Citations

Abstract Paratesticular rhabdomyosarcoma (PT‐RMS) carries a favorable prognosis, but questions persist regarding optimal management. Our goal was to determine the importance of primary tumor resection and surgical assessment of retroperitoneal lymph nodes during staging in patients with PT‐RMS. We analyzed patients with localized PT‐RMS enrolled onto one of four Children's Oncology Group studies (D9602, ARST0331, D9803 or ARST0531). Surgical resection of the primary tumor prior to chemotherapy and radiotherapy was encouraged when possible with retroperitoneal lymph node dissection (RPLND) recommended for patients ≥10 years of age. Among 279 patients (median 8.1 years old), most tumors were resected with negative margins (78.5%) and most patients did not have radiographic enlargement of regional lymph nodes (90.3%). In patients older than 10 years, imaging alone will miss over 51.5% of nodal disease. Five‐year event‐free survival (EFS) was 92.0% (95% CI 88.4%‐95.6%). Sampling ≥7 to 12 retroperitoneal lymph nodes appeared optimal for detecting positive nodes; while there was a trend toward improved EFS among those undergoing template RPLND, this was not statistically significant ( P = .068). Age ( P = .28), N‐stage ( P = .39), T‐stage ( P = .11) and pathologic node involvement ( P = .53) were not associated with overall survival. However, older age and larger tumor size had an additive impact on EFS ( P = .027) though not overall survival ( P = .13). In conclusion, outcomes for patients with PT‐RMS are excellent. Reliance on imaging to detect nodal involvement will miss pathologic node involvement and may result in undertreatment. Surgical nodal staging requires at least 7 to 12 nodes to accurately identify patients with regional nodal disease.

Introduction: Central venous access using peripherally inserted central catheters is frequently used for patients receiving intravenous medications in the hospital or outpatients. Although there are several benefits of peripherally inserted central catheters, such as ease of insertion, low procedure-related risk and higher patient satisfaction, there are complications associated with peripherally inserted central catheter use. Despite some studies evaluating peripherally inserted central catheter line–related complications, the factors associated with peripherally inserted central catheter–related deep venous thrombosis in critically ill medical-surgical patients are poorly described. The objective of this case-control study was to identify the risk factors associated with peripherally inserted central catheter line–related deep venous thrombosis in critically ill medical-surgical intensive care unit patients in a community hospital. Methods: We abstracted relevant clinical data from 21 cases with symptomatic peripherally inserted central catheter–related deep venous thrombosis and 42 controls with peripherally inserted central catheters but no deep venous thrombosis. Results: Of the factors evaluated, female gender, the use of triple lumen peripherally inserted central catheters, larger outer diameter, and open (vs valve) peripherally inserted central catheters were associated with venous thrombosis. In this retrospective study, we did not identify any association of peripherally inserted central catheter–related deep venous thrombosis with a prior history of deep venous thrombosis, use of alteplase, antiplatelet therapy, prophylactic or therapeutic anticoagulation, international normalized ratio, platelet count and the use of peripherally inserted central catheters for total parenteral nutrition. Conclusion: Our study indicates that the catheter size relative to the diameter of the vein could be an important risk factor for the development of peripherally inserted central catheter–related deep venous thrombosis. The study findings should be confirmed in a larger study designed to identify risk factors of peripherally inserted central catheter–related deep venous thrombosis. In the meantime, the peripherally inserted central catheter lines should be used judiciously in critically ill patients.

Background Past research in population health trends has shown that injuries form a substantial burden of population health loss. Regular updates to injury burden assessments are critical. We report Global Burden of Disease (GBD) 2017 Study estimates on morbidity and mortality for all injuries. Methods We reviewed results for injuries from the GBD 2017 study. GBD 2017 measured injury-specific mortality and years of life lost (YLLs) using the Cause of Death Ensemble model. To measure non-fatal injuries, GBD 2017 modelled injury-specific incidence and converted this to prevalence and years lived with disability (YLDs). YLLs and YLDs were summed to calculate disability-adjusted life years (DALYs). Findings In 1990, there were 4 260 493 (4 085 700 to 4 396 138) injury deaths, which increased to 4 484 722 (4 332 010 to 4 585 554) deaths in 2017, while age-standardised mortality decreased from 1079 (1073 to 1086) to 738 (730 to 745) per 100 000. In 1990, there were 354 064 302 (95% uncertainty interval: 338 174 876 to 371 610 802) new cases of injury globally, which increased to 520 710 288 (493 430 247 to 547 988 635) new cases in 2017. During this time, age-standardised incidence decreased non-significantly from 6824 (6534 to 7147) to 6763 (6412 to 7118) per 100 000. Between 1990 and 2017, age-standardised DALYs decreased from 4947 (4655 to 5233) per 100 000 to 3267 (3058 to 3505). Interpretation Injuries are an important cause of health loss globally, though mortality has declined between 1990 and 2017. Future research in injury burden should focus on prevention in high-burden populations, improving data collection and ensuring access to medical care.

AbstractProper cell‐cycle progression is essential for the self‐renewal and differentiation of human pluripotent stem cells (hPSCs). The fluorescent ubiquitination‐based cell‐cycle indicator (FUCCI) has allowed the dual‐color visualization of the G1 and S/G2/M phases in various dynamic models, but its application in hPSCs is not widely reported. In addition, lineage‐specific FUCCI reporters have not yet been developed to analyze complex tissue‐specific cell‐cycle progression during hPSC differentiation. Desiring a robust tool for spatiotemporal reporting of cell‐cycle events in hPSCs, we employed the CRISPR/Cas9 genome editing tool and successfully knocked the FUCCI reporter into the AAVS1 safe harbor locus of hPSCs for stable and constitutive FUCCI expression, exhibiting reliable cell‐cycle‐dependent fluorescence in both hPSCs and their differentiated progeny. We also established a cardiac‐specific TNNT2‐FUCCI reporter for lineage‐specific cell‐cycle monitoring of cardiomyocyte differentiation from hPSCs. This powerful and modular FUCCI system should provide numerous opportunities for studying human cell‐cycle activity, and enable the identification and investigation of novel regulators for adult tissue regeneration.

In previous studies, we found that after cervical spinal cord hemisection at C2 (SH), neuromuscular transmission improved in the rat diaphragm muscle (DIAm). We also found that exogenous brain‐derived neurotrophic factor (BDNF) treatment enhanced neuromuscular transmission, whereas inhibiting activation of its receptor (TrkB) worsened neuromuscular transmission. We hypothesized that expression of BDNF and/or its receptor TrkB at phrenic motoneurons would increase following SH. In the present study, adult male rats underwent SH or sham surgery. Phrenic motoneurons were labeled by injection of cholera toxin B into the DIAm and retrogradely‐labeled phrenic motoneurons were sampled by laser capture microdissection (LCM). BDNF and TrkB receptor (truncated – T1 and full length – FL) mRNA were measured in LCM‐microdissected motoneurons using quantitative real‐time RT‐PCR and expressed as a ratio to ribosomal S16 RNA. We found that BDNF mRNA expression in phrenic motoneurons increased by 3 days after SH (~2‐fold). Similarly, both TrkB.T1 and TrkB.FL mRNA increased by 3 days after SH (~17‐ and ~11‐fold, respectively). It is possible that the relative expression of neurotrophins and their receptors (truncated or full‐length) may determine the time‐course of restoration of phrenic activity following SH. Supported by NIH grants AR51173 and HL37680 and the Mayo Foundation.

Abstract Wiskott-Aldrich syndrome (WAS) is an X-linked disease caused by mutations in the WAS gene, leading to thrombocytopenia, eczema, recurrent infections, autoimmune disease, and malignancy. Hematopoietic cell transplantation (HCT) is the primary curative approach, with the goal of correcting the underlying immunodeficiency and thrombocytopenia. HCT outcomes have improved over time, particularly for patients with HLA-matched sibling and unrelated donors. We report the outcomes of 129 patients with WAS who underwent HCT at 29 Primary Immune Deficiency Treatment Consortium centers from 2005 through 2015. Median age at HCT was 1.2 years. Most patients (65%) received myeloablative busulfan-based conditioning. With a median follow-up of 4.5 years, the 5-year overall survival (OS) was 91%. Superior 5-year OS was observed in patients <5 vs ≥5 years of age at the time of HCT (94% vs 66%; overall P = .0008). OS was excellent regardless of donor type, even in cord blood recipients (90%). Conditioning intensity did not affect OS, but was associated with donor T-cell and myeloid engraftment after HCT. Specifically, patients who received fludarabine/melphalan-based reduced-intensity regimens were more likely to have donor myeloid chimerism <50% early after HCT. In addition, higher platelet counts were observed among recipients who achieved full (>95%) vs low-level (5%-49%) donor myeloid engraftment. In summary, HCT outcomes for WAS have improved since 2005, compared with prior reports. HCT at a younger age continues to be associated with superior outcomes supporting the recommendation for early HCT. High-level donor myeloid engraftment is important for platelet reconstitution after either myeloablative or busulfan-containing reduced intensity conditioning. (This trial was registered at www.clinicaltrials.gov as #NCT02064933.)

11070 Background: Pazopanib is a tyrosine kinase inhibitor approved globally for advanced soft tissue sarcomas. The dose finding phase of this cooperative group trial assessed the dose limiting toxicities (DLT) and the maximally tolerated dose (MTD) of adding pazopanib to neoadjuvant chemoradiation or radiation therapy in children and adults with unresected intermediate/high-risk trunk and extremity non-rhabdomyosarcoma soft tissue sarcomas (NRSTS). Methods: ARST1321, a jointly designed intergroup study lead by Children's Oncology Group and NRG Oncology opened for enrollment in July 2014. Eligible adult and pediatric patients with newly diagnosed, unresected trunk/extremity NRSTS with plans for primary tumor resection were enrolled into either the Chemotherapy Cohort (those with chemosensitive NRSTS > 5 cm, grade 3, including all synovial sarcoma) or the Non-Chemotherapy Cohort (those with chemotherapy insensitive NRSTS of any size, grade 2/3, or any chemosensitive NRSTS for whom no chemotherapy was planned per discretion of patients and treatment teams). In the Chemotherapy Cohort, pazopanib was given with ifosfamide (7.5 grams/m2) and doxorubicin (75 mg/m2) plus 45 Gy preoperative RT starting after cycle 2. Primary tumor was resected at week 13, followed by chemotherapy and pazopanib to week 25. In the Non-Chemotherapy Cohort, pazopanib was given with 50 Gy preoperative RT, primary tumor was resected at week 10, and pazopanib continued to week 25. Feasibility was assessed through week 6 of therapy to determine pazopanib dose escalation/de-escalation based on DLT, total doses of pazopanib, and overall adverse event profile. Results: In the Chemotherapy Cohort, MTD was reached at Dose Level 1 (350 mg/m2 peds; 600 mg adults) with two DLTs (1 grade 3 ALT rise, 1 intolerability to therapy) in 10 patients. In the Non-Chemotherapy Cohort, 11 patients enrolled at Dose Level 1 (350 mg/m2 peds; 600 mg adults) without any observed DLTs and all received ≥75% of prescribed total pazopanib dose; MTD was reached at Dose Level 2 (450 mg/m2 peds; 800 mg adults) with 2 DLTs in ten patients enrolled (1 grade 3 dermatitis and 1 intolerability to therapy) and 9/10 receiving ≥75% of full dose. Conclusions: Pazopanib in combination with chemoradiation or radiation therapy alone was found to be safe in children and adults with NRSTS. Following this finding, ARST1321 opened in both arms using the newly determined pazopanib MTDs. Clinical trial information: NCT02180867.