Treatment-driven selection of chemoresistant Ewing sarcoma tumors with limited drug distribution.

Ewing sarcoma is a bone and soft tissue tumor predominantly affecting adolescents and young adults. To characterize changes in anticancer drug activity and intratumor drug distribution during the evolution of Ewing sarcomas, we used immunodeficient mice to establish pairs of patient-derived xenografts (PDX) at early (initial diagnosis) and late (relapse or refractory progression) stages of the disease from three patients. Analysis of copy number alterations (CNA) in early passage PDX tissues showed that two tumor pairs established from patients which responded initially to therapy and relapsed more than one year later displayed similar CNAs at early and late stages. For these two patients, PDX established from late tumors were more resistant to chemotherapy (irinotecan) than early counterparts. In contrast, the tumor pair established at refractory progression showed highly dissimilar CNA profiles, and the pattern of response to chemotherapy was discordant with those of relapsed cases. In mice receiving irinotecan infusions, the level of SN-38 (active metabolite of irinotecan) in the intracellular tumor compartment was reduced in tumors at later stages compared to earlier tumors for those pairs bearing similar CNAs, suggesting that distribution of anticancer drug shifted toward the extracellular compartment during clonal tumor evolution. Overexpression of the drug transporter P-glycoprotein in late tumor was likely responsible for this shift in drug distribution in one of the cases.

Therapeutic targeting of the RB1 pathway in retinoblastoma with the oncolytic adenovirus VCN-01.

Retinoblastoma is a pediatric solid tumor of the retina activated upon homozygous inactivation of the tumor suppressor RB1 VCN-01 is an oncolytic adenovirus designed to replicate selectively in tumor cells with high abundance of free E2F-1, a consequence of a dysfunctional RB1 pathway. Thus, we reasoned that VCN-01 could provide targeted therapeutic activity against even chemoresistant retinoblastoma. In vitro, VCN-01 effectively killed patient-derived retinoblastoma models. In mice, intravitreous administration of VCN-01 in retinoblastoma xenografts induced tumor necrosis, improved ocular survival compared with standard-of-care chemotherapy, and prevented micrometastatic dissemination into the brain. In juvenile immunocompetent rabbits, VCN-01 did not replicate in retinas, induced minor local side effects, and only leaked slightly and for a short time into the blood. Initial phase 1 data in patients showed the feasibility of the administration of intravitreous VCN-01 and resulted in antitumor activity in retinoblastoma vitreous seeds and evidence of viral replication markers in tumor cells. The treatment caused local vitreous inflammation but no systemic complications. Thus, oncolytic adenoviruses targeting RB1 might provide a tumor-selective and chemotherapy-independent treatment option for retinoblastoma.

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.

Increased delivery of chemotherapy to the vitreous by inhibition of the blood-retinal barrier.

Treatment of retinoblastoma -a pediatric cancer of the developing retina- might benefit from strategies to inhibit the blood-retinal barrier (BRB). The potent anticancer agent topotecan is a substrate of efflux transporters BCRP and P-gp, which are expressed at the BRB to restrict vitreous and retinal distribution of xenobiotics. In this work we have studied vitreous and retinal distribution, tumor accumulation and antitumor activity of topotecan, using pantoprazole as inhibitor of BCRP and P-gp. We used rabbit and mouse eyes as BRB models and patient-derived xenografts as retinoblastoma models. To validate the rabbit BRB model we stained BCRP and P-gp in the retinal vessels. Using intravitreous microdialysis we showed that the penetration of the rabbit vitreous by lactone topotecan increased significantly upon concomitant administration of pantoprazole (P=0.0285). Pantoprazole also increased topotecan penetration of the mouse vitreous, measured as the vitreous-to-plasma topotecan concentration ratio at the steady state (P=0.0246). Pantoprazole increased topotecan antitumor efficacy and intracellular penetration in retinoblastoma in vitro, but did not enhance intratumor drug distribution and survival in mice bearing the intraocular human tumor HSJD-RBT-2. Anatomical differences with the clinical setting likely limited our in vivo study, since xenografts were poorly vascularized masses that loaded most of the vitreous compartment. We conclude that pharmacological modulation of the BRB is feasible, enhances anticancer drug distribution into the vitreous and might have clinical implications in retinoblastoma. CHEMICAL COMPOUNDS INCLUDED IN THIS MANUSCRIPT: Topotecan (PubChem CID: 60700) Pantoprazole sodium (PubChem CID: 15008962).

Nefritis tubulointersticial probada por biopsia: revisión clínico-patológica / Biopsy-proven tubulointerstitial nephritis: a clinicopathological review

Introducción: La nefritis tubulointersticial es una de las causas más frecuentes de lesión renal aguda que puede progresar a enfermedad renal crónica, siendo el uso y abuso de fármacos nefrotóxicos la principal causa. La biopsia renal contribuye al diagnóstico en la mayoría de casos. Objetivo: Realizar una descripción clínico-patológica de pacientes con diagnóstico de nefritis tubulointersticial y su desenlace. Materiales y métodos: Se realizó un estudio descriptivo retrospectivo de casos de nefritis tubulointersticial comprobados mediante biopsia renal, entre 2000 y 2013. Se revisaron las biopsias renales y las historias clínicas para determinar las características histológicas, presentación clínica y evolución. Resultados: Se incluyeron 55 casos, seis niños y 49 adultos, en un rango de edad entre cinco y 81 años; 61,8% de ellos eran hombres. Un total de 40 casos presentaron lesión renal aguda, 10 presentaron enfermedad renal crónica, tres glomerulonefritis rápidamente progresiva, uno síndrome nefrítico y uno proteinuria subnefrótica. Todas las biopsias mostraron inflamación intersticial. La mediana de la creatinina sérica inicial fue de 4,6 mg/dL (rango = 0,7 - 23,0). La nefritis tubulointersticial se asoció a: consumo de antibióticos (27,3%), antinflamatorios no esteroideos (21,8%), tóxicos (7,3%), medicamentos naturistas (5,5%), otras causas (12,7%) y de causa desconocida (25,5%). En 50 pacientes con seguimiento, el 72,0% presentaron remisión clínica completa y 28,0% desarrollaron enfermedad renal crónica. Conclusiones: La nefritis tubulointersticial es una enfermedad de buen pronóstico. En un porcentaje importante de casos no logra determinarse el factor causal, por lo que se recomienda implementar mecanismos de información que permitan determinar la incidencia, prevalencia y factores etiológicos en nuestra población.

Introduction: Tubulointerstitial nephritis is one of the most frequent causes of acute kidney injury that may progress to chronic kidney disease. The use and abuse of nephrotoxic drugs are the main cause. Renal biopsy contributes to diagnosis in most cases. Objective: To perform a clinical and pathologic description of patients diagnosed with tubulointerstitial nephritis and their outcome. Materials and methods:A descriptive, retrospective study for cases of tubulointerstitial nephritis proven by renal biopsy between2000 and 2013 was performed. To determine histological features, clinical presentation and outcome, renal biopsies and clinical records were reviewed. Results: A total of 55 cases were included, six child and 49 adults, on age range of five to 81 years, 61,8% of them were men. Of cases, 40 had acute kidney injury, 10 chronic renal disease, three rapidly progressive glomerulonephritis, one nephritic syndrome, and one sub-nephrotic proteinuria. All biopsies showed interstitial inflammation. The medianof initial serum creatinine was 4,6 mg/dL (0,7 – 23,0). Tubulointerstitial nephritis was associated to: antibiotics (27,3%), nonsteroidal anti-inflammatory drugs (21,8%), toxins (7,3%), herbal medicines (5,5%), others causes (12,7%) and unknown cause (25,5%). From 50 follow-up patients, 72% presented complete remission and 28% chronic kidney disease. Conclusions: Tubulointerstitial nephritis is a renal disease with good prognosis. It is not possible to determine the causative factor in a significant percentage of cases, so it is recommended to implement mechanisms of information to determine the incidence, prevalence and etiologic factors in our population.