Intra-arterial Peptide Receptor Radionuclide Therapy for the Treatment of Hepatic Neuroendocrine Tumor Metastases: Hope or Hype?

Peptide receptor radionuclide therapy (PRRT) confers significant progression-free survival advantage for patients with small bowel grade 1 and 2 well-differentiated neuroendocrine tumors (WD NET). PRRT may also be clinically beneficial for patients with NET of pancreatic, bronchial, and other sites of origin; patients with paragangliomas; as well as for patients with well-differentiated grade 3 NET. Direct intra-arterial (IA) administration of PRRT into the hepatic artery for patients with NET liver metastases may result in higher radiopharmaceutical dose and longer dwell time in the liver tumors while relatively sparing non-tumor liver tissue and other organs such as the kidneys and bone marrow when compared with intravenous (IV) administration. This review summarizes currently available data on IA and IV PRRT dose distribution, reports safety and efficacy of IA PRRT, and proposes future research questions.

Contemporary applications of Y90 for the treatment of hepatocellular carcinoma.

Transarterial radioembolization (TARE) with yttrium-90 (90Y) microspheres has been widely adopted for the treatment of HCC. Recent advances in yttrium-90 (90Y) dosimetry have led to durable local responses. Radiation segmentectomy has become a viable alternative to thermal ablation for early-stage HCC (Barcelona Clinic Liver Cancer 0 and A) and has been commonly used as a bridge to transplant. TARE is also commonly used for downstaging to transplant using traditional lobar dosimetry and radiation segmentectomy techniques. Radiation lobectomy has a dual role in local tumor control and induction of contralateral liver lobe hypertrophy as a bridge to resection for patients with an inadequate future liver remnant. TARE continues to provide disease control for patients with limited vascular invasion and may be an alternative to systemic therapy for patients with localized advanced disease. The potential synergy between TARE and immunotherapy has been recognized, and prospective studies evaluating this combination are needed for patients with Barcelona Clinic Liver Cancer B and C HCC.

A high-content, high-throughput siRNA screen identifies cyclin D2 as a potent regulator of muscle progenitor cell fusion and a target to enhance muscle regeneration.

Cell-mediated regenerative approaches using muscle progenitor cells hold promises for the treatment of many forms of muscle disorders. Their applicability in the clinic, however, is hindered by the low levels of regeneration obtained after transplantation and the large number of cells required to achieve an effect. To better understand the mechanisms that regulate the temporal switch of replicating muscle progenitor cells into terminally differentiated cells and to develop new strategies that could enhance muscle regeneration, we have developed and performed a high-throughput screening (HTS) capable of identifying genes that play active roles during myogenesis. Secondary and tertiary screens were used to confirm the effects of RNAi in vitro and in vivo and to select for candidate hits that significantly increase regeneration into skeletal muscles. Downregulation of cyclin D2 (CCND2) was shown to dramatically enhance myogenic differentiation of muscle progenitor cells and to induce a robust regeneration after cell transplantation into skeletal muscles of dystrophin-deficient mice. Protein interaction network and pathway analysis revealed that CCND2 directly interacts with the cyclin-dependent kinase Cdk4 to inhibit phosphorylation of the retinoblastoma protein (pRb), thus blocking the activation of the myogenic switch during fusion. These studies identify CCND2 as a new key regulator of terminal differentiation in muscle progenitor cells and open new possibilities for the treatment of many forms of muscle disorders characterized by impaired regeneration and loss of muscle mass.