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Sidney Farber, world-renowned paediatric pathologist, made major contributions to his field but is acknowledged as the father of the modern era of chemotherapy. He recognised that folic acid stimulated leukaemic cell growth and enhanced disease progression. He hypothesised that folic acid antagonists would inhibit or arrest the proliferation of cancer cells. His landmark study, published in 1948, demonstrated that a number of folic acid antagonists, including 4-aminopteroyl-glutamic acid (aminopterin) produced temporary remissions in children with acute undifferentiated leukaemia. These observations lead to the development and use of other chemotherapeutic agents, either singly or, more effectively, in combination for treating childhood and adult malignancies. He introduced actinomycin D for the treatment of metastatic and localised Wilms tumour. Under his guidance and leadership, both the 'Jimmy Fund', one of the first comprehensive paediatric oncology treatment centres, and the Children's Cancer Research Foundation, which later became the Dana-Farber Cancer Institute, were founded.

Background. Fifty-seven children with acute lymphoblastic leukemia (ALL) receiving therapy who experienced overt isolated testicular relapse while in bone marrow remission were entered into a study that featured an intensive retreatment regimen. Methods. The objective was to determine whether a change in chemotherapy and local irradiation would prevent subsequent marrow relapse and increase the survival rate. The regimens used (modified Berlin-Frankfurt-Munster or modified New York) delivered acceptable therapy based on analyses of toxicity data. Results. Overall survival at 5 years from the time of testicular relapse was 47%, with an event-free survival of 43%. Events have been documented in 28 of 55 evaluable children. Analysis of these patients revealed that 23 children had bone marrow relapse, 4 children had central nervous system relapse, and 1 child had testicular relapse. In addition, two patients were removed from the study for toxicity, one child for infection (mucormycosis), and five children had a bone marrow transplantation while in remission and became ineligible to continue in the study. Two children were removed at the request of their parents, and nine children were lost to follow-up. Conclusion. Because of their high risk of developing systemic relapse, boys with ALL who experience isolated overt testicular relapse during active therapy should be retreated with intensive treatment.

Multivariate analyses of the clinical course of 1537 children with acute lymphoblastic leukemia (ALL) identified a subgroup which experienced short remission duration and a high incidence of extramedullary relapse. The patients differed from other ALL patients by the presence at diagnosis of two or more of a constellation of clinical and laboratory features: organomegaly or mass disease, E-rosette positivity, hemoglobin level greater than 10 g/dl, leukocyte count greater than 50,000/microliters, male predominance, and older age. This type of presentation of ALL is referred to as the "lymphoma syndrome" (LS) since such patients exhibit a pattern of several clinical and laboratory features which were observed repeatedly but in differing combinations, and some of which clinically resemble lymphoma. A subsequent database from 2231 patients was analyzed. Patients with a mediastinal mass, massive splenomegaly, or massive adenopathy, alone or in combination, had a worse outcome when the patient also had either leukocytosis, E-rosette-positive lymphoblasts, or a normal or near normal hemoglobin (Hb) level at diagnosis. Similarly, the above three laboratory features alone or in combination did not predict less than 40% disease-free survival (DFS) unless they were accompanied by at least one of the clinical features of mass disease. When at least one clinical feature and at least one laboratory feature were present, the overall DFS was 36% 6 years after diagnosis versus 64% for all other patients. The association of these features with poor prognosis remained significant after adjusting for the level of leukocyte count at diagnosis, age at diagnosis, and sex of the patients. Patients with this recurrent syndrome of features do not represent a homogeneous biologic entity but they constitute a subgroup of patients with ALL having a high risk of treatment failure using current therapies, including failure to achieve remission, early relapse, and increased frequency of relapse in extramedullary sites. They deserve early recognition at diagnosis and selection of treatment strategies appropriate for very high risk ALL.

The percent of marrow blasts on day 7 of therapy was determined for 128 children with previously untreated acute lymphoblastic leukemia and white blood count (WBC) greater than or equal to 50,000/microliters and/or lymphomatous features enrolled in the Childrens Cancer Study Group trial of the Berlin Frankfurt Munster 76/79 regimen (CCG-193P). Patients received four-drug induction therapy including vincristine, prednisone, l-asparaginase, and daunomycin. Ninety-seven patients had fewer than 25% marrow blasts on day 7. Of these, 94 survived and maintained remission through day 28 and were designated early responders. Thirty-one patients had greater than 25% marrow blasts on day 7. Of these, 28 survived and achieved remission on day 28 and were designated late responders. The outcome of patients who underwent a day 7 marrow aspiration was similar to those who did not. Early responders had a 77.4% +/- 4.5% (standard deviation) 3-year estimated disease free survival, while late responders had 47.3% +/- 9.8% (P less than 0.001). Early responders had a superior outcome both in the subset with an initial WBC less than 50,000/microliters (P = 0.025) and in the subset with a WBC greater than or equal to 50,000/microliters (P = 0.01). The day 7 marrow response had prognostic value in this population of children with unfavorable presenting features who received four-drug remission induction therapy.

A combination of dietary and host-related factors determines iron and zinc absorption, and several in vitro methods have been developed as preliminary screening tools for assessing bioavailability. An expert committee has reviewed evidence for their usefulness and reached a consensus. Dialyzability (with and without simulated digestion) gives some useful information but cannot predict the correct magnitude of response and may sometimes predict the wrong direction of response. Caco-2 cell systems (with and without simulated digestion) have been developed for iron availability, but the magnitude of different effects does not always agree with results obtained in human volunteers, and the data for zinc are too limited to draw conclusions about the validity of the method. Caco-2 methodologies vary significantly between laboratories and require experienced technicians and good quality cell culture facilities to obtain reproducible results. Algorithms can provide semi-quantitative information enabling diets to be classified as high, moderate, or low bioavailability. While in vitro methods can be used to generate ideas and develop hypotheses, they cannot be used alone for important decisions concerning food fortification policy, selection of varieties for plant breeding programs, or for new product development in the food industry. Ultimately human studies are required for such determinations.

PURPOSE Patients with cancer and chronic inflammatory disorders have used shark cartilage (SC) preparations for many years. Preclinical studies that support their beneficial effects are scanty, and reports of clinical trials have been anecdotal. The proposed mechanisms of antitumor action include direct or indirect inhibition of angiogenesis. Because of the emerging use of SC as an alternative to conventional cancer therapy, this trial was launched to evaluate the safety and efficacy of SC. PATIENTS AND METHODS Sixty adult patients with advanced previously treated cancer (breast, 16 patients; colorectal, 16 patients; lung, 14 patients; prostate, eight patients; non-Hodgkin lymphoma, three patients; brain, one patient; and unknown primary tumor, two patients) were enrolled. Eligibility criteria included confirmation of diagnosis, resistance to conventional therapy, objective measurable disease, life expectancy of 12 weeks or greater, Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, no recent or concomitant anticancer therapy, no prior SC, and informed consent. Patients underwent evaluation of the extent of disease, quality-of-life score (Functional Assessment of Cancer Therapy-General [FACT-G] scale), and hematologic, biochemical, and selected immune function studies at baseline and after 6 and 12 weeks of SC therapy. The dose of SC was 1 g/kg daily orally in three divided doses. Standard criteria were used to evaluate adverse events and response. RESULTS Ten of 60 patients were lost to follow-up(LTFU) or refused further treatment (RFT) before the 6-week evaluation and were not assessable for toxicity and response. Three patients with stable disease at 6 weeks were LTFU or RFT thereafter. Of the 47 fully assessable patients, five were taken off study because of gastrointestinal toxicity or intolerance to SC. Progressive disease (PD) at 6 or 12 weeks occurred in 22 and five patients, respectively. Five patients died of PD while undergoing SC therapy. No complete (CRs) or partial responses (PRs) were noted. Median time to tumor progression in the entire study population was 7+/-9.7 weeks (mean, 11.4 weeks; range, 3.7 to 45.7 weeks). Ten (20%) of 50 assessable patients, or 16.7% of the 60 intent-to-treat patients, had stable disease (SD) for 12 weeks or more. The median time to tumor progression was 27 weeks, the mean was 28.8+/-9.9 weeks, and the range was 18.6 to 45.7 weeks. In this subset, FACT-G scores improved in four patients, were unchanged in four patients, and declined in two patients. Twenty-one adverse events (grade 1, eight events; grade 2, seven events; and grade 3, six events) were recorded, 14 of which were gastroenterologic (nausea, vomiting, constipation). CONCLUSION Under the specific conditions of this study, SC as a single agent was inactive in patients with advanced-stage cancer and had no salutary effect on quality of life. The 16.7% rate of SD was similar to results in patients with advanced cancer treated with supportive care alone.

Dose and dose intensity are believed critical for attaining a maximal therapeutic effect in drug-responsive tumor systems. Childhood acute lymphoblastic leukemia may be an example of such a drug-responsive system as it is cured with current chemotherapy in a majority of cases. Between August 1981 and May 1983, the Childrens Cancer Study Group enrolled 209 children with ALL and unfavorable presenting features in CCG-193P, a trial based on the Berlin Frankfurt Munster 76/79 regimen. The cumulative delivered dose of each medication was recorded prospectively. Patients who completed the intensive portion of therapy in continuous complete remission were ranked by the percentage of protocol required drug delivered from the initiation of therapy to that date. No association was found between delivery of any single drug and subsequent disease-free survival. However, when patients were ranked by the sum of the percentages of protocol vincristine, l-asparaginase, and anthracycline delivered, children in the approximate middle and lower tertiles were 3 and 5 times more likely to have had a subsequent relapse than were those in the upper tertile (P = 0.025, test for trend). Delivery of the full protocol prescribed dose of these agents may have been critical, but corroboration is certainly needed. Only prospective trials can determine if children with acute lymphoblastic leukemia and unfavorable presenting features might benefit from greater use of vincristine, l-asparaginase, and/or anthracycline.

One of the objectives of Childrens Cancer Study Group (CCSG) study 141 (CCG-141) was to determine the frequency of occult testicular leukemia (TL) after 3 years of disease-free survival (DFS) and to retreat boys with occult TL to prolong their subsequent DFS. Of the 494 boys entered on study, 255 (51.6%) were in complete continuous remission (CCR) 3 years after entering remission and an additional eight were in CCR 3 years after localized extramedullary relapse and retreatment; 263 boys were eligible for testicular biopsy. Elective testicular biopsy was performed on 235 (89.4%) boys. Of the 204 (86.8%) boys with negative biopsies, 175 (85.8%) remained in CCR 10 to 12 years after diagnosis and 25 (12.3%) relapsed, 11 (44%) of whom died. Isolated overt TL occurred in four (2.0%) and all remained in CCR 22+ to 60+ months after re-treatment. Of the 26 boys with occult TL, 16 (62%) remained in CCR. Ten (38%) relapsed despite local testicular irradiation and systemic re-treatment; six of the 10 died. Of the 26 boys who did not undergo biopsy, 21 (80.8%) remained in CCR; two (7.7%) developed isolated overt TL. DFS after testicular biopsy was significantly better in boys without occult TL (P = .001). Occult TL after 3 years of CCR represents aggressive minimal-residual disease and carries a worse prognosis than absence of TL. Initial treatment should be directed at obviating occult and overt testicular relapse. Conventional therapy as used in this study was suboptimal in preventing subsequent bone marrow (BM) relapse and death. If occult TR is identified during or at the end of planned therapy, a higher salvage rate may require intensified alternate therapy. As such, testicular biopsies may be clinically useful. Further investigation is limited by the relative rarity of, and the lack of identifying features in boys with occult TL.

Cancer is the major medical cause of death in children between the ages of 1 and 15 years. The annual incidence in the United States is 130 cases per million infants, children, and adolescents, accounting for approximately 6500 new cases annually. Invariably fatal 25 years ago, today cancer is curable in over half of children. This remarkable achievement is the result of more accurate diagnosis, more effective multimodality therapy, selected use of bone marrow transplantation, and improved supportive care. An important component of supportive care is addressing the psychosocial needs and adjustment of children with cancer and their families. Health care professionals involved in childhood cancer are keenly aware of the improved prognosis in virtually every malignancy. Accordingly, preparation for long-term survival rather than anticipatory grieving and preparation for relapse and death is the prime strategy for psychosocial support today. This is particularly true at the time of diagnosis of

A variant of glucose-6-phosphate-dehydrogenase deficiency associated with chronic hereditary hemolytic anemia was discovered in a 9-yr-old white male. The erythrocytes contained 5% of normal enzyme activity, the Km NADP was two to three times normal, the pH optimum was decreased, and the heat stability was markedly decreased. The Km G6PD, electrophoretic mobility (B), and utilization of substrate analogues 2-deoxy-G6P and deamino-NADP were normal. The activity of G6PD in the leukocytes and platelets was 15% and 28% of normal values, respectively, but bactericidal activity and platelet function were unaffected by the deficiency of G6PD.

The activity of terminal deoxynucleotidyl transferase (Tdt) was measured in mononuclear cells of 70 children with acute leukemia, in whom raised levels of Tdt were noted at diagnosis, relapse, or during remission. Serial measurements of Tdt activity were related to the percentage of blasts in the bone marrow and the clinical course of children both during therapy and after its completion. The Tdt values did not predict relapse in children with acute lymphoblastic leukemia nor did the quantitative determination correlate with the percentage of blasts in the bone marrow.

A 31-yr-old female with congenital hypoplastic anemia (Diamond-Blackfan syndrome) whose long course terminated in acute myelogenous leukemia is described. In contrast to Fanconi anemia, malignant transformation rarely occurs in congenital hypoplastic anemia. This patient's diagnosis of congenital hypoplastic anemia is supported by her clinical course, absence of renal abnormalities, a negative family history for hematologic disorders, normal chromosome studies, failure of her skin fibroblasts to transform in culture with SV-40 virus, macrocytic erythrocyte indices, erythrocyte enzyme studies, and bone marrow findings. Only two other cases of malignancy have been reported in patients with congenital hypoplastic anemia. The development of malignancy in these patients suggests that malignant transformation may be a concern in the long-term progression of congenital hypoplastic anemia.

The heart was evaluated by echocardiography in 56 patients at risk for myocardial iron deposition. Fifty-four had congenital anemia for which they required repeated transfusions, and two had primary hemochromatosis. The data, plotted according to one of three functions of the body surface area, were compared to values obtained in 105 normal subjects whose age spanned a similar range. Left ventricular wall thickness, transverse dimension and mass, as well as left atrial transverse dimension, were increased in the majority of patients with chronic iron overload despite the infrequent occurrence of cardiac enlargement on routine chest films (32 per cent) or electrocardiographic abnormality (16 per cent). Left ventricular ejection fraction was normal in all but four patients. These four patients died within a six month follow-up period suggesting that deterioration in systolic function is an indicator of poor prognosis. Our findings indicate that echocardiography provides a simple noninvasive means for assessing changes in cardiac structure and function that should prove useful in the serial evaluation of patients who are at risk for the development of myocardial iron deposition.

With the improved outlook in childhood cancer, the precise role of the pediatrician in the ongoing care of the child with cancer must be redefined and clarified. This article addresses the issue of how the practitioner can best function as an active and constructive member of the multidisciplinary team.

Investigation of in vitro humoral immune responses and immunoregulatory properties of leukemic cell was carried out in 17 children with acute leukemia prior to therapy. Leukemias were of the non-T, non-B-cell type in 13 patients and of T-cell origin in four. Bone marrow and peripheral blood cells consisted of 24-96% lymphoblasts and were generally deficient in surface Ig-positive cells. Induction of Ig secreting cells in response to pokeweed mitogen was markedly decreased in marrow and peripheral mononuclear cell cultures of leukemic patients. Co-culture of leukemic cells with normal lymphocytes led to marked deviations from the expected Ig secreting-cell response of the cell mixtures. The predominant effect was enhancement, as was the case with eight non-T, non-B-cell and one T-cell leukemia samples. Suppression of the Ig secreting-cell response was observed in only three instances, two with non-T, non-B-cell and one with T-cell leukemia samples. These findings implicate non-T, non-B as well as more differentiated leukemic cells in having the potential for modifying Ig production by B cells.

Non-Hodgkin's lymphoma confined to the liver is unusual in adults and has not been reported in children. Two children with primary hepatic and one with hepatosplenic NHL are described. All three patients are males, and both tumors examined for cell surface markers were of B-cell origin. Two patients, treated with chemotherapy and radiation, developed disseminated disease and died with 7 months of diagnosis. A third patient treated aggressively with radiotherapy and multiagent chemotherapy (LSA2–L2 protocol) remains in complete continuous remission 22 months after initiation of therapy. Hepatic NHL, even if well localized at diagnosis appears to warrant an aggressive therapeutic approach. Cancer 52:2285-2288, 1983.

The immunoregulatory activity of bone marrow leukemic blasts from five patients with null-cell acute lymphoblastic leukemia (ALL) and two children with T-cell ALL was evaluated. Blasts were studied in co-culture for their effects on the proliferative responses of normal allogeneic peripheral blood lymphocytes to phytohemagglutinin. Mitomycin C-treated null cell ALL blasts from two of five children suppressed the proliferative responses of normal responder cells by 80% and 58% whereas those from two other children enhanced the responses by 118% and 31%. T-cell leukemic blasts from one patient with T-cell ALL exhibited helper cell activity (26%) and T-leukemic blasts from the other demonstrated suppressor cell activity (53%). The helper cell activity of leukemic blasts was associated with stimulating capacity of null blasts in one-way mixed lymphocyte reactions. In six of seven cases, incubation of blast cells with concanavalin A (20 microgram/ml) for 48 hours prior to co-culture with responder cells did not result in the generation of significant suppressor cell activity. Our study suggests that leukemic blasts from certain patients with 'null' and T-cell ALL may possess spontaneous helper or suppressor cell immunoregulatory activity. This functional heterogeneity of leukemic blasts may help in subclassifying the ALL.

An autosomal recessive mutant (symbol, dan) in the dog causes chondrodysplastic dwarfism and mild anemia as pleiotropic effects. The anemia is characterized by stomatocytosis, macrocytosis, low MCHC, increased osmotic fragility, shortened red cell survival, reticulocytosis, erythroid hyperplasia, and increased iron turnover. Minor changes can be detected in the red cells of heterozygous carriers of the dan gene, but red cell survival is normal and chondrodysplasia is not present. Red cell sodium concentration and water content are increased in anemic dogs and to a lesser degree in carriers. Glutathione deficiency is present. The disorder described here resembles a number of human hemolytic anemias with stomatocytosis, glutathione deficiency, and disordered red cell cation and water content, and further study of the dan mutant, together with investigations of the hereditary human conditions, will elucidate the maintenance of normal red cell cation balance.

An infant with Klippel Trenaunay Syndrome (KTS), a disorder of embryonic development characterized by hemangiomas and hypertrophy of lower extremities, had bilateral nephroblastomatosis diagnosed at 1 year of age. Although the natural course of these tumors is uncertain, lesions of this kind have been suggested as the source of Wilms' tumor. In addition, foci of primitive cells suggested malignant potential. The more extensively involved kidney was removed and the contralateral lesion was treated by irradiation, actinomycin D, and vincristine, resulting in disappearance of the lesions 6 months later. The association of nephroblastic tumors with soft tissue growth disorders is extended to include KTS, and the possible relationship of nephroblastomatosis to Wilms' tumor is discussed.

Summary. 2,3-Dihydroxybenzoic acid was evaluated as a potentially useful, orally effective iron-chelating drug by performing iron balance studies in patients with β-thalassaemia major. The administration of this substance at 25 mg/kg/d to five patients for 8 d caused an average increase in iron excretion of 4.5 mg/d. When the drug was administered at 25 mg/kg q.i.d. to eight patients for 21 d, iron excretion increased to 6.5 mg/d. Chelation was highly specific for iron with changes in magnesium and calcium excretion being insignificant. The drug was well tolerated with side effects limited to gastrointestinal complaints which ameliorated when the drug was taken with food. These studies provide a rationale for further evaluation of 2,3-dihydroxybenzoic acid in patients with iron overload.

Eight-hundred ninety-five previously untreated acute lymphoblastic leukemia (ALL) patients were entered on a protocol designed to provide results of selected immunologic tests. At diagnosis, delayed hypersensitivity tests with four antigens (tetanus, diptheria, candida, and SKSD), immunoglobulin levels, tests for serum inhibition to phytohemagglutinin-stimulated lymphocyte blastogenesis, and HLA-A, B, and C typing were performed. Although delayed lymphocyte blastogenesis have been reported previously to be abnormal in ALL, we did not find them to be associated with disease outcome. Thirty percent of the patients had reduced levels of one or more immunoglobulins. The frequency of remission was less in those patients with decreased IgG and IgA. IgA and IgM showed prognostic importance in remission duration, and all three fractions appeared to have prognostic significance for survival duration. Although none of the HLA types appeared to be associated with significantly increased or decreased success in remission induction, patients with antigens A28 or B12 and patients bearing lymphocyte A11/B35 had shorter remissions. our results indicate that the immunologic factors studied, hypogammaglobulinemia and certain HLA antigens may be related to disease control and outcome in ALL.

Peripheral blood lymphocytes from 13 children with newly diagnosed untreated non-Hodgkin malignant lymphoma were investigated for the proportion of Tμ and Tγ cells. Tumor involvement was classified as stage II in two patients, stage III in five patients, and stage IV in six patients. Diffuse poorly differentiated lymphoblastic histological-type lymphomas, as defined by the Rappaport classification, were found in eight patients. The proportion of Tγ cells was found to be increased and that of Tμ cells decreased in the patient group as compared to levels in healthy controls. A marked imbalance of the Tμ/Tγ ratio was observed in ten of 13 patients. There was no correlation between Tμ/Tγ ratios and stage of the disease. Imbalances of Tμ and Tγ cell proportions are discussed in relation to humoral and cellular immunodeficiencies observed in patients with non-Hodgkin malignant lymphoma.

An intensive multimodal therapy was developed for the treatment of a subpopulation of children with acute lymphoblastic leukemia (ALL) who had a predicted event-free survival of less than 40% on previously reported therapeutic regimens (at high risk for early relapse). Induction with multiagent chemotherapy and radiotherapy to bulky disease-bearing areas (peripheral lymph nodes and mediastinum) was followed by consolidation, CNS prophylaxis, and cyclical remission maintenance therapy. Ninety-six (96%) of 100 previously untreated patients, 1 to 17 years of age, attained a complete remission. Seven patients received other maintenance therapy or a bone marrow transplant in remission. Sixty-six of the remaining 89 (74%) are in continuous complete remission at 22+ to 72+ months (median, 44+ months). Marrow relapse occurred in 15 (17%), CNS relapse in 5 (6%), and testicular relapse in one. Sixty-six of the 93 evaluable patients (71%) (including the induction failures) are event-free survivors. Two patients died of infection during the induction phase. No patient died during consolidation or maintenance without recurrent disease. The patients spent a median of 19, 0, and 0 days hospitalized during induction, consolidation, and maintenance, respectively. The most common complications were bacteremia and mucositis during induction and mucositis and fever during periods of neutropenia in consolidation. Maintenance was well tolerated. We conclude that the treatment protocol is intensive, but the inherent toxicities are manageable with adequate supportive care. The life table--projected event-free survival of 69% +/- 5% 48 months from diagnosis is encouraging.

The performance status of the child with cancer is an important outcome consideration in pediatric oncology research and practice. However, no single measure for children has been available. This is a report of the development and standardization of such a scale. The play-performance scale for children is a parent-rated instrument which records usual play activity as the index of performance. Performance status ratings were obtained on three groups of children: patients (n = 98), patients' siblings (n = 29), and an independent sample of hospital employees' children (n = 40). Children with all types and stages of childhood malignant neoplasms were represented. Test results established the parent as a competent, reliable rater and demonstrated the validity of the scale. Interrater reliability was examined using correlational statistics and percentage agreement. Agreement between parents was good, and there were no systematic rater biases. In addition, parents' ratings significantly discriminated differences in levels of functioning (mean score, patients 75.4 versus siblings 97.4). Correlational and analysis of variance (ANOVA) procedures demonstrated that the play-performance scale was significantly related to the global performance measures of experienced clinicians and was sensitive to change. Inpatients received a mean score of 42.3, outpatients 90.7, and normals 98.2. These findings indicate that the scale is both feasible and effective. It is concise, can be administered repeatedly even to extremely ill patients, and uses parents as observer reporters. The play-performance scale for children provides quantifiable, reproducible, and meaningful data, which is necessary for effective monitoring and management of the child with cancer.

Bone marrow cells from eight children and young adults with acute nonlymphocytic leukemia (ANLL) were classified by morphological and cytochemical criteria. The expression of receptors for complement (C3) and IgG Fc, the binding of immunoglobulin to the surface of leukemic blasts, and the phagocytic ability were investigated and compared with the differentiation/maturation of cells of normal myeloid and monocytic lineages. Cells from two patients with monocytic leukemia exhibited IgG Fc receptors in high proportions. The stage of maturation or differentiation as evaluated by the expression of surface markers did not correlate morphologically with the determined state of maturation in the remaining cases. Simultaneous measurements of cellular RNA and DNA, using flow cytometry, were performed on five patients. An increase in RNA content of leukemic cells was detected in all patients and evidence of aneuploidy was observed in three patients. The cellular RNA content of ANLL was higher than that of ALL. This technique, therefore, appears to be useful as an additional tool for the discrimination of ALL from ANLL and for the rapid detection of aneuploidy.

A 25 year old patient with congenital hypoplastic anemia (Black-fan-Diamond syndrome) is described. This patient was hepatitis-antigen negative, had not received androgens and had a hepatoma develop in a transfusional hemochromatotic liver. Since androgens have been associated with hepatocellular carcinoma, the use of androgenic steroids for other than life-threatening symptoms in this disease should be avoided.In this case report, the patient had been delivered by Caesarean section and weighed only 4 pounds at birth. The mother was O negative, the father A positive, and the infant A positive. Initial red cell count was 2.85 million/cu mm; white cell count, 19,200/cu mm; and hemoglobin 70% of normal. At 3 months of age hemoglobin was 10% of normal. Bone marrow examination revealed marked erythroid hyperplasia. A diagnosis of Blackfan-Diamond syndrome was made. He received blood transfusions every 2 or 3 weeks for the first 4 years of his life. During his lifetime he received 433 units of packed cells for the treatment of congenital hypoplastic anemia. Vitamin-B12, folic acid, and iron were given without benefit. At 8 years of age a spelectomy was done. 20 months after surgery he recovered from pneumonococcal meningitis without sequelae. Progressive signs of hemochromatosis developed and finally progressive signs of heart failure with edema. At 24 years of age severe epigastric pain developed. An open liver biopsy disclosed multiple liver nodules which proved to be hepatoma. Severe ascites followed the surgery. Pulmonary metastases of the liver tumor developed and heart failure. He died at age 25. This patient had received no androgen. He was consistently hepatitis antigen negative. He was prepubertal at the age of 25 and had almost no endogenous androgens. Alpha-fetoglobin was present. This test may be useful as a screening test for hepatoma.

During the National Influenza Immunization Program in 1976, 147 children with neoplastic diseases received Wyeth split-product bivalent influenza vaccine: A/New Jersey/8/76 (HSW1N1), A/Victoria/3/75 (H3N2). Thirteen normal siblings served as controls. Seventy-one patients received two doses of the vaccine four weeks apart. After the second injection of A/NJ/8/76, there was a difference between the response of the patients on chemotherapy and those off therapy greater than or equal to 30 days--38% vs. 76%, P less than 0.01 for four-fold rise and 26% vs. 57%, P less than 0.05 for the attainment of protective (greater than or equal to 32) hemagglutination inhibition (HI) titers. These differences were observed in both leukemia-lymphoma and solid tumor patients. There was a difference in HI titers to A/Vic/75 between patients on and off chemotherapy after a single injection, 34% vs. 71%, P less than 0.001 for a four-fold rise. After the second immunization, only 52% on, and 86% off therapy (P less than 0.05) had a four-fold rise in titers. Thirty-two percent of the patients on treatment who achieved "protective" titers did so only after the second immunization. Immunoglobulin levels and neutropenia did not correlate with the inability to obtain a four-fold rise in titers. Our findings suggest that patients on chemotherapy cannot be effectively vaccinated by a new antigen, and that single yearly boosters may be insufficient for recall of old antigens. Patients off chemotherapy greater than or equal to 30 days respond as normal controls.

Summary Peripheral blood lymphocyte sets and serum immunoglobulins were examined in 15 patients with thalassaemia intermedia, aged between 5 and 30 years. They were divided in three clinical groups: Group I, non-splenectomized, with serum iron (SI) lower than 200 μg/dl; Group II, splenectomized with serum iron lower than 200 μg/dl; and Group III, splenectomized with serum iron levels greater than 200 μg/dl. High absolute lymphocyte counts were observed in the majority of patients, whether splenectomized or not. Following splenectomy, marked increases were observed in absolute number of lymphocytes and percentages of circulating surface immunoglobulin (SIg) bearing B lymphocytes, mouse rosette forming cells (MRFC) and ‘null’ cells. The increases in circulating B lymphocytes following splenectomy were due exclusively to cells bearing SIgM and/or SIgD. No changes were observed in numbers and proportions of circulating SIgA or SIgG bearing cells. Serum IgA levels were high in the majority of patients studied whether splenectomized or not. Following splenectomy increases in serum IgA and serum IgG were observed which seemed to relate to increasing SI levels. No significant changes occurred in serum IgM levels. Absolute numbers of circulating T lymphocytes were unaffected by splenectomy or SI levels. Changes were observed, however, in distribution of T lymphocyte subsets with decreases in number of Tμ cells and concomitant increases in numbers of non-Tμ, non-Tγ cells. Tγ cells were the least affected by splenectomy and increasing SI. The results are compatible with the proposition that iron participates in the regulation of lymphoid cell migration and in the modulation of expression of cell surface markers. The findings also illustrate the role of the spleen in the control of lymphocyte migration and immunoglobulin production.

Childrens Cancer Study Group protocol 141 (CCG-141), a randomized trial, was designed in part to compare 3 v 5 years of maintenance therapy, to evaluate the role of late reinduction, and to identify factors that predict relapse after 3 years of continuous complete remission (CCR) in acute lymphoblastic leukemia (ALL). Of 880 patients entered on study, 827 (94%) achieved complete remission and 499 (56.7%) were in CCR after 3 years of maintenance therapy. Boys were required to have negative testicular biopsies before randomization. A total of 481 patients were eligible for the duration of therapy phase of the study. Of the 310 (64.4%) randomly assigned patients, 101 were entered on regimen A: discontinue therapy; 105 on regimen B: reinduction for 4 weeks, then discontinue therapy; and 104 on regimen C: continue maintenance therapy for 2 more years, then discontinue. After a median follow-up of over 72 months, no significant differences in disease-free survival (DFS) or survival were noted in the three regimens. At 6 years from randomization, 93.0%, 89.1%, and 89.1% of patients on regimens A, B, and C, respectively, remained in CCR. Isolated CNS or overt testicular relapses were not significantly different in any of the study regimens. Isolated testicular relapse after a negative biopsy occurred in only two of 137 randomized males (1.5%). DFS (P = .10) and survival (P = .83) were not significantly different for all boys and girls randomized to regimens A, B, or C. The relapse rate was higher in boys than in girls randomized to discontinue therapy (11% v 4%), but the difference was not statistically significant (P = .14). Except for the presence of occult testicular leukemia (TL) in males, no other factors were identified that predicted for adverse events after 3 years of CCR. We conclude that prolongation of maintenance therapy beyond 3 years does not improve survival or decrease the risk of relapse.

From 1975 to 1978, 880 previously untreated patients with acute lymphoblastic leukemia (ALL) were entered on CCG-141, a protocol designed to determine the importance of clinical predictors of remission-induction, duration of complete continuous remission (CCR), and survival, and to determine the benefit of intensive therapy in patients with a poor prognosis. Patients with initial leukocyte count 20 × 109/1 were randomly assigned to this standard regimen or to a more intensive four-drug regimen (PDN, VCR, LASP, and cyclophosphamide) and a maintenance program consisting of alternating cycles of PDN, VCR, 6-MP, and MTX (POMP) and PDN, VCR, cytosine arabinoside, and Adriamycin (POCA). The overall rate of complete remission (CR) was 93%. Factors associated with a significantly lower rate of CR were: M3 bone marrow (BM) on day 14, CNS leukemia at diagnosis, L3, morphology, less than 40% PAS-positive lymphoblasts, low IgG, age >10 years, and L2 morphology. The relapse rate in patients with an initial leukocyte count 20 × 109/1. By multivariate analysis, adverse predictors of duration of CCR were leukocyte count >50 × 109/1, Hb >10 g/dl, low IgM, massive splenomegaly, age 20 × 109/1. By life table analysis, 80% of patients with good prognostic factors remain in CCR at four years. In patients with poor prognostic factors, the CCR rate at four years is 43%. This study demonstrates the utility of clinical prognostic factors in identifying subsets of patients at low and high probability of treatment failure. Intensive induction and maintenance therapy as used in this protocol did not benefit the poor prognosis group.

The Childrens Cancer Study Group (CCSG) CCG-160 protocol series was designed to evaluate prognostic factors in acute lymphoblastic leukemia (ALL). Patients were assigned to one of three prognostic groups based upon initial WBC count and age. To determine the optimal duration of therapy, CCG-160 patients completing 2 years of treatment in continuous remission were randomized ("late randomization") to discontinue therapy or receive another year of maintenance therapy. The prognostic significance of early response to induction therapy, as measured by the percentage of lymphoblasts in the day-14 bone marrow (d14 BM) aspirate, was evaluated in 2,516 children. For 1,490 patients with complete data, the status of the d 14 BM was a highly significant predictor of disease-free survival (DFS) by univariate and multivariate analysis (P less than .0001). The observed/expected (O/E) failure rate in patients with d14 M1 (less than 5% blasts), M2 (4% to 25% blasts), or M3 (greater than 25% blasts) BM rating who were subsequently M1 on day 28 or day 42, was .87, 1.59, and 2.30, respectively (P less than .0001). Patients with M2 or M3 d14 BM were more likely to have L2 ALL (modified French-American-British [FAB] morphologic classification), P less than .001. The significance of the d14 BM rating persisted after correction was made for WBC count and clinical prognostic groups using current CCSG criteria, except in infants less than 12 months of age. The d14 BM was also the most significant predictor of DFS in 975 patients after late randomization at 2 years following diagnosis. The O/E failure rate in patients with d14 M1, M2, or M3 BM was .88, 1.78, and 2.02, respectively (P = .0002, trend). Other significant predictors of late relapse were prognostic groups (P = .0003, trend) and initial WBC count (P = .004, trend). Predictive for both early and late relapse of ALL, early response should be monitored closely and alternative treatment regimens should be considered for slow responders.

Cyanate reacts with unchanged amino groups of various proteins in a specific irreversible carbamylation reaction. The effect of this molecule on the clotting process and the effects of carbamylation on the clotting proteins and platelet functions were investigated in vitro. An immediate effect on the clotting proteins, not related to pH, was seen in the screening tests prothrombin time, partial thromboplastin time and thrombin time at the highest concentration (100 mM), to a lesser degree at the lower concentration (10 mM). These changes reflected decreases of 19 and 36% respectively in Factor V and X activity, an inhibition of 63-75% of Factors VII, IX, X and XI activity, and 80% inhibition of thrombin activity. The inhibitory changes of carbamylation increased with time. No changes were seen in the activity of Factors I and VIII. Platelet function studies revealed no inhibition of Factor III release; aggregation was abnormal only at high concentrations with epinephrine and collagen induction and partially reversible by resuspension in normal plasma.

Recent revival of interest in the use of vincristine (VCR) for the treatment of idiopathic thrombocytopenic purpura prompted us to evaluate the platelet function of our patients on VCR. Eighteen patients with acute lymphoblastic leukaemia (ALL) in remission, and nine children with solid tumours were studied on 80 occasions at different time intervals after their last VCR dose. A mildly elevated threshold for epinephrine-induced second phase aggregation and a delay in the onset of collagen-induced aggregation was found in patients with ALL not on VCR. Vincristine induced unobtainable second phase aggregation to epinephrine in 67%, 38%, 30% and to ADP in 53%, 13%, 33% of the patients 1 week, 2-3 weeks and 4 weeks respectively after administration. The thrombocytopathy was relative, not absolute, since collagen induced aggregation at all times. Platelet counts, uptake and release of serotonin, bleeding times, clot retractions and release of platelet factor 3 were normal. Platelet adhesion was abnormal in five of 12 patients tested. In vitro platelets are a hundred-fold less sensitive to VCR than in vivo. Cyclic adenosine monophosphate, cyclic guanosine monophosphate and dimethylsulfoxide do not protect platelets from VCR. The exact mechanism by which VCR abolishes second phase aggregation in patients is uncertain. Because of VCR's narrow therapeutic index between thrombocytopenia and thrombocythaemia, the use of VCR should be reserved for life-threatening haematologic disorders when treating non-malignant conditions.

Reports of acute nonlymphoblastic leukemia occurring after successful treatment of Hodgkin and non-Hodgkin lymphoma (NHL) are appearing with increasing frequency. Two years after completion of LSA2-L2 therapy for stage III, poorly differentiated lymphocytic lymphoma, a 16-year-old boy developed a preleukemic state characterized by a refractory macrocytic anemia with excess blasts, dyshematopoiesis, abnormal cluster:colony ratio on in vitro bone marrow culture, and acquired deficiencies of erythrocyte pyruvate kinase, triose phosphate isomerase, and adenylate kinase. Four months later acute myeloblastic leukemia was evident. The RNA index determined by flow cytofluorometry was increased. Four marker chromosomes were found and involved complex translocation of chromosomes 11 and 17 (t11;l17) in 100% of the cells, and chromosomes 4 (t4q;4) in 10% of the cells. A thorough literature search uncovered four other reports of acute nonlymphoblastic leukemia occurring in children treated for NHL and a total of 58 cases in the adult and pediatric age groups. Over 50% of the patients had AML, were mean over 50 years of age, and were treated with radiotherapy and chemotherapy. It is anticipated that additional cases of second malignancies will be reported in this population of patients whose outlook for the curability of the primary malignancy is 75%.

Rubidazone was administered to 24 children with advanced solid tumors or leukemia. The dose ranged from 80 to 150 mg/m2/IV daily to a total dose of 160 to 450 mg/m2/course. This course was repeated at intervals of approximately three weeks. Eighteen of 24 patients (75%) had received adriamycin and daunomycin as part of prior chemotherapy. The major toxic effects observed were myelosuppression, nausea, vomiting, mucositis, and skin rash. Four patients developed abnormal echocardiograms following the rubidazone therapy, 2 manifested clinical cardiac failure, of which one had anthracycline cardiomyopathic changes on autopsy. One of 7 adequately treated ALL patients achieved M2 marrow and improved peripheral counts for 3 weeks. One of the 2 neuroblastoma patients had subjective improvement of bone pain for 2 months. Rubidazone, in a previously heavily treated group of patients used in this study, had dosages of 360 and 450 mg/m2 which produced marrow hypoplasia to aplasia, with only minimal responses.

Cerebrospinal fluid of 24 patients with acute leukemia was studied by DNA/RNA flow cytometry. In six of 15 patients with central nervous system (CNS) relapse, the spinal fluid cells had abnormal DNA stemlines, ranging from near haploid to hyperdiploid. In two additional cases, leukemic cells were identified by a abnormally high RNA content only. One patient had two different aneuploid cell populations in spinal fluid not distinguished by cytologic morphology. Another patient with initial diploid leukemia had CNS relapse characterized by the same DNA stemline long after a triploid DNA stemline emerged in the marrow. DNA/RNA flow cytometry detected leukemic cells that were not identified ("uniform" or "reactive") by cytological criteria in 5/6 patients studied and in addition differentiated lymphoblastic from nonlymphoblastic cell types according to low and high RNA content.

The clinical course of Ph+CML and their terminal blastic stage is described in the following case histories. During blastic phase, cell surface markers, terminal deoxynucleotidyl transferase (TdT) activity, and flow cytometric measurements were used or determination of the blast cell phenotype which was undifferentiated by morphological and cytochemical criteria. A high proportion of blast cells expressed Fc receptors for IgG, TdT activity was normal in both children and RNA measurements of single cells flow cytometry showed a high RNA content in the majority of blasts. These findings are compatible with the phenotype seen in the myelomonocytic leukemias. Flow cytometry appears to be a useful adjunct to immunological methods and TdT activity for the rapid characterization of CML in blastic phase.

The Children's Cancer Study Group's (CCG) clinical trials in acute lymphoblastic leukemia (ALL) prior to 1981 consistently demonstrated that patients presenting with a white blood cell count (WBC) greater than or equal to 50,000/microliter or the "lymphoma syndrome" had a less than 40% 3-year event-free survival (EFS). The Berlin Frankfurt Munster (BFM) 76/79 study suggested that the prognosis of these patients could be improved. Before testing this therapy in a randomized setting, 29 CCG institutions used it for treatment of 209 newly diagnosed children with ALL and an initial WBC greater than or equal to 50,000/microliter or the lymphoma syndrome. In the intensive phases of therapy, 77% of cumulative parenteral doses and 55% of cumulative oral doses were within 10% of protocol requirements or were modified appropriately for reported toxicity. One hundred ninety-five patients achieved remission (93.3%). Eleven patients died in remission (5.6%)--10 during the intensive reinduction/reconsolidation phase. The 4-year EFS (+/- 1 SD) was 62% (+/- 3.7%) with a median follow-up of 40 months. Only one patient has had an isolated CNS relapse. These results appear superior to past CCG studies for high-risk patients and extend observations made from studies of similar therapy.

Serum lactate dehydrogenase activity (LDH) was examined in 66 children with acute lymphoblastic leukemia (ALL), 26 with acute non-lymphocytic leukemia (ANLL), and 116 with non-Hodgkin's lymphoma (NHL). The mean serum LDH value for the ALL and ANLL groups was not significantly different: 970 +/- 105 units/L (mean +/- standard error of the mean) and 817 +/- 161 units/L, respectively. The difference between the LDH values in patients with ALL (970 +/- 105 units/L) and NHL (551 +/- 51 units/L) was significant (P = .001). In 32% of the patients with ALL and 23% of the patients with ANLL, serum LDH values were above 1000 units/L, whereas only 13% of the cases with NHL had values above 1000 units/L. In patients with ALL the LDH levels were correlated with white blood cell counts at the time of diagnosis. In NHL, there was no difference in serum LDH levels among the various histologic subtypes. Values of LDH in stage IV NHL and in ALL were similar.

A child diagnosed with Stage IVB Hodgkin disease at nine and one-half years of age subsequently developed osteosarcoma and acute myelogenous leukemia ten years after her initial diagnosis. She received multiple courses of radiotherapy and several single chemotherapeutic agents for her Hodgkin disease. Theraphy-induced multiple malignancies and intrinsic predisposition to carcinogenesis in this case is discussed.