, MAP remain within the normal range, indicating that appropriate increase in blood pump flow rate has little effect on the cardiac function of hemodialysis patients., (© 2019 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

Background: Computed tomography (CT) is essential for pulmonary nodule detection in diagnosing lung cancer. As deep learning algorithms have recently been regarded as a promising technique in medical fields, we attempt to integrate a well-trained deep learning algorithm to detect and classify pulmonary nodules derived from clinical CT images., Materials and Methods: Open-source data sets and multicenter data sets have been used in this study. A three-dimensional convolutional neural network (CNN) was designed to detect pulmonary nodules and classify them into malignant or benign diseases based on pathologically and laboratory proven results., Results: The sensitivity and specificity of this well-trained model were found to be 84.4% (95% confidence interval [CI], 80.5%-88.3%) and 83.0% (95% CI, 79.5%-86.5%), respectively. Subgroup analysis of smaller nodules (<10 mm) have demonstrated remarkable sensitivity and specificity, similar to that of larger nodules (10-30 mm). Additional model validation was implemented by comparing manual assessments done by different ranks of doctors with those performed by three-dimensional CNN. The results show that the performance of the CNN model was superior to manual assessment., Conclusion: Under the companion diagnostics, the three-dimensional CNN with a deep learning algorithm may assist radiologists in the future by providing accurate and timely information for diagnosing pulmonary nodules in regular clinical practices., Implications for Practice: The three-dimensional convolutional neural network described in this article demonstrated both high sensitivity and high specificity in classifying pulmonary nodules regardless of diameters as well as superiority compared with manual assessment. Although it still warrants further improvement and validation in larger screening cohorts, its clinical application could definitely facilitate and assist doctors in clinical practice., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Aim: To analyse the clinical outcomes of patients with lung cancer treated with first and multiple-line chemotherapy and tyrosine kinase inhibitor (TKI)., Patients & Methods: The present study included a total of 89 patients of whom lung cancer was histologically confirmed between July 2016 and September 2017. Patients' demographics, chemotherapy/TKI treatment details and clinical outcomes were retrieved. The progression-free survivals (PFS) after first-line and multiple-line treatments were evaluated using Kaplan-Meier analysis with log-rank test. Risk factors for progressive disease (PD) were identified using Cox multivariate regression model., Results: A total of 50 males and 39 females were enrolled. About 90% of the tumors were histologically classified as adenocarcinoma, and 77/89 cases (86.5%) were at TNM stage IV. The median PFS for the first-line treatment was 6.17 months. After first-line treatment, more favourable PFS was observed in patients who had prior surgery of lung cancer (P = 0.002). Multivariate analysis showed that patients who had received no prior surgical treatment for lung cancer were at higher risk of PD (OR, 4.311; 95% CI, 1.836 to 10.120; P = 0.0008). Besides, in patients with driver mutations, those who received no TKI treatment were under higher risk of PD compared to those who had been treated with TKI (OR, 4.876; 95% CI, 1.877 to 12.666; P = 0.0011). The median PFS for the multiple-line treatment was 24.67 months. After multiple-line treatments, favourable PFS was associated with tumor histological types of adenocarcinoma (P = 0.041), genetic lesions at exon 19 of EGFR (P = 0.001) and fourth-line treatment (P = 0.001). Risk factors for PD after multiple-line treatments were no prior surgery for lung cancer (OR, 3.335; 95% CI, 1.158 to 9.605; P = 0.0256), no TKI use in multiple-line treatment (OR, 10.095; 95% CI, 2.405 to 42.378; P = 0.0016), and being treated by first-line treatment alone (OR, 30.421; 95% CI, 4.813 to 192.269; P = 0.0003)., Conclusion: The present study demonstrated the benefits of TKI in patients with advanced lung cancer, providing insights into the refinement of the management strategy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Liquid biopsy is emerging as an important approach for tumor genotyping in non-small cell lung cancer, ddPCR and SuperARMS are both methods with high sensitivity and specificity for detecting EGFR mutation in plasma. We aimed to compare ddPCR and SuperARMS to detect plasma EGFR status in a cohort of advanced NSCLC patients., Method: A total of 79 tumor tissues and paired plasma samples were collected. The EGFR mutation status in tissue was tested by ADx-ARMS, matched plasma was detected by ddPCR and SuperARMS, respectively., Results: The EGFR mutation rates were identified as 64.6% (tissue, ARMS), 55.7% (plasma, ddPCR), and 49.4% (plasma, Super ARMS), respectively. The sensitivity of ddPCR was similar with Super-ARMS in plasma EGFR detection (80.4% vs 76.5%), as well as the specificity (89.3% vs 100%). And the McNemar's test showed there was no significant difference (P = .125). The concordance rate between SuperARMS and ddPCR was 91.1%. A significant interaction was observed between cfDNA EGFR mutation status and EGFR-TKIs treatment tested by both methods., Conclusion: Super-ARMS and ddPCR share the similar accuracy for EGFR mutation detection in plasma biopsy; both methods predicted well the efficacy of EGFR-TKIs by detecting plasma EGFR status., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: CTONG0806 assessed the efficacy of pemetrexed versus gefitinib as second-line treatment in advanced nonsquamous nonsmall-cell lung cancer (NSCLC) harboring wild-type epidermal growth factor receptor (EGFR)., Patients and Methods: Patients with locally advanced or metastatic nonsquamous NSCLC harboring wild-type EGFR, detected by direct sequencing, and previously treated with platinum-based chemotherapy were randomized to receive gefitinib (250 mg/day) orally or pemetrexed (500 mg/m(2)) i.v. on day 1 of a 21-day cycle until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). The Independent Review Committee (IRC) evaluated all pictorial data., Results: From February 2009 to August 2012, 161 patients were enrolled, and 157 were assessable (81 in the gefitinib arm, 76 in the pemetrexed arm). Baseline characteristics were balanced between the two arms. The median PFSs were 4.8 versus 1.6 months in the pemetrexed and gefitinib arms, respectively [hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.40-0.75, P < 0.001] as confirmed by IRC evaluation (5.6versus 1.7 months, HR 0.53, 95% CI 0.38-0.75, P < 0.001). The median overall survival (OS) showed a trend of superiority in the pemetrexed arm (12.4 versus 9.6 months, HR 0.72, 95% CI 0.49-1.04, P = 0.077). Quality-of-life assessment showed no marked difference between the arms. No unexpected adverse events were found. Of 108 patients with sufficient DNA samples, EGFR mutation status was re-tested by Scorpion amplification refractory mutation system (ARMS); 32 (29.6%) tested positive (19 in the pemetrexed arm, 13 in the gefitinib arm; median PFS: 8.1 versus 7.0 months, HR 0.94, 95% CI 0.43-2.08, P = 0.877)., Conclusions: CTONG0806 is the first trial to show significant improvement in PFS and an improved OS trend with pemetrexed compared with gefitinib as second-line setting treatment of EGFR wild-type advanced nonsquamous NSCLC. ARMS is superior to direct sequencing in excluding false-negative patients., Clinicaltrialsgov Identifier: NCT00891579., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Purpose: Cisplatin is the most common chemotherapeutic agent for loco-regionally advanced nasopharyngeal carcinoma (NPC); however, toxicity is a limiting factor for some patients. We retrospectively compared the efficacy and toxicity of weekly docetaxel-based and cisplatin-based concurrent chemoradiotherapy in loco-regionally advanced NPC., Methods and Materials: Eighty-four patients with Stage III and IVA-B NPCs, treated between 2007 and 2008, were retrospectively analyzed. Thirty received weekly docetaxel-based concurrent chemotherapy, and 43 were given weekly cisplatin-based concurrent chemotherapy. Radiotherapy was administered using a conventional technique (seven weeks, 2.0 Gy per fraction, total dose 70-74 Gy) with 6-8 Gy boosts for some patients with locally advanced disease., Results: Median follow-up time was 42.3 months (range, 8.6-50.8 months). There were no significant differences in the 3-year loco-regional failure-free survival (85.6% vs. 92.3%; p=0.264), distant failure-free survival (87.0% vs. 92.5%; p=0.171), progression-free survival (85.7% vs. 88.4%; p=0.411) or overall survival (86.5% vs. 92.5%, p=0.298) of patients treated concurrently with docetaxel or cisplatin. Severe toxicity was not common in either group., Conclusions: Weekly docetaxel-based concurrent chemoradiotherapy is potentially effective and has a tolerable toxicity; however, further investigations are required to determine if docetaxel is superior to cisplatin for advanced stage NPC.

Background & Objective: Neoadjuvant chemotherapy for stage IIIA non-small cell lung cancer (NSCLC) remains controversial. The role of the expressions of P53, K-ras, HER2, vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), CD44, and matrix metalloproteinase-9 (MMP-9) in predicting efficacy of neoadjuvant chemotherapy on stage IIIA NSCLC is still unclear although they have been found to be related to prognosis. This study was to determine the predictive effect of multi-gene expression on treatment outcome of neoadjuvant chemotherapy for resectable stage IIIA NSCLC., Methods: Expressions of p53, K-ras, HER2, VEGF, EGFR, CD44, MMP-9 in the patients enrolled in the prospective randomized controlled trial were detected by immunohistochemistry. The treatment efficacies of combination (neoadjuvant chemotherapy combined with surgery) group (36 patients) and surgery alone group (32 patients) were compared., Results: The high gene expression rate was 58.3% in combination group, and 40.6% in surgery alone group(P=0.145). In combination group, no significant difference of disease-free survival rate (P=0.903) and survival time (P=0.238) was found between patients with histopathologic regression and patients without histopathologic regression; high gene expression had no correlation with pathologic regression (P= 0.862); the mean disease-free survival time was significantly lower in high gene expression subgroup than in low gene expression subgroup [(14.1+/-9.8) months vs. (27.2+/-13.6) months, P=0.032]; the 2-year disease-free survival rate was 38.1% in high gene expression subgroup, and 46.7% in low gene expression subgroup (P=0.607)., Conclusions: Pathologic regression after neoadjuvant chemotherapy has no correlation with disease-free survival rate and survial time. The high gene expression maybe indicate high risk of postoperative metastasis; the necessity of postoperative chemotherapy needs further study.

Objective: To study the reasonable dosage for paraplatin according to different dosage calculations., Methods: A prospective, randomized, single-blinded study on 54 patients with advanced non-small-cell lung cancer (NSCLC) treated with paraplatin was conducted. Patients were divided to 2 groups. In group A, paraplatin dosage was calculated according to patients' body surface, and in group B, it was calculated according to the area under the curve (AUS). Hematological toxicity, response rate and survival rate in the two groups of patients were compared., Results: Neutropenia in group A and group B was seen in 77.8% and 37.0% (P < 0.05), and thrombocytopenia in 18.5% and 3.7% (P > 0.05) of patients, respectively. Hemoglobin decrease was seen in 48.2% of patients in both groups. The average quantity of paraplatin given in one cycle of treatment was 535.93 +/- 106.71 mg and 398.52 +/- 71.72 mg (P < 0.01) respectively. The average time interval between treatment cycles was 27.04 +/- 5.30 d and 22.85 +/- 2.80 d (P < 0.05). The response rate and survival rate of patients in group A and B were 22.2% versus 48.2% (P < 0.05), and 40.7% versus 44.4% (P > 0.05) respectively, but the median survival time was identical (12 months) in the two groups., Conclusion: NSCLC patients given paraplatin with dosages calculated on the basis of AUC have higher response rate and less severe hematological toxicity than those given paraplatin with dosages on the basis of body surface. However, the median survival time and survival rate have no statistical differences between the two groups of patients.

Objective: To study the clinical application of needle video-assisted thoracoscopic biopsy in the pathologic diagnosis and staging for advanced lung cancer., Methods: Ninety-four patients were diagnosed as having advanced lung cancer staged IIIa-IV by chest X-ray, computed tomography and magnetic resonance imaging, for which a pathologic diagnosis was not made by sputum and pleural effusion cytology or bronchoscopic examination. Needle video-assisted thoracoscopic biopsy was performed for primary lesions, mediastinal lymph nodes, metastatic lesions in the lungs and the chest wall., Results: Pathologic samples were obtained in 89 of the 94 patients by needle video-assisted thoracoscopic surgery. The successful rate was 95%. After operation, the pathologic diagnosis was confirmed to be lung cancer in all the 89 patients. Adenocarcinoma was found in 47 patients, squamous carcinoma in 23, adenosquamous carcinoma in 12, and small cell lung cancer in 7. Compared to the clinical diagnosis before operation, the pathologic diagnosis post-operation was changed in 15 patients. Pneumothorax and mild haemoptysis occurred in 4 patients and 2 of the cases respectively. All the patients were followed for 8 - 18 months with computed tomography and physical examination. No implantation metastasis was found., Conclusion: Needle video-assisted thoracoscopic biopsy is an effective diagnostic measure for patients with advanced lung cancer for which pathologic diagnosis, typing and staging are not determined by routine examinations.