Acute Lymphoblastic Leukemia, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for acute lymphoblastic leukemia (ALL) provide recommendations for management of ALL, with a focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. This selection from the NCCN Guidelines for ALL focuses on treatment recommendations for adults with newly diagnosed Ph-negative ALL based on current evidence.

The Use of Extracorporeal Membrane Oxygenation as a Bridge to Bone Marrow Transplantation in a Patient With High-risk Acute Myeloid Leukemia.

An 18-year-old girl with high-risk acute myeloid leukemia developed Streptococcus mitis septic shock and multiorgan dysfunction syndrome, including biventricular failure. Due to the anticipated reversibility of her cardiogenic shock, her young age, and her favorable survival chance after an allogeneic hematopoietic stem cell transplant, she was placed on full circulatory support with venoarterial extracorporeal membrane oxygenation as a bridge to her successful hematopoietic stem cell transplantation 2 months later. This highlights the importance of prognostication in patient selection for extracorporeal life support. A multidisciplinary approach is essential to each case until more definite initiation criteria, risk stratification, and treatment protocols are established.

Acute Lymphoblastic Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Acute Lymphoblastic Leukemia (ALL) focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. Given the complexity of ALL treatment regimens and the required supportive care measures, the NCCN ALL Panel recommends that patients be treated at a specialized cancer center with expertise in the management of ALL This portion of the Guidelines focuses on the management of Ph-positive and Ph-negative ALL in adolescents and young adults, and management in relapsed settings.

Patterns of medication use at end of life by pediatric inpatients with cancer.

OBJECTIVE: To describe medication utilization patterns by pediatric inpatients with cancer during their last week of life. METHODS: This retrospective study used data from the Vizient Clinical Database/Resource Manager, a national compilation of clinical and resource use data from over 100 academic medical centers and affiliates. Patients (0-21 years) with malignancy who died during hospitalization (2010-2017) were included (N = 1659). Medications were categorized as opioid, benzodiazepine, gastrointestinal related, chemotherapy, anti-infectives, or vasopressors. Exposure to each group was ascertained for all patients at 1 week and 1 day prior to death. Factors associated with exposure were examined using generalized estimating equations, and summarized using adjusted odds ratios (aORs). RESULTS: Over the last week of life, there was increased use of opioids (76% to 82%, aOR = 1.55, P < .001) and benzodiazepines (53% to 66%, aOR = 1.36, P = .02), while gastrointestinal-related medication use decreased (92% to 89%, aOR = 0.69, P = .001). Patients had decreased exposure to chemotherapy (10% to 5%, aOR = 0.46, P < .001) and anti-infectives (82% to 73%, aOR = 0.41, P = .002). Vasopressor use increased as death approached (15% to 28%, aOR = 1.67, P = .04). Factors significantly associated with exposure varied with medication category, and included age, race, length of stay, malignancy type, death in the intensive care unit, history of hematopoietic stem cell transplant, and do-not-resuscitate status. CONCLUSION: During the week preceding death, administration of symptom management medications increased for children with cancer, but use was not universal. Potentially life-sustaining medications were often continued. Variability in utilization suggests differences in provider/family decision making that warrant further study to develop an evidence-based approach to end-of-life care.

Guidelines Insights: Acute Lymphoblastic Leukemia, Version 1.2019.

Survival outcomes for older adults with acute lymphoblastic leukemia (ALL) are poor and optimal management is challenging due to higher-risk leukemia genetics, comorbidities, and lower tolerance to intensive therapy. A critical understanding of these factors guides the selection of frontline therapies and subsequent treatment strategies. In addition, there have been recent developments in minimal/measurable residual disease (MRD) testing and blinatumomab use in the context of MRD-positive disease after therapy. These NCCN Guidelines Insights discuss recent updates to the NCCN Guidelines for ALL regarding upfront therapy in older adults and MRD monitoring/testing in response to ALL treatment.

MKL1 and MKL2 play redundant and crucial roles in megakaryocyte maturation and platelet formation.

Serum response factor and its transcriptional cofactor MKL1 are critical for megakaryocyte maturation and platelet formation. We show that MKL2, a homologue of MKL1, is expressed in megakaryocytes and plays a role in megakaryocyte maturation. Using a megakaryocyte-specific Mkl2 knockout (KO) mouse on the conventional Mkl1 KO background to produce double KO (DKO) megakaryocytes and platelets, a critical role for MKL2 is revealed. The decrease in megakaryocyte ploidy and platelet counts of DKO mice is more severe than in Mkl1 KO mice. Platelet dysfunction in DKO mice is revealed by prolonged bleeding times and ineffective platelet activation in vitro in response to adenosine 5'-diphosphate. Electron microscopy and immunofluorescence of DKO megakaryocytes and platelets indicate abnormal cytoskeletal and membrane organization with decreased granule complexity. Surprisingly, the DKO mice have a more extreme thrombocytopenia than mice lacking serum response factor (SRF) expression in the megakaryocyte compartment. Comparison of gene expression reveals approximately 4400 genes whose expression is differentially affected in DKO compared with megakaryocytes deficient in SRF, strongly suggesting that MKL1 and MKL2 have both SRF-dependent and SRF-independent activity in megakaryocytopoiesis.

Metastatic gastrinoma in a pediatric patient with Zollinger-Ellison syndrome.

Metastatic neuroendocrine tumors of childhood are extremely rare, and as such present diagnostic and therapeutic challenges. Here, we report a case of gastrinoma with extensive hepatic metastases in a pediatric patient with Zollinger-Ellison Syndrome who underwent orthotopic liver transplant followed by cytotoxic chemotherapy, somatostatin analog therapy, and immune modulation.

Resilience Curriculum Improves Skills of Pediatric Fellows in Delivery of Difficult News.

BACKGROUND: Delivering difficult news to families is an essential but challenging skill. Pediatric trainees report limited confidence in this skill and perform poorly in simulation. We implemented the American Academy of Pediatrics (AAP) Resilience Curriculum and evaluated performance and self-efficacy in delivering difficult news. METHODS: The AAP Resilience Curriculum, using the SPIKES (Set-up, Perception, Invitation, Knowledge, Empathy, and Summary) framework, was taught to pediatric fellows. Fellows' performance during simulations with standardized patients before and after curriculum implementation was scored with a SPIKES checklist. Pre- and post-test surveys assessed self-efficacy in delivering difficult news. RESULTS: Fellows (n=19) significantly improved their performance in delivering difficult news, increasing the median SPIKES checklist scores from 78% to 90% completion (P<0.001). Pediatric fellows (n=35) reported improved confidence from 3.4/5 to 3.9 (P=0.01). CONCLUSIONS: Pediatric fellows demonstrated significant improvement in their ability to deliver difficult news during a simulated patient encounter and reported increased self-efficacy in delivering difficult news.

ProxTom lymphatic vessel reporter mice reveal Prox1 expression in the adrenal medulla, megakaryocytes, and platelets.

Lymphatic vessels (LVs) are important structures for antigen presentation, for lipid metabolism, and as conduits for tumor metastases, but they have been difficult to visualize in vivo. Prox1 is a transcription factor that is necessary for lymphangiogenesis in ontogeny and the maintenance of LVs. To visualize LVs in the lymph node of a living mouse in real time, we made the ProxTom transgenic mouse in a C57BL/6 background using red fluorescent LVs that are suitable for in vivo imaging. The ProxTom transgene contained all Prox1 regulatory sequences and was faithfully expressed in LVs coincident with endogenous Prox1 expression. The progenies of a ProxTom × Hec6stGFP cross were imaged using two-photon laser scanning microscopy, allowing the simultaneous visualization of LVs and high endothelial venules in a lymph node of a living mouse for the first time. We confirmed the expression of Prox1 in the adult liver, lens, and dentate gyrus. These intensely fluorescent mice revealed the expression of Prox1 in three novel sites: the neuroendocrine cells of the adrenal medulla, megakaryocytes, and platelets. The novel sites identified herein suggest previously unknown roles for Prox1. The faithful expression of the fluorescent reporter in ProxTom LVs indicates that these mice have potential utility in the study of diseases as diverse as lymphedema, filariasis, transplant rejection, obesity, and tumor metastasis.

Serum response factor is an essential transcription factor in megakaryocytic maturation.

Serum response factor (Srf) is a MADS-box transcription factor that is critical for muscle differentiation. Its function in hematopoiesis has not yet been revealed. Mkl1, a cofactor of Srf, is part of the t(1;22) translocation in acute megakaryoblastic leukemia, and plays a critical role in megakaryopoiesis. To test the role of Srf in megakaryocyte development, we crossed Pf4-Cre mice, which express Cre recombinase in cells committed to the megakaryocytic lineage, to Srf(F/F) mice in which functional Srf is no longer expressed after Cre-mediated excision. Pf4-Cre/Srf(F/F) knockout (KO) mice are born with normal Mendelian frequency, but have significant macrothrombocytopenia with approximately 50% reduction in platelet count. In contrast, the BM has increased number and percentage of CD41(+) megakaryocytes (WT: 0.41% ± 0.06%; KO: 1.92% ± 0.12%) with significantly reduced ploidy. KO mice show significantly increased megakaryocyte progenitors in the BM by FACS analysis and CFU-Mk. Megakaryocytes lacking Srf have abnormal stress fiber and demarcation membrane formation, and platelets lacking Srf have abnormal actin distribution. In vitro and in vivo assays reveal platelet function defects in KO mice. Critical actin cytoskeletal genes are down-regulated in KO megakaryocytes. Thus, Srf is required for normal megakaryocyte maturation and platelet production partly because of regulation of cytoskeletal genes.

Role for MKL1 in megakaryocytic maturation.

Megakaryoblastic leukemia 1 (MKL1), identified as part of the t(1;22) translocation specific to acute megakaryoblastic leukemia, is highly expressed in differentiated muscle cells and promotes muscle differentiation by activating serum response factor (SRF). Here we show that Mkl1 expression is up-regulated during murine megakaryocytic differentiation and that enforced overexpression of MKL1 enhances megakaryocytic differentiation. When the human erythroleukemia (HEL) cell line is induced to differentiate with 12-O-tetradecanoylphorbol 13-acetate, overexpression of MKL1 results in an increased number of megakaryocytes with a concurrent increase in ploidy. MKL1 overexpression also promotes megakaryocytic differentiation of primary human CD34(+) cells cultured in the presence of thrombopoietin. The effect of MKL1 is abrogated when SRF is knocked down, suggesting that MKL1 acts through SRF. Consistent with these findings in human cells, knockout of Mkl1 in mice leads to reduced platelet counts in peripheral blood, and reduced ploidy in bone marrow megakaryocytes. In conclusion, MKL1 promotes physiologic maturation of human and murine megakaryocytes.

Bi-allelic deletions within 13q14 and transient trisomy 21 with absence of GATA1s in pediatric acute megakaryoblastic leukemia.

Oligonucleotide array comparative genomic hybridization, karyotype and fluorescence in situ hybridization analyses were employed to delineate the cytogenetic abnormalities in a case of pediatric acute megakaryoblastic leukemia. Here we present a unique genetic profile that includes bi-allelic deletions within 13q14, where the retinoblastoma tumor suppressor gene (RB1) resides, as well as isolated trisomy 21 without a concomitant mutation in the hematopoietic transcription factor GATA1s and translocation (17;22), that does not involve the megakaryoblastic leukemia 1 (MKL1) gene located on chromosome 22. Alteration of the RB1 gene is most likely the critical leukemogenic event in this patient.

Novel report of an adrenal adenoma in a newborn.

An adrenal mass in a newborn usually suggests a diagnosis of neuroblastoma or hemorrhage. A 6-week-old girl was referred for evaluation of a left adrenal mass. The initial findings were most consistent with an adrenal hemorrhage. On surveillance imaging, the lesion was characterized as a complex cystic mass. The patient subsequently developed lesions in the right adrenal gland and liver as well as multiple cutaneous lesions. Although the contralateral adrenal and hepatic lesions resolved spontaneously, the left adrenal and cutaneous lesions persisted. Subsequent imaging revealed that the mural components of the left adrenal mass had increased in size, and at age 13 months, a laparoscopic left adrenalectomy was performed. A benign adrenal adenoma with myxoid changes was reported on surgical pathology. This is the first reported case in a newborn.