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Objectives Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate that targets delta-like protein 3 (DLL3) on small cell lung cancer (SCLC) tumors, is internalized and releases the toxin pyrrolobenzodiazepine to induce cell death. This open label phase I study was the first study of Rova-T in Japanese patients. The aim of this study was to evaluate, safety, pharmacokinetics, and preliminary efficacy of Rova-T in Japanese patients with advanced recurrent SCLC. Materials and methods Patients received Rova-T (0.2 or 0.3 mg/kg) by intravenous infusion on Day (D) 1 of each 6-week cycle for 2 doses and dexamethasone (8 mg BID oral) on D-1, D1, and D2 of each 6-week cycle. Retreatment with Rova-T was permitted for patients who tolerated their initial doses and then progressed after disease control (defined as stable disease or better) was observed for at least 12 weeks after their last dose of Rova-T. Results Rova-T exhibited toxicity that was generally manageable in Japanese patients (N = 29). No dose-limiting toxicities were experienced. The most common treatment-related adverse events (≥25% of patients, all grades) were platelet count decreased, pleural effusion, peripheral edema, aspartate aminotransferase increased, white blood cell count decreased, neutrophil count decreased, alanine aminotransferase increased, hypoalbuminaemia, anemia and decreased appetite. Safety and pharmacokinetics exposures were similar to previous observations in non-Japanese populations. Per investigator assessment of DLL3 high patients, 17% (3/18) had confirmed partial responses, and the disease control rate was 56%, mPFS was 2.9 months, and mOS was 7.4 months. Conclusions These preliminary data support further exploration of Rova-T treatment in Japanese patients with SCLC in global studies. This trial was registered with ClinicalTrials.gov as NCT03086239.

8557 Background: SCLC rapidly recurs after first-line platinum therapy, and while several agents are approved in the relapsed/refractory setting, there is no approved agent or existing standard of care for third-line in Japan. Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate targeting Delta-like 3 protein (DLL3), an atypical Notch ligand that is highly expressed in SCLC but not in normal tissue. This was the first study evaluating safety, PK, and preliminary anti-tumor activity of Rova-T in Japanese pts. Methods: This was an open label Phase 1, 3+3 dose-escalation study of Rova-T in Japanese pts with advanced recurrent SCLC (NCT03086239). Eligibility: progressive disease after ≥2 prior systemic regimens incl. ≥1 platinum-based regimen; ECOG 0-1. Pts received 0.2 or 0.3 mg/kg Rova-T IV on Day 1 of a 6-week cycle for 2 cycles. Objective was to evaluate safety, tolerability, PK, and preliminary efficacy and expression of DLL3. Antitumor activity was measured by RECISTv1.1, and DOR, PFS, OS were evaluated. Results: 29 pts were treated with Rova-T (6 at 0.2mg/kg, 23 at 0.3 mg/kg). Median age 68 yrs; 76% male; 64% DLL3 high (≥75% expression); 86% DLL3 positive (≥25%). 20 pts (69%) had received ≥3 prior lines of therapy. Similar PK and AEs were seen compared to previous studies in non-Japanese pts. The most frequently reported study drug-related AEs were platelet count decreased, pleural effusion, oedema peripheral, and aspartate aminotransferase increased, the majority Grade 1/2. No DLTs occurred, and both dose levels were tolerated. Three pts previously treated with ≥3 prior lines of therapy had confirmed partial response by investigator (10% of all pts; 17% of DLL3 high pts). For DLL3 high pts, mDOR was 3.0 mos (95% CI: 2.9, 4.1), mPFS was 2.9 mos (1.2-3.6), and mOS was 7.4 mos (4.1-11.9). Individual responses were analyzed in detail and radiographic data with tumor shrinkage will be shown. Conclusions: Rova-T demonstrated a manageable safety profile with promising preliminary efficacy in Japanese SCLC pts, in particular pts with DLL3 high expression. These data support further exploration of Rova-T treatment in Japanese pts with SCLC in global Phase 3 studies. Clinical trial information: NCT03086239.

To take up the three-dimensional axisymmetric gate slot concerining with the gate slot possessed in hydraulic equipment, such as, a gate valve, the state of cavitation of the gate slot was investigated by Acoustic Emisson (AE) measurement. The relationship between AE energy level and cavitation condition was analyzed by the root-mean-square (RMS) of acoustic wave. Moreover, a new AE parameter "relative accumulated intensity (RAI)" was defined in order to estimate the erosion tendency of cavitation. Combining with the result of impulsive pressure measurement, the relationship between the erosive damage and the high amplitude generation of AE wave is confirmed by using RAI. In consideration of deflector effect, the AE measurement showed that the conical shape installed on the upstream side of gate slot makes the cavitation erosion increased, and the offset shape on the downstream side of gate slot makes the cavitation erosion decreased significantly.

残留性有機汚染物質（POPs）として懸念される有機フッ素化合物，ペルフルオロオクタンスルホン酸（PFOS）およびペルフルオロオクタン酸（PFOA）のメカノケミカル（MC）処理に注目した．酸化カルシウム（CaO）を反応助剤とし，小型遊星ボールミル（ミル回転数700 rpm）を用いておよそCa/F（mol比）=2でPFOS，PFOAのMC処理を行った結果，どちらの物質とも3時間の処理で80%以上分解することが明らかとなった．処理後は，炭酸カルシウム（CaCO3）やフッ化カルシウム（CaF2）の生成が確認され，C–F結合やC–C結合の開裂反応によって分解反応が促進することが示された．また，有価なCaF2の生成により，マテリアルリサイクルの可能性も見出された．

Cavitation in a 3D axisymmetric rectangular groove occurred in various types of cavitation, such as vortex cavitation, cloud cavitation, traveling cavitation and sheet cavitation. In this experimental study, some aspects of cavitating flow were clarified. Prediction and experimental calculations were also made for incipient cavitation of both the cavitating vortex ring in the groove and the sheet cavitation at the downstream of the groove. The calculations indicate that the observed cavitation is not vaporous cavitation, but gaseous cavitation. The results of this study are useful for understanding the cavitation in this type of groove structure in order to control cavitation damage.

Hollow-jet valve has been utilized to control the water supply extensively under high static pressure. For the valve used underwater, cavitation erosion will probably be caused. However, such a trouble has not been studied yet in detail. Therefore a similar model of hollow-jet valve was made in which plunger stroke is changeable as the prototype valve. The aim of this paper is to clarify the characteristics of cavitation-induced vibration related to the erosion around the upstream casing and six splitters in the valve, to estimate the ventilation effect to decrease the erosion as well as the vibration, and also to make clear the difference of flow pattern in the valve between underwater and in air.

In this paper, to make clear the mechanism of cavitation damage around a hollow-jet valve, cavitation damage test was conducted in a hollow-jet model valve. The eroded surfaces of specimens were observed by Scanning Electron Microscope (SEM) at different times of the test. Cavitation aspects were also observed photographically by a high-speed camera. It was found that the damage occurs in cavitating flows around a hollow-jet valve with two patterns. One is characterized by a big plastic crater, which seems to be generated by one blow event of cavitating vortex collapse near a specimen surface. Another is due to a small brittle irregular pit formed by the cumulative effects of many weaker blows. The former is the main cause to lead serious damage. The high-speed photographic observations of the cavitation aspects showed that more cavitating vortices in middle cavitation number state occur than these in other states. The damage tests also illustrated that the middle state is the most dangerous for cavitation damage around a hollw-jet valve.

In order to clarify the mechanism of water-jet erosion, we systematically investigate the erosion-standoff-distance curves, the erosion-time curves, and detailed aspects of the eroded surface for two typical types of nozzles, i.e., conical and cylindrical nozzles. Clearly, the erosion-time curves are markedly different at the 1st peak, at the valley and at the 2nd peak. Hence, the mechanism of erosion is significantly changed with an increase in the standoff distance χ.

Objective Genetic polymorphisms were identified in the 5′-flanking region of the human CYP2C9 gene, and their effects on the phenotype were evaluated on the basis of the luciferase reporter gene assay and the in vivo pharmacokinetics of phenytoin. Methods Genetic polymorphisms were screened by polymerase chain reaction–single-strand conformational polymorphism analysis, following sequencing with DNA samples obtained from 50 healthy volunteers and 133 adult epileptic patients. HepG2 hepatoma cells were cotransfected with various sequence patterns of 5′-flanking region–luciferase reporter gene constructs. Pharmacokinetic parameters of phenytoin in relation to the corresponding sequence patterns were estimated by the Bayesian method, and the results were compared with in vitro activities. Results Genetic analysis revealed the existence of 7 single nucleotide polymorphisms (SNPs). Allele frequencies of TC transition at position −1912 (T-1912C), C-1886G, C-1566T, G-1538A, C-1189T, G-982A, and A-162G were 0.019, 0.019, 0.077, 0.019, 0.579, 0.019, and 0.003, respectively. Some mutations occurred simultaneously, and a total of 6 sequence patterns (patterns 1–6) were observed. The luciferase reporter gene assay indicated that the presence of mutation(s) resulted in a reduction in luciferase activity of 41.4% (pattern 2) to 86.8% (pattern 5) compared with the activity of the wild-type construct. The calculated intrinsic clearance of phenytoin was also lower (up to a 40% reduction for pattern 2) when a mutation(s) was present. Conclusion In addition to the two major mutations in the coding region (CYP2C9*2 and CYP2C9*3), mutations in the 5′-flanking region of the human CYP2C9 gene appear to contribute to the large interindividual variability in drug metabolism activity. Clinical Pharmacology & Therapeutics (2001) 70, 175–182; doi: 10.1067/mcp.2001.117367