Intimal sarcoma is an extremely rare, life-threatening malignant neoplasm. Murine double minute 2 (MDM2) amplification is observed in >70% of intimal sarcomas. Milademetan, an MDM2 inhibitor, may provide clinical benefit in this patient population. We conducted a phase Ib/II study in patients with MDM2-amplified, wild-type TP53 intimal sarcoma as a substudy of a large nationwide registry for rare cancers in Japan. Milademetan (260 mg) was administered orally once daily for 3 days every 14 days, twice in a 28-day cycle. Of 11 patients enrolled, 10 were included in the efficacy analysis. Two patients (20%) showed durable responses for >15 months. Antitumor activity correlated with TWIST1 amplification (P = 0.028) and negatively with CDKN2A loss (P = 0.071). Acquired TP53 mutations were detected in sequential liquid biopsies as a novel exploratory resistance mechanism to milademetan. These results suggest that milademetan could be a potential therapeutic strategy for intimal sarcoma. Significance: Strategies to optimize outcomes could include the use of new biomarkers (TWIST1 amplification and CDKN2A loss) to select patients with MDM2-amplified intimal sarcoma who might benefit from milademetan and combination with other targeted treatments. Sequential liquid biopsy of TP53 can be used to evaluate disease status during treatment with milademetan. See related commentary by Italiano, p. 1765. This article is highlighted in the In This Issue feature, p. 1749

We report the case of a 68-year-old woman with acute thrombotic thrombocytopenic purpura (TTP) that developed after pneumococcal vaccination. She was found in a confusional state with high fever 15 days after vaccination. Laboratory data showed hemolytic anemia and thrombocytopenia, and blood smear showed fragmented erythrocytes. TTP was diagnosed based on the clinical presentation, and was subsequently confirmed by the absence of ADAMTS13 activity and the presence of inhibitor against ADAMTS13 in serum. She was successfully treated using plasma exchange and corticosteroids, and no recurrence has been identified. This appears to represent the first report of TTP following pneumococcal vaccination.

The introduction of combined antiretroviral therapy (ART) has reduced the mortality of patients with human immunodeficiency virus‐1 infection worldwide. However, malignant lymphoma is a severe and frequent complication seen in patients with acquired immunodeficiency syndrome (AIDS). The diagnostic criteria for some categories of AIDS‐related lymphoma were revised in the World Health Organization International Classification of Lymphoma, fourth edition. The purpose of this study was to assess the clinicopathological characteristics of Japanese patients with AIDS‐related lymphoma according to the revised classification. In this retrospective study, 207 AIDS‐related lymphoma cases diagnosed between 1987 and 2012 in Japan were subjected to histological subtyping and clinicopathological analyses. Diffuse large B‐cell lymphoma (DLBCL) was the predominant histological subtype throughout the study period (n = 104, 50%). Among the DLBCL cases, 24% were of the germinal center (GC) type and 76% were of the non‐GC type. Non‐GC‐type cases showed a significantly lower 1‐year survival rate (43%) than the GC‐type cases (82%). Cases of Burkitt lymphoma (n = 57, 28%), plasmablastic lymphoma (n = 16, 8%), primary effusion lymphoma (n = 9, 4%), Hodgkin lymphoma (n = 8, 4%), and large B‐cell lymphoma arising in Kaposi sarcoma‐associated herpesvirus‐associated multicentric Castleman disease (n = 2, 1%) were also observed. Hodgkin lymphoma was more common in patients receiving ART (11.1%) than in ART‐naïve patients (1.4%). Statistical analyses identified CD10 negativity, BCL‐6 negativity, Epstein–Barr virus positivity, and Kaposi sarcoma‐associated herpesvirus positivity as risk factors for poor prognosis. This information will help in the early diagnosis of lymphoma in patients with AIDS.

PAX5 is a transcription factor that is required for the development and maintenance of B cells. Promyelocytic leukemia (PML) is a tumor suppressor and proapoptotic factor. The fusion gene PAX5-PML has been identified in acute lymphoblastic leukemia with chromosomal translocation t(9;15)(p13;q24). We have reported previously that PAX5-PML dominant-negatively inhibited PAX5 transcriptional activity and impaired PML function by disrupting PML nuclear bodies (NBs). Here we demonstrated the leukemogenicity of PAX5-PML by introducing it into normal mouse pro-B cells. Arrest of differentiation was observed in PAX5-PML-introduced pro-B cells, resulting in the development of acute lymphoblastic leukemia after a long latency in mice. Among the transactivation targets of PAX5, B cell linker protein (BLNK) was repressed selectively in leukemia cells, and enforced BLNK expression abrogated the differentiation block and survival induced by PAX5-PML, indicating the importance of BLNK repression for the formation of preleukemic state. We also showed that PML NBs were intact in leukemia cells and attributed this to the low expression of PAX5-PML, indicating that the disruption of PML NBs was not required for the PAX5-PML-induced onset of leukemia. These results provide novel insights into the molecular mechanisms underlying the onset of leukemia by PAX5 mutations.