Extramedullary Myeloid Leukemia in the Setting of a Myeloproliferative Neoplasm.

Extramedullary acute myeloid leukemia (EML), also known as myeloid sarcoma (MS), is an extramedullary solid mass derived from the proliferation of myeloblasts outside of the bone marrow. EML can present independently or concurrently with intramedullary acute myeloid leukemia (iAML). It can happen de novo or secondary to iAML, myeloproliferative neoplasm (MPN), chronic myelomonocytic leukemia (CMML), or myelodysplastic syndrome (MDS). We present a 57-year-old female with a history of Janus kinase 2 (JAK-2)-positive essential thrombocythemia (ET) evolving into EML in the setting of a persistent TP53 mutation. We discuss the essential diagnostic studies including tissue biopsy and fluorodeoxyglucose positron emission tomography/computed tomography (F-FDG PET/CT) imaging. We also investigate the significance of cytogenetics and next-generation sequencing (NGS) along with the unique pathogenesis, treatment and prognostic implications.

Tumor-Derived Extracellular Vesicles Predict Clinical Outcomes in Oligometastatic Prostate Cancer and Suppress Antitumor Immunity.

PURPOSE: SABR has demonstrated clinical benefit in oligometastatic prostate cancer. However, the risk of developing new distant metastatic lesions remains high, and only a minority of patients experience durable progression-free response. Therefore, there is a critical need to identify which patients will benefit from SABR alone versus combination SABR and systemic agents. Herein we provide, to our knowledge, the first proof-of-concept of circulating prostate cancer-specific extracellular vesicles (PCEVs) as a noninvasive predictor of outcomes in oligometastatic castration-resistant prostate cancer (omCRPC) treated with SABR. METHODS AND MATERIALS: We analyzed the levels and kinetics of PCEVs in the peripheral blood of 79 patients with omCRPC at baseline and days 1, 7, and 14 after SABR using nanoscale flow cytometry and compared with baseline values from cohorts with localized and widely metastatic prostate cancer. The association of omCRPC PCEV levels with oncological outcomes was determined with Cox regression models. RESULTS: Levels of PCEVs were highest in mCRPC followed by omCRPC and were lowest in localized prostate cancer. High PCEV levels at baseline predicted a shorter median time to distant recurrence (3.5 vs 6.6 months; P = .0087). After SABR, PCEV levels peaked on day 7, and median overall survival was significantly longer in patients with elevated PCEV levels (32.7 vs 27.6 months; P = .003). This suggests that pretreatment PCEV levels reflect tumor burden, whereas early changes in PCEV levels after treatment predict response to SABR. In contrast, radiomic features of 11C-choline positron emission tomography and computed tomography before and after SABR were not predictive of clinical outcomes. Interestingly, PCEV levels and peripheral tumor-reactive CD8 T cells (TTR; CD8+ CD11ahigh) were correlated. CONCLUSIONS: This original study demonstrates that circulating PCEVs can serve as prognostic and predictive markers to SABR to identify patients with "true" omCRPC. In addition, it provides novel insights into the global crosstalk, mediated by PCEVs, between tumors and immune cells that leads to systemic suppression of immunity against CRPC. This work lays the foundation for future studies to investigate the underpinnings of metastatic progression and provide new therapeutic targets (eg, PCEVs) to improve SABR efficacy and clinical outcomes in treatment-resistant CRPC.

Calibration and standardization of extracellular vesicle measurements by flow cytometry for translational prostate cancer research.

Extracellular vesicles (EVs) are microscopic particles released naturally in biofluids by all cell types. Since EVs inherits genomic and proteomic patterns from the cell of origin, they are emerging as promising liquid biomarkers for human diseases. Flow cytometry is a popular method that is able to detect, characterize and determine the concentration of EVs with minimal sample preparation. However, the limited awareness of the scientific community to utilize standardization and calibration methods of flow cytometers is an important roadblock for data reproducibility and inter-laboratory comparison. A significant collaborative effort by the Extracellular Vesicle Flow Cytometry Working Group has led to the development of guidelines and best practices for using flow cytometry and reporting data in a way to improve rigor and reproducibility in EV research. At first look, standardization and calibration of flow cytometry for EV detection may seem burdensome and technically challenging for non-academic laboratories with limited technical training and knowledge in EV flow cytometry. In this study, we build on prior research efforts and provide a systematic approach to evaluate the performance of a high sensitivity flow cytometer (herein Apogee A60-Micro Plus) and fine-tune settings to improve detection sensitivity for EVs. We performed calibration of our flow cytometer to generate data with comparable units (nanometers, MESF). Finally, we applied our optimized protocol to measure the concentrations of prostate-derived EVs in healthy individuals and prostate cancer patients. In conclusion, our proof-of-feasibility study can serve as a scientific and technical framework for other groups motivated in using flow cytometry for EV research.

Improved post-ASCT survival of relapsed/refractory classical Hodgkin lymphoma patients in the era of novel agents.

Utilization of novel agents such as brentuximab vedotin (BV) and check-point inhibitors (CI) has increased in patients with relapsed/refractory (r/r) classical Hodgkin Lymphoma (cHL). We conducted a retrospective study of 209 patients who had ASCT for r/r cHL at our institution and compared outcomes of those who had ASCT from 2010-2018 (cohort 2, n = 110) with those who had ASCT between 2000 and 2009 (cohort 1, n = 99). The median OS was 7.6 years for cohort 1 [HR 2.08; 95% CI 1.14-3.80; p = 0.017] and not reached for cohort 2; with 4-year improved OS difference of 15% (80% vs 65%) in cohort 2 vs cohort 1. The median PFS of cohort 1 was 30 months vs 39 months for cohort 2[HR 1.24; 95% CI 0.82-1.88; p = 0.3]. This study highlights improved OS of r/r cHL patients who have received ASCT in the novel agent era due to the exposure to agents such as BV and CIs.

Coronavirus Disease 2019-Associated Bilateral Massive Pulmonary Emboli Caused Death in a Healthy 35-Year-Old Patient.

Coronavirus disease 2019 (COVID-19) infection was first reported in December 2019. Within three months, the virus caused a global pandemic that has affected the whole world's dynamics. Many causes of death due to COVID-19 infection have been identified, involving but not limited to atypical acute respiratory distress syndrome, hypercoagulability, renal failure, and a proinflammatory cytokine storm, often associated with multiorgan failure. We report the case of a young, previously healthy patient who developed massive pulmonary emboli due to COVID-19 infection, resulting in death.

Tel1ATM and Rad3ATR kinases promote Ccq1-Est1 interaction to maintain telomeres in fission yeast.

The evolutionarily conserved shelterin complex has been shown to play both positive and negative roles in telomerase regulation in mammals and fission yeast. Although shelterin prevents the checkpoint kinases ATM and ATR from fully activating DNA damage responses at telomeres in mammalian cells, those kinases also promote telomere maintenance. In fission yeast, cells lacking both Tel1 (ATM ortholog) and Rad3 (ATR ortholog) fail to recruit telomerase to telomeres and survive by circularizing chromosomes. However, the critical telomere substrate(s) of Tel1(ATM) and Rad3(ATR) was unknown. Here we show that phosphorylation of the shelterin subunit Ccq1 on Thr93, redundantly mediated by Tel1(ATM) and/or Rad3(ATR), is essential for telomerase association with telomeres. In addition, we show that the telomerase subunit Est1 interacts directly with the phosphorylated Thr93 of Ccq1 to ensure telomere maintenance. The shelterin subunits Taz1, Rap1 and Poz1 (previously established inhibitors of telomerase) were also found to negatively regulate Ccq1 phosphorylation. These findings establish Tel1(ATM)/Rad3(ATR)-dependent Ccq1 Thr93 phosphorylation as a critical regulator of telomere maintenance in fission yeast.