Are There Differences in the Causes and Complications of Mandibular Third Molar Extraction in Older Patients Compared to Younger Patients?

BACKGROUND: Although most impacted third molars (ITMs) are extracted in the teens and early 20s, some undergo extractions after their 40s. It is unclear whether the reasons for extraction, the degree of impaction, and complications differ in patients in an older age group compared with a younger age group. PURPOSE: The purpose of this study was to measure the association between age and 1) reason for extraction and 2) postoperative complications. STUDY DESIGN, SETTING, SAMPLE: This was a retrospective cohort study of patients who had undergone surgical extraction of at least one mandibular ITM at a single institution. We excluded 1) age under 20 years, 2) follow-up period of less than 1 week, and 3) tooth extraction under general anesthesia. PREDICTOR VARIABLE: The primary predictor variable was age, classified into 3 groups (20s:20-29; 30s:30-39; over 40s: 40 and greater). MAIN OUTCOME VARIABLE(S): The primary outcome variables were the reason for extraction (prophylactic or symptomatic) and the presence of complications. The secondary outcome variable was type of complication (postoperative infection, dry socket, neurosensory disturbance, presenting pain over 1 month, retained root requiring secondary treatment). COVARIATES: The covariates were sex, laterality of ITM, and difficulty of extraction as measured by the difficulty index, a measure based on depth, orientation, and ramus relationship/space available, with a higher score indicating greater difficulty. ANALYSES: χ2 test was performed to analyze the association of categorical outcome variables and covariates. Level of statistical significance was set at P < .05. RESULTS: Of a total of 831 eligible subjects, there were 555 (66.8%), 159 (19.1%), and 117 (14.1%) in the 20s, 30s, and over 40s age groups, respectively. The percentage of symptomatic extraction of ITM was significantly higher in the over-40 age group compared with the 20s group (92.3 vs 69.4%, (P < .001). Complication rate also significantly differed between over 40s group and the 20s group (7.7 vs 1.8%, P < .001). Difficulty index and indications for ITM extraction were significantly different between groups (P < .001). CONCLUSION AND RELEVANCE: Symptoms, difficulty, and complications related to ITM increase at over 40 years of age. This should be taken into consideration during the joint clinical decision-making process with patients with ITM.

Monolithic digital patterning of polydimethylsiloxane with successive laser pyrolysis.

The patterning of polydimethylsiloxane (PDMS) into complex two-dimensional (2D) or 3D shapes is a crucial step for diverse applications based on soft lithography. Nevertheless, mould replication that incorporates time-consuming and costly photolithography processes still remains the dominant technology in the field. Here we developed monolithic quasi-3D digital patterning of PDMS using laser pyrolysis. In contrast with conventional burning or laser ablation of transparent PDMS, which yields poor surface properties, our successive laser pyrolysis technique converts PDMS into easily removable silicon carbide via consecutive photothermal pyrolysis guided by a continuous-wave laser. We obtained high-quality 2D or 3D PDMS structures with complex patterning starting from a PDMS monolith in a remarkably low prototyping time (less than one hour). Moreover, we developed distinct microfluidic devices with elaborated channel architectures and a customizable organ-on-a-chip device using this approach, which showcases the potential of the successive laser pyrolysis technique for the fabrication of devices for several technological applications.

All-in-one microfluidic design to integrate vascularized tumor spheroid into high-throughput platform.

The development of a scalable and highly reproducible in vitro tumor microenvironment (TME) platform still sheds light on new insights into cancer metastasis mechanisms and anticancer therapeutic strategies. Here, we present an all-in-one injection molded plastic array three-dimensional culture platform (All-in-One-IMPACT) that integrates vascularized tumor spheroids for highly reproducible, high-throughput experimentation. This device allows the formation of self-assembled cell spheroids on a chip by applying the hanging drop method to the cell culture channel. Then, when the hydrogel containing endothelial cells and fibroblasts is injected, the spheroid inside the droplet can be patterned together in three dimensions along the culture channel. In just two steps above, we can build a vascularized TME within a defined area. This process does not require specialized user skill and minimizes error-inducing steps, enabling both reproducibility and high throughput of the experiment. We have successfully demonstrated the process, from spheroid formation to tumor vascularization, using patient-derived cancer cells (PDCs) as well as various cancer cell lines. Furthermore, we performed combination therapies with Taxol (paclitaxel) and Avastin (bevacizumab), which are used in standard care for metastatic cancer. The All-in-One IMPACT is a powerful tool for establishing various anticancer treatment strategies through the development of a complex TME for use in high-throughput experiments.

Vascularization of iNSC spheroid in a 3D spheroid-on-a-chip platform enhances neural maturation.

In vitro platforms for studying the human brain have been developed, and brain organoids derived from stem cells have been studied. However, current organoid models lack three-dimensional (3D) vascular networks, limiting organoid proliferation, differentiation, and apoptosis. In this study, we created a 3D model of vascularized spheroid cells using an injection-molded microfluidic chip. We cocultured spheroids derived from induced neural stem cells (iNSCs) with perfusable blood vessels. Gene expression analysis and immunostaining revealed that the vascular network greatly enhanced spheroid differentiation and reduced apoptosis. This platform can be used to further study the functional and structural interactions between blood vessels and neural spheroids, and ultimately to simulate brain development and disease.

Anchor-IMPACT: A standardized microfluidic platform for high-throughput antiangiogenic drug screening.

In vitro models are becoming more advanced to truly present physiological systems while enabling high-throughput screening and analysis. Organ-on-a-chip devices provide remarkable results through the reconstruction of a three-dimensional (3D) cellular microenvironment although they need to be further developed in terms of multiple liquid patterning principle, material properties, and scalability. Here we present a 3D anchor-based microfluidic injection-molded plastic array culture platform (Anchor-IMPACT) that enables selective, space-intensive patterning of hydrogels using anchor-island for high-throughput angiogenesis evaluation model. Anchor-IMPACT consists of a central channel and an anchor-island, integrating the array into an abbreviated 96-well plate format with a standard microscope slide size. The anchor-island enables selective 3D cell patterning without channel-to-channel contact or any hydrogel injection port using an anchor structure unlike conventional culture compartment. The hydrogel was patterned into defined regions by spontaneous capillary flow under hydrophilic conditions. We configured multiple cell patterning structures to investigate the angiogenic potency of colorectal cancer cells in Anchor-IMPACT and the morphological properties of the angiogenesis induced by the paracrine effect were evaluated. In addition, the efficacy of anticancer drugs against angiogenic sprouts was verified by following dose-dependent responses. Our results indicate that Anchor-IMPACT offers not only a model of high-throughput experimentation but also an advanced 3D cell culture platform and can significantly improve current in vitro models while providing the basis for developing predictive preclinical models for biopharmaceutical applications.

Patient-Derived Microphysiological Systems for Precision Medicine.

Patient-derived microphysiological systems (P-MPS) have emerged as powerful tools in precision medicine that provide valuable insight into individual patient characteristics. This review discusses the development of P-MPS as an integration of patient-derived samples, including patient-derived cells, organoids, and induced pluripotent stem cells, into well-defined MPSs. Emphasizing the necessity of P-MPS development, its significance as a nonclinical assessment approach that bridges the gap between traditional in vitro models and clinical outcomes is highlighted. Additionally, guidance is provided for engineering approaches to develop microfluidic devices and high-content analysis for P-MPSs, enabling high biological relevance and high-throughput experimentation. The practical implications of the P-MPS are further examined by exploring the clinically relevant outcomes obtained from various types of patient-derived samples. The construction and analysis of these diverse samples within the P-MPS have resulted in physiologically relevant data, paving the way for the development of personalized treatment strategies. This study describes the significance of the P-MPS in precision medicine, as well as its unique capacity to offer valuable insights into individual patient characteristics.

Understanding organotropism in cancer metastasis using microphysiological systems.

Cancer metastasis, the leading cause of cancer-related deaths, remains a complex challenge in medical science. Stephen Paget's "seed and soil theory" introduced the concept of organotropism, suggesting that metastatic success depends on specific organ microenvironments. Understanding organotropism not only offers potential for curbing metastasis but also novel treatment strategies. Microphysiological systems (MPS), especially organ-on-a-chip models, have emerged as transformative tools in this quest. These systems, blending microfluidics, biology, and engineering, grant precise control over cell interactions within organ-specific microenvironments. MPS enable real-time monitoring, morphological analysis, and protein quantification, enhancing our comprehension of cancer dynamics, including tumor migration, vascularization, and pre-metastatic niches. In this review, we explore innovative applications of MPS in investigating cancer metastasis, particularly focusing on organotropism. This interdisciplinary approach converges the field of science, engineering, and medicine, thereby illuminating a path toward groundbreaking discoveries in cancer research.

Revealing the clinical potential of high-resolution organoids.

The symbiotic interplay of organoid technology and advanced imaging strategies yields innovative breakthroughs in research and clinical applications. Organoids, intricate three-dimensional cell cultures derived from pluripotent or adult stem/progenitor cells, have emerged as potent tools for in vitro modeling, reflecting in vivo organs and advancing our grasp of tissue physiology and disease. Concurrently, advanced imaging technologies such as confocal, light-sheet, and two-photon microscopy ignite fresh explorations, uncovering rich organoid information. Combined with advanced imaging technologies and the power of artificial intelligence, organoids provide new insights that bridge experimental models and real-world clinical scenarios. This review explores exemplary research that embodies this technological synergy and how organoids reshape personalized medicine and therapeutics.

Recapitulating the Cancer-Immunity Cycle on a Chip.

The cancer-immunity cycle is a fundamental framework for understanding how the immune system interacts with cancer cells, balancing T cell recognition and elimination of tumors while avoiding autoimmune reactions. Despite advancements in immunotherapy, there remains a critical need to dissect each phase of the cycle, particularly the interactions among the tumor, vasculature, and immune system within the tumor microenvironment (TME). Innovative platforms such as organ-on-a-chip, organoids, and bioprinting within microphysiological systems (MPS) are increasingly utilized to enhance the understanding of these interactions. These systems meticulously replicate crucial aspects of the TME and immune responses, providing robust platforms to study cancer progression, immune evasion, and therapeutic interventions with greater physiological relevance. This review explores the latest advancements in MPS technologies for modeling various stages of the cancer-immune cycle, critically evaluating their applications and limitations in advancing the understanding of cancer-immune dynamics and guiding the development of next-generation immunotherapeutic strategies.

Vascularized tissue on mesh-assisted platform (VT-MAP): a novel approach for diverse organoid size culture and tailored cancer drug response analysis.

This study presents the vascularized tissue on mesh-assisted platform (VT-MAP), a novel microfluidic in vitro model that uses an open microfluidic principle for cultivating vascularized organoids. Addressing the gap in 3D high-throughput platforms for drug response analysis, the VT-MAP can host tumor clusters of various sizes, allowing for precise, size-dependent drug interaction assessments. Key features include capability for forming versatile co-culture conditions (EC, fibroblasts and colon cancer organoids) that enhance tumor organoid viability and a perfusable vessel network that ensures efficient drug delivery and maintenance of organoid health. The VT-MAP enables the culture and analysis of organoids across a diverse size spectrum, from tens of microns to several millimeters. The VT-MAP addresses the inconsistencies in traditional organoid testing related to organoid size, which significantly impacts drug response and viability. Its ability to handle various organoid sizes leads to results that more accurately reflect patient-derived xenograft (PDX) models and differ markedly from traditional in vitro well plate-based methods. We introduce a novel image analysis algorithm that allows for quantitative analysis of organoid size-dependent drug responses, marking a significant step forward in replicating PDX models. The PDX sample from a positive responder exhibited a significant reduction in cell viability across all organoid sizes when exposed to chemotherapeutic agents (5-FU, oxaliplatin, and irinotecan), as expected for cytotoxic drugs. In sharp contrast, PDX samples of a negative responder showed little to no change in viability in smaller clusters and only a slight reduction in larger clusters. This differential response, accurately replicated in the VT-MAP, underscores its ability to generate data that align with PDX models and in vivo findings. Its capacity to handle various organoid sizes leads to results that more accurately reflect PDX models and differ markedly from traditional in vitro methods. The platform's distinct advantage lies in demonstrating how organoid size can critically influence drug response, revealing insights into cancer biology previously unattainable with conventional techniques.

Patient-derived tumor spheroid-induced angiogenesis preclinical platform for exploring therapeutic vulnerabilities in cancer.

This study addresses the demand for research models that can support patient-treatment decisions and clarify the complexities of a tumor microenvironment by developing an advanced non-animal preclinical cancer model. Based on patient-derived tumor spheroids (PDTS), the proposed model reconstructs the tumor microenvironment with emphasis on tumor spheroid-driven angiogenesis. The resulting microfluidic chip system mirrors angiogenic responses elicited by PDTS, recapitulating patient-specific tumor conditions and providing robust, easily quantifiable outcomes. Vascularized PDTS exhibited marked angiogenesis and tumor proliferation on the microfluidic chip. Furthermore, a drug that targets the vascular endothelial growth factor receptor 2 (VEGFR2, ramucirumab) was deployed, which effectively inhibited angiogenesis and impeded tumor invasion. This innovative preclinical model was used for investigating distinct responses for various drug combinations, encompassing HER2 inhibitors and angiogenesis inhibitors, within the context of PDTS. This integrated platform could potentially advance precision medicine by harmonizing diverse data points within the tumor microenvironment with a focus on the interplay between cancer and the vascular system.

Angio-Net: deep learning-based label-free detection and morphometric analysis of in vitro angiogenesis.

Despite significant advancements in three-dimensional (3D) cell culture technology and the acquisition of extensive data, there is an ongoing need for more effective and dependable data analysis methods. These concerns arise from the continued reliance on manual quantification techniques. In this study, we introduce a microphysiological system (MPS) that seamlessly integrates 3D cell culture to acquire large-scale imaging data and employs deep learning-based virtual staining for quantitative angiogenesis analysis. We utilize a standardized microfluidic device to obtain comprehensive angiogenesis data. Introducing Angio-Net, a novel solution that replaces conventional immunocytochemistry, we convert brightfield images into label-free virtual fluorescence images through the fusion of SegNet and cGAN. Moreover, we develop a tool capable of extracting morphological blood vessel features and automating their measurement, facilitating precise quantitative analysis. This integrated system proves to be invaluable for evaluating drug efficacy, including the assessment of anticancer drugs on targets such as the tumor microenvironment. Additionally, its unique ability to enable live cell imaging without the need for cell fixation promises to broaden the horizons of pharmaceutical and biological research. Our study pioneers a powerful approach to high-throughput angiogenesis analysis, marking a significant advancement in MPS.

Integrating Vascular Phenotypic and Proteomic Analysis in an Open Microfluidic Platform.

This research introduces a vascular phenotypic and proteomic analysis (VPT) platform designed to perform high-throughput experiments on vascular development. The VPT platform utilizes an open-channel configuration that facilitates angiogenesis by precise alignment of endothelial cells, allowing for a 3D morphological examination and protein analysis. We study the effects of antiangiogenic agents─bevacizumab, ramucirumab, cabozantinib, regorafenib, wortmannin, chloroquine, and paclitaxel─on cytoskeletal integrity and angiogenic sprouting, observing an approximately 50% reduction in sprouting at higher drug concentrations. Precise LC-MS/MS analyses reveal global protein expression changes in response to four of these drugs, providing insights into the signaling pathways related to the cell cycle, cytoskeleton, cellular senescence, and angiogenesis. Our findings emphasize the intricate relationship between cytoskeletal alterations and angiogenic responses, underlining the significance of integrating morphological and proteomic data for a comprehensive understanding of angiogenesis. The VPT platform not only advances our understanding of drug impacts on vascular biology but also offers a versatile tool for analyzing proteome and morphological features across various models beyond blood vessels.

Clinical Implication of HER2 Aberration in Patients With Metastatic Cancer Using Next-Generation Sequencing: A Pan-Tumor Analysis.

PURPOSE: Human epidermal growth factor receptor 2 (HER2) protein expression or gene amplification is a significant predictive biomarker for identifying patients with cancer, who may benefit from HER2-targeted therapy. The aim of this study was to survey the proportion of patients who had HER2 aberration and to investigate the correlation between HER2 amplification and HER2 overexpression in immunohistochemistry (IHC) as a real-world data. METHODS: We surveyed the incidence of HER2 aberration including mutation (single-nucleotide variant [SNV]), amplification (copy-number variation), and fusion by next-generation sequencing (NGS) in 2,119 patients with cancer from Samsung Medical Center in South Korea. RESULTS: Of 2,119 patients with cancer, 189 patients (8.9%) had HER2 aberration in their tumor specimen. Of 189 patients, 113 (5.3%) patients had HER2 amplification, 82 (3.9%) patients had HER2 mutations, and 11 (0.5%) patients had HER2 fusion. Of note, 10 patients (0.5%) had concurrent HER2 amplification and HER2 fusion. In addition, we identified that HER2 protein overexpression was strongly related to HER2 amplification by NGS. Of 74 patients with HER2 amplification only by NGS test, 64 patients (86.5%) had HER2 overexpression by IHC. Of 10 patients with concurrent HER2 amplification and fusion, 80% patients were HER2 overexpression. Among 51 patients with only HER2 mutation (SNV), 9 patients (17.6%) were HER2 (+). Interestingly, almost all patients with colorectal cancer (11 of 12) with HER2 amplification had very strong HER2 overexpression (3+) in their tumor specimen. CONCLUSION: In conclusion, we showed that when patients with metastatic cancer receive NGS test, approximately 8.9% have HER2 aberrations in their tumor specimen. Most patients have HER2 amplification, and a small percentage of patients have HER2 fusion. A great majority of patients with HER2 amplification and/or HER2 fusion had HER2 (+) tumor by IHC.

Patient-derived exosomes facilitate therapeutic targeting of oncogenic MET in advanced gastric cancer.

Gastric cancer (GC) with peritoneal metastases and malignant ascites continues to have poor prognosis. Exosomes mediate intercellular communication during cancer progression and promote therapeutic resistance. Here, we report the significance of exosomes derived from malignant ascites (EXOAscites) in cancer progression and use modified exosomes as resources for cancer therapy. EXOAscites from patients with GC stimulated invasiveness and angiogenesis in an ex vivo three-dimensional autologous tumor spheroid microfluidic system. EXOAscites concentration increased invasiveness, and blockade of their secretion suppressed tumor progression. In MET-amplified GC, EXOAscites contain abundant MET; their selective delivery to tumor cells enhanced angiogenesis and invasiveness. Exosomal MET depletion substantially reduced invasiveness; an additive therapeutic effect was induced when combined with MET and/or VEGFR2 inhibition in a patient-derived MET-amplified GC model. Allogeneic MET-harboring exosome delivery induced invasion and angiogenesis in a MET non-amplified GC model. MET-amplified patient tissues showed higher exosome concentration than their adjacent normal tissues. Manipulating exosome content and production may be a promising complementary strategy against GC.

3D microengineered vascularized tumor spheroids for drug delivery and efficacy testing.

Tumor angiogenesis is regarded as a promising target for limiting cancer progression because tumor-associated vasculature supplies blood and provides a path for metastasis. Thus, in vitro recapitulation of vascularized tumors is critical to understand the pathology of cancer and identify the mechanisms by which tumor cells proliferate, metastasize, and respond to drugs. In this study, we microengineered a vascularized tumor spheroid (VTS) model to reproduce the pathological features of solid tumors. We first generated tumor-EC hybrid spheroids with self-assembled intratumoral vessels, which enhanced the uniformity of the spheroids and peritumoral angiogenic capacity compared to spheroids composed only with cancer cells. Notably, the hybrid spheroids also exhibited expression profiles associated with aggressive behavior. The blood vessels sprouting around the hybrid spheroids on the VTS chip displayed the distinctive characteristics of leaky tumor vessels. With the VTS chip showing a progressive tumor phenotype, we validated the suppressive effects of axitinib on tumor growth and angiogenesis, which depended on exposure dose and time, highlighting the significance of tumor vascularization to predict the efficacy of anticancer drugs. Ultimately, we effectively induced both lymphangiogenesis and angiogenesis around the tumor spheroid by promoting interstitial flow. Thus, our VTS model is a valuable platform with which to investigate the interactions between tumor microenvironments and explore therapeutic strategies in cancer. STATEMENT OF SIGNIFICANCE: We conducted an integrative study within a vascularized tumor spheroid (VTS) model. We first generated tumor-EC hybrid spheroids with self-assembled intratumoral vessels, which enhanced the uniformity of the spheroids and peritumoral angiogenic capacity compared to spheroids composed only with cancer cells. Through RNA sequencing, we elucidated that the tumor-EC hybrid spheroids exhibited expression profiles associated with aggressive behavior such as cancer progression, invasion and metastasis. The blood vessels sprouting around the hybrid spheroids on the VTS chip displayed the distinctive characteristics of leaky tumor vessels. We further validated the suppressive effects of axitinib on tumor growth and angiogenesis, depending on exposure dose and time. Ultimately, we effectively induced both lymphangiogenesis and angiogenesis around the tumor spheroid by promoting interstitial flow.

Engineering Organ-on-a-Chip to Accelerate Translational Research.

We guide the use of organ-on-chip technology in tissue engineering applications. Organ-on-chip technology is a form of microengineered cell culture platform that elaborates the in-vivo like organ or tissue microenvironments. The organ-on-chip platform consists of microfluidic channels, cell culture chambers, and stimulus sources that emulate the in-vivo microenvironment. These platforms are typically engraved into an oxygen-permeable transparent material. Fabrication of these materials requires the use of microfabrication strategies, including soft lithography, 3D printing, and injection molding. Here we provide an overview of what is an organ-on-chip platform, where it can be used, what it is composed of, how it can be fabricated, and how it can be operated. In connection with this topic, we also introduce an overview of the recent applications, where different organs are modeled on the microscale using this technology.

Sensory change after implant surgery: related factors for recovery.

Objectives: This retrospective study aimed to analyze data on nerve damage in patients who complained of sensory changes after dental implant surgery, the clinical results according to proximity of the implant fixture to the inferior alveolar nerve (IAN) canal, and the factors affecting recovery of sensation. Materials and Methods: The electronic medical records of 64 patients who had experienced sensory change after implant surgery were reviewed. Patients were classified by sex, age, implant installation sites, recovery rate and the distance between the implant fixture and IAN canal on computed tomography (CT). The distance was classified into Group I (D>2 mm), Group II (2 mm≥D>0 mm), and Group III (D≤0 mm). Results: The 64 patients were included and the mean age was 57.3±7.3 years. Among the 36 patients who visited our clinic more than two times, 21 patients (58.3%) reported improvement in sensation, 13 patients (36.1%) had no change in sensation, and 2 patients (5.6%) reported worsening sensation. In Group II, symptom improvement was achieved in all patients regardless of the removal of the implant fixture. In Group III, 8 patients (40.0%) had reported symptom improvement with removal of the implant fixture, and 2 patients (33.3%) of recovered patients showed improvement without removal. Removal of the implant fixture in Group III did not result in any significant difference in recovery (P=0.337), although there was a higher possibility of improvement in sensation in removal cases. Conclusion: Clinicians first should consider removing the fixture when it directly invades the IAN canal. However, in cases of sensory change after dental implant surgery where the drill or implant fixture did not invade the IAN canal, other indirect factors such as flap elevation and damage due to anesthesia should be considered as causes of sensory change. Removal of the implant should be considered with caution in these situations.

MET gene alterations predict poor survival following chemotherapy in patients with advanced cancer.

Background: To aid in oncology drug development, we investigated MET proto-oncogene receptor tyrosine kinase gene aberrations in 2,239 oncology patients who underwent next-generation sequencing (NGS) in clinical practice. Materials and methods: From November 2019 to January 2021, 2,239 patientswith advanced solid tumors who visited oncology clinics underwent NGS. The NGS panel included >500 comprehensive NGS tests using archival tissue specimens. Programmed death-ligand 1(PD-L1) 22C3 assay results and clinical records regarding initial chemotherapy were available for 1,137 (50.8%) and 1,761 (78.7%) patients, respectively for overall survival (OS) analysis. Results: The 2,239 patients represented 37 types of cancer. The NGS panel included >500 genes, microsatellite instability status, tumor mutational burden, and fusions. The most common cancer types were colorectal (N = 702), gastric (N = 481), and sarcoma (N = 180). MET aberrations were detected in 212 patients. All MET-amplified tumors had microsatellite stable status, and 8 had a high tumor mutational burden. Of 46 patients with MET-amplified cancers, 8 had MET-positive protein expression by immunohistochemistry (2+ and 3+). MET fusion was detected in 10 patients. Partner genes of MET fusion included ST7, TFEC, LRRD1, CFTR, CAV1, PCM1, HLA-DRB1, and CAPZA2. In survival analysis, patients with amplification of MET gene fusion had shorter OS and progression-free survival (PFS) than those without. Thus, MET aberration was determined to be a factor of response to chemotherapy. Conclusion: Approximately 2.1% and 0.4% of patients with advanced solid tumors demonstrated MET gene amplification and fusion, respectively, and displayed a worse response to chemotherapy and significantly shorter OS and PFS than those without MET gene amplification or fusion.

Reducing tumor invasiveness by ramucirumab and TGF-ß receptor kinase inhibitor in a diffuse-type gastric cancer patient-derived cell model.

BACKGROUND: Diffuse-type gastric cancer (GC) is known to be more aggressive and relatively resistant to conventional chemotherapy. Hence, more optimized treatment strategy is urgently needed in diffuse-type GC. METHODS: Using a panel of 10 GC cell lines and 3 GC patient-derived cells (PDCs), we identified cell lines with high EMTness which is a distinct feature for diffuse-type GC. We treated GC cells with high EMTness with ramucirumab alone, TGF-ß receptor kinase inhibitor (TEW-7197) alone, or in combination to investigate the drug's effects on invasiveness, spheroid formation, EMT marker expression, and tumor-induced angiogenesis using a spheroid-on-a-chip model. RESULTS: Both TEW-7197 and ramucirumab treatments profoundly decreased invasiveness of EMT-high cell lines and PDCs. With a 3D tumor spheroid-on-a-chip, we identified versatile influence of co-treatment on cancer cell-induced blood vessel formation as well as on EMT progression in tumor spheroids. The 3D tumor spheroid-on-a-chip demonstrated that TEW-7197 + ramucirumab combination significantly decreased PDC-induced vessel formation. CONCLUSIONS: In this study, we showed TEW-7197 and ramucirumab considerably decreased invasiveness, thus EMTness in a panel of diffuse-type GC cell lines including GC PDCs. Taken together, we confirmed that combination of TEW-7197 and ramucirumab reduced tumor spheroid and GC PDC-induced blood vessel formation concomitantly in the spheroid-on-a-chip model.