Prognostic value of patient-derived xenograft engraftment in pediatric sarcomas.

The goals of this work were to identify factors favoring patient-derived xenograft (PDX) engraftment and study the association between PDX engraftment and prognosis in pediatric patients with Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma. We used immunodeficient mice to establish 30 subcutaneous PDX from patient tumor biopsies, with a successful engraftment rate of 44%. Age greater than 12 years and relapsed disease were patient factors associated with higher engraftment rate. Tumor type and biopsy location did not associate with engraftment. PDX models retained histology markers and most chromosomal aberrations of patient samples during successive passages in mice. Model treatment with irinotecan resulted in significant activity in 20 of the PDXs and replicated the response of rhabdomyosarcoma patients. Successive generations of PDXs responded similarly to irinotecan, demonstrating functional stability of these models. Importantly, out of 68 tumor samples from 51 patients with a median follow-up of 21.2 months, PDX engraftment from newly diagnosed patients was a prognostic factor significantly associated with poor outcome (p = 0.040). This association was not significant for relapsed patients. In the subgroup of patients with newly diagnosed Ewing sarcoma classified as standard risk, we found higher risk of relapse or refractory disease associated with those samples that produced stable PDX models (p = 0.0357). Overall, our study shows that PDX engraftment predicts worse outcome in newly diagnosed pediatric sarcoma patients.

Tissue Compatibility of SN-38-Loaded Anticancer Nanofiber Matrices.

Delivery of chemotherapy in the surgical bed has shown preclinical activity to control cancer progression upon subtotal resection of pediatric solid tumors, but whether this new treatment is safe for tumor-adjacent healthy tissues remains unknown. Here, Wistar rats are used to study the anatomic and functional impact of electrospun nanofiber matrices eluting SN-38-a potent chemotherapeutic agent-on several body sites where pediatric tumors such as neuroblastoma, Ewing sarcoma, and rhabdomyosarcoma arise. Blank and SN-38-loaded matrices embracing the femoral neurovascular bundle or in direct contact with abdominal viscera (liver, kidney, urinary bladder, intestine, and uterus) are placed. Foreign body tissue reaction to the implants is observed though no histologic damage in any tissue/organ. Skin healing is normal. Tissue reaction is similar for SN-38-loaded and blank matrices, with the exception of the hepatic capsule that is thicker for the former although within the limits consistent with mild foreign body reaction. Tissue and organ function is completely conserved after local treatments, as assessed by the rotarod test (forelimb function), hematologic tests (liver and renal function), and control of clinical signs. Overall, these findings support the clinical translation of SN-38-loaded nanofiber matrices to improve local control strategies of surgically resected tumors.

SN-38-loaded nanofiber matrices for local control of pediatric solid tumors after subtotal resection surgery.

In addition to surgery, local tumor control in pediatric oncology requires new treatments as an alternative to radiotherapy. SN-38 is an anticancer drug with proved activity against several pediatric solid tumors including neuroblastoma, rhabdomyosarcoma and Ewing sarcoma. Taking advantage of the extremely low aqueous solubility of SN-38, we have developed a novel drug delivery system (DDS) consisting of matrices made of poly(lactic acid) electrospun polymer nanofibers loaded with SN-38 microcrystals for local release in difficult-to-treat pediatric solid tumors. To model the clinical scenario, we conducted extensive preclinical experiments to characterize the biodistribution of the released SN-38 using microdialysis sampling in vivo. We observed that the drug achieves high concentrations in the virtual space of the surgical bed and penetrates a maximum distance of 2 mm within the tumor bulk. Subsequently, we developed a model of subtotal tumor resection in clinically relevant pediatric patient-derived xenografts and used such models to provide evidence of the activity of the SN-38 DDS to inhibit tumor regrowth. We propose that this novel DDS could represent a potential future strategy to avoid harmful radiation therapy as a primary tumor control together with surgery.

Anderson-hynes pyeloplasty in patients less than 12 months old. Is the laparoscopic approach safe and feasible?

PURPOSE: The aim of our study is to compare the outcomes of open and laparoscopic pyeloplasty in children less than 12 months of age. PATIENTS AND METHODS: We reviewed all medical charts of patients less than 12 months old who underwent pyeloplasty from January 2007 to February 2013. We divided them in two groups: Open pyeloplasty (OP) and laparoscopic pyeloplasty (LP). The following data were analyzed: age, sex, weight, US measurements, operative time, hospital stay, complications, and success rate. Quantitative data were analyzed with the Student t test or Mann-Whitney U test, and chi-square test or Fisher test for qualitative data. RESULTS: Fifty-eight patients (46 boys and 12 girls) with a mean age of 4.66 months (±3.05) were included. Mean age was 4.25 months and 5.15 months in OP and LP group respectively. Mean weight was 6.78 kg and 7.02 kg in OP and LP groups. There were no statistical differences in age, weight, and sex between OP and LP groups. There were no statistical differences in preoperative ultrasonography measurements. Mean posterior-anterior (PA) pelvis diameter was 28.57 mm and 23.94 mm in OP and LP groups, respectively. Mean calices diameter were 10.86 mm and 10.96 mm in OP and LP groups, respectively. Mean operative time was 129.53 minutes in the OP group and 151.92 minutes in the LP group with statistical differences (P=0.018). Mean hospital stay was 6.34 days in the OP group and 3.46 in the LP group with statistical differences (P<0.05). No intraoperative and postoperative complications were found in either group. Hydronephrosis improved in all patients, and no patient needed a repeated pyeloplasty. CONCLUSION: The laparoscopic approach of Anderson-Hynes pyeloplasty in patients less than 12 months old is a safe procedure with the same outcomes as the open approach.