Current status of endoscopic ultrasound-guided antitumor treatment for pancreatic cancer.

Endoscopic ultrasound (EUS) was developed in the 1990s and has significantly transformed pancreatic tumor diagnosis. Subsequently, EUS has rapidly shifted from being a purely diagnostic procedure to being used in a wide range of interventional procedures. Recently, new therapeutic techniques, such as EUS-guided fine needle injection (EUS-FNI) or radiofrequency ablation (RFA), have been developed to deliver various antitumor agents. Despite technological advancements, pancreatic cancer (PC) has a poor prognosis and improvements in treatment outcomes are urgently required. One of the reasons for the limited response to antitumor agents in PC is the abundant desmoplasia and hypovascular nature of the tumor, complicating drug delivery into the tumor. Thus, changing the tumor microenvironment may be important to enhance the effectiveness of chemotherapy, and direct injection of antitumor agents into the tumor under EUS guidance can help overcome treatment challenges in PC. Treatment approaches using the EUS-FNI or RFA technique are expected to further improve the prognosis of PC. Therefore, this study reviewed the existing literature on EUS-guided antitumor therapy, specifically highlighting its application in PC to address the current challenges and to identify potential advancements in the field.

Local Sustained Chemotherapy of Pancreatic Cancer Using Endoscopic Ultrasound-Guided Injection of Biodegradable Thermo-Sensitive Hydrogel.

Purpose: Endoscopic ultrasound-guided fine-needle injection (EUS-FNI) offers a promising minimally invasive approach for locally targeted management of advanced pancreatic cancer. However, the efficacy is limited due to the rapid plasma clearance of chemotherapeutic agents. Injectable hydrogels can form drug release depots, which provide a feasible solution for optimizing targeted chemotherapy through EUS-FNI. Methods: A drug delivery system was developed, consisting of gemcitabine (GEM) and thermo-sensitive hydrogel (PLGA-PEG-PLGA, PPP). The injectability, gel formation ability, biocompatibility and sustained drug delivery properties of PPP hydrogel were verified in vitro and in vivo. The effects of GEM/PPP hydrogel on cell proliferation, invasion, metastasis, and apoptosis were explored through co-culturing with PANC-1 cells. The therapeutic effects of GEM/PPP hydrogel on xenograft mice were compared with those of GEM, ethanol and polidocanol using the precisely targeted EUS-FNI technology. Tumor sections were examined by H&E, Ki-67, and TUNEL staining. Results: GEM/PPP hydrogel exhibited excellent injectability, biocompatibility, and the capability of sustained drug delivery for up to 7 days by forming a gel triggered by body temperature. It demonstrated the best therapeutic effects, significantly reducing proliferation, invasion and migration of PANC-1 cells while promoting apoptosis. After precise injection using EUS-FNI technology, GEM/PPP hydrogel resulted in a reduction of tumor weight by up to 75.96% and extending the survival period by 14.4 days with negligible adverse effects. Pathological examination revealed no systemic toxicity and significant apoptosis and minimal proliferation as well. Conclusion: The combination of GEM/PPP hydrogel and EUS-FNI technology provides an optimal approach of precise chemotherapy for pancreatic cancer, builds a bridge for clinical translation of basic research, and brings great hope for innovation of minimally invasive treatment modalities. The first-hand EUS image data obtained in this study also serves as a crucial reference for future clinical trials.

STNM01, the RNA oligonucleotide targeting carbohydrate sulfotransferase 15, as second-line therapy for chemotherapy-refractory patients with unresectable pancreatic cancer: An open label, phase I/IIa trial.

Background: The impact of stroma-targeting therapy on tumor immune suppression is largely unexplored. An RNA oligonucleotide, STNM01, has been shown to repress carbohydrate sulfotransferase 15 (CHST15) responsible for tumor proteoglycan synthesis and matrix remodeling. This phase I/IIa study aimed to evaluate the safety and efficacy of STNM01 in patients with unresectable pancreatic ductal adenocarcinoma (PDAC). Methods: This was an open-label, dose-escalation study of STNM01 as second-line therapy in gemcitabine plus nab-paclitaxel-refractory PDAC. A cycle comprised three 2-weekly endoscopic ultrasound-guided locoregional injections of STNM01 at doses of 250, 1,000, 2,500, or 10,000 nM in combination with S-1 (80-120 mg twice a day for 14 days every 3 weeks). The primary outcome was the incidence of dose-liming toxicity (DLT). The secondary outcomes included overall survival (OS), tumor response, changes in tumor microenvironment on immunohistopathology, and safety (jRCT2031190055). Findings: A total of 22 patients were enrolled, and 3 cycles were repeated at maximum; no DLT was observed. The median OS was 7.8 months. The disease control rate was 77.3%; 1 patient showed complete disappearance of visible lesions in the pancreas and tumor-draining lymph nodes. Higher tumoral CHST15 expression was associated with poor CD3+ and CD8+ T cell infiltration at baseline. STNM01 led to a significant reduction in CHST15, and increased tumor-infiltrating CD3+ and CD8+ T cells in combination with S-1 at the end of cycle 1. Higher fold increase in CD3+ T cells correlated with longer OS. There were 8 grade 3 adverse events. Interpretation: Locoregional injection of STNM01 was well tolerated in patients with unresectable PDAC as combined second-line therapy. It prolonged survival by enhancing T cell infiltration in tumor microenvironment. Funding: The present study was supported by the Japan Agency for Medical Research and Development (AMED).

Endoscopic ultrasound-guided injectable therapy for pancreatic cancer: A systematic review.

BACKGROUND: Given the low survival rate in pancreatic cancer, new therapeutic techniques have been explored, especially for unresectable or borderline resectable disease. Endoscopic ultrasound (EUS) provides real-time imaging and minimally invasive access for local and targeted injection of anti-tumor agents directly into the pancreatic tumor. Limited studies have been reported using this technique for the treatment of pancreatic ductal adenocarcinoma (PDAC). AIM: To evaluate the progress made with EUS-guided injectable therapies in the treatment of PDAC. METHODS: All original articles published in English until July 15, 2021, were retrieved via a library-assisted literature search from Ovid Evidence-Based Medicine Reviews and Scopus databases. Reference lists were reviewed to identify additional relevant articles. Prospective clinical studies evaluating the use of EUS-guided injectable therapies in PDAC were included. Studies primarily directed at non-EUS injectable therapies and other malignancies were excluded. Retrieved manuscripts were reviewed descriptively with on critical appraisal of published studies based on their methods and outcome measures such as safety, feasibility, and effectiveness in terms of tumor response and survival. Heterogeneity in data outcomes and therapeutic techniques limited the ability to perform comparative statistical analysis. RESULTS: A total of thirteen articles (503 patients) were found eligible for inclusion. The EUS-injectable therapies used were heterogeneous among the studies consisting of immunotherapy (n = 5) in 59 patients, chemotherapy (n = 1) in 36 patients, and viral and other biological therapies (n = 7) in 408 patients. Eleven of the studies reviewed were single armed while two were double armed with one randomized trial and one non-randomized comparative study. Overall, the included studies demonstrated EUS-guided injectable therapies to be safe and feasible with different agents as monotherapy or in conjunction with other modalities. Promising results were also observed regarding their efficacy and survival parameters in patients with PDAC. CONCLUSION: EUS-guided injectable therapies, including immunotherapy, chemotherapy, and viral or other biological therapies have shown minimal adverse events and potential efficacy in the treatment of PDAC. Comparative studies, including controlled trials, are required to confirm these results in order to offer novel EUS-based treatment options for patients with PDAC.

Role of endoscopic ultrasound in anticancer therapy: Current evidence and future perspectives.

The digestive system is one of the most common sites of malignancies in humans. Since gastrointestinal tumors represent a massive global health burden both in terms of morbidity and health care expenditures, scientists continuously develop novel diagnostic and therapeutic methods to ameliorate the detrimental effects of this group of diseases. Apart from the well-established role of the endoscopic ultrasound (EUS) in the diagnostic course of gastrointestinal and hepatobiliary malignancies, we have recently become acquainted with a vast array of its therapeutic possibilities. A multitude of previously established, evidence-based methods that might now be guided by the EUS emerged: Radiofrequency ablation, brachytherapy, fine needle injection, celiac plexus neurolysis, and endoscopic submucosal dissection. In this review we endeavored to provide a comprehensive overview of the role of these methods in different malignancies of the digestive system, primarily in the treatment and symptom control in pancreatic cancer, and additionally in the management of hepatic, gastrointestinal tumors, and pancreatic cysts.

Development of a new reagent for endoscopic ultrasound-guided celiac plexus neurolysis and tumor ablation therapy

BACKGROUND: Both endoscopic ultrasound-guided celiac plexus neurolysis (EUS-CPN) and tumor ablation using ethanol are very common procedures, and the utility of these therapies has already been reported in prominent journals. However, their effectiveness appears temporary and insufficient, especially EUS-CPN. We therefore have to consider new reagents for improving the results. The present study examined the best concentration of ethanol and povidone iodine mixed with atelocollagen for more effective therapies. METHODS: The effects of the new reagents were confirmed in three live pigs. At first, we injected three kinds of reagents (including indigo carmine) in three separate areas of para-aortic tissue under EUS guidance in one pig. At more than 4 hours after injection, we checked ethanol injection sites after dissection. In next study, we performed EUS-guided injection of a total of six kinds of reagents (two kinds of ethanol, three kinds of povidone iodine, and control atelocollagen) into the livers of two living pigs. After 2 weeks, we examined tissue damage to the liver in the two pigs. RESULTS: The 75% ethanol (absolute ethanol 3.75 mL + 1% atelocollagen 1.25 mL + a very small amount of indigo carmine) was seen like blue gel, and still remained in the para-aortic tissue. Brownish areas of povidone iodine mixed with 3% atelocollagen exhibited clear, regular borders with greatly reduced infiltration into surrounding tissue compared to others. CONCLUSION: We concluded that 75% ethanol mixed with 1% atelocollagen appears optimal for EUS-CPN. Povidone iodine mixed with 3% atelocollagen may be suitable for small tumor ablation therapy.

Local drug delivery to a human pancreatic tumor via a newly designed multiple injectable needle.

Endoscopic ultrasound-guided fine needle injection (EUS-FNI) has been proposed as a novel technique for local delivery of antitumor agents to refractory tumors, including pancreatic cancer. However, the present outcome of this strategy remains insufficient, and further improvements as well as novel agents and injection devices are required. The aim of the study was to determine the feasibility of a newly designed 'multiple injectable needle' (MIN) for EUS-FNI and the resulting improvements in the drug distribution to the tumor in comparison with straight-type needles. Human pancreatic cancer BxPC-3 cells or orthotopic tumor were transplanted subcutaneously into athymic rats. Ethanol was injected into subcutaneous tumors using a MIN or straight-type needle. Sequential sections of subcutaneous tumors were stained with hematoxylin and eosin, and tumors and injury areas were quantified using ImageJ software. In the orthotopic tumors, injection of the outer needle of the MIN, advancement of the inner needle and ethanol infusion were monitored by EUS. Injury volume of subcutaneous tumors using a MIN was greater than that with the straight-type needles, except for large tumors. Injecting process using MIN was monitored with endoscopic ultrasound (EUS). This study showed improvement in the drug distribution in a tumor, following injection with MIN compared to straight-type needles, suggesting the novel device to be feasible for use in EUS-FNI.