Paxton V. Dickson

Bevacizumab-induced transient remodeling of the vasculature in neuroblastoma xenografts results in improved delivery and efficacy of systemically administered chemotherapy.

Purpose: Dysfunctional tumor vessels can be a significant barrier to effective cancer therapy. However, increasing evidence suggests that vascular endothelial growth factor (VEGF) inhibition can effect transient “normalization” of the tumor vasculature, thereby improving tumor perfusion and, consequently, delivery of systemic chemotherapy. We sought to examine temporal changes in tumor vascular function in response to the anti-VEGF antibody, bevacizumab. Experimental Design: Established orthotopic neuroblastoma xenografts treated with bevacizumab were evaluated at serial time points for treatment-associated changes in intratumoral vascular physiology, penetration of systemically administered chemotherapy, and efficacy of combination therapy. Results: After a single bevacizumab dose, a progressive decrease in tumor microvessel density to <30% of control was observed within 7 days. Assessment of the tumor microenvironment revealed a rapid, sustained decrease in both tumor vessel permeability and tumor interstitial fluid pressure, whereas intratumoral perfusion, as assessed by contrast-enhanced ultrasonography, was improved, although this latter change abated by 1 week. Intratumoral drug delivery mirrored these changes; penetration of chemotherapy was improved by as much as 81% when given 1 to 3 days after bevacizumab, compared with when both drugs were given concomitantly, or 7 days apart. Finally, administering topotecan to tumor-bearing mice 3 days after bevacizumab resulted in greater tumor growth inhibition (36% of control size) than with monotherapy (88% bevacizumab, 54% topotecan) or concomitant administration of the two drugs (44%). Conclusions: Bevacizumab-mediated VEGF blockade effects alterations in tumor vessel physiology that allow improved delivery and efficacy of chemotherapy, although careful consideration of drug scheduling is required to optimize antitumor activity.

Adeno-Associated Virus Vector-Mediated Systemic Delivery of IFN-β Combined with Low-Dose Cyclophosphamide Affects Tumor Regression in Murine Neuroblastoma Models

Purpose: Type I IFNs (IFN-α/β) have shown significant antitumor activity in preclinical models but limited efficacy and significant toxicity in clinical trials. We hypothesized that the antitumor activity of type I IFNs could be enhanced by chronic, low-dose systemic delivery and sought to test this in murine neuroblastoma models. Experimental Design: Continuous liver-generated expression of human IFN-β (hINF-β) was achieved through a gene therapy–mediated approach using adeno-associated virus vectors encoding hIFN-β (AAV hINF-β). Orthotopic localized retroperitoneal and disseminated models of neuroblastoma were established using three different xenografts. Immunohistochemical analysis and ELISA were used to evaluate the antiangiogenic effect of therapy. Results: The development of both localized orthotopic (retroperitoneal) and disseminated neuroblastoma was prevented in all mice expressing hINF-β. Continued growth of established retroperitoneal tumors, treated with AAV hINF-β as monotherapy, was significantly restricted, and survival for mice with established, disseminated disease was significantly prolonged following administration of AAV hINF-β. Analysis of treated tumors revealed a significant antiangiogenic effect. Mean intratumoral vessel density was diminished and expression of the angiogenic factors vascular endothelial growth factor and basic fibroblast growth factor were both decreased. Finally, combination therapy in which AAV hIFN-β was used together with low-dose cyclophosphamide resulted in regression of both established retroperitoneal and disseminated disease. Conclusions: AAV-mediated delivery of hIFN-β when used as monotherapy was able to restrict neuroblastoma growth due in part to inhibition of angiogenesis. When used in combination with conventional chemotherapy, AAV hIFN-β was able to effect complete tumor regression.

Continuous Delivery of IFN-β Promotes Sustained Maturation of Intratumoral Vasculature

IFNs have pleiotropic antitumor mechanisms of action. The purpose of this study was to further investigate the effects of IFN-β on the vasculature of human xenografts in immunodeficient mice. We found that continuous, systemic IFN-β delivery, established with liver-targeted adeno-associated virus vectors, led to sustained morphologic and functional changes of the tumor vasculature that were consistent with vessel maturation. These changes included increased smooth muscle cell coverage of tumor vessels, improved intratumoral blood flow, and decreased vessel permeability, tumor interstitial pressure, and intratumoral hypoxia. Although these changes in the tumor vasculature resulted in more efficient tumor perfusion, further tumor growth was restricted, as the mature vasculature seemed to be unable to expand to support further tumor growth. In addition, maturation of the intratumoral vasculature resulted in increased intratumoral penetration of systemically administered chemotherapy. Finally, molecular analysis revealed increased expression by treated tumors of angiopoietin-1, a cytokine known to promote vessel stabilization. Induction of angiopoietin-1 expression in response to IFN-β was broadly observed in different tumor lines but not in those with defects in IFN signaling. In addition, IFN-β–mediated vascular changes were prevented when angiopoietin signaling was blocked with a decoy receptor. Thus, we have identified an alternative approach for achieving sustained vascular remodeling—continuous delivery of IFN-β. In addition to restricting tumor growth by inhibiting further angiogenesis, maturation of the tumor vasculature also improved the efficiency of delivery of adjuvant therapy. These results have significant implications for the planning of combination anticancer therapy. (Mol Cancer Res 2007;5(6):531–42)

Avoiding misdiagnosing neuroblastoma as Wilms tumor

PURPOSE Although occasionally difficult, distinguishing abdominal neuroblastoma (NBL) from Wilms tumor (WT) at presentation is important, as surgical management differs significantly. We reviewed our 20-year experience (1987-2006) treating patients with NBL, focusing on those with an initial diagnosis of WT, to determine presenting features that would have suggested the correct preoperative diagnosis. METHODS Retrospective case cohort study reviewing charts and imaging of patients with NBL initially diagnosed clinically with WT. Preoperative symptoms, laboratory studies, and imaging were evaluated. Similar variables were assessed in the 20 patients with WT most recently treated at our institution. RESULTS Nine patients with NBL were identified as those who had an exploratory laparotomy with a preoperative diagnosis of WT; 8 underwent nephrectomy at exploration. Children with NBL had symptoms such as fever and weight loss at presentation (67%) more often than patients with WT (20%). Preoperative computed tomography demonstrated intratumoral calcifications, vascular encasement, or both in 78% of patients with NBL but were never seen in WT patients. Of interest, preoperative urinary catecholamines were elevated in 5 patients ultimately diagnosed with NBL. CONCLUSION Although NBL can be mistaken for WT at presentation, the presence of constitutional symptoms, or intratumoral calcification or vascular encasement on preoperative imaging should heighten suspicion for NBL. In addition, laboratory evaluation, including urinary catecholamines, should be completed before surgery when the etiology of an abdominal tumor is uncertain.

The Microbiology of Secondary and Postoperative Pancreatic Infections Implications for Antimicrobial Management

HYPOTHESIS We reviewed our experience with secondary pancreatic infections with a focus on preemptive intervention and the potential alteration of the recovered microbial flora. The pathogens associated with postoperative pancreatic infections were analyzed with respect to nonenteric organisms, if any, that were recovered. We hypothesized that our findings might alter the antimicrobial management of these patients. DESIGN Retrospective review. SETTING Hospitals affiliated with the University of Tennessee Health Science Center, Memphis. PATIENTS Patients developing secondary and postoperative pancreatic infections following severe acute pancreatitis. METHODS Factors examined relative to secondary pancreatitis included preoperative antibiotic use and antecedent extrapancreatic infections potentially implicated in seeding the pancreatic bed. Patients who had elective resection received 24 to 48 hours of antibiotic prophylaxis. RESULTS Twenty-two patients required surgery for secondary infections following severe acute pancreatitis, with 29 pathogenic isolates being recovered. Of these 22 patients, 14 received vancomycin hydrochloride prior to surgical intervention. Of those 14 patients, 6 had isolates recovered at the time of surgery that were positive for Enterococcus faecalis and 5 of these isolates were vancomycin resistant. Eight of the 22 patients received antifungal prophylaxis with no fungi recovered from intraoperative culture. However, 2 of the 14 patients who did not receive empiric therapy had isolates that were positive for fungi. Five patients who required an urgent operation for sepsis had pathogenic isolates that were similar to those recovered from central lines. Postoperative infections occurred in 40 of 225 patients (17.8%) who had an elective pancreatic resection, with 72 pathogenic isolates being recovered. Of these 40 patients, 22 (55.0%) had polymicrobial infections. Of the 72 pathogenic isolates recovered from patients, 34 (47.2%) were gram-positive organisms, 15 (20.8%) were fungal organisms, and 17 (23.6%) were drug-resistant bacteria. CONCLUSIONS Prolonged vancomycin use in patients with severe acute pancreatitis is associated with the acquisition of vancomycin-resistant enterococci. Empiric antifungal therapy may reduce the incidence of secondary fungal pancreatic infections. Systemic bloodstream infections at extrapancreatic sites can lead to seeding of pancreatic pseudocysts. Postoperative infections frequently include gram-positive, fungal, and drug-resistant organisms, and empiric therapy directed at these pathogens should be utilized until definitive culture results are obtained.

Management of Pancreatic Neuroendocrine Tumors

Pancreatic neuroendocrine tumors account for 1% to 2% of pancreatic neoplasms and may occur sporadically or as part of a hereditary syndrome. Patients may present with symptoms related to hormone secretion by functional tumors or to locally advanced or metastatic nonfunctional tumors. Asymptomatic pancreatic neuroendocrine tumors are increasingly detected incidentally during abdominal imaging performed for other reasons. The management of localized pancreatic neuroendocrine tumors is surgical resection. Hepatic metastases are common and their management involves a variety of liver-directed therapies, which should be tailored according to extent of disease, symptoms, presence of extrahepatic metastases, and patient performance status.

The efficacy of combination therapy using adeno-associated virus—interferon β and trichostatin A in vitro and in a murine model of neuroblastoma

PURPOSE Trichostatin A (TSA) is a potent histone deacetylase inhibitor and has demonstrated significant antitumor activity against a variety of cancer cell lines. Type I interferons have also shown significant antitumor as well as antiangiogenic activity. In this study, we examined the effectiveness of combination therapy of TSA and interferon beta (IFN-beta) on human neuroblastoma cells in vitro and in vivo using a murine model of retroperitoneal neuroblastoma. MATERIALS AND METHODS For in vitro experiments, plated human neuroblastoma cells (NB-1643 and NB-1691) were treated with vehicle or with IFN-beta, TSA, or both for 24 hours. Cytotoxicity was assessed by counting cells and expressing the results as a percentage of controls. Expression of the tumor suppressor p21(Waf1) was assessed by Western blot. For in vivo experiments, retroperitoneal neuroblastomas were established in severe combined immune deficiency (SCID) mice. Interferon beta was given using a gene therapy approach, administering 1.5 x 10(10) particles of an adeno-associated virus vector encoding human IFN-beta (AAV hIFN-beta) via tail vein as a single dose per mouse. Trichostatin A was given at a dose of 5 mg/kg every 48 hours subcutaneously. Treatment groups included controls, AAV hIFN-beta alone, TSA alone, and AAV hIFN-beta together with TSA. Tumor volume was assessed 2 weeks after the treatment began. RESULTS After 24 hours, treatment with IFN-beta, TSA, and a combination of both resulted in a 45.3%, 68.1%, and 75% reduction in cell count relative to controls in the NB-1691 cell line. In the NB-1643 line, cell counts were reduced by 23%, 58%, and 62.3% respectively. In addition, NB-1691 cells treated with TSA showed increased expression of p21(Waf1) on Western blot. For in vivo experiments, control-, AAV hIFN-beta-, TSA-, and combination-treated tumors had the following final volumes: 1577.7 +/- 264.2 mm(3) (n = 3); 128.5 +/- 74.4 mm(3) (n = 4; P = .0001); 1248.7 +/- 673.9 mm(3) (n = 4; P = .48); and 127.5 +/- 36.8 mm(3) (n = 4; P = .0007), respectively. CONCLUSION Neuroblastoma, because of its unique biology, continues to be a challenging tumor to treat, and many times these tumors are refractory to standard chemotherapeutic regimens. These data show that both TSA and IFN-beta inhibit neuroblastoma growth and that the combination may potentially provide a unique way to treat this difficult disease.

Soft tissue sarcomas: Staging principles and prognostic nomograms

Soft tissue sarcomas (STS) are a rare and heterogenous group of tumors that often represent a management challenge. The American Joint Committee on Cancer system is currently used to stage tumors and direct treatment. Limitations of the current STS staging system, future potential direction for pre‐operative staging, as well as the benefit of predictive nomograms for filling current knowledge gaps are all discussed. J. Surg. Oncol. 2015 111:532–539. Published 2014. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Delivery of Antiangiogenic Agents for Cancer Gene Therapy

The understanding that tumor growth and metastasis are angiogenesis dependent processes has led to interest in targeting tumor vasculature in anticancer therapy. Furthermore, recent insights into the molecular interactions that orchestrate physiologic and pathologic angiogenesis have resulted in a variety of antiangiogenic strategies. A gene therapy-mediated approach for the delivery of antiangiogenic agents has several advantages, including the potential for sustained expression. However, the choice of angiogenesis inhibitor, method of gene delivery, and target/site for transgene expression are important variables to be considered when designing this approach. Here we review the major alternatives within each of these categories and provide illustrative examples of their use in preclinical models.

Evaluation, Staging, and Surgical Management for Adrenocortical Carcinoma: An Update from the SSO Endocrine and Head and Neck Disease Site Working Group

This is the first of a two-part review on adrenocortical carcinoma (ACC), a rare and aggressive malignancy that often presents at an advanced stage. Most patients present with symptoms related to cortisol and/or androgen excess. Appropriate biochemical evaluation and imaging is important in assessing the extent of disease, operative planning, and oncologic surveillance for patients with ACC. For patients with locoregional disease, potential cure requires margin-negative resection, and accumulating evidence suggests that regional lymphadenectomy should be performed. Although laparoscopic adrenalectomy is reported by some to be adequate for localized ACC, open resection in the hands of an experienced adrenal surgeon is the gold standard for operative management of this disease. Cure is rare following disease relapse, however select patients with severe symptoms related to hormone excess or pain may benefit from resection of local or distant recurrence. For best oncologic outcomes, it is recommended that all patients with ACC be treated at centers with multidisciplinary expertise in management of this rare and aggressive malignancy.