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The Pharmaceuticals and Medical Devices Agency (PMDA) has approved hundreds of new drugs in recent years. We retrospectively analyzed the new drugs approved in Japan from 2008 to 2019, and identify the first-in-world approvals and clarify the current drug lag. The new drug and the drug lag were defined as a drug with a new active substance and a difference between the approval date in Japan and the international birth date, respectively. Among 400 new drugs approved in Japan during the last 12 years, 80 (20.0%) were first approved in Japan, and 320 were outside Japan (the United States: 202, 50.5%; Europe: 82, 20.5%; other regions: 36, 9.0%). Of these, 45 new drugs have not yet been approved outside Japan, and the remaining 355 have been globally approved in Japan and overseas. The number of new drug approvals were the largest in oncology followed by metabolic/endocrine and infectious diseases. The median drug lags (year) among all 400 new drugs and 355 new drugs with global approvals were 4.3 and 4.7 in the first tertile (2008-2011), 1.5 and 2.6 in the second tertile (2012-2015), and reduced to 1.3 and 2.2 in the third tertile (2016-2019), respectively. Substantial drug lag remains in neurology, psychiatry, and therapeutic areas where the number of new drug approvals was relatively small. Collectively, one-fifth of the new drugs approved in Japan are first-in-world approvals. Drug lag has been greatly decreased, although it still exists.

Aim To evaluate outcomes as well as prognostic factors of transarterial chemoembolization (TACE) in intermediate-stage hepatocellular carcinoma (HCC) with preserved liver function to determine positioning of TACE. Methods Of 158 treatment-naive patients with intermediate-stage HCC who received initial TACE from February 2007 to January 2016, 113 patients met the following inclusion criteria: no combined therapy within 4 weeks after initial TACE, and Child-Pugh score under 7. Response rate and overall survival were evaluated. The prognostic factors were investigated in univariate and multivariate analyses using Cox proportional hazards models. The deterioration of liver function after repeated TACE was also evaluated. Results The response rate was 92.7% (complete response, 63.3%; partial response, 29.4%). The median survival time was 45.2 months. Survival rates at 1, 2, and 3 years were 90.4%, 77.0%, and 60.8% respectively. Age ≥ 75 years (P = 0.022), serum α-fetoprotein level ≥ 200 ng/mL (P = .010), tumor number ≥ 11 (P = 0.008), and heterogeneous enhancement on dynamic computed tomography (P = 0.024) were poor prognostic factors. The deterioration rate of Child-Pugh score and albumin-bilirubin grade was 18.5% and 12.3%, respectively, after the first TACE, 15.6% and 5.1%, respectively, after the second TACE, and 14.5% and 11.1%, respectively, after the third TACE. Conclusion Superselective TACE can achieve high tumor response rates with prolonged overall survival for patients with intermediate-stage HCC with preserved liver function. Age, serum α-fetoprotein level, tumor number ≥ 11, and heterogeneous enhancement on dynamic computed tomography indicated significantly poor prognosis.

Introduction To assess the efficacy of combined therapy involving bland transarterial embolization using gelatin sponge particles (bland GS-TAE) followed by transarterial chemoembolization using lipiodol mixed with anticancer agents and GS particles (Lip-TACE) to reduce the adverse events and increase the therapeutic effect of Lip-TACE in the treatment of huge (≥10 cm) hepatocellular carcinoma (HCC). Material and methods Twenty-one consecutive patients with huge HCCs (≥10 cm in diameter) were enrolled in this study. First, bland GS-TAE was performed to reduce the tumor volume, and then Lip-TACE was performed to control the remaining tumor at intervals of around three weeks. Tumor response, survival, and adverse events of this combined therapy were assessed. Results The tumor response was assessed three months after combined TACE, with complete response in 38.1% and partial response in 57.1% of cases. Severe adverse events were seen in two patients, acute cholecystitis and tumor rupture. The median survival time was 2.7 years, and the one-, two-, three-, and five-year overall survival rates were 76.2%, 66.7%, 42.9%, and 25.0%, respectively. Conclusion Combined therapy involving bland GS-TAE followed by Lip-TACE can be performed safety and may improve survival in patients with huge HCCs.

Inpyrfluxam is a new, broad-spectrum, succinate dehydrogenase inhibitor (SDHI) fungicide discovered by the Sumitomo Chemical Company. This compound shows strong growth suppression of Basidiomycota and Ascomycota fungi and efficiently controls Asian soybean rust (ASR). In Brazil, soybean farmers are struggling to control this disease owing to the development of resistance against major fungicides, including SDHIs. Interestingly, inpyrfluxam is effective in controlling ASR, even in fields with putative SDHI-resistant populations, suggesting this compound as a new solution for soybean farmers. The internal code of inpyrfluxam at Sumitomo Chemical is S-2399. It is being developed globally as INDIFLIN with its first registration and sales anticipated in 2020. In this chapter the discovery of inpyrfluxam and its biological profile are reported.

AIMS To clarify the rationales of delay or difference in the review of new drug applications among regulatory authorities for new drugs, those first approved in the world being in Japan. METHODS Among 80 new drugs first approved in Japan from 2008 to 2019, we identified those subsequently approved in the USA or Europe. Significant delays in approval time (boxplot outliers) and the rationales for the delays were assessed among the Pharmaceuticals and Medical Devices Agency (PMDA), the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). RESULTS Of the 80 Japan-first approvals, 25 and 24 were approved in the USA and Europe, respectively, and their median approval times in Japan, the USA and Europe were 285, 334 and 477 days, respectively. Significant delays were identified for pirfenidone (1806 days, FDA), alogliptin benzoate (1856 days, FDA), insulin degludec (1457 days, FDA) and romosozumab (750 days, PMDA; 994 days, FDA; 748 days, EMA). Due to concerns about cardiovascular risk, alogliptin benzoate and insulin degludec were requested for additional clinical trials by the FDA, and romosozumab required a much longer review period than the standard approval time in all three regions. CONCLUSIONS Among the new drugs significantly delayed in approval time in Japan, the USA or Europe, there were some differences in the requirements, the participating regions and the assessment of clinical trials. The regulatory views on the cardiovascular risk also differed among the three regions. These divergences may be associated with the differences in approval histories.

We aimed to analyze clinical features and treatment outcomes of otitis media caused by antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), i.e. otitis media with AAV (OMAAV).This survey was performed between December 2013 and February 2014. The study began with a preliminary survey to 123 otolaryngology institutions in Japan to inquire about their experiences with OMAAV patients during the past 10 years, and was followed by a questionnaire survey to investigate clinical and laboratory findings. OMAAV was defined using the criteria described in the text.Two hundred and thirty-five patients classified as OMAAV were enrolled in this study. They were characterized as follows: (1) disease onset with initial signs/symptoms due to intractable otitis media with effusion or granulation, which did not respond to ordinary treatments such as antibiotics and insertion of tympanic ventilation tubes, followed by progressive hearing loss; (2) predominantly female (73%) and older (median age: 68 years); (3) predominantly myeloperoxidase (MPO)-ANCA-positive (60%), followed by proteinase 3 (PR3)-ANCA-positive (19%) and both ANCAs-negative (16%); (4) frequently observed accompanying facial palsy (36%) and hypertrophic pachymeningitis (28%); and (5) disease often involving lung (35%) and kidney (26%) lesions. Four factors associated with OMAAV were found to be related to an unfavorable clinical course threatening the patient's hearing and/or lives, namely facial palsy, hypertrophic pachymeningitis, both ANCAs-negative phenotype, and disease relapse. The occurrence of hypertrophic pachymeningitis was associated with facial palsy (p 0.05), both ANCAs-negative phenotype (p 0.001), and headache (p 0.001). The administration of corticosteroid together with an immunosuppressant was an independent predicting factor for lack of disease relapse (odds ratio [OR] = 1.90, p = 0.03) and an improvement in hearing loss (OR =2.58, p = 0.0002).Since OMAAV has novel clinical features, the disease may be categorized as a subentity for the classification of AAV.

To develop an implantable port in which a microcatheter can be inserted for a combination therapy of repeated transarterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC) for advanced liver cancer. The design of a currently used implantable port was modified. A funnel part was constructed in the port. The septum was punctured by a 20-gauge indwelling needle, and 2.0-Fr non-tapered microcatheter was inserted into the port. In the in vitro studies, the advance of a microcatheter out of the funnel part was evaluated via seven different septum puncture sites. A 5-Fr indwelling catheter connected to the port was placed in a vascular model, and a microcatheter catheterization was evaluated. In an in vivo study, the port–catheter system was implanted in the hepatic artery in a pig. A microcatheter was percutaneously inserted through the port into the hepatic arterial branches, and embolization was performed. In the in vitro studies, the microcatheter was smoothly advanced out of the port and catheterizations into the hepatic arteries were successful via all septum puncture sites. In the in vivo study, repeated selective embolization through the port was successfully conducted on 7, 14 and 21 days after the implantation. The developed implantable port can be used for repeated catheter insertion into the hepatic artery. The combination of repeated TACE and HAIC could be possible using this device.

Single-incision laparoscopic surgery has recently received more attention. We developed a novel simple technique of gasless transumbilical single-incisional laparoscopic-assisted appendectomy (TUSILAA) and retrospectively analyzed our initial experience. TUSILAA has been attempted in 50 consecutive patients with acute appendicitis. The vertical incision through the umbilicus was used for laparoscopic access and the abdominal wall was lifted by a Kent retractor set system. Our technique was successful in 45 out of 50 (90 %) patients. The median operating time was 59 min (range 35–140). The median length of postoperative hospital stay was 4 days (range 2–12). None of the cases were converted to open appendectomy. There were no perioperative surgical complications. Our novel technique, gasless TUSILAA, is safe and feasible with acceptable operative time and excellent cosmetic result. Furthermore, this procedure has the advantage of cost-effectiveness since any disposable instruments including trocars, staplers, or expensive devices are not required. Therefore, this could be used as the first-choice surgical procedure for selected patients with uncomplicated acute appendicitis.

Purpose As stereotactic radiotherapy (SRT) becomes widespread, precise information including number, location, and margin of lesions is required when magnetic resonance (MR) imaging of brain metastasis is performed. We compare methods using 2 separate injections and a single injection for the administration of a double dose of contrast medium for contrastenhanced MR imaging. Materials and methods We divided 40 patients with brain metastasis into 2 groups of 20 patients. Group A received 2 separate injections (0.2 + 0.2 mL/kg) of contrast medium (gadoteridol); Group B received a single injection of the same total dose (0.4 mL/kg). Group A underwent spin echo (SE) T1-weighted imaging (T1WI) and magnetization prepared rapid acquisition with gradient echo sequence (MPRAGE) after each injection, and Group B underwent the same MR studies at the same timing as Group A. We evaluated the number, signal-to-noise ratio (SNR), diameter, margin delineation, and volume of lesions and compared them between early and delayed studies by the 2 methods. Results The number of detected lesions was largest in delayed studies of MPRAGE in both groups. The SNR of the lesions was statistically lower in early studies of Group A than other studies. Delayed studies of Group B showed statistically better margin delineation than other studies on both SE-T1WI and MPRAGE studies. Diameter and enhanced volume were statistically significantly larger on delayed phase than early phase in both groups. Conclusion Use of a single injection of double-dose contrast medium and longer delay time may improve margin delineation of lesions for the study of brain metastasis. Enhanced volume was larger on delayed phase, and it may influence selection of therapeutic strategy.

The purpose of this pilot study was to assess the effectiveness of repeated bland-TAE using small-size microspheres for liver metastases. To date, there have been no publications as to whether bland-TAE could be effective for nonhypervascular liver tumors.Bland-TAE with 100-μm, calibrated microspheres was performed in two chemoresistant patients: one with colorectal metastases and the other with gastric metastases. Both patients had multiple tumors in the entire liver. An implantable port-catheter system was placed in the hepatic artery to conduct repeated embolizations, thereby achieving enough efficacies. Microspheres were injected via the port until the disappearance of the tumor stains. Angiographies via the port were conducted 1, 3, 7, and 14 days after bland-TAE to evaluate the patency of the hepatic artery.The hepatic artery started to recanalize 1 day after TAE and tumor stains appeared again during the 14 days. In both patients, bland-TAE was repeated four times in intervals of 14-21 days. The enhanced CTs showed necrotic changes and the decrease in size of the tumors. The serum CEA level decreased from 2,989 to 70 ng/ml and from 174 to 48 ng/ml, respectively. Bilomas and a liver abscess developed as complications.Repeated bland-TAE using 100-μm microspheres injected via an implantable port-catheter system could be effective for liver metastases, although the caution of biliary injury is needed.

The purpose of this study is to evaluate the pharmacokinetics and histopathological findings of transarterial chemoembolization (TACE) using cisplatin powder mixed with degradable starch microspheres (DSM) (Cis/DSM-TACE) compared with cisplatin arterial infusion (Cis-AI). Eighteen rabbits with VX2 liver tumors were divided into two groups: Cis/DSM-TACE (n = 9) and Cis-AI (n = 9) groups. In the Cis/DSM-TACE group, a mixture of cisplatin powder and DSM was injected until stasis of hepatic arterial flow was achieved. In the Cis-AI group, cisplatin solution was infused. The platinum concentrations in VX2 tumors in the Cis/DSM-TACE group at 24 and 72 h were significantly elevated compared with those in the Cis-AI group (P = .016 and .019, respectively). There were no significant differences in the platinum concentrations in plasma. Histopathological examination revealed the presence of several microspheres inside the tumors at 1 h, which completely disappeared at 24 h. Tumor cell apoptosis at 1 h in the Cis/DSM-TACE group was more frequently observed compared with that in the Cis-AI group (P = .006). TACE using cisplatin powder mixed with DSM provides a higher drug concentration in tumors, thereby achieving stronger antitumor effects compared with arterial infusion of cisplatin solution.

OBJECTIVE. Response rates to systemic chemotherapy for unresectable pancreatic cancer are low. The purposes of this phases 1 and 2 study of intraarterial therapy were to ascertain the recommended dose of intraarterial chemoinfusion and to evaluate the efficacy and safety of this therapy. SUBJECTS AND METHODS. Pancreatic arteries originating from the superior mesenteric artery (the anterior and posterior inferior pancreaticoduodenal and the dorsal pancreatic) were embolized to achieve a single blood supply from the celiac artery to manage pancreatic cancer, and a catheter-port system was placed. Intraarterial 5-fluorouracil (5-FU) and IV gemcitabine (fixed dose of 1000 mg/m2) were administered. In phase 1, doses of 5-FU were increased from 750 to 1000 mg/m2. In phase 2, tumor response, toxicity, and survival time were assessed. RESULTS. A total of 20 patients were enrolled. In 19 patients (95%), the technique to unify the pancreatic blood supply was successful. No severe toxicity was observed with escalati...

This study was designed to clarify the advantages of biodegradable stents in terms of mucosal reaction and biodegradation after placement. We designed a biodegradable stent and assessed stent degradation and changes in the normal bile ducts of dogs. The biodegradable stent is a balloon-expandable Z stent consisting of poly-l-lactic acid (PLLA) with a diameter of 6 mm and a length of 15 mm. We assessed four groups of three beagle dogs each at 1, 3, 6, and 9 months of follow-up. After evaluating stent migration by radiography and stent and bile duct patency by cholangiography, the dogs were sacrificed to remove the bile duct together with the stent. The bile duct lumen was examined macroscopically and histologically, and the stent degradation was examined macroscopically and by scanning electron microscopy (SEM). Bile duct obstruction was absent and none of the stents migrated. Macroscopic evaluation showed moderate endothelial proliferation in the bile ducts at the implant sites at 3 and 6 months and a slight change at 9 months. Slight mononuclear cell infiltration was histologically identified at all time points and epithelial hyperplasia that was moderate at 3 months was reduced to slight at 6 and 9 months. Stent degradation was macroscopically evident in all animals at 9 months and was proven by SEM in two dogs at 6 months and in all of them at 9 months. Our results suggest that PLLA bioabsorbable stents seems to be useful for implantation in the biliary system with further investigation.

Purpose This multicenter prospective study was conducted to evaluate the safety and the efficacy of uterine artery embolization (UAE) with gelatin sponge for symptomatic leiomyomas. Materials and Methods Patients with symptomatic uterine leiomyomas were enrolled and treated with UAE. In phase I, nine patients were evaluated for safety. In phase II, 24 patients were accrued, and an intent-to-treat analysis was performed on all 33 patients. The primary endpoint was safety. Secondary endpoints included technical success, hospital stay, change in symptoms, leiomyoma volume on magnetic resonance (MR) imaging, and incidence of treatment failure. Results UAE procedures were performed for all 33 patients. Two patients were lost to follow-up at 3 and 12 months. The median follow-up period was 33.4 months. Minor adverse events (AEs) occurred in 10 patients (33%); major AEs of permanent amenorrhea and leiomyoma expulsion occurred in two (6%). The most common AE was transient amenorrhea. Technical success was achieved in all patients. The median hospital stay was 5 days. At 12 months after UAE, menorrhagia had improved in 90% of patients, pelvic pain in 78%, and bulk-related symptoms in 97%. The mean reduction in leiomyoma volume on MR imaging at 12 months was 61%. Treatment failure occurred in one patient, who underwent hysterectomy for recurrent menorrhagia at 21 months. Conclusions UAE with gelatin sponge is safe, with efficacy comparable to other embolic agents based on published data. Gelatin sponge should be an option for UAE, but a prospective comparison versus other standard UAE embolic agents may be warranted.

Nano-order metal pattern printing on plastic substrates was established by using hard stamp nanoprint lithography (NPL). A spin-on-glass (SOG) material, which is almost the same as quartz in composition, was used as the material for the hard stamp. The SOG acted as a positive-tone electron beam (EB) resist. Nanopatterns were fabricated by using electron beam lithography (EBL), and a developed pattern of SOG was used as the hard stamp. Further, two types of release coating methods were utilized. One method used a conventional silan coupling agent and the other, a chromium layer. After comparing the results of the methods, we found that the chromium layer formed a smooth surface and therefore used this layer as the release layer. In addition, chromium was changed to Cr"2O"3 because of the exposure to atmospheric air. Gold was used as the transfer metal and was deposited on the hard stamp covered with the chromium release layer. This stamp was then placed in contact with a PET substrate at 80^oC for 30min. A gap width of less than 30nm of gold was transferred onto the PET substrate. This process is very simple, and yet, it makes it possible to obtain a very high resolution metal pattern transfer by using hard stamp NPL.

Arterial infusion chemotherapy for unresectable pancreatic cancer may be an attractive strategy. We are currently developing a new interventional radiology technique to unify the pancreatic blood supply for chemoinfusion. In this article, we evaluated the feasibility, therapeutic potential, and limitations of this technique.Twenty-eight patients with advanced pancreatic cancer were retrospectively reviewed. After the superior mesenteric artery was embolized, the drug distribution to the tumor was evaluated by a unified CT angiography system.In all patients, tumors had dual arterial blood supplies from both the celiac and superior mesenteric arteries. Unification of pancreatic blood supply was successful in 14 patients (50%). The whole pancreatic tumor was exclusively supplied by the celiac artery in these patients. In the remaining 14 patients, a part of the tumor was still supplied by the superior mesenteric artery even after embolization. In most failed cases, the tumor had invaded to the root of the small-bowel mesentery or transverse mesocolon. By contrast, unification of the pancreatic blood supply could be achieved in cases invading to the stomach and duodenum. The whole liver was also successfully supplied by arterial infusion from the celiac artery after embolization.Our novel technique for arterial infusion chemotherapy is simple, feasible, and well tolerated. Furthermore, arterial chemoinfusion may be a breakthrough in selected patients with unresectable pancreatic cancer.

We report a case of cystic echinococcosis (CE) caused by Echinococcusgranulosus, for which a modified percutaneous evacuation (PEVAC) treatment was applied. The patient had immigrated from Peru to Japan and had 2 hydatid cystic masses, 1 located in segment (S)5 of the liver and the other in S3 (5.3 and 3.5 cm in diameter, respectively), both of which were visualized as pseudotumors by ultrasound (US) examinations. Albendazole treatment showed no effects and surgical treatment was refused. After punctuation of the S5 cyst under US guidance and S3 with CT guidance, 10- and 12-French gauge catheters, respectively, with multiple side holes were inserted. About 60 ml of the cyst contents was drawn out from the S5 lesion and 2 ml from the S3 lesion. Using repetitive manual injections and aspiration of small amounts of hypertonic saline, the remaining cyst content was removed as much as possible, after which 20 and 10 ml of 98% ethanol was injected into the S5 and S3 lesions, respectively. A short-term evaluation during the 4 month-period following the procedure using US revealed nearly complete evacuation of the S5 lesion, whereas that at S3 remained as a pseudo-solid mass. We consider that percutaneous treatment is a safe therapeutic modality for hydatid cysts. This is the first case report of CE treated percutaneously in Japan.

Stable gold film electrodes were fabricated by a combination of sputtered gold and an epoxy adhesion layer on a glass substrate using the template-stripped technique. An XRR scan analysis indicated the thickness and roughness of the gold layer to be on the order of 10 nm and subnanometer, respectively. In spite of their small thickness, the electrode had sufficient conductivity and stuck to the subject during the electrochemical measurements as did the usual gold working electrodes.

Systemic chemotherapy and chemoradiotherapy, the standard treatments, do not satisfactorily improve the poor prognosis of unresectable pancreatic cancer. The authors administered arterial infusion of 5-fluorouracil (5-FU) combined with concurrent radiation therapy to enhance the antitumor effect of chemotherapy. The purpose of this study was to examine the efficacy and safety of this combined therapy.One or two catheters were placed into the pancreas-supplying arteries angiographically. To obtain adequate drug distribution, the positions of the catheters were determined in accordance with the results of CT during arterial injection of contrast material. A dose of 333 mg/m2/d of 5-FU was continuously infused for 5 days a week for 5 weeks, with concurrent radiation therapy (50 Gy at 2.0 Gy per fraction). Twenty patients with unresectable pancreatic cancer were enrolled in this study.Of the 20 patients, 19 (95%) completed the scheduled course of this combined therapy. Fourteen patients showed a partial response (response rate, 70%). Serum cancer antigen 19-9 (CA 19-9) levels were reduced by more than 50% in 16 of 18 patients (80%). The 1-year and 3-year survival rates were 40% and 17%, respectively, with a median survival time of 11.0 months. Grade 3 or worse nonhematologic toxicity was observed in 11 patients (55%), but there were no life-threatening toxicities or complications.Arterial infusion of 5-FU combined with concurrent radiation therapy is tolerable and can produce a high response rate with encouraging survival duration for unresectable pancreatic cancer.

Previous reports have shown the effectiveness of adjuvant hepatic arterial infusion chemotherapy (HAIC) in pancreatic cancer. However, percutaneous catheter placement is technically difficult after pancreatic surgery. The purpose of this study was to evaluate the feasibility and outcome of HAIC using a coaxial technique compared with conventional technique for postoperative pancreatic cancer. 93 consecutive patients who received percutaneous catheter-port system placement after pancreatectomy were enrolled. In 58 patients from March 2006 to August 2010 (Group A), a conventional technique with a 5-Fr indwelling catheter was used and in 35 patients from September 2010 to September 2012 (Group B), a coaxial technique with a 2.7-Fr coaxial catheter was used. The overall technical success rates were 97.1 % in Group B and 86.2 % in Group A. In cases with arterial tortuousness and stenosis, the success rate was significantly higher in Group B (91.7 vs. 53.8 %; P = 0.046). Fluoroscopic and total procedure times were significantly shorter in Group B: 14.7 versus 26.7 min (P = 0.001) and 64.8 versus 80.7 min (P = 0.0051), respectively. No differences were seen in the complication rate. The 1 year liver metastasis rates were 9.9 % using the conventional system and 9.1 % using the coaxial system (P = 0.678). The overall median survival time was 44 months. There was no difference in the survival period between two systems (P = 0.312). The coaxial technique is useful for catheter placement after pancreatectomy, achieving a high success rate and reducing fluoroscopic and procedure times, while maintaining the safety and efficacy for adjuvant HAIC in pancreatic cancer.

レーザーと走査型プローブ顕微鏡を組み合わせた光励起走査型プローブ顕微鏡を開発し，単一分子の電気特性や光物性を計測する技術についてまとめた．電導性原子間力顕微鏡や走査型トンネル顕微鏡を使って金基板に形成させた有機分子自己組織化膜の単一分子レベルでのトンネル電導の定量化や画像化を行った．また，レーザーと電導性原子間顕微鏡や走査トンネル顕微鏡を組み合わせた単一分子スケールでの光物性を計測するレーザー励起走査プローブ顕微鏡を開発し，有機薄膜の局所的な（光）電気物性の計測を行い，分子レベルの空間分解能とフェムト秒の時間分解能を達成できることを明らかにした．

We attempted to evaluate diagnosis and characterization and to access therapeutic effects in cases of hepatocellular carcinoma (HCC) by contrast enhanced ultrasound (CEUS) using Coded Harmonic Angio (CHA) with Levovist, an intravenous ultrasound contrast agent. Fifty-seven HCC foci in 39 patients, including 37 HCC foci in 28 patients before and after transcatheter arterial chemoembolization or radio frequency ablation, were examined by CEUS using the CHA mode, which is under development. This mode uses digitally encoded pulse sequences that identify and suppress nonmoving tissue signals and enhance contrast signals from Levovist in a gray-scale format. In all cases, abundant tortuous intratumoral blood flow was visualized in the early vascular phase by continuous transmission, while tumor stain was recognized by consecutive 1-to-2 second intermittent transmission. Residual tumor area after treatment was also clearly depicted by intratumoral blood flow and partial enhancement. CEUS using CHA with Levovist is likely to become important in the qualitative diagnosis of hepatic tumor and to improve the efficacy of treatment for HCC.

Nonlinear optical properties can be enhanced at the excited state due to changes of electronic distribution. Femtosecond (fs) hyper-Rayleigh scattering measurement systems were constructed in order to quantitatively evaluate hyperpolarizability both at the ground and the excited states in solutions. Excitation of nitrostyrylpyridinium or crystal violet at 400 nm or 550 nm by fs laser resulted in one-photon or two-photon fluorescence at the wavelength to probe the HRS signals.

1. The effect of cicletanine, a novel antihypertensive agent with natriuretic activity, on blood pressure and progression of renal failure in 5–6 nephrectomized spontaneously hypertensive rats with salt loading was examined. 2. All nephrectomized rats were randomly assigned to one of four groups and their diet was changed from a normal- to a high-salt (5.5% NaCl) diet for the next 10 weeks. Either 10 or 50 mg/kg per day cicletanine (low- and high-dose cicletanine, respectively) or 10 mg/kg per day trichlormethiazide were administered to rats during this period once a day. During the experimental period, urine volume, urinary excretion of sodium, protein, prostaglandin (PG) E2 and 6-keto-PGF1α and systolic blood pressure (SBP) were measured every 2 weeks. 3. Systolic blood pressure was significantly reduced by the administration of trichlormethiazide and the higher dose of cicletanine, but not by the lower dose of cicletanine. 4. In contrast with changes to SBP, levels of serum creatin- ine in rats treated with both doses of cicletanine were significantly lower than in controls (0.57±0.12, 0.78±0.12 and 1.68±0.26 mg/dL for high- and low-dose cicletanine and control, respectively). 5. Urinary excretion of both PGE2 and 6-keto-PGF1α were significantly increased in groups treated with high and low doses of cicletanine compared with control. In rats treated with trichlormethiazide, PGE2 and 6-keto-PGF1α levels were significantly decreased compared with control. 6. In contrast with changes in SBP, marked glomerular sclerosis with hyalinosis found in the control group was not ameliorated by trichlormethiazide treatment. These changes were not observed in rats treated with low- and high-dose cicletanine, particularly those treated with the higher dose of cicletanine. 7. These data suggest that administration of cicletanine has a beneficial protective effect regarding the progression of renal failure, regardless of the level of blood pressure, through a direct and/or indirect action on the glomerulus.

Optical pumping effect on the third order optical nonlinearity of poly(3-dodecylthiophene) was investigated by 2 beam degenerate four wave mixing technique using low repetition rate femtosecond Ti:S amplifier. Four wave mixing signal from the sample was significantly enhanced by optical pumping at 400 nm. Femtosecond time resolved studies on four wave mixing and excited state dynamics of the entitled compound were carried out to elucidate the mehcanism of enhancement. Exciton formed by optical pumping in one dimensional polymer backbone might presumably play an important rule on the enhancement of four wave mixing amplitude.

Purpose To compare the efficacy, complications, and inflammatory levels in partial splenic embolization (PSE) with coils or gelatin sponge (GS) particles with or without intraarterial antibiotic agents. Materials and Methods Forty-four patients with hypersplenism treated by PSE were assessed. GS particles were used in 31 patients, and coils were used in 13 patients. In 17 of the 31 patients who received GS, GS suspended in antibiotic solution was injected via the splenic artery. In the other 14 patients, antibiotic agents were not used. In all 13 coil group patients, an antibiotic solution was intraarterially injected before embolization. Platelet counts were compared between the GS and coil groups. Complications and serum C-reactive protein (CRP) levels were compared among the three groups. Results There were no significant differences in platelet counts and platelet increased ratios at 6 months (10.0 × 10 4 /µL and 193% in the GS group vs 9.0 × 10 4 /µL and 221% in the coil group), and no significant differences in frequencies of complications. However, one splenic abscess occurred in a patient treated with GS without antibiotics, resulting in death. The mean serum CRP level in the GS with antibiotic group at 2 weeks was significantly lower than in the other two groups. Conclusions The efficacy of PSE is similar with the use of coils versus GS particles. Prophylactic intraarterial antibiotic treatment could be useful in preventing inflammatory reactions after PSE.

BACKGROUND The aim of this study was to evaluate the safety and feasibility for single-incision laparoscopic cholecystectomy (SILC) by retrospective comparison with conventional laparoscopic cholecystectomy (CLC) in a local community hospital. METHODS SILC was introduced and performed in 57 patients for benign gallbladder diseases. Their clinical data were compared with those of 62 patients treated with CLC. They included patient demographic data and operative outcomes. RESULTS SILC was attempted in 57 patients and 52 cases (91.2%) were successfully completed. There were no statistical differences between the 2 groups in terms of operative time, blood loss, and postoperative complications. The length of hospital stay in the SILC group was significantly shorter compared with CLC (P < 0.0001). CONCLUSIONS SILC has been successfully introduced in a local community hospital. The safety and feasibility was also confirmed. The SILC procedure may become 1 standard option for the treatment of benign gallbladder diseases.

To evaluate the feasibility of combining placement of a transjugular intrahepatic portosystemic shunt (TIPS) and transcatheter hepatic segmental artery chemoembolization with Lipiodol (Seg-Lp-TAE) in patients with cirrhosis, esophagogastric varices, and hepatocellular carcinoma (HCC).Five patients with bleeding or large, high-flow esophagogastric varices and HCC were treated by TIPS and Seg-Lp-TAE.The mean portosystemic pressure gradient decreased from 20.8 cm H2O to 7.8 cm H2O after TIPS. The direct portogram and endoscopic examination revealed reduction of varices. At 6 months, one shunt had functionally occluded and could not be reopened; the other TIPS remained functional. Follow-up CT and the changes of alpha fetoprotein indicated effective therapy of Seg-Lp-TAE for HCC. Four patients are in stabile clinical condition at 9, 6, 1, and 1 months after the combined therapy; one died after 14 months due to decompensated liver cirrhosis.The combined therapy of TIPS and Seg-Lp-TAE will become a new interventional approach for patients with HCC and esophagogastric varices.

A new method was proposed in order to increase the recording density of optical disks based on the instantaneous and transient photobleaching of organic dyes showing strong absorption at the wavelength of laser diodes. The control of laser diode intensity by excitation laser power was demonstrated in a polymerfilm dispersed with a phthalocyanine derivative.

Alternate Langmuir-Blodgett (LB) films consisting of a ruthenium(II)-bipyridine complex and ammonium amphiphiles exhibit a strong second-harmonic generation (SHG) on irradiation with nanosecond neodymium-doped yttrium aluminium garnet 1064 nm laser pulses. We successfully demonstrated that the SHG intensity from the LB films was reversibly modulated when the films were exposed to nanosecond 355 nm laser pulses. The switching time for the optical modulation of SHG was determined to be less than 2 ps from a subpicosecond dye laser pump-probe SHG experiment. The mechanism for the optical modulation of SHG was ascribed to a change in the molecular hyperpolarizability of the ruthenium complex on going from the ground state to the excited state.

Several cytokines are known to play roles in the pathogenesis of human glomerulonephritis. Recently, some studies proposed a possible relationship between interleukin-4 (IL-4) and glomerulonephritis. To investigate the involvement of IL-4 in human glomerulonephritis, we evaluated renal biopsy specimens using immunohistochemical procedures. Our study revealed that the glomeruli in immunoglobulin A nephropathy and lupus nephritis (World Health Organization grades II and IV) contained IL-4-positive cells, which were CD-3- and CD-4-positive T lymphocytes. CD-8-, CD-14-, CD-19-, or CD-56-positive cells did not react with anti-IL-4. CD-23-positive cells were not observed in the sections used in this study. Interleukin-4-positive cells were not found in the normal control kidney tissues. The degree of the glomerular IL-4-positive cell index correlated well with the glomerular hypercellularity index, but not with any other clinical or histopathologic parameters. Therefore, the present study offers more reliable evidence concerning the association between IL-4 and human glomerulonephritis.

We developed segmental Lp-TAE, which is transcatheter hepatic sub-subsegmental, subsegmental, or segmental chemoembolization using Lipiodol introduced into the tumor-bearing hepatic sub-subsegment, subsegment, or segment as the target area. A total of 98 patients with nonresectable hepatocellular carcinoma (HCC) undergoing segmental Lp-TAE (Seg-Lp-TAE) were studied, and the relationship between the CT pattern observed after Seg-Lp-TAE (Seg-Lp-CT) and the therapeutic results obtained in those patients was evaluated. Seg-Lp-CT was classified into four types (type I, homogeneous; type II, defective; type III, inhomogeneous; and type IV, only slight accumulation, if any) according to the Lipiodol accumulation pattern observed after Seg-Lp-TAE. The cumulative nonrecurrence rates of type I were higher than those of types II–IV. The cumulative survival rates of type Ia, in which Lp accumulation is also seen around the main tumor, were the highest (93.8% at 1 year, 85.9% at 2 years, 85.9% at 3 years, and 57.3% at 4 years). The cumulative survival rates achieved with Seg-Lp-TAE were 89.2% at 1 year, 69.4% at 2 years, 58.9% at 3 years, 44.0% at 4 years, and 30.2% at 5 years, which were higher than those achieved with conventional Lp-TAE. Seg-Lp-TAE is very useful in the treatment of HCC limited to one sub-subsegment, subsegment, or segment, and it is important to choose subsubsegmental, subsegmental, subsegmental, or segmental Lp-TAE on the basis of the size and site of the tumor as well as the type and the number of feeding arteries.

Electrocochleography using the transtympanic electrode technique was performed on 86 deaf ears. Auditory nerve action potential was detected in 9 ears, in 5 of which deafness was caused by cerebellopontine angle tumor or surgery. A low threshold of the cochlear microphonics' response was also observed in some of the cases with deafness caused by mumps or cerebellopontine angle tumor. Various pathophysiological states of the inner ear can be observed, even in cases showing the same total deafness when measured by audiometer.

To clarify the efficacy of transcatheter hepatic sub-subsegmental, subsegmental, and segmental arterial chemoembolization using lipiodol (subseg/seg lip-TACE) for hepatocellular carcinoma (HCC), long-term outcomes of patients who had been treated using subseg/seg lip-TACE alone were retrospectively examined.Subjects comprised 199 patients with HCC (T1/2/≥3=30/108/61; Child-Pugh A/B/C=115/52/32; Japan Integrated Staging [JIS] score≤1/2/≥3=88/64/47) who underwent subseg/seg lip-TACE using lipiodol mixed with an anticancer drug followed by injection of gelatin sponge particles. Each patient was followed-up every 3 months, and repeat subseg/seg lip-TACE and/or conventional lip-TACE was performed in cases showing recurrence. One-, 3-, 5-, 7-, and 10-year cumulative survival rates were calculated. Subgroup analyses were performed by stratifying the population according to T-factor, Child-Pugh classification, and JIS score.Median duration of follow-up was 3.8 years (range 0.2 to 16.4). Median overall survival was 3.8 years. One-, 3-, 5-, 7- and 10-year survival rates were 91.5, 66.1, 38.8, 20.3, and 9.4% for all patients, and 95.5, 76.9, 51.9, 27.9 and 20.4% for patients with JIS≤1, respectively. Significant survival differences were found across two subgroups of staging systems (T2 vs. T3≤[P=0.0012] and JIS score≤1 vs. 2 [P=0.0036]).This study demonstrated that subseg/seg lip-TACE is a feasible treatment for obtaining prolonged survival in patients with localized HCC showing rich vasculature. Outcomes are influenced by both tumor stage and liver function, as seen in the best prolonged survival in patients with JIS score≤1.

Transcatheter chemoembolization using Lipiodol (Lp) mixed with chemotherapeutic agents followed by Gelfoam particle injection only to the tumor-bearing hepatic segment (segmental Lp transcatheter hepatic artery embolization) (TAE) was applied to more than 100 patients with hepatocellular carcinoma and metastatic liver cancer. For segmental Lp-TAE, knowledge of the variations of intrahepatic arterial anatomy is important. Furthermore, the catheters and guidewires, volume of Lp, kinds and dose of chemotherapy, preparation of the mixture of Lp and chemotherapy (Lp-emulsion), method of injection of Lp-emulsion and Gelfoam particles, as well as the follow-up computed tomography examination are key items to the success of the procedure and are reviewed.

A patient with collagenofibrotic glomerulopathy associated with hepatic persinusoidal fibrosis is described. Renal biopsy revealed that the glomerular tufts contained homogeneous material that was proved by electron microscopy to be collagen fibers. The material was reactive to anti-type III collagen monoclonal antibody. Liver biopsy also showed an increase of type III collagen fibers in the perisinusoidal area. Since the serum procollagen III peptide level was elevated in this patient, fibrosis may have been simultaneously activated in kidney and liver by some unknown condition.

Lipoprotein glomerulopathy is a disease characterized by intraglomerular lipoprotein thrombi and abnormal lipid metabolism similar to type III hyperlipoproteinemia. Recently, glomerular lesions compatible with lipoprotein glomerulopathy were found in a 38-year-old man. In this case, plasma apolipoprotein (apo) E level was elevated, and the apo E isoform was heterozygous E2/3, similar to most of the reported cases of lipoprotein glomerulopathy. However, the plasma levels of triglyceride and total cholesterol were within their respective normal ranges. Review in 11 cases revealed that lipoprotein glomerulopathy was not always associated with hyperlipidemia, and that apo E abnormality was always recognized. These findings suggest that lipoprotein thrombi associated with lipoprotein glomerulopathy are not induced via systemic hyperlipidemia but may be formed by intraglomerular accumulation of lipoprotein composed of abnormal apo E.

Performance of nonresonant tunnel conduction through a self-assembled monolayer of conjugated molecules fabricated on gold (111) was determined by virtue of nanometer-scale electrical probe measurement using a conductive atomic force microscope. Electrical measurements with nanometer spatial resolution enabled mapping of tunnel current as well as efficiency of tunnel conduction through molecular wire by analyzing length dependence on current. A series of conjugated molecules with different numbers of oligothiophene rings proved to possess a high tunnel-conduction efficiency.

Brain abscess associated with an arteriovenous fistula (AVF) is sometimes difficult to diagnose and tends to recur. We report a case of recurrent brain abscess due to a pulmonary AVF (PAVF). A 69-year-old woman with a mass in the left cerebral peduncle had taken a progressively worse and shown decorticate rigidity. After an intravenous antibiotic for fever of unknown origin was changed, her condition gradually improved. She was discharged with the help of a cane. Thirty-one months later, she suffered left hemiparesis. Magnetic resonance imaging revealed a cystic mass in the right lateral frontal lobe. At surgery, we confirmed pus in the cyst. A PAVF was detected and was treated with coil embolization. The left hemiparesis improved and the postoperative course was uneventful. Exhaustive study is absolutely necessary to detect the etiology of recurrent brain abscess and to achieve a cure.

過去10年間に長崎大学耳鼻咽喉科を受診し, 蝸電図あるいは聴性脳幹反応Auditory Brainstem Response (ABR) を施行して詐聴と診断し得た82名について検討を行った。 昭和54-58年の前期5年間と昭和59-63年の後期5年間を比較すると, 症例数は約2倍, 当科にて蝸電図またはABRを行った全症例に対する比も約1.5倍と増加しており, 70歳以上の高齢者症例も増加していた。

The purpose of this study was to investigate the potential pharmacokinetic advantage of pancreatic arterial infusion chemotherapy of 5-fluorouracil (5-FU) with temporary unification of the pancreatic blood supply for advanced pancreatic cancer in an animal model.Nine pigs were divided into three groups of three pigs each. 5-FU (20 mg/kg) was infused via jugular vein (group I), celiac artery (group II), and celiac artery with balloon occlusion of the superior mesenteric artery (SMA; group III). At 0, 10, 30, and 60 minutes after drug infusion, the concentrations of 5-FU were measured in plasma and tissues including the liver, pancreatic head, pancreatic uncinate process, and duodenum. Areas under the concentration-time curve (AUCs) were calculated and statistically compared.The temporary unification of the pancreatic blood supply by converting from dual blood supply through the celiac artery and SMA into a single celiac arterial supply was confirmed by dye injection. Mean AUCs in the pancreas head and liver were significantly higher for groups II and III compared with group I (P.05). In contrast, there were no significant differences in plasma 5-FU concentrations between groups. In addition, the AUC in the pancreatic uncinate process was significantly higher for group III compared with groups I and II (P.05).Pancreatic arterial infusion chemotherapy allows efficient regional drug delivery into the pancreas and liver. Importantly, the unification of the pancreatic blood supply may be required to induce maximum efficacy of arterial infusion chemotherapy for the tumor in the pancreatic uncinate process.

The purpose of this study was to investigate whether diffusion-weighted magnetic resonance imaging (DWI) is useful for early detection of the response of hepatic colorectal metastases to hepatic arterial infusion chemotherapy (HAIC) with 5-fluorouracil (5-FU). The subjects were 12 patients with hepatic colorectal metastases. The indwelling catheter for HAIC was placed in the hepatic artery, and 1000 mg/m2 5-FU was given repeatedly once a week. DWI was performed before and 9 days after HAIC. The minimum and mean apparent diffusion coefficient (ADC) values (minADC and meanADC) were measured. The relative change in ADC values (%ADC) and the relative change in tumor size on follow-up CT after 3 months (reduction ratio) were determined. Liver metastases were divided into two groups, responder and nonresponder. The correlation between %ADC and reduction ratio was determined, and %ADC was compared between the two groups. Eleven patients successfully completed HAIC over the 3-month period; 48 metastatic lesions were evaluated. Positive correlations were observed for relative change between %minADC and reduction ratio (r = 0.709) and between %meanADC and reduction ratio (r = 0.536). Both %minADC and %meanADC were significantly greater in the responder group than in the nonresponder group. With the threshold determined as < 3.5%, the receiver-operating curve analysis showed higher sensitivity and specificity values for %minADC (100% and 92.6%, respectively) than for %meanADC (66.7% and 74.1%, respectively). In conclusion, the relative change in minimum ADC values on DWI may be useful for early detection of the response of liver metastases to HAIC with 5-FU.

We describe herein a patient who had hepatic metastases with an arteriovenous shunt and was treated by hepatic arterial infusion chemotherapy. The arteriovenous shunt was diagnosed by (99m)Tc-macroaggregated albumin scintigraphy and hepatic venous embolization was performed to reduce shunt flow.

The purpose of this study was to investigate the pharmacological advantages of transarterial chemoembolization (TACE) with cisplatin powder for hypervascular hepatic tumors in animal experiments. VX2 tumors were transplanted to the livers of nine rabbits. Cisplatin (1 mg/kg) was infused into the proper hepatic artery. In the cisplatin-HAI group, cisplatin solution was infused. In the cisplatin-GS-TACE group, after infusion of cisplatin solution, gelatin sponge particles were used for embolization. In the cisplatin-Lp-TACE group, after infusion of a cisplatin powder and lipiodol (10 mg/ml) suspension, gelatin sponge particles were used for embolization. Before and after administration, platinum concentrations in plasma were measured. Using liver specimens that were excised 60 min after infusion, platinum concentrations in tumorous and nontumorous liver tissues were measured. The mean platinum concentration in tumorous tissue was 0.88 microg/ml for the cisplatin-HAI group, 1.23 microg/ml for the cisplatin-GS-TACE group, and 12.65 microg/ml for the cisplatin-Lp-TACE group. The platinum concentration for the cisplatin-Lp-TACE group was significantly higher than that for the cisplatin-HAI group (p = 0.004) and the cisplatin-GS-TAE group (p = 0.004). The mean platinum concentration in nontumorous liver tissue was 0.98 microg/ml for the cisplatin-HAI group, 1.13 microg/ml for the cisplatin-GS-TACE group, and 1.09 microg/ml for the cisplatin-Lp-TACE group; no significant differences were seen. At both 5 and 10 min after infusion, the platinum concentrations for the cisplatin-Lp-TACE group were lower than those for the other two groups. The present results suggest that TACE using cisplatin powder/lipiodol suspension and gelatin sponge for hypervascular hepatic tumors has a number of pharmacological advantages.

To retrospectively clarify the utility of metallic stent placement for the treatment of the malignant obstruction of the superior vena cava (SVC) in 71 patients with VC syndrome (SVCS) on the basis of long-term follow-up data. Seventy-one patients underwent stent placement and were followed until death. The applicability of the spiral Z-stent (S-Z-stent) mainly used the initial and follow-up results, stent placement for bilateral BCV obstruction and the value of concurrent anticancer therapy were studied. The technical success rate was 100%, the initial clinical success rate was 87% (62/71), the primary clinical patency rate was 88% (57/65), and the secondary clinical patency rate was 95% (62/65). The obstruction rate of the stent was 12% (8/65), and an additional stent was useful for relief of recurrent SVCS. Survival of 57 patients in whom there was no recurrence of SVCS until death ranged from 1 week to 29 months (mean, 5.4 months and the S-Z-stent appeared to be suitable for the treatment of the malignant obstruction of SVC. Unilateral stent placement was effective for relief of SVCS with bilateral BCV obstruction. Patients who received concurrent anticancer therapy survived 2 months longer than those who did not. Stent placement is an effective treatment for SVCS. Further, the utility of S-Z-stent for SVCS, an additional stent for recurrence, unilateral stent for patients with bilateral BCV obstruction, and anticancer therapy after stent placement were verified.

Femtosecond dynamics of color changes due to photoinduced electron transfer and reverse reactions in polymeric 4,4′-bipyridinium di-iodides salts were studied with a fs laser pump–probe technique. The characteristic color change was shown to take place in less than 1 ps by fs-laser excitation of an ion-pair charge-transfer band, which may be applied to ultrafast THz all-optical switching devices using visible light.