Chemotherapy for extraocular retinoblastoma.

Because few patients with extraocular retinoblastoma are seen in the United States and Europe, it has been difficult to establish the optimal role of chemotherapy in such cases. We examined the efficacy of two chemotherapy combinations (cisplatin/etoposide and cyclophosphamide/doxorubicin) in patients with extraretinal retinoblastoma, administered prior to radiotherapy in four patients with recurrent or advanced primary disease. Responses were evaluable in three patients, each of whom was treated by both chemotherapy regimens and radiotherapy. Multimodality therapy promises to be of benefit to patients with extraocular retinoblastoma, and future studies will explore alternative chemotherapy combinations for this purpose.

Fatal Pneumocystis pneumonia in a child treated for focal segmental glomerulosclerosis.

A 4-year-old female with nephrotic syndrome secondary to focal segmental glomerulosclerosis (FSGS) was treated with pulse methylprednisolone and chlorambucil therapy. She subsequently developed fatal Pneumocystis carinii pneumonia (PCP). This is the first report of a pediatric patient whose treatment for FSGS resulted in PCP, raising the issue of PCP prophylaxis for these patients.

Prolonged thrombocytosis in mice after 5-fluorouracil results from failure to down-regulate megakaryocyte concentration. An experimental model that dissociates regulation of megakaryocyte size and DNA content from megakaryocyte concentration.

Rodents treated with 150 mg/kg of 5-fluorouracil (5-FU) exhibit a marked and prolonged rebound thrombocytosis, suggesting that feedback control of one or more megakaryocyte characteristics (size, polyploidy, or concentration) is altered. To determine the changes in megakaryocytes that lead to such a profound thrombocytosis, C3H mice were injected with 150 mg/kg 5-FU, and platelet and megakaryocyte responses were examined at frequent intervals from days 1 through 25. After 5-FU injection, all megakaryocyte indices decreased, as did platelet number. However, the decrease in platelets to one third of control was greater than the decreases in megakaryocyte indices, suggesting that thrombocytopoiesis was ineffective from days 3 through 7 post 5-FU. Megakaryocyte size began to recover on day 4, followed by polyploid DNA content on day 5, and megakaryocyte concentration and platelets at 7.5 days. Megakaryocyte size peaked on days 6 through 8 (1.25 x normal), followed by megakaryocyte polyploid DNA content on day 8, megakaryocyte concentration on days 9 through 12 (2 1/2 to 3x normal), and platelets on days 12 through 15 (2x normal). Platelet levels are thought to be important in the feedback regulation of megakaryocytes; however, only polyploid DNA content distributions showed a close inverse relationship to platelet counts during both the recovery and rebound thrombocytosis phases after 5-FU. In contrast, megakaryocyte size peaked before platelet recovery commenced, while megakaryocyte concentration increased in parallel with platelets from 7.5 to 10 days post 5-FU and continued to be maintained at 2 to 3 times normal through day 13, despite platelet levels that were more than twice normal. Both megakaryocyte size and polyploid DNA content distributions shifted toward lower values in response to the rebound thrombocytosis (DNA content on day 10 and size on days 12 and 13). Splenectomy did not substantially alter the pattern of post 5-FU rebound thrombocytosis or megakaryocyte response from that seen in intact mice, indicating that splenic megakaryocytes are not responsible for the prolonged thrombocytosis seen after this drug. In summary, the prolonged thrombocytosis after 5-FU administration results from failure to down-regulate the number of precursors entering the differentiating megakaryocyte compartment. These data indicate that megakaryocyte size and DNA content are responsive to different feedback controls than megakaryocyte concentration in this model system.

An analysis of megakaryocytopoiesis in the C3H mouse: an animal model whose megakaryocytes have 32N as the modal DNA class.

The modal DNA content of normal marrow megakaryocytes from species so far examined usually has been reported to be 16N. In this report we describe an exception in the C3H mouse whose megakaryocytes have a modal DNA content of 32N. Female C3H/HEN mice had an average DNA content distribution of 14% 8N, 37% 16N, 43% 32N, and 6% 64N. Male C3H/HEN mice had somewhat higher proportions of 32N and 64N megakaryocytes (average DNA content distribution of 12% 8N, 29% 16N, 47% 32N, and 12% 64N) than females. All 11 other mouse strains examined had 16N as the modal megakaryocyte DNA content, although the proportions in the various polyploid DNA classes showed some strain variation. Megakaryocyte size was similar among all 12 strains evaluated, and mean platelet volume (MPV) of C3H/HEN mice differed from only 1 of the other 4 strains analyzed. Platelet counts of C3H/HEN mice were similar to those of six, and slightly but significantly lower than those of five other mouse strains examined. Compared with megakaryocyte concentrations of other mouse strains studied, that of C3H/HEN mice was similar to seven, somewhat higher than one, and slightly lower than three strains. Offspring from reciprocal matings of C57BL/6 and C3H/HEN mice had megakaryocyte DNA distributions intermediate between those of the parent strains, suggesting that a higher gene dosage of some component is responsible for the right-shifted megakaryocyte DNA content distribution phenotype of C3H mice. The proportions of 32N and 64N megakaryocytes increased in C3H/HEN mice in response to acute thrombocytopenia, as did those of CBA/CAJ mice used as a comparative strain. In summary, megakaryocytes of the C3H mouse have a higher average DNA content but similar platelet count, MPV, and megakaryocyte size and concentration as those of most other mouse strains. These results suggest that the number of platelets produced per unit of C3H megakaryocyte DNA is less than that for other mice.

Skeletal scintigraphy in patients with bilateral retinoblastoma.

One hundred-seventeen radionuclide bone scans were performed on 46 patients with bilateral retinoblastoma between diagnosis and 19 years from diagnosis for the purpose of detecting skeletal metastases or other malignant neoplasms of bone that might develop in this group of patients at high risk for a second malignancy. Only one child, who had been symptomatic for 1.5 years, had a scan positive for metastasis at diagnosis. Scans in three additional children became positive (in one after the development of metastatic disease involving bone and soft tissue but not bone marrow 2 years after the diagnosis of retinoblastoma, and in two others after the development of osteosarcoma at 10.5 and 16 years from the diagnosis of retinoblastoma). Our data indicate that bone scans should not remain as part of the initial staging of patients with bilateral retinoblastoma unless there is clinical or pathologic evidence of extraocular disease at diagnosis. The performance of skeletal scintigraphy also is not warranted, with the expectation of diagnosing a second malignant neoplasm (namely osteosarcoma).

Purpura fulminans. A case for heparin therapy.

A 6.5-year-old boy developed purpura fulminans. He had no evidence of congenital protein C deficiency. He responded readily to heparin therapy with resolution of his coagulopathy. The coagulopathy resumed rapidly after heparin therapy was interrupted to allow for surgical procedures. Despite correction of his coagulopathy with heparin, surgical amputation of his leg was necessary because of inadequate perfusion.

The use of bone marrow aspirations and lumbar punctures at the time of diagnosis of retinoblastoma.

Lumbar punctures (n = 115) and bone marrow aspirations (n = 114) were performed as part of the routine initial diagnostic evaluation of 115 children with retinoblastoma. Three spinal fluid examinations were positive for tumor cells, and bone marrow smears of three children demonstrated clumps of tumor cells. Five of the six positive studies were in patients with stage IV (extraglobar) disease. These results show that demonstrable CSF or bone marrow involvement is so infrequent an event at diagnosis in patients without symptoms, signs, or histologic evidence of tumor dissemination (stages I-II) as to support a recommendation that these studies need not be performed routinely in such patients. If, after enucleation, there is evidence of extraglobar extension, or if patients have symptoms or signs of CNS or systemic spread (stages III or IV), both procedures should be performed to accurately stage disease and provide baseline measurements of tumor involvement for monitoring of response to chemotherapy and/or irradiation. These results have importance in terms of justification of invasive work-up of most (greater than 85%) affected children, and cost containment.