Biomechanics of regenerated esophageal tissue following the implantation of a tissue engineered CellspanTM Esophageal Implant.

The esophagus is a tubular organ with a multi-laminated tissue structure that functions to transport nutrition from the oral cavity to the stomach. Several diseases of the esophagus including congenital disorders require complete surgical esophagectomy. Ideally, segmental removal of the diseased/damaged tissue would spare the unaffected tissue and preserve organ function. To this end, a novel tissue engineered implant, the CellspanTM Esophageal Implant (CEI) was used to repair the esophagus following segmental resection of the thoracic esophagus in a porcine model. The current study investigated the mechanical strength and the associated tissue architecture of the CEI-stimulated tissue. The CEI bridged the proximal and distal native esophageal ends to restore the conduit by stimulating a regeneration process that progressed from a fibrovascular scar at 30-days to a fully epithelialized lumen at 90-days, followed by submucosal regeneration and regeneration of a 'laminated' adventitia with smooth muscle development in the 365-day cohort. The mechanical strength of the newly developed tissue as well as the flanking native tissue were assessed using a probe-burst pressure test (ASTM D6797-15). The burst pressures at all three time points were comparable to the native tissue flanking the implant. In addition, the overall pressure required to burst through both the native and regenerated tissues increased with increasing time post-implantation.

Esophageal regeneration following surgical implantation of a tissue engineered esophageal implant in a pediatric model.

Diseases of the esophagus, damage of the esophagus due to injury or congenital defects during fetal esophageal development, i.e., esophageal atresia (EA), typically require surgical intervention to restore esophageal continuity. The development of tissue engineered tubular structures would improve the treatment options for these conditions by providing an alternative that is organ sparing and can be manufactured to fit the exact dimensions of the defect. An autologous tissue engineered Cellspan Esophageal ImplantTM (CEI) was surgically implanted into piglets that underwent surgical resection of the esophagus. Multiple survival time points, post-implantation, were analyzed histologically to understand the tissue architecture and time course of the regeneration process. In addition, we investigated CT imaging as an "in-life" monitoring protocol to assess tissue regeneration. We also utilized a clinically relevant animal management paradigm that was essential for long term survival. Following implantation, CT imaging revealed early tissue deposition and the formation of a contiguous tissue conduit. Endoscopic evaluation at multiple time points revealed complete epithelialization of the lumenal surface by day 90. Histologic evaluation at several necropsy time points, post-implantation, determined the time course of tissue regeneration and demonstrated that the tissue continues to remodel over the course of a 1-year survival time period, resulting in the development of esophageal structural features, including the mucosal epithelium, muscularis mucosae, lamina propria, as well as smooth muscle proliferation/migration initiating the formation of a laminated adventitia. Long term survival (1 year) demonstrated restoration of oral nutrition, normal animal growth and the overall safety of this treatment regimen.

Future paradigms for precision oncology.

Research has exposed cancer to be a heterogeneous disease with a high degree of inter-tumoral and intra-tumoral variability. Individual tumors have unique profiles, and these molecular signatures make the use of traditional histology-based treatments problematic. The conventional diagnostic categories, while necessary for care, thwart the use of molecular information for treatment as molecular characteristics cross tissue types.This is compounded by the struggle to keep abreast the scientific advances made in all fields of science, and by the enormous challenge to organize, cross-reference, and apply molecular data for patient benefit. In order to supplement the site-specific, histology-driven diagnosis with genomic, proteomic and metabolomics information, a paradigm shift in diagnosis and treatment of patients is required.While most physicians are open and keen to use the emerging data for therapy, even those versed in molecular therapeutics are overwhelmed with the amount of available data. It is not surprising that even though The Human Genome Project was completed thirteen years ago, our patients have not benefited from the information. Physicians cannot, and should not be asked to process the gigabytes of genomic and proteomic information on their own in order to provide patients with safe therapies. The following consensus summary identifies the needed for practice changes, proposes potential solutions to the present crisis of informational overload, suggests ways of providing physicians with the tools necessary for interpreting patient specific molecular profiles, and facilitates the implementation of quantitative precision medicine. It also provides two case studies where this approach has been used.

Central neurocytoma responsive to topotecan, ifosfamide, carboplatin.

A 5-year-old male presented with spinal cord drop metastasis from a recurrent neurocytoma. Topotecan (0.5 mg/m(2)) and carboplatin (250 mg/m(2)) were administered on days 1-3 and ifosfamide (1,800 mg/m(2)) on days 1-5, every 21 days, for three cycles and resulted in complete response without severe complications. A literature review yielded 20 patients with central neurocytoma but no complete responses. The complete response of central neurocytoma to chemotherapy only reported here should be helpful to those caring for patients with this rare tumor.