Irinotecan for children with relapsed solid tumors.

Irinotecan is expected to become a new drug for childhood solid tumors. Sixteen children with relapsed solid tumors received irinotecan 180 mg/m2/day for 3 consecutive days, repeated once after 25 days off. Their original tumors were neuroblastoma in 7, rhabdomyosarcoma in 3, nephroblastoma and undifferentiated sarcoma in 2 each, and primitive neuroectodermal tumor and leiomyosarcoma in 1 each. The average age at trials was 6 years. Partial response was achieved in 5 (31.3%) (neuro-blastoma, rhabdomyosarcoma, nephroblastoma, undifferentiated sarcoma, and leiomyosarcoma), and decrease in tumor marker in the other 2. Irinotecan appears promising, and could become included in the first-line treatment.

Advanced-stage gastrointestinal stromal tumor treated with imatinib in a 12-year-old girl with a unique mutation of PDGFRA.

A 12-year-old girl presented with a large abdominal tumor. At surgery, a huge pedunculated extraluminal tumor was found arising from the greater curvature of the stomach and invading the surrounding structures, and there were also a submucosal tumor measuring 5 x 4 x 4 cm and multiple intramural nodules beside the main tumor. These lesions, which were removed with 1.0-cm surgical margins, were immunohistochemically positive for c-kit (CD117) and CD34. A diagnosis of gastrointestinal stromal tumor (GIST) was made. The huge size of the tumor (3.6 kg in weight and 36 x 25 x 25 cm in diameter), the invasion of the surrounding structures, and the increased mitotic figures indicated the GIST had malignant potential. Sequence analysis of the polymerase chain reaction product of RNAs from the tumor cells revealed a novel platelet-derived growth factor receptor alpha (PDGFRA) mutation, which would exhibit biologic consequences similar to those of the c-kit mutation. The patient underwent a 3-month course of imatinib mesylate as adjuvant chemotherapy because of the possible risk for tumor recurrence. She is now doing well without any evidence of recurrence or metastasis 25 months after the surgery. Only 9 cases of GIST have been reported in children, and a review of those cases revealed GISTs in children would be associated with a better prognosis than in adults and that one third of pediatric GISTs presented with intestinal obstruction in the newborn period.

Histologic survey of neuroblastomas after intensive induction chemotherapy.

BACKGROUND: Histology after intensive induction chemotherapy is expected to become a beacon indicating when and how extensively radical surgery and lymph node dissection should be performed in advanced neuroblastoma. A thorough histologic review of surgical specimens was undertaken. PROCEDURE: All specimens from 34 patients who were pretreated intensively (> or =3 cycles) with recent chemotherapy were reviewed. Thirty patients were >12 months of age with stage 3/4 disease, and 4 were <12 months of age but with MYCN-amplified stage 4 diseases. After 3 to 7 cycles (mean, 4.3 cycles) of induction chemotherapy, patients underwent radical surgery of the primary tumor and lymph nodes in all retroperitoneal sections. A single pathologist reviewed all of the specimens, and histologic chemotherapeutic effects were graded as: (+++), <1% viable tumor; (++), 1%-10% viable tumor; (+), 11%-50% viable tumor; (+/-), 51%-90% viable tumor; and (-), >91% viable tumor. RESULTS: Grade (+++) effects were observed in 56% of patients treated with the new regimens, whereas grade (+++) was seen in only 20% treated with regimens before 1991. Operation time and blood loss were 7 hr and 6 min (P = 0.087) and 646 ml (P = 0.064), respectively, in patients with >5 cycles (mean, 5.3 cycles) of chemotherapy, while they were 7 hr and 50 min and 1,168 ml, respectively, in those with approximately 3 cycles (mean, 3.2 cycles). Histologically, metastases were found in the contralateral nodes beyond the aorta in 92% of those whose tumor originated on the left, and in 80% of those with tumors occurring on the right. CONCLUSIONS: Five cycles of induction chemotherapy did not improve histologic chemotherapeutic effects, but helped to facilitate a shorter operation time and less blood loss than 3 cycles of chemotherapy. Surgery after 5 cycles of (98)A(3) also appears to be easier to perform than that after 3 cycles of A(1)/new A(1). Only 14% of the children treated before 1985 with the St. Jude protocols experienced grade (+++) chemotherapeutic effects, and 22% of the patients treated before 1991 with regimen A(1), or new A(1) of the Study Group of Japan showed grade (+++) effects, whereas 56% of the patients treated after 1991 with either regimen A(3) or (98)A(3) exhibited grade (+++) chemotherapeutic effects. Histologic chemotherapeutic effects were roughly parallel with a good prognosis.

Pulmonary metastases after nephrectomy only for small, stage I/favorable-histology Wilms' tumor.

The prognosis for children with Wilms' tumor is reported to be excellent in those who are less than 2 years of age at diagnosis and who have a stage I/favorable-histology tumor with specimen weight less than 550 g. We report on a patient with Wilms' tumor who belonged to this group but who developed pulmonary metastases, and we discuss the diagnostic and therapeutic problems in such patients. The importance of careful evaluation of the renal sinus should be emphasized.

An infant with systemic hypertension, renal artery stenosis, and neuroblastoma.

A newborn girl with neuroblastoma presented with hypertension (blood pressure 200/140 mm Hg). The concentration of active renin in the ipsilateral renal vein was exceedingly high compared with those in the other venous systems, and angiography results showed narrowing of the contralateral 2 renal arteries. The tumor regressed in size after chemotherapy, but the blood pressure remained high. Percutaneous transluminal angioplasty (PTA) for the left renal arteries was performed twice, the first one at 5 months of age, which achieved some success in the recovery of impaired kidney function. At 8 months of age, she underwent radical resection of the neuroblastoma and removal of the right kidney, and the blood pressure promptly returned to normal postoperatively. The current patient represents the second youngest, well-documented case of renovascular hypertension with neuroblastoma in early infancy.

Proinflammatory cytokinemia associated with transient myeloproliferative disorder in down syndrome.

A transient myeloproliferative disorder (TMD) occurs in 10% of the infants with Down syndrome. While most cases resolve within a few months, in 20% of them TMDs are life-threatening or fatal. We encountered 4 patients with TMD, including 1 patient who died of liver failure and disseminated intravascular coagulation. Suspecting involvement of proinflammatory cytokines, we serially assayed them in patients' sera. Cytokines were significantly more abundant in patients than in controls. Interleukins 1 and 2, tumor necrosis factor alpha, interferon gamma, and granulocyte-macrophage colony-stimulating factor were greatly increased, especially in the infant who died. Sustained cytokinemia is likely to participate in TMD pathophysiology, and very high serum concentrations might predict a poor outcome.

Current treatment and future directions in neuroblastoma.

OBJECTIVE: The International Neuroblastoma Staging System (INSS) and Pathology Classification (INPC) were applied to analyze the results of treatment of 644 patients with neuroblastoma treated in Japan during the years from 1995 to 1999, and it was found that the pathology classification (INPC) showed the strongest relevance to prognosis compared to other factors such as stage, MYNC amplification, DNA ploidy and 1p-deletion. Current results of treatment for advanced neuroblastoma are still not satisfactory, so innovative therapeutic methods have been sought during the past 10 years. METHODS: Prospects for irinotecan and recombinant human endostatin (rhEndostatin) were studied expertimentally and clinically. RESULTS: Irinotecan is a water-soluble derivative of camptothecin, which is isolated from a Chinese tree, Camptotheca acuminata; Its effectiveness against neuroblastoma was confirmed by in vivo preclinical studies, and phase I clinical trials in Japan concluded the maximum tolerated dose of this agent is 160-180 mg/m2/day for 3 consecutive days, repeated after 25 days off. Phase II trials with this dose began, and we could obtain some encouraging results with the clinical use of irinotecan. rhEndostatin has been studied in in vivo experimental models. The action of rhEndostatin was quite different from those of other cytotoxic chemotherapeutic agents, and continuous administration of this substance showed a more marked anti-effect than its intermittent use. CONCLUSION: Irinotecan appears to be promising when it is given to the patients neuroblastoma, whereas rhEndostatin needs to have more preclinical studies before it is used in patients.