Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare disorder caused by severe ADAMTS13 deficiency [1]. Between 2001 and 2020, only 226 patients with cTTP were reported worldwide [2]. As of 2021, we identified 67 patients with cTTP in Japan alone [3,4]. Theoretically, patients with cTTP are at a high risk for thrombosis due to COVID-19 infection. This is attributed to the increase in plasma von Willebrand factor levels and decrease in plasma ADAMTS13 activity with disease severity in patients with COVID-19 infection [5].Recently, Dykes et al. reported a case in which COVID-19 vaccination exacerbated the cTTP condition [6]. This patient developed an acute ischemic stroke with mild thrombocytopenia shortly after receiving the COVID-19 vaccine (mRNA-1273). To date, over 10 cases of de novo immune TTP have been reported following COVID-19 vaccination worldwide [7,8]. However, there have been no other reports of COVID-19 vaccine-induced flare of cTTP. In Japan, two types of mRNA-based vaccines, BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna), are available. We administered a questionnaire survey in Japanese patients with cTTP regarding the adverse events after vaccination in October 2021, when double doses of vaccinations were almost completed in Japanese applicants who were ≥ 12 years of age.The questionnaire was sent to physicians who were treating patients with cTTP. Of the 67 Japanese patients with cTTP, 58 were alive and 6 were under 12 years of age. According to the questionnaire survey of 42 patients, 38 had completed vaccination twice, and 4 patients had not * Masanori Matsumoto

Plasma exchange (PEX) using fresh frozen plasma has considerably reduced the mortality rate in patients with immunemediated thrombotic thrombocytopenic purpura (iTTP). However, some patients still do not survive even with treatment, but little information is available regarding which treatment these patients received. This study was conducted to obtain this information in 240 patients who met the current iTTP diagnostic criteria and completed at least 30 days of follow-up except for deceased cases. These patients were divided into three groups: survivors (n = 195), TTP-related deaths (n = 32), and other cause of death (n = 13). In the TTP-related death group, 26 of 32 patients experienced sudden death, mostly following radical hypotension and bradycardia. The median follow-up time after admission was 5.0 days, and the median number of PEX sessions was 2.5. Nine patients underwent autopsy and had cardiac microvascular thrombi in arterioles. Levels of lactate dehydrogenase, total bilirubin, serum creatinine, and d-dimer were significantly higher in the TTP-related death group than in the survivors group. Frequent PEX (> 20 sessions) was not associated with TTP-related death. In the acute phase of iTTP, patients with substantial organ damage caused by microthrombi have a greater mortality risk, even after just a few PEX sessions.

Summary Ectopic ACTH (adrenocorticotrophic hormone) syndrome (EAS) is rarely associated with small-cell lung cancer (SCLC). Although chemotherapy is initially effective for SCLC, complicated EAS scarcely improves. Recently, immune checkpoint inhibitors have been used to treat SCLC. Atezolizumab plus chemotherapy for SCLC improved progression-free survival compared to conventional chemotherapy. However, little has been reported on the efficacy of the combination therapy for SCLC with EAS. We report a 72-year-old male who presented with 4-week history of leg oedema, proximal myopathy, weight loss, and worsened symptoms of diabetes and hypertension. Laboratory findings revealed hypokalaemia, increased plasma ACTH, and serum cortisol levels. Cortisol levels were not suppressed by the high-dose dexamethasone test. Chest and abdominal CT revealed a right lower lobe tumour with multiple metastases on the hilar lymph nodes, liver, lumbar spine, and bilateral enlarged adrenal glands. The patient was diagnosed with stage 4B SCLC with EAS. Hypercortisolaemia was then treated with metyrapone and atezolizumab plus chemotherapy, which was started for SCLC. After 10 days, the tumour shrank noticeably, and the ACTH level drastically decreased concomitantly with low cortisol levels with symptoms of fever, appetite loss, and general fatigue. Hydrocortisone treatment was initiated, and the symptoms resolved immediately. We describe a case of SCLC with EAS treated with atezolizumab plus chemotherapy, presenting with adrenal insufficiency. Close observation is required for patients with adrenal insufficiency receiving atezolizumab plus chemotherapy because of its stronger effect. Furthermore, advances in cancer therapy and care for endocrine paraneoplastic syndrome needs to be adapted. Learning points The immune checkpoint inhibitor atezolizumab has recently been approved for the treatment of small-cell lung cancer (SCLC). Approximately 1–6% of tumour ectopically produce ACTH and cause ectopic ACTH syndrome (EAS) as an endocrine paraneoplastic syndrome. The use of combined chemotherapy and atezolizumab in the ectopic ACTH syndrome secondary to small-cell lung cancer may cause a precipitous fall in circulating ACTH/cortisol, resulting in symptomatic adrenal insufficiency The advances in cancer therapy and treatment for endocrine paraneoplastic syndrome need to be adapted.

Introduction Severe COVID‐19 is associated with an important increase of von Willebrand factor and mild lowering of ADAMTS13 activity that may, in the presence of a strong inflammatory reaction, increase the risk of acute thrombotic thrombocytopenic purpura (TTP). Although acute episodes of immune‐mediated TTP associated with COVID‐19 or SARS‐CoV‐2 vaccination have been reported, data about clinical evolution of hereditary TTP (hTTP) during the pandemic are scarce. Method We conducted a survey among adult patients of the International Hereditary TTP Registry about SARS‐CoV‐2 vaccination, COVID‐19, and occurrence of acute hTTP episodes. Results Of 122 adult hTTP patients invited to participate, 86 (70.5%) responded. Sixty‐five had been vaccinated (75.6%), of which 14 had received in addition a booster, resulting in 139 individual vaccine shots. Although vaccinations in patients on plasma prophylaxis were done within 1 week of the last plasma infusion, all 23 patients treated with plasma on demand were vaccinated without prior plasma infusions. One patient on uninterrupted weekly plasma infusions presented within 3 days from his second vaccination with neurological symptoms and computed tomography scan 9 days later showed subacute ischemic/hemorrhagic frontal lobe infarction. A second male patient developed acute myocarditis after his second dose of mRNA‐1273 vaccine. Twelve (14%) patients had COVID‐19, associated with an acute hTTP episode in three of them: one patient had a transient ischemic attack, one a stroke, and a pregnant woman was hospitalized to intensify plasma treatment. Discussion The risk of an acute episode triggered by COVID‐19 seems higher than following vaccination in hTTP patients, who can be safely vaccinated against SARS‐CoV‐2.

While the term “social investment” is hardly ever used in Japan, “investment in tomorrow” and “investment in people” have been repeatedly used to justify policy expansion for childcare and human resource development since the first decade of the 21st century. Although Japan is shifting its spending patterns, it is necessary to look into policy development and discourse in order to understand its qualitative features. This chapter argues that a stratified social investment was quietly diffused in Japan. Despite the expansion of social spending on the younger generation, stratification progressed due to the heavy reliance on private spending and indifference to universal access and redistribution. Government papers show that the typical reasoning behind social investment policies is missing. The protagonists of social investment in Japan were policymakers and bureaucrats concerned with a declining and aging population. Family policy was expanded to meet the needs of middle-class, dual-earner households. The ruling Liberal Democratic Party, however, was an antagonist since it relied on support from the religious right, which holds an anti-feminism ideology. Big business acted as both a protagonist and an antagonist: It is an ardent advocator of human resource development, but it is opposed to spending its resources on skill formation. Such a constellation of actors has shaped stratified social investment in Japan.