The commissioning and acceptance of a commercially manufactured radiotherapy beam tissue compensating filter system.

The principles of tissue compensation in radiotherapy and the methods for their implementation on the GE RT/Plan computer are briefly described. The HEK Medizintechnik GmbH Medical Systems Tissue Compensator cutting device is described, along with the testing procedure adopted for its commissioning and quality assurance testing of the total system. The HEK machine hardware proved to be well engineered, but there were many deficiencies in the software supplied to interface it to the planning computer. Most errors were fatal to the program producing a compensator but a number of errors allowed the cutter to manufacture shapes which on close inspection turned out to be incorrect. These faults were traced to incorrect algorithms and/or incorrect software implementation. It is stressed that the software errors were entirely the responsibility of HEK and that the GE equipment and software were not deficient in any way. However, the experiences of the Adelaide group suggest that caution should be exercised when purchasing two pieces of interacting equipment from separate suppliers.

VA cooperative study on alcoholic hepatitis. II: Prognostic significance of protein-calorie malnutrition.

Three hundred and fifty-two patients with alcoholic hepatitis were evaluated for protein-calorie malnutrition (PCM). In order to facilitate data analysis of nutritional status, a PCM score was calculated for each patient using eight nutritional parameters. The PCM score correlated significantly with mortality, clinical severity of the liver disease, and biochemical liver dysfunction. When 30 day changes in the PCM scores were compared with 30 day caloric intake (expressed as percent basal energy expenditure (BEE], a marginally significant correlation was observed (p = 0.05). However, those patients who showed improvement in their PCM score over 30 days of hospitalization also improved their 6-mo and 1-yr survival. These data indicate that nutrition, as determined by the PCM score, has prognostic significance. Additional studies are needed to establish the beneficial role for vigorous protein-calorie nutritional therapy in the management of alcoholic hepatitis.

Prognostic significance of vacuoles in L1 lymphoblasts in childhood acute lymphoblastic leukaemia: a report from Children's Cancer Study Group.

From February 1975 to February 1977, 880 patients with acute lymphoblastic leukaemia were enrolled on Children's Cancer Study Group protocol 141 designed to evaluate prognostic factors and more intensive therapy for patients with poor prognosis. 765 diagnostic bone marrow aspirates from 23 institutions were available for classification using the French-American-British system. 60 of 615 patients with L1 morphology had vacuolated lymphoblasts. Patients with vacuolated lymphoblasts had a better disease-free survival (P = 0.14) and a significantly better survival (P = 0.03) but the presence of vacuoles was associated with a low initial WBC and an age range associated with improved prognosis for disease-free and over-all survival.

Phase II study of 4'-(9-acridinylamino)methanesulfon-m-anisidide (NSC 249992) in children with acute leukemia and lymphoma.

Phase I clinical studies of 4'-(9-acridinylamino)methanesulfon-m-anisidide (AMSA) using several dose schedules have shown acceptable toxicity and antitumor responses in acute leukemia and several carcinomas. Thirty-eight children with acute leukemia and non-Hodgkin's lymphoma were treated with AMSA in a total dose of 140 to 600 mg/sq m given as a daily i.v. infusion in 2 to 5 days. Maximal tolerated dose was 600 mg/sq m given in 5 days. Complete and partial remissions were seen in four of 18 patients with acute lymphocytic leukemia, zero of eight patients with acute nonlymphocytic leukemia, and one of five patients with non-Hodgkin's lymphoma. Marrow aplasia and remissions were also seen with lower doses. The major toxic effects were mucositis, fever, and sepsis which were dose related. Mild nausea and vomiting, transient elevation of serum glutamic oxaloacetic-acid-transaminase, and bilirubin were noted. All of these patients had had prior anthracycline therapy. Abnormal echocardiograms were seen in 14 of 23 patients who had echocardiograms done before and after AMSA. Seven developed congestive heart failure in association with sepsis in five and with epicardial disease in one. We conclude that AMSA possesses significant activity in childhood leukemia and lymphoma and that studies of AMSA in combination with other effective agents should be done.

Marrow transplantation for juvenile osteopetrosis.

Two children with the juvenile form of osteopetrosis were treated with marrow transplants from their HLA identical siblings. Following transplantation each child exhibited extensive bone reabsorption with a marked augmentation of osteoclastic function attributable to donor osteoclasts, including remodeling of bone with expansion of intramedullary hematopoiesis and correction of associated abnormalities of thymic factor and natural killer cells. Osteopetrosis ultimately recurred in one patient in whom engraftment of donor hematopoietic elements was not achieved. Our studies indicate that marrow transplantation will correct osteopetrosis but that permanent reconstitution necessitates sustained engraftment of marrow precursors of cells with osteoclastic activity.

Cardiac changes with cyclophosphamide.

Serial echocardiographic (ECHO) studies were obtained on 40 pediatric patients (pts) treated with greater than or equal to 80 mg/kg cyclophosphamide (CPM) (range 80-200 mg/kg) in 1 week. Patients were treated for solid tumors and prior to marrow transplant. Echo changes occurred in 10/13 pts who received CPM greater than or equal to 170 mg/kg over four days, and in 11/19 pts who received 120-140 mg/kg dose over two days and who had previously received greater than or equal to 100 mg/m2 anthracyclines with or without radiation. No changes were seen in eight pts who had 80-160 mg/kg CPM and less than 100 mg/m2 anthracyclines. The observed changes occurred approximately 1 week after CPM and persisted for days to weeks. Pericardial effusion seen in 15 pts was successfully treated with furosemide in 13. Two died with hemorrhagic pancarditis. Other changes seen were increased end diastolic left ventricular diameter, decreased fractional shortening and abnormal left ventricular preejection period/ejection time ratios. Thus, cardiac effects of high dose CPM are not rare in children. Patients receiving greater than 170 mg/kg CPM in 1 week or 120 mg/kg in 1 week after greater than or equal to 100 mg/m2 anthracyclines are at particular risk.

DR-positive maternal engrafted T cells in a severe combined immunodeficiency patient without graft-versus-host disease.

A 2 1/2-year-old male infant with severe combined immunodeficiency was documented by HLA typing and the presence of a female karyotype in the few spontaneously dividing cells to have an intrauterine-derived maternal lymphocyte graft. The presence of DR antigens on the engrafted maternal E rosette-forming T cells was demonstrated by both cytotoxicity and immunofluorescence techniques using both conventional and monoclonal antihuman DR antisera. These DR antigens were of the same allospecificity, DR4, as the mother's peripheral blood B cells. The patient's B cells and monocytes expressed DR alloantigens DR4 and DR3, corresponding to his genotype. Although fresh maternal lymphocytes react strongly in vitro against patient non-T cells, the engrafted maternal T lymphocytes no longer show this activity. Furthermore, clinical evidence suggesting mild graft-versus-host disease was completely resolved by the end of his first year. The presence of the DR-positive maternal cells may reflect the survival of a group of activated suppressor cells mediating graft tolerance of host tissue.

Association between pre-transplant natural kill and graft-versus-host disease after stem-cell transplantation.

Natural killer activity against herpes simplex virus type 1 infected fibroblasts NK(HSV-1) was studied prospectively in patients undergoing allogenic bone-marrow or fetal-tissue stem-cell transplantation. Thirteen patients showed evidence of engraftment and survived long enough to develop graft-versus-host disease (GvHD). Of this group, all of the seven having normal NK(HSV-1) activity before transplantation acquired GvHD and the six having low NK(HSV-1) had no evidence of GvHD. These results were independent of mode of preparation of patients for transplantation, source of stem cells used, or cytomegalovirus infections, and they suggest that this assay reflects a host-determined function capable of stimulating GvHD.

Successful transplantation of marrow from an HLA-A, -B, -D mismatched heterozygous sibling donor into an HLA-D-homozygous patient with aplastic anemia.

A patient with aplastic anemia who was found to be homozygous for an HLA-D determinant shared by her unrelated parents achieved sustained engraftment and full restoration of hematopoietic and lymphoid function following a transplant from an HLA-A and -B nonidentical, ABO incompatible sibling who was heterozygous for the shared HLA-D specificity. Transplantation was complicated by transient graft-versus-host disease of moderate severity, which resolved completely following treatment with antithymocyte globulin and prednisone. The case indicates that patients found to be HLA-D-homozygous may be successfully transplanted from HLA-D-heterozygous sibling donors despite HLA-A and HLA-B incompatibilities, and thus further demonstrates the importance of the HLA-D region as a marker of donor-host histocompatibility.

Reconstitution in severe combined immunodeficiency by transplantation of marrow from an unrelated donor.

A patient with severe combined immunodeficiency received seven transplants of bone marrow from an HLA-B-compatible and HLA-D-compatible unrelated donor in an attempt to provide immunologic reconstitution. The first four transplants achieved restricted engraftment with evidence of rudimentary immunologic function. A fifth transplant, given after low-dose cyclophosphamide, produced reconstituion of cell-mediated immunity. Marrow aplasia developed after recontamination with a nonpathogenic microflora. Transplantation of marrow previously stored in liquid nitrogen was ineffective. A subsequent transplant, administered after high-dose cyclophosphamide, achieved durable engraftment, with complete hematopoietic and immunologic reconstitution. Seventeen months after transplantation, full functional engraftment persists. Graft-versus-host disease has been chronic and moderately severe, but limited to the skin and oral mucosa. Transplantation of marrow from unrelated histocompatible donors may provide a useful treatment for patients with severe combined immunodeficiency or aplastic anemia who lack a matched sibling or related donor.

Ionized calcium: serum levels during symptomatic hypocalcemia.

The concentration (activity) of ionized calcium in serum [Ca-++] was measured in nine patients with symptomatic hypocalcemia of diverse etiology. In all nine patients the [Ca-++] was smaller than or equal to 2.50 mg/dl. No significant correlation was found between the [Ca-++] and serum levels of either total calcium or phosphate. Use of the McLean-Hastings nomogram failed to reveal any significant statistical correlation between the predicted [Ca-++] values and those actually measured. These data indicate that: (1) symptomatic hypocalcemia occurs when levels of ionized calcium in serum fall near or below a critical threshold concentration of 2.50 mg/dl and (2) the [Ca-++] must be measured directly to confirm the clinical impression of hypocalcemia.