Analgesic efficacy and safety of percutaneous thermal ablation plus cementoplasty for painful bone metastases: a systematic review and meta-analysis.

PURPOSE: To conduct a systematic review and meta-analysis of publications to evaluate the analgesic efficacy and safety of percutaneous thermal ablation (PTA) plus percutaneous cementoplasty (PCP) (PTA + PCP) for painful bone metastases. METHODS: We searched PubMed, Cochrane Library and Embase for articles published up to October 2022. Outcomes were a 10-point pain scale, morphine equivalents daily dose (MEDD) and complications. A subgroup confined to spinal bone metastases was analyzed. RESULTS: Twenty-one articles were selected for the analysis. The 21 selected articles involved a total of 661 cases. The pooled pain scales at pre-PTA + PCP, 1 day, 1 week and 1-, 3-, and 6 months post-PTA + PCP were 7.60 (95% confidence interval [CI], 7.26-7.95, I2 = 89%), 3.30 (95% CI, 2.25-4.82, I2 = 98%), 2.58 (95% CI, 1.99-3.35, I2 = 94%), 2.02 (95% CI, 1.50-2.71, I2 = 93%), 1.78 (95% CI, 1.26-2.53, I2 = 95%), and 1.62 (95% CI, 1.14-2.31, I2 = 88%), and in the subgroup, 7.97 (95% CI, 7.45-8.52, I2 = 86%), 3.01 (95% CI, 1.43-6.33, I2 = 98%), 2.95 (95% CI, 1.93-4.51, I2 = 95%), 2.34 (95% CI, 1.82-3.01, I2 = 68%), 2.18 (95% CI, 1.57-3.03, I2 = 78%), and 2.01 (95% CI, 1.16-3.48, I2 = 86%). Mean MEDD decreased up to 3 months post-PTA + PCP in 4 articles. The overall pooled major complication rate was 4% (95% CI, 2-6%, I2 = 2%). CONCLUSIONS: The updated systematic review and meta-analysis indicates that PTA + PCP for painful bone metastases is safe, and can lead to rapid and sustained pain reduction.

Safety, tolerability, and pharmacokinetics of half-life extended SARS-CoV-2-neutralizing monoclonal antibodies AZD7442 (tixagevimab/cilgavimab) in healthy Japanese adults.

INTRODUCTION: The aim of this study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of AZD7442 (tixagevimab/cilgavimab) in healthy Japanese adults. METHODS: In this randomized, double-blind, placebo-controlled, phase 1 study, AZD7442 was administered intramuscularly (300 or 600 mg) or intravenously (300 or 1000 mg) to healthy Japanese adults. Primary endpoints were safety, tolerability, and pharmacokinetics. Anti-drug antibodies and neutralizing antibody activities were secondary endpoints. RESULTS: A total of 40 participants were randomized to receive AZD7442 (n = 30) or placebo (n = 10). Adverse events (AEs) occurred in 12 (40%) and 3 (30%) participants, respectively; there were no deaths, serious AEs, or AEs leading to study withdrawal. Tixagevimab and cilgavimab had mean half-lives of 82.1-95.9 and 77.9-92.0 days, respectively, which were generally similar regardless of administration route. SARS-CoV-2-neutralizing antibody titers were >4-fold higher than baseline levels from Day 8 to Day 211 in participants receiving AZD7442. CONCLUSIONS: AZD7442 was well tolerated in healthy Japanese adults, with predictable pharmacokinetics and an extended half-life, consistent with previous studies. CLINICALTRIALS: gov, NCT04896541.

Short-Term Efficacy (at 12 Weeks) and Long-Term Safety (up to 52 Weeks) of Omega-3 Free Fatty Acids (AZD0585) for the Treatment of Japanese Patients With Dyslipidemia　- A Randomized, Double-Blind, Placebo-Controlled, Phase III Study.

BACKGROUND: This study is the first to evaluate the short-term efficacy and long-term safety of AZD0585, a mixture of omega-3 free fatty acids, in Japanese patients with dyslipidemia.Methods and Results:In this randomized double-blind placebo-controlled Phase III study, 383 patients were randomized to 2 g AZD0585, 4 g AZD0585, or placebo once daily for 52 weeks. Eligible patients had low-density lipoprotein cholesterol (LDL-C) levels controlled regardless of statin use, and triglyceride levels between 150 and 499 mg/dL. The least-squares (LS) mean percentage changes in triglyceride concentrations from baseline to the 12-week endpoint (mean of measurements at Weeks 10 and 12) in the 2 and 4 g AZD0585 and placebo groups were -15.57%, -21.75%, and 11.15% respectively (P<0.0001 for both AZD0585 doses vs. placebo). No clinically significant changes from baseline to the 12-week endpoint in total cholesterol, LDL-C, and LDL-C/apolipoprotein (Apo) B were found with AZD0585. High-density lipoprotein cholesterol (HDL-C) was slightly increased and very low-density lipoprotein cholesterol, non-HDL-C, ApoC-II, and ApoC-III were decreased with AZD0585 compared with placebo at the 12-week endpoint. Lipid profiles up to Week 52 were consistent with those up to the 12-week endpoint. No clinically important safety concerns were raised. CONCLUSIONS: AZD0585 significantly decreased serum triglyceride levels compared with placebo at the 12-week endpoint and was generally safe and well tolerated in Japanese patients with dyslipidemia.

Safety, Tolerability, and Pharmacokinetics of Single and Multiple Oral Doses of an Omega-3-Carboxylic Acid Formulation in Healthy Male Japanese Subjects: A Phase 1 Single-Blind, Randomized, Placebo-Controlled Trial.

OM3-CA (omega-3-carboxylic acids) is a complex mixture of omega-3 carboxylic acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which is approved in the United States for the treatment of hypertriglyceridemia. As part of its clinical development in Japan, we performed a phase 1 study to investigate the safety, tolerability, and pharmacokinetics after single and multiple doses of OM3-CA in healthy male Japanese subjects. Eighteen Japanese subjects were allocated to receive 2 or 4 g/day OM3-CA, or placebo (n = 6 per group). In addition, 6 white subjects received 4 g/day OM3-CA. The primary objective was to determine the safety and tolerability of OM3-CA. Plasma concentrations of EPA and DHA were adjusted for baseline values for pharmacokinetic analysis. Overall, OM3-CA was well tolerated in healthy Japanese subjects. Two Japanese subjects in each group and 5 white subjects experienced adverse events (AEs). Alanine aminotransferase increase was the most common AE in Japanese subjects, also seen with placebo, and diarrhea was the most common AE in white subjects. The maximum plasma concentrations of EPA and DHA were observed 5-6 hours postdose. The pharmacokinetic profiles of EPA and DHA after administration of OM3-CA were comparable between Japanese and white subjects.

[A case of advanced gastric cancer successfully treated with TS-1/CDDP combination chemotherapy, able to maintain CR for more than two years against multiple liver metastases].

INTRODUCTION: In recent years, a high success rate of combination chemotherapy with TS-1/CDDP has been reported against advanced gastric carcinoma. We, this time, experienced a case of advanced hemorrhagic gastric cancer with multiple hepatic metastases for which total gastrectomy was performed, followed by postoperative combination chemotherapy with TS-1/CDDP which culminated in achieving CR for the liver metastases. CASE REPORT: The patient was a 59-year-old woman who was hospitalized for a type IV gastric carcinoma in the upper part of the gastric body. Further examination revealed liver (S 2, S 5, S 7) and lymph node metastases. Due to hemorrhage from the tumorous lesion, the treatment strategy selected was total gastrectomy followed by postoperative chemotherapy. Operative and clinicopathological findings revealed a mass lesion of MLU, type IV, 16.0x14.0 cm, sT 3 (SE), sH 1 (bilobular multiple metastases) and CY 0, and por 1, pT 2 (SS), pN 1 (+) [23/38], int, INF beta, ly 3 and v 1, respectively. Combination chemotherapy with TS-1/CDDP was instituted after surgery. As for the dosing method of combination chemotherapy,the patient was treated with a course of TS-1 80 mg daily divided into two doses over 21 days continuously, followed by a 14-day cessation of the drug,together with a dose of CDDP 70 mg on day 8. The patient received a total of four courses. At the completion of the third chemotherapy course, her multiple hepatic metastases disappeared. Further, the preoperative CA 19-9 level of 370 U/mL returned to normal after chemotherapy. Adverse events observed were leukopenia and thrombocytopenia, both of which were judged to be grade 2. At two years and nine months, the patient is being followed on an outpatient basis without any sign of postoperative recurrent disease. CONCLUSION: We experienced a patient who was successfully treated with combination chemotherapy and demonstrated disappearance of her multiple hepatic metastases, showing a clinical response of CR lasting for more than two years against the metastases. It was inferred that this regimen of TS-1/CDDP is an effective treatment modality not only as preoperative but also postoperative chemotherapy after surgery for advanced gastric carcinoma.

Effects of Food on the Pharmacokinetics of Omega-3-Carboxylic Acids in Healthy Japanese Male Subjects: A Phase I, Randomized, Open-label, Three-period, Crossover Trial.

AIMS: Omega-3-carboxylic acids (OM3-CA) contain omega-3 free fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as carboxylic acids. Food intake is known to affect the bioavailability of ethyl ester fatty acid formulations. We conducted a phase I study to investigate the effects of the timing of OM3-CA administration relative to food intake on the pharmacokinetics of EPA and DHA. METHODS: In this randomized, open-label, three-period crossover study, Japanese healthy male subjects were administered 4×1 g OM3-CA capsules with continued fasting, before a meal, or after a meal. All subjects fasted for ≥10 h prior to drug/meal administration. The primary objective was to examine the effect of meal timing on the pharmacokinetics of EPA and DHA after OM3-CA administration. The secondary objectives were to examine the safety and tolerability of OM3-CA. RESULTS: A total of 42 Japanese subjects was enrolled in the study. The baseline-adjusted maximum concentration and area under the concentration-time curve from 0 to 72 h for EPA, DHA, and EPA +DHA were lower in the fasting and before meal conditions than in the after meal condition. The maximum total EPA, total DHA, and total EPA+DHA concentrations were reached later when administered in fasting conditions than in fed conditions, indicating slower absorption in fasting conditions. Diarrhea was reported by five, six, and no subjects in the fasting, before meal, and after meal conditions, respectively. CONCLUSIONS: The timing of OM3-CA administration relative to food intake influences the systemic bioavailability of EPA and DHA in healthy Japanese male subjects. TRIAL REGISTRATION: NCT02372344.

Infrequent mutation of the human envoplakin gene is closely linked to the tylosis oesophageal cancer locus in sporadic oesophageal squamous cell carcinomas.

Envoplakin (EVPL) is a member of the desmosomal plaque proteins attached to desmosomal cadherin and keratin filaments. The EVPL gene has been mapped to the tylosis oesophageal cancer (TOC) locus on chromosome 17q25, where it has been demonstrated to be frequently deleted in both familial and sporadic forms of oesophageal squamous cell carcinoma (OSC). In this study, we examined EVPL gene mutations in 10 OSC cell lines and 20 sporadic OSCs using reverse transcription-polymerase chain reaction single-strand conformational analysis (RT-PCR SSCP) followed by direct sequencing. We observed one somatic mutation (GCG to ACG at codon 1104, Ala to Thr: 1/20, 5%) in the central rod domain and 5 intragenic polymorphic sites, where frequent loss of heterozygosity (LOH) (63%) was detected. No mutations were detected in the OSC cell lines. The rate of EVPL gene mutation was quite low in contrast to the frequency of LOH on the TOC locus in sporadic OSCs, and the high incidence of oesophageal cancer development in tylosis families. Our results suggest that EVPL might not be the target gene responsible for OSC, despite its strong candidacy in terms of character and localization.

Human PinX1, a potent telomerase inhibitor, is not involved in human gastrointestinal tract carcinoma.

PinX1 was isolated as a Pin2/TRF1 binding protein that also binds to the telomerase catalytic subunit hTERT. The gene is a potent telomerase inhibitor and a putative tumor suppressor since it inhibits telomerase activity and affects tumorigenicity in nude mice. This study investigated aberrations of PinX1 gene in gastrointestinal tract carcinomas (GITCs). We examined mutations, mRNA expression and promoter methylation of PinX1 gene in 15 GITC cell lines, and 20 patients with primary GITC. We found a missense mutation at codon 254 (AGC/TGC) in a colon and an esophageal carcinoma cell line, and in cancerous and matching normal tissues of 2 patients with primary GITC (10%). It might be a benign polymorphism. No hyper-methylation was found in the promoter region and the treatment by 5-Aza-2'-deoxycytidine did not affect PinX1 mRNA expression level in any of the cell lines. It was concluded that the human PinX1 does not affect tumorigenesis of human GITC.

Influence of a human protease inhibitor on surgical stress induced immunosuppression.

BACKGROUND/AIM: Postoperative tissue injury and immunosuppression can occur after major surgery. In this study, we explore the potential benefits of administering a protease inhibitor to treat immunosuppression caused by surgical stress. METHODS: Sixteen patients with esophageal cancer were preoperatively allocated at random into two equal groups. A urinary trypsin inhibitor, ulinastatin (UTI), was intravenously administered to the treatment (UTI) group at a dose of 150,000 U every 12 h from the start of surgery until postoperative day 5, whereas the control group received a placebo. One unit of UTI was defined as the amount of UTI necessary to inhibit the activity of 2 microg of bovine pancreatic trypsin by 50%. We measured the plasma levels of polymorphonuclear neutrophil elastase, interleukin 8, circulating T lymphocyte subsets, and mitogenic activity and in vitro production of tumor necrosis factor alpha in lipopolysaccharide-stimulated whole blood. RESULTS: The postoperative serum value of polymorphonuclear neutrophil elastase was significantly lower in the UTI group, but the interleukin 8 concentrations did not significantly vary between the two groups. On the other hand, the severity of the postoperative immunosuppression was reduced in the UTI group, and immune functions, such as the numbers of T lymphocytes, the mitogenic activity of lymphocytes, and the level of tumor necrosis factor alpha production in whole blood, recovered significantly earlier in the UTI group. CONCLUSION: These data suggest that a protease-modulating therapy may be a new strategy for the treatment of surgical stress induced immune dysfunction.