Iuliana D. Bobanga

Chemokines as Cancer Vaccine Adjuvants

We are witnessing a new era of immune-mediated cancer therapies and vaccine development. As the field of cancer vaccines advances into clinical trials, overcoming low immunogenicity is a limiting step in achieving full success of this therapeutic approach. Recent discoveries in the many biological roles of chemokines in tumor immunology allow their exploitation in enhancing recruitment of antigen presenting cells (APCs) and effector cells to appropriate anatomical sites. This knowledge, combined with advances in gene therapy and virology, allows researchers to employ chemokines as potential vaccine adjuvants. This review will focus on recent murine and human studies that use chemokines as therapeutic anti-cancer vaccine adjuvants.

Factors influencing disease recurrence after ileocolic resection in adult and pediatric onset Crohn's disease

BACKGROUND Factors influencing recurrence of ileocecal Crohns disease (CD) after surgical resection may differ between adolescents and adults. METHODS CD patients who underwent ileocecectomy were retrospectively divided into pediatric onset (age at diagnosis ≤ 16 years, n = 34) and adult onset (>16, n = 108) patients to evaluate differences in risks of endoscopic and clinical recurrence. RESULTS In 142 patients, rates of any recurrence, endoscopic recurrence, and clinical recurrence at 5 years were 78%, 88%, and 65%, respectively. Risks of recurrence were similar between groups. Younger patients were more likely to be on immunologics preoperatively and more likely to be started on immunoprophylaxis postoperatively. Immediate postoperative prophylaxis was predictive of delayed clinical recurrence only in the older group. CONCLUSIONS Despite increased preoperative and postoperative immunoprophylaxis in younger patients, recurrence rates of CD after ileocecectomy do not differ between these groups. Immediate postoperative prophylaxis was predictive of delayed clinical recurrence only in patients with adult onset CD.

Murine leukemia virus envelope gp70 is a shared biomarker for the high-sensitivity quantification of murine tumor burden

The preclinical development of anticancer drugs including immunotherapeutics and targeted agents relies on the ability to detect minimal residual tumor burden as a measure of therapeutic efficacy. Real-time quantitative (qPCR) represents an exquisitely sensitive method to perform such an assessment. However, qPCR-based applications are limited by the availability of a genetic defect associated with each tumor model under investigation. Here, we describe an off-the-shelf qPCR-based approach to detect a broad array of commonly used preclinical murine tumor models. In particular, we report that the mRNA coding for the envelope glycoprotein 70 (gp70) encoded by the endogenous murine leukemia virus (MuLV) is universally expressed in 22 murine cancer cell lines of disparate histological origin but is silent in 20 out of 22 normal mouse tissues. Further, we detected the presence of as few as 100 tumor cells in whole lung extracts using qPCR specific for gp70, supporting the notion that this detection approach has a higher sensitivity as compared with traditional tissue histology methods. Although gp70 is expressed in a wide variety of tumor cell lines, it was absent in inflamed tissues, non-transformed cell lines, or pre-cancerous lesions. Having a high-sensitivity biomarker for the detection of a wide range of murine tumor cells that does not require additional genetic manipulations or the knowledge of specific genetic alterations present in a given neoplasm represents a unique experimental tool for investigating metastasis, assessing antitumor therapeutic interventions, and further determining tumor recurrence or minimal residual disease.

Outcome differences between young children and adolescents undergoing kidney transplantation.

BACKGROUND/PURPOSE Although graft loss remains the biggest challenge for all pediatric kidney transplant (KT) recipients, unique challenges exist within different age groups. We aim to evaluate the different characteristics and graft survival outcomes of young children and adolescents undergoing KT. METHODS Children who underwent isolated KT between 2000 and 2013 at our institution were included in this retrospective analysis. Patient characteristics and outcomes were compared using students t-test, chi-square test, Kaplan-Meier curve and Cox proportional hazards model. RESULTS Of 73 children who underwent KT, 31 were <12 (young children), and 42 were ≥ 12 years old (adolescents). Overall patient survival was 100%. The younger group had superior 5-year (100% vs. 75.5%) and 10-year (94.4% vs. 43.8%) graft survival (p=0.008). Factors predictive of poor graft survival on multivariate analysis were older age at transplantation (HR 1.2, CI 1-1.4, p=0.047), female gender (HR 9.0, CI 1.9-43, p=0.006), and acute rejection episodes (HR 13, CI 2-90, p=0.008). The most common causes of graft loss were acute and chronic rejection episodes and immunosuppression nonadherence. CONCLUSION Adolescents undergoing KT have inferior graft survival compared to younger children. In adjusted modeling, children with older age, female gender, and acute rejection episodes have inferior graft survival.

CCL3 augments tumor rejection and enhances CD8+ T cell infiltration through NK and CD103+ dendritic cell recruitment via IFNγ

ABSTRACT Inflammatory chemokines are critical contributors in attracting relevant immune cells to the tumor microenvironment and driving cellular interactions and molecular signaling cascades that dictate the ultimate outcome of host anti-tumor immune response. Therefore, rational application of chemokines in a spatial-temporal dependent manner may constitute an attractive adjuvant in immunotherapeutic approaches against cancer. Existing data suggest that the macrophage inflammatory protein (MIP)-1 family and related proteins, consisting of CCL3 (MIP-1α), CCL4 (MIP-1β), and CCL5 (RANTES), can be major determinant of immune cellular infiltration in certain tumors through their direct recruitment of antigen presenting cells, including dendritic cells (DCs) to the tumor site. In this study, we examined how CCL3 in a murine colon tumor microenvironment, CT26, enhances antitumor immunity. We identified natural killer (NK) cells as a major lymphocyte subtype that is preferentially recruited to the CCL3-rich tumor site. NK cells contribute to the overall IFNγ content, CD103+ DC accumulation, and augment the production of chemokines CXCL9 and CXCL10 for enhanced T cell recruitment. We further demonstrate that both soluble CCL3 and CCL3-secreting irradiated tumor vaccine can effectively halt the progression of established tumors in a spatial-dependent manner. Our finding implies an important contribution of NK in the CCL3 – CD103+ DC – CXCL9/10 signaling axis in determining tumor immune landscape within the tumor microenvironment.

Foker Technique for the Management of Pure Esophageal Atresia: Long-Term Outcomes at a Single Institution

INTRODUCTION We present the short- and long-term outcomes in the management of pure long-gap esophageal atresia (LGEA) using the Foker technique (FT) of esophageal elongation by external axial traction at a single institution. METHODS All patients undergoing esophageal atresia (EA) repair with FT over a 10-year period were included in the study. Demographic data, birth weight, gestational age, associated anomalies, management, and short- and long-term outcomes were studied. RESULTS Five patients (three males) were treated with FT in the study period, all with LGEA, with a mean birth weight of 1,926 g (range, 541-2,890 g). Four infants had associated anomalies. Primary repair after FT axial traction was achieved in four patients after a mean traction time of 13 days (range, 12-15 days). FT failed in one patient who had esophageal perforation from traumatic orogastric tube placement at birth and extensive matting of the esophagus at the time of FT attempt. The mean age at definitive esophageal anastomosis was 11.5 weeks (range, 8-14 weeks). In three of the five patients, traction sutures from the distal esophageal segment tore away, requiring a thoracotomy for replacement. One of the four patients had a confined leak at the anastomosis. All four patients developed strictures at the anastomosis, requiring serial dilations (mean 12 dilations, range 6-21 dilations), and three of those patients underwent a thoracotomy for stricture resection (two patients) or stricturoplasty (one patient). On long-term follow-up, all patients in whom a primary anastomosis was achieved had their gastrostomy closed and were on full oral feeds. CONCLUSION FT was successful in achieving a primary anastomosis in 80% of the patients with LGEA, with a significant morbidity but favorable long-term outcomes.

Imaging Modalities for Adrenocortical Tumors

Incidental adrenal masses are increasingly being detected due to the more frequent use of high-resolution thoraco-abdominal imaging techniques. Almost all adrenal masses can be definitively characterized using imaging and biochemical studies alone. The majority of adrenal cortical tumors are benign. Densitometry using unenhanced computed tomography (UCT) and CT contrast medium washout testing, magnetic resonance imaging (MRI) with chemical shift averaging, and fluorine-18 fluorodeoxyglucose positron emission computed tomography ([FDG] PET/CT) are the principal modalities used to help differentiate a benign from a malignant adrenal mass. In most patients, a single imaging study is sufficient to characterize an adrenal mass and secondary imaging studies are unnecessary. Key elements that help guide management include a prior history of malignancy, the functional status of the mass, and whether the imaging phenotype is suggestive of benign or malignant disease. The imaging phenotype can be distinguished based on the size, morphology, lipid content, intravenous washout characteristics, and metabolic activity of the adrenal mass. When the imaging phenotype and the clinical and biochemical evaluation are consistent with a nonfunctioning adenoma, follow-up imaging is recommended in 3–6 months and then annually for 1–2 years, with repeat hormonal evaluation on an annual basis for 5 years.

New Treatments and New Therapies

Significant strides have been made in the area of cancer immunotherapy, sometimes referred to as the fourth discipline to fight cancer, in addition to surgery, chemotherapy and radiation therapy. This chapter will focus on the emerging therapies and strategies that are in late preclinical phases of development or currently being utilized in early clinical trials. Some of these promising therapies may have applications in the treatment of pediatric solid tumors while others may remain preclinical yet provide a limited forecast of the possibilities that lie on the horizon of pediatric cancer care. This chapter will specifically discuss immune-based (cellular, vaccine, and monoclonal), anti-angiogenesis, and gene and antisense therapies to provide a conceptual foundation of understanding these novel and emerging cancer strategies.

Oesophageal pseudodiverticulum after foregut duplication cyst excision: Case report and literature review.

Oesophageal pseudodiverticula rarely occur after excision of benign oesophageal neoplasms. While management and outcomes have been reported in the adult leiomyoma literature, sparse data exist on the occurrence and management of pseudodiverticula after foregut duplication cyst excision. We discuss our experience with a paediatric patient and review relevant literature regarding operative techniques and surgical outcomes.

Abstract 1174: VCAM-1 enhances immune evasion in a murine model of metastatic cervical cancer

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Surface over-expression of Vascular Cell Adhesion Molecule-1 (VCAM-1) has recently been identified as a mechanism used by metastatic breast cancer cells to provide pro-survival advantages. It has been previously shown that the metastatic and immune-resistant mouse cervical cancer cell line, A17 has a significantly increased expression of VCAM-1 compared with the primary parental tumor cell line, TC1-P0. Using this metastatic tumor model, we first modulated the surface expression levels of VCAM-1 on A17 in vitro by using an shRNA knockdown approach. We then inoculated these cells intra-venously (iv) and subcutaneously (sq) into C57BL/6 background mice and athymic nude mice to interrogate how VCAM-1 expression affects surrounding immune cell interactions within the tumor microenvironment. To further characterize VCAM-1 dependent immune responses, we used intravital 2-photon laser-scanning microscopy (2P-LPS) to dynamically visualize immune-tumor cells interaction. We observed that VCAM-1 down-regulation reduces the primary tumor growth kinetics in C57BL/6 mice but exhibited similar growth kinetics in nude mice, suggesting that VCAM-1 levels are not responsible for the intrinsic primary tumor growth differences in vivo. Moreover, VCAM-1 down-regulated cell lines showed decreased lung metastasis in both immune-competent mice and athymic nude mice. Furthermore, the metastatic lung parenchyma in mice injected with the non-silencing shVCAM-1 control exhibited immune cell infiltrates with a predominance of M2 polarized macrophages and an altered cytokine production. This may be responsible for decreased susceptibility to immune surveillance. Together, our results demonstrate that tumor-associated VCAM-1 expression helps aggressive tumors circumvent effective immune surveillance, and may represent a target for the development of immune-mediated therapy in metastatic cervical cancer. Citation Format: Francesca Scrimieri, Iuliana Dit Bobanga, Saada Eid, David J. Corn, Deborah Barkauskas, Jay Jay Myers, Alex Y. Huang. VCAM-1 enhances immune evasion in a murine model of metastatic cervical cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1174. doi:10.1158/1538-7445.AM2014-1174