Therapeutic efficacy of camptothecin derivatives against human malignant melanoma xenografts.

Camptothecin (CPT) and some of its derivatives are currently used in several clinical studies with patients bearing leukaemias, lymphomas, and malignancies of various solid tissues. Therefore, it is important to establish parameters and conditions that will allow the drugs to exhibit maximal anti-cancer effectiveness with minimal toxic effects. We tested several water-insoluble CPT derivatives for their ability to inhibit growth of human melanoma tumours xenografted in nude mice. We found that anti-tumour effectiveness and drug-induced toxicity depended on (a) the CPT derivative; (b) the drug dose administered; (c) the mode of administration; and (d) the scheduling of drug administration. For all practical purposes, oral administration of the CPT derivative, 9-nitrocamptothecin, has produced the best overall results.

Functional domains of the human C1q A-chain.

This brief review was inspired by discussions relating to the IIIrd. International C1 Workshop (this volume) and the realization that certain functional properties of the C1q molecule are limited exclusively to the A-chain. The collagen-like region of the A-chain contains a major binding site for non-immunoglobulin substances, which include C-reactive protein, serum amyloid P, LPS and DNA. This binding site is immediately adjacent to, and partially overlapping with, an arthritis-modulating epitope common to the C1q A-chain and various types of collagen, including cartilage type II collagen. At the N-terminal end of the C1q A-chain is a leader peptide sequence that anchors the intact C1q molecule firmly in the membrane of macrophages, the C1q molecule can thus be classified as a type II membrane protein, functioning as an additional receptor for molecules known to react with C1q in fluid phase such as the Fc region of IgG, LPS and polyanionic molecules (e.g. chondroitin sulphate, heparin, dextran sulphate etc.). The various domains within the A-chain, and their respective functions (or potential functions), are presented and discussed in the context of the intact C1 molecule and with regard to any wider functional relevance.

Efficacy of camptothecin congeners in the treatment of human breast carcinoma xenografts.

We have shown recently that the plant alkaloid camptothecin and some of its derivatives inhibit growth of human breast carcinoma cells in vitro and induce complete regression of human breast tumors grown in nude mice. Because of the use of camptothecin derivatives in several clinical studies with patients bearing various types of cancer, in this report, we have investigated and described parameters and conditions that can modulate the anticancer effectiveness and cytotoxicity of these drugs when administered as suspensions. It is demonstrated that the antitumor effectiveness and drug-induced toxicity depend on the camptothecin derivative, the drug dose administered, the route of administration, and the scheduling of drug administration. 9-aminocamptothecin administered i.m. generates the best results, but for all practical purposes, 9-nitrocamptothecin administered orally appeared to be the camptothecin derivative and route of administration of choice. Further, we report the partial response of one breast tumor to camptothecin and propose that this tumor may require chemotherapy with a camptothecin derivative followed by an anticancer drug with a different mechanism of cell-killing activity.

Late hemodynamic results after orthotopic heart transplantation in early infancy.

To study the late hemodynamic results after infant orthotopic heart transplantation, five late survivors, as of October 1988, underwent right and left cardiac catheterization and endomyocardial biopsy. Mean age at transplantation was 1.4 +/- 1.5 months. Mean post-transplantation period was 17 +/- 5.6 months. All patients were on maintenance immunotherapy. The systemic and mixed venous saturations were normal, with no intracardiac shunt. The atrial and pulmonary artery anastomoses were widely patent. Three patients had coarctation of the aorta with a respective gradient of 24, 26, and 30 mm Hg; two were successfully treated by balloon angioplasty. The right-side hemodynamics were normal in all patients. Left ventricular pressures were elevated only in the patients with coarctation. The ventricular ejection fraction was normal. The right ventricular endomyocardial biopsy revealed no evidence of rejection. The mean cardiac index was 4.7 liter/min/m2 (range, 3.68-5.9). These data indicate excellent hemodynamic results and support orthotopic heart transplantation as therapy for selected neonates and infants with incurable heart disease.

Maprotiline poisoning in a child.

A 6-year-old girl presented with tonic-clonic seizures and generalized convulsions lasting several minutes. A serum drug screen revealed maprotiline, and the estimated intake was 12 mg/kg. Despite initial neurologic impairment on discharge, follow-up 6 months later showed normal neurologic function in the patient. This report describes that case and discusses the toxicity associated with maprotiline and its management.

Chest radiography in infant cardiac allotransplantation.

Heart transplants were performed in seven infants at Loma Linda University Medical Center from 1985 to 1987. Five of these seven patients survived. In this report, the radiographic appearance of the chest is presented before surgery, immediately after surgery, and during a documented episode of rejection. The most current available chest radiograph is also presented. Acute rejection was confirmed by clinical, echocardiographic, and ECG findings. The only pulmonary infection encountered was mycoplasma pneumonitis. Four patients developed gastrointestinal rotavirus infections and were shown to have dilated proximal small-bowel folds on upper gastrointestinal studies. At the time of this writing, the prognosis for the five surviving infants is good. We conclude that the radiographs of infants who have received heart transplants show an unusual cardiac contour and slight cardiomegaly. Increasing cardiomegaly can alert one to early rejection. Prominent folds in the small bowel are of uncertain origin and significance, but they may be related to infection resulting from immunosuppression.

Mustard operation in the 1st month of life.

Since April 1976, nine infants less than 1 month of age underwent a Mustard intraatrial baffle procedure. All had transposition of the great arteries and were persistently symptomatic or hypoxic after the Rashkind balloon atrioseptostomy. Two had an associated large ventricular septal defect patched at the time of physiologic correction. The average age of the infants was 11.6 days (range 36 hours to 28 days). Weight averaged 3.4 kg (range 2.5 to 4.2). In all the Mustard procedure was performed using deep hypothermic circulatory arrest, averaging 71 minutes (range 48 to 88) at a mean core temperature of 13 degrees C. An average of 2.8 days of postoperative ventilatory assistance was required. One death occurred in a 28 day old male infant with an associated ventricular septal defect who, the morning after operation, had a sudden unresponsive cardiac standstill. The postoperative hospitalization period averaged 15 days (range 10 to 23). Follow-up evaluation has extended from 4 to 63 months (average 31). Six patients were restudied 2 to 21 months postoperatively. One had obstruction of the superior limb of the baffle, which had separated from the right atrial wall permitting a modest right to left shunt. She has had uneventful repair employing a unique modification of Senning's operation. Another child has asymptomatic partial obstruction of the superior limb of the baffle demonstrated angiographically. None has pulmonary venous obstruction and all have prevailing normal sinus rhythm. Significant right ventricular dysfunction has been demonstrated in one. Early correction in these persistently symptomatic or hypoxic neonates with transposition of the great arteries with or without a ventricular septal defect has obviated the need for palliative operations and produced gratifying early and late results.

Biologic reconstruction of the right ventricular outflow tract. Preliminary experimental analysis and clinical application in a neonate with type I truncus arteriosus.

A unique concept of right ventricular outflow tract reconstruction is presented. Applications of this concept, employing a glutaraldehyde-preserved heterograft mitral valve leaflet mounted directly to the right ventricle, was studied in six immature goat models. Interval evaluation of these models demonstrated no significant outflow tract obstruction or aneurysm. Only one animal had significant pulmonary outflow regurgitation angiographically at the time of sacrifice. All heterograft valve leaflets showed a degree of calcification and/or retraction directly related to the time interval between implant and sacrifice. Encouraging early results were obtained with this method of pulmonary outflow tract reconstruction in a 2,400 gram neonate with type I truncus arteriosus.

Anatomic correction of interrupted aortic arch complex in neonates.

Anatomic correction of interrupted aortic arch complex by direct aortic anastomosis was accomplished in five neonates ranging in age from 2 to 19 days. Three had type B and two had type A interruption of the aortic arch. All operations were performed through a transverse bilateral thoracotomy by use of hypothermic circulatory arrest. The descending thoracic aorta is widely mobilized to the level of the diaphragm. The ductus arteriosus is completely excised and the descending aortic segment is anastomosed end to side to the ascending aorta. The large ventricular septal defect is patched with Dacron velour, and atrial communications are closed with running suture. Three of the babies survived surgery and are making satisfactory clinical progress. All three have been restudied on a routine basis. They were found to have excellent anatomic repairs with no residual intracardiac shunts. There was a peak systolic gradient of 8 mm Hg at the aortic anastomosis in the second survivor; however, she does not have ascending aortic hypertension. The first and last survivors have no aortic gradients. It is recommended that a newborn with interrupted aortic arch complex be subjected to corrective surgery as the procedure of choice. Excellent results may be expected when surgery is done prior to irreversible metabolic decompensation of the patient.

Corrected transposition. Another approach for repair of associated intracardiac malformations.

A variety of surgical approaches have been used for repair of cardiac lesions associated with corrected transposition of the great vessels. These techniques have met with variable success and generally high surgical mortality rates. In an effort to simplify the surgical approach to repair of ventricular septal defect and replacement of left atrioventricular valve in a 4-year-old youngster, we chose to correct the defects through a left posterolateral thoracotomy and through the left atrium utilizing profound hypothermia and circulatory arrest. Ease of intracardiac assessment and repair and postoperative results to date have been most gratifying.

Interrupted aortic arch complex: successful total correction in the neonate.

Two neonates subjected to definitive repair of interrupted aortic arch complex during the first week of life are presented. Results correlated well with preoperative status. Our definition of complete correction, including direct aortic anastomosis, is discussed along with the surgical strategy employed for successful repair of this otherwise dismal anomaly.