Cellular dormancy in minimal residual disease following targeted therapy.

BACKGROUND: Breast cancer mortality is principally due to tumor recurrence, which can occur following extended periods of clinical remission that may last decades. While clinical latency has been postulated to reflect the ability of residual tumor cells to persist in a dormant state, this hypothesis remains unproven since little is known about the biology of these cells. Consequently, defining the properties of residual tumor cells is an essential goal with important clinical implications for preventing recurrence and improving cancer outcomes. METHODS: To identify conserved features of residual tumor cells, we modeled minimal residual disease using inducible transgenic mouse models for HER2/neu and Wnt1-driven tumorigenesis that recapitulate cardinal features of human breast cancer progression, as well as human breast cancer cell xenografts subjected to targeted therapy. Fluorescence-activated cell sorting was used to isolate tumor cells from primary tumors, residual lesions following oncogene blockade, and recurrent tumors to analyze gene expression signatures and evaluate tumor-initiating cell properties. RESULTS: We demonstrate that residual tumor cells surviving oncogenic pathway inhibition at both local and distant sites exist in a state of cellular dormancy, despite adequate vascularization and the absence of adaptive immunity, and retain the ability to re-enter the cell cycle and give rise to recurrent tumors after extended latency periods. Compared to primary or recurrent tumor cells, dormant residual tumor cells possess unique features that are conserved across mouse models for human breast cancer driven by different oncogenes, and express a gene signature that is strongly associated with recurrence-free survival in breast cancer patients and similar to that of tumor cells in which dormancy is induced by the microenvironment. Although residual tumor cells in both the HER2/neu and Wnt1 models are enriched for phenotypic features associated with tumor-initiating cells, limiting dilution experiments revealed that residual tumor cells are not enriched for cells capable of giving rise to primary tumors, but are enriched for cells capable of giving rise to recurrent tumors, suggesting that tumor-initiating populations underlying primary tumorigenesis may be distinct from those that give rise to recurrence following therapy. CONCLUSIONS: Residual cancer cells surviving targeted therapy reside in a well-vascularized, desmoplastic microenvironment at both local and distant sites. These cells exist in a state of cellular dormancy that bears little resemblance to primary or recurrent tumor cells, but shares similarities with cells in which dormancy is induced by microenvironmental cues. Our observations suggest that dormancy may be a conserved response to targeted therapy independent of the oncogenic pathway inhibited or properties of the primary tumor, that the mechanisms underlying dormancy at local and distant sites may be related, and that the dormant state represents a potential therapeutic target for preventing cancer recurrence.

Pseudo-continuous arterial spin labelling shows high diagnostic performance in the detection of postoperative residual lesion in hyper-vascularised adult brain tumours.

OBJECTIVES: Our aim was to evaluate the contribution of pseudo-continuous arterial spin labelling (pCASL) in the detection of a postoperative residual lesion in adult brain tumours. METHODS: Seventy-five patients were prospectively included. Following the results of preoperative DSC-PWI assessment, intra-axial lesions, including high-grade gliomas (n = 43) and certain metastases (n = 14), were classified as hyper-vascular (HV+ group, n = 57); other lesions, including low-grade gliomas and certain metastases, were classified as non-hyper-vascular (HV- group, n = 18). To confirm the absence/presence of a residual lesion or disease progression, postoperative MRI including pCASL sequence and follow-up-MRI were performed within 72 h and 1-6 months after the resection, respectively. Two raters evaluated the images. Mean and maximal ASL cerebral blood flow (CBF) values were measured in the perioperative region and normalised to the contralateral tissue. The pCASL-CBF maps and post-contrast T1WI were visually assessed for residual lesion. Quantitative data were analysed with unpaired Student t and Mann-Whitney U tests and the visual diagnostic performance with the McNemar test. RESULTS: In the HV+ group, the mean normalised CBF was 1.97 ± 0.59 and 0.97 ± 0.29 (p < 0.0001, AUC = 0.964, cut-off = 1.27) for patients with or without residual tumours, respectively. The mean normalised CBF was not discriminative for assessing residual tumours in the HV- group (p = 0.454). Visual CBF evaluation allowed 92.98% patients belonging to the HV+ group to be correctly classified (sensitivity 93.02%, specificity 92.86%, p < 0.001). Visual evaluation was correlated with contrast enhancement evaluation and with the mean normalised CBF values (r = 0.505, p < 0.0001 and 0.838, p < 0.0001, respectively). CONCLUSION: Qualitative and quantitative ASL evaluation shows high diagnostic performance in postoperative assessment of hyper-perfused tumours. In this case, postoperative pCASL may be useful, especially if contrast injection cannot be performed or when contrast enhancement is doubtful. KEY POINTS: • Evaluation of postoperative residual lesion in the case of brain tumours is an imaging challenge. • This prospective monocentric study showed that increased normalised cerebral blood flow assessed by pseudo-continuous arterial spin labelling (pCASL) correlates well with the presence of a residual tumour in the case of hyper-vascular tumour diagnosed on preoperative MRI. • Qualitative and quantitative pCASL is an informative sequence for hyper-vascular residual tumour, especially if acquired more than 48 h after brain tumour surgery, when contrast enhancement can give ambiguous results due to blood-brain barrier disruption.

Angiogenesis in residual cancer and roles of HIF-1α, VEGF, and MMP-9 in the development of residual cancer after radiofrequency ablation and surgical resection in rabbits with liver cancer.

BACKGROUND: The aim of the study was to investigate the changes of blood flow signal in residual cancer after ultrasound-guided radiofrequency ablation (RFA) treatment of rabbit liver cancer over time, and to analyse the correlation between changes in blood flow signal and changes in hypoxia-inducible factor 1-alpha (HIF-1α), vascular endothelial growth factor (VEGF), and matrix metalloproteinase-9 (MMP-9) in residual cancer tissue after RFA. MATERIALS AND METHODS: One hundred and ten rabbits were randomly selected, VX2 tumour cells were implanted subcutaneously, tumour cells were implanted in liver. Ninety rabbits were divided into three groups: Group 1 - untreated controls, Group 2 - RFA group, Group 3 - surgical resection group. Tumour size, blood flow signal, microvessel density (MVD) in liver cancer were assessed. RESULTS: Correlation of HIF-1a, VEGF, MMP-9 mRNA and protein expressions with blood flow signal in residual cancer were observed. Liver tumour was 2.3 ± 0.32 cm, significant differences in the grade of blood flow signal were noted among different time points (days 0, 3, 7, and 14; p < 0.05). Significant differences were also observed between the surgical resection and RFA groups at the same time points (p < 0.05). The MVD in the RFA group was lower than that in the control group, but higher than that in the surgical resection group. The immunohistochemical scores for VEGF and MMP-9 in the RFA group were lower than those in the control group, but higher than those in the surgical resection group. The grade of ultrasound blood flow signal was positively correlated with the expression of two angiogenesis-related factors, VEGF and MMP-9, and the MVD in the control, RFA, and surgical resection groups. CONCLUSIONS: There is a higher risk of tumour recurrence with RFA than with surgical resection.

The Likelihood of Remnant Nonfunctioning Pituitary Adenomas Shrinking Is Associated with the Lesion's Blood Supply Pattern.

OBJECTIVE: Nonfunctioning pituitary adenomas (NFPA) often shrink after transsphenoidal surgery. However, little is known about the predictors of spontaneous NFPA regression. The aim of this study was to determine whether the blood supply pattern of remnant NFPA lesions was associated with the likelihood of such lesions shrinking. METHODS: A total of 37 remnant tumors in 31 patients who were treated at the Department of Neurosurgery, Yamagata University Hospital, were included in this study. All patients underwent preoperative dynamic 3.0T magnetic resonance imaging (MRI) to evaluate their tumors' arterial blood supplies, followed by endoscopic transsphenoidal surgery and intraoperative 1.5T MRI. Follow-up MRI scans were obtained at 1-2 weeks and 3-6 postoperative months. RESULTS: We detected tumor shrinkage in 15 of 37 (40.5%) remnant tumors on follow-up MRI scans obtained at 3-6 postoperative months. Remnant tumors were found in rostral and caudal locations in 21 and 16 cases, respectively. Rostral remnant tumors were significantly more likely to shrink (P < 0.0001). The tumors were classified into 3 groups according to their blood supply patterns (23 ascending, 6 descending, and 2 monophasic). The ascending blood supply pattern was found to be a positive predictor of tumor shrinkage (P = 0.002). Furthermore, no remnant tumors with rich blood supplies underwent spontaneous regression (P < 0.0001). CONCLUSIONS: Evaluations of the blood supplies of remnant NFPA via preoperative dynamic MRI and the locations of the remnant tumors could be useful for predicting postoperative tumor shrinkage.

Enhancing acute myeloid leukemia therapy - monitoring response using residual disease testing as a guide to therapeutic decision-making.

INTRODUCTION: Current standards for monitoring the response of acute myeloid leukemia (AML) are based on morphologic assessments of the bone marrow and recovery of peripheral blood counts. A growing experience is being developed to enhance the detection of small amounts of AML, or minimal residual disease (MRD). Areas covered: Available techniques include multi-color flow cytometry (MFC) of leukemia associated immunophenotypes (LAIP), quantitative reverse transcriptase polymerase chain reaction (QRT-PCR) for detecting fusion and mutated genes (RUNX1-RUNX1T1, CBFB-MYH11, and NPM1), overexpression of genes such as WT1, and next generation sequencing (NGS) for MRD. Expert commentary: While MRD monitoring is standard of care in some leukemia subsets such as acute promyelocytic leukemia, this approach for the broader AML population does not universally predict outcomes as some patients may experience relapse in the setting of undetectable leukemia while others show no obvious disease progression despite MRD positivity. However, there are instances where MRD can identify patients at increased risk for relapse that may change recommended therapy. Currently, prospective investigations to define clinically relevant MRD thresholds are ongoing. Risk-adapted trials are needed to best define the use of MRD in the follow up of AML patients after initial induction therapy.

Experimental study on residual tumor angiogenesis after cryoablation.

OBJECTIVE: To explore the mechanism and significance of tumor angiogenesis by observing changes of micro-vessel density (MVD) and expression of vascular endothelial growth factor (VEGF) in residual tumor tissues after cryoablation. MATERIALS AND METHODS: A total of 18 nude mice xenograft models with transplanted lung adenocarcinoma cell line A549 were established and randomly divided into 3 groups when the maximum diameter of tumor reached 1 cm: control, cisplatin (DDP) and cryoablation. The nude mice were sacrificed after 21-d cryoablation to obtain the tumor tissues. Then immunohistochemistry was applied to determine MVD and the expression of VEGF in tumor tissues. RESULTS: The tumor volumes of control group, DDP group and cryoablation group were 1.48 ± 0.14 cm3, 1.03 ± 0.12 cm3 and 0.99 ± 0.06 cm3 respectively and the differences were significant (P < 0.01), whereas MVD values were 21.1 ± 0.86, 24.7 ± 0.72 and 29.2 ± 0.96 (P < 0.01) and the positive expression rates of VEGF were 36.2 ± 1.72%, 39.0 ± 1.79% and 50.8 ± 2.14% (P < 0.01), respectively, showing that MVD was proportional to the positive expression of VEGF (r = 0.928, P < 0.01). CONCLUSIONS: Cryoablation can effectively inhibit tumor growth, but tumor angiogenesis significantly increases in residual tumors, with high expression of VEGF playing an important role in the residual tumor angiogenesis.

Potential use of contrast-enhanced ultrasound (CEUS) in the detection of metastatic superficial lymph nodes in melanoma patients.

PURPOSE: Malignant melanoma represents a significant and growing public health burden worldwide. Ultrasonography is the most useful diagnostic modality for regional lymph nodal staging. Because any focal areas of cortical lobulation or thickening-swelling should also be considered as a sign of metastases, we are going to report the usefulness of contrast-enhanced ultrasonography (CEUS) in the differential diagnosis of benign or malignant lymph nodes in patients with malignant melanoma based on blood stream patterns and investigate the diagnostic capability. PATIENTS AND METHODS: After the excision of cutaneous melanoma with positive excision margins but with negative sentinel lymph node, 540 patients underwent US of superficial lymph nodes. The inclusion criteria for CEUS consisted of both major signs (absence of the echogenic hilus, round shape, and peripheral capsular vascularity) and minor ones (the presence of focal cortical thickening). The diagnostic capability was evaluated by comparing the cytological findings with the enhancement pattern on CEUS.  RESULTS: US in combination with CEUS correctly classified 534/540 patients. CEUS applied to lymph nodes with focal cortical thickening on grayscale US confirmed great sensitivity (0.98) and specificity (0.99) but above all, it showed a markedly improved accuracy of 0.99. The likelihood ratios confirmed the good performance of the methods used. CONCLUSION: CEUS increases the diagnostic accuracy of US in the differential diagnosis of benign and malignant LNs but it also allows us, when possible, to avoid unnecessary invasive operations such as LN FNAC. Moreover, CEUS may guide FNAC in the case of focal cortical thickening on the basis of hypoperfusion, with a reduction in the number of false negatives and much earlier detection of nodal metastatic foci.

The perivascular niche regulates breast tumour dormancy.

In a significant fraction of breast cancer patients, distant metastases emerge after years or even decades of latency. How disseminated tumour cells (DTCs) are kept dormant, and what wakes them up, are fundamental problems in tumour biology. To address these questions, we used metastasis assays in mice and showed that dormant DTCs reside on microvasculature of lung, bone marrow and brain. We then engineered organotypic microvascular niches to determine whether endothelial cells directly influence breast cancer cell (BCC) growth. These models demonstrated that endothelial-derived thrombospondin-1 induces sustained BCC quiescence. This suppressive cue was lost in sprouting neovasculature; time-lapse analysis showed that sprouting vessels not only permit, but accelerate BCC outgrowth. We confirmed this surprising result in dormancy models and in zebrafish, and identified active TGF-ß1 and periostin as tumour-promoting factors derived from endothelial tip cells. Our work reveals that stable microvasculature constitutes a dormant niche, whereas sprouting neovasculature sparks micrometastatic outgrowth.

Multimodal treatment of hemorrhagic pituitary metastasis as first manifestation of renal cell carcinoma.

BACKGROUND: Metastatic tumors involving the pituitary gland are very rare, with only few cases reported so far in the literature. CASE DESCRIPTION: We report a case of a man who presented with an extremely vascular hemorrhagic pituitary metastasis as the first manifestation of renal cell carcinoma. The patient was successfully treated with staged procedures, including preoperative tumor vasculature embolization followed by transsphenoidal tumor resection. CONCLUSIONS: This is the first report describing multimodality treatment of a patient with pituitary metastasis of unknown origin requiring presurgical embolization before successful tumor removal.

Contemporary surgical management of cardiac paragangliomas.

BACKGROUND: Cardiac paragangliomas are an extremely rare subset of chromaffin cell tumors that develop from neural crest cells. METHODS: Between March 2004 and October 2010, 7 male patients from our two institutions who underwent surgical resection of cardiac paraganglioma were retrospectively reviewed. RESULTS: In 5 patients, paragangliomas originated from the roof of the left atrium, and in 2 patients, they originated from the aortic root. Hospital mortality was 14%. CONCLUSIONS: Complete surgical resection remains the mainstay of therapy and can be curative, but carries a significant risk of intraoperative bleeding and usually requires cardiopulmonary bypass and often complex resection techniques, including cardiac autotransplantation.

[Preoperative portal vein embolization with Amplatzer(®) vascular plugs (AVP): a review of 17 cases]. / Embolisation portale préopératoire par Amplatzer(®) Vascular Plugs (AVP) : 17 patients.

The purpose was to determine the efficacy and technical particularities related to the use of Amplatzer(®) Vascular Plugs (AVP) for preoperative portal vein embolization. Between 2005 and 2009, a total of 48 type I AVP were embolized into the portal venous system of 17 patients (51-83 years) prior to extended hepatic resection where the residual liver volume (RLV) was deemed sufficient (RLV < 35-40% in patients with underlying hepatocellular disease, < 25-30% in patients with normal liver). AVP were used alone in seven patients and combined to other embolization agents in 10 patients (coils: n=5, microparticles: n=1, resorbable gel foam: n=4). The procedure was technically successful in 100% of cases with immediate success rate of 94.1% (imcomplete embolization of a segmental branch of segment VIII). The procedure was well tolerated clinically in 94.1% of cases, and in 100% of cases based on laboratory values. The rate of recanalization on follow-up CT at 5 weeks (2-22) was 11.7%. The rate of complications, major (left portal vein thrombosis following right portal vein embolization) and minor (one case of portovenous fistula), was 11.7%. The rate of RLV growth was from +13 to +285 cm(3) (mean at +122 cm(3)), or +4.98 to +78.51% (mean at +33.3%) (hepatocellular carcinoma: mean of +30.7%, metastases: mean of +19.7%). The rate of surgical candicacy was 94.1% (two patients were excluded: insufficient growth of RLV, development of peritoneal carcinomatosis). AVP appear to be reliable and effective for the preoperative embolization of the portal vein, with low morbidity and sufficient growth of RLV.

The antiangiogenic agent ZD4190 prevents tumour outgrowth in a model of minimal residual carcinoma in deep tissues.

BACKGROUND: Tumour cells may persist at the operative site after seemingly adequate surgery. Radiotherapy is often given in an attempt to prevent repopulation, but this modality cannot be relied upon to prevent locoregional recurrence. An alternative strategy is to take advantage of the requirement of tumour cells to develop an independent blood supply and block this process to prevent recurrence. METHODS: In this study, we evaluate the effect of the angiogenesis inhibitor, ZD4190, using a rodent model of residual carcinoma in deep tissues, mimicking the clinical scenario where low numbers of malignant cells persist at the operative site. RESULTS: The tumour burden that could be eliminated was dependent on the site where the cells were implanted. Immediate treatment with ZD4190 prevented outgrowth of up to 2.5 x 10(5) cells in the rectus muscle and 1 x 10(5) in the gastrocnemius, whereas control animals developed large tumours. When more than 2.5 x 10(6) cells were implanted into the rectus or 1 x 10(6) into the gastrocnemius and treatment was maintained for 3 weeks, the carcinomas that developed in ZD4190-treated animals showed a reduced microvessel density and increased necrosis when compared with the vehicle-treated controls, but an infiltrative growth pattern was common. CONCLUSION: These findings suggest that antiangiogenic agents have a role to play in preventing outgrowth of residual carcinoma and are likely to be most effective when the tumour burden is minimal.

Increased expression of vascular endothelial growth factor in hepatocellular carcinoma after transcatheter arterial chemoembolization.

BACKGROUND: Changes in the biological behavior of residual viable hepatocellular carcinoma (HCC) tissue after transcatheter arterial chemoembolization (TACE) remain unclear. Several studies have reported that TACE inhibits tumor angiogenesis and induces tumor cell apoptosis, while other studies have found that TACE stimulates tumor angiogenesis and thus increases the proliferative activity of the tumor cells to some degree. PURPOSE: To investigate the intratumoral microvessel density (MVD) and vascular endothelial growth factor (VEGF) expression in residual surviving cancerous tissue after TACE in HCC. MATERIAL AND METHODS: Tumor specimens from 63 histopathologically diagnosed patients were studied: 42 comprising the control group (treated by surgery alone) and 21 comprising the TACE group (those treated by TACE 1-2 times prior to surgical resection). The number of VEGF-positive cells, MVD, and microvessel diameter were measured. RESULTS: The MVD was 51.69+/-18.17 and 58.57+/-15.75 in the control and TACE groups, respectively. There was no significant difference between the two groups (t=1.48, P>0.05). The microvessel diameter was 17.62+/-10.54 microm and 15.79+/-7.65 microm in the control and TACE groups, respectively, indicating no significant difference between the two groups (t=0.71, P>0.05). The number of VEGF-positive cells in the TACE group, i.e., 243.66+/-88.88, was higher than that in the control group, i.e., 138.26+/-65.24 (t=5.34, P<0.01). TACE increased VEGF expression in the residual surviving HCC tissues, and there was a positive correlation between VEGF expression and MVD (r=0.4936, t=4.4329, P<0.05) in the HCC tissue. CONCLUSION: The study indicates that the residual surviving cancerous tissue in HCC after TACE has a rich vascularity. TACE increases VEGF expression in the residual surviving cancerous tissue.

Vascularity and angiogenesis as predictors of growth in optic pathway/hypothalamic gliomas.

OBJECT: The authors' aim in conducting this study was to investigate retrospectively the prognostic significance of angiogenic features in optic pathway/hypothalamic gliomas (OPHGs) in children. METHODS: Patients were identified in whom a diagnosis of OPHG was made using pathological analysis at the Toronto Hospital for Sick Children between 1985 and 2002. Tumor specimens were reviewed for diagnostic accuracy and adequacy of the specimen. Sections were immunostained with factor VIII to assess microvessel density (MVD). A ratio of alpha-smooth muscle actin to factor VIII immunostaining was calculated to arrive at a vascular maturity index (VMI). Vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) immunostaining were performed to evaluate angiogenic factors. In addition, the MIB-1 labeling index (LI) was used to assess proliferation. These factors were evaluated with respect to progression-free survival (PFS). Forty-one of 60 patients originally identified had adequate samples and follow up for inclusion in the study. Of these, eight patients had coexisting neurofibromatosis Type 1. Twenty-eight patients experienced tumor progression after the initial treatment (surgery with or without adjuvant treatment). Thirty-eight patients are still alive. A high MVD (> 21 vessels/1.2 mm2) was associated with a significantly higher rate of progression compared with a low MVD (< 21 vessels/1.2 mm2; p = 0.017). Microvessel density was also predictive of reduced PFS on multivariate analysis stratified for extent of resection (p = 0.04), and VMI as well as intensity and distribution of VEGF and VEGFR staining and the MIB-1 LI were not significantly associated with PFS. CONCLUSIONS: These findings suggest that MVD is the best current predictor of PFS in incompletely resected OPHGs. This information highlights the importance of angiogenesis in regard to low-grade gliomas.

Sonographic evaluation of early-stage breast cancers that undergo neoadjuvant chemotherapy.

OBJECTIVE: We prospectively evaluated low-stage breast cancers treated with neoadjuvant chemotherapy using whole-volume sonography and color Doppler imaging. METHODS: Thirty-four women with breast cancer (mean maximum size, 2.4 cm) received neoadjuvant chemotherapy with doxorubicin and docetaxel. Targeted whole-volume sonography of tumor sites was performed before and after chemotherapy to assess mass size, color pixel speed-weighted density, and American College of Radiology Breast Imaging Reporting and Data System sonographic characteristics. After chemotherapy, tumor sites were excised by lumpectomy or mastectomy. RESULTS: Three (11.3%) of 34 patients had a complete histologic response. After chemotherapy, correlation was r = 0.716 between final histologic and sonographic sizes. Compared with histologic residual tumors, sonography had 4 false-negative results, 3 false-positive results, and 27 true-positive results (sensitivity, 87%), with no false-negative results among a subgroup of tumors of 7 mm and larger (sensitivity, 100%). The 3 cases with false-positive results were histologic fibrosis or biopsy changes. Mean speed-weighted density was 0.015 before and 0.0082 after chemotherapy (P = .03). After chemotherapy, vascularity was less common within (P = .06) or adjacent to (P = .009) masses or in tumor sites (P = .05). Prechemotherapy variables of gray scale characteristics and vascularity were compared with final histologic size, and all had P > .20. CONCLUSIONS: Postchemotherapy sensitivity of sonography was high for residual tumors of 7 mm or larger. Correlation was moderate between histologic and sonographic final tumor sizes. False-positive results were caused by fibrosis or biopsy-related changes. False-negative results occurred with residual tumor size of 6 mm or smaller. After chemotherapy, vascularity usually decreased, and this was not specific for complete response. Before chemotherapy, no vascular or gray scale feature at initial imaging predicted complete responders.

Pituitary surgery complicated by haemorrhagic necrosis of residual tumour.

Haemorrhagic necrosis of residual pituitary tumour following partial excision has not previously been well described. This is differentiated from post-operative sellar haematoma due to inadequate haemostasis on the basis of absent free clot. The authors report two cases of large macroadenomas with significant supra-sellar extension which were complicated by haemorrhagic necrosis of residual tumour following initial surgery. The literature is reviewed and possible pathophysiogical mechanisms are discussed.

Synergy between angiostatin and endostatin: inhibition of ovarian cancer growth.

Ovarian cancer is the leading cause of fatality among gynecological malignancies. Ovarian cancer growth is angiogenesis-dependent, and an increased production of angiogenic growth factors such as vascular endothelial growth factor is prognostically significant even during early stages of the disease. Therefore, we investigated whether antiangiogenic treatment can be used to inhibit the growth of ovarian cancer in an experimental model system. Mouse angiostatin (kringle 1-4) and endostatin were expressed in yeast. Purified angiostatin and endostatin were then used to treat established ovarian cancers in athymic mice. These studies showed that both angiostatin and endostatin inhibited tumor growth. However, angiostatin treatment was more effective in inhibiting ovarian cancer growth when compared with endostatin in parallel experiments. Residual tumors obtained from angiostatin- and endostatin-treated animals showed decreased number of blood vessels and, as a consequence, increased apoptosis of tumor cells. Subsequently, the efficacy of a combined treatment with angiostatin and endostatin was investigated. In the presence of both angiostatic proteins, endothelial cell proliferation was synergistically inhibited. Similarly, a combination regimen using equal amounts of angiostatin and endostatin showed more than additive effect in tumor growth inhibition when compared with treatment with individual angiostatic protein. These studies demonstrate synergism between two angiostatic molecules and that antiangiogenic therapy can be used to inhibit ovarian cancer growth.

An unusual case of multiple recurrence of a glomangioma.

Glomus tumour is a benign lesion arising from the glomus apparatus of the skin and subcutaneous tissue. Glomangioma is the angiomatous variant, which is uncommon. We report a very rare presentation of a glomangioma with multiple recurrences. We advocate preoperative angiography to delineate the extent of the lesion to facilitate complete excision.

Neoadjuvant chemotherapy for hypervascular malignant brain tumors of childhood.

Some large hypervascular brain tumors pose an exceptional challenge to surgical resection, particularly in young children with small blood volumes. To limit blood loss during resection of hypervascular tumors, the authors used upfront chemotherapy as the primary treatment modality in 2 young children. This produced a dramatic reduction in tumor size and vascularity and greatly facilitated definitive surgical removal.