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The growth and dissemination of tumors rely on an altered vascular network, which supports their survival and expansion and provides accessibility to the vasculature and a route of transport for metastasizing tumor cells. The remodeling of vascular structures through generation of new vessels (for example, via tumor angiogenesis) is a well studied, even if still quite poorly understood, process in human cancer. Antiangiogenic therapies have provided insight into the contribution of angiogenesis to the biology of human tumors, yet have also revealed the ease with which resistance to antiangiogenic drugs can develop, presumably involving alterations to vascular signaling mechanisms. Furthermore, cellular and/or molecular changes to pre-existing vessels could represent subtle pre-metastatic alterations to the vasculature, which are important for cancer progression. These changes, and associated molecular markers, may forecast the behavior of individual tumors and contribute to the early detection, diagnosis and prognosis of cancer. This review, which primarily focuses on the blood vasculature, explores current knowledge of how tumor vessels can be remodeled, and the cellular and molecular events responsible for this process.

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PURPOSE: We analyzed the association between unilateral multicystic dysplastic kidney and subsequent contralateral infundibular stenosis, which can result in progressive calyceal dilatation, and has been linked to global hyperfiltration injury and renal impairment. MATERIALS AND METHODS: During the last 10 years 200 children presented with unilateral multicystic dysplastic kidney. Of these children 5 subsequently exhibited contralateral infundibular stenosis. We reviewed the published data on multicystic dysplastic kidney as well as infundibular stenosis to examine this association further. RESULTS: Three patients underwent open surgical exploration since rapid progression with associated parenchymal thinning was detected. Literature review failed to identify any discussion of infundibular stenosis in studies focusing on long-term followup of children with a unilateral multicystic dysplastic kidney. Several case reports and case series discuss this condition in association with other collecting system anomalies. However, these anomalies are hypothesized to be part of a disease spectrum resulting from aberrant formation of the collecting system. Bilateral involvement has been reported in fewer than 10 cases. CONCLUSIONS: Our cases represent a part of the spectrum of pyelocalyceal dysgenesis that can have bilateral involvement of varying degrees. Of particular concern was the delayed presentation in some of our patients and the progressive nature of the lesions. Although exceedingly rare, we wish to highlight the association of multicystic dysplastic kidney and progressive infundibular stenosis of the contralateral kidney and renal impairment.

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UNLABELLED: The aim of this study was to evaluate the use of quantitative gravity-assisted drainage (GAD) using >50% residual activity as an indicator to confirm obstruction in diuretic renography in the investigation of hydronephrosis and hydroureteronephrosis in infants and children. This was evaluated in 2 groups: furosemide clearance half-time (t 1/2) > 20 min (obstructed range) and t 1/2 = 10-20 min (indeterminate range). METHODS: Two hundred children (155 boys, 45 girls; age range, 2 d to 16 y; median age, 26 wk) were studied over a 2-y period. One hundred thirty-five F+20 (diuretic given 20 min after radiopharmaceutical) and 65 F+0 (simultaneous administration of diuretic and radiopharmaceutical) studies were performed with intravenous administration of 99mTc-mercaptoacetyltriglycine (MAG3) and furosemide. At the end of the 20-min diuretic phase, a 5-min post-GAD image was obtained, and the percentage of residual activity was calculated by comparison with the last 5 min of the diuretic phase. All patients were monitored for 6-12 mo, and the final diagnoses were based on either surgical findings or conservative management with follow-up sonography or 99mTc-MAG3 studies. Results of the diuretic renography using quantitative GAD were then compared with the final diagnoses. RESULTS: A renal unit was defined as a kidney and its ureter. In the 200 patients studied, 256 hydronephrotic renal units were analyzed: 10 units showed no function, 1 unit showed poor function, 131 units had t 1/2 < 10 min, 62 units had t 1/2 > 20 min, and 52 units had t 1/2 = 10-20 min. Of the 131 renal units with t 1/2 < 10 min, there was only 1 case of obstruction. Using GAD > 50% residual activity for the diagnosis of obstruction in 62 renal units with t 1/2 > 20 min, the sensitivity was 88.4%, the specificity was 73.7%, and the accuracy was 83.9%. Similarly, using GAD > 50% residual activity for the diagnosis of obstruction in 52 units with t 1/2 = 10-20 min, the sensitivity was 100%, the specificity was 79.5%, and the accuracy was 82.7%. CONCLUSION: The quantitation of GAD > 50% residual activity in diuretic renography can help to differentiate between obstruction and nonobstruction in renal units with t 1/2 > 20 min and t 1/2 = 10-20 min. The quantitation of GAD when t 1/2 < 10 min is not useful because obstruction has already been excluded.

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PURPOSE: The major aim of treating vesicoureteral reflux in children is the prevention of renal scars. Dimercapto-succinic acid (DMSA) is the modality of choice for detecting renal scars. We documented the incidence of new renal scarring and measured changes in differential renal function after ureteral reimplantation using DMSA studies. MATERIALS AND METHODS: We evaluated 45 boys and 98 girls with a median age of 2 years who had vesicoureteral reflux and underwent ureteral reimplantation. DMSA scans were done preoperatively and at a median of 3.4 years postoperatively. Maximal reflux grade was III in 84 children (59%), IV in 27 (19%) and V in 6 (4%). RESULTS: Preoperatively DMSA studies showed scarred or contracted kidneys in 106 of the 143 patients (74%). After reimplantation mean change in differential function was 2.5%. New scars developed in 3 children (2%). We noted greater than 6% decrease in relative differential function without new scarring in 7 cases (5%). CONCLUSIONS: The incidence of new renal scars in our study using DMSA was lower than that in previous series using excretory urography and imaging. Surgical correction of vesicoureteral reflux may offer better protection of kidneys in childhood than previously believed.

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OBJECTIVE: To investigate whether a history of recurrent urinary tract infection (UTI) and/or the presence of day-wetting/urge symptoms might influence the contractile responses to the cholinergic agonist carbachol or to the sensory neuropeptide neurokinin A (NKA) in the urinary bladder in children. PATIENTS AND METHODS: Small detrusor strips were taken from the margin of the cystotomy incision of the bladder dome during surgery to correct vesico-ureteric reflux (VUR) in 62 children (aged 4 months to 12 years) or for unrelated bladder conditions in five controls (aged 3 months to 13 years). Concentration-response curves to carbachol and NKA were constructed using organ-bath techniques, and results compared for age, sex, weight of the detrusor strip, UTI history or day-wetting syndrome. RESULTS: The contractile responses to NKA were no different for any of the features investigated. The contractile response to carbachol and NKA in detrusor from control and VUR patients was not significantly different. The children with a history of UTI were significantly older than those without. The contractility in response to carbachol was greater in older girls (aged 4-12 years) than younger girls (< 4 years) and than in all boys (< 4 years and 4-12 years; ANOVA P = 0.013). The mean (SEM) maximum contractile response to carbachol in the group of 20 young children (4-30 months) with previous UTI was 3.0 (0.3) g, whereas the maximum response in the age-matched group of 11 without UTI was 1.8 (0.3) g (P = 0.046). There were no significant differences in maximum responses between those with day-wetting and those without (aged > 4 years), although there was a significant difference in pD2 value, at 6.19 (0.13) and 5.58 (0.14), respectively (P = 0.018). CONCLUSION: Carbachol produced a larger contractile response in detrusor from children with a history of UTI than from those without, indicating possible alterations in muscarinic receptor characteristics. An increased sensitivity to muscarinic stimulation in day-wetting children was also suggested, whereas NKA is unlikely to be involved in any of these pathophysiological conditions.

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UNLABELLED: The purpose of this study was to evaluate the feasibility of modifying diuresis renography by the simultaneous administration of 99mTc-mercaptoacetyltriglycine (MAG3) and furosemide in the investigation of hydronephrosis and hydroureteronephrosis in infants and children. Two parameters were assessed: the diuretic response in normal kidneys and the ability of the F+0 study to differentiate between renal obstruction and nonobstruction and to identify the level of obstruction in cases of renal obstruction. METHODS: Seventy-two patients (48 males, 24 females; age 2 d to 7 y; median age 6 wk) with sonographic diagnoses of hydronephrosis or hydroureteronephrosis were reviewed prospectively over a 3-y period. All patients had prior sonographic studies and micturating cystourethrography. Bladder catheterization was not routinely performed and was undertaken only if the child had suspected vesicoureteric junction (VUJ) obstruction or grade II or more vesicoureteric reflux. A weight-adjusted dose of 99mTc-MAG3 (maximum 200 MBq, minimum 20 MBq) and 1 mg/kg of furosemide (maximum 40 mg) were administered intravenously at the same time. Posterior imaging of the kidneys and bladder was performed for 20 min and followed by gravity-assisted drainage or imaging after voiding. All patients were followed-up for 6-12 mo, and the final diagnoses were based on either surgery or conservative management with repeated sonography or follow-up 99mTc-MAG3 studies (or both). The results of the F+0 diuresis renography were then compared with the final diagnoses. RESULTS: A renal unit was defined as a kidney and its ureter. There were 151 renal units with 1 patient having bilateral duplex kidneys, 6 patients having unilateral duplex kidneys and 1 patient having a solitary kidney. Fifty-five normal renal units and 96 abnormal renal units on the basis of sonographic findings were assessed. The furosemide clearance half-time for the 55 normal renal units was 1.3-6.3 min (mean 3.8 min). Of the 96 abnormal renal units, 53 were classified as nonobstructed and 43 were classified as obstructed. Of the 53 renal units classified as nonobstructed, there were 48 true-negative studies and 5 false-negative studies; of the 43 renal units classified as obstructed, there were 40 true-positive studies and 3 false-positive studies. The sensitivity was 88.9%, specificity was 94.1% and accuracy was 91.7%. The level of obstruction, either pelviureteric junction or VUJ, was also correctly identified. CONCLUSION: F+0 diuresis renography shows excellent diuretic responses in normal kidneys and is a valid method for the investigation of hydronephrosis and hydroureteronephrosis in infants and children.

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UNLABELLED: The aims of this study were to validate 99mTc-dimercaptosuccinic acid (DMSA) scintigraphy appearances with histopathological features of scarring; to evaluate the sensitivity and specificity of 99mTc-DMSA and ultrasound for the detection of renal scarring; to compare planar, pinhole and SPECT techniques when using 99mTc-DMSA; and to compare 99mTc-DMSA and ultrasound renal length measurement. METHODS: Reflux nephropathy was induced in large white pigs using established methods. To ensure that the abnormalities detected were scars and not inflammatory changes, the pigs were not studied until 3 mo after the treated episode of acute pyelonephritis confirmed by 99mTc-DMSA. RESULTS: Twenty pigs were enrolled in the study. Eleven reached the end point, but only nine pigs (18 kidneys) were available for analysis. Thirty-four scars were identified pathologically; 24 were present macroscopically and a further 10 were seen only on microscopy. Technetium-99m-DMSA abnormalities correlated with scars histopathologically with an accuracy of 92% versus that of ultrasound, 75% (p < 0.001). Technetium-99m-DMSA more accurately identified scarring with a higher sensitivity (76% versus 29%) and specificity (98% versus 92%) than ultrasound. On the 99mTc-DMSA study, pinhole imaging had the highest accuracy (92%) when compared with planar (90%) and SPECT (87%) data. These differences were not statistically significant. Renal lengths as measured on 99mTc-DMSA more closely correlated with length measurement at pathological examination than ultrasound. Technetium-99m-DMSA measurement was, on average, 6% higher than pathology, and ultrasound was, on average, 22% lower. CONCLUSION: Technetium-99m-DMSA appears to be the preferred method for the detection of renal cortical scarring and accurate renal length measurement when compared with ultrasound examination.

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BACKGROUND: Pelvi-ureteric junction obstruction has been increasingly diagnosed in infants, mostly as a consequence of antenatal ultrasound examinations. METHODS: Of 55 infants below the age of 12 months who underwent dismembered pyeloplasty over a 7-year period, we aimed to determine the patterns and outcome of associated vesico-ureteric reflux that was present in 15 (28%) of the 53 infants in whom follow-up was available. RESULTS: A total of eight infants had resolution of their reflux with conservative management and the median time to resolution was 15 months. Five infants proceeded to ureteroneocystotomy. CONCLUSIONS: Given the association of vesico-ureteric reflux and pelvi-ureteric junction obstruction, routine cystography is recommended when the diagnosis of pelvi-ureteric junction obstruction is made.

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OBJECTIVE: To assess the impact of internal ureteric stenting on the surgical outcome of dismembered pyeloplasty in infants under the age of 12 months. PATIENTS AND METHODS: The case records of 53 of 55 infants with the diagnosis of congenital pelvi-ureteric junction obstruction who underwent dismembered pyeloplasty over a 6-year period were available for review. A total of 63 renal units were treated surgically. The policy for urinary drainage changed during this period from predominantly nephrostomy or no drainage to that of internal ureteric stenting. RESULTS: The post-operative mean (SD) length of stay for stented and non-stented cases was 5.9 (1.8) and 12.4 (5.4) days, respectively (P < 0.001). The mean length of stay for patients with bilateral and unilateral pyeloplasty was 9.7 (4.9) and 8.0 (4.7) days, respectively (P = 0.19). Urinary leaks occurred in non-stented anastomoses and not in stented anastomoses. All three cases which later required revision pyeloplasty had had significant complications associated with urinary leaks. With a minimum follow-up of 24 months, a favourable outcome, as determined by radio-isotope imaging, was achieved in 48 of 51 infants (94%) for whom follow-up data were available. CONCLUSION: The use of internal ureteric stenting in dismembered pyeloplasty performed in infants < 12 months old has, in our hands, led to a dramatic reduction in operative morbidity. The routine use of internal ureteric stents at the time of pyeloplasty is justified.

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UNLABELLED: Diuretic renography performed in the neonatal period has been reported to be unreliable in diagnosing obstruction. METHODS: The scans of 27 neonates (age up to 28 days; mean 17 days) with a total of 53 renal units were reviewed; a renal unit being defined as comprising a kidney and its ureter. All were referred following perinatal ultrasound diagnosis of hydronephrosis or hydroureteronephrosis. The neonates had standard diuretic renography using MAG3 with a frusemide dose of 1 mg/kg followed by another image obtained after gravity-assisted drainage. RESULTS: There were 17 normal undilated renal units showing excellent diuretic responses with clearance half-times of 0.6-7.7 min. Eighteen renal units were diagnosed as having pelvi-ureteric junction (PUJ) obstruction, with surgical confirmation in all. Eight were diagnosed as unobstructed and of these seven were confirmed nonobstructed by serial imaging using ultrasound and MAG3, but one subsequently had pyeloplasty performed for PUJ obstruction. One unit was indeterminate for PUJ obstruction but had good clearance with gravity-assisted drainage and was shown to be unobstructed on repeat studies. Of nine units diagnosed as having vesico-ureteric junction (VUJ) obstruction, eight had surgical confirmation and one remains of uncertain final diagnosis. Co-existing VUJ obstruction could not be diagnosed in two units with PUJ obstruction because of insufficient radiotracer drainage through the tight stenosis into the ureter. CONCLUSION: An adequate diuretic response is present in the neonatal period using MAG3 and this allows for reliable diagnosis of obstruction. An unobstructed or indeterminate result necessitates follow-up imaging to ensure obstruction does not develop. Co-existing VUJ obstruction may be missed in a scan showing PUJ obstruction.

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Technetium-99m mercaptoacetyltriglycine (MAG3) is the most recently introduced renal radiopharmaceutical in Australia and is established as the agent of choice for use in diuresis renography, particularly in neonates and infants. It provides superior anatomical information compared to previously used agents. Three cases are reported in which MAG3 diuresis renography was performed in neonates, who were found to have hydronephrosis detected antenatally. In two neonates, a previously unrecognized horseshoe kidney was demonstrated and in case 3 there were scan features characteristic of a ureterocele. It is highly unlikely that these abnormalities would have been delineated with 99mTc dimethyltriamine pentaacetic acid (DTPA) study, as confirmed in case 1, because of the relatively poor uptake of DTPA when compared to MAG3.

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The role of diuresis renography (DR) in the evaluation of pelvi-ureteric junction obstruction is well established. However, problems may be encountered when applying this technique to patients after pyeloplasty because of the role of gravity-assisted drainage (GAD) in this post-operative group. Twenty-three radionuclide studies that were performed in 21 children were reviewed. All children underwent standard DR and all then had an additional view performed after GAD. In 12 children evaluated in a preoperative assessment for possible obstruction, 5 were obstructed on both DR and after GAD, 1 was equivocal on DR but drained after GAD, and 6 were not obstructed in either part of the study. In 11 children assessed after pyeloplasty, 5 were obstructed on DR but not obstructed on GAD, 3 were not obstructed in both studies, 1 was obstructed in both, and 2 were equivocal on DR but not obstructed after GAD. It can be concluded that when assessing patients, particularly those who have undergone pyeloplasty, DR should be supplemented with an additional view acquired after gravity-assisted drainage.

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A prospective study examining the incidence of dimercaptosuccinic acid (DMSA) abnormalities in children at the time of acute urinary tract infection, the progression of these abnormalities following treatment and their correlation with the presence of vesicoureteral reflux is reported. DMSA scans performed within 72 hours of presentation in 65 previously healthy children with acute urinary tract infection were abnormal in 34 (52%). The scan appearances of 30 of 36 (83%) initially abnormal kidneys improved or became normal on the repeat DMSA study performed at 3 to 6 months after the acute urinary tract infection. A cystogram demonstrated significant vesicoureteral reflux in 11 of 45 cases (24%). Of these 11 cases 10 had abnormal DMSA studies and 1 had dilated upper tracts on ultrasound. Several conclusions may be drawn from our study. The incidence of DMSA abnormalities at the time of acute urinary tract infection is high but these abnormalities tend to resolve with time. An abnormal DMSA study at the time of urinary tract infection identifies most children with significant vesicoureteral reflux, and in our series a combination of ultrasound and DMSA identified all cases. This study may have major implications for the clinical investigation of children with urinary tract infection.

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A series of 208 patients was prospectively assessed for reflux nephropathy by intravenous urography (IVU) and 99mTc-dimercaptosuccinate (DMSA) scintigraphy. All patients were studied at least 3 months after their most recent urinary tract infection and micturating cystourethrography (MCU) was performed prior to the scintigraphic studies. DMSA scintigraphy detected significantly more cortical abnormalities than did IVU. There was also a correlation between cortical abnormalities in the DMSA studies and the degree of reflux on MCU. The validity of DMSA as a cortical imaging agent is evaluated and the histological evidence for its efficacy derived from the animal model is reviewed, lending weight to its establishment as the "gold standard" for renal cortical scarring.

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Renal cortical studies were performed in 19 children with renal transplants. There were 10 normal studies and 9 abnormal studies, 8 of which showed multiple large focal peripheral cortical defects. The following factors showed a positive correlation: (a) the ischemia time of the transplant kidney was significantly shorter in patients with normal studies; (b) cadaver grafts were more likely to have abnormal scan appearances than living related donor grafts; and (c) in four of the five patients with double renal arteries, the scans were abnormal in multiple sites. A possible pathophysiologic mechanism to explain these scan appearances is asymptomatic segmental graft infarction secondary to progressive vascular disease. These infarcts may be a long-term sequela of ischemic insult at the time of or prior to the insertion of the renal allograft.

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Dimercaptosuccinic acid (DMSA) studies were performed in 113 infants less than 1 year old at risk of renal scarring. Of these patients 86 presented with urinary tract infection and 27 were asymptomatic. A voiding cystourethrogram was performed in all cases and excretory urography (IVP) was done in 99. More abnormalities were detected by DMSA study when compared to scars on IVP. When both studies were abnormal there was an excellent correlation on a site by site basis. Fever or systemic disorder was not a reliable sign to determine whether there was upper tract involvement with infection. The incidence of DMSA abnormalities in infants increased with high grade vesicoureteral reflux and decreased with low grade reflux. There was no significant difference in the incidence of abnormal kidneys between the infected and noninfected groups, suggesting that renal scarring may occur with sterile reflux.

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