Primary takotsubo syndrome with recurrent prolactinoma.

Both peripartum cardiomyopathy (PPCM) and takotsubo syndrome (TTS) are diagnoses of exclusion and are thus considered a heterogeneous disease group. TTS is generally triggered by psychogenic or physical stress. Recently, the anti-angiogenic factor cleaved prolactin has been noted as a cause of PPCM, but the precise mechanisms of these diseases remain unexplained. An 87-year-old female with a past surgical history, including transsphenoidal endoscopic surgery to remove a pituitary prolactinoma, recently underwent surgery to repair a left-sided femoral neck fracture and developed dyspnea followed by back pain; shortly after, she became embarrassed by fecal incontinence. Her initial electrocardiogram showed T wave inversions with QT prolongation leading to sustained ventricular tachycardia. No obstructive coronary artery disease was found on emergent coronary angiography, and the left ventriculography findings were consistent with TTS. After acute-phase treatment, she was diagnosed with recurrent prolactinoma based on her head magnetic resonance imaging findings. This patient's high levels of prolactin may have played a role in the pathogenesis of TTS. Learning objective: Peripartum cardiomyopathy and takotsubo syndrome (TTS) are diagnosed by exclusion, and their precise mechanisms remain unknown. We present a case of TTS associated with a prolactinoma.

Heart Failure Management Capability and Exacerbation of Heart Failure　- A 6-Month Prospective Cohort Study.

Background: In households with older individuals, where a patient is experiencing heart failure (HF), effective cooperation between patients and caregivers is crucial for disease management. However, there is limited evidence regarding the impact of cooperative HF management on the incidence of exacerbation. Therefore, the aim of this 6-month prospective cohort study was to investigate the association between HF management capability and exacerbations. Methods and Results: The study enrolled outpatients (age ≥65 years) with chronic HF from a cardiology clinic and their caregivers. Self-care capabilities among patients and caregivers were evaluated using the Self-Care of Heart Failure Index (SCHFI) and Caregiver Contribution-SCHFI, respectively. Total scores were calculated using the highest score for each item. During the follow-up period, 31 patients experienced worsening HF. The analysis revealed no significant association between the total HF management score and HF exacerbation among all eligible patients. However, in patients with preserved left ventricular ejection fraction (LVEF), high HF management capability of the family unit was associated with a reduced risk of HF exacerbation, even after adjusting for the severity of HF. Conclusions: In older patients with HF and preserved LVEF, effective HF management may contribute to a lower risk of exacerbations.

Effectiveness of drug postmarketing all-case surveillance as a safety measure in Japan.

INTRODUCTION: The drug pharmacovigilance system in Japan is similar to those in the European Union (EU) and the United States. As a unique Japanese pharmacovigilance program, postmarketing all-case surveillance (PMACS) is required. PMACS plays a key role for postmarketing activities, but there are challenges that place much burden on PMACS conduct. This study investigates the impact of PMACS on postmarketing activities in Japan and proposes its potential improvement. This study also seeks the possibility to expand PMACS beyond Japan. MATERIALS AND METHODS: Reexamination reports issued from 2017 to 2019 were identified in September 2020 by searching 'reexamination report' and '201701' to '201912' on the Pharmaceuticals and Medical Devices Agency website. The corresponding Package Insert (PI) change orders and premarketing review reports were also identified. Reviewing these regulatory documents allowed for investigation of the PMACS impact on postmarketing activities. RESULTS: More than half (57%) of the drugs with PMACS had 'Limited dosing experience in Japan' as a reason for the PMACS requirement. As a safety measure, no PI change orders were imposed on 33% and 28% of drugs with and without PMACS, respectively. The means of the number of PI change orders were 2.23 and 2.14 for drugs with and without PMACS, respectively. There were no reexamination reports mentioning any concerns related to efficacy. DISCUSSION AND CONCLUSION: PMACS should not be imposed only because of limited dosing experience in Japan at the premarketing stage. Rather, PMACS should focus on (1) collection of safety data (not efficacy), (2) necessity of distribution control, and/or (3) collection of case details for drugs with a limited treated population. PMACS also has the potential to be utilized in the EU and the United States, as their regulatory frameworks are acceptable for PMACS. Naglazyme (galsulfase) is a case where the PMACS-like studies have been required in each region. PLAIN LANGUAGE SUMMARY: Effectiveness of data collection for all patients who receive a new drug as a safety measure in Japan: Introduction:: In Japan, a drug company is obligated to conduct data collection after a new drug launch as an approval condition. The obligation is a unique Japanese requirement where a company must collect data from all patients receiving the drug in Japan in cooperation with hospitals. This is expected to contribute to intensive data collection and better drug distribution control and could potentially be useful in countries beyond Japan. However, no clear criteria have been established for decision making, despite the significant burden for companies and hospitals. Therefore, this study aimed to investigate the impact of the obligation on safety measures and efficacy data collection and propose a potentially improved drug scope to impose the obligation.Materials and Methods:: Reexamination of reports issued by the Pharmaceuticals and Medical Devices Agency between 2017-2019.Results:: More than half (57%) of the included drugs had 'Limited dosing experience in Japan' as a reason for the obligation being required. However, regulatory order to change drug label, an action based on safety signal identification, was imposed on 33% and 28% of drugs with and without the obligation, respectively. The means of the number of the label change orders were 2.23 and 2.14 for drugs with and without obligation, respectively. Meanwhile, some drugs were highlighted as potential factors for better application of the obligation.Conclusion:: According to these results, the obligation should be imposed on a limited number of drugs by focusing not on dosing experience in Japan but on safety (not efficacy) data collection, necessity of distribution control, and/or collection of case details for drugs with a limited treated population. The obligation also has the potential to be utilized in the EU and the United States, as their regulatory frameworks are acceptable for the obligation.

[A CASE OF IgG4-RELATED DISEASE OF THE URETER DIAGNOSED BY TRANSVAGINAL ULTRASOUND-GUIDED BIOPSY].

IgG4-related disease (IgG4-RD) is a chronic inflammatory disorder that systemically causes tissue fibrosis due to infiltration of IgG4-positive plasma cells. Here, we reported a rare case of ureteral IgG4-RD that formed a nodular lesion and diagnosed by trans-vaginal ultrasound-guided needle biopsy.A 72-year-old woman presented with loss of appetite. The patient underwent Computed Tomography (CT), and she was pointed out the thickening of the left side bladder wall. So we performed a transurethral bladder biopsy under lumber anesthesia, but histopathological findings were almost normal. After that, she developed pyelonephritis repeatedly. We performed CT again. A CT revealed a nodular lesion at the end of her left ureter and hydronephrosis. The tumor was gradually getting larger. So we performed placement the ureteral stent for urinary tract obstruction. Left ureteral urine cytology was classIIIa. We performed transvaginal ultrasound needle biopsy for the nodular lesion of the left ureter. Histopathological findings showed infiltration of lymphocytes and fibrosis and infiltration of IgG4 positive plasma cells: the ratio of IgG4/IgG positive cells>0.6, 30>IgG4 positive plasma cells/high power field. The serum IgG and IgG4 levels were also elevated 1,943 and 210 mg/dl. We finally diagnosed IgG4-RD of the ureter and started using steroid for her treatment. One month later, the tumor had reduced after steroid treatment. The ureteral stent was removed. Since then, recurrent ureteral obstruction of the left ureter has not occurred.IgG4-RD of the ureter with nodular type is rare, and the imaging findings are similar to malignant tumors. Accurate diagnosis is very important to rule out malignancy. In our case, transvaginal needle biopsy was helpful to reach final diagnosis.

Promotion of Japan's participation in global clinical trials.

The number of global clinical trials including Japan is increasing but still much lower than those including the USA and Europe. The regulatory requirements for clinical trials have been harmonized among Japan, USA, and Europe, and the quality of clinical trials is kept high in these regions. Xofluza (baloxavir marboxil) for influenza approved in Japan under the SAKIGAKE Designation System is a good example of clinical trials including Japan. To include Japan in more global clinical trials, stakeholders should work more collaboratively, and increase the perception that clinical trials can be conducted appropriately and efficiently in Japan. Further measures for better management of clinical trials should also be developed. These would ultimately lead to improved benefits for patients with timely access to new drugs.

Usefulness of Implementing Comprehensive Pharmaceutical Care for Metastatic Renal Cell Carcinoma Outpatients Treated with Pazopanib.

BACKGROUND: Pazopanib is an effective treatment option for renal cell carcinoma (RCC). However, the therapy is often limited by the appearance of adverse events (AEs), including nausea/vomiting, hepatic impairment, hand-foot syndrome, diarrhea, hypertension and oral mucositis. Early management of AEs is, therefore, extremely important in order to maximize treatment outcomes. PATIENTS AND METHODS: This non-randomized controlled before-and-after study was carried out to evaluate the effectiveness of our comprehensive pharmaceutical interventions in 37 outpatients receiving pazopanib for RCC (experimental group). Data were compared with those obtained from 13 patients before the start of pharmaceutical intervention (control group). RESULTS: The incidence rates of grade 2 or more nausea and anorexia were significantly lower in the experimental, than in the control group (3% versus 38% for nausea, respectively, p=0.003; 8% versus 46% for anorexia, respectively, p=0.005). Importantly, non-adherence based on patient self-assessment was not observed with intervention (0% versus 38%, p<0.001). Consequently, the median total dose of pazopanib was increased by the intervention (72,600 versus 18,200 mg, p=0.002). Moreover, the median time to treatment failure was significantly longer with intervention than before (10.2 versus 1.7 months, HR=0.23, 95% CI=0.110-0.499, p<0.001). These findings suggest that our interventions are highly effective for enhancing treatment outcomes.

Early tumor shrinkage as a predictive factor of metastatic renal cell carcinoma in molecular targeted therapy: A single institutional study.

The aim of the present study was to investigate the impact of metastatic sites and early tumor shrinkage (eTS) as prognostic predictive factors of metastatic renal cell carcinoma (mRCC) in molecular targeted therapy. A total of 209 advanced RCC cases treated with sorafenib, sunitinib, axitinib, pazopanib, temsirolimus and everolimus from our single institution were included in the present study. Several known prognostic predictive factors, including metastatic sites and the rate of eTS, were analyzed by Kaplan-Meier survival estimate analysis followed by Cox's proportional hazards model analysis. eTS was measured by three independent physicians. Four metastatic sites in the liver, bone, lymph nodes and brain as well as greater eTS were identified as potential independent predictors of overall survival (OS) in several cohorts: i) Metastatic RCC (n=194); ii) metastatic clear cell RCC (n=119); and iii) mRCC patients with eTS data (n=127). In sub-analyses of patients treated with each 1st line tyrosine kinase inhibitor, eTS was identified as a potentially potent predictor of OS in patients treated with axitinib. The liver, bone, lymph nodes, brain metastases and eTS were identified as independent predictive factors of OS by analyzing a limited Japanese cohort.

Regulatory/Scientific Supports for Micro-, Small-, and Medium-Sized Enterprises (SMEs) With Medicinal Products Provided by the PMDA and EMA.

Micro-, small-, and medium-sized enterprises (SMEs) have been considered as key players who can bring innovative medicinal products and/or technologies into the field. However, they may need much regulatory/scientific supports to provide their products, technologies, or services to the market in a timely way. Both the Pharmaceuticals and Medical Devices Agency (PMDA) and the European Medicines Agency (EMA), regulatory authorities for medicinal products in Japan and the EU, respectively, have prepared supportive measures for SMEs from the early phase of product/technology development to the postmarketing phase. With respect to supports for SMEs, both agencies have provided similar SME-specific supportive activities, including routine administrative assistance, consultations about product development strategy from an early phase, as well as specific regulatory/scientific issues and fee incentives. In addition, there is a system to register SME status in the EU, which can be a tool for regulators to know how much potential SME-driven activities have and with whom they should communicate to provide necessary supports. Furthermore, as new technologies and novel products from SMEs are not limited to the region where they are developed, close communication about these topics between the PMDA and the EMA will contribute to advancing patients' access to necessary medicinal products.

Delayed nivolumab-induced hepatotoxicity during pazopanib treatment for metastatic renal cell carcinoma: An autopsy case.

INTRODUCTION: Pazopanib, a tyrosine kinase inhibitor, and nivolumab, an immune checkpoint inhibitor, are both considered to cause hepatotoxicity with different pathophysiology. We report a case in which a patient died of severe hepatotoxicity who was presumed to have been caused by the administration of nivolumab followed by pazopanib for metastatic renal cell carcinoma. CASE PRESENTATION: A 74-year-old male with metastatic renal cell carcinoma was treated with nivolumab as a third-line treatment. However, nivolumab was subsequently discontinued, as it caused severe thyroiditis. About 2 months after the final dose of nivolumab was administered, pazopanib was initiated as a fourth-line treatment. The patient suffered from lethal hepatic failure and died 18 days after the initiation of pazopanib treatment. An autopsy revealed that CD8-positive lymphocytes had infiltrated the thyroid gland and liver. CONCLUSION: The patient was considered to have died of severe hepatic failure due to the aggravation of mild nivolumab-induced immune-related hepatitis by pazopanib.

A Case of Renal Oncocytoma with Renal Venous Tumor Thrombus.

Renal oncocytoma is generally regarded as a benign renal tumor. We herein report a case of large renal oncocytoma with renal venous tumor thrombus. The patient may need to be carefully followed up because hematogenous metastasis may occur.

Effects of early diuretic response to carperitide in acute decompensated heart failure treatment: A single-center retrospective study.

BACKGROUND: Diuretic response is a strong predictor of outcome for admitted patients of acute decompensated heart failure (ADHF). However, little is known about the effects of early diuretic response to carperitide. METHODS: We retrospectively analyzed records of 85 patients hospitalized for ADHF who received carperitide as initial treatment and <40 mg furosemide during the early period. The eligible patients were divided into good diuretic responder (GR) group and poor diuretic responder (PR) group on the basis of median urinary volume. RESULTS: The PR group demonstrated older age, lower body mass index (BMI), lower estimated glomerular filtration rate, and higher blood urea nitrogen (BUN) level, left ventricular ejection fraction, and ß-blockers prescribed at baseline than the GR group. The incidence of worsening renal function (WRF) was significantly higher in the PR group than in the GR group. There was no correlation between early intravenous furosemide dose and urinary volume (Spearman correlation, ρ = 0.111, p = 0.312). Multivariate analysis showed that the statistically significant independent factors associated with poor diuretic response to carperitide were BMI (Odds ratio (OR) = 0.82, 95% confidence interval (CI) 0.68-0.94, p = 0.004) and BUN (OR = 1.07, 95%CI 1.01-1.15, p = 0.018). Kaplan-Meier analysis indicated a lower event-free rate in the PR group than in the GR group (log-rank, p = 0.007). CONCLUSIONS: BMI and BUN levels on admission were significant determinants of early poor diuretic response to carperitide. Early poor diuretic response to carperitide was associated with future poor outcomes.

Clinical Impact of Consolidative and Salvage Radiotherapy for Lymph Node Metastasis in Upper Urinary Tract Urothelial Carcinoma.

A 75-year-old Japanese male was referred to our institution for the evaluation of a left ureteral tumor in the ureterovesical junction. Computed tomography and pathologic examination under ureteroscopy revealed an invasive left ureteral urothelial carcinoma with left obturator nodal metastasis without distant metastasis. First, the patient underwent systemic chemotherapy (gemcitabine and cisplatin chemotherapy). We then performed left radical nephroureterectomy and extended lymph node dissection. Pathological examination revealed that the tumor was a high-grade invasive urothelial carcinoma with left common iliac and pelvic lymph node metastasis (pT3N2). Unfortunately, metastases appeared in the common iliac and para-aortic lymph nodes immediately after the operation; therefore, the previous first-line chemotherapy was readministered and second-line chemotherapy (gemcitabine and paclitaxel chemotherapy) was also performed. We also performed consolidative radiotherapy and salvage radiotherapy (boost, 20 Gy/10 fractions to the inferior para-aortic, and left common iliac regions containing swollen lymph nodes). The patient has shown no evidence of recurrence or metastasis even approximately 4 years after the initial diagnosis of advanced UUT-UC with lymph node metastasis. Our case suggests that consolidative or salvage radiotherapy combined with surgery and chemotherapy may provide clinical benefit for selected cases of advanced UUT-UC with lymph node metastasis.

What to Know About Medicines With New Active Ingredients Approved in FY 2016 / 2016 in Japan and EU: A Brief Comparison of New Medicines Approved in Japan and the EU in 2016.

The Pharmaceuticals and Medical Devices Agency (PMDA) in Japan and the European Medicines Agency (EMA) have a long-standing experience of reviews of new medicines, and they meet their target pre-market review periods. In FY 2016 / 2016, 112 and 83 new medicines were approved in Japan and EU, respectively. Out of these medicines, 41 and 27 medicines containing new active ingredients were approved with total pre-market review periods of 209 days and 428 days in Japan and EU, respectively. Approximately one-third of these medicines were reviewed by the Agencies in close timing, within 1 year between pre-market review applications in Japan and in EU. Taking into account the increasing number of global clinical trials and constant number of consultations or scientific advice related to global clinical trials in Japan, it is clear that the importance of the continuous, collaborative relationship between EMA and PMDA is more and more crucial, as it does facilitate close and timely exchange of information and opinions on products and technologies under development. There already are effective collaborative frameworks between PMDA and EMA in addition to daily communication, and our findings support the development and best use of regulatory tools such as consultation services and scientific advice/protocol assistance for the benefit of the pharmaceutical industry but mostly of patients.

A Comparison of PMDA and EMA Consultations for Regulatory and Scientific Matters in Drugs and Regenerative Medicine Products.

The Pharmaceuticals and Medical Devices Agency (PMDA) and the European Medicines Agency (EMA) have provided a wide range of regulatory and scientific consultation menus to cover any development stage of drugs and regenerative medicine products, respectively. The current study compares Consultations by PMDA and Scientific Advice by EMA in terms of consultation types, consultation performances, and specific consultation procedures with timelines. Each agency sets intensive but highly professional procedures and timelines in order to provide sufficient advice in a timely manner. Both agencies complete the consultation process for approximately 3 months while an application is reviewed by experts and close communication with the applicant is provided. Although PMDA and EMA have some differences of approaches to provide well-considered scientific opinions as quickly as possible, both agencies have made efforts to support the development of better products for patients. Sharing technical insights through consultation experiences will contribute to earlier access of patents to new products in both Japan and the EU.

The Current Status of Sakigake Designation in Japan, PRIME in the European Union, and Breakthrough Therapy Designation in the United States.

Following the Breakthrough Therapy Designation system in 2012 in the United States, the Sakigake Designation was introduced in 2015 in Japan, and PRIME (PRIority MEdicines) was started in 2016 in the European Union. Each system aims at giving patients better access to innovative drugs and regenerative medicine products by providing product developers with generous regulatory and scientific support from an early development stage. So far, the designation systems have operated independently in each region, and no products with the same indication have been designated commonly under the 3 designation systems. However, no designation system excludes a product designated under another system, which allows the possibility of an applicant to seek all 3 designations; this may happen in the near future. Therefore, an understanding of the current situation under each designation system will contribute to effective operation of each system as well as identification of further collaborative activities between the European Medicines Agency; Japan's Ministry of Health, Labour and Welfare/Pharmaceuticals and Medical Devices Agency; and the United States Food and Drug Administration. Such collaborations can be successful because these organizations have already established a close relationship through international activities such as the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and the International Coalition of Medicines Regulatory Authorities (ICMRA).

Blockade of senescence-associated microRNA-195 in aged skeletal muscle cells facilitates reprogramming to produce induced pluripotent stem cells.

The low reprogramming efficiency in cells from elderly patients is a challenge that must be overcome. Recently, it has been reported that senescence-associated microRNA (miR)-195 targets Sirtuin 1 (SIRT1) to advance cellular senescence. Thus, we hypothesized that a blockade of miR-195 expression could improve reprogramming efficiency in old skeletal myoblasts (SkMs). We found that miR-195 expression was significantly higher in old SkMs (24 months) isolated from C57BL/6 mice as compared to young SkMs (2 months, 2.3-fold). Expression of SIRT1 and telomerase reverse transcriptase (TERT) was downregulated in old SkMs, and transduction of old SkMs with lentiviral miR-195 inhibitor significantly restored their expression. Furthermore, quantitative in situ hybridization analysis demonstrated significant telomere elongation in old SkMs transduced with anti-miR-195 (1.7-fold increase). It is important to note that blocking miR-195 expression markedly increased the reprogramming efficiency of old SkMs as compared to scramble (2.2-fold increase). Transduction of anti-miR-195 did not alter karyotype or pluripotency marker expression. Induced pluripotent stem cells (iPSCs) from old SkMs transduced with anti-miR-195 successfully formed embryoid bodies that spontaneously differentiated into three germ layers, indicating that deletion of miR-195 does not affect pluripotency in transformed SkMs. In conclusion, this study provided novel evidence that the blockade of age-induced miR-195 is a promising approach for efficient iPSC generation from aging donor subjects, which has the potential for autologous transplantation of iPSCs in elderly patients.

Plasma endoglin as a marker to predict cardiovascular events in patients with chronic coronary artery diseases.

Recent clinical studies have revealed that the expression of endoglin, an accessory protein for the TGF-ß receptor, is increased in patients with atherosclerotic diseases. The plasma endoglin level is thought to represent endothelial activation, inflammation, and senescence. To clarify the significance of plasma endoglin in chronic coronary artery disease. Human umbilical vein endothelial cells (HUVECs) were cultured to examine changes in soluble endoglin (s-endoglin) levels caused by atherogenic stimulation in vitro. We studied 318 patients with stable coronary artery disease who underwent a successful percutaneous coronary intervention (PCI). Patients with acute coronary syndrome were excluded. Major adverse cardiovascular events (MACE) were congestive heart failure, acute myocardial infarction, stroke, and sudden cardiac death. All patients were followed-up to examine MACE after the procedure. We confirmed that the levels of s-endoglin was increased in the culture medium of HUVECs by senescence, tumor necrosis factor-α and hydrogen peroxide. In a clinical study, mean follow-up period was 1055 ± 612 days (49-2136 days) with 27 incidents of MACE (8.5%). We divided patients into three groups according to the plasma s-endoglin levels. Kaplan-Meier curves revealed that the highest endoglin group had a significantly higher MACE rate than the lowest endoglin group (log-rank test, p = 0.009). A Cox proportional hazards model showed that chronic kidney disease, left ventricular ejection fraction and s-endoglin level were significant factors to predict MACE. Plasma endoglin could be a marker to predict cardiovascular events in patients with chronic coronary artery disease after PCI.

Granzyme B as a novel factor involved in cardiovascular diseases.

Apoptosis plays an important role in cardiovascular diseases such as atherosclerosis, ischemic heart disease, and congestive heart failure. Previous studies have demonstrated that oxidative stress, physiological stress, and inflammatory cytokines such as tumor necrosis factor and Fas ligand are involved in apoptosis of cardiovascular system. We demonstrate that another apoptosis-related pathway, i.e. granzyme B/perforin system is involved in cardiovascular diseases. Expression of granzyme B, a member of serine protease family is increased in acute coronary syndrome, coronary artery disease with end-stage renal disease, and subacute stage of acute myocardial infarction. Although granzyme B is extensively researched in immunological disorders, the role of granzyme B/perforin system was not clear in the cardiovascular field. In addition, little is known regarding the inhibition of granzyme B system in the clinical situation. In this review we demonstrate recent findings of granzyme B in cardiovascular diseases and possible therapeutic applications of inhibiting the granzyme B/perforin system.