Signaling Pathways Crucial for Craniofacial Development Revealed by Endothelin-A Receptor-Deficient Mice

AbstractMost of the bone and cartilage in the craniofacial region is derived from cephalic neural crest cells, which undergo three primary developmental events: migration from the rhombomeric neuroectoderm to the pharyngeal arches, proliferation as the ectomesenchyme within the arches, and differentiation into terminal structures. Interactions between the ectomesenchymal cells and surrounding cells are required in these processes, in which defects can lead to craniofacial malformation. We have previously shown that the G-protein-coupled endothelin-A receptor (ETA) is expressed in the neural crest-derived ectomesenchyme, whereas the cognate ligand for ETA, endothelin-1 (ET-1), is expressed in arch epithelium and the paraxial mesoderm-derived arch core; absence of either ETA or ET-1 results in numerous craniofacial defects. In this study we have attempted to define the point at which cephalic neural crest development is disrupted in ETA-deficient embryos. We find that, while neural crest cell migration in the head of ETA−/− embryos appears normal, expression of a number of transcription factors in the arch ectomesenchymal cells is either absent or significantly reduced. These ETA-dependent factors include the transcription factorsgoosecoid, Dlx-2, Dlx-3, dHAND, eHAND, and Barx1, but not MHox, Hoxa-2, CRABP1, or Ufd1. In addition, the size of the arches in E10.5 to E11.5 ETA−/− embryos is smaller and an increase in ectomesenchymal apoptosis is observed. Thus, ETA signaling in ectomesenchymal cells appears to coordinate specific aspects of arch development by inducing expression of transcription factors in the postmigratory ectomesenchyme. Absence of these signals results in retarded arch growth, defects in proper differentiation, and, in some mesenchymal cells, apoptosis. In particular, this developmental pathway appears distinct from the pathway that includesUFD1L, implicated as a causative gene in CATCH 22 patients, and suggests parallel complementary pathways mediating craniofacial development

Superior survival with pediatric-style chemotherapy compared to myeloablative allogeneic hematopoietic cell transplantation in older adolescents and young adults with Ph-negative acute lymphoblastic leukemia in first complete remission: analysis from CALGB 10403 and the CIBMTR

Acute lymphocytic leukaemia; ChemotherapyLeucemia linfocítica aguda; QuimioterapiaLeucèmia limfocítica aguda; QuimioteràpiaOptimal post-remission therapy for adolescents and young adults (AYAs) with Ph-negative acute lymphoblastic leukemia (ALL) in first complete remission (CR1) is not established. We compared overall survival (OS), disease-free survival (DFS), relapse, and non-relapse mortality (NRM) for patients receiving post-remission therapy on CALGB 10403 to a cohort undergoing myeloablative (MA) allogeneic hematopoietic cell transplantation (HCT) in CR1. In univariate analysis, OS was superior with chemotherapy compared to MA allogeneic HCT (3-year OS 77% vs. 53%, P < 0.001). In multivariate analysis, allogeneic HCT showed inferior OS (HR 2.00, 95% CI 1.5–2.66, P < 0.001), inferior DFS (HR 1.62, 95% CI 1.25–2.12, P < 0.001), and increased NRM (HR 5.41, 95% CI 3.23–9.06, P < 0.001) compared to chemotherapy. A higher 5-year relapse incidence was seen with chemotherapy compared to allogeneic HCT (34% vs. 23%, P = 0.011). Obesity was independently associated with inferior OS (HR 2.17, 95% CI 1.63–2.89, P < 0.001), inferior DFS (HR 1.97, 95% CI 1.51–2.57, P < 0.001), increased relapse (1.84, 95% CI 1.31–2.59, P < 0.001), and increased NRM (HR 2.10, 95% CI 1.37–3.23, P < 0.001). For AYA ALL patients in CR1, post-remission therapy with pediatric-style chemotherapy is superior to MA allogeneic HCT for OS, DFS, and NRM

Haploidentical vs. sibling, unrelated, or cord blood hematopoietic cell transplantation for acute lymphoblastic leukemia

The role of haploidentical hematopoietic cell transplantation (HCT) using posttransplant cyclophosphamide (PTCy) for acute lymphoblastic leukemia (ALL) is being defined. We performed a retrospective, multivariable analysis comparing outcomes of HCT approaches by donor for adults with ALL in remission. The primary objective was to compare overall survival (OS) among haploidentical HCTs using PTCy and HLA-matched sibling donor (MSD), 8/8 HLAmatched unrelated donor (MUD), 7 /8 HLA-MUD, or umbilical cord blood (UCB) HCT. Comparing haploidentical HCT to MSD HCT, we found that OS, leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and acute graft-versus-host disease (aGVHD) were not different but chronic GVHD (cGVHD) was higher in MSD HCT. Compared with MUD HCT, OS, LFS, and relapse were not different, but MUD HCT had increased NRM (hazard ratio [HR], 1.42; P = .02), grade 3 to 4 aGVHD (HR, 1.59; P = .005), and cGVHD. Compared with 7/8 UD HCT, LFS and relapse were not different, but 7/8 UD HCT had worse OS (HR, 1.38; P = .01) and increased NRM (HR, 2.13; P <_ .001), grade 3 to 4 aGVHD (HR, 1.86; P = .003), and cGVHD (HR, 1.72; P <_ .001). Compared with UCB HCT, late OS, late LFS, relapse, and cGVHD were not different but UCB HCT had worse early OS (<_18 months; HR, 1.93; P < .001), worse early LFS (HR, 1.40; P = .007) and increased incidences of NRM (HR, 2.08; P < .001) and grade 3 to 4 aGVHD (HR, 1.97; P < .001). Haploidentical HCT using PTCy showed no difference in survival but less GVHD compared with traditional MSD and MUD HCT and is the preferred alternative donor HCT option for adults with ALL in complete remission

Reappraising the Role of Allogeneic Hematopoietic Stem Cell Transplantation in Relapsed and Refractory Hodgkin&rsquo;s Lymphoma: Recent Advances and Outcomes

Hodgkin&rsquo;s lymphoma is a rare yet highly curable disease in the majority of patients treated with modern chemotherapy regimens. For patients who fail to respond to or relapse after initial systemic therapies, treatment with high-dose chemotherapy and autologous hematopoietic stem cell transplantation can provide a cure for many with chemotherapy-responsive lymphoma. Patients who relapse after autologous transplant or those with chemorefractory disease have poor prognosis and represent a high unmet need. Allogeneic hematopoietic stem cell transplantation provides a proven curative therapy for these patients and should be considered, especially in young and medically fit patients. The use of newer agents in this disease such as brentuximab vedotin and immune checkpoint inhibitors can help bring more patients to transplantation and should be considered as well

Sociodemographic disparities in chemotherapy and hematopoietic cell transplantation utilization among adult acute lymphoblastic and acute myeloid leukemia patients

IntroductionIdentifying sociodemographic disparities in chemotherapy and hematopoietic cell transplantation (HCT) utilization for acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) may improve survival for underserved populations. In this study, we incorporate neighborhood socioeconomic status (nSES), marital status, and distance from transplant center with previously studied factors to provide a comprehensive analysis of sociodemographic factors influencing treatments for ALL and AML.MethodsUsing the California Cancer Registry, we performed a retrospective, population-based study of patients ≥15 years old with ALL (n = 3,221) or AML (n = 10,029) from 2003 through 2012. The effect of age, sex, race/ethnicity, marital status, nSES, and distance from nearest transplant center on receiving no treatment, chemotherapy alone, or chemotherapy then HCT was analyzed.ResultsNo treatment, chemotherapy alone, or chemotherapy then HCT were received by 11%, 75%, and 14% of ALL patients and 36%, 53%, and 11% of AML patients, respectively. For ALL patients ≥60 years old, HCT utilization increased from 5% in 2005 to 9% in 2012 (p = 0.03). For AML patients ≥60 years old, chemotherapy utilization increased from 39% to 58% (p&lt;0.001) and HCT utilization from 5% to 9% from 2005 to 2012 (p&lt;0.001). Covariate-adjusted analysis revealed decreasing relative risk (RR) of chemotherapy with increasing age for both ALL and AML (trend p &lt;0.001). Relative to non-Hispanic whites, lower HCT utilization occurred in Hispanic [ALL, RR = 0.80 (95% CI = 0.65-0.98); AML, RR = 0.86 (95% CI = 0.75-0.99)] and non-Hispanic black patients [ALL, RR = 0.40 (95% CI = 0.18-0.89); AML, RR = 0.60 (95% CI = 0.44-0.83)]. Compared to married patients, never married patients had a lower RR of receiving chemotherapy [ALL, RR = 0.96 (95% CI = 0.92-0.99); AML, RR = 0.94 (95% CI = 0.90-0.98)] or HCT [ALL, RR = 0.58 (95% CI = 0.47-0.71); AML, RR = 0.80 (95% CI = 0.70-0.90)]. Lower nSES quintiles predicted lower chemotherapy and HCT utilization for both ALL and AML (trend p &lt;0.001).ConclusionsOlder age, lower nSES, and being unmarried predicted lower utilization of chemotherapy and HCT among ALL and AML patients whereas having Hispanic or black race/ethnicity predicted lower rates of HCT. Addressing these disparities may increase utilization of curative therapies in underserved acute leukemia populations