A novel camptothecin derivative, ZBH-01, exhibits superior antitumor efficacy than irinotecan by regulating the cell cycle.

BACKGROUND: Irinotecan (CPT-11) is a classic chemotherapeutic agent that plays an important role in the clinical treatment of metastatic colon cancer and other malignant tumors. We previously designed a series of novel irinotecan derivatives. In this study, we select one representative, ZBH-01, to investigate its sophisticated antitumor mechanism in colon tumor cells. METHODS: The cytotoxic activity of ZBH-01 on colon cancer cells was evaluate by MTT or Cell Counting Kit-8 (CCK8) assay, 3D and xenograft model. The inhibitory effect of ZBH-01 on TOP1 was detected by DNA relaxation assay and Immuno Complex of Ezyme (ICE) bioassay. The molecular mechanism of ZBH-01 was explored by Next-Generation Sequencing (NGS), bioinformatics analyses, flow cytometry, qRT-PCR, and western blot etc. RESULTS: ZBH-01 can induce obvious DNA damage and has superior antitumor activity against colon cancer cells compared to CPT-11 and SN38 (7-Ethyl-10-hydroxy camptothecin, the in vivo active form of CPT-11) both in vivo and in vitro. Its inhibitory effect on topoisomerase I (TOP1) was also comparable with these two control drugs. There are a much larger number of 842 downregulated and 927 upregulated mRNAs in ZBH-01 treatment group than that in the controls. The most significantly enriched KEGG pathways for these dysregulated mRNAs were DNA replication, the p53 signaling pathway, and the cell cycle. After constructing a protein-protein interaction (PPI) network and screening out a prominent cluster, 14 involved in the cell cycle process was identified. Consistently, ZBH-01 induced G0/G1 phase arrest in colon cancer cells, while CPT-11/SN38 caused S phase arrest. The initiation of apoptosis by ZBH-01 was also superior to CPT-11/SN38, followed by the increased expression of Bax, active caspase 3, and cleaved-PARP, and decreased expression of Bcl-2. Additionally, CCNA2 (cyclin A2), CDK2 (cyclin-dependent kinase 2), and MYBL2 (MYB proto-oncogene like 2) might be involved in the G0/G1 cell cycle arrest induced by ZBH-01. CONCLUSIONS: ZBH-01 can be an antitumor candidate drug for preclinical study in the future.

Clinicopathologic Features and Prognosis of Melanoma in Northeast China: A Region-Based Cohort Study of 229 Consecutive Cases.

Melanoma has been reported in many parts of East Asia. However, there are no reports on the epidemiology of melanoma in Northeast China. In this study, we collected demographic, clinicopathologic, and treatment data of patients with melanoma treated at the First Hospital of Jilin University (Changchun, China). A total of 229 consecutive nonselective cases were analyzed for the incidence and clinicopathologic characteristics of melanoma. The median overall survival was 53.5 months. The 1-year, 3-year, and 5-year survival rates were 86.3, 66.4, and 44.8%, respectively. The median disease-free survival was 33.1 months, and the 1-year, 3-year, and 5-year disease-free survival rates were 75.0, 48.5, and 35.8%, respectively. Multivariate analysis showed that disease stage, Eastern Cooperative Oncology Group score, and lactic dehydrogenase were independent prognostic factors of overall survival. Pathologic subtype and stage were independent prognostic factors of disease-free survival. Furthermore, vascular invasion was a prognostic factor for overall survival in acral melanoma and a prognostic factor for disease-free survival in cutaneous melanoma. Compared with the Caucasian population, the population of Northeast China showed significant differences in disease location, pathologic subtype, gene status, and survival prognosis. In summary, our study showed that vascular invasion might be a prognostic factor in patients with acral and cutaneous melanoma.

Employing single valency polyphenol to prepare metal-phenolic network antitumor reagents through FeOOH assistance.

Metal-phenolic networks (MPNs) have been conventionally formed by the coordination of metal ions and polyphenols, which can responsively release metal ions and polyphenols under the trigger of tumor microenvironment (TME), showing high potential in the field of antitumor. However, MPNs are mainly limited to multi-valency polyphenols, and the unavailability of single valency polyphenols greatly hinders their applications even though they have excellent antitumor activity. Herein, we demonstrate a FeOOH assisted preparation method for MPNs antitumor reagent by introducing the complexes of Fe3+, H2O and polyphenol (Fe(H2O)x-polyphenoly) in the preparation process, which overcomes the shortage of single valency polyphenols. Taking apigenin (Ap) as an example, Fe(H2O)x-Apy complexes are foremost formed, in which the Fe(H2O)x is capable of hydrolyzing to generate FeOOH, thus producing Fe3+-Ap networks-coated FeOOH nanoparticles (FeOOH@Fe-Ap NPs). Under the stimulation of the TME, FeOOH@Fe-Ap NPs could release Fe2+ and Ap, realizing ferroptosis and apoptosis for tumor combination therapy. In addition, FeOOH can shorten transverse relaxation time, acting as a T2-weighted magnetic resonance imaging contrast agent. The current efforts provide an alternative strategy for constructing MPNs by exploiting single valency polyphenols, which strengthens the potential of MPNs in antitumor applications.

A simple method for eyelid reconstruction with an advancement flap after resection of a minor nevus on the eyelid margin.

We developed a simple and effective method for eyelid reconstruction after resection of a minor nevus on the eyelid margin. With a vertical advancement flap to repair the defect, all patients were satisfied with the cosmetic and functional results of the eyelids, and no significant complications occurred.

Analysis of molecular pathologic and clinical features of 36 patients with pulmonary sarcomatoid carcinoma.

BACKGROUND: Pulmonary sarcomatoid carcinoma (PSC) is a heterogeneous disease with poor prognosis. It is essential to understand the molecular basis of its progression in order to devise novel therapeutic strategies. The aim of this study was to identify the pathological mutations in PSC through next generation sequencing technology (NGS), and provide reference for the diagnosis and molecular targeted therapy. MATERIALS AND METHODS: Thirty-sex patients with pathologically confirmed PSC who underwent surgical tumor resection at The First Hospital of Jilin University and Jilin Cancer Hospital from June 2011 to June 2017 were enrolled. Thirteen patients were successfully followed up and detailed clinical data were obtained. NGS was performed for the exons of entire oncogenes. Kaplan-Meier method was used for the univariate analysis, and the Cox proportional risk regression model was used for multivariate analysis. RESULTS: A total of 19 highly frequent mutations were identified, of which the KRAS, BRCA1 and ALK mutations were significantly correlated with the overall survival (OS). Multivariate analysis showed that KRAS mutation was an independent factor affecting the OS of PSC patients. CONCLUSION: The KRAS mutation is an independent prognostic factor for PSC, and patients harboring the KRAS mutation had significantly shorter OS compared to patients with wild type KRAS. The characteristic mutation landscape of PSC may guide clinical targeted therapy.

Pembrolizumab in Chinese patients with advanced melanoma: 3-year follow-up of the KEYNOTE-151 study.

Survival is generally poor for Chinese patients with advanced melanoma because of high rates of acral and mucosal melanoma and limited therapeutic options. The first analysis of the phase 1b KEYNOTE-151 study showed second-line pembrolizumab was well tolerated and had clinically meaningful antitumor activity in Chinese patients with advanced melanoma. Three-year follow-up is presented. Eligible patients were of Chinese descent and had unresectable stage III/IV melanoma that progressed after first-line therapy. Patients received pembrolizumab 2 mg/kg every 3 weeks for ≤35 cycles. Primary end points were safety and objective response rate (ORR). Secondary end points included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Response was assessed per RECIST v1.1 by blinded independent central review. Subgroup analyses were conducted by melanoma subtype and BRAF and PD-L1 status (acral melanoma only). 103 patients were enrolled; median follow-up duration (time from first dose to data cutoff [July 13, 2020]) was 44.6 months (IQR, 39.1-46.2). Any-grade treatment-related adverse events (TRAEs) occurred in 85.4% of patients, and grade 3/4 TRAEs in 12.6%. No grade 5 TRAEs occurred. Three patients discontinued pembrolizumab because of TRAEs (immune-mediated hepatitis, pneumonia, and arthritis). Immune-mediated AEs and infusion reactions occurred in 34.0% (grade 3/4, 2.9%). ORR was 17.6% (95% CI, 10.8-26.4; 1 complete response/17 partial responses), and median DOR was 13.8 months (range, 2.7-37.4+). Median PFS was 2.8 months (95% CI, 2.7-3.5) and 36-month PFS rate was 5.0%. Median OS was 13.2 months (95% CI, 10.4-16.5) and 36-month OS rate was 22.3%. Median OS for patients with known melanoma subtype was 14.8 months for acral, 13.5 months for nonacral cutaneous, and 7.4 months for mucosal melanoma. Among the acral subgroup, median OS was 22.8 months for PD-L1-positive disease, 8.4 months for PD-L1-negative disease, 18.5 months for BRAF wild-type disease, and 5.8 months for BRAF-mutant disease. Over 3 years' follow-up, second-line pembrolizumab continued to show manageable safety, clinically meaningful antitumor activity, and durable responses in Chinese patients with advanced melanoma. Subgroup analysis suggested particular benefit in PD-L1-positive and BRAF wild-type acral melanoma, although small subgroup sizes preclude definitive conclusions. Clinical trial registration: https://clinicaltrials.gov, identifier NCT02821000.

Prognostic impact of Breslow thickness in acral melanoma: A retrospective analysis.

BACKGROUND: Evidence for the prognostic importance of tumor thickness in acral melanoma (AM) patients is limited. OBJECTIVE: The objective of the study was to determine the prognostic impact of Breslow thickness in AM. METHODS: This multicenter study enrolled patients diagnosed with localized AM between January 1, 2000 and December 31, 2017. Melanoma-specific survival (MSS) in different tumor thickness strata (T1-T4: ≤1, >1-2, >2-4, >4 mm, respectively) was estimated by the Kaplan-Meier method. Comparisons were performed by the log-rank test and multivariable Cox regression. RESULTS: A total of 853 patients with clinical N0 (cN0) AM were included in the analysis. The median follow-up time was 60.1 months. The median MSS in patients with T1-T4 disease was not reached, 111.0, 92.8, and 67.1 months, respectively. MSS differed significantly among cN0 patients with T1-T3 AM (log-rank P = .004, .012, <0.001 for T1 vs T2, T2 vs T3, and T1 vs T3, respectively); however, there was no significant difference between T3 and T4 AM (hazard ratio = 0.82, 95% CI, 0.62-1.09). Six-subgroup analyses confirmed that survival outcomes were similar between different subgroups with tumor thickness >2 mm. LIMITATIONS: The limitations were retrospective design and some missing variables. CONCLUSIONS: There was no association between tumor thickness and survival in AM patients with a Breslow thickness >2 mm.

Advanced Acral Melanoma Therapies: Current Status and Future Directions.

OPINION STATEMENT: Melanoma is one of the deadliest malignancies. Its incidence has been significantly increasing in most countries in recent decades. Acral melanoma (AM), a peculiar subgroup of melanoma occurring on the palms, soles, and nails, is the main subtype of melanoma in people of color and is extremely rare in Caucasians. Although great progress has been made in melanoma treatment in recent years, patients with AM have shown limited benefit from current therapies and thus consequently have worse overall survival rates. Achieving durable therapeutic responses in this high-risk melanoma subtype represents one of the greatest challenges in the field. The frequency of BRAF mutations in AM is much lower than that in cutaneous melanoma, which prevents most AM patients from receiving treatment with BRAF inhibitors. However, AM has more frequent mutations such as KIT and CDK4/6, so targeted therapy may still improve the survival of some AM patients in the future. AM may be less susceptible to immune checkpoint inhibitors because of the poor immunogenicity. Therefore, how to enhance the immune response to the tumor cells may be the key to the application of immune checkpoint inhibitors in advanced AM. Anti-angiogenic drugs, albumin paclitaxel, or interferons are thought to enhance the effectiveness of immune checkpoint inhibitors. Combination therapies based on the backbone of PD-1 are more likely to provide greater clinical benefits. Understanding the molecular landscapes and immune microenvironment of AM will help optimize our combinatory strategies.

Copper Ion and Ruthenium Complex Codoped Polydopamine Nanoparticles for Magnetic Resonance/Photoacoustic Tomography Imaging-Guided Photodynamic/Photothermal Dual-Mode Therapy.

Phototherapy, such as photodynamic therapy (PDT) and photothermal therapy (PTT), refers to the therapeutic strategy using a visible or near-infrared (NIR) laser to generate free radicals or heat for noninvasive and localized tumor treatment. However, limited by the low photoconversion efficiency of therapeutic agents, a single treatment method can hardly lead to complete tumor ablation, even when enhancing the power density of the laser and/or prolonging the irradiation duration. In this work, copper ion and ruthenium complex codoped polydopamine nanoparticles (Cu(II)/LRu/PDA NPs) are designed for PDT/PTT dual-mode therapy. The doped LRu in the NPs can generate reactive oxygen species under visible laser irradiation and enable PDT. Because of the strong absorption in the NIR region, PDA can not only generate heat for PTT under irradiation but also be used for photoacoustic tomography (PAT) imaging. Meanwhile, the doping of Cu(II) in the NPs through the coordination with PDA facilitates T1-weighted magnetic resonance imaging (MRI). Thus, MR/PAT imaging-guided PDT/PTT dual-mode therapy is achieved. The in vivo experiments indicate that the Cu(II)/LRu/PDA NPs can accumulate in HeLa tumors with a retention rate up to 8.34%ID/g. MR/PAT imaging can clearly identify the location and boundary of the tumors, permitting precise guidance for phototherapy. Under the combined effect of PDT and PTT, a complete ablation of HeLa tumors is achieved. The current work provides an alternative nanoplatform for performing PDT/PTT dual-mode therapy, which can be further guided by MR/PAT imaging.

Prognostic value of ulceration varies across Breslow thicknesses and clinical stages in acral melanoma: a retrospective study.

BACKGROUND: Ulceration is regarded as an adverse prognostic factor and is used together with tumour thickness to subcategorize patients with cutaneous melanoma. However, the prognostic impact of ulceration in acral melanoma (AM) is controversial. OBJECTIVES: To assess the prognostic impact of ulceration in AM and the variability across different Breslow thicknesses and clinical stages. METHODS: A multicentre retrospective study of patients diagnosed with AM between January 2000 and December 2017. Differences in melanoma-specific survival (MSS) between patients with and without ulceration were assessed using the multivariable Cox proportional hazards model and log-rank test. RESULTS: Among 1053 enrolled patients, 62.6% had ulceration. After a median follow-up of 61 months, patients with ulceration had a lower median MSS than those without: 66.1 months, 95% confidence interval (CI) 60.0-86.0 vs. not reached; hazard ratio 1.41, 95% CI 1.09-1.82; P = 0.012. Among patients with thin (≤ 1 mm) melanoma, the survival curves of patients with vs. without ulceration clearly separated over time (P < 0.001). No association between ulceration and MSS was observed for melanomas of thickness > 1 mm (subgroups of T2, T3 and T4; all P-values > 0.05) or patients with stage III disease (hazard ratio 1.09, 95% CI 0.71-1.68, P = 0.39). CONCLUSIONS: Ulceration is an independent negative prognostic factor for patients with AM, but the impact varies across Breslow thicknesses and clinical stages. Ulceration has a significant effect on prognosis for patients with thin (≤ 1 mm) melanoma, but there was no association between ulceration and survival in intermediate/thick AM or stage III AM. What is already known about this topic? Ulceration status is used together with Breslow tumour thickness to subcategorize patients into different stages according to the America Joint Committee on Cancer melanoma staging system. As one distinctive subtype of cutaneous melanoma, acral melanoma (AM) is characterized by poor survival outcomes due to delayed diagnosis and a high prevalence of negative prognostic and genetic features. The prognostic impact of ulceration in AM is still controversial. What does this study add? This was the first large-scale study to assess the prognostic and staging values of ulceration in patients with AM. Ulceration has a significant effect on prognosis for patients with thin (≤1 mm) melanoma, but no association between ulceration and survival was found in intermediate/thick or stage III AM. These findings should be considered when using ulceration-based staging systems.

Dexamethasone Induces Apoptosis of Embryonic Palatal Mesenchymal Cells Through the GATA-6/Bone Morphogenetic Protein-2/p38 MAPK Pathway.

ABSTRACT: Exposure to dexamethasone (DEX) causes cleft palate at high rates. Our previous studies proved that GATA binding protein 6 (GATA-6)/bone morphogenetic protein-2 (BMP-2) mediated apoptosis is related to DEX-induced cleft palate, but the specific mechanism is still unclear. The goal of this research was to understand the mechanism of apoptosis in cleft palate formation induced by DEX. Palatal mesenchymal cells from mouse embryos on embryonic day 13 were isolated as the experimental group, GATA-6 was silenced by GATA-6 small interfering Ribonucleic Acid (RNA). Cell Counting Kit-8, flow cytometry and Western Blot were applied to detect cell proliferation ability, cell cycle, the proportion of apoptotic cells, and the expression of apoptosis- related proteins of GATA-6 knockdown palatal mesenchymal cells. Further proteins on the BMP-2/Mitogen-activated protein kinase (MAPK) pathways were detected using Western Blot. T results showed that knockdown of GATA-6 by siRNA significantly decreased cell proliferation and increased the expression of apoptosis-related proteins. Bone morphogenetic protein-2/P38 mitogen Activated protein kinase (P38 MARK) pathway proteins decreased significantly among the GATA-6 knockdown group, DEX-cleft palate group and control +DEX groups. The results indicated that the GATA-6/BMP-2/P38 MAPK athway was involved in the apoptosis caused by GATA-6 silencing, which may be the possible mechanism of DEX inducing cleft palate.

Long-time measurements of line-integrated plasma electron density using a two-color homodyne optical fiber interferometer.

A two-color homodyne Mach-Zehnder (M-Z) optical fiber interferometer with wavelengths of 1.55 and 1.31 µm was developed for long-time measurement of line-integrated plasma electron density. A novel phase difference demodulation algorithm based on a single 3 × 3 optical coupler was implemented in a two-color optical fiber interferometer scheme for the first time. Our laboratory tests showed that this new optical fiber interferometer could determine the phase shift due to the low-frequency ambient vibration and could maintain high phase resolution measurement. The resolution of the new interferometer was less than 0.04 rad in 1000 s, corresponding to a line-averaged electron density of less than 1.0 × 1019 m-2. Actual plasma discharge experiments performed on KTX-CTI, which is a new compact torus injector (CTI) constructed at the Keda Torus eXperiment (KTX), showed that this interferometer has excellent several-second stability.

Prospective study of clinical characteristics of melanoma patients with retinopathy caused by a high-dose interferon α-2b.

Retinopathy is a rare side effect of interferon α-2b treatment. The goal of this study was to prospectively investigate the clinical characteristics of Chinese patients with melanomas who developed retinopathy following high doses of interferon α-2b (HD-IFN) therapy. The study included 56 melanoma stage I-III patients that were treated with HD-IFN. Fourty-three patients developed HD-IFN-induced retinopathies. Forty-three melanoma patients (76%) developed retinopathy after being treated with HD-IFN. Among these patients, 49% had cotton-wool spots, 19% had retinal hemorrhage, and 30% had retinal hemorrhage. The median time of occurrence of retinopathy was 4 weeks after treatment, and the median time of duration was 4 weeks. No patient showed other symptoms except one who had blurred vision. A comparison of clinical characteristics (age, gender, primary site, stage, and ulceration) and laboratory examinations (white blood cell and platelet counts, hemoglobin, serum lactate dehydrogenase, alanine transaminase, aspartate aminotransferase, triiodothyronine, thyroxine, thyroid-stimulating hormone, and lipid) between the HD-IFN-induced retinopathy patients and nonretinopathy patients did not show any significant differences (P > 0.05). Although all patients that developed retinopathy had diabetes or hypertension, an equal percentage of patients were without retinopathy had diabetes or hypertension. HD-IFN therapy in patients with melanomas may induce mild retinopathy. Our results; however, do not necessarily suggest to discontinue the HD-IFN treatment because retinopathy is a reversible disorder.

Effect of melanoma stem cells on melanoma metastasis.

Cancer stem cells (CSCs) are involved in the metastatic process, the resistance of many types of cancer to therapeutic treatments and consequently the onset of recurrences. The CSC concept therefore significantly extends our understanding of melanoma biology. More recently, melanoma stem cells (MSCs) have been described in melanoma as expressing specific biomarkers. These primitive melanoma cells are not only capable of self-renewal and differentiation plasticity, but may also confer virulence via immune evasion and multidrug resistance, and potentially, via vasculogenic mimicry and transition to migratory and metastasizing derivatives. This review will present the specific biomarkers of MSCs, including CD133, ATP binding cassette subfamily B member 5, CD271, CD20 and aldehyde dehydrogenase, which can regulate the transduction of tumor-related signals. These signal molecules can reversely act on tumor cells and regulate tumor angiogenesis, leading to the occurrence of melanoma metastasis. Targeting these specific biomarkers could inhibit the progression of melanoma and may help the development of novel therapeutic strategies for melanoma.

Topical Timolol Combined Intralesional Injection of Diprospan in the Treatment of Elevated Localized Mixed Infantile Hemangiomas and a Discussion for Proper Timing for Injection.

BACKGROUND: Although infantile hemangiomas (IHs) are usually self-limiting, residual elevated appearance may remain. Topical beta-blockers are effective in superficial IHs management, while intralesionally injected diprospan is effective at treating deep, localized IHs. A single application of topical timolol or injected diprospan has obvious limitations. Therefore, for elevated, localized mixed IHs, we applied topical timolol combined with intralesionally injected diprospan, using their respective advantages to maximize benefits. PURPOSE: To evaluate the clinical efficacy and safety of topical timolol combined with intralesionally injected diprospan for the treatment of elevated, localized mixed IHs and identify the optimal injection time. METHODS: Infants with elevated, localized mixed IHs in the proliferative phase were treated with injected diprospan combined with topical timolol between March 2018 and March 2020. The injection was administered only when the tumor surface was higher than that of the surrounding tissue. The patients were asked to return every 4 weeks for a treatment response evaluation, and complications were recorded. RESULTS: Thirty-six patients with elevated, localized mixed IHs (thickness >3 mm on Doppler ultrasound) were recruited. The mean age at treatment initiation was 3.58 ±â€Š1.50 months (range: 1.00-6.00 months). The follow-up period ranged from 9 to 24 months. Considering the size of the IH at the end of treatment, regression was observed in 31 (86.1%) cases, stabilization was observed in 5 (13.9%) cases, and no treatment failure was observed. All the IHs improved in color and height after treatment. CONCLUSION: Topical timolol combined with intralesionally injected diprospan is an effective and safe treatment for elevated, localized mixed IH. The injection is needed only when we forecast the elevated tissue may remain after regression.

Pemetrexed-based chemotherapy for non-small-cell lung cancer patients with EGFR exon 20 insertion mutation: a multicenter study.

BACKGROUND: Chemotherapy is the major choice for advanced non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor exon 20 insertion (EGFR ex20ins). The efficacy of pemetrexed-based with other chemotherapy regimens and EGFR ex20ins subtypes in this population has not been well studied. METHODS: We screened patients with EGFR ex20ins by next-generation sequencing (NGS) from a large cohort. The clinicopathologic and medical information were collected in advanced NSCLC patients with EGFR ex20ins. We also compared the clinical outcomes among patients with different subtypes of EGFR ex20ins. RESULTS: We retrospectively collected 119 stage IIIB/IV NSCLC patients with EGFR ex20ins from 9142 NSCLC patients across China from June 2013 to December 2018. The subtypes of EGFR ex20ins included A767_V769dupASV (33/119, 27.73%), S768_D770dupSVD (19/119, 15.97%), N771_H773dupNPH (11/119, 9.24%), A763_Y764insFQEA (2/119, 1.68%) and others (54/119, 45.38%). A total of 64.7% (77/119) of patients received pemetrexed-based first-line chemotherapy and 13.45% (16/119) of patients received pemetrexed-based second-line chemotherapy. Pemetrexed-based chemo-treated patients had longer median progression-free survival (PFS) than patients without pemetrexed-based chemo-treated (5.5 vs. 3.0 months, P=0.0026). Survival data was available for 66 patients and the median overall survival (OS) was 24.7 months. Pemetrexed-based chemo-treated patients had longer OS tendency than patients without pemetrexed-based chemo-treated (25.0 vs. 19.6 months, P=0.0769). Patients harboring A767_V769dupASV had better OS than other subtypes of EGFR ex20ins but without statistical significance (P=0.0676). Multivariate analysis revealed that histological type of NSCLC and bone-metastasis before treatment were independent prognostic factors for OS in all patients after adjusting all characteristic and treatment factors (P<0.05). CONCLUSIONS: To the best of our knowledge, it is the largest cohort study of advanced NSCLC patients with EGFR ex20ins across China. Pemetrexed-based treatment could have better control of disease than non-pemetrexed-based chemotherapies in this population. Furthermore, more effective agents are expected for patients harboring EGFR ex20ins.

Optical fiber interferometer application for high electron density measurements on compact torus plasmas.

An optical fiber Mach-Zehnder interferometer at a wavelength of 1.55 µm has been developed for measurements of high electron density on compact torus (CT) plasmas with a high time resolution of 0.1 µs and high phase resolution of 6.4 × 10-4 rad. To improve density measurement accuracy, the phase noise of the interferometer has been investigated in detail and optimized. In the bench test, the interferometer was calibrated using a piezoelectric ceramic actuator with known stroke. Initial results on CT plasma show that the optical fiber interferometer provides reliable density measurements at two spatial locations and the bulk velocity of plasma can be determined by the method of time of flight.

The Clinicopathological and Survival Profiles Comparison Across Primary Sites in Acral Melanoma.

BACKGROUND: The clinicopathological and survival profiles across primary sites in acral melanoma (AM) are still controversial and unclear. METHODS: This is a multi-center retrospective study. Clinicopathological data of AM patients diagnosed between 1 January 2000 and 31 December 2017 from 6 large tertiary hospitals in China were extracted. Chi square tests were used to compare basic characteristics between primary sites of sole, palm and nail bed. Melanoma-specific survival (MSS) differences based on primary sites were compared by log-rank tests and multivariate Cox regressions were used to identify prognostic factors for MSS. RESULTS: In total, 1157 AM patients were included. The sole group had a more advanced initial stage, deeper Breslow thickness, higher recurrence rate and distant metastases risk (all P < 0.05). The proportion of age < 65 years and ulceration were statistically lower in nail bed and palm groups, respectively. A total of 294 patients underwent sentinel lymph node biopsy and rates of positive SLN status had no statistical difference across primary sites. Among 701 patients with genetic profiles, the mutational frequency of BRAF, C-KIT, and PDGFRA were similar except for NRAS (higher in sole group, P = 0.0102). The median MSS of sole, nail bed and palm patients were 65.0 months, 112.0 months, and not reached, respectively (log-rank P = 0.0053). In multivariate analyses, primary site, initial stage, ulceration and recurrence were the prognostic factors for MSS in overall population, but the statistical significance varied over primary sites. CONCLUSIONS: Substantial clinicopathological and survival heterogeneities exist across different primary sites in the AM population. Sole melanoma has worse prognosis compared with palm and nail bed subtypes.

A Phase Ib Study of Pembrolizumab as Second-Line Therapy for Chinese Patients With Advanced or Metastatic Melanoma (KEYNOTE-151).

BACKGROUND: Pembrolizumab shows robust antitumor activity and favorable safety in metastatic melanoma. KEYNOTE-151 evaluated pembrolizumab in Chinese patients, who have more aggressive melanoma subtypes than other populations. METHODS: Chinese patients aged ≥18years with advanced melanoma previously treated with one line of therapy received pembrolizumab 2 mg/kg every 3 weeks for 35 cycles or until confirmed disease progression, intolerable toxicity, or study withdrawal. Primary end points were objective response rate (ORR) per RECIST v1.1 by blinded independent central review and safety. Key secondary end points included duration of response (DOR) and progression-free survival (PFS) per RECIST v1.1 and overall survival (OS). RESULTS: Median age was 52 years (N=103); 37.9% had acral and 14.6% had mucosal melanoma. Median follow-up was 7.9months at data cutoff (December 27, 2017). ORR was 16.7% (95% CI, 10.0-25.3%) (1 complete, 16 partial responses). Disease control rate was 38.2%. ORR was 15.8% for acral, 13.3% for mucosal melanoma. Median DOR was 8.4months; 65.6% of patients had response duration ≥6months. Median PFS was 2.8months (95% CI, 2.7-3.5months); 6-month rate was 20.4%. Median OS was 12.1months (95% CI, 9.6months-not reached); 6-month rate, 75.7%; 12-month rate, 50.6%. Treatment-related AEs (TRAEs) occurred in 87 (84.5%) patients; 9 (8.7%) experienced grade 3/4 TRAE and 2 (1.9%) discontinued because of TRAE; none died. Two deaths occurred that were unrelated to treatment. CONCLUSIONS: Pembrolizumab was well tolerated and provided clinically meaningful antitumor activity as second-line therapy in Chinese patients with advanced melanoma.

Role of GATA-6 and Bone Morphogenetic Protein-2 in Dexamethasone-Induced Cleft Palate Formation in Institute of Cancer Research Mice.

The mechanism of cleft palate induction by dexamethasone is not fully known. Bone morphogenetic protein-2 (BMP-2) has been associated with dexamethasone-induced osteoporosis. In this study, the authors induced cleft palate models in Institute of Cancer Research mice by dexamethasone to investigate the role of BMP-2 and its transcriptional element GATA-6. The authors injected different doses of dexamethasone into pregnant mice (E13), and assessed the histology of the palatal shelf and the expression levels of BMP-2, GATA-6, and specific apoptosis-related proteins. The results showed that cleft palate formation was dependent on dexamethasone dosage, with high incidence (50.55%) at high concentration (50 mg/kg) compared with the low doses (6 mg/kg, 38.10%). Transmission electron microscopy revealed significant cellular changes of the cleft palate shelf, including loose cell connection, cellular swelling, as well as reduced extracellular matrix and mitochondria. Following exposure to dexamethasone, the apoptotic rate in the palate increased with elevated dosage. Western blotting analysis indicated that the expression levels of GATA-6 and BMP-2 were reduced, while the levels of apoptotic proteins bax and caspase-3 were increased. The results of authors' study suggested that dexamethasone-induced cleft palate formation involved apoptosis occurred in a dose-dependent manner. BMP-2 and GATA-6 mediated dexamethasone-induced cleft palate formation.