Isatuximab with pomalidomide-dexamethasone in relapsed/refractory multiple myeloma: post-marketing surveillance in Japan.

This post-marketing surveillance assessed the safety and effectiveness of isatuximab plus pomalidomide and dexamethasone (Isa-Pd) for relapsed or refractory multiple myeloma (RRMM) during real-world use in Japan. Data from 211 individuals with RRMM treated with Isa-Pd in Japan between October 2020 and October 2021 were collected, with follow-up for up to 12 months after initiation of Isa-Pd or until treatment discontinuation. The incidence of adverse drug reactions (ADRs), ADRs of special interest (infusion reactions, bone marrow suppression, infections, cardiac disorders, other ADRs of Grade ≥ 3), and serious ADRs was assessed. Best overall response and overall response rate (ORR) were determined. In the safety analysis set (n = 120), ADR incidence was 57.5%. Most ADRs were hematologic, and serious ADRs occurred in 28.3%. Bone marrow suppression occurred in 46.7% of participants (19.2% serious), infusion reactions in 18.3% (6.7% serious), infections in 11.7% (8.3% serious), and a serious cardiac disorder in one participant; other Grade ≥ 3 ADRs were reported in 3.3% (1.7% serious). In the effectiveness analysis set (n = 108), the most common best overall response was very good partial response (24.1%), and ORR was 51.9%. These findings support the safety and effectiveness of Isa-Pd for RRMM in real-life settings in Japan.

Safety and effectiveness of clofarabine in Japanese patients with relapsed/refractory acute lymphoblastic leukaemia: a post-marketing surveillance study.

OBJECTIVE: Clofarabine is used to treat acute lymphoblastic leukaemia, but evidence of its safety and effectiveness in Japanese patients is limited. We evaluated the safety and effectiveness of clofarabine in patients with relapsed/refractory acute lymphoblastic leukaemia in real-world clinical practice in Japan. METHODS: An observational, multicenter, post-marketing, all-case surveillance was conducted for safety. Effectiveness analyses were conducted in patients aged ≤21 years and those treated with clofarabine monotherapy and combination therapy (clofarabine plus etoposide and cyclophosphamide). RESULTS: In the all-case survey, 260 of 264 registered patients were eligible for safety analysis. Among the 225 patients eligible for effectiveness analysis, 139 were aged ≤21 years. For monotherapy and combination therapy, 20/31 and 34/88 patients were eligible, respectively. In the all-case survey, the median age was 16.0 years, and 47.7% of patients were <15 years old. Adverse drug reaction incidence was 83.5% and the most common were hematologic toxicities. The best overall response rates in the population aged ≤21 years were complete remission, 29.7%; complete remission without platelet recovery, 7.3% and partial remission, 10.9%. The rest (52.2%) were classified as ineffective. The sum of complete remission, complete remission without platelet recovery and partial remission rates (effectiveness rate) was 47.8% (66/138 patients). The effectiveness rates in the monotherapy and combination therapy surveys were 10.0% (2/20 patients) and 58.8% (20/34 patients), respectively. CONCLUSIONS: These post-marketing surveys provide real-world evidence of the safety and effectiveness of clofarabine regimens, including monotherapy and combination therapy in Japanese patients with relapsed/refractory acute lymphoblastic leukaemia. The safety and effectiveness profiles were comparable with those of previous prospective studies.

Baseline characteristics may impact treatment duration of cabazitaxel in patients with mCRPC: a subanalysis of data from a post-marketing surveillance.

OBJECTIVE: Cabazitaxel has demonstrated improvements in overall survival among patients with metastatic castration-resistant prostate cancer (mCRPC) in the pivotal comparison clinical trials TROPIC, PROSELICA and CARD. However, these trials include mCRPC patients with similar characteristics, and there are limited data on how baseline characteristics affect treatment discontinuation in the patient population. METHODS: To assess individual factors that may impact the discontinuation rate of cabazitaxel treatment, we conducted a post hoc analysis of data from a nationwide all-case, post-marketing surveillance of cabazitaxel in Japan. Patients were grouped according to the number of cabazitaxel treatment cycles received (1-2 and ≥3 cycles). Predictive factors were identified through multivariate logistic regression analysis. RESULTS: Across 660 patients with metastatic castration-resistant prostate cancer, 70.2% received ≥3 cycles of cabazitaxel treatment. Those receiving 1-2 cycles of cabazitaxel had a greater proportion of patients with poorer Eastern Cooperative Oncology Group Performance Status, presence of lung and liver metastases, higher prostate-specific antigen level and prior radiation therapy at baseline. Regardless of the number of cabazitaxel cycles received, the primary reason for discontinuation was progression of disease rather than adverse events. Compared with those receiving 1-2 cycles, a lower proportion of patients receiving 3-10 and ≥11 cycles of cabazitaxel treatment experienced adverse events. Multivariate analysis showed a significant association between early discontinuation and presence of liver lesions, poorer Eastern Cooperative Oncology Group Performance Status and higher prostate-specific antigen level at baseline. CONCLUSIONS: Post-marketing surveillance data suggest physicians should individualize cabazitaxel treatment based on certain patient characteristics at baseline.

Real-world effectiveness of third-line cabazitaxel in patients with metastatic castration-resistant prostate cancer: CARD-like analysis of data from a post-marketing surveillance in Japan.

BACKGROUND: The CARD trial was conducted in patients with metastatic castration-resistant prostate cancer (mCRPC) who had received docetaxel and experienced disease progression within 1 year on an androgen receptor-axis-targeted therapy (ARAT). Subsequent treatment with cabazitaxel had improved clinical outcomes compared with an alternative ARAT. This study aims to confirm the effectiveness of cabazitaxel in real-world patients in Japan and compare their characteristics with those of patients from the CARD trial. METHODS: This was a post-hoc analysis of a nationwide post-marketing surveillance registering all patients who were prescribed cabazitaxel in Japan between September 2014 and June 2015. Included patients had received docetaxel and ≤ 1 year of an ARAT (abiraterone or enzalutamide) prior to receiving cabazitaxel or an alternative ARAT, as their third-line therapy. The primary effectiveness endpoint was the time to treatment failure (TTF) of the third-line therapy. Patients were matched (1:1) from the cabazitaxel and second ARAT arms based on propensity score (PS). RESULTS: Of the 535 patients analysed, 247 received cabazitaxel and 288 the alternative ARAT as their third-line therapy, of which, 91.3% (n = 263/288) received abiraterone and 8.7% (n = 25/288) received enzalutamide as their second third-line ARAT. Patients in the cabazitaxel and second ARAT arms had TNM classification of M1 or MX in 73.3% and 68.1%, Gleason score of 8-10 in 78.5% and 79.2% and mean (standard deviation) serum PSA levels of 483 (1370) and 594 (1241) ng/mL, respectively. Initial cabazitaxel dose was ≤ 20 mg/m2 in 61.9% (n = 153/247) of the patients in the cabazitaxel arm. The median TTF (95% confidence interval [CI]) of the third-line therapy was 109 (94-128) days for cabazitaxel and 58 (57-66) days for the second ARAT, with a hazard ratio (95% CI) of 0.339 (0.279-0.413) favouring cabazitaxel. Similar results were obtained after PS-matching, with a hazard ratio (95% CI) of 0.323 (95% CI 0.258-0.402) favouring cabazitaxel. CONCLUSIONS: Consistent with the CARD trial, cabazitaxel demonstrated superior effectiveness over a second alternative ARAT in a real-world patient population in Japan, despite the population having more advanced disease status and a lower dose of cabazitaxel being more frequently administered, than in the CARD trial.

Comparison of Weight Reduction, Change in Parameters and Safety of a Very Low Carbohydrate Diet in Comparison to a Low Carbohydrate Diet in Obese Japanese Subjects with Metabolic Disorders.

Recently, low-carbohydrate diets (LCDs) have gained worldwide attention. LCDs are potentially effective for Japanese overweight and obese individuals with metabolic disorders. However, few randomized trials of LCDs have focused on the difference between LCDs and VLCDs. We conducted a randomized, prospective study of 42 Japanese, obese adults aged 28-65 years to evaluate the efficacy and safety of LCD and VLCD. To ensure the accuracy of the study, all test meals were provided, and compliance was checked using a smartphone app. Body composition measurements and blood tests were performed before and after the 2-month dietary intervention. The results showed that both methods significantly reduced body weight and fat, and also improved lipid abnormalities and liver function. In the current study, the reductions in weight and fat were comparable. The results of a questionnaire at the end of the study indicated that the LCD was easier to carry out than the VLCD, suggesting that the LCD was sustainable. The present study was unique in that it was a randomized, prospective study of Japanese subjects and that accurate data were obtained by providing meals.

Comprehensive analysis of the associations between clinical factors and outcomes by machine learning, using post marketing surveillance data of cabazitaxel in patients with castration-resistant prostate cancer.

BACKGROUND: We aimed to evaluate relationships between clinical outcomes and explanatory variables by network clustering analysis using data from a post marketing surveillance (PMS) study of castration-resistant prostate cancer (CRPC) patients. METHODS: The PMS was a prospective, multicenter, observational study of patients with metastatic, docetaxel-refractory CRPC treated with cabazitaxel in Japan after its launch in 2014. Graphical Markov (GM) model-based simulations and network clustering in 'R' package were conducted to identify correlations between clinical factors and outcomes. Factors shown to be associated with overall survival (OS) in the machine learning analysis were confirmed according to the clinical outcomes observed in the PMS. RESULTS: Among the 660 patients analyzed, median patient age was 70.0 years, and median OS and time-to-treatment failure (TTF) were 319 and 116 days, respectively. In GM-based simulations, factors associated with OS were liver metastases, performance status (PS), TTF, and neutropenia (threshold 0.05), and liver metastases, PS, and TTF (threshold 0.01). Factors associated with TTF were OS and relative dose intensity (threshold 0.05), and OS (threshold 0.01). In network clustering in 'R' package, factors associated with OS were number of treatment cycles, discontinuation due to disease progression, and TTF (threshold 0.05), and liver and lung metastases, PS, discontinuation due to adverse events, and febrile neutropenia (threshold 0.01). Kaplan-Meier analysis of patient subgroups demonstrated that visceral metastases and poor PS at baseline were associated with worse OS, while neutropenia or febrile neutropenia and higher number of cabazitaxel cycles were associated with better OS. CONCLUSIONS: Neutropenia may be a predictive factor for treatment efficacy in terms of survival. Poor PS and distant metastases to the liver and lungs were shown to be associated with worse outcomes, while factors related to treatment duration were shown to positively correlate with better OS.

Long-Term Safety and Effectiveness of Thyrotropin Alfa in Japanese Patients: A Post-Marketing Surveillance Study.

INTRODUCTION: Real-world evidence of the safety and effectiveness of recombinant human thyroid-stimulating hormone (rhTSH; thyrotropin alfa) in Japanese patients is lacking. METHODS: This was a post-marketing surveillance study that included all Japanese patients who received thyrotropin alfa, either as a supporting diagnostic from January 2009 to December 2016, or as adjunctive treatment for ablation from May 2012 to October 2018. Information was collected on patient demographics, thyroid cancer characteristics, adverse drug reactions (ADRs), scintigraphy, serum thyroglobulin (Tg) testing, and hypothyroidism symptoms. RESULTS: A total of 9268 patients were included in the safety analysis and 9031 in the effectiveness analysis. In the safety analysis set, 3444 patients received thyrotropin alfa as a diagnostic and 5822 received it as treatment. ADRs occurred in 7.1% (n = 660) of patients, including 9.4% (n = 324) of patients who received thyrotropin alfa as a diagnostic and 5.8% (n = 336) of patients who received it as treatment. Nausea was the most common ADR (4.0% of overall safety population). Among patients who received thyrotropin alfa as a diagnostic (n = 1835), the Tg test was positive in 53.6% after the second dose. The scintigram was rated as "readable" in 3023 of the 3054 patients included in this analysis (99.0%). Of the 765 patients who were included in the assessment of response to ablation at 6 months to 1 year after the procedure, 621 (81.2%) were considered to have had "treatment success". There were no significant differences in the proportions of patients who had hypothyroidism symptoms before the first and after the second dose of thyrotropin alfa. CONCLUSION: In this large post-marketing surveillance study, thyrotropin alfa was well tolerated and showed effectiveness that was comparable to that observed in randomised, controlled trials.

Real-world efficacy and safety of two doses of cabazitaxel (20 or 25 mg/m2) in patients with castration-resistant prostate cancer: results of a Japanese post-marketing surveillance study.

BACKGROUND: The recommended starting dose of cabazitaxel for castration-resistant prostate cancer (CRPC) is 25 mg/m2 in Japan and Europe. Although lower doses are established alternatives based on randomized controlled trials, the safety and efficacy of 25 and 20 mg/m2 in real-world settings are not well established. Therefore, we investigated the safety and efficacy of cabazitaxel at the recommended starting dose or a lower dose (20 mg/m2) in real-world clinical practice. METHODS: We compared the safety and efficacy of cabazitaxel between patients who received cabazitaxel at starting doses of 25 and 20 mg/m2 (C25 and C20, respectively) in a Japanese post-marketing surveillance study of 662 patients with docetaxel-refractory CRPC. Safety was assessed in terms of adverse drug reactions (ADRs). Prostate-specific antigen (PSA) response rate, overall survival (OS), and time-to-treatment failure (TTF) were compared between the C25 and C20 groups in unmatched patients and after applying propensity score matching. RESULTS: The C20 and C25 groups comprised 190 and 159 patients without matching and 112 patients per group after matching. In unmatched patients, any-grade (C25 vs C20: 89.3% vs 78.4%, Fisher's p < 0.01) and grade ≥ 3 (81.1% vs 61.1%) ADRs were more frequent in the C25 group. Neutropenia (any grade: 61.6% vs 54.2%; grade ≥ 3: 55.3% vs 42.6%) and febrile neutropenia (grade ≥ 3: 30.2% vs 14.7%) were more frequent in the C25 group. In matched patients, the PSA response rate (reduction in PSA ≥30% from a baseline ≥5 ng/mL) was 26.4 and 32.0% in the C20 and C25 groups, respectively, median OS was 291 days (95% CI 230-not reached) versus not reached (hazard ratio 0.73, 95% CI 0.50-1.08), and TTF favored C25 (hazard ratio 0.75, 95% CI 0.57-0.99). CONCLUSIONS: Clinicians should consider the patient's risk of clinically significant ADRs and prophylactic granulocyte colony stimulating factor when selecting the starting dose of cabazitaxel for CRPC. Some patients at high risk of ADRs or unfit patients may benefit from a lower starting dose of 20 mg/m2, whereas fit patients may be candidates for a starting dose of 25 mg/m2. TRIAL REGISTRATION: Not applicable.

Cabazitaxel in patients aged ≥80 years with castration-resistant prostate cancer: Results of a post-marketing surveillance study in Japan.

OBJECTIVES: Data on the safety and efficacy of cabazitaxel in patients aged ≥80 years with castration-resistant prostate cancer (CRPC) are limited. We report the safety (adverse drug reactions [ADRs]) and efficacy (overall survival [OS], time to treatment failure [TTF], and prostate-specific antigen [PSA] response rates) in patients aged <80 or ≥80 years treated with cabazitaxel for CRPC in clinical practice. MATERIALS AND METHODS: We performed post-hoc subgroup analyses of a Japanese post-marketing surveillance study involving 662 patients with CRPC treated with cabazitaxel between September 2014 and June 2016. RESULTS: In patients aged <80 (n = 610) and ≥80 years (n = 49), median PSA at baseline was 168.7 and 109.0 ng/mL, and 86.7% and 83.7% of patients were previously treated with enzalutamide and/or abiraterone. ADRs (all grade) occurred in 77.2% and 79.6% of patients aged <80 and ≥80 years, with grade three/worse ADRs in 61.8% and 63.3% of patients. Hematologic toxicities were the most common grade three/worse ADRs, including neutropenia, febrile neutropenia, and anemia in both subgroups. No specific ADRs were observed in patients aged ≥80 years. The PSA response and median OS and TTF were 28.3%, 292 days, and 116 days in patients aged ≥80 years, and 29.7%, 319 days, and 125 days in patients aged <80 years. CONCLUSION: Cabazitaxel could be a treatment option for CRPC in patients aged ≥80 years based on its safety and efficacy profiles. This is the first report to investigate the safety and efficacy of cabazitaxel in patients aged ≥80 years with CRPC.

Safety and efficacy of cabazitaxel in 660 patients with metastatic castration-resistant prostate cancer in real-world settings: results of a Japanese post-marketing surveillance study.

OBJECTIVE: To evaluate the real-world safety and efficacy of cabazitaxel in Japanese patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with a docetaxel-containing regimen. METHODS: This prospective multicenter observational study registered all patients with mCRPC treated with cabazitaxel following its launch in Japan in September 2014. Patient enrollment continued until at least 500 patients were enrolled. Adverse drug reactions (ADRs) were evaluated according to CTCAE ver. 4.0. Efficacy endpoints were assessed for up to 1 year, and included prostate specific antigen (PSA) response rates (defined as a decrease of ≥30% or ≥50% from baseline), overall survival (OS), and time to treatment failure (TTF). RESULTS: A total of 660 mCRPC patients were enrolled across 316 centers by June 2016. Frequent ADRs (any grade) were neutropenia (49.1%), febrile neutropenia (18.0%) and anemia (15.0%). Most ADRs occurred in cycle 1. Neutropenia and febrile neutropenia were significantly less frequent in patients who received prophylactic granulocyte colony-stimulating factor. The PSA response rates for decrease of ≥30% or ≥50% from baseline were 28.1% and 17.5%, respectively, in patients with baseline PSA of ≥5 ng/ml. Median OS and TTF were 319 days (95% confidence interval: 293.0-361.0) and 116 days (95% confidence interval: 108.0-135.0), respectively. CONCLUSIONS: This study of cabazitaxel in 660 Japanese patients treated in real-world settings, the largest study of cabazitaxel to date, demonstrated a safety profile that was generally consistent with those of pivotal clinical studies. Cabazitaxel was also effective in terms of the PSA response, OS, and TTF.

Characteristics of an actuator-driven pulsed water jet generator to dissecting soft tissue.

This paper reports characteristics of an actuator-driven pulsed water jet generator applied, in particular, to dissect soft tissues. Results of experiments, by making use of high speed recording of optical visualization and varying nozzle diameter, actuator time interval, and their effects on dissection performance are presented. Jet penetration characteristics are compared with continuous water jet and hence potential assessment of pulsed water jets to clinical applications is performed.

[A fatal case of pulmonary non-tuberculous mycobacteriosis with reactive AA amyloidosis].

We report a very rare fatal case of reactive AA amyloidosis following pulmonary non-tuberculous mycobacteriosis (PNTM). A 61-year-old woman with a history of PNTM since 1992, whose treatment was difficult because of liver dysfunction and drug eruption caused by antibiotics, had been hospitalized due to recurrent pulmonary bacterial infection. She complained of leg edema in January, 2000, and nephrotic syndrome was diagnosed in February. After diarrhea and abdominal pain appeared in March, she was admitted to our hospital with worsening edema, and dizziness on April 28. Despite treatment, she died on May 5, 2000. Autopsy revealed PNTM and diffuse systemic depositions of amyloid A protein in heart, kidney and gastrointestinal tract. PNTM, often resistance to antibacterial agents, is increasing recently. This case suggests that it is necessary to take care of amyloidosis when various systemic symptoms are observed in chronic inflammatory disease.

[A case of Ortner syndrome caused by primary pulmonary hypertension].

Left vocal cord palsy is a rare complication of pulmonary hypertension (also known as Ortner syndrome). Here we report a case of a patient with Ortner syndrome caused by primary pulmonary hypertension (PPH). The patient was a 28-year-old woman, who complained of persistent hoarseness and dyspnea on effort. A left vocal cord palsy, as well as PPH, was diagnosed, suggesting that pulmonary artery dilatation associated with PPH led to left recurrent laryngeal nerve palsy. This case suggests that PPH should be suspected in any case with unexplained left vocal cord palsy.

[A case of the multiple peripheral pulmonary artery branch stenosis].

A 31-year-old woman in whom primary pulmonary hypertension had been diagnosed at age 18, was admitted because of dyspnea on exertion and for evaluation of pregnancy risk. The perfusion scanning was not diagnostic, but chest CT suggested stenosis of pulmonary arteries instead of primary pulmonary hypertension. Echocardiograms and cardiac catheterization revealed pulmonary hypertension of pulmonary arterial pressure 71/13 (mean 39) mmHg with no cardiac defects. Selective pulmonary angiograms showed multiple stenosis of pulmonary arteries with poststenotic dilatations. We diagnosed multiple peripheral pulmonary artery branch stenosis with the pulmonary hypertension because systemic vasculitis was excluded because there were no signs of inflammation or any systemic arterial invlolvement This case was thought to be congenital, considering her history of over 30 years. In reports from western countries, maternal rubella and familial factors were important etiologic factors of this disease. Few cases have been reported in Japan and all cases, including the present case, were unrelated to the specific etiological factors. We recommended her to use birth control and have been observing her very carefully since the progression of the pulmonary hypertension is the major determinant of her prognosis.