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Background Lipusu is the first commercialized liposomal formulation of paclitaxel and has demonstrated promising efficacy against locally advanced lung squamous cell carcinoma (LSCC) in a small‐scale study. Here, we conducted a multicenter, randomized, phase 3 study to compare the efficacy and safety of cisplatin plus Lipusu (LP) versus cisplatin plus gemcitabine (GP) as first‐line treatment in locally advanced or metastatic LSCC. Methods Patients enrolled were aged between 18 to 75 years, had locally advanced (clinical stage IIIB, ineligible for concurrent chemoradiation or surgery) or metastatic (Stage IV) LSCC, had no previous systemic chemotherapy and at least one measurable lesion as per the Response Evaluation Criteria in Solid Tumors (version 1.1) before administration of the trial drug. The primary endpoint was progression‐free survival (PFS). The secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety profiles. To explore the possible predictive value of plasma cytokines for LP treatment, plasma samples were collected from the LP group at baseline and first efficacy evaluation time and were then subjected to analysis by 45‐Plex ProcartaPlex Panel 1 to detect the presence of 45 cytokines using the Luminex xMAP technology. The correlation between treatment outcomes and dynamic changes in the levels of cytokines were evaluated in preliminary analyses. Results The median duration of follow‐up was 15.4 months. 237 patients in the LP group and 253 patients in the GP group were included in the per protocol set (PPS). In the PPS, the median PFS was 5.2 months versus 5.5 months in the LP and GP group (hazard ratio [HR]: 1.03, P = 0.742) respectively. The median OS was 14.6 months versus 12.5 months in the LP and GP group (HR: 0.83, P = 0.215). The ORR (41.8% versus 45.9%, P = 0.412) and DCR (90.3% versus 88.1%, P = 0.443) were also similar between the LP and GP group. A significantly lower proportion of patients in the LP group experienced adverse events (AEs) leading to treatment interruptions (10.9% versus 26.4%, P < 0.001) or treatment termination (14.3% versus 23.1%, P = 0.011). The analysis of cytokine levels in the LP group showed that low baseline levels of 27 cytokines were associated with an increased ORR, and 15 cytokines were associated with improved PFS, with 14 cytokines, including TNF‐α, IFN‐γ, IL‐6, and IL‐8, demonstrating an overlapping trend. Conclusion The LP regimen demonstrated similar PFS, OS, ORR and DCR as the GP regimen for patients with locally advanced or metastatic LSCC but had more favorable toxicity profiles. The study also identified a spectrum of different cytokines that could be potentially associated with the clinical benefit in patients who received the LP regimen., Cisplatin plus Lipusu (LP) regimen has comparable efficacy and more favorable toxicity profiles compared with cisplatin plus gemcitabine (GP) regimen for patients with advanced LSCC. The study also demonstrated that LP had a significant impact on the levels of plasma cytokines and a spectrum of cytokines were associated with clinical benefit in patients who received LP. Thus, our results provided a new option for patients with advanced LSCC.

Crizotinib, a multitargeted MET/ALK/ROS1 tyrosine kinase inhibitor, has been approved for the treatment of ROS1 fusion–positive non‐small cell lung cancers (NSCLCs). However, “on‐target” or “off‐target” resistance alterations often emerge that confer the drug resistance. Patients with ROS1‐rearranged NSCLC who develop crizotinib resistance, especially those acquiring “off‐target” resistance mutations, still lack effective therapeutic options for after crizotinib treatment. Herein, we reported a patient with stage IVb lung adenocarcinoma harboring ROS1 fusion, who acquired a BRAF V600E and lost the ROS1 fusion after progression on crizotinib. It was deduced that the V600E may originate from a subclone with an extremely low fraction that was independent of ROS1 fusion–positive cells. The patient was subsequently treated with dabrafenib and trametinib combination and achieved a partial response lasting for more than 6 months. Our study revealed that BRAF V600E can confer the crizotinib resistance in ROS1 fusion–positive NSCLC and presented the first case showing that the treatment with dabrafenib and trametinib can serve as an effective option for later‐line treatment for this molecular‐defined subgroup. Key Points Patients with ROS1‐rearranged non‐small cell lung cancer (NSCLC) who acquire “off‐target” resistance mutations to crizotinib still lack effective therapeutic options for after crizotinib treatment.This report describes the case of a patient with ROS1‐rearranged NSCLC who acquired a BRAF V600E and lost the ROS1 fusion after crizotinib failure.The case was subsequently treated with dabrafenib and trametinib combination and achieved a partial response lasting for more than 6 months.This is the first article reporting that treatment with dabrafenib and trametinib may serve as an effective option for later‐line treatment for patients harboring resistant BRAF V600E., Rearrangements of the ROS1 gene occur in 1%–2% of non‐small cell lung cancers, characterizing a distinct molecular subgroup. This article reports a case of stage IVb lung cancer in a patient with ROS1 fusion who acquired a BRAF V600E fusion after progression on crizotinib.

Introduction Blocking vascular endothelial growth factor pathway can enhance the efficacy of EGFR tyrosine kinase inhibitors in EGFR-mutant NSCLC. ACTIVE is the first phase 3 study conducted in the People's Republic of China evaluating apatinib, a vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor, plus gefitinib as first-line therapy in EGFR-mutant NSCLC. Methods Treatment-naive patients with stage IIIB or IV nonsquamous NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and EGFR exon 19 deletion or exon 21 L858R mutation were randomized 1:1 to receive oral gefitinib (250 mg/d), plus apatinib (500 mg/d; apatinib [A] + gefitinib [G] group), or placebo (placebo [P] + gefitinib [G] group). Stratification factors were mutation type, sex, and performance status. The primary end point was progression-free survival (PFS) by blinded independent radiology review committee (IRRC). Secondary end points were investigator-assessed PFS, overall survival, quality of life (QoL), safety, etc. Next-generation sequencing was used to explore efficacy predictors and acquired resistance. Results A total of 313 patients were assigned to the A + G (n = 157) or P + G group (n = 156). Median IRRC PFS in the A + G group was 13.7 months versus 10.2 months in the P + G group (hazard ratio 0.71, p = 0.0189). Investigator- and IRRC-assessed PFS were similar. Overall survival was immature. The most common treatment-emergent adverse events greater than or equal to grade 3 were hypertension (46.5%) and proteinuria (17.8%) in the A + G group and increased alanine aminotransferase (10.4%) and aspartate aminotransferase (3.2%) in the P + G group. QoL in the two groups had no statistical differences. Post hoc analysis revealed PFS benefits tended to favor the A + G group in patients with TP53 exon 8 mutation. Conclusions Apatinib + gefitinib as first-line therapy had superior PFS in advanced EGFR-mutant NSCLC versus placebo + gefitinib. Combination therapy brought more adverse events but did not interfere QoL. Trial Registration NCT02824458.

ALK-positive histiocytosis is a rare malignancy which was first described in 2008 and recognized as a systemic histiocytic disorder that can affect multiple organs. Less than 20 cases were reported to date, and much fewer cases were presented as disseminated disease, especially with lung and central nervous system (CNS) involvement. The clinical presentation, cytologic and histologic features were diverse in prior reported cases. Diagnosis relied on clinical, pathological findings and might be determined by molecular identification of anaplastic lymphoma kinase (ALK) gene translocation. Exclusion of other tumors such as Erdheim-Chester disease, Langerhans cell histiocytosis (LCH) and histiocytic sarcoma are required. Because of their rarity and diverse features, no standard treatment was applied so far. Here we reported a 51-year-old Asian female patient documented as ALK-positive histiocytosis with lung, intracranial and lymph nodes involvement. Surgery for left frontal tumor resection was performed. Of note was the presence of foam-like histiocytes, epithelioid cells and Touten-like histiocytes scattered in the lesion, emperipolesis also could be observed. Histiocytes were positive immunostaining for CD68/PGM-1, CD163 and ALK1 in cytoplasmic pattern. Fluorescence in situ hybridization (FISH) analysis confirmed ALK gene translocation and next generation sequencing (NGS) revealed KIF5B-ALK fusion. The patient received treatment of second-generation ALK inhibitor-alectinib after diagnosed and showed durable remission. Therefore, our case highlights a new treatment option for this rare entity.

Response Evaluation Criteria in Solid Tumors (RECIST 1.1) is classical and popular for public. However, there are some problems recently. For example, partial response ranges from 30% to 99%, objective response is dichotomous, so there may be some heterogeneity. New metrics for evaluating the efficacy have been investigating, such as early tumor shrinkage, time to response and depth of response (DpR). DpR has been used in hematologic malignancies and is considered as a predictor of efficiency. In solid tumors, DpR was firstly proposed by Mansmann et al. in metastatic colorectal cancer (mCRC) and defined as the percentage of tumor shrinkage, which is a continuous metric, and could avoid the information loss due to dichotomization of responses that has been widely applied to several kinds of solid tumors. Some authors have found associations between DpR and OS, DpR is a valuable surrogate endpoint for mCRC, metastatic breast cancer, metastatic melanoma and advanced pancreatic cancer. However, the predictive value of DpR is still uncertain in the research of lung cancer and gastric cancer. Which indicating that a mature and unified application standard has not yet been formed for DpR. This article summarizes researches on the DpR as a predictor of the long-term outcomes for solid tumors, it also discusses the challenges and limitations in the applications of DpR.

Rationale: Platinum-based chemotherapy is one of treatment mainstay for patients with advanced lung squamous cell carcinoma (LUSC) but it is still a "one-size fits all" approach. Here, we aimed to investigate the predictive and monitoring role of circulating cell-free DNA (cfDNA) profiling for the outcome of first-line chemotherapy in patients with advanced LUSC. Methods: Peripheral blood samples of 155 patients from a phase IV trial and 42 cases from an external real-world cohort were prospectively collected. We generated a copy number variations-based classifier via machine learning algorithm to integrate molecular profiling of cfDNA, named RESPONSE SCORE (RS) to predict the treatment outcome. To monitor the treatment efficacy, cfDNA samples collected at different time points were subjected to an ultra-deep sequencing platform. Results: The results showed that patients with high RS showed substantially higher objective response rate than those with low RS in training set (P < 0.001), validation set (P < 0.001) and real-world cohort (P = 0.019). Furthermore, a significant difference was observed in both progression-free survival (training set, P < 0.001; validation set: P < 0.001; real-world cohort: P = 0.019) and overall survival (training set, P < 0.001; validation set: P = 0.037) between high and low RS group. Notably, variant allele frequency (VAF) calculated from an ultra-deep sequencing platform significantly reduced in patients experienced a complete or partial response after 2 cycles of chemotherapy (P < 0.001), while it significantly increased in these of non-responder (P < 0.001). Moreover, VAF undetectable after 2 cycles of chemotherapy was correlated with markedly better objective response rate (P < 0.001) and progression-free survival (P < 0.001) than those with detectable VAF. Conclusions: These findings indicated that the RS, a circulating cfDNA sequencing-based stratification index, could help to guide first-line chemotherapy in advanced LUSC. The change of VAF is valuable to monitor the treatment response.

We report on a high conversion efficiency tunable laser at 426 nm by adopting an external frequency-doubling cavity pumped by a diode laser. For the frequency-doubling process at 426 nm, the major challenge of increasing the conversion efficiency is mode-match degradation originating from the severely thermal effect. Here, we find that the center of the equivalently thermal lens is not at the center of the nonlinear crystal. We minimize the variation of beam parameters of the Gaussian beam in the external cavity by optimizing the center of the thermal lens to beam waist. As a result, the mode-match degradation is reduced as the incident power is increased. Finally, a 405 mW blue light is obtained with the conversion efficiency of 81%.

Increasing the conversion efficiency of second harmonic generation (SHG) is an area of interest in research. We report a high-efficiency 532 nm laser generation, with a conversion efficiency of 94.04 ± 0.115% from the pump depletion of 98.1% ± 0.1%, by accurately quantifying the round-trip loss and the transmissivity of the input mirror using our proposed scheme. The optimal conversion efficiency of the cavity-enhanced frequency doubling process is independent of the waist and is determined by the pump depletion, round-trip loss, and transmissivity of the input mirror. These results show that the cavity-enhanced frequency doubling process is not necessary to set the focusing parameter at the optimal single-pass conversion. These results provide a guide for future research on high-efficiency SHG.

Subject To evaluate physicians' current practice, attitudes toward, and knowledge of cancer pain management in China. Methods We conducted a face-to-face survey of physicians (oncologists, internists, hematologists) who are responsible for the care of cancer patient of 11 general hospitals in Sichuan, China between December 2011 and December 2013. Statistical analyses were performed using SPSS (SPSS, Chicago, IL) software. Setting and Design A 23-item questionnaire was designed and distributed to 550 physicians in 11 medical facilities in China. Results Five hundred (90.90%) physicians responded. About one-third (32.6%) of physicians assessed patients' pain rarely, and 85.5% never or occasionally treated patients' cancer pain together with psychologists. More than half of physicians indicated that opioid dose titration in patients with poor pain control and assessment of the cause and severity of pain were urgently needed knowledge for cancer pain management. Inadequate assessment of pain and pain management (63.0%), patients' reluctance to take opioids (62.2%), and inadequate staff knowledge of pain management (61.4%) were the three most frequently cited barriers to physicians' pain management. Conclusions Physicians' positive attitudes toward cancer pain management need to be encouraged, and active professional analgesic education programs are needed to improve pain management in China.

Incidence of cerebral vascular disease (CVD) is higher in patients with diabetes mellitus (DM) than that in individuals without DM, and neuronal apoptosis determines the severity of cerebral infarction. However, there is no effective therapy for CVD. Granulocyte-colony stimulating factor (G-CSF), a potent hematopoietic factor, could inhibit apoptosis of hematopoietic progenitor cells. However, its effect on neuronal cells is still unclear. In this study, we investigated the anti-apoptosis properties of G-CSF in neurons following focal cerebral ischemia in diabetic rats. The diabetic condition was generated in rats by intravenous injection of streptozotocin. After 6 weeks, diabetic rats underwent middle cerebral artery occlusion (MCAO) and received subcutaneous administration of G-CSF (50 microg/kg) daily for 7, 14 or 21 days. We analyzed the changes in neurological severity scores, infarct volume, number of apoptotic neurons, and the expression of G-CSF receptor, phosphorylated signal transducer and activator of transcription 3 (pSTAT3), cellular inhibitor of apoptosis protein 2 (cIAP2), Bcl-2, and Bax in the brain tissue. Bax is a pro-apoptotic member of the Bcl-2 protein family. The DM rats treated with G-CSF not only showed the reduced infarct volume and decreased apoptosis cell number, but also presented improved neurological scores. The G-CSF also increased the expression of pSTAT3, Bcl-2, and cIAP2 proteins as well as Bcl-2 mRNA, but inhibited Bax protein expression in the brain. These results indicate that G-CSF partially increases neuronal survival by affecting apoptosis pathways. G-CSF provides a potential treatment for stroke and other neurological dysfunction accompanied by neuronal apoptosis.

112 Background: Pain is the most frequent and persistent symptom experienced by cancer patients. Thus, exploring how to achieve the best outcome of cancer pain management in China is clearly extremely important. Our study focuses on the Chinese physicians' current clinical practice, attitudes, toward and barriers to opioid use, and knowledge of cancer pain management. Methods: A face to face survey include 23 items was designed and conducted to the doctors working with cancer pain managements (oncologists, internists, hematologists, et al) responsible for the care of patients with cancer in 11 tertiary hospitals in China. Descriptive statistics were used to characterize the total sample and for multiple choice questions and each item. Chi-square analysis was used to examine the difference between categorical variables. Results: 500 questionnaires were received out of 550. Most (62.2%) physicians assessed patients’ cancer pain every day, but 85.5% never or occasionally treated patients’ cancer pain together with psychologists. Most respondents appreciated that > 50% of patients with cancer experience severe chronic pain warranting analgesic therapy (73.5%), and that this therapy could control pain adequately in > 50% of patients (77.2%). More than half of physicians indicated that opioid dose titration in patients with poor pain control and assessment of the cause and severity of pain were urgently needed knowledge for cancer pain management. A majority (65.0%) of physicians responded incorrectly (60.0% agreed and 5.0% had no opinion) that they would increase the dosage of a potent opioid and administer it every 4 h as needed (q4h PRN). Inadequate assessment of pain and pain management (63.0%), patients' reluctance to take opioids (62.2%), and inadequate staff knowledge of pain management (61.4%) were the three most frequently barriers to physicians’ pain management. Conclusions: Our results revealed that physician education in cancer pain management in China does not currently provide the necessary levels of knowledge and skills. Therefore, effective strategies and professional education are still needed to encourage physicians’ concern with, experience in, and knowledge of cancer pain management in China.

BACKGROUND: Maintenance chemotherapy is widely provided to patients with small cell lung cancer (SCLC). However, the benefits of maintenance chemotherapy compared with observation are a subject of debate. METHODOLOGY AND PRINCIPAL FINDINGS: To identify relevant literature, we systematically searched the Medline, Embase, and Cochrane Central Register of Controlled Trials databases. Eligible trials included patients with SCLC who either received maintenance chemotherapy (administered according to a continuous or switch strategy) or underwent observation. The primary outcome was 1-year mortality, and secondary outcomes were 2-year mortality, overall survival (OS), and progression-free survival (PFS). Of the 665 studies found in our search, we identified 14 relevant trials, which together reported data on 1806 patients with SCLC. When compared with observation, maintenance chemotherapy had no effect on 1-year mortality (odds ratio [OR]: 0.88; 95% confidence interval [CI]: 0.66-1.19; P = 0.414), 2-year mortality (OR: 0.82; 95% CI: 0.57-1.19; P = 0.302), OS (hazard ratio [HR]: 0.87; 95% CI: 0.71-1.06; P = 0.172), or PFS (HR: 0.87; 95% CI: 0.62-1.22; P = 0.432). However, subgroup analyses indicated that maintenance chemotherapy was associated with significantly longer PFS than observation in patients with extensive SCLC (HR, 0.72; 95% CI: 0.58-0.89; P = 0.003). Additionally, patients who were managed using the continuous strategy of maintenance chemotherapy appeared to be at a disadvantage in terms of PFS compared with patients who only underwent observation (HR, 1.27; 95% CI: 1.04-1.54; P = 0.018). CONCLUSIONS/SIGNIFICANCE: Maintenance chemotherapy failed to improve survival outcomes in patients with SCLC. However, a significant advantage in terms of PFS was observed for maintenance chemotherapy in patients with extensive disease. Additionally, our results suggest that the continuous strategy is inferior to observation; its clinical value needs to be investigated in additional trials.