Research Spotlight

Fuji, T., Y. Umeda, A. Nyuya, F. Taniguchi, T. Kawai, K. Yasui, T. Toshima, K. Yoshida, T. Fujiwara, A. Goel and T. Nagasaka (2019). “Detection of circulating microRNAs with Ago2 complexes to monitor the tumor dynamics of colorectal cancer patients during chemotherapy.” Int J Cancer 144(9): 2169-2180.

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Because of the different forms of circulating miRNAs in plasma, Argonaute2 (Ago2)-miRNAs and extracellular vesicles (EV-miRNAs), we examined the two forms of extracellular miRNAs in vitro and developed a unique methodology to detect circulating Ago2-miRNAs in small volumes of plasma. We demonstrated that Ago2-miR-21 could be released into the extracellular fluid by active export from viable cancer cells and cytolysis in vitro. As miR-21 and miR-200c were abundantly expressed in both metastatic liver sites and primary lesions, we evaluated Ago2-miR-21 as a candidate biomarker of both active export and cytolysis while Ago2-miR-200c as a biomarker of cytolysis in plasma obtained from colorectal cancer (CRC) patients before treatment and in a series of plasma obtained from CRC patients with liver metastasis who received systemic chemotherapy. The measurement of Ago2-miR-21 allowed us to distinguish CRC patients from subjects without CRC. The trend in DeltaCt values for Ago2-miR-21 and -200c during chemotherapy could predict tumor response to ongoing treatment. Thus, capturing circulating Ago2-miRNAs from active export can screen patients with tumor burdens, while capturing them from passive release by cytolysis can monitor tumor dynamics during chemotherapy treatment.

Forero-Torres, A., R. Ramchandren, A. Yacoub, M. S. Wertheim, W. J. Edenfield, P. Caimi, M. Gutierrez, L. Akard, C. Escobar, J. Call, D. Persky, S. Iyer, D. J. DeMarini, L. Zhou, X. Chen, F. Dawkins and T. J. Phillips (2019). “Parsaclisib, a potent and highly selective PI3Kdelta inhibitor, in patients with relapsed or refractory B-cell malignancies.” Blood 133(16): 1742-1752.

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This phase 1/2 study assessed parsaclisib (INCB050465), a next-generation, potent, and highly selective phosphatidylinositol 3-kinase delta (PI3Kdelta) inhibitor, in patients with relapsed or refractory B-cell malignancies, alone or in combination with a Janus kinase 1 inhibitor (itacitinib) or chemotherapy (rituximab, ifosfamide, carboplatin, and etoposide). Seventy-two patients received parsaclisib monotherapy (5-45 mg once daily). Expansion doses were 20 and 30 mg once daily; intermittent dosing at 20 mg (once daily for 9 weeks, then once weekly) was explored. No dose-limiting toxicities were identified, and maximum tolerated dose was not reached. Most common nonhematologic treatment-emergent adverse events (TEAEs) were diarrhea/colitis (36%), nausea (36%), fatigue (31%), and rash (31%). Grade 3/4 neutropenia occurred in 19% of patients. Serious TEAEs (>2 patients) were diarrhea/colitis (n = 9), pyrexia (n = 4), hypotension (n = 3), and sepsis (n = 3). Aspartate and alanine transaminase elevations occurring before treatment discontinuation were grade 1, except 1 grade 3 event each, secondary to sepsis. Two patients experienced 3 fatal parsaclisib-unrelated TEAEs (respiratory failure; respiratory failure and sepsis). In non-Hodgkin lymphoma (NHL), objective response rates to monotherapy were 71% in follicular lymphoma, 78% in marginal zone lymphoma, 67% in mantle cell lymphoma, and 30% in diffuse large B-cell lymphoma; 93% of responses occurred at first assessment ( approximately 9 weeks). Parsaclisib has demonstrated antitumor activity in relapsed or refractory B-cell NHL with the potential for improved long-term patient outcomes. Phase 2 studies in relapsed or refractory B-cell NHL subtypes are ongoing. This trial was registered at www.clinicaltrials.gov as #NCT02018861.

Dewan, P., P. S. Jhund, L. Shen, M. C. Petrie, W. T. Abraham, M. Atif Ali, C. H. Chen, A. S. Desai, K. Dickstein, J. Huang, S. Kiatchoosakun, K. S. Kim, L. Kober, W. T. Lai, Y. Liao, U. M. Mogensen, B. H. Oh, M. Packer, J. L. Rouleau, V. Shi, A. S. Sibulo, Jr., S. D. Solomon, P. Sritara, K. Swedberg, H. Tsutsui, M. R. Zile and J. J. V. McMurray (2019). “Heart failure with reduced ejection fraction: comparison of patient characteristics and clinical outcomes within Asia and between Asia, Europe and the Americas.” Eur J Heart Fail 21(5): 577-587.

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AIMS: Nearly 60% of the world’s population lives in Asia but little is known about the characteristics and outcomes of Asian patients with heart failure with reduced ejection fraction (HFrEF) compared to other areas of the world. METHODS AND RESULTS: We pooled two, large, global trials, with similar design, in 13 174 patients with HFrEF (patient distribution: China 833, India 1390, Japan 209, Korea 223, Philippines 223, Taiwan 199 and Thailand 95, Western Europe 3521, Eastern Europe 4758, North America 613, and Latin America 1110). Asian patients were younger (55.0-63.9 years) than in Western Europe (67.9 years) and North America (66.6 years). Diuretics and devices were used less, and digoxin used more, in Asia. Mineralocorticoid receptor antagonist use was higher in China (66.3%), the Philippines (64.1%) and Latin America (62.8%) compared to Europe and North America (range 32.8% to 49.6%). The rate of cardiovascular death/heart failure hospitalization was higher in Asia (e.g. Taiwan 17.2, China 14.9 per 100 patient-years) than in Western Europe (10.4) and North America (12.8). However, the adjusted risk of cardiovascular death was higher in many Asian countries than in Western Europe (except Japan) and the risk of heart failure hospitalization was lower in India and in the Philippines than in Western Europe, but significantly higher in China, Japan, and Taiwan. CONCLUSION: Patient characteristics and outcomes vary between Asia and other regions and between Asian countries. These variations may reflect several factors, including geography, climate and environment, diet and lifestyle, health care systems, genetics and socioeconomic influences.

Devarbhavi, H., S. K. Asrani and P. S. Kamath (2019). “Reply to: “Alcohol-associated liver disease, not hepatitis B, is the major cause of cirrhosis in Asia”.” J Hepatol 70(5): 1033.

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A recent multi-centre study from India with the specific aim of determining the aetiology of chronic liver diseases among new patients seen in an inpatient setting (n = 13,014) concluded that HBV was the most common cause of chronic liver disease (33.3%), followed by HCV (21.6%), alcohol (17.3%), and non-alcoholic fatty liver disease (12.8%). When stratified by presence of cirrhosis (n = 4,413), alcohol was the most common cause (34.3%); a significant limitation of this data was that more than 99% of patients with cirrhosis were decompensated and may not accurately reflect the burden of cirrhosis. Further there was significant regional heterogeneity within different regions of India; viral hepatitis B and C being more common in northern and eastern regions compared to southern regions where alcohol was more common. With increasing global coverage of universal vaccination against hepatitis B in India and the easy availability and affordability of direct-acting antivirals including provision for free treatments for hepatitis C in certain groups and regions, the burden of liver disease from B and C is expected to decrease in the future. Liver disease from alcohol is likely to increase in India in the absence of government policies aimed at reducing alcohol consumption. (Excerpt from text, responding to commentary on authors’ study, Burden of liver diseases in the world. J Hepatol 2019; 70(1): pp. 151-171.)

Clark, R. H. and V. N. Tolia (2019). “The Use of Oxygen at Discharge: Is It Safe? Is It Effective?” Pediatrics 143(5): e20190372.

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Oxygen is one of the most commonly used therapies in premature infants. Like all drugs, it can be both therapeutic and toxic. In his 2004 commentary, “A Cautionary Tale About Supplemental Oxygen: The Albatross of Neonatal Medicine,” Dr Silverman provided us with an important history lesson: what we believe to be true is not always true, and with great intent, we can do great harm. Over the last decade, clinical studies of oxygen dosing and oxygen saturation targets5 have only increased the intensity of Dr Silverman’s message. Although recommendations regarding oxygen use in the delivery room and in the NICU have changed on the basis of clinical trials and careful analysis of the evidence, the evidence regarding oxygen use after discharge is far less clear, and variation in practice is endemic. In their article “Home Oxygen and 2-Year Outcomes of Preterm Infants With Bronchopulmonary Dysplasia [BPD],” DeMauro et al have added to our understanding of the efficacy and safety of this practice. Many clinicians believe that home oxygen therapy improves growth, reduces pulmonary complications, and promotes better neurodevelopmental outcomes, although none of these beliefs are supported by high-quality evidence. In this propensity score–matched cohort study, DeMauro et al conclude that “postdischarge oxygen was associated with marginally improved growth and increased resource use but no difference in neurodevelopmental outcomes.” (Excerpt from text of this commentary, p. e20190372: 1.)