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Although radiotherapy is one of the most important curative treatments for cancer, its clinical application is associated with undesired therapeutic effects on normal or healthy tissues. The use of targeted agents that can simultaneously achieve therapeutic and imaging functions could constitute a potential solution. Herein, we developed 2-deoxy-d-glucose (2DG)-labeled poly(ethylene glycol) (PEG) gold nanodots (2DG-PEG-AuD) as a tumor-targeted computed tomography (CT) contrast agent and radiosensitizer. The key advantages of the design are its biocompatibility and targeted AuD with excellent sensitivity in tumor detection via avid glucose metabolism. As a consequence, CT imaging with enhanced sensitivity and remarkable radiotherapeutic efficacy could be attained. Our synthesized AuD displayed linear enhancement of CT contrast as a function of its concentration. In addition, 2DG-PEG-AuD successfully demonstrated significant augmentation of CT contrast in both in vitro cell studies and in vivo tumor-bearing mouse models. In tumor-bearing mice, 2DG-PEG-AuD showed excellent radiosensitizing functions after intravenous injection. Results from this work indicate that 2DG-PEG-AuD could greatly potentiate theranostic capabilities by providing high-resolution anatomical and functional images in a single CT scan and therapeutic capability.

Few studies have analyzed the discrepancy between breast pathologic complete response (B-pCR) and axillary node pCR (N-pCR) rates and their impact on survival outcomes in different intrinsic subtypes of early breast cancer after neoadjuvant chemotherapy (NAC). We retrospectively reviewed B-pCR, N-pCR, and total (breast and axillary node) pCR (T-pCR) after NAC to assess the discrepancy and outcomes between 2005 and 2017. A total of 968 patients diagnosed with cT1-4c, N1-2, and M0 breast cancer were enrolled in the study. The median age was 49 years and the median follow-up time was 45 months. Of these patients, 213 achieved T-pCR, 31 achieved B-pCR with axillary node pathologic non-complete response (N-non pCR), 245 achieved N-pCR with breast pathologic non-complete response (B-non pCR), and 479 achieved total (breast and axillary node) pathologic non-complete response (T-non pCR) after NAC. The highest B-pCR and N-pCR rates were found in the hormone receptor-negative, human epidermal growth factor receptor 2-positive HR(-)HER2(+) subtype, while the lowest B-pCR rate was found in the HR(+)HER2(-) subtype. The N-pCR rate was correlated to the B-pCR rate (P

Photodynamic therapy (PDT), which involves the generation of reactive oxygen species (ROS) through interactions of a photosensitizer (PS) with light and oxygen, has been applied in oncology. Over the years, PDT techniques have been developed for the treatment of deep-seated cancers. However, (1) the tissue penetration limitation of excitation photon, (2) suppressed efficiency of PS due to multiple energy transfers, and (3) insufficient oxygen source in hypoxic tumor microenvironment still constitute major challenges facing the clinical application of PDT for achieving effective treatment. We present herein a PS-independent, ionizing radiation-induced PDT agent composed of yttrium oxide nanoscintillators core and silica shell (Y2O3:Eu@SiO2) with an annealing process. Our results revealed that annealed Y2O3:Eu@SiO2 could directly induce comprehensive photodynamic effects under X-ray irradiation without the presence of PS molecules. The crystallinity of Y2O3:Eu@SiO2 was demonstrated to enable the generation of electron-hole (e--h+) pairs in Y2O3 under ionizing irradiation, giving rise to the formation of ROS including superoxide, hydroxyl radical and singlet oxygen. In particular, combining Y2O3:Eu@SiO2 with fractionated radiation therapy increased radio-resistant tumor cell damage. Furthermore, photoacoustic imaging of tumors showed re-distribution of oxygen saturation (SO2) and reoxygenation of the hypoxia region. The results of this study support applicability of the integration of fractionated radiation therapy with Y2O3:Eu@SiO2, achieving synchronously in-depth and oxygen-insensitive X-ray PDT. Furthermore, we demonstrate Y2O3:Eu@SiO2 exhibited radioluminescence (RL) under X-ray irradiation and observed the virtually linear correlation between X-ray-induced radioluminescence (X-RL) and the Y2O3:Eu@SiO2 concentration in vivo. With the pronounced X-RL for in-vivo imaging and dosimetry, it possesses significant potential for utilization as a precision theranostics producing highly efficient X-ray PDT for deep-seated tumors.

Gene-based therapies have emerged as a new modality for combating a myriad of currently incurable diseases. However, the fragile nature of gene therapeutics has significantly hampered their biomedical applications. Correspondingly, the development of gene-delivery vectors is of critical importance for gene-based therapies. To date, a variety of gene-delivery vectors have been created and utilized for gene delivery. In general, they can be categorized into viral- and non-viral vectors. Due to safety issues associated with viral vectors, non-viral vectors have recently attracted much more research focus. Of these non-viral vectors, polymeric vectors, which have been preferred due to their low immunogenicity, ease of production, controlled chemical composition and high chemical versatility, have constituted an ideal alternative to viral vectors. In particular, biodegradable polymers, which possess advantageous biocompatibility and biosafety, have been considered to have great potential in clinical applications. In this context, the aim of this review is to introduce the recent development and progress of biodegradable polymers for gene delivery applications, especially for their chemical structure design, gene delivery capacity and additional biological functions. Accordingly, we first define and categorize biodegradable polymers, followed by describing their corresponding degradation mechanisms. Various types of biodegradable polymers resulting from natural and synthetic polymers will be introduced and their applications in gene delivery will be examined. Finally, a future perspective regarding the development of biodegradable polymer vectors will be given.

Background: Neoadjuvant chemotherapy (NAC) is the standard approach for downstaging of locally advanced breast cancer and can improve breast conservation rates. A pathological complete response (pCR) after NAC associated with favorable long-term outcomes has been described. There is still a high locoregional recurrence (LRR) rate after NAC and the influence of age on LRR after NAC is unclear. This study analyzed the relationship between age and LRR after NAC. Methods: Two hundred and sixty-three patients with invasive breast cancer who received NAC followed by mastectomy or breast conserving surgery (BCS) were enrolled. Concurrent weekly epirubicin and docetaxel was the NAC regimen. Results: Twenty-nine patients (11%) achieved a pCR after NAC. In univariate analysis, age

Background Neoadjuvant chemotherapy (NAC) has been the standard treatment for locally advanced breast cancer for the purpose of downstaging or for conversion from mastectomy to breast conservation surgery (BCS). Locoregional recurrence (LRR) rate is still high after NAC. The aim of this study was to determine predictive factors for LRR in breast cancer patients in association with the operation types after NAC. Methods Between 2005 and 2017, 1047 breast cancer patients underwent BCS or mastectomy after NAC in Chang Gung Memorial Hospital, Linkou. We obtained data regarding patient and tumor characteristics, chemotherapy regimens, clinical tumor response, tumor subtypes and pathological complete response (pCR), type of surgery, and recurrence. Results The median follow-up time was 59.2 months (range 3.13–186.75 months). The mean initial tumor size was 4.89 cm (SD ± 2.95 cm). Of the 1047 NAC patients, 232 (22.2%) achieved pCR. The BCS and mastectomy rates were 41.3% and 58.7%, respectively. One hundred four patients developed LRR (9.9%). Comparing between patients who underwent BCS and those who underwent mastectomy revealed no significant difference in the overall LRR rate of the two groups, 8.8% in BCS group vs 10.7% in mastectomy group (p = 0.303). Multivariate analysis indicated that independent factors for the prediction of LRR included clinical N2 status, negative estrogen receptor (ER), and failure to achieve pCR. In subgroups of multivariate analysis, only negative ER was the independent factor to predict LRR in mastectomy group (p = 0.025) and hormone receptor negative/human epidermal growth factor receptor 2 positive (HR−/HER2 +) subtype (p = 0.006) was an independent factor to predict LRR in BCS patients. Further investigation according to the molecular subtype showed that following BCS, non-pCR group had significantly increased LRR compared with the pCR group, in HR−/HER2 + subtype (25.0% vs 8.3%, p = 0.037), and HR−/HER2− subtype (20.4% vs 0%, p = 0.002). Conclusion Clinical N2 status, negative ER, and failure to achieve pCR after NAC were independently related to the risk of developing LRR. Operation type did not impact on the LRR. In addition, the LRR rate was higher in non-pCR hormone receptor-negative patients undergoing BCS comparing with pCR patients.

Background: Neoadjuvant chemotherapy (NAC) has been the standard treatment for locally advanced breast cancer for the purpose of downstaging or for conversion from mastectomy to breast conservation surgery (BCS). There is still a high locoregional recurrence (LRR) rate after NAC. The aim of this study was to determine predictive factors for locoregional recurrence (LRR) in breast cancer patients after NAC. Materials and Methods: Between 2005 and 2017, 1047 breast cancer patients underwent BCS or mastectomy after NAC in Chang Gung Memorial Hospital, Linkou. We obtained data regarding patient and tumor characteristics, chemotherapy regimens, clinical tumor response, tumor subtypes and pathological complete response (pCR), type of surgery, and recurrence.Results: The median follow-up time was 45.1 months (range 0.1-160.3 months). The mean initial tumor size was 4.89 cm (SD ±2.95 cm). Of the 1047 NAC patients, 232 (22.2%) achieved pCR. The BCS and mastectomy rates were 41% and 59%, respectively. Overall, 240 patients experienced tumor recurrence (22.9%). Thirty-five cases of LRR (14.3%) were noted following BCS, of which 4.3% achieved pCR. Multivariate analysis indicated that independent factors for the prediction of LRR included hormone receptor negative/human epidermal growth factor receptor 2 positive (HR-/HER2+) subtype, HR-/HER2- subtype, and failure to achieve pCR. Further investigation according to the molecular subtype showed that following BCS, HR-/HER2+ non-pCR group had significantly increased LRR compared with the HR+/HER2+ pCR group (22.2% vs 6.3%, pConclusion: Pathological response after NAC is related to the risk of developing LRR. The LRR rate was higher in non-pCR patients after NAC, especially in hormone receptor-negative patients undergoing BCS. Therefore, both the pathological response status and molecular subtype should be carefully considered when considering candidates for BCS after NAC.

As the silicon technology shrinking transistors to deep nanometer, the IO speed and logic density drive up the package design complexity drastically. The design performance validation is no longer scalable by resorting to traditional electrical modeling owing to the computation speed and memory gated by fine line geometry, layer count and increasingly higher bandwidth. While the electrical modeling remains to be the choice for selected critical nets, the full physical design verification becomes impractical electrically. On the other hand, system users demand all I/O and all powers to meet the same stringent specifications. We hereby report a fast, effective, large-scale verification method by cross-correlating physical parameter and shape compliance to the electrical design rule and template respectively. The method can further extract electrical parameters such as spreading inductance of a power distribution network (PDN) with using the concept of square inductance. The approach is implemented in the Xilinx’s 16nm 10GS/s RFSoC FPGA product package design.

In this study, the catalytic activities of the steam methane reforming (SMR) reactions with two catalysts, including nickel–scandia-stabilized zirconia (Ni–SSZ) and copper/nickel–scandia-stabilized zirconia (Cu/Ni–SSZ), were examined and compared. The microstructure and crystallinity of the as-prepared catalysts were characterized by scanning electron microscopy, Raman spectroscopy, and X-ray diffraction. Mass spectrometer was applied in the outlet streams, in order to simultaneously monitor the time-dependent kinetics in the reactor for an activity test and conversion examination. Finally, thermogravimetric analysis (TGA) and Raman spectrometer were implemented for further verification of carbon residuals on the catalysts. It was found that the incorporation of Cu on Ni–SSZ imposed significant constraints on the growth of nickel crystallites from NiO during the annealing process in reducing atmospheres. The methane conversion of Ni–SSZ and Cu/Ni–SSZ catalysts (annealed at 300 °C for 2 h) was 36.2 and 26.0%, respectively. However, the amount of carbon residuals on Cu/Ni–SSZ catalyst (300 °C for 2 h) was 18.6%, which is lower than that of the Ni–SSZ catalysts (33.2%) from TGA results. Further Raman experiments revealed that more graphite-like carbon residuals and less defects or amorphous carbons (IG/ID = 2.0) were found in the case of Cu/Ni–SSZ catalysts (300 °C for 2 h). Among the catalysts in this study, the Cu/Ni–SSZ catalyst (300 °C for 2 h) is considered as a promising catalyst for SMR reaction, since it has a fair methane conversion, and characterized higher CO2 selectivity and lower CO selectivity without compromising the hydrogen purity. More importantly, the least amount of carbon residuals was found in Cu/Ni–SSZ catalyst (300 °C for 2 h), which assured a better lifetime.

Herein, we report a new type of biodegradable, high surface-area gold nanodandelions (GNDs). This report possesses important features and some are the first of its kind: (1) the large scale green synthesis of GNDs with high monodispersity and a circa 100% yield with consistent chemistry, manufacturing and controls (CMC); (2) cellular/physiological degradability of GNDs leading to its disassembly into debris, which is indicative of the potential for possible body clearance; (3) precision control of the chemicophysical properties of the GNDs including shape, petal number and size, all can be judiciously fine-tuned by the synthetic parameters; (4) highly efficient radiotheranostics of GNDs encompassing better enhanced computed tomography (CT) contrast and pronounced X-ray induced reactive oxygen species (ROS) generation than conventional spherical gold nanoparticles (AuNP). It is noteworthy that the GNDs demonstrate a unique combinational effect of radiosensitization (production of superoxide anions and hydroxyl radicals) and type II photodynamic interaction (generation of singlet oxygen). Given the above, our reported GNDs are promising in clinical translation as radiotheranostics.

A 73-year-old man presented with a warty thickening of the skin on his hands and feet, which had been present for more than 1 year. He also reported general weakness, poor appetite and a weight loss of 8 kg over 6 months. The palms of his hands and soles of his feet had a rugose appearance with a

Nanoparticle-based imaging contrast agents have drawn tremendous attention especially in multi-modality imaging. In this study, we developed mesoporous silica nanoparticles (MSNs) for use as dual-modality contrast agents for computed tomography (CT) and near-infrared (NIR) optical imaging (OI). A microwave synthesis for preparing naked platinum nanoparticles (nPtNPs) on MSNs (MSNs-Pt) was developed and characterized with physicochemical analysis and imaging systems. The high density of nPtNPs on the surface of the MSNs could greatly enhance the CT contrast. Inductively coupled plasma mass spectrometry (ICP-MS) revealed the MSNs-Pt compositions to be ~14% Pt by weight and TEM revealed an average particle diameter of ~50 nm and covered with ~3 nm diameter nPtNPs. To enhance the OI contrast, the NIR fluorescent dye Dy800 was conjugated to the MSNs-Pt nanochannels. The fluorescence spectra of MSNs-Pt-Dy800 were very similar to unconjugated Dy800. The CT imaging demonstrated that even modest degrees of Pt labeling could result in substantial X-ray attenuation. In vivo imaging of breast tumor-bearing mice treated with PEGylated MSNs-Pt-Dy800 (PEG-MSNs-Pt-Dy800) showed significantly improved contrasts in both fluorescence and CT imaging and the signal intensity within the tumor retained for 24 h post-injection.

BACKGROUND AND AIM The risk of cholangiocarcinoma (cCC) arising from choledochal cyst (CC-CC) is imminent, if the latter not treated appropriately in time. Epithelial-to-mesenchymal transition (EMT) is considered a critical step for various solid cancers, which is regulated by the microRNA-200 (miR-200) family. The aim of this study was to assess the role of miR-200 family in the pathogenesis of CC-CC. METHODS Sixteen patients with CC-CC were enrolled and 254 patients with conventional cCC served as clinicopathologic controls. Fifty-four cCC were selected to compare the miR-200 family expression and immunohistochemical characteristics. Gain-and loss-of-function studies of miR-200 family were conducted using the cCC cell lines. RESULTS CC-CC were younger (P

We retrospectively reviewed 32 ears from 30 adult patients with chronic otitis media who underwent revision tympanoplasty using cartilage graft (performed by a single surgeon) from January 10, 2011, to May 10, 2016. All procedures were performed using an endaural incision for both temporalis fascia graft and tragal cartilage graft harvesting. The overall surgical success rate was 93.3%. The average preoperative hearing level was 43.1 ± 17.3 dBHL, and the average postoperative hearing level was 39.2 ± 18.2 dBHL, representing a significant improvement. The average air-bone gap was 19.4 ±7.6 dB preoperatively and 16.9 ± 9.9 dB postoperatively. Also of note, the improvement in air-bone gap reached the level of significance at 500 Hz (p = 0.023). We conclude that using cartilage graft in revision tympanoplasty is a safe and reliable technique with good surgical outcomes. Using one single endaural incision for both fascia and cartilage harvesting is simple while achieving aesthetic wound healing.

Colorectal cancer (CRC) is one of the leading causes of cancer-deaths worldwide. Methods for the early in situ detection of colorectal adenomatous polyps and their precursors – prior to their malignancy transformation into CRC – are urgently needed. Unfortunately at present, the primary diagnostic method, colonoscopy, can only detect polyps and carcinomas by shape/morphology; with sessile polyps more likely to go unnoticed than polypoid lesions. Here we describe our development of polyp-targeting, fluorescently-labeled mesoporous silica nanoparticles (MSNs) that serve as targeted endoscopic contrast agents for the early detection of colorectal polyps and cancer. In vitro cell studies, ex vivo histopathological analysis, and in vivo colonoscopy and endoscopy of murine colorectal cancer models, demonstrate significant binding specificity of our nanoconstructs to pathological lesions via targeting aberrant α-L-fucose expression. Our findings strongly suggest that lectin-functionalized fluorescent MSNs could serve as a promising endoscopic contrast agent for in situ diagnostic imaging of premalignant colonic lesions.

e12101 Background: The pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) correlates with better outcome in specific subtype of breast cancer and the axillary nodal pCR (N-pCR) rate are more common than breast pCR (B-pCR). While only a few studies to compare the survival in terms of B-pCR and N-pCR, and no study compare between the outcome for those non pCR either in breast or axillary node. Methods: A cohort of 968 cytologically proved nodal metastatic breast cancer (cT1~4N1~2) received NAC in a single medical center between 2005~2017 were analyzed retrospectively. NAC regimen included anthracycline and taxanes in all patients, Trastuzumab was used in 308(70.3%) HER2(+) patients. The percentage of both breast and axillary pCR (T-pCR) 、B-pCR and N-pCR were compared in different subtypes. The impact of T-pCR、B-pCR and N-pCR to DFS and OS were analyzed using univariate and multivariate Cox proportional hazard model. Results: The median follow-up time was 45 months. The median age was 49 years old, average tumor size was 4.2cm, and 543 (56.1%) patients were N1 disease. 382(39.5%) patients were HR(+) HER2(-), 222(22.9%)were HR(+)HER2(+),216(22.3%) were HR(-)HER2(+) and 148(15.3%) were HR(-)HER2(-). After NAC, T-pCR was found in 213 (22.0%) patients, B-pCR and N non-pCR in 31 patients, N-pCR and B non-pCR in 245 patients and T non-pCR in 479 patients. N-pCR rate(47.3%) were significantly higher than B-pCR(25.2%) and this trend found in all subtypes ( P

A user friendly interface can enhance the efficiency of data entry, which is crucial for building a complete database. In this study, two user interfaces (traditional pull-down menu vs. check boxes) are proposed and evaluated based on medical records with fever medication orders by measuring the time for data entry, steps for each data entry record, and the complete rate of each medical record. The result revealed that the time for data entry is reduced from 22.8 sec/record to 3.2 sec/record. The data entry procedures also have reduced from 9 steps in the traditional one to 3 steps in the new one. In addition, the completeness of medical records is increased from 20.2% to 98%. All these results indicate that the new user interface provides a more user friendly and efficient approach for data entry than the traditional interface.

Summary Two-photon activated-photodynamic therapy (TPA-PDT) allows for spatially selective treatment of cancers, and enhances the tissue penetration depth of incident light. The three dimensional (3D) interface energy transfers in hexagonal mesoporous silica nanoparticles (MSNs) can significantly enhance the photodynamic effect. By providing a well-defined mesoporous nanostructure, we established an efficient and controllable energy transfer mechanism via the facile modification of a two-photon antenna molecule and photosensitizer on different topological domains in the MSN. The cytotoxicity induced by the singlet oxygen, generated following relay of energy transfer, was demonstrated in both in vitro and in vivo breast cancer models. Therefore, our results contribute new insight to the highly efficient energy transfer within a single nanoparticle for two-photon activated PDT, worthwhile for studying its potential for development in clinical translation.

e12506Background: To clarify whether the Asia-Pacific breast cancer patients get small decline mortality in comparison to American white, we compared the survival differences between 2 decades(2000...

The risk of cholangiocarcinoma (cCC) arising from choledochal cyst (CC-CC) is imminent, if the latter not treated appropriately in time. Epithelial-to-mesenchymal transition (EMT) is considered a critical step for various solid cancers, which is regulated by the microRNA-200 (miR-200) family. The aim of this study was to assess the role of miR-200 family in the pathogenesis of CC-CC.Sixteen patients with CC-CC were enrolled and 254 patients with conventional cCC served as clinicopathologic controls. Fifty-four cCC were selected to compare the miR-200 family expression and immunohistochemical characteristics. Gain-and loss-of-function studies of miR-200 family were conducted using the cCC cell lines.CC-CC were younger (P 0.01), more female- predominated (P 0.01), and rarely associated with lithiasis (P 0.01) compared with those of cCC. miR-200 family was down-regulated in CC-CC, while miR-200 family was paradoxically up-regulated in cCC (P 0.01). CC-CC exhibited overt overexpression of mesenchymal markers including ZEB1, Twist, Snail, and vimentin as well an aberrant E-cadherin expression in comparison with cCC. In vitro migration assay showed that cCC cells bearing lower miR-200 s levels exhibited stronger migration ability. Invasive ability of cCC cells was increased after miR-200 s knockdown, accompanied by up-regulation of mesenchymal markers.CC-CC was characterized by distinct demographics, precipitating factors, and down-regulation of miR-200 family, compared with those of cCC. The pathogenesis of CC-CC might partly link to the silencing of miR-200 family, acting via ZEB1-directed EMT activation.

The unique optical properties of gold nanorods (GNRs) have recently drawn considerable interest from those working in in vivo biomolecular sensing and bioimaging. Especially appealing in these applications is the plasmon-enhanced photoluminescence of GNRs induced by two-photon excitation at infrared wavelengths, owing to the significant penetration depth of infrared light in tissue. Unfortunately, many studies have also shown that often the intensity of pulsed coherent irradiation of GNRs needed results in irreversible deformation of GNRs, greatly reducing their two-photon luminescence (TPL) emission intensity. In this work we report the design, synthesis, and evaluation of mesoporous silica-encased gold nanorods (MS-GNRs) that incorporate photosensitizers (PSs) for two-photon-activated photodynamic therapy (TPA-PDT). The PSs, doped into the nano-channels of the mesoporous silica shell, can be efficiently excited via intra-particle plasmonic resonance energy transfer from the encased two-photon excited gold nanorod and further generates cytotoxic singlet oxygen for cancer eradication. In addition, due to the mechanical support provided by encapsulating mesoporous silica matrix against thermal deformation, the two-photon luminescence stability of GNRs was significantly improved; after 100 seconds of 800 nm repetitive laser pulse with the 30 times higher than average power for imaging acquisition, MS-GNR luminescence intensity exhibited ~260% better resistance to deformation than that of the uncoated gold nanorods. These results strongly suggest that MS-GNRs with embedded PSs might provide a promising photodynamic therapy for the treatment of deeply situated cancers via plasmonic resonance energy transfer.