Reiko Ashida

EUS-guided choledochoduodenostomy for palliative biliary drainage in patients with malignant biliary obstruction: Results of long-term follow-up

Five patients with obstructive jaundice caused by malignant periampullary biliary stenosis underwent EUS-guided choledochoduodenostomy (EUS-CDS) from the first portion of the duodenum using a convex echoendoscope and a needle knife. All the steps of the procedure including passage dilatation and the plastic stent placement were performed through the accessory channel of the echoendoscope over the guide wire. Stent insertion was technically successful in all five patients. The procedure was also clinically effective in relieving jaundice in all cases. One patient developed pneumoperitoneum, which resolved with conservative management. Stent exchange was successful in seven of eight attempts in patients with stent occlusion. One failure was due to tumor invasion to the choledochoduodenal fistula. Stent patency was maintained in the remaining patients throughout their survival period. The average stent patency was 211.8 days. EUS-CDS from the first portion of the duodenum appears to be feasible and safe in cases of obstructive jaundice caused by distal bile duct obstruction.

AP-1 and colorectal cancer

Activator protein-1 (AP-1) is a transcription factor that consists of either a Jun-Jun homodimer or a Jun-Fos heterodimer. AP-1 regulates the expression of multiple genes essential for cell proliferation, differentiation and apoptosis. Numerous reports suggest that AP-1 plays an important role in various human diseases. Among them, the roles relating to human cancers have been strongly suggested for a long time. In human cancers, colorectal cancer is still a leading cause of morbidity and mortality in the world. Since there are some reports about the role of AP-1 in colorectal cancer response to a number of stimuli, such as cytokines and growth factors, and oncogenic transformation, therapeutic inhibition of AP-1 activity has attracted considerable interest. Here, we demonstrate the biological properties of AP-1 and its role in colorectal cancer, and discuss a possibility of an AP-1 inhibitor, an adenovirus dominant-negative mutant of c-Jun, as a therapeutic a gent for gene therapy.

Acousto-chemical manipulation of drug distribution: In vitro study of new drug delivery system

In vitro experiments were conducted for developing a novel drug delivery system (DDS). In the previous study, we achieved destruction of tissue structures by the combined use of pulsed ultrasound and liquid microbubble precursors, i.e., phase change nanodroplets (PCNDs). Here, fundamental studies were carried out to investigate the possibility of a DDS utilizing the phenomena. Gels with aqueous regions filled with PCNDs and sham drugs (black ink particles) were used as tissue mimicking samples with locally injected PCNDs and drugs. The exposure of samples to focused ultrasound pulses at 1.1 MHz with an acoustic intensity of 3.2 kW/cm2 was found to cause the transport of the sham drug toward the transducer. The transport speeds were about 0.34 and 0.1 mm/s, in and out of the focal zone of the transducer, respectively. Focal zone shifting during the exposure with an appropriate timing resulted in an enhanced drug transport while maintaining the initial speed of 0.34 mm/s. Our results suggested that the spatial distribution of locally injected drugs can be manipulated using ultrasound pulses when drugs are injected with PCNDs. As a control experiment, the effect of Sonazoid®, a commercially available microbubble contrast agent, was investigated. No drug transport was observed using Sonazoid® at a bubble number density one order of magnitude higher than that used in the PCND experiments. The pressure resistance properties of PCND and Sonazoid® might be related to the absence of the drug transport phenomena in case of Sonazoid®.

Familial pancreatic cancer: Concept, management and issues

Familial pancreatic cancer (FPC) is broadly defined as two first-degree-relatives with pancreatic cancer (PC) and accounts for 4%-10% of PC. Several genetic syndromes, including Peutz-Jeghers syndrome, hereditary pancreatitis, hereditary breast-ovarian cancer syndrome (HBOC), Lynch syndrome, and familial adenomatous polyposis (FAP), also have increased risks of PC, but the narrowest definition of FPC excludes these known syndromes. When compared with other familial tumors, proven genetic alterations are limited to a small proportion (< 20%) and the familial aggregation is usually modest. However, an ethnic deviation (Ashkenazi Jewish > Caucasian) and a younger onset are common also in FPC. In European countries, “anticipation” is reported in FPC families, as with other hereditary syndromes; a trend toward younger age and worse prognosis is recognized in the late years. The resected pancreases of FPC kindred often show multiple pancreatic intraepithelial neoplasia (PanIN) foci, with various K-ras mutations, similar to colorectal polyposis seen in the FAP patients. As with HBOC patients, a patient who is a BRCA mutation carrier with unresectable pancreatic cancer (accounting for 0%-19% of FPC patients) demonstrated better outcome following platinum and Poly (ADP-ribose) polymerase inhibitor treatment. Western countries have established FPC registries since the 1990s and several surveillance projects for high-risk individuals are now ongoing to detect early PCs. Improvement in lifestyle habits, including non-smoking, is recommended for individuals at risk. In Japan, the FPC study group was initiated in 2013 and the Japanese FPC registry was established in 2014 by the Japan Pancreas Society.

Endoscopic ultrasound‐guided ethanol injection in the pancreas in a porcine model: A preliminary study

Background and Aim:  Despite aggressive multimodal treatments, survival rates for patients with pancreatic cancer remain disappointing. Local progression is problematic, and minimally invasive procedures allowing locoregional control are needed. In this study, we attempted endoscopic ultrasound (EUS)‐guided injection of ethanol into the pancreas.

Controlled induction of mechanical bioeffects with pulsed ultrasound and chemical agents

We aim to develop a novel low-invasive and effective treatment method of pancreatic tumor with synergistic effects of ultrasound and locally injected chemical agents such as anti-tumor drugs. In the treatment, controlling the spatial and temporal distribution of the agents by mechanical effects of ultrasound (cavitation) is a key process. To apply the mechanical effects to pancreases, a deep-seated organ, sensitizers for reducing the required acoustic intensity are essential. As preliminary experiments, we evaluated a formulation of superheated perfluorocarbon droplet, phase change nano droplet (PCND) as such a sensitizer. Effects on destruction of tissue structures were investigated ex vivo. It was found that ultrasound pulses with intensity higher than 2.2 kW/cm2 was enough to induce mechanical effects of ultrasound in chicken breast tissues in the presence of PCND while no damages were observed in the absence of PCND. Increasing pulse intensity or PCND concentration increased destructed volume. It was found that pulse duration should be longer than 100 cycles and increasing duration more than 300 cycles does not increase the destructed volume significantly. Results obtained suggested that PCND works as a sensitizer for inducing mechanical effects in tissues.

Endoscopic Ultrasound and Related Technologies for the Diagnosis and Treatment of Pancreatic Disease - Research Gaps and Opportunities: Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop

Abstract A workshop was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases to address the research gaps and opportunities in pancreatic endoscopic ultrasound (EUS). The event occurred on July 26, 2017 in 4 sessions: (1) benign pancreatic diseases, (2) high-risk pancreatic diseases, (3) diagnostic and therapeutics, and (4) new technologies. The current state of knowledge was reviewed, with identification of numerous gaps in knowledge and research needs. Common themes included the need for large multicenter consortia of various pancreatic diseases to facilitate meaningful research of these entities; to standardize EUS features of different pancreatic disorders, the technique of sampling pancreatic lesions, and the performance of various therapeutic EUS procedures; and to identify high-risk disease early at the cellular level before macroscopic disease develops. The need for specialized tools and accessories to enable the safe and effective performance of therapeutic EUS procedures also was discussed.

EUS and related technologies for the diagnosis and treatment of pancreatic disease: research gaps and opportunities—Summary of a National Institute of Diabetes and Digestive and Kidney Diseases workshop

A workshop was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases to address the research gaps and opportunities in pancreatic EUS. The event occurred on July 26, 2017 in 4 sessions: (1) benign pancreatic diseases, (2) high-risk pancreatic diseases, (3) diagnostic and therapeutics, and (4) new technologies. The current state of knowledge was reviewed, with identification of numerous gaps in knowledge and research needs. Common themes included the need for large multicenter consortia of various pancreatic diseases to facilitate meaningful research of these entities; to standardize EUS features of different pancreatic disorders, the technique of sampling pancreatic lesions, and the performance of various therapeutic EUS procedures; and to identify high-risk disease early at the cellular level before macroscopic disease develops. The need for specialized tools and accessories to enable the safe and effective performance of therapeutic EUS procedures also was discussed.

Assessment with cone-beam computed tomography of intrafractional motion and interfractional position changes of resectable and borderline resectable pancreatic tumours with implanted fiducial marker

OBJECTIVE The volume of targets to which a high radiation dose can be delivered is limited for pancreatic radiotherapy. We assessed changes in movements of pancreatic tumours between simulation and treatment and determined compensatory margins. METHODS For 23 patients, differences in implanted fiducial marker motion magnitude (MMM) and mean marker position (MMP) between four-dimensional CT and cone-beam CT were measured. Subsequently, residual uncertainty was simulated after no action level (NAL) and extended no action level (eNAL) protocols were adopted. RESULTS With no correction, respective 95th percentile of MMM were 4.5 mm, 6.2 mm and 16.0 mm and systematic (random) errors of MMP were 2.8 mm (3.3 mm), 3.2 mm (2.0 mm) and 5.9 mm (4.0 mm) in the left-right (L-R), anteroposterior (A-P) and superoinferior (S-I) directions, so that large margins were required (L-R, 10.5 mm; A-P, 11.7 mm; and S-I, 24.8 mm). NAL reduced systematic errors of MMP, but resultant margins remained large (L-R, 8.0 mm; A-P, 9.6 mm; and S-I, 18.1 mm). eNAL compensated for time trends and obtained minimal margins (L-R, 6.7 mm; A-P, 6.7 mm; and S-I, 15.2 mm). CONCLUSION Motion magnitude and position of pancreatic tumours during simulation are frequently not representative of that during treatment. eNAL compensated for systematic interfractional position change and would be a practical approach for improving targeting accuracy. Advances in knowledge: Considerably large margins, especially in the S-I direction, were required to compensate for intrafractional motion and interfractional position changes of the pancreatic tumour. An application of eNAL was an effective strategy to diminish these margins.

Safety and Effectiveness of Gemcitabine in 855 Patients with Pancreatic Cancer under Japanese Clinical Practice Based on Post-marketing Surveillance in Japan

OBJECTIVE When gemcitabine was approved as an anti-cancer drug, there were limited data for Japanese patients treated with gemcitabine. Generally, advanced or metastatic pancreatic cancer patients experience poor prognosis and suffer from debilitating disease-related symptoms. Reports and information on gemcitabine use within a large patient pool will be beneficial to aid physicians. Therefore, this post-marketing surveillance was conducted as a non-interventional, observational study on the use of gemcitabine in a clinical practice setting in Japan. METHODS Patients had no previous treatment with gemcitabine and were diagnosed with pancreatic cancer by an attending physician. Patients were registered between May 2001 and December 2003 in Japan. The patients were treated with gemcitabine. Data such as patient background, treatment details, adverse events, tumor response, serum CA19-9 levels and drug-related symptom improvement were assessed. RESULTS Of the 890 patients registered for the study, 855 were included in the analysis of gemcitabine for safety. Four hundred and forty-three (51.9%) patients reported drug-related adverse events, with 97 patients (11.4%) experiencing serious adverse events. The incidence of interstitial lung disease was 0.7% (six patients). Six hundred patients were evaluated for tumor response. The overall response rate was 6.0% and the disease control rate was 54.0%. CA19-9 decreased in 63.6% of the 335 evaluable patients, with a ≥75% decrease seen in 19.4% of the total group. Drug-related symptom improvement was observed in 27.0% of the 686 evaluable patients. CONCLUSIONS This large-scale surveillance could confirm the safety of gemcitabine for Japanese pancreatic cancer patients as well as elucidate the efficacy profile, measured by drug-related symptom improvement, for Japanese pancreatic cancer patients.