Novel use of an established agent: Topotecan is anti-angiogenic in experimental Wilms tumor.

BACKGROUND/PURPOSE: Antiangiogenic agents offer a new approach to the treatment of aggressive neoplasms, yet very few agents are available for current use. The authors have shown previously the efficacy of antiangiogenic therapy in experimental Wilms tumor, using an investigative antibody. They hypothesized that topotecan, administered in a regimen targeting endothelial cells, would suppress tumor growth and angiogenesis in experimental Wilms tumor. METHODS: Experimental tumors were induced in the left kidneys of athymic mice by injection of cultured Wilms tumor cells. Topotecan (0.36, 0.6, 1.0, 2.0, and 3.0 mg/kg) or vehicle was injected intraperitoneally in 2 cycles over a 6-week period. Fluorescein angiograms and platelet endothelial cell adhesion molecule-1 staining of primary tumors were performed to ascertain vascular architecture. Endothelial apoptosis was assessed by TdT-mediated dUTP nick end labeling assay. RESULTS: Tumor weights were reduced significantly in treated versus control animals, even in the lowest-dose group. Endothelial cell staining and angiography results showed relatively sparse vascularity in treated xenografts. Endothelial apoptosis was observed in treated but not control tumors. CONCLUSIONS: Topotecan, delivered in an "antiangiogenic" regimen, even at very low doses, significantly inhibited growth of experimental Wilms tumors. No adverse effects were noted at low doses. Thus, the established chemotherapy agent topotecan may be useful in a novel role: as antiangiogenic therapy. J Pediatr Surg 36:1781-1784.

Combination antiangiogenic therapy: increased efficacy in a murine model of Wilms tumor.

BACKGROUND/PURPOSE: Antibody to vascular endothelial growth factor (anti-VEGF) suppresses tumor growth and metastasis in experimental Wilms tumor. However, tumor growth accelerates if antibody is withdrawn. As recently shown, low-dose, frequently administered topotecan, a topoisomerase-1 inhibitor, has anti-angiogenic activity. The authors hypothesized that combined topotecan/anti-VEGF therapy would suppress tumor growth and metastasis more durably than either agent alone. METHODS: Xenografts were induced by intrarenal injection of human Wilms tumor cells in athymic mice (n = 59). Mice were divided into control (n = 10), anti-VEGF (n = 16), topotecan (n = 17), and topotecan plus anti-VEGF (n = 16) groups. All control and half the treated mice were killed at week 6. Remaining ("rebound") mice were maintained without treatment until week 8. Tumor vasculature was mapped by fluorescein angiography/PECAM immunostaining. Endothelial apoptosis was assessed by TUNEL assay. RESULTS: 6 weeks: Tumor weights were reduced significantly in treated mice (P <.003 v control). Seven of ten control and 1 of 25 treated mice displayed lung metastases (P <.003). Rebound tumors were largest in topotecan-only, intermediate in antibody-treated, and smallest in combination-treated mice. Immunostaining and angiography results showed sparse vascularity in treated xenografts. Endothelial apoptosis was observed only in treated tumors. CONCLUSION: Combination low-dose topotecan and anti-VEGF antibody therapy is antiangiogenic and suppresses tumor growth and metastasis in experimental Wilms tumor more durably than either agent alone.

Uroepithelium in a colonic diverticulum.

Giant colonic diverticula are rare entities and often present in adulthood as acute diverticulitis. The authors present a case of giant colonic pseudodiverticulum lined with uroepithelium causing bowel obstruction in a neonate. The presence of uroepithelium in a colonic pseudodiverticuium remains unexplained and to the authors' knowledge unreported. This heterotopic tissue may be a result of an embryonic rest or could be urachal in origin adhering initially to the colon and eventually detaching from the umbilicus. These lesions should be resected because of the risk of infection, perforation, or obstruction.

Cloacal exstrophy: a unified management plan.

BACKGROUND/PURPOSE: The belief that patients with cloacal exstrophy have a short and therefore useless colon is all too common. Frequently, the colon is used for urinary or vaginal reconstruction, and the possibility of a pull-through is lost. In the authors' experience, the use of a unified management plan allowed most patients to undergo pull-through and avoid a permanent stoma. METHODS: Twenty-five patients were treated for cloacal exstrophy in the authors' institution from 1985 through 1999. In all patients, bladder closure, omphalocele repair, and creation of a colostomy were performed at birth. All available colon, no matter how small, was incorporated into the fecal stream. After at least 1 year, patients were assessed for the ability to form solid stool through their stoma. Normal colonic length, capacity to form solid stool, or success with a bowel management regimen through the stoma were considered indications for pull-through. Genitourinary reconstruction was contingent on the colorectal plan. RESULTS: Colonic length ranged from normal in 12 patients, 40 to 70 cm in 3 patients, 10 to 30 cm in 4 patients, and less than 10 cm in 2 patients. All 25 patients underwent pull-through. Three are totally continent, 4 are continent with occasional soiling, 11 remain clean with a bowel management regimen, and 4 are too young to assess. One patient was clean, but now refuses bowel management. Two early patients, both with less than 10 cm of colon, now have ileostomies. CONCLUSIONS: During neonatal repair, a colostomy should be formed incorporating all pieces of colon, no matter how small. With time, most patients will be able to form solid stool, and a pull-through should be undertaken if that ability exists. Decisions regarding genitourinary reconstruction should be made only after the gastrointestinal plan is established to achieve the optimal use of available bowel.

The nonoperative management of fistula-in-ano.

BACKGROUND/PURPOSE: Fistulotomy is the accepted treatment for infants with perianal fistula. Although recurrence rates range from 0% to 68%. Based on the experience of a senior colleague who noted that babies suffering from perianal fistula follow a self-limited course the authors decided to determine if this observation was accurate. METHODS: A conservative approach to perianal abscess and fistula was used prospectively in 18 male infants. Abscesses were to be drained only if the baby was very uncomfortable or febrile. Once a fistula developed the authors continued observation until the fistula healed. Data are expressed as mean +/- SD. Mean follow-up period was 37 months. RESULTS: Mean age at onset of symptoms was 4 +/- 3 months. Fistulas developed in 14 patients (77%). All fistulas healed without operation. Four patients had abscesses drained for discomfort (n = 3) or fever (n = 1). No patient required antibiotics. Mean duration of symptoms was 6 +/- 4 months. Four patients in whom fistulas did not form healed after incision (n = 3) or spontaneous drainage (n = 1). All patients currently are asymptomatic. CONCLUSIONS: In healthy neonates, perianal abscess and fistula are self-limited conditions rarely requiring surgical drainage and not requiring antibiotics. The conservative management of perianal abscess and fistula in healthy infants appears to be safe and effective.

Continent appendicostomy in the bowel management of fecally incontinent children.

BACKGROUND: Fecal incontinence is common in children who have anorectal malformations, Hirschsprung's Disease, and spina bifida and can negatively impact their emotional and social development. Enemas have been used as an artificial way to keep children clean and to improve their quality of life. This method is unpleasant for many children, particularly when they reach adolescence. Malone in 1990 described an alternative method in which the appendix is used as a conduit to administer an antegrade enema. METHODS: The authors describe their experience with this new procedure, modified by them, and used in 20 patients. In the original procedure, the base of the appendix is divided, inverted, and reimplanted into the cecum with an antireflux technique. The authors simplify this by plicating the cecum around the appendix to create a one-way valve mechanism but leaving the appendix in its original position. The authors also mobilize the cecum and exteriorize the appendix at the umbilicus to create an inconspicuous stoma. If the native appendix is absent a neoappendix was created from a flap of cecum. RESULTS: Nineteen of 20 patients (95%) are now completely clean 24 hours a day. Stricture of the stoma occurred in two patients and required revision. Leakage at the appendicostomy site occurred in three patients, and two required a tighter plication. CONCLUSIONS: The technique is used to change the route of enema administration, and is only used in patients for whom bowel management with rectal enemas has been proven successful. The appendix must be preserved whenever possible in patients at risk for fecal incontinence.