Do Obese Children Have Poor Patient-reported Outcomes After Closed Reduction and Percutaneous Pin Fixation of Supracondylar Humerus Fractures?

BACKGROUND: Nearly 1 in 5 American children are obese. The primary purpose of this study is to evaluate the relationship between childhood obesity and perioperative complications, patient-reported outcomes (PRO), and functional recovery after closed reduction and percutaneous pinning (CRPP) of type II and III supracondylar humerus fractures. METHODS: Retrospective review of patients treated operatively with CRPP of Wilkins modification of the Gartland classification type II and III supracondylar humerus fractures was performed over a 1-year timeframe (July 1, 2016 to July 1, 2017). One hundred forty-four patients under the age of 16 treated were identified. Obesity was defined as body mass index (BMI) at or above the 95th percentile for age. Obesity as a risk factor for poor outcomes was assessed. The primary outcome measure was postoperative PRO [quick-DASH, Patient Reported Outcomes Measurement Information System (PROMIS)-UE, PROMIS Global Health, and PROMIS Pain scores]. RESULTS: Mean age at surgery was 5.9 years (SD=2.1, 1.07 to 12.2) and mean age at final follow-up (3.3 y) was 8.8 (SD=2.14, 4 to 16). Mean patient BMI was 17.2 (SD=4.48, 12.4 to 56.2). Sixty-six patients were female (45.8%) and 78 patients were male (54.2%). In all, 31 of 144 patients (21.5%) met criteria for obesity. Obesity (95th percentile for BMI or above) was not associated with a higher rate of complications overall (χ2=1.29, P=0.256), range of motion loss (χ2=0.2, P=0.655) or requirement of postoperative physical therapy (χ2=0.17, P=0.678). Seventy-five patients were available and willing to participate in the outcomes score assessments. Mean follow-up for this cohort of 75 patients was 3.3 years (SD=0.31, 2.85 to 3.88). There were no differences in PROMIS pain, PROMIS upper extremity function, PROMIS general health, or quick-DASH scores when comparing obese with nonobese patients. CONCLUSIONS: Obesity is a growing concern in the United States and its effect on long-term outcomes after CRPP of supracondylar humerus fractures is unknown. The present study demonstrates no difference in complications or PRO among obese patients compared with nonobese patients. LEVEL OF EVIDENCE: Level IV-retrospective cohort study.

Selective inhibition of protein arginine methyltransferase 5 blocks initiation and maintenance of B-cell transformation.

Epigenetic events that are essential drivers of lymphocyte transformation remain incompletely characterized. We used models of Epstein-Barr virus (EBV)-induced B-cell transformation to document the relevance of protein arginine methyltransferase 5 (PRMT5) to regulation of epigenetic-repressive marks during lymphomagenesis. EBV(+) lymphomas and transformed cell lines exhibited abundant expression of PRMT5, a type II PRMT enzyme that promotes transcriptional silencing of target genes by methylating arginine residues on histone tails. PRMT5 expression was limited to EBV-transformed cells, not resting or activated B lymphocytes, validating it as an ideal therapeutic target. We developed a first-in-class, small-molecule PRMT5 inhibitor that blocked EBV-driven B-lymphocyte transformation and survival while leaving normal B cells unaffected. Inhibition of PRMT5 led to lost recruitment of a PRMT5/p65/HDAC3-repressive complex on the miR96 promoter, restored miR96 expression, and PRMT5 downregulation. RNA-sequencing and chromatin immunoprecipitation experiments identified several tumor suppressor genes, including the protein tyrosine phosphatase gene PTPROt, which became silenced during EBV-driven B-cell transformation. Enhanced PTPROt expression following PRMT5 inhibition led to dephosphorylation of kinases that regulate B-cell receptor signaling. We conclude that PRMT5 is critical to EBV-driven B-cell transformation and maintenance of the malignant phenotype, and that PRMT5 inhibition shows promise as a novel therapeutic approach for B-cell lymphomas.

De novo CD5+ diffuse large B-cell lymphoma: Adverse outcomes with and without stem cell transplantation in a large, multicenter, rituximab treated cohort.

De novo CD5+ diffuse large B-cell lymphomas (DLBCL) are a distinct subgroup of DLBCL with poor prognosis. However the role of rituximab-containing therapy and salvage stem cell transplantation in this patients' population remain to be defined. We retrospectively reviewed clinical features and outcomes of 102 patients with de novo CD5+ DLBCL treated with rituximab-containing therapy at nine different institutions. By Hans' criteria, 64 patients had activated B-cell (ABC) subtype, 24 germinal center B-cell (GCB) subtype, and 14 were not evaluated. No patients had a myc translocation. Eighty-three patients were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP), 7 with rituximab, etoposide, cyclophosphamide, doxorubicin, vincristine, prednisone (R-EPOCH), and 6 with R-CHOP with methotrexate, 3 g/m(2) . The overall response rate to front-line therapy was 85%. The 3-year progression free survival (PFS) and overall survival (OS) for all patients were 40 and 65%, respectively. The 3-year PFS for ABC- and GCB-subtypes was 34 and 45%, respectively. The 3-year OS for ABC- and GCB-subtypes was 62 and 67%, respectively. The median time to second treatment failure was 3 months and 1 month for ABC- and GCB-subtypes, respectively. Twenty of 28 (71%) transplanted patients with autologous, allogeneic, or both, relapsed. This study confirms the poor prognosis of de novo CD5+ DLBCL in a large multi-center cohort despite initial rituximab-containing chemotherapy and suggests that stem cell transplantation fails to salvage the majority of these patients. Approaches to prevent recurrence and/or novel therapies for relapsed disease are needed for this subgroup of DLBCL patients.

Combination anti-CD74 (milatuzumab) and anti-CD20 (rituximab) monoclonal antibody therapy has in vitro and in vivo activity in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with a median survival of 3 years despite chemoimmunotherapy. Rituximab, a chimeric anti-CD20 monoclonal antibody (mAb), has shown only modest activity as single agent in MCL. The humanized mAb milatuzumab targets CD74, an integral membrane protein linked with promotion of B-cell growth and survival, and has shown preclinical activity against B-cell malignancies. Because rituximab and milatuzumab target distinct antigens and potentially signal through different pathways, we explored a preclinical combination strategy in MCL. Treatment of MCL cell lines and primary tumor cells with immobilized milatuzumab and rituximab resulted in rapid cell death, radical oxygen species generation, and loss of mitochondrial membrane potential. Cytoskeletal distrupting agents significantly reduced formation of CD20/CD74 aggregates, cell adhesion, and cell death, highlighting the importance of actin microfilaments in rituximab/milatuzumab-mediated cell death. Cell death was independent of caspase activation, Bcl-2 family proteins or modulation of autophagy. Maximal inhibition of p65 nuclear translocation was observed with combination treatment, indicating disruption of the NF-κB pathway. Significant in vivo therapeutic activity of combination rituximab and milatuzumab was demonstrated in a preclinical model of MCL. These data support clinical evaluation of combination milatuzumab and rituximab therapy in MCL.

FTY720 increases CD74 expression and sensitizes mantle cell lymphoma cells to milatuzumab-mediated cell death.

Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with a short median survival despite multimodal therapy. FTY720, an immunosuppressive drug approved for the treatment of multiple sclerosis, promotes MCL cell death concurrent with down-modulation of phospho-Akt and cyclin D1 and subsequent cell-cycle arrest. However, the mechanism of FTY720-mediated MCL cell death remains to be fully clarified. In the present study, we show features of autophagy blockage by FTY720 treatment, including accumulation of autolysosomes and increased LC3-II and p62 levels. We also show that FTY720-induced cell death is mediated by lysosomal membrane permeabilization with subsequent translocation of lysosomal hydrolases to the cytosol. FTY720-mediated disruption of the autophagic-lysosomal pathway led to increased levels of CD74, a potential therapeutic target in MCL that is degraded in the lysosomal compartment. This finding provided rationale for examining combination therapy with FTY720 and milatuzumab, an anti-CD74 mAb. Treatment of MCL cell lines and primary tumor cells with FTY720 and milatuzumab resulted in statistically significant enhanced cell death, which was synergistic in blastic variant MCL cell lines. Significant in vivo therapeutic activity of combination treatment was also demonstrated in a preclinical, in vivo model of MCL. These findings support clinical evaluation of this combination in patients with MCL.

Human leukocyte antigen type and posttransplant lymphoproliferative disorder.

BACKGROUND: Posttransplant lymphoproliferative disorder (PTLD) is an infrequent but serious complication of solid organ transplantation. Early detection and initiation of therapy may improve outcomes. The purpose of this study was to identify human leukocyte antigen (HLA) type as risk and prognostic factors for PTLD. METHODS: A review was undertaken to identify PTLD cases treated at our institution over the past 25 years. Logistic regression and Cox Proportional Hazards were used to model risk factors for PTLD and clinical outcomes in patients with PTLD. RESULTS: One hundred six cases of PTLD were identified with 1392 solid-organ transplant recipient controls. Epstein-Barr virus (EBV) seronegative status pretransplant (odds ratio [OR] = 7.61, 95% confidence interval [95% CI] = 3.83-15.1) and receipt of a nonkidney transplant were associated with an increased risk of PTLD. Being African American and receipt of a living-related kidney transplant were associated with a decreased risk of PTLD. The HLA-B40 group was a risk factor for PTLD in EBV-seronegative individuals (OR = 8.38, 95% CI = 2.18-32.3), whereas HLA-B8 was a risk factor for PTLD in EBV-seropositive individuals (OR = 3.29, 95% CI = 1.52-7.09). Specific HLA types were not associated with graft failure or mortality after PTLD diagnosis. In PTLD patients, central nervous system (CNS) involvement, bone marrow involvement, T-cell PTLD, and age were associated with increased mortality. CONCLUSION: Human leukocyte antigen-B40 group and HLA-B8 were identified as novel susceptibility factors for PTLD in EBV-seropositive and EBV-seronegative individuals, respectively. Multicentered, large prospective studies of PTLD with correlative immunologic work are needed to test the significance of these observed associations.