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Background & Aims Hepatocellular carcinoma (HCC) can be treated effectively if detected at an early stage. Recommended surveillance strategies for at-risk patients include ultrasound with or without α-fetoprotein (AFP), but their sensitivity is suboptimal. We sought to develop a novel, blood-based biomarker panel with improved sensitivity for early-stage HCC detection. Methods In a multicenter, case-control study, we collected blood specimens from patients with HCC and age-matched controls with underlying liver disease but without HCC. Ten previously reported methylated DNA markers (MDMs) associated with HCC, methylated B3GALT6 (reference DNA marker), and 3 candidate proteins, including AFP, were assayed and analyzed by a logistic regression algorithm to predict HCC cases. The accuracy of the multi-target HCC panel was compared with that of other blood-based biomarkers for HCC detection. Results The study included 135 HCC cases and 302 controls. We identified a multi-target HCC panel of 3 MDMs (HOXA1, EMX1, and TSPYL5), B3GALT6 and 2 protein markers (AFP and AFP-L3) with a higher sensitivity (71%, 95% CI: 60–81%) at 90% specificity for early-stage HCC than the GALAD score (41%, 95% CI: 30–53%) or AFP ≥7.32 ng/mL (45%, 95% CI: 33–57%). The AUC for the multi-target HCC panel for detecting any stage HCC was 0.92 compared with 0.87 for the GALAD score and 0.81 for AFP alone. The panel performed equally well in important subgroups based on liver disease etiology, presence of cirrhosis, or sex. Conclusions We developed a novel, blood-based biomarker panel that demonstrates high sensitivity for early-stage HCC. These data support the potential for liquid biopsy detection of early-stage HCC to clinically benefit at-risk patients. This study was registered on ClinicalTrials.gov ( NCT03628651 ).

Secreted proteins in the bone marrow microenvironment play critical roles in acute myeloid leukemia (AML). Through an ex vivo functional screen of 94 cytokines, we identified that the pro-inflammatory cytokine interleukin-1 (IL-1) elicited profound expansion of myeloid progenitors in ∼67% of AML patients while suppressing the growth of normal progenitors. Levels of IL-1β and IL-1 receptors were increased in AML patients, and silencing of the IL-1 receptor led to significant suppression of clonogenicity and in vivo disease progression. IL-1 promoted AML cell growth by enhancing p38MAPK phosphorylation and promoting secretion of various other growth factors and inflammatory cytokines. Treatment with p38MAPK inhibitors reversed these effects and recovered normal CD34+ cells from IL-1-mediated growth suppression. These results highlight the importance of ex vivo functional screening to identify common and actionable extrinsic pathways in genetically heterogeneous malignancies and provide impetus for clinical development of IL-1/IL1R1/p38MAPK pathway-targeted therapies in AML.

We have compared the actual contribution of surfactant deficiency in respiratory distress syndrome to left-to-right shunting across a patent ductus arteriosus in premature infants with severe RDS by performing serial phospholipid analysis of tracheal aspirates and echocardiograms, and we have correlated these findings with the infants' clinical courses and management of ventilation. This analysis was combined with surgical or pharmacologic closure of PDA if a significant shunt existed. Qualitative surfactant abnormalities at birth and the subsequent maturation of phospholipids after birth were similar in all three groups of infants (Group 1, RDS alone; Group 2, RDS+PDA in infants weighing >1.2 kg; Group 3, RDS+PDA in infants ≤ 1.2 kg). The largest infants had isolated RDS (Group 1) and, after a brief period of stabilization after birth, had declining ventilatory and oxygen requirements. Infants in Group 2 had a gradual decrease in ventilatory and oxygen requirements which was accelerated markedly by cessation of PDA shunting. Infants in Group 3 had increasing ventilatory and oxygen requirements despite a maturing tracheal aspirate phospholipid pattern; their course, especially if they were asphyxiated, was characterized by early development of a significant left-to-right shunt and worsening clinical condition which improved following ablation of the shunt. The data suggest that severe RDS presents as a developmental spectrum and provides the justification for a controlled trial of very early closure of the PDA in the very low-birth-weight infant with severe RDS.

The course and complications of fifty-two infants with patent ductus arteriosus requiring closure were assessed prospectively. Twenty-six infants with a PDA received indomethacin for pharmacologic closure of the PDA, and 26 underwent ligation. The current study analyzes and compares the longitudinal follow-up with respect to somatic growth, neurologic function, psychomotor and mental development, and renal, ophthalmologic, and audiologic function in 21 infants in each group who entered the follow-up. No selective morbidity was attributable to PDA closure with indomethacin when compared to surgically treated infants.