Randomized, placebo-controlled, multicenter trial of granulocyte-macrophage colony-stimulating factor as infection prophylaxis in oncologic surgery. Leukine Surgical Prophylaxis Research Group.

PURPOSE: Postoperative infections are a frequent source of preventable morbidity and mortality in the oncologic population. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a potent modulator of immune effector cells in vitro and in vivo. This study was conducted to determine whether GM-CSF, when administered perioperatively, could reduce the incidence of surgical infections in cancer patients. METHODS: This was a prospective, randomized, placebo-controlled, multicenter study. Cancer patients at high risk of infectious surgical morbidity were randomized to receive GM-CSF 125 microg/m2 per day or placebo subcutaneously for 8 days beginning 3 days preoperatively. Routine antibiotic prophylaxis was administered to all patients. RESULTS: Three hundred ninety-nine patients were enrolled, with 198 randomized to receive GM-CSF. Twenty-one percent of patients experienced infections during the first 2 weeks postoperatively, and there was no difference in infection rate between the study groups. The most common sites of infection were respiratory tract (53%) and surgical wound (25%). The duration of operation and American Society of Anesthesiology (ASA) physical status classification were the most significant predictors of infection in multivariate analysis. GM-CSF was well tolerated and was not associated with fever. CONCLUSION: The eligibility criteria for this study were successful at defining a patient subgroup at high risk for postoperative infections. At an immunomodulatory dose of 125 microg/m2 per day, GM-CSF was safe and well tolerated, but did not reduce the incidence of postoperative infections in this high-risk oncologic population. Infectious morbidity in surgical oncology remains an important subject for continued clinical investigation.

Dysregulation of cytokine expression in monocytes from HIV-positive individuals.

Because HIV may alter the production of inflammatory factors produced by monocytes, the expression of tumor necrosis factor alpha (TNF-alpha), tissue factor (TF), interleukin (IL)-1 beta, and IL-6 was evaluated in 47 HIV-seropositive persons and seronegative control subjects. RNA was extracted from freshly isolated lipopolysaccharide (LPS)-stimulated or unstimulated monocytes. Cytokine and TF expression was quantitated by dot blot hybridization or a reverse transcription polymerase chain reaction (RT-PCR). A significant depression of TF mRNA was observed in LPS-stimulated monocytes (66% less in AIDS, 20% less in AIDS-related complex (ARC), and 0% less in asymptomatic patients), whereas normal responses were observed for TNF-alpha, IL-1 beta, and IL-6. When constitutive expression was measured in unstimulated monocytes by RT-PCR, a differential pattern was also observed. TNF-alpha and IL-1 beta were positive in 85% of asymptomatic persons, compared with only 27% of ARC and 42% of AIDS patients. Expression of IL-6 was observed in lower proportions, 27-30%, with no significant differences among disease states. All samples were negative for TF. Thus, the regulation of inflammatory molecules is differentially altered in individuals with HIV infection. TF is preferentially down-regulated, compared with TNF-alpha, IL-1 beta, and IL-6, in LPS-stimulated monocytes as patients progress to AIDS. TNF-alpha and IL-1 beta are preferentially up-regulated, compared with IL-6 and TF, in unstimulated monocytes in asymptomatic persons, with a loss of up-regulation as patients progress to AIDS.

Hemorrhagic colitis with Escherichia coli O157:H7 preceding adult hemolytic uremic syndrome.

Escherichia coli serotype O157:H7 is a rarely identified organism that has recently been associated with hemorrhagic colitis in all age groups and with the hemolytic uremic syndrome (HUS) in children. We now report the development of HUS in two young women following enteric infection with E coli O157:H7. Both patients were hospitalized because of the severity of their colitis. They later developed major hemolysis requiring transfusion and significant renal failure requiring, in one case, hemodialysis. One patient underwent laparotomy, where sterile ascites, marked right colonic edema, and intraserosal hemorrhage were noted. Both women survived and are currently improving. Fecal E coli serotype O157:H7 was sought only after routine cultures were negative and features of HUS were recognized. The search for the E coli was facilitated by the continued availability of stool cultures obtained early in the course of the illness. The source of infection was not ascertained, but ingestion of untreated water was a feature of both cases. The HUS is a potential complication of the hemorrhagic colitis associated with E coli serotype O157:H7 and may develop in adults as well as children following enteric infection with this organism.

Phase III study of granulocyte-macrophage colony-stimulating factor in advanced HIV disease: effect on infections, CD4 cell counts and HIV suppression. Leukine/HIV Study Group.

OBJECTIVE: To evaluate the effect of adjuvant granulocyte-macrophage colony-stimulating factor (GM-CSF) (sargramostim, yeast-derived recombinant human GM-CSF) on incidence and time to opportunistic infection or death, plasma HIV-RNA, and CD4 cell count in patients with advanced HIV disease. METHODS: This Phase III randomized, double-blind, placebo-controlled trial enrolled subjects with CD4 cell counts < or = 50 x 10(6)/l or < or = 100 x 10(6)/l with a prior AIDS-defining illness on stable antiretroviral therapy. Subjects were stratified by baseline HIV-RNA level (> or = or < 30,000 copies/ml) and randomized to receive subcutaneous injections of GM-CSF 250 microg or placebo three times per week for 24 weeks. Subjects were permitted to continue on blinded drug for up to 20 months. Subjects were evaluated for infections, plasma HIV-RNA, lymphocyte counts, changes in antiretroviral therapy, toxicity, and survival. RESULTS: Three-hundred and nine subjects received at least one dose of study drug, 70% completed 24 weeks of therapy. Groups were well matched at baseline. Significant increases in CD4 cell and neutrophil counts were observed at 1, 3, and 6 months in the GM-CSF group. GM-CSF significantly reduced the incidence of overall infections (78% placebo versus 67% GM-CSF; P = 0.03) and delayed time to first infection (56 days placebo versus 97 days GM-CSF; P = 0.04). No statistical difference in cumulative opportunistic infections was observed between groups; however, among subjects without an opportunistic infection prior to study, the GM-CSF group demonstrated a trend towards fewer subjects with an opportunistic infection on study (26% placebo versus 8% GM-CSF; P = 0.08). Change in HIV-RNA was not significantly different between groups, but significantly fewer GM-CSF subjects with baseline viral load < 30,000 copies/ml had changes in antiretroviral therapy for increased viral load (42% placebo versus 21% GM-CSF; P = 0.01). In patients with HIV-RNA levels below the limit of detection at baseline, more GM-CSF patients maintained an undetectable viral load at 24 weeks (54% placebo versus 83% GM-CSF; P = 0.02). GM-CSF was well tolerated. CONCLUSIONS: GM-CSF significantly increased CD4 cell count and decreased virological breakthrough and overall infection rate in subjects with advanced HIV disease.

Phase I/II trial of the type I soluble recombinant human interleukin-1 receptor in HIV-1-infected patients.

Interleukin-1 (IL-1) produced in peripheral blood mononuclear cell (PBMC) cultures or added exogenously has been shown to upregulate HIV expression in vitro. Inhibition of IL-1 in HIV-infected individuals may inhibit HIV activation and slow disease progression. Recombinant human IL-1 receptor (rHu-IL-1R), the soluble extracellular portion of the human type I IL-1 receptor, inhibits HIV expression in acutely infected primary PBMCs and in the chronically infected promonocytic cell line, U1. We, therefore, conducted a phase I/II trial of the soluble rHu-IL-1R in HIV-1-infected individuals with CD4 T cell counts <300/microl to evaluate its safety and activity. Twelve evaluable patients were enrolled at three rHu-IL-1R dose levels:125 (n=3), 500 (n=3), and 1250 (n=6) microg/m2 per dose by subcutaneous (s.c.) injection three times a week for 8 weeks, followed by a 4 week observation period. rHu-IL-1R was safe and well tolerated. There were no deaths, no treatment-related grade 3/4 events, and no premature study discontinuations because of adverse events. The maximum tolerated dose was not reached. Seven patients reported improvements in one or more symptoms, including weight gain (3), improved energy level (4), decreased diarrhea (1), decreased night sweats (1), improvement in psoriatic arthritis (1), and improvement in a nonspecific chronic diffuse skin rash (1). Of 3 evaluable patients with Kaposi's sarcoma, 1 remained stable and 2 showed minimal progression. No consistent trends in absolute CD4 counts or percentages, quantitative HIV cultures, or serum p24 antigen, beta2-microglobulin, or triglyceride levels were observed. rHu-IL-1R is safe and well tolerated at the doses tested but induced no consistent changes in objective markers of HIV disease. Symptomatic improvements will require confirmation in randomized, placebo-controlled trials.

Recombinant tumor necrosis factor receptor p75 fusion protein (TNFR:Fc) alters endotoxin-induced activation of the kinin, fibrinolytic, and coagulation systems in normal humans.

The effects of inhibition of tumor necrosis factor (TNF) on cell and protease activation were evaluated in 18 normal volunteers given endotoxin (4 ng/kg, i.v.) after an infusion of low (10 mg/m2 i.v., n = 6) or high dose (60 mg/m2 i.v., n = 6) recombinant human dimeric TNF receptor protein (TNFR:Fc) or its vehicle (placebo n = 6). Activation of the coagulation system occurred by 2 h in the TNFR:Fc vehicle-placebo group manifested by decreased prekallikrein functional levels and increased levels of prothrombin F1+2 fragments (p < 0.0001). High or low dose TNFR:Fc delayed the fall in prekallikrein functional levels by 1 h and 4 h, respectively (p < 0.0002), but did not inhibit the increase in circulating levels of prothrombin F1+2 fragments. In contrast, endothelium activation, characterized by increased levels of tissue plasminogen activator, plasminogen activator inhibitor-1, and von Willebrand Factor antigen was blunted by both low and high dose TNFR:Fc (p < 0.001). While the endotoxin-associated decrease in platelet number was not altered, platelet-derived beta-thromboglobulin peak levels were blunted and delayed by TNFR:Fc (p < 0.02). Increased levels of neutrophil elastase were attenuated by low and high dose TNFR:Fc (p < 0.001). These results suggest that although TNF is functionally linked to the activation of endothelium, neutrophils, coagulation, and fibrinolysis, alternative pathways are present in vivo that result in activation of the kallikrein-kinin system after endotoxin-induced TNF release. These alternative pathways may limit some of the anti-inflammatory effects of TNFR:Fc.

A randomized, double-blind, phase I/II trial of tumor necrosis factor and interferon-gamma for treatment of AIDS-related complex (Protocol 025 from the AIDS Clinical Trials Group).

To determine safety and efficacy of tumor necrosis factor (TNF) and interferon-gamma (IFN gamma) in the treatment of patients with acquired immunodeficiency syndrome (AIDS)-related complex, a randomized, double-blind study was conducted. Twenty-five patients with AIDS-related complex and CD4 lymphocytes less than or equal to 500 x 10(6)/L attended an AIDS Clinical Trials Unit of a tertiary referral center. Patients were administered tumor necrosis factor (TNF) (10 micrograms/m2) or IFN gamma (10 micrograms/m2), or both intramuscularly three times weekly for 16 weeks. Side effects from all three preparations included fever, constitutional symptoms, and local reactions. No significant hematologic, hepatic, renal, or coagulation abnormalities were observed. CD4 lymphocyte counts, beta 2-microglobulin, p24 antigen levels, and anti-p24 antibody did not change significantly during therapy. Similarly, no significant change was noted in rates of HIV isolation from peripheral blood mononuclear cells or plasma. TNF and IFN gamma were tolerable after premedication with acetaminophen; however, no significant change in markers of human immunodeficiency virus infection was demonstrated. These cytokines alone do not appear to be of benefit, nor do they appear to hasten the progression of HIV infection.

Lack of in vivo effect of granulocyte-macrophage colony-stimulating factor on human immunodeficiency virus type 1.

Neutropenia complicates HIV disease or its treatment in a large proportion of patients. Hematopoietic growth factor support has been tested in a number of clinical settings in HIV disease and has been demonstrated to be of benefit for specific parameters. One consideration regarding the use of hematopoietic growth factors in HIV disease is their potential effect on HIV viral burden, since alterations in HIV expression have been documented with certain cytokines in vitro. It has also been reported that some cytokines, notably GM-CSF, potentiate the antiviral properties of thymidine analogs such as zidovudine (AZT) in vitro. We tested these observations in vivo. Twelve HIV-positive patients with a CD4 cell count < or = 200/mm3 or HIV plasma viremia who were receiving a stable dose of zidovudine were enrolled into three dose cohorts of yeast-derived GM-CSF at 50, 125, or 250 micrograms/m2 daily by subcutaneous self-injection for 28 days. Measurements of HIV activity included serum acid-dissociated HIV p24 antigen levels, plasma and peripheral blood mononuclear cell (PBMC) limiting dilution HIV culture, and plasma HIV quantitative competitive polymerase chain reaction (PCR). Serum and intracellular zidovudine levels were measured as well as hematologic, immunologic, and toxicity parameters. Virologic measures showed neither significant upregulation nor downregulation of serum acid-dissociated HIV p24 antigen, plasma and PBMC HIV culture, or PCR in association with GM-CSF administration. A trend toward increased intracellular AZT levels was noted, but this did not achieve statistical significance (p = 0.073). CD4 and CD8 lymphocytes were essentially unaffected while absolute neutrophil counts increased with GM-CSF administration as expected. These data suggest that administration of GM-CSF does not perturb HIV activity or immunologic parameters in patients receiving AZT for advanced HIV disease. No potentiation of AZT antiviral effect was demonstrated.

Coarctation of the aorta in children and adolescents. Surgical treatment and review of 120 patients.

Between September 1967 and April 1975, a total of 120 patients between one day and 20 years of age underwent surgery for coarctation of the thoracic aorta. Thirty-two patients were below two years of age (group 1) and 88 were above two years (group 3). All patients in group 1 initially had congestive heart failure. Twenty-eight had associated cardiac defects, and 18 had signficant pulmonary arterial hypertension (greater than 50 mm Hg). Operative deaths occurred only in group 1, all in infants below five months of age. Common features in the 13 deaths were congestive heart failure, pulmonary hypertension, patent ductus arteriosus, large ventricular septal defect, concomitant pulmonary arterial bandling or open-heart procedures. The only recurrence occurred in an infant first operated at 14 days of age. Resection of aortic coarctation can be safely performed as an elective procedure; however, it still presents a high surgical risk in infants with associated intracardiac defects. Late follow-up shows the salutary effects of repair of the coarctation on hypertension.

Treatment of acquired chronic esophagopleural fistula by endoscopic cauterization.

Successful treatment of an eight-year-old esophagopleural fistula by means of endoscopic cauterization with an alkaline solution is reported. Previous therapeutic attempts with other more conventional measures had failed. The technique of the successful treatment is described. No complications could be attributed to its use.

Congenital aortic stenosis. Experience with 43 patients.

Between September, 1967, and January, 1975, 43 patients underwent intracardiac repair for congenital aortic stenosis at the Buffalo Children's Hospital. The patients ranged in age from 2 days to 24 years, 6 of them being below one year of age. Valvular aortic stenosis was found in 21 cases (4 infants [Group I-A] and 17 older patients [Group I-B]), discrete subaortic membranous diaphragm in 11 (Group II); diffuse subvalvular muscular obstruction in 3 (Group III), supravalvular stenosis in 4 (Group IV), and multiple-level obstruction in 4 (2 infants [Group V-A] and 2 older patients [Group V-B]). Preoperatively, 58 per cent of the patients were symptomatic and 67 per cent had abnormal electrocardiograms. Associated congenital cardiac defects were found in 28 per cent of the cases. The over-all hospital mortality rate was 9 per cent (3 patients in Group I-A and one in Group V-A), with no deaths occurring in patients older than 3 months of age at the time of operation. Two late deaths occurred (Groups I-B and V-B). A complete heart block developed in one patient (Group III). The average intraoperative peak systolic left ventricular-aortic gradient decreased in all groups after repair but progressively increased in the late hemodynamic studies obtained in symptomatic patients. Six patients were reoperated upon for recurrent obstruction. Late results were evaluated on the basis of symptoms, electrocardiographic findings, valve function, and hemodynamic data. They showed excellent or satisfactory results in 59 per cent of the patients in Group I-B, in 45 per cent in Group II, in 66 per cent in Group III, and in 25 per cent in Group I-V. Results were fair or poor in Groups, I-A, V-A, and V-B. In children and adolescents, effective relief of the obstruction and of the symptoms can be obtained with minimal operative risk and minimal morbidity. In symptomatic infants, despite the high operative mortality rate, surgical intervention is indicated because of the poor prognosis.

Mustard procedure after Baffes operation.

Patients in whom Baffes' procedure has been done for palliative treatment of transposition of the great arteries may develop symptom recurrence later in life that deserves further treatment. A modified Mustard procedure is suitable for this purpose; the main difficulty in performing a formal Mustard operation is the proximity of the superior vena cava and of the inferior vena caval graft openings that enable the left pulmonary veins to drain without obstruction into the new atrium. This report deals with a 15-year-old patient in whom a modified Mustard technique was employed as a palliative method.

Coarctation of the aorta and severe aortic insufficiency: What to repair first?

A new surgical approach is proposed for patients with coarctation of the aorta associated with severe aortic valvular insufficiency. The valvular lesion should be repaired first and the coarctation corrected during a second operation; both interventions should be done during the same hospital stay. We base our approach on the belief that improved coronary perfusion can be achieved when the aortic insufficiency is corrected first. The disadvantages of the opposite surgical approach, such as anticoagulation problems, renal underperfusion, and hypertensive complications are easily avoided.

Granulocyte-macrophage colony-stimulating factor as infection prophylaxis in high-risk oncologic surgery.

BACKGROUND: A method of augmenting host defenses against bacterial pathogens could result in a decrease in postoperative infections. Given its effects on leukocyte proliferation and function, it is possible that prophylactic granulocyte-macrophage colony-stimulating factor (GM-CSF) could reduce the incidence and severity of infections in high-risk surgical patients. The current study was undertaken to determine the safety and hematologic effects of perioperative GM-CSF. METHODS: Cancer patients undergoing operations with a high risk of postoperative infection were treated perioperatively for 10 days with subcutaneous GM-CSF. Cohorts were treated with GM-CSF at 125 micrograms/m2/day (12 patients) and 250 micrograms/m2/day (11 patients). RESULTS: There were no severe or life-threatening toxicities associated with GM-CSF. Mean maximum neutrophil counts during the first 5 postoperative days were 16.3 +/- 9.14 and 24.5 +/- 7.60 at 125 and 250 micrograms/m2, respectively (P = 0.04). Only one wound infection was diagnosed during this study. CONCLUSIONS: GM-CSF may be safely administered perioperatively at doses that augment neutrophil number and function. An ongoing randomized clinical trial will determine the impact of GM-CSF on postoperative infection.

The safety and efficacy of GM-CSF as an adjuvant in hepatitis B vaccination of chronic hemodialysis patients who have failed primary vaccination.

BACKGROUND: End-stage renal disease and the need for chronic hemodialysis is an indication for hepatitis B vaccination, but up to half of dialysis patients fail to respond to a 40 microg/dose i.m. three-dose primary series of recombinant hepatitis B vaccine. Only another 10-20% respond to additional boosting doses of vaccine. PATIENTS AND METHODS: Since GM-CSF has been shown to be an effective adjuvant for hepatitis B vaccine in healthy subjects and multiple animal vaccine models, we conducted a randomized, double-blind trial of GM-CSF with recombinant hepatitis B vaccine in chronic hemodialysis patients. Patients with negative hepatitis B surface antibody and antigen who had received at least three doses of recombinant hepatitis B vaccine without response (antibody titre < 10 mIU/ml) were randomized to placebo, 40 microg, or 80 microg of GM-CSF given with 40 microg recombinant hepatitis B vaccine i.m. at the same site. Clinical and laboratory studies for safety assessment were done on days 1 and 3, and hepatitis B surface antibody titres were measured at baseline and days 21 and 180 after the study injections. RESULTS: No significant local or systemic toxicity was noted from the co-injections. The rates of response and geometric mean titre (GMT) were equivalent among all three study groups: placebo 6/10 developed antibodies, GMT 22.1 mIU/ml; 40 microg GM-CSF 3/10 developed antibodies, GMT 5.4 mIU; and 80 microg GM-CSF 3/8 developed antibodies, GMT 9.7 mIU/ml. Six months after vaccination, antibody titres were available for 11 of the 12 day 21 positive responders; only 4 of these 11 patients remained antibody positive at 6 months. CONCLUSION: GM-CSF given in a single 40 microg and 80 microg i.m. dose was not an effective adjuvant with hepatitis B vaccine in chronic hemodialysis patients who had previously failed to respond to hepatitis B immunization.

Comparison of neutrophil and monocyte function by microbicidal cell-kill assay in patients with cancer receiving granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, or no cytokine after cytotoxic chemotherapy: a phase II trial.

Functional effects of recombinant human granulocyte colony-stimulating factor (rhG-CSF) and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) were prospectively measured by harvesting blood samples from 51 oncology patients (21 who were receiving no cytokines, 14 receiving rhGM-CSF, and 16 who were receiving rhG-CSF) just before cytotoxic chemotherapy (baseline) immediately before the last cytokine dose (pre), 2 hours after the last cytokine dose (post), and 48 hours after the pre period (follow-up). Neutrophils and monocytes were separated and functional effects were measured by comparing cell-kill percentages, as determined by a microbial cell-kill assay against Staphylococcus aureus and Candida albicans. Optimal cell concentrations (2 x 10(6) monocytes/ml; 4 x 10(6) neutrophils/ml) and effector-to-cell ratios (1:50) were initially determined with blood samples harvested from 23 healthy volunteers. Results in oncology patients indicated that rhGM-CSF improved monocyte-killing activity against S. aureus at follow-up, compared with controls (p = 0.0094) and compared with monocytes from rhG-CSF-treated patients at the post period (p = 0.014). Cell-killing percentage of the rhGM-CSF-treated patients was also enhanced against C. albicans during the post period, compared with controls (p = 0.011) and rhG-CSF-treated patients (p = 0.067). Neutrophil activity was not altered by either cytokine. In conclusion, monocyte-induced microbial killing was enhanced in oncology patients receiving rhGM-CSF after cytotoxic chemotherapy, compared with patients receiving rhG-CSF or no cytokines. No differences in neutrophil activity were observed between patients receiving either cytokine.

Corrective treatment of isolated ventricular septal defect in infancy.

Intracardiac correction of VSD in infants should be indicated if the mortality and morbidity of the operation at this age group is lower than cumulative mortality of pulmonary artery banding plus second-staged procedure mortality. Experience with closure of VSD in 23 patients under 1 yr of age with 4% mortality and low morbidity is presented. Indications for operation are: (1) intractable heart failure; (2) persistence or progression of pulmonary hypertension; and (3) failure of banding procedure. Deep hypothermia and circulatory arrest facilitated the intracardiac repair in all patients. Mortality and morbidity related to the banding procedure are emphasized, and it is suggested that banding be restricted only to patients with associated coarctation of the aorta or to patients with multiple muscular ventricular septal defects in whom left ventriculotomy can be safely performed at an older age.

Thermodilution cardiac output measurement in infants and small children following intracardiac surgery.

A modified catheter has been used in conjunction with a thermodilution cardiac output computer for postoperative assessment of cardiac function in infants and children. Because of the small amount of fluid required for each determination and the simplicity of the technique, serial measurements can be done safely. Its use has contributed to the early detection of low output states. It has also proven to be a useful tool for estimating the optimal heart rate in each patient and for assessing the effectiveness of therapeutic measures.

Intracardiac repair of isolated ventricular septal defects below two years of age.

Experience with closure of ventricular septal defect in 32 patients under two years is presented. Indications for correction were: (a) intractable heart failure; (b) persistence of progression of pulmonary artery hypertension; (c) failure of pulmonary artery banding; (d) elective closure after banding. In all but one case, the correction was done under the surface induced deep hypothermia with limited cardiopulmonary bypass and total circulatory arrest. Mortality and morbidity of the pulmonary artery banding procedure and of early closure discussed. For the corrective procedure the mortality was 3%. It is emphasized that whenever clinical or hemodynamic data support persistence or progression of pulmonary artery hypertension, corrective repair should be performed without delay. It is further suggested that pulmonary artery banding should be restricted to patients with ventricular septal defect and associated coarctation of the aorta and to patients with multiple muscular ventricular septal defects.

Surgical treatment of the "parachute mitral valve" complex in infancy (report of a case).

The case is presented of a 15-month-old male, affected by severe mitral valve regurgitation associated to aortic coarctation. The surgical treatment consisted in replacement of the mitral valve by a Hancock prosthesis followed, at a second state, by resection of the coarctation. The mitral insufficiency was secondary to an anomaly of the subvalvular apparatus of the "Parachute Valve" type. The incidence of defects associated to congenital mitral insufficiency is commented. The surgical indications for replacement or repair of these anomalies in infancy are discussed, and the surgical results achieved to data are analysed. Emphasis is made on the convenience, in case the corrective procedure requires valvular replacement, of implanting a low-profile biological prosthesis, which does not require anticoagulant therapy.