A model system. Integration of services for cancer treatment.

The care of pediatric cancer patients continues to grow in complexity. Paradoxically, treatment regimens grow more intensive, while regulatory pressures mandate more outpatient care. The challenge is to integrate services around episodes of illness and encounters over periods of 1-3 years. The approach of the author's clinic has been to create seamless relationships that place the patient at the center of care and address the major boundaries patients face. The inpatient-outpatient boundary has been effectively breached by an inpatient case manager and the simultaneous temporary rotation of an inpatient nurse to the outpatient area for specialty training. Discharge planning has been improved by sharing a nurse with the clinic's major home health care company, providing a direct clinic-home health liaison for patients. Ongoing formal evaluations have documented the effects of the institution of each part of the program. These surveys have indicated that inpatient staff participating in the outpatient rotation are more satisfied with the continuity of care and the availability of divisional resources. Patient satisfaction was extremely high and pediatric oncology discharge planning was rated significantly higher than other pediatric services. Despite rapid growth of the oncology service since 1985 and the personal intensity of care, length of stay has shortened and the number of staff has not required excessive increases to meet the needs of the new model.

The desmoplastic round cell tumor: a new solid tumor of childhood.

Three patients with a new, pathologically distinct solid tumor of childhood have been treated recently. The disease is characterized by male predominance, adolescent onset, an extensive abdominal primary tumor, and aggressive metastases to regional lymph nodes, liver, and lung. Two patients presented with vague abdominal pain and the third with testicular pain. All three noted fatigue and malaise of less than two months' duration with minimal associated weight loss. Computed tomography (CT) scans of the abdomen and chest were obtained for initial preoperative staging, and then all three underwent surgical exploration. Widespread disease was found in each case. In no instance was complete tumor extirpation possible because of extensive peritoneal spread and lymphatic and hepatic metastases. Histologically, all three tumors consisted of round blue cells with a dense desmoplastic reaction and focal rhabdoid features. Immunohistochemical markers for epithelial, neural, and muscle elements were positive. Aggressive multidrug chemotherapeutic regimens were used in each case, and all three patients are alive and well but with known residual disease. We conclude that in cases of the desmoplastic round cell tumor of childhood, CT scans underestimate the extent of disease, and exploratory laparotomy is necessary for diagnosis and appropriate staging. Surgery is usually palliative because of extensive spread. Awareness of this newly recognized aggressive solid tumor of childhood is essential to define its natural history and guide the development of effective multidisciplinary therapeutic regimens.

A statewide study of the public attitudes toward child abuse.

A statewide survey of adults revealed that they are well informed about some aspects of child abuse. They had a generally good intuitive understanding of the characteristics of abused children and child abusers, but a majority seemed to have a "deviance" perspective on child abuse. They considered abusers as abnormal and intractable. While three-quarters of the respondents were aware that they are obligated to report cases of child abuse to the authorities, one-fifth knew someone who had abused a child, but only a third of these actually reported the case.

Surgical management of recalcitrant heel pain.

A minimal incision approach to the treatment of heel spur syndrome has been presented. This procedure is indicated when the surgeon thinks that conservative modalities have failed to alleviate heel pain. Knowledge of anatomic structures is imperative.

Does social work education make a difference?

To test the hypothesis that state employees with social work education are better prepared for social work positions than are their colleagues without such education, data were collected in five areas, using different instruments and approaches. The data sets were scores on state merit tests for family service workers, employees' quality assurance scores, ratings of employees from supervisors, measures of employees' commitment to social work values, and measures of employees' confidence in their educational preparedness. Overall, employees with social work degrees, either bachelor's or master's, were better prepared than were those without social work degrees.

Autologous bone marrow transplantation for acute lymphoblastic leukemia.

Forty-four children with acute lymphoblastic leukemia (ALL) who had relapsed (N = 43) or had refractory disease (N = 1) were intensively treated with combination chemotherapy, had remission bone marrow (BM) harvested and purged in vitro with monoclonal antibodies specific for leukemia-associated antigens, underwent postharvest ablative chemotherapy and radiotherapy and subsequently were infused with their autologous marrow. Of the 44 patients treated between November 1980 and January 1988, 19 relapsed, 10 died of complications, and 15 remained in complete remission for a median of 28.5 months (range, 10+ to 94+). Event-free survival (EFS) (+/- SE) at 5 years after autologous transplantation was 29 +/- 8%. For the 26 patients whose initial remission was greater than 2 years, event-free survival was 51 +/- 10%. These results compare favorably with allogeneic transplantation and chemotherapy trials for patients with relapsed ALL, and provide an alternative transplantation option for children without histocompatible donors.

A non-human primate model for the study of oral iron chelators.

Recent studies have demonstrated that parenteral deferroxamine can prolong life in patients with iron overload. We have developed a non-human primate model of iron overload and have accurately determined negative iron balance in parenteral and oral studies of deferroxamine and a new chelator, desferrithiocin. Cebus monkeys were loaded with iron dextran (10 mg/kg twice weekly) until their serum contained a transferrin saturation greater than 75%, and (in two animals) liver biopsies showed iron loading. When complete iron balance studies were performed at this time, basal iron balance was -53 +/- 11 micrograms (N = 4), providing a low background for provocative studies. Iron balance was determined for intramuscular (N = 2) and oral (N = 3) deferroxamine, as well as intramuscular (N = 1) and oral (N = 4) desferrithiocin. The pattern of iron excretion after parenteral deferroxamine strongly resembled that of the iron-loaded, transfused human. Desferrithiocin was found to have significant activity as an oral chelator. This Cebus monkey model accurately determines negative iron balance and readily permits precise comparison of iron chelators given parenterally or orally. This model may offer an important step between rodent and human trials of promising new iron chelators.

Molecular defect in the membrane skeleton of blood bank-stored red cells. Abnormal spectrin-protein 4.1-actin complex formation.

During liquid preservation under blood bank conditions, red cell membranes inexorably undergo damage that decreases erythrocyte survival after transfusion. Accordingly, we have surveyed membrane skeletal protein interactions during storage. We uncovered a decrease in the in vitro formation of spectrin-actin complex in the absence (50%) or presence (60%) of protein 4.1. Actual formation of the spectrin-actin-protein 4.1 complex fell in a linear fashion during the storage period. This fall in spectrin-actin interaction tightly correlated with the decline in total red cell phospholipid (R = 0.9932) measured simultaneously. This decrement of spectrin-actin association could be restored to greater than 70% of normal values by preincubation of stored spectrin with 50 mM dithiothreitol. This storage injury to spectrin-actin interaction might weaken the membrane skeleton and lead to decreased red cell survival. In vitro reversibility of the damage by reducing agents suggests a possible new direction for prolonging the shelf life of stored blood.

Iron metabolism in K562 erythroleukemic cells.

Iron delivery to K562 cells is enhanced by desferrioxamine through induction of transferrin receptors. Experiments were performed to further characterize this event with respect to iron metabolism and heme synthesis. In control cells, up to 85% of the iron taken up from iron-transferrin was incorporated into ferritin, 7% into heme, and the remainder into compartments not yet identified. In cells grown with desferrioxamine, net accumulation of intracellular desferrioxamine (14-fold) was observed and iron incorporation into ferritin and heme was inhibited by 86% and 75%, respectively. In contrast, complete inhibition of heme synthesis in cells grown with succinylacetone had no effect on transferrin binding or iron uptake. Exogenous hemin (30 microM) inhibited transferrin binding and iron uptake by 70% and heme synthesis by 90%. These effects were already evident after 2 h. Thus, although heme production could be reduced by desferrioxamine, succinylacetone, and hemin, cell iron uptake was enhanced only by the intracellular iron chelator. The effects of exogenous heme are probably unphysiologic and the greater inhibition of iron flow into heme can be explained by effects on early steps of heme synthesis. We conclude that in this cell model a chelatable intracellular iron pool rather than heme synthesis mediates regulation of iron uptake.

Analysis of the ternary interaction of the red cell membrane skeletal proteins spectrin, actin, and 4.1.

Spectrin dimers interact weakly with F-actin under physiological solvent conditions (with an association constant of about 5 X 10(3) M-1 at 20 degrees C). In the presence of the membrane skeletal constituent, protein 4.1, strong binding is observed; an analysis of the profiles for formation of a ternary complex leads to an association constant of about 1 X 10(12) M-2. This association becomes weaker at low ionic strength, whereas the opposite applies to the spectrin-actin interaction. The stability of the ternary complex is maximal at physiological ionic strength and somewhat above. The effect of temperature in the range 0-20 degrees C on the formation of the ternary complex is small, whereas the spectrin-actin interaction almost vanishes at low temperature. There is no detectable calcium sensitivity in either the binary or the ternary system within the limits of precision of our assay. The ternary complex resembles the natural system in the membrane in that the actin is resistant to dissociation and unavailable in the deoxyribonuclease assay; after selective proteolytic destruction of spectrin and 4.1, all the actin becomes available. In the absence of 4.1, spectrin dimers do not measurably protect the actin against dissociation.

High yield purification of protein 4.1 from human erythrocyte membranes.

Protein 4.1 has been purified from human erythrocyte membranes by a simple method employing the nonionic detergent Tween 20 and anion exchange chromatography. The procedure results in the production of large quantities of protein 4.1, which retains immunoreactivity and the functional properties of binding to spectrin and enhancing the interaction of spectrin and actin.

A genetic defect in the binding of protein 4.1 to spectrin in a kindred with hereditary spherocytosis.

Indirect evidence suggests that the genetic defect in hereditary spherocytosis lies in the erythrocyte membrane skeleton, a submembranous meshwork of proteins (principally spectrin, actin, and protein 4.1) responsible for membrane shape and structural stability. To test this premise we systematically assayed the interactions of spectrin, the major skeletal protein, in six kindreds with autosomal dominant hereditary spherocytosis. In one these kindreds, enhancement of spectrin-actin binding by protein 4.1 was reduced, owing to a 39 +/- 4 per cent decrease (mean +/- S.D) in the binding of normal protein 4.1 by spectrin, in all of four members with the disorder. The defective spectrin was separated into two populations by affinity chromatography on immobilized normal protein 4.1. One population (41 +/- 2 per cent) lacked the ability to bind 4.1, but the other functioned normally. Presumable, the nonfunctional spectrin was the product of the autosomal dominant gene responsible for the hereditary spherocytosis in this kindred.

Augmentation of vincristine neurotoxicity by irradiation of peripheral nerves.

Four cases are presented in which children receiving radiation therapy and combination chemotherapy had unilateral severe and prolonged neurotoxic effects. Augmentation of vincristine neurotoxicity by irradiation of peripheral nerves is suggested.