Oxygenation saturation index in neonatal hypoxemic respiratory failure.

BACKGROUND: This study aimed to assess the validity of the oxygenation saturation index (OSI) and the ratio of oxygen saturation to the fraction of inspired oxygen (FIO2) (S/F ratio) with percutaneous oxygen saturation (OSISpO2 and the Sp/F ratio) and to evaluate the correlation between these values and the oxygen index (OI). It also determined their cut-off values for predicting OI in accordance with neonatal hypoxic respiratory failure severity. METHODS: We reviewed the data of 77 neonates (gestational age 31.7 ± 6.1 weeks; birthweight, 1768 ± 983 g) requiring invasive mechanical ventilation between 2013 and 2020, 1233 arterial blood gas samples in total. We calculated the OI, OSISpO2, OSI with arterial oxygen saturation (SaO2) (OSISaO2), Sp/F ratio, and the ratio of SaO2 to FIO2 (Sa/F ratio). RESULTS: The regression and Bland-Altman analysis showed good agreement between OSISpO2 or the Sp/F ratio and OSISaO2 or the Sa/F ratio. Although a significant positive correlation was found between OSISpO2 and OI, OSISpO2 was overestimated in SpO2 > 98% with a higher slope of the fitted regression line than that below 98% of SpO2. Furthermore, receiver-operating characteristic curve analysis using only SpO2 ≤ 98% samples showed that the optimal cut-off points of OSISpO2 and the Sp/F ratio for predicting OI were: OI 5, 3.0 and 332; OI 10, 5.3 and 231; OI 15, 7.7 and 108; OI 20, 11.0 and 149; and OI 25, 17.1 and 103, respectively. CONCLUSION: The cut-off OSISpO2 and Sp/F ratio values could allow continuous monitoring for oxygenation changes in neonates with the potential for wider clinical applications.

The combination of ruxolitinib and Bcl-2/Mcl-1 inhibitors has a synergistic effect on leukemic cells carrying a SPAG9::JAK2 fusion.

JAK2 rearrangements can occur in Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL). Here, we performed functional analysis of the SPAG9::JAK2 fusion, which was identified in a pediatric patient with Ph-like ALL, to establish molecular targeted therapy. Ba/F3 cells expressing SPAG9::JAK2 generated by retroviral transduction (Ba/F3-SPAG9-JAK2), proliferated in the absence of IL-3, and exhibited constitutive phosphorylation of the tyrosine residues in the JAK2 kinase domain of the fusion protein and STAT3/STAT5. Mutation of tyrosine residues in the JAK2 kinase domain (SPAG9::JAK2 mut) abolished IL-3 independence, but had no influence on STAT3/STAT5 phosphorylation levels. Gene expression analysis revealed that Stat1 was significantly upregulated in Ba/F3-SPAG9-JAK2 cells. STAT1 was also phosphorylated in Ba/F3-SPAG9-JAK2 but not SPAG9-JAK2 mut cells, suggesting that STAT1 is key for SPAG9::JAK2-mediated cell proliferation. Consistently, STAT1 induced expression of the anti-apoptotic proteins, BCL-2 and MCL-1, as did SPAG9::JAK2, but not SPAG9::JAK2 mut. Ruxolitinib abrogated Ba/F3-SPAG9-JAK2-mediated proliferation in vitro, but was insufficient in vivo. Venetoclax (a BCL-2 inhibitor) or AZD5991 (an MCL-1 inhibitor) enhanced the effects of ruxolitinib on Ba/F3-SPAG9-JAK2 in vitro. These findings suggest that activation of the JAK2-STAT1-BCL-2/MCL-1 axis contributes to SPAG9::JAK2-related aberrant growth promotion. BCL-2 or MCL-1 inhibition is a potential therapeutic option for B-ALL with SPAG9::JAK2 fusion.

[HLA-mismatched bone marrow transplantation with post-transplant cyclophosphamide for pediatric patients with aplastic anemia].

Post-transplant cyclophosphamide (PTCy) has improved the efficacy of HLA-mismatched hematopoietic cell transplantation (HCT) by decreasing the risk of graft-versus-host disease (GVHD) and nonrelapse mortality. If an HLA-matched donor is not available, GVHD prophylaxis with PTCy can also be used for HLA-mismatched HCT in patients with pediatric aplastic anemia (AA). We report two cases of pediatric AA that were treated with HLA-mismatched HCT with reduced-intensity conditioning and PTCy. We administered 50 mg/kg/day Cy for GVHD prophylaxis on days 3 and 4, and tacrolimus and mycophenolate mofetil (or methotrexate) were initiated from day 5. In both the cases, the time to engraftment was favorable and GVHD and infection were controllable. PTCy probably allows us to expand donor candidates in pediatric AA when an HLA-matched donor is not available; however, further studies regarding optimal conditioning regimens and late complications are required.

Reduced B7-H3 expression by PAX3-FOXO1 knockdown inhibits cellular motility and promotes myogenic differentiation in alveolar rhabdomyosarcoma.

B7-H3 (also known as CD276) is associated with aggressive characteristics in various cancers. Meanwhile, in alveolar rhabdomyosarcoma (ARMS), PAX3-FOXO1 fusion protein is associated with increased aggressiveness and poor prognosis. In the present study, we explored the relationship between PAX3-FOXO1 and B7-H3 and the biological roles of B7-H3 in ARMS. Quantitative real time PCR and flow cytometry revealed that PAX3-FOXO1 knockdown downregulated B7-H3 expression in all the selected cell lines (Rh-30, Rh-41, and Rh-28), suggesting that PAX3-FOXO1 positively regulates B7-H3 expression. Gene expression analysis revealed that various genes and pathways involved in chemotaxis, INF-γ production, and myogenic differentiation were commonly affected by the knockdown of PAX3-FOXO1 and B7-H3. Wound healing and transwell migration assays revealed that both PAX3-FOXO1 and B7-H3 were associated with cell migration. Furthermore, knockdown of PAX3-FOXO1 or B7-H3 induced myogenin expression in all cell lines, although myosin heavy chain induction varied depending on the cellular context. Our results indicate that PAX3-FOXO1 regulates B7-H3 expression and that PAX3-FOXO1 and B7-H3 are commonly associated with multiple pathways related to an aggressive phenotype in ARMS, such as cell migration and myogenic differentiation block.

Large difference between Enghoff and Bohr dead space in ventilated infants with hypoxemic respiratory failure.

BACKGROUND: Ventilated neonates with hypoxemic respiratory failure (HRF) may show a ventilation-perfusion (V/Q) mismatch. OBJECTIVE: To evaluate the difference between the Bohr (Vd, Bohr ) and Enghoff (Vd, Enghoff ) dead spaces in infants by using volumetric capnography based on ventilator graphics and capnograms. METHODS: This study enrolled 46 ventilated infants (mean birth weight, 2239 ± 640 g; mean gestational age, 35.5 ± 3.3 weeks). We performed volumetric capnography and calculated Vd, Bohr and Vd, Enghoff when arterial blood sampling was necessary for treatment. According to the oxygenation index (OI) based on the Montreux definition of neonatal acute respiratory distress syndrome, each measurement was classified into the HRF (OI ≥ 4) or control (OI < 4) group. Then, a regression analysis was performed to evaluate the correlation between the OI and the difference between Vd, Enghoff and Vd, Bohr . RESULTS: The median Vd, Enghoff /tidal volume (VT ) was significantly higher in the HRF group (0.55 [interquartile range, 0.47-0.68]) than in the control group (0.46 [0.37-0.57]). The HRF group showed a larger difference between Vd, Enghoff /VT and Vd, Bohr /VT than the control group (median, 0.22 [0.15-0.29] vs. 0.10 [0.06-0.14], respectively). Moreover, the regression analysis of the relationship between OI and Vd, Enghoff /VT - Vd, Bohr /VT showed a positive correlation (r = .60, p < .001). CONCLUSION: Ventilated neonates with hypoxemic respiratory failure showed a large difference between Vd, Enghoff and Vd, Bohr , possibly reflecting a low V/Q mismatch and right-to-left shunting.

Reduction in minute alveolar ventilation causes hypercapnia in ventilated neonates with respiratory distress.

Hypercapnia occurs in ventilated infants even if tidal volume (VT) and minute ventilation (VE) are maintained. We hypothesised that increased physiological dead space (Vd,phys) caused decreased minute alveolar ventilation (VA; alveolar ventilation (VA) × respiratory rate) in well-ventilated infants with hypercapnia. We investigated the relationship between dead space and partial pressure of carbon dioxide (PaCO2) and assessed VA. Intubated infants (n = 33; mean birth weight, 2257 ± 641 g; mean gestational age, 35.0 ± 3.3 weeks) were enrolled. We performed volumetric capnography (Vcap), and calculated Vd,phys and VA when arterial blood sampling was necessary. PaCO2 was positively correlated with alveolar dead space (Vd,alv) (r = 0.54, p < 0.001) and Vd,phys (r = 0.48, p < 0.001), but not Fowler dead space (r = 0.14, p = 0.12). Normocapnia (82 measurements; 35 mmHg ≤ PaCO2 < 45 mmHg) and hypercapnia groups (57 measurements; 45 mmHg ≤ PaCO2) were classified. The hypercapnia group had higher Vd,phys (median 0.57 (IQR, 0.44-0.67)) than the normocapnia group (median Vd,phys/VT = 0.46 (IQR, 0.37-0.58)], with no difference in VT. The hypercapnia group had lower VA (123 (IQR, 87-166) ml/kg/min) than the normocapnia group (151 (IQR, 115-180) ml/kg/min), with no difference in VE.Conclusion: Reduction of VA in well-ventilated neonates induces hypercapnia, caused by an increase in Vd,phys. What is Known: • Volumetric capnography based on ventilator graphics and capnograms is a useful tool in determining physiological dead space of ventilated infants and investigating the cause of hypercapnia. What is New: • This study adds evidence that reduction in minute alveolar ventilation causes hypercapnia in ventilated neonates.

B-Cell Precursor-Acute Lymphoblastic Leukemia With EBF1-PDGFRB Fusion Treated With Hematopoietic Stem Cell Transplantation and Imatinib: A Case Report and Literature Review.

A 9-year-old girl was diagnosed with B-cell precursor-acute lymphoblastic leukemia (BCP-ALL). Although she entered remission after induction therapy, she relapsed 15 months after maintenance therapy cessation. Since further investigation revealed EBF1-PDGFRB fusion, her condition was treated as BCR-ABL1-like acute lymphoblastic leukemia. She was started on a tyrosine kinase inhibitor, imatinib, and chemotherapy and underwent umbilical cord blood transplantation following reduced intensity conditioning. She has remained in complete remission for 36 months after cord blood transplantation. This case demonstrates the successful use of a tyrosine kinase inhibitor to treat BCP-ALL with a fusion transcript and highlights the need for a standardized treatment protocol.

Functional analysis of a novel fusion protein PAX5-KIDINS220 identified in a pediatric Ph-like ALL patient.

PAX5-KIDINS220 (PAX5-K220) is a novel chimeric fusion gene identified in a pediatric Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) patient, but the function of the encoded fusion protein has not yet been analyzed. Here, we report the functional analysis of PAX5-K220 in vitro. We successfully generated PAX5-K220 expressing cells and demonstrate that PAX5-K220 is a nuclear protein. Luciferase reporter assay reveals that PAX5-K220 inhibits wild-type PAX5 transcriptional activity in a dominant-negative fashion like other PAX5-related fusion proteins, and may contribute to lymphocyte differentiation block. However, although identified in Ph-like ALL, PAX5-K220 does not induce IL-3-independent proliferation when transduced in the IL-3-dependent Ba/F3 murine leukemia cells, but rather attenuates growth. These results reveal that PAX5-K220 certainly shares the character with other PAX5-related fusion proteins rather than other fusion proteins with tyrosine kinase activity identified in Ph-like ALL, and did not contribute to proliferation activity. Precise functional analysis of each differently partnered PAX5 fusion protein is warranted in the future for better understanding of PAX5-related translocations and their effects.

KMT2A-rearranged infantile acute myeloid leukemia masquerading as juvenile myelomonocytic leukemia.

Mixed lineage leukemia [MLL; now known as lysine methyltransferase 2A (KMT2A)] rearrangement-positive acute myeloid leukemia (AML) and juvenile myelomonocytic leukemia (JMML) are distinct diseases, although age of susceptibility (infancy or early childhood) and abnormal monocytosis are common clinical features. Here, we report two cases of KMT2A-rearranged infantile AML masquerading as JMML at initial presentation. Both cases showed leukocytosis accompanied by atypical monocytosis. However, in both cases, leukemic blasts were absent at the initial examination. Thus, a diagnosis of JMML was suspected. However, initial cytogenetic analysis revealed that both cases had an 11q23 rearrangement, which is atypical in JMML. Eventually, due to the emergence of leukemic blasts and further cytogenetic studies, both cases were diagnosed with infantile AML with a KMT2A rearrangement. Although one patient remains in complete remission after the completion of AML appropriate chemotherapy, the other died of AML due to treatment failure. Our experience suggests that AML with KMT2A rearrangement should be considered for the differential diagnosis of infantile cases with atypical monocytosis suggestive of JMML. Cytogenetic studies, including fluorescence in situ hybridization analysis of KMT2A, may be helpful in distinguishing between AML with KMT2A rearrangement and JMML.

Sorafenib Therapy for Pediatric Acute Myeloid Leukemia with FMS-like Tyrosine Kinase 3-internal Tandem Duplication Mutations: 2 Case Reports.

Sorafenib is a promising agent for treating pediatric refractory acute myeloid leukemia (AML) exhibiting FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD); however, its optimal use needs to be established. We report 2 cases of refractory pediatric FLT3-ITD-positive AML treated with sorafenib. Case 1 underwent stem cell transplantation (SCT) without entering remission, despite the use of chemotherapy. This patient relapsed despite receiving post-SCT sorafenib. Chemotherapy combined with sorafenib successfully achieved complete remission in case 2. This patient received post-SCT sorafenib and remains in complete remission. The combination of pre-SCT and post-SCT sorafenib may thus be effective for pediatric refractory FLT3-ITD-positive AML.

Ph-like acute lymphoblastic leukemia with a novel PAX5-KIDINS220 fusion transcript.

Although "paired box 5" (PAX5)-related fusion genes are well documented in childhood B-cell precursor acute lymphoblastic leukemia (ALL), these types of fusion with the exception of PAX5-JAK2 are rarely seen in patients with gene expression profiles similar to those of BCR-ABL1 (Philadelphia)-positive ALL (Ph-like ALL). We report a novel fusion of the genes PAX5 and "kinase D-interacting substrate of 220 kDa" (KIDINS220, also known as ARMS) in a Ph-like ALL. As PAX5 is a master regulator of B-lymphocyte differentiation, PAX5 rearrangements induce a differentiation block in B lymphocytes. KIDINS220 is a mediator of multiple receptor signaling pathways, interacts with both T- and B-cell receptors, and is necessary for sustained extracellular signal-regulated kinase (ERK) signaling. Although functional studies are needed, the PAX5-KIDINS220 fusion protein might not only inhibit wild-type PAX5 function, but also promote sustained activation of the ERK signaling pathway through upregulation of KIDINS220. © 2016 Wiley Periodicals, Inc.

Serial investigation of PTPN11 mutation in nonhematopoietic tissues in a patient with juvenile myelomonocytic leukemia who was treated with unrelated cord blood transplantation.

After allogeneic stem-cell transplantation, nonhematopoietic tissues contain donor-derived cells; however, whether cells from malignant hematological disease can also be found in nonhematopoietic tissues is unclear. This report describes a juvenile myelomonocytic leukemia (JMML) case with a typical PTPN11 mutation (p.E76K) at different allele frequencies in the bone marrow mononuclear cells, buccal smear cells, and fingernails at diagnosis, which was suggestive of PTPN11 somatic mosaicism; however, the PTPN11 mutation in the buccal smear cells and fingernails was lost after unrelated cord blood transplantation. These results suggest that JMML-derived cells may migrate into and reside in nonhematopoietic tissues and furthermore that these cells can be eradicated by cord blood transplantation.