[All large necrotic and hemorrhagic kidney tumors in children are not necessarily malignant: A case of a 7-month-old child]. / Les volumineuses tumeurs rénales nécrotiques et hémorragiques ne sont pas toutes malignes même en pédiatrie : à propos d'un cas chez un enfant de 7 mois.

We report the case of a large tumor in the left kidney with necrotic and hemorrhagic features in a 7-month-old child, which was clinically and radiologically suggestive of a nephroblastoma. The tumor was a nodular mass measuring 8cm in diameter occupying two thirds of the kidney and presenting areas of necrosis and hemorrhage. No capsular rupture or renal sinus infiltration were found. Adjacent renal parenchyma appeared mascroscopically normal. Histologically, the tumor showed a strictly tubulopapillary architectural pattern with numerous psammomas. The initial hypothesis was a purely epithelial nephroblastoma. However, this hypothesis was rejected due to some immunohistochemical and histological characteristics and the final diagnosis was a metanephric adenoma. Metanephric adenoma is an exceptionally rare benign renal tumor in children. However, pathologists need to keep it in mind because simple surgical excision is curative.

Inhibition of cyclooxygenase-2 disrupts tumor vascular mural cell recruitment and survival signaling.

Much evidence supports an important role for the inducible enzyme cyclooxygenase-2 (COX-2) in tumor angiogenesis. Previous studies have focused on the role of COX-2 in stimulating endothelial proliferation, with blockade of this enzyme impairing endothelial homeostasis. However, recent data suggest that COX-2 also regulates molecules implicated in endothelial trafficking with pericytes/vascular mural cells (VMC), an interaction crucial to vessel stability. We investigated the role of COX-2 in vascular assembly by testing the effect of the specific COX-2 inhibitor SC-236 in an orthotopic xenograft model of human Wilms' tumor. Tumor growth was significantly suppressed by SC-236 (78% at day 28, 55% at day 35). Perfusion studies and immunostaining showed a marked decrease in vasculature, particularly in small vessels. Specifically, SC-236 inhibited participation of VMC in xenograft vessels. SC-236-treated tumors developed segmentally dilated, architecturally erratic tumor vessels with decreased nascent pericytes and scant mature VMC. Although vascular endothelial growth factor expression was unchanged, expression of the chemokine receptor CXCR4 was decreased in tumor vessels, consistent with defective homing of vascular progenitor cells. Vascular expression of phosphorylated platelet-derived growth factor receptor-beta was also diminished, indicating impaired VMC-endothelial trafficking. Consistent with the key role of this interaction in vessel homeostasis, vascular cells in SC-236-treated tumors displayed markedly diminished phosphorylated Akt, indicating disrupted survival signaling. These results show that SC-236 causes defective vascular assembly by attenuating incorporation of VMC into tumor vessels, impairing endothelial survival, and raise the possibility that blockade of COX-2 may provide therapeutic synergies with antiangiogenic molecules that more selectively target endothelial cells.

[Expression of Stat3, HIF-1alpha and VEGF in Wilms' tumor].

OBJECTIVE: To study the expression of signal transducer and activator of transcription 3 (Stat3), hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) in Wilms' tumor and their roles in the development of Wilms' tumor. METHODS: The expression of Stat3, HIF-1alpha and VEGF were detected by the immunohistochemical staining in 52 specimens from Wilms' tumor tissues, 47 from adjacent kidney tissues and 8 from normal kidney tissues. The expression intensity was analyzed by computer image processing. RESULTS: The expression of Stat3, HIF-1 and VEGF were significantly up-regulated in Wilms' tumor tissues compared to those in adjacent tissues and normal kidney tissues (P < 0.05). Stat3 and VEGF proteins in Wilms' tumor tissues of stage III-IV and high risk histopathology were significantly higher than those of stage I-II and low risk histopathology. The higher expression of HIF-1 in Wilms' tumor tissues was shown in tumors with high risk histopathology and tumor size > or = 6 cm. CONCLUSIONS: Increased expression of Stat3, HIF-1 and VEGF were found in Wilms' tumor tissues, and may be related to the development and angiogenesis of Wilms' tumor. Stat3 may regulate the expression of HIF-1 and VEGF, so it could be an effective target for inhibiting VEGF expression and angiogenesis of Wilms' tumor.

The prognostic significance of angiogenesis and the effect of vascular endothelial growth factor on angiogenic process in Wilms' tumour.

AIMS: There is a subgroup of patients with Wilms' tumour (WT) having favourable clinicopathological features but adverse outcome. We aimed to investigate the prognostic significance of angiogenesis and whether it can be used for predicting which patients will fall into this category, and the possible role of vascular endothelial growth factor (VEGF) on angiogenesis in WT. METHODS: Tumours in nephrectomy specimens from 63 WT patients were investigated for neovascularisation and VEGF expression by immunohistochemistry. The endothelial cells were highlighted by anti-CD34 and anti-CD31, and the microvessels in the hot-spots were counted. Correlations between the microvessel density (MVD), VEGF expression, clinicopathological features and prognosis were studied. RESULTS: Among 21 patients with follow-up data, favourable histology was detected in 17, seven of which died of disease. Patients with highly vascular tumours showed significantly poorer prognosis than those with low vascular tumours. There was no significant relationship between angiogenesis and VEGF expression. VEGF immunostaining revealed various patterns in different components of WT. CONCLUSIONS: We suggest that high MVD can be used as an indicator of poor prognosis with WT patients displaying favourable histology and there might be some additional growth factors other than VEGF which may also be responsible for angiogenesis in WTs.

rAAV-mediated long-term liver-generated expression of an angiogenesis inhibitor can restrict renal tumor growth in mice.

It is now well established that tumor growth is angiogenesis dependent. Inhibition of angiogenesis, therefore, is likely to be an effective anticancer approach. A gene therapy-mediated approach to the delivery of antiangiogenic agents using adeno-associated virus (AAV) vectors has a number of advantages, including the potential for sustained expression. We have constructed a rAAV vector in which the expression of a soluble, truncated form of the vascular endothelial growth factor receptor-2 (Flk-1), a known inhibitor of endothelial cell activation, is driven by a composite beta-actin-based promoter. After intraportal injection of this vector, high-level, stable transgene expression was generated in mice. This established a systemic state of angiogenesis inhibition; sera from these mice inhibited endothelial cell activation in vitro and Matrigel plug neovascularization in vivo. Significant antitumor efficacy was observed in two murine models of pediatric kidney tumors. Tumor development was prevented in 10 of 15 (67%) mice, with significant growth restriction of tumors in the remaining mice. For the first time, long-term, in vivo expression of a functional angiogenesis inhibitor has been established using rAAV, with resultant anticancer efficacy in a relevant, orthotopic tumor model. These findings establish the feasibility of using rAAV vectors in antiangiogenic gene therapy.

Vascular remodeling marks tumors that recur during chronic suppression of angiogenesis.

The potential for avoiding acquired resistance to therapy has been proposed as one compelling theoretical advantage of antiangiogenic therapy based on the normal genetic status of the target vasculature. However, previous work has demonstrated that tumors may resume growth after initial inhibition if antiangiogenic blockade is continued for an extended period. The mechanisms of this recurrent growth are unclear. In these studies, we characterized molecular changes in vasculature during apparent resumption of xenograft growth after initial inhibition by vascular endothelial growth factor blockade, "metronome" topotecan chemotherapy, and combined agents in a xenograft murine model of human Wilms' tumor. Tumors that grew during antiangiogenic blockade developed as viable clusters surrounding strikingly remodeled vessels. These vessels displayed significant increases in diameter and active proliferation of vascular mural cells and expressed platelet-derived growth factor-B, a factor that functions to enhance vascular integrity via stromal cell recruitment. In addition, remodeled vessels were marked by expression of ephrinB2, required for proper assembly of stromal cells into vasculature. Thus, enhanced vascular stability appears to characterize tumor vessel response to chronic antiangiogenesis, features that potentially support increased perfusion and recurrent tumor growth.

Studies on tumor induced angiogenesis.

Methods were developed to test angiogenic response to human tumor implants and various biologic agents in the cornea of rabbits and non-human primates (Macaca arctoides). Crude PDGF preparations were found to have significant angiogenic effect. Purified, recombinant PDGF preparations were also effective inhibitors (e.g. pentoxifylline (Px) (which also were found to release PgI2 and t-PA) inhibited human tumor implant induced angiogenesis and reduced spontaneous metastases in 3 transplantable murine tumors (Furth-Columbia Wilms' tumor in Furth-Wistar rats, C-1300 neuroblastoma in A/J mice and HM-Kim mammary carcinoma in Wistar rats) but not in the NIH adenocarcinoma in Balb/c mice. Sodium diethyldithiocarbamate (DDTC), a metal complexing agent with special affinity to copper and anti-thyroid as well as, immune stimulating activity was shown to be anti-angiogenic and to potentiate the effect of Px. The anti-fibrinolytic agents epsilon amino caproic acid (EACA) and tranaxamic acid (t-AMCHA) were anti-angiogenic. DDTC and Px were synergistic from this point of view.

Effects of potent VEGF blockade on experimental Wilms tumor and its persisting vasculature.

We characterized the effect of potent vascular endothelial growth factor (VEGF) blockade on early-stage Wilms tumor xenograft growth, vasculature and metastasis. VEGF is a key mediator of both physiologic and tumor angiogenesis. We recently described that potent VEGF blockade induces regression of established Wilms tumor xenografts and vessels, also reducing the size but not the incidence of pre-existing metastases. In these studies, we examined the effects of potent VEGF blockade on earlier stages of experimental Wilms tumors, focusing on tumor growth, vasculature and metastasis. Athymic mice received intrarenal human Wilms tumor cell implants. Biweekly treatment with vehicle or the VEGF-Trap, a high-affinity soluble decoy receptor incorporating regions of VEGFR1 and VEGFR2, was begun 1 week later (100 or 500 micrograms/dose, n=20 in each group). Mice were euthanized at week 6 to examine tumor weight, incidence of lung metastases, vascularity and expression of angiogenic factors. A cohort of mice was examined 2 weeks after cessation of treatment. Compared to controls, VEGF-Trap treated tumors were significantly smaller (100 micrograms/dose: 92.7% smaller, p=0.0017; 500 micro g/dose: 99.0% smaller, p=0.0009). The incidence of lung metastasis also decreased significantly (p<0.0055). VEGF-Trap nearly eradicated tumor vasculature. Rare persisting vessels were characterized by large caliber, quiescence (lacking proliferation/apoptosis) and arterialization (both phenotypic and molecular). Potent VEGF blockade caused near-arrest of experimental Wilms tumor growth, resulted in nearly avascular tumors, and also decreased the incidence and size of metastases. Persistent vessels in tumors treated with VEGF-Trap displayed specific morphologic and molecular features, suggestive of arterialization. Future strategies that target these persisting vessels may enhance the efficacy of VEGF blockade therapy.

Expression and prognostic relevance of vascular endothelial growth factor (VEGF) and its receptor (FLT-1) in nephroblastoma.

AIMS: To investigate the prognostic relevance of vascular endothelial growth factor (VEGF) and its receptor Flt-1 in nephroblastoma and whether tumour microvessel density (MVD) immunoreactivity, determined by the CD31 antigen, is related to the expression of VEGF and Flt-1. METHODS: The expression of VEGF and Flt-1 and MVD were investigated by means of immunohistochemical analysis in 62 Wilms's tumours. Patients were treated preoperatively with chemotherapy and had a mean follow up of 5.7 years. RESULTS: In general, VEGF and Flt-1 were expressed in normal kidney parenchyma and to a variable extent in the three main components of Wilms's tumour, namely: the blastemal, epithelial, and stromal cells. In tumour tissue, 52% and 47% of blastemal cells were positive for VEGF and Flt-1, respectively. A non-significant correlation was found between the expression of VEGF and Flt-1 in blastemal and epithelial cells and the clinicopathological stage. MVD was significantly higher in VEGF and Flt-1 positive tumours than in VEGF and Flt-1 negative tumours. Univariate analysis showed that the expression of VEGF and Flt-1 in blastemal cells was indicative of clinical progression and tumour specific survival. In addition, MVD expression was indicative of clinical progression. Epithelial staining was of no prognostic value. In a multivariate analysis, VEGF protein expression by blastemal cells was an independent prognostic marker for clinical progression. CONCLUSIONS: These results indicate that VEGF and Flt-1 protein expression are closely related to MVD and seem to be an important predictor for poor prognosis in treated patients with Wilms's tumour. Therefore, the expression of these molecules in primary Wilms's tumour may be useful in identifying those patients at high risk of tumour recurrence and in guiding antiangiogenic treatment.

Distribution of fucosubstance in kidney and related neoplasms. Absence of lectin-reactive alpha-fucose from the vasculature of bilateral Wilm's tumors.

Two alpha-fucose-binding lectins, Ulex europaeus agglutinin I (UEA I) and Lotus tetragonolobus agglutinin, were employed to compare and contrast the distribution of fucosubstance in normal human kidneys and a variety of renal tumors. The study employed a total of 31 kidneys surgically removed for the presence of a variety of tumors, including 11 unilateral Wilms' tumors, two cases of bilateral Wilms' tumors, 13 renal cell carcinomas, two congenital mesoblastic nephromas, one renal oncocytoma, one neuroblastoma metastatic to the kidney, and one clear cell sarcoma of the kidney. The results show that UEA I-reactive fucosubstance is detected in vascular endothelium of all kidneys and tumors, except bilateral Wilms' tumors. The presence of UEA I-reactive alpha-fucose in the vasculature of unilateral but not bilateral Wilms' tumors defines a unique histochemical distinction between the two groups of tumors. Conceivably, this property might be exploited as a screening procedure for the more aggressive bilateral neoplasms. Other findings detail histochemical differences between UEA I and L tetragonolobus agglutinin, as evidenced by the ability of one lectin to stain a particular cell type that is not reactive with the other lectin.

Pathological angiogenesis in a murine model of human Wilms' tumor.

BACKGROUND/PURPOSE: Pathological vascular architecture is a feature of neoangiogenic processes such as diseases of the retina and tumor growth. The authors hypothesized that experimental human Wilms' tumors would display a vascular architecture similar to retinal diseases that are driven by vascular endothelial growth factor (VEGF). METHODS: Human Wilms' tumors were established in the right kidneys of nude mice. After 4.5 weeks of tumor growth, fluorescein angiograms were performed before death. Representative sections of tumors and contralateral, control kidneys were evaluated by fluorescent microscopy. RESULTS: Fluorescein angiograms demonstrated a characteristic pathological architecture. Vascular tortuosity, capillary tufting, and hemorrhage were noted. These features were not present in normal kidneys. CONCLUSIONS: Vascular architecture of Wilms' tumor displays the specific features previously described in diseases of the retina, which have been shown to be driven by VEGF, suggesting that neoangiogenesis in this model is also VEGF driven.

Superior mesenteric artery injury during nephrectomy for Wilms' tumor.

Iatrogenic injury to the aorta or its major branches during nephrectomy for Wilms' tumor in children is rarely reported but may be more common than is currently acknowledged. We identified four patients with ligation of the superior mesenteric artery (SMA) that occurred during nephrectomy for nephroblastoma and another child in whom SMA thrombosis developed postoperatively. All of the tumors were on the left side. Interruption of the SMA was recognized intraoperatively in all four children, and primary repair was done. In three patients, appearance of the bowel remained normal before repair of the injury. Three of the arteries were repaired by primary reanastomosis, and one was joined with an interpositioned hypogastric artery graft. None of these patients had gastrointestinal complications postoperatively. In the fifth patient, SMA thrombosis developed after repair of an aortic tear during nephrectomy. This patient required subsequent small bowel resection for bowel infarction and died in the perioperative period. Every surgeon treating children with Wilms' tumor should be aware of the possibly distorted vascular anatomy and take precautions to avoid such a significant injury. Attempts at early ligation of the vessels may not be justified until the renal vasculature is clearly identified.

All angiogenesis is not the same: Distinct patterns of response to antiangiogenic therapy in experimental neuroblastoma and Wilms tumor.

BACKGROUND/PURPOSE: Neuroblastoma and Wilms tumor exhibit different patterns of metastasis, invasion, and therapeutic response. Vascular endothelial growth factor (VEGF) is an angiogenic factor expressed in both tumors. The authors hypothesized that because the clinical behavior of these tumors differs, the response to anti-VEGF therapy would be distinct, and tumor vascular architectures would reflect this distinction. METHODS: Xenografts were induced by intrarenal injection of cultured cells in athymic mice. After 1 week, anti-VEGF antibody or vehicle were administered for 5 weeks before sacrifice. Additional animals were maintained for 3 weeks after termination of antibody injections to assess rebound growth of tumors. Fluorescein angiography was performed in selected animals. RESULTS: Neuroblastoma control and treated tumor weights were not significantly different (1.48 g v 0.77 g, P =.34). By comparison, as previously reported, antibody-treated Wilms tumors were growth inhibited. Angiograms of treated (but not control) neuroblastomas displayed novel rounded structures at vessel branches, which the authors term terminal vascular bodies (TVBs). Wilms tumor vessels displayed no such alteration. CONCLUSIONS: Neuroblastoma xenografts are less effectively suppressed by anti-VEGF antibody than Wilms tumors. Neuroblastoma vascular architecture displays a novel alteration during antibody administration, which attenuates when antibody is withdrawn. These studies suggest that angiogenesis is differently regulated in experimental neuroblastoma and Wilms tumor.

[Significance of parasitic blood supply in malignant retroperitoneal tumours (author's transl)]. / Die Bedeutung der parasitären Gefässversorgung bei malignen retroperitonealen Tumoren.

Twenty-one neoplastic retroperitoneal tumours- in particular Wilm's tumours and neuroblastomas of the suprarenal glands in children - are analyzed angiographically and the significance of the parasitic blood supply evaluated. More than half of the tumours had penetrating or perforating vessels, but in only 50% there were operative and histologic signs of tumour spread into neighbouring structures. The remaining tumours had vascular adhesions. A hint may be the demarcation and the slight vascularity of the tumours. The value of the presence of penetrating or perforating vessels must not be overestimated regarding the spread of the tumour and inoperability.

[Wilms' tumor in adults. Apropos of a case]. / Tumeur de Wilms de l'adulte. A propos d'une observation.

Nephroblastoma is a rare tumor in adult. We report here one case in which all the radiological examination were performed. The diagnosis was made by histological study. As a rule, except if some signs are present, it's impossible to suggest diagnosis on X-rays.

[Adult Wilms' tumor: a case report].

We present a case report of adult Wilms' tumor and reviewed from 1981. A 22-year-old woman with chief complaints of gross hematuria and right backache was introduced to our hospital in March 1998. Abdominal computed tomography (CT) revealed a solitary irregular mass (5.0 cm) at the lower pole of right kidney with no contrast medium enhancement. Angiography showed a hypovascular character, but irregular vascularization was found in the tumor. We performed a radical nephrectomy with a preoperative diagnosis of malignant renal tumor. Finally, adult Wilms' tumor (epithelial type) was diagnosed by pathological examination. We retrospectively studied the clinical and radiological features in 16 reported cases of adult Wilms' tumor from 1981. The average age was distinctly younger than that of renal cell carcinoma. Nearly half of the cases were at an advanced clinical stage (direct invasion or metastasis to other organs) at first consultation. Radiologically, Wilms' tumor tends to be visualized as a low density mass in the precontrast CT scan (75.0%) and hypovascular tumor by selective angiography (84.6%). Although this is not a definitive character to distinguish adult Wilms' tumor from renal cell carcinoma, it may be useful information for differential diagnosis.

Neuropeptide Y receptors in renal cell carcinomas and nephroblastomas.

Numerous peptide receptors are overexpressed in human cancer, permitting in vivo tumor targeting. Among such receptors, those for the neurotransmitter neuropeptide Y (NPY) are overexpressed in various tumors. Since NPY can play a role in the kidney, NPY receptor expression and/or endogenous production of peptides of the NPY family (NPY, PYY, PP) were evaluated in 40 renal cell carcinomas (RCCs) and 18 nephroblastomas. NPY receptor protein expression was investigated by in vitro autoradiography using (125)I-labeled PYY in competition with NPY receptor subtype-selective analogs. NPY, PYY and PP production was assessed immunohistochemically. Fifty-six percent of RCCs expressed the Y1 receptor subtype in moderate density, and 80% of nephroblastomas expressed Y1 and Y2 subtypes in moderate to high density. Y1 was also highly expressed in intratumoral blood vessels. In selected cases, NPY was observed in nerve fibers in close association with intratumoral blood vessels and in the vicinity of tumor cells, while no PYY or PP was detected immunohistochemically in these sites. NPY receptors on renal tumor cells and tumor blood vessels may therefore be the molecular targets of endogenous NPY released by intratumoral nerve fibers. With regard to clinical applications, NPY receptors may act as in vivo targets for receptor-directed therapy of RCCs and nephroblastomas for which alternative therapeutic approaches are still required.