Beneficial Effect of Combining Radiotherapy and Transarterial Chemoembolization on Patient Survival in Hepatocellular Carcinomas and Macrovascular Invasion Treated with Sorafenib.

BACKGROUND: Approximately 10-40% of hepatocellular carcinoma (HCC) patients have definite vascular invasion at the time of diagnosis. Without curative treatment options, these patients have an abysmal prognosis with a median survival of only a few months following systemic therapy. However, supportive evidence of combining multiple locoregional treatments with systemic therapy is limited. This study compared the outcomes of sorafenib alone versus multimodality therapy with sorafenib, radiotherapy (RT), and transarterial chemoembolization (TACE) in advanced HCC patients with macrovascular invasion (MaVI). METHODS: The process took place over a nine-year period between March 2009 and October 2017, wherein 78 HCC patients with MaVI who underwent either sorafenib therapy alone (n = 49) or combined sorafenib/RT/TACE (n = 29) therapy were chosen for the retrospective study. We compared the overall survival (OS) between the two groups using the Cox regression hazard model and adjusted imbalances using propensity score matching (PSM). RESULTS: At the last follow-up, 76 patients had died, with a median follow-up time of 4.8 months for all patients and 31 months for those who were alive. Patients treated with sorafenib/RT/TACE had superior OS compared to those treated with sorafenib alone, showing a median survival of 9.3 vs. 2.7 months and a one-year survival of 37.1% vs. 6.1% (p < 0.001). In the multivariable analysis, new diagnosis or recurrence of HCC and treatment modalities (sorafenib alone vs. sorafenib/RT/TACE) were independent prognostic factors for OS. Compared to patients treated with sorafenib alone, significantly better OS was further verified using PSM (p < 0.001) in patients who received multiple therapeutic modalities. CONCLUSION: Multimodality therapy with sorafenib/RT/TACE increased OS threefold versus sorafenib therapy alone in HCC patients with MaVI. This study offers promising benefits of combined locoregional and systemic therapy for advanced HCC in current patient management and prospective clinical trials.

Gastrointestinal Endoscopy Performed by Gastroenterologists: Opportunistic Screening Strategy for Newly Diagnosed Head and Neck Cancers.

Aim: Approximately 66% of head and neck cancers are diagnosed at an advanced stage. This prospective study aimed to detect newly diagnosed head and neck cancers using regular upper gastrointestinal (UGI) endoscopy with oral-pharynx-larynx examination. Methods: A total of 2,849 patients underwent UGI endoscopy with an additional oral-pharynx-larynx examination. Patients aged < 20 years, those who were pregnant, had a history of head and neck cancers, were undergoing emergency endoscopy, and had a poor laryngopharyngeal view were excluded. The symptoms, incidence, location, pathology, and stage of malignant neoplasms were investigated. Results: A total of 2,720 patients were enrolled. Endoscopically observable 23 abnormal findings (0.85%) included 18 (0.66%) benign lesions and 5 (0.18%) newly diagnosed malignant neoplasms. Notably, 4 (80%) of 5 patients with malignant neoplasms were diagnosed at an early stage (Stage 0, I, and II). Conclusions: UGI endoscopy with oral-pharynx-larynx examination can achieve opportunistic head neck cancer screening and is recommended for every patient in endoscopy units.

Rabies Virus Glycoprotein-Mediated Transportation and T Cell Infiltration to Brain Tumor by Magnetoelectric Gold Yarnballs.

T lymphocyte infiltration with immunotherapy potentially suppresses most devastating brain tumors. However, local immune privilege and tumor heterogeneity usually limit the penetration of immune cells and therapeutic agents into brain tumors, leading to tumor recurrence after treatment. Here, a rabies virus glycoprotein (RVG)-camouflaged gold yarnball (RVG@GY) that can boost the targeting efficiency at a brain tumor via dual hierarchy- and RVG-mediated spinal cord transportation, facilitating the decrease of tumor heterogeneity for T cell infiltration, is developed. Upon magnetoelectric irradiation, the electron current generated on the GYs activates the electrolytic penetration of palbociclib-loaded dendrimer (Den[Pb]) deep into tumors. In addition, the high-density GYs at brain tumors also induces the disruption of cell-cell interactions and T cell infiltration. The integration of the electrolytic effects and T cell infiltration promoted by drug-loaded RVG@GYs deep in the brain tumor elicits sufficient T cell numbers and effectively prolongs the survival rate of mice with orthotopic brain tumors.

Gene-Embedded Nanostructural Biotic-Abiotic Optoelectrode Arrays Applied for Synchronous Brain Optogenetics and Neural Signal Recording.

Optogenetics is a recently established neuromodulation technique in which photostimulation is used to manipulate neurons with high temporal and spatial precision. However, sequential genetic and optical insertion with double brain implantation tends to cause excessive tissue damage. In addition, the incorporation of light-sensitive genes requires the utilization of viral vectors, which remains a safety concern. Here, by combining device fabrication design, nanotechnology, and cell targeting technology, we developed a new gene-embedded optoelectrode array for neural implantation to enable spatiotemporal electroporation (EP) for gene delivery/transfection, photomodulation, and synchronous electrical monitoring of neural signals in the brain via one-time implantation. A biotic-abiotic neural interface (called PG) composed of reduced graphene oxide and conductive polyelectrolyte 3,4-ethylenedioxythiophene-modified amphiphilic chitosan was developed to form a nanostructural hydrogel with assembled nanodomains for encapsulating nonviral gene vectors (called PEI-NT-pDNA) formulated by neurotensin (NT) and polyethylenimine (PEI)-coupled plasmid DNA (pDNA). The PG can maintain high charge storage ability to respond to a minimal current of 125 µA for controllable gene delivery. The in vitro analysis of PG-PEI-NT-pDNA on the microelectrode array chip showed that the microelectrodes provided electrically inductive electropermeabilization, which permitted gene transfection into localized rat adrenal pheochromocytoma cells with a strong green fluorescent protein expression that was up to 8-fold higher than that in nontreated cells. Furthermore, the in vivo implantation enabled on-demand spatiotemporal gene transfection to neurons with 10-fold enhancement of targeting ability compared with astrocytes. Finally, using the real optogenetic opsin channelrhodopsin-2, the flexible neural probe incorporated with an optical waveguide fiber displayed photoevoked extracellular spikes in the thalamic ventrobasal region after focal EP for only 7 days, which provided a proof of concept for the use of photomodulation to facilitate neural therapies.

IL-15 Overcomes Hepatocellular Carcinoma-Induced NK Cell Dysfunction.

NK cells have potent antitumor capacity. They are enriched in the human liver, with a large subset specialized for tissue-residence. The potential for liver-resident versus liver-infiltrating NK cells to populate, and exert antitumor functions in, human liver tumors has not been studied. We examined liver-resident and liver-infiltrating NK cells directly ex vivo from human hepatocellular carcinomas (HCCs) and liver colorectal (CRC) metastases, compared with matched uninvolved liver tissue. We found that NK cells were highly prevalent in both HCC and liver CRC metastases, although at lower frequencies than unaffected liver. Up to 79% of intratumoral NK cells had the CXCR6+CD69+ liver-resident phenotype. Direct ex vivo staining showed that liver-resident NK cells had increased NKG2D expression compared to their non-resident counterparts, but both subsets had NKG2D downregulation within liver tumors compared to uninvolved liver. Proliferation of intratumoral NK cells (identified by Ki67) was selectively impaired in those with the most marked NKG2D downregulation. Human liver tumor NK cells were functionally impaired, with reduced capacity for cytotoxicity and production of cytokines, even when compared to the hypo-functional tissue-resident NK cells in unaffected liver. Coculture of human liver NK cells with the human hepatoma cell line PLC/PRF/5, or with autologous HCC, recapitulated the defects observed in NK cells extracted from tumors, with downmodulation of NKG2D, cytokine production, and target cell cytotoxicity. Transwells and conditioned media confirmed a requirement for cell contact with PLC/PRF/5 to impose NK cell inhibition. IL-15 was able to recover antitumor functionality in NK cells inhibited by in vitro exposure to HCC cell lines or extracted directly from HCC. In summary, our data suggest that the impaired antitumor function of local NK cells reflects a combination of the tolerogenic features inherent to liver-resident NK cells together with additional contact-dependent inhibition imposed by HCC itself. The demonstration that IL-15 can recover hepatic NK cell function following tumor exposure supports its inclusion in immunotherapy strategies.

Conductive nanogel-interfaced neural microelectrode arrays with electrically controlled in-situ delivery of manganese ions enabling high-resolution MEMRI for synchronous neural tracing with deep brain stimulation.

Chronic brain stimulation has become a promising physical therapy with increased efficacy and efficiency in the treatment of neurodegenerative diseases. The application of deep brain electrical stimulation (DBS) combined with manganese-enhanced magnetic resonance imaging (MEMRI) provides an unbiased representation of the functional anatomy, which shows the communication between areas of the brain responding to the therapy. However, it is challenging for the current system to provide a real-time high-resolution image because the incorporated MnCl2 solution through microinjection usually results in image blurring or toxicity due to the uncontrollable diffusion of Mn2+. In this study, we developed a new type of conductive nanogel-based neural interface composed of amphiphilic chitosan-modified poly(3,4 -ethylenedioxythiophene) (PMSDT) that can exhibit biomimic structural/mechanical properties and ionic/electrical conductivity comparable to that of Au. More importantly, the PMSDT enables metal-ligand bonding with Mn2+ ions, so that the system can release Mn2+ ions rather than MnCl2 solution directly and precisely controlled by electrical stimulation (ES) to achieve real-time high-resolution MEMRI. With the integration of PMSDT nanogel-based coating in polyimide-based microelectrode arrays, the post-implantation DBS enables frequency-dependent MR imaging in vivo, as well as small focal imaging in response to channel site-specific stimulation on the implant. The MR imaging of the implanted brain treated with 5-min electrical stimulation showed a thalamocortical neuronal pathway after 36 h, confirming the effective activation of a downstream neuronal circuit following DBS. By eliminating the susceptibility to artifact and toxicity, this system, in combination with a MR-compatible implant and a bio-compliant neural interface, provides a harmless and synchronic functional anatomy for DBS. The study demonstrates a model of MEMRI-functionalized DBS based on functional neural interface engineering and controllable delivery technology, which can be utilized in more detailed exploration of the functional anatomy in the treatment of neurodegenerative diseases.

Neurotensin-Conjugated Reduced Graphene Oxide with Multi-Stage Near-Infrared-Triggered Synergic Targeted Neuron Gene Transfection In Vitro and In Vivo for Neurodegenerative Disease Therapy.

Delivery efficiency with gene transfection is a pivotal point in achieving maximized therapeutic efficacy and has been an important challenge with central nervous system (CNS) diseases. In this study, neurotensin (NT, a neuro-specific peptide)-conjugated polyethylenimine (PEI)-modified reduced graphene oxide (rGO) nanoparticles with precisely controlled two-stage near-infrared (NIR)-laser photothermal treatment to enhance the ability to target neurons and achieve high gene transfection in neurons. First-stage NIR laser irradiation on the cells with nanoparticles attached on the surface can increase the permeability of the cell membrane, resulting in an apparent increase in cellular uptake compared to untreated cells. In addition, second-stage NIR laser irradiation on the cells with nanoparticles inside can further induce endo/lysosomal cavitation, which not only helps nanoparticles escape from endo/lysosomes but also prevents plasmid DNA (pDNA) from being digested by DNase I. At least double pDNA amount can be released from rGO-PEI-NT/pDNA under NIR laser trigger release compared to natural release. Moreover, in vitro differentiated PC-12 cell and in vivo mice (C57BL/6) brain transfection experiments have demonstrated the highest transfection efficiency occurring when NT modification is combined with external multi-stage stimuli-responsive NIR laser treatment. The combination of neuro-specific targeting peptide and external NIR-laser-triggered aid provides a nanoplatform for gene therapy in CNS diseases.

Dual-Targeting Lactoferrin-Conjugated Polymerized Magnetic Polydiacetylene-Assembled Nanocarriers with Self-Responsive Fluorescence/Magnetic Resonance Imaging for In Vivo Brain Tumor Therapy.

Maintaining a high concentration of therapeutic agents in the brain is difficult due to the restrictions of the blood-brain barrier (BBB) and rapid removal from blood circulation. To enable controlled drug release and enhance the blood-brain barrier (BBB)-crossing efficiency for brain tumor therapy, a new dual-targeting magnetic polydiacetylene nanocarriers (PDNCs) delivery system modified with lactoferrin (Lf) is developed. The PDNCs are synthesized using the ultraviolet (UV) cross-linkable 10,12-pentacosadiynoic acid (PCDA) monomers through spontaneous assembling onto the surface of superparamagnetic iron oxide (SPIO) nanoparticles to form micelles-polymerized structures. The results demonstrate that PDNCs will reduce the drug leakage and further control the drug release, and display self-responsive fluorescence upon intracellular uptake for cell trafficking and imaging-guided tumor treatment. The magnetic Lf-modified PDNCs with magnetic resonance imaging (MRI) and dual-targeting ability can enhance the transportation of the PDNCs across the BBB for tracking and targeting gliomas. An enhanced therapeutic efficiency can be obtained using Lf-Cur (Curcumin)-PDNCs by improving the retention time of the encapsulated Cur and producing fourfold higher Cur amounts in the brain compared to free Cur. Animal studies also confirm that Lf targeting and controlled release act synergistically to significantly suppress tumors in orthotopic brain-bearing rats.

Amifostine-conjugated pH-sensitive calcium phosphate-covered magnetic-amphiphilic gelatin nanoparticles for controlled intracellular dual drug release for dual-targeting in HER-2-overexpressing breast cancer.

We developed a surfactant-free method utilizing amifostine to stably link a targeting ligand (Herceptin) to amphiphilic gelatin (AG)-iron oxide@calcium phosphate (CaP) nanoparticles with hydrophobic curcumin (CUR) and hydrophilic doxorubicin (DOX) encapsulated in the AG core and CaP shell (AGIO@CaP-CD), respectively. This multi-functional nanoparticle system has a pH-sensitive CaP shell and degradable amphiphilic gelatin (AG) core, which enables controllable sequential release of the two drugs. The dual-targeting system of AGIO@CaP-CD (HER-AGIO@CaP-CD) with a bioligand and magnetic targeting resulted in significantly elevated cellular uptake in HER2-overexpressing SKBr3 cells and more efficacious therapy than delivery of targeting ligand alone due to the synergistic cell multi-drug resistance/apoptosis-inducing effect of the CUR and DOX combination. This nanoparticle combined with Herceptin and iron oxide nanoparticles not only provided a dual-targeting functionality, but also encapsulated CUR and DOX as a dual-drug delivery system for the combination therapy. This study further demonstrated that the therapeutic efficacy of this dual-targeting co-delivery system can be improved by modifying the application duration of magnetic targeting, which makes this combination therapy system a powerful new tool for in vitro/in vivo cancer therapy, especially for HER2-positive cancers.

Change of scaling-induced proinflammatory cytokine on the clinical efficacy of periodontitis treatment.

Proinflammatory cytokines are key inflammatory mediators in periodontitis. This study aimed to investigate the relationship between proinflammatory cytokines in saliva and periodontal status. To investigate the usefulness of cytokines in the therapeutic approach for periodontal disease, the relationship between stimulated cytokine changes and the periodontitis treatment outcome was investigated in this study. Saliva was obtained from 22 patients diagnosed by dentists as having chronic periodontitis. The proinflammatory cytokine (interleukin-1α (IL-1α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor α (TNF-α), and tumor necrosis factor ß (TNF-ß)) levels were determined using a commercially available kit. The IL-1ß and IL-6 levels increased, whereas the TNF-ß levels decreased with the severity of periodontitis (4 mm pocket percentage). Poststimulation IL-1α, IL-6, and IL-8 levels were higher in patients who had an improved treatment outcome. The differences of IL-6 levels (cut point: 0.05 µg/g) yielded a sensitivity and specificity of 90.0% and 81.82%, respectively, for predicting the periodontitis treatment outcome. Among the proinflammatory cytokines, stimulated IL-6 was an excellent marker for predicting the periodontitis treatment outcome.

Long-term percutaneous endoscopic gastrostomy: characteristic computed tomographic findings.

Patients with a long-term PEG may suffer from complications and received physical and endoscopic examinations. However, these examinations do not provide information between skin and stomach. We present the findings of computed tomography (CT) for patients with long-term percutaneous endoscopic gastrostomy (PEG). After 1 year PEG (183 patients), 57 patients had received CT examinations. Skin indentation, soft-tissue thickening, peritoneal gap, internal bumper migration, and clinical abnormalities detected by CT examination were recorded. Thickness of subcutaneous fat, muscle, and abdominal wall along the tract were measured. The same parameters at 3 cm away from the tract were obtained for comparison. CT demonstrated that 28 (49.1%) patients present soft-tissue thickening, 19 (33.3%) patients present skin indentation, and 24 (42.1%) patients present a peritoneal gap. One patient with internal bumper migration, 3 patients had buried bumper syndrome, 2 patients had gastric herniation, and 1 patient had esophageal cancer metastasizes to the PEG site. Thickness of subcutaneous fat, muscle, and abdominal wall decreased significant. CT can provide detailed anatomy and orientation along the PEG tube. Familiarity of the CT appearance can minimize potential complications before PEG tube replacement.