Building towards Precision Oncology for Pancreatic Cancer: Real-World Challenges and Opportunities.

The advent of next-generation sequencing (NGS) has provided unprecedented insight into the molecular complexity of pancreatic ductal adenocarcinoma (PDAC). This has led to the emergence of biomarker-driven treatment paradigms that challenge empiric treatment approaches. However, the growth of sequencing technologies is outpacing the development of the infrastructure required to implement precision oncology as routine clinical practice. Addressing these logistical barriers is imperative to maximize the clinical impact of molecular profiling initiatives. In this review, we examine the evolution of precision oncology in PDAC, spanning from germline testing for cancer susceptibility genes to multi-omic tumor profiling. Furthermore, we highlight real-world challenges to delivering precision oncology for PDAC, and propose strategies to improve the generation, interpretation, and clinical translation of molecular profiling data.

p53 Nongenotoxic Activation and mTORC1 Inhibition Lead to Effective Combination for Neuroblastoma Therapy.

Purpose: mTORC1 inhibitors are promising agents for neuroblastoma therapy; however, they have shown limited clinical activity as monotherapy, thus rational drug combinations need to be explored to improve efficacy. Importantly, neuroblastoma maintains both an active p53 and an aberrant mTOR signaling.Experimental Design: Using an orthotopic xenograft model and modulating p53 levels, we investigated the antitumor effects of the mTORC1 inhibitor temsirolimus in neuroblastoma expressing normal, decreased, or mutant p53, both as single agent and in combination with first- and second-generation MDM2 inhibitors to reactivate p53.Results: Nongenotoxic p53 activation suppresses mTOR activity. Moreover, p53 reactivation via RG7388, a second-generation MDM2 inhibitor, strongly enhances the in vivo antitumor activity of temsirolimus. Single-agent temsirolimus does not elicit apoptosis, and tumors rapidly regrow after treatment suspension. In contrast, our combination therapy triggers a potent apoptotic response in wild-type p53 xenografts and efficiently blocks tumor regrowth after treatment completion. We also found that this combination uniquely led to p53-dependent suppression of survivin whose ectopic expression is sufficient to rescue the apoptosis induced by our combination.Conclusions: Our study supports a novel highly effective strategy that combines RG7388 and temsirolimus in wild-type p53 neuroblastoma, which warrants testing in early-phase clinical trials. Clin Cancer Res; 23(21); 6629-39. ©2017 AACR.

Heterogeneous Uptake of Nanoparticles in Mouse Models of Pediatric High-Risk Neuroblastoma.

Liposomal chemotherapeutics are exemplified by DOXIL® are commonly used in adult cancers. While these agents exhibit improved safety profile compared to their free drug counterparts, their treatment response rates have been ~ 20%, often attributed to the heterogeneous intratumoral uptake and distribution of liposomal nanoparticles. Non-invasive and quantitative monitoring of the uptake and distribution of liposomal nanoparticles in solid tumors could allow for patient stratification and personalized cancer nanomedicine. In this study, the variability of liposomal nanoparticle intratumoral distribution and uptake in orthotopic models of pediatric neuroblastoma was investigated using a liposomal nanoprobe visualized by high-resolution computed tomography (CT). Two human neuroblastoma cell lines (NGP: a MYCN-amplified line, and SH-SY5Y a MYCN non-amplified line) were implanted in the renal capsule of nude mice to establish the model. Intratumoral nanoparticle uptake was measured at tumor ages 1, 2, 3 and 4 weeks post implantation. The locations of uptake within the tumor were mapped in the 3-dimensional reconstructed images. Total uptake was measured by integration of the x-ray absorption signal over the intratumoral uptake locations. Both tumor models showed significant variation in nanoparticle uptake as the tumors aged. Observation of the uptake patterns suggested that the nanoparticle uptake was dominated by vascular leak at the surface/periphery of the tumor, and localized, heterogeneous vascular leak in the interior of the tumor. Slow growing SH-SY5Y tumors demonstrated uptake that correlated directly with the tumor volume. Faster growing NGP tumor uptake did not correlate with any tumor geometric parameters, including tumor volume, tumor surface area, and R30 and R50, measures of uptake localized to the interior of the tumor. However, uptake for both SH-SY5Y and NGP tumors correlated almost perfectly with the leak volume, as measured by CT. These results suggest that the uptake of nanoparticles is heterogeneous and not governed by tumor geometry. An imaging nanoprobe remains the best measure of nanoparticle uptake in these tumor models.

Transmembrane adaptor protein PAG1 is a novel tumor suppressor in neuroblastoma.

Neuroblastoma (NB) is the most common extracranial pediatric solid tumor with high mortality rates. The tyrosine kinase c-Src has been known to play an important role in differentiation of NB cells, but the mechanism of c-Src regulation has not been defined. Here, we characterize PAG1 (Cbp, Csk binding protein), a central inhibitor of c-Src and other Src family kinases, as a novel tumor suppressor in NB. Clinical cohort analysis demonstrate that low expression of PAG1 is a significant prognostic factor for high stage disease, increased relapse, and worse overall survival for children with NB. PAG1 knockdown in NB cells promotes proliferation and anchorage-independent colony formation with increased activation of AKT and ERK downstream of c-Src, while PAG1 overexpression significantly rescues these effects. In vivo, PAG1 overexpression significantly inhibits NB tumorigenicity in an orthotopic xenograft model. Our results establish PAG1 as a potent tumor suppressor in NB by inhibiting c-Src and downstream effector pathways. Thus, reactivation of PAG1 and inhibition of c-Src kinase activity represents an important novel therapeutic approach for high-risk NB.

G-CSF Promotes Neuroblastoma Tumorigenicity and Metastasis via STAT3-Dependent Cancer Stem Cell Activation.

Increasing evidence suggests that inflammatory cytokines play a critical role in tumor initiation and progression. A cancer stem cell (CSC)-like subpopulation in neuroblastoma is known to be marked by expression of the G-CSF receptor (G-CSFR). Here, we report on the mechanistic contributions of the G-CSFR in neuroblastoma CSCs. Specifically, we demonstrate that the receptor ligand G-CSF selectively activates STAT3 within neuroblastoma CSC subpopulations, promoting their expansion in vitro and in vivo. Exogenous G-CSF enhances tumor growth and metastasis in human xenograft and murine neuroblastoma tumor models. In response to G-CSF, STAT3 acts in a feed-forward loop to transcriptionally activate the G-CSFR and sustain neuroblastoma CSCs. Blockade of this G-CSF-STAT3 signaling loop with either anti-G-CSF antibody or STAT3 inhibitor depleted the CSC subpopulation within tumors, driving correlated tumor growth inhibition, decreased metastasis, and increased chemosensitivity. Taken together, our results define G-CSF as a CSC-activating factor in neuroblastoma, suggest a comprehensive reevaluation of the clinical use of G-CSF in these patients to support white blood cell counts, and suggest that direct targeting of the G-CSF-STAT3 signaling represents a novel therapeutic approach for neuroblastoma.

Minimally invasive surgical management of benign breast lesions.

Benign breast disease is common among women, and when symptomatic, definitive surgical management is preferred by both clinicians and patients. Given the nonmalignant nature of these lesions, an important factor in treatment is cosmesis. Novel minimally invasive techniques for breast lesions are rapidly emerging and demonstrate good efficacy, safety and cosmesis. This review will describe minimally invasive techniques of breast lesions via surgical and percutaneous approaches and discuss the outcomes, advantages and limitations for each. Based on promising initial results, the future standard of care for benign breast lesions may focus on one or more of these minimally invasive techniques.

G-CSF receptor positive neuroblastoma subpopulations are enriched in chemotherapy-resistant or relapsed tumors and are highly tumorigenic.

Neuroblastoma is a neural crest-derived embryonal malignancy, which accounts for 13% of all pediatric cancer mortality, primarily due to tumor recurrence. Therapy-resistant cancer stem cells are implicated in tumor relapse, but definitive phenotypic evidence of the existence of these cells has been lacking. In this study, we define a highly tumorigenic subpopulation in neuroblastoma with stem cell characteristics, based on the expression of CSF3R, which encodes the receptor for granulocyte colony-stimulating factor (G-CSF). G-CSF receptor positive (aka G-CSFr(+) or CD114(+)) cells isolated from a primary tumor and the NGP cell line by flow cytometry were highly tumorigenic and capable of both self-renewal and differentiation to progeny cells. CD114(+) cells closely resembled embryonic and induced pluripotent stem cells with respect to their profiles of cell cycle, miRNA, and gene expression. In addition, they reflect a primitive undifferentiated neuroectodermal/neural crest phenotype revealing a developmental hierarchy within neuroblastoma tumors. We detected this dedifferentiated neural crest subpopulation in all established neuroblastoma cell lines, xenograft tumors, and primary tumor specimens analyzed. Ligand activation of CD114 by the addition of exogenous G-CSF to CD114(+) cells confirmed intact STAT3 upregulation, characteristic of G-CSF receptor signaling. Together, our data describe a novel distinct subpopulation within neuroblastoma with enhanced tumorigenicity and a stem cell-like phenotype, further elucidating the complex heterogeneity of solid tumors such as neuroblastoma. We propose that this subpopulation may represent an additional target for novel therapeutic approaches to this aggressive pediatric malignancy.

Use of Mitomycin C for Refractory Esophageal Stricture following Tracheoesophageal Fistula Repair.

Esophageal stricture is a well-described complication following tracheoesophageal fistula repair. Herein, we report two patients who had persistent esophageal strictures after several months of repeat balloon dilatations. Each patient was treated with a single application of topical mitomycin C in addition to esophageal dilatation, which resulted in complete resolution of the stricture.

Current readings: surgical repair experience of congenital chest wall deformities.

Major advancements have been made in the surgical repair of congential chest wall deformities. This review highlights selected readings of the experience in correction of pectus excavatum and pectus carinatum. In particular, it summarizes the current standard of care and outcomes of new and modified procedures for patients with chest wall deformities.

Measurement of pulmonary circulation parameters using time-resolved MR angiography in patients after Ross procedure.

OBJECTIVE: The purposes of our study were to retrospectively evaluate the pulmonary circulation parameters of pulmonary transit time and pulmonary blood volume in patients after Ross procedures using time-resolved MR angiography and to investigate associations with right ventricular dysfunction in the same group of patients. MATERIALS AND METHODS: Sixteen patients who had undergone a Ross procedure (12 men, four women; mean age, 42.13 +/- 14.24 years; age range, 21-68 years) and 16 age- and sex-matched control patients (12 men, 4 women; mean age, 42.25 +/- 14.62 years; age range, 21-68 years) were evaluated using cardiac MRI and Argus postprocessing software. Right and left ventricular volumetric parameters, including ejection fraction, end-systolic volume, and end-diastolic volume, were measured from cine true fast imaging with steady-state precession images. Pulmonary circulation parameters, including pulmonary transit time, were measured using dynamic time-resolved MR angiography and pulmonary blood volume was calculated. Pulmonary circulation parameters were correlated with volumetric parameters. The results were statistically analyzed using the Mann-Whitney U test, paired-samples Student's t test, Pearson's correlation, and linear regression. RESULTS: Pulmonary circulation parameters were significantly prolonged in patients after the Ross procedure compared with control patients (p < 0.01). Strong correlations exist between pulmonary circulation parameters and right ventricular function, especially pulmonary transit time and right ventricular ejection fraction (R > 0.60, p < 0.001). CONCLUSION: Patients after undergoing the Ross procedure had prolonged pulmonary transit times compared with normal control patients; this and other pulmonary circulation parameters best correlate with worsened right ventricular ejection fraction and may be predictors of right ventricular dysfunction in this group of patients.