Hemangioma is a benign tumor of infancy whose hallmark is rapid growth during the first year of life followed by slow regression during early childhood. The proliferating phase is characterized by abundant immature endothelial cells, the involuting phase by prominent endothelial-lined vascular channels and endothelial apoptosis, and the involuted phase by few remaining capillary-like vessels surrounded by loose fibrofatty tissue. Nothing is known about the mechanisms that contribute to the adipogenesis during this spontaneous regression. We postulated that mesenchymal stem cells (MSCs) reside in the tumor and preferentially differentiate into adipocytes. To test this hypothesis, we isolated MSCs from 14 proliferating and five involuting hemangiomas by taking advantage of the well known selective adhesion of MSCs to bacteriologic dishes. These hemangioma-derived MSCs (Hem-MSCs) are similar to MSCs obtained from human bone marrow, expressing the cell surface markers SH2 (CD105), SH3, SH4, CD90, CD29, smooth muscle ␣-actin, and CD133 but not the hematopoietic markers CD45 and CD14 or the hematopoietic/endothelial markers CD34, CD31, and kinase insert domain receptor (KDR). HemMSCs exhibited multilineage differentiation with robust adipogenic potential that correlated with the proliferating phase. The numbers of adipogenic Hem-MSCs were higher in proliferating-phase than in involuting-phase tumors and higher than in normal infantile skin. Furthermore, HemMSCs exhibited a random pattern of X-chromosomal inactivation, indicating that these cells are not clonally derived. In summary, we have identified MSCs as a novel cellular constituent in infantile hemangioma. These MSCs may contribute to the adipogenesis during hemangioma involution.

Oncogenic gene fusions are hybrid genes that result from structural DNA rearrangements, leading to deregulated activity. Fusions involving the neuregulin-1 gene (NRG1) result in ErbB-mediated pathway activation and therefore present a rational candidate for targeted treatment. The most frequently reported NRG1 fusion is CD74-NRG1, which most commonly occurs in patients with invasive mucinous adenocarcinomas (IMAs) of the lung, although several other NRG1 fusion partners have been identified in patients with lung cancer, including ATP1B1, SDC4, and RBPMS. NRG1 fusions are also present in patients with other solid tumors, such as pancreatic ductal adenocarcinoma. In general, NRG1 fusions are rare across different types of cancer, with a reported incidence of <1%, with the notable exception of IMA, which represents z2%e10% of lung adenocarcinomas and has a reported incidence of z10%e30% for NRG1 fusions. A substantial proportion (z20%) of NRG1 fusion-positive non-small-cell lung cancer cases are nonmucinous adenocarcinomas. ErbB-targeted treatments, such as afatinib, a pan-ErbB tyrosine kinase inhibitor, are potential therapeutic strategies to address unmet treatment needs in patients harboring NRG1 fusions.

Endometriosis, the growth of ectopic endometrial tissue, is a chronic recurrent disease affecting 10% of the female population causing dyspareunia, pelvic pain, dysmenorrhea, and infertility. Suppression of ovarian activity is the cornerstone of medical therapy with limited benefit and severe adverse effects. Angiogenesis plays a major role in the development of endometriosis suggesting that anti-angiogenic therapy would offer a new therapeutic approach. We report successful treatment of endometriosis in estrogen-supplemented ovariectomized mice by transient overexpression (6 to 10 days of duration) of the gene for a natural angiogenesis inhibitor angiostatin, delivered to the peritoneum by a replication-deficient adenovirus vector (AdAngiostatin). Established endometriosis was eradicated in 14 of 14 AdAngiostatintreated animals, whereas 11 of 13 control animals showed full disease development. Administered to normal cycling mice for the same transient period, AdAngiostatin caused impaired ovarian function with suppressed corpus luteum development, decreased production of estradiol and progesterone, decreased ovarian and uterine weight, and increased body weight. AdAngiostatin treatment lowered the levels of sex steroids but did not induce total castration. Gene therapy with angiogenic inhibitors is a highly effective treatment for endometriosis, even in a host with preserved estrogen levels. However, local or targeted delivery of the gene must be considered to avoid prolonged systemic effects and impaired ovarian function. Endometriosis, the growth of functional endometrial tissue containing both glands and stroma outside the uterine cavity, is a chronic recurrent disease affecting a large number of women. Classic symptoms of endometriosis are dyspareunia, chronic pelvic pain, dysmenorrhea, and infertility. Affected women often have a poor quality of life and the disease is associated with significant health costs.1 Approximately 10% of the general female population suffer from endometriosis 2 and almost 70% of young women with chronic pelvic pain have the disorder.3 Among infertile women, the prevalence of endometriosis is 20 to 40% and presence of endometriosis decreases the success rate of in vitro fertilization. 4 Moreover, there is an association between untreated endometriosis and development of ovarian cancer.

Introduction: BIBF 1120 (planned brand name Vargatef) is a novel, oral, triple angiokinase inhibitor targeting three receptor classes involved in blood vessel formation. The objectives of this phase I, openlabel dose-escalation study were to determine the safety, tolerability, and maximum tolerated dose (MTD) of BIBF 1120 with pemetrexed in patients with recurrent advanced-stage non-small cell lung carcinoma.Patients and Methods: Patients harboring a tumor of any non-small cell lung carcinoma histology, previously treated with one first-line platinum-based chemotherapy regimen, received a BIBF 1120 starting dose of 100 mg bid (days 2-21) with pemetrexed 500 mg/m 2 (day 1) over a 21-day cycle. Previous

It has been shown that intratumor administration of an adenovirus vector expressing IL-12 produces a potent T cellmediated response that leads to significant tumor regression in a murine breast cancer model. IP-10 and MIG are CXC chemokines that recruit mononuclear cells in vivo. In addition to their chemotactic roles, IP-10 and MIG inhibit angiogenesis. We tested whether the addition of IP-10 or MIG may both enhance the antitumor immune response of IL-12 through T cell recruitment and inhibit tumor growth through angiostasis. Adenovirus vectors expressing IP-10 or MIG and/or IL-12 were administered intratumorally in a

In this study, we used intratumor delivery of adenoviral vectors to induce a selective anti-tumor response by combining the potent angiogenesis inhibitor murine angiostatin (adenovirus (Ad)-angiostatin) with the powerful immune simulator and angiostatic cytokine murine IL-12 (Ad-IL-12). In a murine model of breast carcinoma, intratumor injection of Ad-angiostatin delayed mean tumor growth, as compared with control virus with an initial regression of tumor growth, in 65% of treated animals. However, all treated animals eventually succumbed to the tumors. Mice injected with Ad-IL-12 alone responded with an initial regression in 20% of treated animals, with only 13% developing a total regression. Coinjection of the vectors resulted in 96% of the treated animals developing an initial regression, with 54% undergoing a total regression of the tumor. These mice were resistant to tumor rechallenge and developed a strong CTL response. Frozen tumor sections were stained for microvessel density using an Ab against murine CD31, an endothelial cell marker. Automated image analysis revealed the mean microvessel density following the administration of Ad-angiostatin and Ad-IL-12 alone or in combination was significantly reduced compared with the control-treated tumor. In summary, we have shown that a short-term course of antiangiogenic therapy combined with immunotherapy can effectively shrink a solid tumor and vaccinate the animal against rechallenge. The rationale for this therapy is to limit the tumor size by attacking the vasculature with angiostatin, thereby allowing IL-12 to mount a T cell-specific response against the tumor Ag.

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Angiostatin, an internal fragment of plasminogen, has been shown to inhibit the process of angiogenesis or neovascularization. In this study, we have expressed the cDNA for murine angiostatin under the control of the human cytomegalovirus promoter from a human type-5 adenovirus and shown that this vector produces a protein which retains biological activity. Angiostatin expression was determined by Northern blot analysis and Western immunoblotting. Ad-angiostatin, but not a control vector Ad-dl70, significantly reduced the viability of infected human umbilical cord vein endothelial cells (HUVEC) in vitro. In an in vivo model of basic fibroblast growth factorinduced angiogenesis, Ad-angiostatin (1 ؋ 10 9 pfu) could inhibit endothelial cell migration and the formation of capillaries within a Matrigel plug which had been implanted for one week subcutaneously into C57BL/6 mice. Endothelial cells in these plugs had an altered, rounded, phenotype with dark picnotic nuclei indicative of apoptosis, which was confirmed using transmission electron microscopy. In contrast, endothelial cells from bFGF alone or in combination with the control vector-treated plugs retained the long spindle shape characteristic of endothelial cells. Tumors in situ that are smaller than 3 mm in diameter, exist in a pre-vascular state and are limited in their ability to grow without perfusion from the blood supply.