A New Bitterness Evaluation Index Obtained Using the Taste Sensor for 48 Active Pharmaceutical Ingredients of Pediatric Medicines.

The aim of this study was to evaluate bitterness by using "CCDP; Change in concentration-dependent potential" considering dose-dependency of active pharmaceutical ingredients (APIs) as new and useful bitterness evaluation index compared with bitter sensor output value which is conventional bitterness evaluation index for 48 pediatric medicines from the recent edition of the WHO model list of essential medicines for children (7th edn, 2019). Solutions (0.01, 0.03, 0.1 mM) of the compounds were evaluated by an artificial taste sensor using membranes sensitive to bitterness. The dose-response slope of the sensor outputs was defined as CCDP. On the basis of principal component analysis of CCDPs, chlorpromazine hydrochloride, amitriptyline hydrochloride, propranolol hydrochloride, primaquine phosphate and haloperidol were predicted to express the strongest levels of basic bitterness, surpassing that of quinine hydrochloride. Correlation analysis (Fisher's exact tests and multiple regression analysis) was performed to determine the relation between CCDPs and various physicochemical properties participated in hydrophilicity and hydrophobicity. It is revealed that contribution physicochemical factors are different by individual basic bitterness sensor (AC0, AN0 or BT0), and this result becomes the criterion of the sensor choice to evaluate basic bitterness intensity using basic bitterness sensors. Hydrophobic and hydrophilic interactions could be simulated by ligand docking modeling for haloperidol, miconazole and quinine hydrochloride. The pharmaceutical products need a bitterness evaluation in consideration of concentration-dependency to vary in a dose depending on a patient individual. Thus, it was concluded that CCDP correlated to hydrophilicity and hydrophobicity is useful as a bitterness evaluation index of APIs in pediatric medicines.

Splenic marginal zone lymphoma uncovered after a 10-year follow up as anemia of unknown cause.

A 75-year-old man was referred to our hospital for evaluation of persistent anemia. Despite repeated diagnostic tests, including bone marrow aspiration, the cause of his anemia remained unknown. On each occasion, computed tomography had revealed neither swollen lymph nodes nor splenomegaly. After a 10-year follow-up period, he was admitted with general fatigue and had developed splenomegaly as well as the anemia. Bone marrow biopsy revealed increased abnormal lymphocytes with short villi that were positive for CD11c, CD19, CD20, and kappa chain, but not for CD5, CD10, CD23, or cyclin D1, according to flow cytometry. The bone marrow biopsy sample showed nodular proliferation of small to medium-sized abnormal lymphocytes. Based on these findings, the patient was diagnosed as having splenic marginal zone lymphoma, a rare indolent B-cell neoplasm. Although his splenomegaly diminished after eight cycles of weekly rituximab monotherapy, the anemia did not improve, and abnormal lymphocytes remained detectable in his bone marrow. The patient was then treated with bendamustine monotherapy for six cycles, after which the anemia resolved, and he has since been in good condition. Although rare, it is important to consider splenic marginal zone lymphoma during the differential diagnosis of patients with a long history of anemia of unknown cause.

Diagnostic and therapeutic single-operator cholangiopancreatoscopy in biliopancreatic diseases: Prospective multicenter study in Japan.

AIM: To assess the utility and safety of single-operator cholangiopancreatoscopy (SOCPS) using the SpyGlass system in widespread clinical application for biliary and pancreatic diseases. METHODS: This study was a prospective case series conducted in 20 referral centers in Japan. There were 148 patients who underwent SOCPS; 124 for biliary diseases and 24 for pancreatic diseases. The attempted interventions were SOCPS examination, SOCPS-directed tissue sampling, and therapy for stone removal, among others. The main outcomes were related to the procedure success rate in terms of visualizing the target lesions, SOCPS-directed adequate tissue sampling, and complete stone removal. RESULTS: A total of 148 patients were enrolled for the diagnosis of indeterminate biliary and pancreatic lesions or treatment of biliary and pancreatic disease. The overall procedure success rate of visualizing the target lesions was 91.2% (135/148). The overall procedural success rates of visualizing the target lesions of diagnostic SOCPS in the bile duct and pancreatic duct were 95.5% (84/89) and 88.2% (15/17), respectively. DIAGNOSIS: the overall adequate tissue for histologic examination was secured in 81.4% of the 86 patients who underwent biopsy under SOCPS (bile duct, 60/75, 80.0%; pancreatic duct, 10/11, 90.9%). The accuracy of histologic diagnosis using SOCPS-directed biopsies in indeterminate bile duct lesions was 70.7% (53/75). In the pancreatic duct, the accuracy of SOCPS visual impression of intraductal papillary mucinous neoplasm was 87.5% (14/16). Stone therapy: complete biliary and pancreatic stone clearance combined with SOCPS-directed stone therapy using electrohydraulic lithotripsy or laser lithotripsy was achieved in 74.2% (23/31) and 42.9% (3/7) of the patients, respectively. Others: SOCPS using the SpyGlass system was used in cannulation of the cystic duct in two patients and for passing across the obstructed self-expandable metallic stent for a malignant biliary stricture in two patients. All procedures were successful in both SOCPS-guided therapies. The incidence of procedure-related adverse events was 5.4% (8/148). CONCLUSION: SOCPS with direct visualization and biopsy for diagnosis and SOCPS-directed therapy for biliary and pancreatic diseases can be safely performed with a high success rate. The clinical trial was registered at UMIN CTR (http://www.umin.ac.jp). The registration identification number is UMIN000015155.

New digital cholangiopancreatoscopy for diagnosis and therapy of pancreaticobiliary diseases (with videos).

BACKGROUND: Recently, a new digital cholangiopancreatoscopy (DCPS) has been developed. The aim of this study is to retrospectively evaluate the utility of new DCPS in patients with pancreaticobiliary diseases. METHODS: Digital cholangiopancreatoscopy was used in 26 patients (16 men) with pancreaticobiliary diseases that could not be diagnosed and treated by standard endoscopic retrograde cholangiopancreatography (ERCP). The procedures included DCPS-guided tissue sampling and interventions. Technical success and adverse events were evaluated. RESULTS: Among the 26 patients, 19 patients were classified for diagnostic purposes and seven for therapeutic purposes. The detailed breakdown of the particular conditions and numbers of patients was as follows: indeterminate bile duct (BD) lesion, indeterminate pancreatic duct (PD) lesion, lithotripsy by yttrium aluminum garnet-laser or electrohydraulic lithotripsy, removal of migrated BD stent and PD stent, and guidewire passing across the biliary stricture. The overall technical success rates of visualizing the target lesions and therapeutic interventions were 100% and 85.7%, respectively. The incidence of procedure-related adverse events among the patients was 7.7% (2/26). Cholangitis developed in one of the patients and post-endoscopic sphincterotomy bleeding in one patient. All adverse events were successfully treated by conservative therapy. CONCLUSION: Digital cholangiopancreatoscopy has a high potential for providing an accurate diagnosis and facilitating therapy in patients with pancreaticobiliary diseases.

Effectiveness of the J-Tip Guidewire for Selective Biliary Cannulation Compared to Conventional Guidewires (The JANGLE Study).

BACKGROUND: Wire-guided cannulation has become a common biliary cannulation technique worldwide. Different guidewires with various tip shapes and materials have been reportedly used for wire-guided cannulation. However, there are apparently no studies reporting changes in the biliary cannulation rate according to the type of guidewire used. AIMS: We evaluated the effectiveness of the J-tip guidewire for biliary cannulation. METHODS: We conducted a prospective, multicenter, controlled study involving patients with a native papilla who required biliary cannulation. We allocated the patients to the J-tip guidewire or angled-tip guidewire groups (groups J and A, respectively). If biliary cannulation was not achieved within 10 min, the GW was changed and cannulation was continued. RESULTS: Groups J and A consisted of 66 and 65 enrolled patients, respectively. The biliary cannulation rate with a single guidewire for the first 10 min was 84.8 % (56/66) for group J and 80.0 % (52/65) for group A. The final success rate for biliary cannulation was 100 % in both groups. The mean times necessary for biliary cannulation were 285.8 and 267.6 s in group J and group A, respectively. The incidence rates of complications (i.e., all mild pancreatitis) were 3.0 % (2/66) and 6.2 % (4/65) in group J and group A, respectively. The mean amylase concentrations were 168.0 and 297.7 IU/L in group J and group A, respectively. There were no significant differences in any results between both groups. CONCLUSION: The biliary cannulation rate of the J-tip guidewire was not significantly different from those of standard guidewires.

Endoscopic ultrasound-guided placement of plastic vs. biflanged metal stents for therapy of walled-off necrosis: a retrospective single-center series.

BACKGROUND AND STUDY AIMS: Recently, a novel fully covered and biflanged metal stent (BFMS)dedicated to the drainage of walled-off necrosis(WON) was developed. The aim of this study was to retrospectively evaluate the safety, efficacy, and cost performance of drainage of WON using the novel BFMS compared with a traditional plastic stent. PATIENTS AND METHODS: A total of 70 patients with symptomatic WON were treated under endoscopic ultrasound (EUS) guidance. Initial drainage was conducted using the single gateway technique with placement of one or more plastic stents or a single BFMS.If drainage was unsuccessful,direct endoscopic necrosectomy (DEN)was performed. RESULTS: There were no statistically significant differences in rates of technical success, clinical success,and adverse events between plastics stents and BFMS, despite the size of WON in the BFMS group being significantly larger than that in the plastic stent group (105.6 vs. 77.1 mm; P=0.003).The mean procedure times for the first EUS-guided drainage and for re-intervention were significantly shorter in the BFMS group than in the plastic stent group (28.8±7.1 vs. 42.6±14.2, respectively,for drainage, P<0.001; and 34.9±8.5 vs.41.8±7.6, respectively, for re-intervention, P<0.001). There was no statistically significant difference in the total cost between plastic stent and BFMS use in the treatment of WON ($5352vs. $6274; P=0.25). CONCLUSIONS: Plastic stents and BFMS were safe and effective for the treatment of WON. In particular,BFMS placement appeared to be preferable for initial EUS-guided drainage and additional reintervention(e.g. DEN) as it reduced the procedure time. Prospective randomized controlled trials are warranted.

Expanding endoscopic interventions for pancreatic pseudocyst and walled-off necrosis.

BACKGROUND: Recently, several endoscopists have described the usefulness of the endoscopic ultrasonography (EUS)-guided, single transluminal gateway technique (SGT) using transmural placement of single or multiple plastic stents or metal stents for a pancreatic pseudocyst (PC) and walled-off necrosis (WON). Moreover, the uses of the multiple transluminal gateway technique (MTGT) and single transluminal gateway transcystic multiple drainages (SGTMD) for complicated pancreatic walled-off necrosis have recently been reported. The aim of this study is to evaluate retrospectively the feasibility and efficacy of endotherapy for the treatment of complicated PC and WON cases. METHODS: Eighty-nine patients with a PC (n = 14) and WON (n = 75) were treated under EUS guidance. RESULTS: In a total of 89 cases using SGT in combination with MTGT or SGTMD, the present study showed a technical success rate of 100 %, a final clinical success rate of 97.8 %, an adverse event during procedure rate of 0 %, an early adverse event rate of 12.4 %, and a mortality rate of 2.2 %. CONCLUSIONS: Even complicated WON cases can be treated using combination endotherapies, although a surgical approach as well as a percutaneous approach should be considered in the cases refractory to endoscopic therapies.

Mid-term outcome of endoscopic sphincterotomy combined with large balloon dilation.

BACKGROUND AND AIM: Endoscopic sphincterotomy (ES) combined with large balloon dilation (ESLBD) can be useful for extracting large and multiple bile duct stones. Although there are many studies on the feasibility and short-term outcome, there are few reports about mid- to long-term outcome after ESLBD. The aim of our study is to prospectively evaluate the mid-term outcome of ESLBD. METHODS: One hundred eighty-three patients who underwent ESLBD between November 2006 and May 2012 were included. The patients were followed up periodically after the procedure until April 2013. Papillary dilation was performed at the time of initial ES or prior ES. Early and late adverse events and stone recurrence were evaluated in this study. RESULTS: The patients' mean age was 76.6 ± 10.7 years. Surgically altered anatomy was present: Billroth I gastrectomy (2), Billroth II gastrectomy (13), and gastrectomy with Roux-en Y reconstruction (18). Seventy-eight (42.6%) patients had periampullary diverticulum. Prior ES had been performed in 40 (21.9%) patients. The mean follow-up period was 43.5 ± 19.7 months (range 11-78). Eight (4.4%) patients had stone recurrence. There was rare stone recurrence after initial ESLBD treatment and native gastrointestinal anatomy. Univariate and multivariate analyses showed that prior ES and previous history of stone recurrence were predictive of stone recurrence (P < 0.001). CONCLUSION: At mid-term outcome, ESLBD is associated with a low rate of recurrent bile duct stones, although long-term follow up is needed.

Successful treatment of chronic disseminated intravascular coagulation using recombinant human soluble thrombomodulin in a dialysis patient with dissecting aortic aneurysm.

A 62-year-old man had a history of acute aortic dissection (Stanford type A) and had been diagnosed with polycystic kidney disease three years earlier, and then developed end-stage renal failure. He was referred with chief complaints of difficult hemostasis and consecutive hemorrhagic episodes at the puncture site of the shunt soon after dialysis introduction. We suspected chronic disseminated intravascular coagulation (DIC) due to mild thrombocytopenia and a fibrinolytic system abnormality. Plasma factor XIII activity was decreased, but no inhibitor was detected. In addition, contrast-enhanced computed tomography showed exacerbation of a dissecting aortic aneurysm. We finally diagnosed chronic DIC and secondary factor XIII deficiency associated with the aortic aneurysm. We selected treatment involving recombinant human soluble thrombomodulin (rTM) because he was on maintenance dialysis and required long-term follow-up bofore the operation. Hemostatic function improved with regular administration of rTM, and was well-controlled preoperatively.

Safety trial of high-intensity focused ultrasound therapy for pancreatic cancer.

AIM: To evaluate the safety and clinical application of high-intensity focused ultrasound (HIFU) therapy for unresectable pancreatic cancer (PC). METHODS: Thirty PC patients (16 cases in stage III and 14 cases in stage IV) with visualized pancreatic tumors were admitted for HIFU therapy as an optional local therapy in addition to systemic chemotherapy or chemoradiotherapy. Informed consent was obtained. This study began at the end of 2008 and was approved by the ethics committee of our hospital [Institutional Review Board (IRB): 890]. The HIFU device used was the FEP-BY02 (Yuande Bio-Medical Engineering, Beijing, China). RESULTS: The mean tumor size after HIFU therapy changed to 30.9 ± 1.7 mm from 31.7 ± 1.7 mm at pre-therapy. There were no significant changes in tumor size, mean number of treatment sessions (2.7 ± 0.1 mm), or mean total treatment time (2.4 ± 0.1 h). The rate of symptom relief effect was 66.7%. The effectiveness of primary lesion treatment was as follows: complete response, 0; partial response, 4; stable disease, 22; progressive disease, 4. Treatment after HIFU therapy included 2 operations, 24 chemotherapy treatments, and 4 best supportive care treatments. Adverse events occurred in 10% of cases, namely pseudocyst formation in 2 cases and mild pancreatitis development in 1. However, no severe adverse events occurred in this study. CONCLUSION: We suggest that HIFU therapy is safe and has the potential to be a new method of combination therapy for PC.

Successful bortezomib/dexamethasone induction therapy with lenalidomide in an elderly patient with primary plasma cell leukemia complicated by renal failure and pulmonary hypertension.

Primary plasma cell leukemia (PPCL) is a rare disease that progresses rapidly. In such cases, it is difficult to achieve remission, and early intensive chemotherapy is recommended. We herein describe the case of a 76-year-old man with PPCL complicated by renal failure and pulmonary hypertension. Bortezomib/dexamethasone induction therapy with lenalidomide was administered in association with continuous hemodiafiltration (CHDF). Complete remission was achieved after a single course of treatment, resulting in the cessation of CHDF. With the patient in remission, the administration of beraprost and bosentan resulted in improvements in the pulmonary hypertension. The results of this case report support the use of bortezomib/lenalidomide/dexamethasone combination therapy as an effective treatment for elderly PPCL patients with various complications.

Efficacy and safety of endoscopic papillary large balloon dilation for large bile duct stones in elderly patients.

BACKGROUND: Minimally invasive interventions for choledocholithiasis are preferable in elderly patients because they tend to have multiple underlying disorders or a decreased activity of daily living. Endoscopic sphincterotomy and endoscopic papillary balloon dilation have been recognized as first-line treatments for choledocholithiasis excluding difficult cases such as large stones or multiple stones. Recently, the safety and efficacy of endoscopic papillary large balloon dilation (EPLBD) for difficult choledocholithiasis cases have been reported, although scarcely in elderly patients. AIMS: To investigate whether EPLBD can be safety and effectively performed in patients aged 75 years or older. METHODS: The medical records of 165 patients who underwent EPLBD from November 2006 to August 2013 were analyzed retrospectively. The patients were divided into 2 groups: Group A (≥ 75 years); Group B (<75 years). RESULTS: Some underlying diseases were significantly more common in Group A than in Group B (P < 0.05). However, there was no significant difference in the success rates in the first session (96.2 vs 95.0 %, P = 0.970) and in the final success rates (100 % in both groups) between Group A and Group B. The adverse event rates (2.9 vs 5.0 %, P = 0.783) and recurrence rates of choledocholithiasis (6.7 vs 10.0 %, P = 0.444) were not significantly different. Regarding patients with an altered anatomy, the EPLBD outcome was not significantly different. CONCLUSION: EPLBD can be safely performed for elderly patients similarly to younger patients.

Clinical evaluation of a prototype multi-bending peroral direct cholangioscope.

BACKGROUND: Although peroral direct cholangioscopy (PDCS) is emerging as an alternative to traditional mother-daughter cholangioscopy, it is associated with high failure rates. The aim of the present study was to evaluate the ability to insert and carry out interventions using a prototype multi-bending PDCS. PATIENTS AND METHODS: Prospective, observational clinical feasibility study was done in 41 patients with a variety of biliary diseases. A multi-bending PDCS prototype was inserted using a free-hand technique, a guidewire alone, or with a 5-Fr diameter anchoring balloon. Diagnostic and therapeutic procedures were carried out. RESULTS: The free-hand direct insertion technique failed in all attempted cases (n = 7). Of the remaining 34 cases, successful rate of PDCS insertion into the distal bile duct was achieved by passing the PDCS over a guidewire alone (n = 6) and/or with a guidewire plus anchoring balloon (n = 28) for an overall successrate of 88.2% (30/34). In 13 (92.9%) patients without an underlying biliary stricture, PDCS insertion proximal to the bifurcation was possible. In 25 cases, biliary interventions were attempted including biopsy (n = 13), stone removal (n = 6), stent removal (n = 1), and intraductal electrohydraulic lithotripsy (n = 2) and were successful in 22 (88%). Other than two patients with procedure-related cholangitis with a mild grade of severity, no complications were observed. CONCLUSIONS: Using a novel multi-bending prototype peroral direct cholangioscope, cholangioscopy had a high diagnostic and therapeutic success rate only when passed over a guidewire and anchoring balloon but not with the free-hand insertion technique. Comparative studies of direct cholangioscopy are warranted.

Technique of endoscopic ultrasonography-guided pancreatic duct intervention (with videos).

To date, several endoscopic ultrasonography (EUS)-guided interventions have been reported. Of these interventions, EUS-guided pancreatic duct (PD) intervention seems to be the most difficult and challenging procedure to accomplish. We provide suggestions for EUS-guided PD intervention, which includes PD stenting and the rendezvous technique following EUS-guided pancreatography. PD stenting is performed between the PD and the gastrointestinal tract (stomach, duodenum, or jejunum). The rendezvous technique is performed using a guidewire across the papilla or anastomotic site for retrograde stent insertion. EUS-guided PD intervention is still challenging because it is not established yet. Thus, although EUS-guided PD intervention seems to be promising, it should be performed in selected patients such as those of failed standard endoscopic retrograde cholangiopancreatography.

Bulky pulmonary mucosa-associated lymphoid tissue lymphoma treated with yttrium-90 ibritumomab tiuxetan.

An 84-year-old woman was admitted to our hospital with nonproductive cough and dyspnea on exertion. Computed tomography (CT) scan revealed extensive consolidation in the right lung. She was diagnosed with pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma using CT-guided lung biopsy. Her pulmonary images and respiratory symptoms did not improve two months after receiving 4 cycles of rituximab weekly; therefore, yttrium-90 ibritumomab tiuxetan was chosen as salvage therapy. The abnormal shadow on her pulmonary images was significantly reduced two months later, and she had no symptoms without nonhematological toxicities. She has had no progression for 18 months. Furthermore, radiation pneumonitis has not also been observed. We herein reported bulky pulmonary MALT lymphoma treated with yttrium-90 ibritumomab tiuxetan.

Real-time virtual sonography visualization and its clinical application in biliopancreatic disease.

AIM: To evaluate the usefulness of real-time virtual sonography (RVS) in biliary and pancreatic diseases. METHODS: This study included 15 patients with biliary and pancreatic diseases. RVS can be used to observe an ultrasound image in real time by merging the ultrasound image with a multiplanar reconstruction computed tomography (CT) image, using pre-scanned CT volume data. The ultrasound used was EUB-8500 with a convex probe EUP-C514. The RVS images were evaluated based on 3 levels, namely, excellent, good and poor, by the displacement in position. RESULTS: By combining the objectivity of CT with free scanning using RVS, it was possible to easily interpret the relationship between lesions and the surrounding organs as well as the position of vascular structures. The resulting evaluation levels of the RVS images were 12 excellent (pancreatic cancer, bile duct cancer, cholecystolithiasis and cholangiocellular carcinoma) and 3 good (pancreatic cancer and gallbladder cancer). Compared with conventional B-mode ultrasonography and CT, RVS images achieved a rate of 80% superior visualization and 20% better visualization. CONCLUSION: RVS has potential usefulness in objective visualization and diagnosis in the field of biliary and pancreatic diseases.

Is the double-guidewire technique superior to the pancreatic duct guidewire technique in cases of pancreatic duct opacification?

BACKGROUND AND AIMS: Pancreatic duct guidewire placement (P-GW) techniques include both the injection cannulation technique with a contrast medium and wire-guided cannulation without contrast injection for selective biliary cannulation; the latter is the so-called "double-guidewire technique" (D-GW). The aim of this study was to compare the outcomes between P-GW and D-GW for biliary cannulation. METHODS: The procedures for biliary cannulation with a naïve papilla were performed in a total of 363 cases. We divided the patients chronologically, according to the time period during which the procedures were performed, into two groups: group A, P-GW performed from March 2008 to June 2009; and group B, D-GW performed from July 2009 to December 2010. The success rates and complication rates were evaluated in each group. RESULTS: Biliary cannulation was successful in 31 (81.6%) patients in the P-GW group and 34 patients (82.9%) in the D-GW group. The onsets of postendoscopic retrograde cholangiopancreatography pancreatitis (PEP) occurred in the P-GW and D-GW groups were four (10.5%) and three (7.3%) patients, respectively, and all were mild cases (P = 0.616). The frequency of hyperamylasemia and the serum amylase level tended to be lower in the D-GW group than in the P-GW group (P = 0.213). There was a statistically significant difference on the onsets of PEP in the GW and non-GW groups (P = 0.04, 8.9% and 1.1%, respectively). CONCLUSIONS: Both the D-GW and P-GW techniques were equally effective for difficult biliary cannulation. Furthermore, the complication rates, including PEP, were similar in both techniques. A prospective randomized trial is warranted.