Which Is More Suitable for First-Line Treatment of Extensive-Stage Small Cell Lung Cancer, PD-L1 Inhibitors Versus PD-1 Inhibitors? A Systematic Review and Network Meta-Analysis.

BACKGROUND: In this network meta-analysis (NMA), the efficiency and safety of PD-1 inhibitors + chemotherapy and PD-L1 inhibitors + chemotherapy were compared in the first-line therapy of patients with extensive-stage small cell lung cancer (ES-SCLC). METHODS: We searched research databases, conference abstracts, and trial registries and subsequently chose relevant studies and extracted dates. The NMA was conducted to estimate the efficiency and safety of the PD-1 inhibitors + chemotherapy and PD-L1 inhibitors + chemotherapy on overall survival (OS), progression-free survival (PFS), overall remission rate (ORR), and adverse events (AEs). Studies were assessed for quality. Subgroup analyses were used to evaluate study heterogeneity. RESULTS: We included six randomized trials with a total of 3163 patients. Direct comparisons showed that patients who received either PD-1 inhibitors + chemotherapy (HR: 0.71, 95% CI: 0.57-0.87) or PD-L1 inhibitors + chemotherapy (HR: 0.74, 0.61-0.89) demonstrated significantly longer OS than those who received placebo + chemotherapy. The results of the NMA showed that no significant differences in OS (HR 0.96 95% CI: 0.72-1.3), PFS (HR 0.83, 95% CI: 0.51-1.4), and ORR (OR 1.3 95% CI: 0.66-2.5) were observed for PD-1 inhibitors + chemotherapy compared with PD-L1 inhibitors + chemotherapy, but the Bayesian ranking revealed that patients receiving PD-1 inhibitors + chemotherapy tended to have longer OS, PFS benefit, and better treatment response than patients receiving PD-L1 inhibitors + chemotherapy. In terms of safety, no significant difference was observed in their safety profiles. CONCLUSION: In comparison to placebo + chemotherapy, PD-L1 inhibitors + chemotherapy and PD-1 inhibitors + chemotherapy significantly improved survival for ES-SCLC. According to the available data, PD-L1 inhibitors + chemotherapy and PD-1 inhibitors + chemotherapy had equivalent efficacy and safety; however, the level of evidence of this type of comparison is limited.

The Importance of Marital Status in the Morbidity and Prognosis of Lung Metastasis in Newly Diagnosed Ovarian Cancer.

Objective: The study aimed to evaluate the risk factors for the morbidity and prognosis of lung metastases (LM) in patients with newly diagnosed ovarian cancer (OC), and further explore the important role of marital status. Materials and methods: Based on the Surveillance, Epidemiology, and End Results (SEER) dataset, OC patients from 2010 and 2019 were retrospectively analyzed. Logistic regression analysis and Kaplan-Meier method were applied to evaluate the vital factors of incidence and survival outcome in LM population. Cox regression analysis was performed to identify risk factors for the prognosis of OC patients with LM. The predictive potential was showed by two established nomograms and examined by the concordance index (C-index), calibration curves, the area under the curve (AUC), decision curve analyses (DCAs) and clinical impact curves (CICs). Results: There are 25,202 eligible OC patients were enrolled in the study, the morbidity of LM at 5.61%. Multivariable logistic regression models illustrated that chemotherapy (P<0.01), surgical treatment of bilateral or more areas (P<0.01), T stage (P<0.01), N1 stage (P<0.01), bone metastasis (P<0.01), brain metastasis (P<0.01) and liver metastasis (P<0.01) were all significantly connected with LM in OC. Multivariable Cox regression analyses illustrated that unmarried, radiotherapy, elder people and positive cancer antigen 125 (CA-125) were significantly associated with shorter survival time, while chemotherapy made contributions to improve survival. Our study found that marital relationships promoted LM and was associated with the better prognosis, while unmarried patients had the opposite results. With the further development of our research, the cross-action of social, economic and psychological factors together determined the great impact of marital status on the morbidity and prognosis of OC patients combined with LM. Finally, the stability of the models was proved by internal verification. Conclusion: The population-based cohort study provides references for guiding clinical screening and individualized treatment of OC patients with LM. Under the influence of society and economy, marital status is closely related to the morbidity and prognosis of OC, which can be an important direction to explore the risk of OC lung metastasis in the future.

The prognostic implications of SIRTs expression in breast cancer: a systematic review and meta-analysis.

BACKGROUND: Sirtuins (SIRTs) have key roles in cancer progression. However, the prognostic implications of SIRTs in breast cancer (BC) remains a subject of debate and controversy. Thus, we performed a meta-analysis to identify the precise prognostic value of SIRTs in BC patients. METHODS: Systematic literature searching was conducted in PubMed, Cochrane Library, Web of Science, and Embase databases. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to estimate the association of SIRTs expression and survival outcomes in BC patients. RESULTS: A total of 22 original studies with 6317 patients were eligible for this meta-analysis. The results showed that in patients with BC, elevated SIRTs levels were associated with shorter overall survival (OS) and disease-free survival (DFS) both in univariate (HR = 1.56, 95% CI 1.21-2.00; HR = 1.67, 95% CI 1.32-2.12, respectively) and multivariate analysis models (HR = 2.11, 95% CI 1.48-3.00; HR = 1.70, 95% CI 1.20-2.39, respectively). Notably, further subgroup analysis revealed that overexpression of SIRT1 and SIRT6 predicted poor OS (HR = 2.65, 95% CI 1.54-4.56; HR = 2.53, 95% CI 1.64-3.90, respectively) and DFS (HR = 1.65, 95% CI 1.07-2.56; HR = 2.74; 95% CI 1.88-4.01, respectively) in BC. CONCLUSIONS: Our data has elucidated that SIRT1 and SIRT6 could serve as prognostic biomarkers for patients with BC and may contribute to refined patient management.

A Honeycomb-Like Bismuth/Manganese Oxide Nanoparticle with Mutual Reinforcement of Internal and External Response for Triple-Negative Breast Cancer Targeted Therapy.

Triple-negative breast cancer (TNBC) exhibits aggressive behavior and high levels of metastasis owing to its complex heterogeneous structure and lack of specific receptors. Here, tumor cell membrane (CM)-coated bismuth/manganese oxide nanoparticles (NPs) with high indocyanine green (ICG) payload up to 50.6 wt% (mBMNI NPs) for targeted TNBC therapy are constructed. The extra-high drug load Bi@Bi2 O3 @MnOx NPs (honey-comb like structure) are formed by Kirkendall effect and electrostatic attraction. After modified with CM, they can home into tumor sites precisely, where they respond to internal overexpressed glutathione (GSH), releasing Mn2+ for chemodynamic therapy (CDT) with GSH depletion, while H2 O2 degrades into O2 enabling relief of tumor hypoxia. In response to external near-infrared irradiation, mBMNI NPs intelligently generate vigorous heat and single oxygen (1 O2 ) for photothermal therapy (PTT) and photodynamic therapy (PDT) owing to high load. Importantly, O2 production and GSH consumption during the internal response reinforce external PDT, while the heat generated through PTT during the external response promotes internal CDT. The honeycomb-like structure with high ICG load and mutual reinforcement between internal and external response results in excellent therapeutic effects against TNBC.

Correction: Multi-functional bismuth-doped bioglasses: combining bioactivity and photothermal response for bone tumor treatment and tissue repair.

[This corrects the article DOI: 10.1038/s41377-018-0007-z.].

Ultralong tumor retention of theranostic nanoparticles with short peptide-enabled active tumor homing.

Computer tomography (CT) and magnetic resonance imaging (MRI) are noninvasive cancer imaging methods in clinics. Hence, a material that enables MRI/CT dual-modal imaging-guided therapy is in high demand. Currently, the available materials lack active tumor targeting, deep tumor penetration, and ultralong tumor retention and may lose their imaging elements. To overcome these drawbacks, herein, nanoparticles (NPs) were deveopled by integrating an MRI contrast-enhancing chelated gadolinium (Gd) complex within a doxorubicin (DOX)-loaded protective silica shell as well as a CT imaging/photothermal biocompatible bismuth (Bi) nano-core, which surface-displayed an MCF-7 breast tumor-homing peptide (AREYGTRFSLIGGYR, termed AR); we found that the resultant NPs AR-Bi@SiO2-Gd/DOXNPs could home to and penetrate deep into the tumors with the unexpected ultralong retention of at least 14 days (as determined by CT/MRI imaging) and the tumor retention half-life of 104.5 h (as determined by ICP-MS analysis) under the guidance of the AR peptide. These NPs can be further used to image tumors with significantly increased sharp contrasts via both CT and MRI, which are much better than the commercial standard contrast agents; moreover, they significantly inhibit tumor growth via the synergistic action of both Bi-enabled photothermal therapy and DOX-induced chemotherapy. The NPs are cleared by the spleen, liver and kidney and then excreted from the body along with faeces and urine. The precise tumor targeting and ultralong tumor retention of these unique NPs would enable both precise tumor detection for early diagnosis and signal-persistent tumor tracking for monitoring the treatment with only a single injection of these NPs.

Enhancing Osteosarcoma Killing and CT Imaging Using Ultrahigh Drug Loading and NIR-Responsive Bismuth Sulfide@Mesoporous Silica Nanoparticles.

Despite its 5-year event-free survival rate increasing to 60-65% due to surgery and chemotherapy, osteosarcoma (OS) remains one of the most threatening malignant human tumors, especially in young patients. Therefore, a new approach that combines early diagnosis with efficient tumor eradication and bioimaging is urgently needed. Here, a new type of mesoporous silica-coated bismuth sulfide nanoparticles (Bi2 S3 @MSN NPs) is developed. The well distributed mesoporous pores and large surface areas hold great promise for drug protection and encapsulation (doxorubicin (DOX), 99.85%). Moreover, the high photothermal efficiency of Bi2 S3 @MSNs (36.62%) offers great possibility for cancer synergistic treatment and highly near-infrared-triggered drug release (even at an ultralow power density of 0.3 W cm-2 ). After covalently conjugated to arginine-glycine-aspartic acid (RGD) peptide [c(RGDyC)], the NPs exhibit a high specificity for osteosarcoma and finally accumulate in the tumor cells (tenfold more than peritumoral tissues) for computed tomography (CT) imaging and tumor ablation. Importantly, the synergistic photothermal therapy-chemotherapy of the RGD-Bi2 S3 @MSN/DOX significantly ablates the highly malignant OS. It is further proved that the superior combined killing effect is achieved by activating the mitochondrial apoptosis pathway. Hence, the smart RGD-Bi2 S3 @MSN/DOX theranostic platform is a promising candidate for future applications in CT monitoring and synergistic treatment of malignant tumors.

Actively Targeted Deep Tissue Imaging and Photothermal-Chemo Therapy of Breast Cancer by Antibody-Functionalized Drug-Loaded X-Ray-Responsive Bismuth Sulfide@Mesoporous Silica Core-Shell Nanoparticles.

A theranostic platform combining synergistic therapy and real-time imaging attracts enormous attention but still faces great challenges, such as tedious modifications and lack of efficient accumulation in tumor. Here, a novel type of theranostic agent, bismuth sulfide@mesoporous silica (Bi2S3@ mPS) core-shell nanoparticles (NPs), for targeted image-guided therapy of human epidermal growth factor receptor-2 (HER-2) positive breast cancer is developed. To generate such NPs, polyvinylpyrrolidone decorated rod-like Bi2S3 NPs are chemically encapsulated with a mesoporous silica (mPS) layer and loaded with an anticancer drug, doxorubicin. The resultant NPs are then chemically conjugated with trastuzumab (Tam, a monoclonal antibody targeting HER-2 overexpressed breast cancer cells) to form Tam-Bi2S3@mPS NPs. By in vitro and in vivo studies, it is demonstrated that the Tam-Bi2S3@mPS bear multiple desired features for cancer theranostics, including good biocompatibility and drug loading ability as well as precise and active tumor targeting and accumulation (with a bismuth content in tumor being ≈16 times that of nontargeted group). They can simultaneously serve both as an excellent contrast enhancement probe (due to the presence of strong X-ray-attenuating bismuth element) for computed tomography deep tissue tumor imaging and as a therapeutic agent to destruct tumors and prevent metastasis by synergistic photothermalchemo therapy.

Multi-functional bismuth-doped bioglasses: combining bioactivity and photothermal response for bone tumor treatment and tissue repair.

Treatment of large bone defects derived from bone tumor surgery is typically performed in multiple separate operations, such as hyperthermia to extinguish residual malignant cells or implanting bioactive materials to initiate apatite remineralization for tissue repair; it is very challenging to combine these functions into a material. Herein, we report the first photothermal (PT) effect in bismuth (Bi)-doped glasses. On the basis of this discovery, we have developed a new type of Bi-doped bioactive glass that integrates both functions, thus reducing the number of treatment cycles. We demonstrate that Bi-doped bioglasses (BGs) provide high PT efficiency, potentially facilitating photoinduced hyperthermia and bioactivity to allow bone tissue remineralization. The PT effect of Bi-doped BGs can be effectively controlled by managing radiative and non-radiative processes of the active Bi species by quenching photoluminescence (PL) or depolymerizing glass networks. In vitro studies demonstrate that such glasses are biocompatible to tumor and normal cells and that they can promote osteogenic cell proliferation, differentiation, and mineralization. Upon illumination with near-infrared (NIR) light, the bioglass (BG) can efficiently kill bone tumor cells, as demonstrated via in vitro and in vivo experiments. This indicates excellent potential for the integration of multiple functions within the new materials, which will aid in the development and application of novel biomaterials.

Multifunctional Cu39S28 Hollow Nanopeanuts for In Vivo Targeted Photothermal Chemotherapy.

Actively targeted hollow nanoparticles may play key roles in precise anti-cancer therapy. Here, unique Cu39S28 hollow nanopeanuts (HNPs) were synthesized via a facile one-step method and the formation mechanism was illustrated. The as-synthesized Cu39S28 HNPs exhibit outstanding photothermal conversion efficiency (41.1%) and drug storage capacity (DOX, 99.5 %). At the same time, the DOX drug loading nanocomposites have shown great sensitive response of release to either pH value or near infrared ray (NIR). In particular, the folic acid (FA) can easily conjugate with the synthesized Cu39S28 HNPs without further modification to get a targeted effect. The FA modified Cu39S28 HNPs showed an efficiently targeting effect in vitro and could considerably enhance the tumor-targeting effect more than 10 times in vivo. Moreover, the synthetical hyperthermia and drug release from Cu39S28 HNPs when under 808 nm laser could significantly improve the therapeutic efficacy compared with photothermal or chemotherapy alone both in vitro and in vivo. The histological studies in main organs also proved the well biocompatibility, while the tumor sites were in seriously destruction due to the accumulation of the nanocomposites and the combined photothermal chemo therapy effect. Therefore, the multi-functional nanocomposites is excellent antitumor agents due to their superb therapy effect in breast cancer.

Anti-stokes fluorescent probe with incoherent excitation.

Although inorganic anti-Stokes fluorescent probes have long been developed, the operational mode of today's most advanced examples still involves the harsh requirement of coherent laser excitation, which often yields unexpected light disturbance or even photon-induced deterioration during optical imaging. Here, we demonstrate an efficient anti-Stokes fluorescent probe with incoherent excitation. We show that the probe can be operated under light-emitting diode excitation and provides tunable anti-Stokes energy shift and decay kinetics, which allow for rapid and deep tissue imaging over a very large area with negligible photodestruction. Charging of the probe can be achieved by either X-rays or ultraviolet-visible light irradiation, which enables multiplexed detection and function integration with standard X-ray medical imaging devices.

Infrared broadband emission of bismuth-doped barium-aluminum-borate glasses.

We report near infrared broadband emission of bismuth-doped barium-aluminum-borate glasses. The broadband emission covers 1.3microm window in optical telecommunication systems. And it possesses wide full width at half maximum (FWHM) of ~200nm and long lifetime as long as 350micros. The luminescent properties are quite sensitive to glass compositions and excitation wavelengths. Based on energy matching conditions, we suggest that the infrared emission may be ascribed to 3P1? 3P0 transition of Bi+. The broad infrared emission characteristics of this material indicate that it might be a promising candidate for broadband optical fiber amplifiers and tunable lasers.

Bismuth- and aluminum-codoped germanium oxide glasses for super-broadband optical amplification.

Broadband infrared luminescence from bismuth-doped germanium oxide glasses prepared by a conventional melting-quenching technique was discovered. The absorption spectrum of the glasses covered a wide range from the visible to the near-infrared wavelength regions and consisted of five broad peaks below 370, 500, 700, 800, and 1000 nm. The fluorescence spectrum exhibited broadband characteristics (FWHM) greater than 300 nm with a maximum at 1300 nm pumped by an 808-nm laser. The fluorescence lifetime at room temperature decreased with increasing Bi2O3 concentration in the glass. Codoping of aluminum and bismuth was indispensable for the broadband infrared luminescence in GeO2:Bi, Al glass.