James S. Miser

Chromosome Translocation in Peripheral Neuroepithelioma

PERIPHERAL neuroepithelioma (peripheral neuroblastoma) is an uncommon malignant tumor of the peripheral nervous system with a histologic appearance similar to that of classical childhood neuroblast...

Cytogenetic characterization of selected small round cell tumors of childhood

Small, round, blue-cell tumors (SRCT), including rhabdomyosarcoma, Ewings sarcoma of bone and soft tissue, mesenchymal chondrosarcoma, small cell osteosarcoma, hemangiopericytoma, neuroblastoma, peripheral neurectodermal tumor (peripheral neuroepithelioma of bone and soft tissue), and the malignant small cell tumor of the thoracopulmonary region described by Askin (Askins tumor), are often difficult to distinguish by light microscopy. We have evaluated the cytogenetics of these tumors by studying 24 tumor explants in short-term culture and 22 tumor cell lines. In Ewings sarcoma (a tumor of unknown histogenesis), and in peripheral neuroepithelioma and Askins tumor (tumors with evidence of neural origin), we have observed an indistinguishable t(11;22) translocation.

Ifosfamide with mesna uroprotection and etoposide: an effective regimen in the treatment of recurrent sarcomas and other tumors of children and young adults.

One hundred twenty-four children and young adults with recurrent tumors, predominantly sarcomas, were treated with the combination of ifosfamide, etoposide, and the uroprotector, mesna (2-mercaptoethane sulphonate), in a phase II trial. The treatment regimen consisted of 12 cycles of therapy administered every 3 weeks. After evaluation of the tumor response to chemotherapy alone, radiation or surgery was used to eradicate residual sites of metastatic disease where possible. At the present time, 77 patients are evaluable for response to the chemotherapy; 43 of the patients have experienced a significant reduction in the tumor size in response to the chemotherapy alone (39 partial responses [PR] and four complete responses [CR]). Sixteen of 17 patients with Ewings sarcoma, nine of 13 with rhabdomyosarcoma, four of eight with peripheral neuroepithelioma, three of eight with osteosarcoma, and 11 of 31 with other tumors have responded with a PR or CR. The toxicity of the regimen was acceptable. Moderate or severe toxicity evaluated on a per cycle basis included: neutropenia, 97%; thrombocytopenia, 32%; nephrotoxicity, less than 1%; mucositis, 1%; neurologic toxicity, 2%; nausea and vomiting, 13%; hemorrhagic cystitis, less than 1%. Fever was present after 33% of cycles and sepsis following 7%. One patient died due to sepsis and pancytopenia. At the present time, only seven of the 43 patients who responded to the chemotherapy regimen have relapsed, with a median follow-up of 10 weeks after the response. This drug combination is highly active in the treatment of recurrent sarcomas and other tumors in children and young adults.

The prevalence of pain in a pediatric and young adult cancer population

&NA; The prevalence and nature of pain in the population of children and young adults with malignancy treated by the Pediatric Branch of the National Cancer Institute were assessed over a 6 month period. One hundred and thirty‐nine patients were evaluated during 161 in‐patient days and 195 out‐patient clinic visits. Approximately 50% of the patients assessed in the hospital and 25% of the patients assessed in the out‐patient clinic were found to be experiencing some degree of pain at the time of assessment. Therapy‐related pain predominated in both in‐patients and out‐patients; only one‐third of the pain experienced by in‐patients and less than 20% of the pain experienced by out‐patients was due to tumor. Tumor pain was due primarily to bony invasion. In order to control pain in those individuals experiencing pain, narcotic analgesics were being used by one‐half of the in‐patients and one‐third of the out‐patients. Overall pain control was good, with the median visual analogue scale score being 26 mm on a 0–100 mm scale. During the study period 7 patients were identified to have chronic pain for greater than 1 year following eradication of all known tumor from the site of pain. One was receiving massive doses of narcotics (120 mg/day of methadone) apparently out of proportion to his underlying pain.

Transdermal fentanyl for pain control in patients with cancer

&NA; Five cancer patients experienced satisfactory pain relief for periods of 3–156 days using continuous transdermal delivery of the narcotic fentanyl. The patients, aged 16–68 years, had all been experiencing pain and were either unable to take oral analgesic medications or these agents were ineffective in controlling pain. Doses were adjusted to individual patient needs and varied from 75 &mgr;g/h to 350 &mgr;/h (median = 225 &mgr;g/h). Plasma fentanyl levels reflected the administered dose and remained constant throughout the treatment. Transdermal delivery of narcotics provides a new option for the cancer patient unable to achieve satisfactory analgesia with oral medications.

Long-term follow-up of Ewing's sarcoma of bone treated with combined modality therapy

Between 1968 and 1980, 107 consecutive patients with Ewings sarcoma of bone were entered on three sequential combined modality treatment protocols (S2, S3, S4) at the National Cancer Institute (NCI). Protocol treatment involved 4 cycles of two drug [cyclophosphamide (CTX) and vincristine (VCR)] or three drug [CTX and VCR with either actinomycin-D (ACT-D) or doxorubicin (ADR)] regimens and local irradiation (50 Gy) to the involved bone. Eighty patients presented with localized disease and 27 patients had metastatic disease at presentation, including 11 patients with multiple metastatic sites. With a median potential follow-up of greater than 15 yrs (range 8-20 yrs), 28 pts (27%) remain alive. Disease-free (DFS) and overall survival (OS) decreased most rapidly during the initial 5 yrs of follow-up with 5-yr DFS of 29% and 5-yr OS of 39%. Only two patients with metastases at presentation are long term (greater than 5 yr) survivors. For localized disease patients, the 2, 5, 10, and 15 yr DFS and OS are 52%, 37%, 35%, and 33% DFS and 68%, 51%, 39%, and 34% OS, respectively. Eleven patients relapsed locally as the first site of failure. Using the Cox proportional hazards model, four significant variables for both DFS and OS were recognized, including metastatic disease at presentation, age greater than 25 yrs, high LDH in localized disease patients, and central primary tumor in localized disease patients in decreasing order of significance. We conclude that a majority of these patients with Ewings sarcoma of bone relapsed within 5 yrs of presentation although late relapse (5-15 yrs) did occur. Local failure occurred in 20% of patients using these combined modality treatments but had no impact on overall survival.

Cytosine arabinoside cerebrospinal fluid kinetics

To better characterize the disposition of cytosine arabinoside (Ara‐C) in cerebrospinal fluid (CSF), its kinetics were studied in seven patients with meningeal leukemia in complete remission. After intraventricular injection of 30 mg Ara‐C, CSF and plasma samples were obtained over a 24‐hr period. Ara‐C levels were measured by a reverse‐phase HPLC assay (with a sensitivity of 0.5µM in CSF and 1.0 µM in plasma) that readily separated Ara‐C from its major metabolite uracil arabinoside (Ara‐U). Elimination of Ara‐C from CSF followed a biphasic pattern, with an initial t½ of 1 hr and a terminal t½ of 3.4 hr. Ara‐C clearance from CSF was 0.42 ml/min, suggesting that drug elimination was primarily by CSF bulk flow. The ratio of the AUC of Ara‐U to the AUC of Ara‐C was 0.08, indicating only minor metabolism of Ara‐C to Ara‐U in CSF, in contrast to that after systemic Ara‐C. Despite initial CSF Ara‐C concentrations exceeding 2 mM, Ara‐C was not detectable in plasma in any patient. Intraventricular Ara‐C results in very high levels in CSF, but systemic tissues are relatively spared from exposure to Ara‐C.

Treatment of peripheral neuroepithelioma in children and young adults.

Seventeen patients with peripheral neuroepithelioma were treated with an intensive chemotherapy regimen of vincristine, Adriamycin (Adria Laboratories, Columbus, OH), and cyclophosphamide (VADRIAC) in combination with radiation therapy. Fifteen patients with stage III (seven) or stage IV (eight) at presentation were treated on a more intensive regimen including total body irradiation (TBI) (8 Gy). Two patients with stage I (one) or II (one) disease received a less intensive chemotherapy regimen of VADRIAC. Therapy was completed within 6 to 7 months in all patients. The disease arose in the chest wall in 12 patients, pelvis in three patients, and extremity in two patients. Sixteen of the 17 (94%) patients achieved a complete remission. With a median follow-up of 18 months, ten patients remain in complete remission with an actuarial survival of 68% and an actuarial relapse-free survival of 56% at 12 months. On the basis of our initial experience with this tumor, we believe that peripheral neuroepithelioma is a chemoresponsive and radioresponsive tumor.

Evaluation of growth hormone release and human growth hormone treatment in children with cranial irradiation-associated short stature

We studied nine children who had received cranial irradiation for various malignancies and subsequently experienced decreased growth velocity. Their response to standard growth hormone stimulation and release tests were compared with that in seven children with classic GH deficiency and in 24 short normal control subjects. With arginine and L-dopa stimulation, six of nine patients who received radiation had a normal GH response (greater than 7 ng/ml), whereas by design none of the GH deficient and all of the normal children had a positive response. Only two of nine patients had a normal response to insulin hypoglycemia, with no significant differences in the mean maximal response of the radiation and the GH-deficient groups. Pulsatile secretion was not significantly different in the radiation and GH-deficient groups, but was different in the radiation and normal groups. All subjects in the GH-deficient and radiation groups were given human growth hormone for 1 year. Growth velocity increased in all, with no significant difference in the response of the two groups when comparing the z scores for growth velocity of each subjects bone age. We recommend a 6-month trial of hGH in children who have had cranial radiation and are in prolonged remission with a decreased growth velocity, as there is no completely reliable combination of GH stimulation or release tests to determine their response.

Pain as a presenting symptom in children and young adults with newly diagnosed malignancy.

&NA; The incidence and nature of pain in 92 children and young adults presenting with newly diagnosed malignancy at the Pediatric Branch of the National Cancer Institute over a 26 month period were assessed. At the time of their initial evaluation, 72 of the total 92 patients were experiencing pain that had been present for a median of 74 days (range 3–821 days) prior to initiation of cancer treatment. In 57 patients, pain had been an initial symptom of cancer; 42 patients had experienced sleep disturbance due to pain. Following the institution of cancer therapy, pain persisted for a median of 10 days. One patient died of malignancy after 5 months without resolution of her pain, and only 4 had persistent pain for greater than 9 months after the start of treatment. Persistent pain is an important symptom of cancer in children and young adults and is often present for long periods before the diagnosis of malignancy is made. Cancer in children usually responds rapidly to modern therapy, and pain usually persists only briefly after the initiation of treatment.