On teaching psychoanalysis in antianalytic times: a polemic.

The author argues that in the current attitudinal climate, characterized by significant denigration of psychoanalysis coming from biologically oriented psychiatrists, academic psychologists, pharmaceutical firms, insurance companies, managed care organizations, anxious taxpayers, and revisionist critics of Freud, psychoanalysts need to adapt their training and supervisory practices to take into account the preconceptions of many of those seeking training as psychotherapists. Specifically, we need to appreciate the nature of the transferences toward analysts and analysis that exist in the wider mental health community and in the general public. These include assumptions that analysts are cold, arrogant, rigid, and worshipful toward Freud (who is himself seen as cold, arrogant, rigid, and narcissistic), and the prevalent misconception that psychoanalysis has been empirically discredited. Analysts need to find creative and honest ways, some of which are suggested by the author, to challenge the distortions in these stereotypes and to respond nondefensively and generatively to the grains of truth they contain. The essay concludes with some reminders of the legitimate strengths of the psychoanalytic tradition that suggest that its future is not as bleak as its disparagers have assumed.

Immunological and virological analyses of persons infected by human immunodeficiency virus type 1 while participating in trials of recombinant gp120 subunit vaccines.

We have studied 18 participants in phase I/II clinical trials of recombinant gp120 (rgp120) subunit vaccines (MN and SF-2) who became infected with human immunodeficiency virus type 1 (HIV-1) during the course of the trials. Of the 18 individuals, 2 had received a placebo vaccine, 9 had been immunized with MN rgp120, and seven had been immunized with SF-2 rgp120. Thirteen of the 18 infected vaccinees had received three or four immunizations prior to becoming infected. Of these, two were placebo recipients, six had received MN rgp120, and five had received SF-2 rgp120. Only 1 of the 11 rgp120 recipients who had multiple immunizations failed to develop a strong immunoglobulin G antibody response to the immunogen. However, the antibody response to rgp120 was transient, typically having a half-life of 40 to 60 days. No significant neutralizing activity against the infecting strain was detected in any of the infected individuals at any time prior to infection. Antibody titers in subjects infected despite vaccination and in noninfected subjects were not significantly different. Envelope-specific cytotoxic T-lymphocyte responses measured after infection were infrequent and weak in the nine vaccinees who were tested. HIV-1 was isolated successfully from all 18 individuals. Sixteen of these strains had a non-syncytium-inducing (NSI) phenotype, while two had a syncytium-inducing (SI) phenotype. NSI strains used the CCR5 coreceptor to enter CD4+ cells, while an SI strain from one of the vaccinees also used CXCR4. Viruses isolated from the blood of rgp120 vaccinees were indistinguishable from viruses isolated from control individuals in terms of their inherent sensitivity to neutralization by specific monoclonal antibodies and their replication rates in vitro. Furthermore, genetic sequencing of the env genes of strains infecting the vaccinees did not reveal any features that clearly distinguished these viruses from contemporary clade B viruses circulating in the United States. Thus, despite rigorous genetic analyses, using various breakdowns of the data sets, we could find no evidence that rgp120 vaccination exerted selection pressure on the infecting HIV-1 strains. The viral burdens in the infected rgp120 vaccine recipients were also determined, and they were found to be not significantly different from those in cohorts of placebo-vaccinated and nonvaccinated individuals. In summary, we conclude that vaccination with rgp120 has had,to date, no obvious beneficial or adverse effects on the individuals we have studied.

Suppression of cornified envelope formation and type 1 transglutaminase by epidermal growth factor in neoplastic keratinocytes.

Epidermal growth factor (EGF) is a potent mitogen for keratinocytes. Although the role of the EGF receptor in cell proliferation has been extensively studied, the consequences of EGF receptor activation with respect to cell differentiation remain less well characterized. Our studies demonstrate that stimulation of the EGF receptor substantially suppresses cellular differentiation in squamous cell carcinoma lines that overexpress the EGF receptor, as assessed by an EGF-dependent reduction of cornified envelope formation. Only a modest ligand-dependent decrease in cornified envelope formation was observed in normal keratinocytes. The response is dependent on the concentration of EGF and is evident after 1-2 days of EGF treatment. With extended EGF treatment, the messenger RNA levels for involucrin, a major structural component of the cornified envelope, were unaltered by EGF. In contrast, membrane-associated transglutaminase enzyme activity, which predominantly represents type 1 (keratinocyte) transglutaminase, is markedly inhibited by EGF. The lost of type 1 transglutaminase activity is associated with reduced levels of the messenger RNA and protein. These studies suggest that the functional consequences of EGF receptor activation in squamous cell carcinomas involve not only aberrant growth regulation, but, additionally, reduction of terminal differentiation capacity.

Prophylaxis and therapy with factor VII concentrate (human) immuno, vapor heated in patients with congenital factor VII deficiency: a summary of case reports.

Hereditary factor VII deficiency is a rare autosomal recessive condition, usually associated with normal or reduced levels of a functionally defective molecule. The available means of treating this condition in North America presents serious health risks to the patient. Transfusion with fresh frozen plasma carries a risk of volume overload and a significant risk for viral transmission. Sustained prothrombin complex therapy is associated with a high risk for thrombogenic complications. This communication describes the use of Factor VII Concentrate (Human) Immuno, Vapor Heated--an intermediate purity factor VII concentrate from Immuno A.G.--for the treatment of 13 patients with factor VII deficiency. Treatment regimens described include those for long-term prophylaxis (three children), acute hemorrhages (two children, one adult), peripartum prophylaxis (one patient), and surgical coverage (two children, four adults). Prophylaxis and therapy were successful in all cases, the medication was well-tolerated, and there were no complications. In the three cases of long-term prophylaxis in children, doses of 10-50 IU/kg were given one to three times a week; one patient has undergone long-term prophylaxis for approximately 8 years, one patient for 1 year, and one patient for 1 1/2 years. Three cases in which Factor VII Concentrate was principally used for treatment of acute episodes of bleeding are described. One infant received Factor VII Concentrate on about 50 occasions for treatment of mucosal bleeding; a correction to 40-100% resulted in cessation of bleeding within 15 min in all cases. For treatment of an episode of intracranial bleeding, an 8-year-old boy received a dose of 37 IU/kg Factor VII Concentrate every 6 hr for peak factor VII levels of approximately 100% and troughs as low as 4% over the 11-day treatment period. A 37-year-old adult male with intracranial bleeding received alternating doses of 16 IU/kg and 8 IU/kg every 6 hr for 10 days with peak factor VII levels in the upper thirties (%). The peak favor VII level during surgical coverage with Factor VII Concentrate (neurosurgery, open reduction of ankle bones, dental surgery, pituitary adenoma surgery, closed liver biopsy) was approximately 100% in all cases, with trough levels ranging from 8 to 65% over treatment periods of 24 hr to 16 days using treatment intervals of 6-12 hr.

Results of pediatric oncology group protocol 8104 for infants with stages D and DS neuroblastoma.

PURPOSE: We determined the complete response and survival rates for infants with disseminated (stage D) neuroblastoma that followed therapy identical to that for regional disease. In those infants whose disease excluded cortical bone metastases (stage DS), we determined complete response rates achieved either spontaneously or with stage D therapy. PATIENTS AND METHODS: Eighty-eight patients with metastatic disease received induction chemotherapy followed by a second operation, the results of which determined additional therapy. Twenty-five patients were observed after diagnosis, without chemotherapy, until a second operation. RESULTS: The complete response (CR) rates for patients with stage D disease after induction chemotherapy and postinduction surgery were 26% and 52%, respectively, and for immediately treated patients with stage DS disease 69% and 77%, respectively. Fifty-four percent of initially observed patients with stage DS disease achieved CR after a second operation; 44% were never treated beyond these two operations. Five-year actuarial survival rates for patients with stage D and for all those with stage DS disease were 60% (SE = 6%) and 90% (SE = 5%), respectively. CONCLUSIONS: Improved survival rates for patients with stage D disease were achieved on this protocol but remained considerably lower than those for infants with less extensive disease. Rates of survival for patients with stage DS disease were achieved with therapy less aggressive than in published series.

Cyclophosphamide/doxorubicin vs. cisplatin/teniposide in the treatment of children older than 12 months of age with disseminated neuroblastoma: a Pediatric Oncology Group Randomized Phase II study.

This prospective study was designed to estimate the response rates and to compare two drug pairs, cyclophosphamide/doxorubicin (Cy/A) and cisplatin/teniposide (P1/VM) in previously untreated patients with disseminated neuroblastoma > 12 months of age at diagnosis. Estimated complete clinical response rates after five courses of therapy were 13% (70 patients) and 22% (64 patients) for Cy/A and P1/VM, respectively (P = 0.17). After surgical removal of residual tumors in patients with partial response, the complete response rates were 27% and 34% (P = 0.50), respectively. The overall CR/PR rates after induction and surgery were 59% and 73% (P = 0.077). There was no significant difference in event free survival (P = 0.48) or survival (P = 0.40). Five year survival on the two arms were 14% (SE = 5%) and 12% (SE = 4%), respectively. Toxicity was significant but manageable. The Cy/A arm had significantly higher hematopoietic toxicity but significantly lower GI toxicity. Significant allergic reactions were seen with the P1/VM arm, none in the Cy/A arm. Given the activity of these two regimens, further therapy with a combination of these regimens is suggested.

Thoracic neuroblastoma: a Pediatric Oncology Group study.

Ninety-six patients with thoracic neuroblastoma were studied in a prospective fashion. Median age at presentation was 0.9 years. Forty-eight percent of the patients presented with stage A disease, 20% stage B, 13% stage C, 17% stage D, and 2% stage DS. Seventy-five patients have been followed for greater than 4 years. A posterior mediastinal mass was diagnosed on incidental chest roentgenograms performed for nontumor-related symptoms in 49% of the cases. Sixteen percent of the cases presented with neurological symptoms and 14% of the patients presented with acute respiratory distress. Urinary catecholamines were elevated in 76% of the cases. Complete surgical resection was carried out in 47% of the cases, while incomplete resection or biopsy was performed in 45%. No operation was performed in 3 patients. Minor surgical complications occurred in 20% of the patients, and 3% of the patients had significant perioperative complications. One patient died as a complication of therapy. Overall actuarial survival was 88% at 4 years. This study confirms the favorable outcome in children with mediastinal neuroblastoma. The basic biology of thoracic neuroblastomas seems to differ from that of other sites in that the majority of patients present at a younger age with localized disease or regional lymph node metastases, and have an improved survival even after correcting for age and stage. While complete excision is recommended, if possible, radical surgical procedures are not indicated since an excellent prognosis is associated with combined modality therapy.

Infants with neuroblastoma and regional lymph node metastases have a favorable outlook after limited postoperative chemotherapy: a Pediatric Oncology Group study.

PURPOSE: Infants less than or equal to 1 year of age with neuroblastoma (NB) have a favorable outlook with minimal to moderate therapy. Patients with complete or partial removal of the primary tumor but positive intracavitary lymph nodes (Pediatric Oncology Group [POG] stage C) have a higher risk for recurrent disease. To determine the importance of distinguishing infants with POG stage C NB from those with POG stage B disease and to assess the efficacy and toxicity of treating POG stage C infants with limited, postoperative chemotherapy, a study was conducted by the POG. PATIENTS AND METHODS: Forty-four eligible POG stage C infants received cyclophosphamide 150 mg/m2 orally on days 1 to 7 and Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) 35 mg/m2 intravenously (IV) on day 8 (CYC/ADR), every 3 weeks for five courses followed by second-look surgery. No continuation therapy was given if surgical and pathologic complete response (CR) was achieved. Secondary therapy with five courses of cisplatin 90 mg/m2 on day 1 followed by teniposide (VM-26) 100 mg/m2 on day 3 (CDP/VM) was given to infants with gross residual tumor after CYC/ADR and second-look surgery. RESULTS: Thirty-four infants achieved CR after CYC/ADR alone, three after CYC/ADR and second-look surgery, two after CYC/ADR, surgery, and maintenance therapy, and two after alternative treatment with CDP/VM (total CR rate, 42 of 44). The 3-year survival and disease-free survival are both 93%. Toxicity was nominal. CONCLUSIONS: Infants with POG stage C NB have a favorable outlook, which is similar to infants with POG stage B NB; the surgical staging procedure for distinguishing these infant subsets may not be necessary. Future studies should focus on the reduction of treatment toxicity and efficacy maintenance, and address methods to identify infants at risk for failure.

Serum lactate dehydrogenase in childhood neuroblastoma. A Pediatric Oncology Group recursive partitioning study.

On the basis of an extensive recursive partitioning analysis of 668 patients with newly diagnosed neuroblastoma registered on Pediatric Oncology Group (POG) studies between October 1981 and May 1987, four major subsets of patients were created. Important prognostic factors included the patient's stage of disease, age, and level of serum lactate dehydrogenase (LDH). After adjusting for these factors, no other clinical prognostic factors were significant. The implications for protocol design are that (a) fine tuning of current therapy should be sought for the two favorable disease patient subsets, while (b) novel aggressive therapies are needed for the two unfavorable disease patient subsets where the overwhelming majority are dying. This article may serve as a model for others investigating prognostic factors. The data were divided into two subsets: one was used for an exploratory analysis; the other was used to confirm the exploratory findings. Despite spite the large number of statistical tests performed, the likelihood that the findings can be attributed to chance can be dismissed as virtually zero.

The prognostic significance of autologous bone marrow transplant in advanced neuroblastoma.

This report provides strong evidence for conducting a controlled randomized clinical trial of autologous bone marrow transplantation versus conventional chemotherapy in childhood neuroblastoma, which is disseminated beyond the intracavity nodes, and which is diagnosed in children older than 12 months of age. On the basis of two Pediatric Oncology Group (POG) studies, one a surgery plus conventional chemotherapy study (POG 8441) and the other an elective autologous transplant pilot protocol (POG 8340), there was no significant prognostic benefit of switching in remission from the surgery plus chemotherapy protocol to the transplant protocol (P = .91) or of switching in remission from the surgery plus chemotherapy protocol to any transplant (P = .75). The analysis is based on 116 patients achieving a complete or partial remission, 32 of whom received transplants on the pilot protocol, and 17 of whom received transplants outside the pilot protocol. While potential selection bias precludes cause-effect conclusions, these data strongly suggest that a large randomized trial of autologous bone marrow transplantation should be conducted before accepting this form of therapy as standard.

Radiotherapy improves the outlook for patients older than 1 year with Pediatric Oncology Group stage C neuroblastoma.

Children older than 1 year of age who have neuroblastoma with complete or partial removal of the primary tumor and positive intracavitary lymph nodes (Pediatric Oncology Group [POG] stage C) are a small but higher-risk subset of patients. To further evaluate the importance of identifying patients with POG stage C neuroblastoma and to assess the efficacy and toxicity of adding concurrent radiation therapy (RT) to chemotherapy (CT) in these children, a randomized study was conducted. Eligible patients received cyclophosphamide 150 mg/m2 orally days 1 to 7 and Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) 35 mg/m2 intravenously (IV) on day 8 (CYC/ADR) every 3 weeks for five courses with or without RT to primary tumor and regional lymph nodes (24 to 30 Gy/16 to 20 fractions). Second-look surgery was advised to evaluate response and to remove residual disease. Continuation therapy alternated CYC/ADR every 3 weeks with cisplatin 90 mg/m2 day 1 followed by teniposide 100 mg/m2 day 3 (CDP/VM) for two courses each. Secondary CT with CDP/VM alone was available for patients not achieving complete response (CR) following induction treatment and second-look surgery. Of 29 eligible patients randomized to CT alone, 13 achieved CR, and nine are disease-free (NED) 1 to 52 months (median, 35 months) off therapy. Twenty-two of 33 eligible cases treated with CT/RT attained CR, and 19 are NED 1 to 77 months (median, 23 months) off therapy. Local and metastatic relapses occurred in both arms. Differences in CR, event-free survival, and survival rates were significant, P = .013, .009, and .008, respectively. Surgical compliance was excellent and complications uncommon. Therapy was tolerable in both groups but hematopoietic toxicity was more common in the CT/RT arm. We conclude that POG stage C neuroblastoma in children older than 1 year of age is a higher-risk group that should be identified, that CT/RT provides superior initial and long-term disease control compared with CT alone in this patient subset, and that the occurrence of metastatic failures in both treatment groups suggests a need for more aggressive chemotherapy.

Primary extrarenal Wilms' tumor in children.

We report three additional cases of primary extrarenal Wilms' tumor and review those cases previously documented. Analysis of the location, histopathology, treatment, and survival of these cases supports the following conclusions: Wilms' tumor may occur in an extrarenal location without primary renal involvement and must be included in the differential diagnosis of abdominal, pelvic, and inguinal masses; an extrarenal location supports a more frequent occurrence of ectopic metanephric blastema than was previously recognized or origin of Wilms' tumor from a more primitive mesodermal tissue; and the natural history and prognosis of extrarenal and renal Wilms' tumors appears similar.

Epstein-Barr virus-associated lymphoproliferative disorder. Applications of immunoperoxidase and molecular biologic techniques.

A 17-year-old boy with fever and cervical lymphadenopathy developed multiple-organ failure and died three weeks after hospital admission. A lymph node biopsy specimen demonstrated a florid immunoblastic infiltrate that was suspicious for a malignant lymphoma. By using immunoperoxidase and molecular biologic techniques, evidence was presented for an Epstein-Barr virus-associated lymphoproliferative disorder.

Localized neuroblastoma treated by surgery: a Pediatric Oncology Group Study.

A prospective study was designed to evaluate the outcome of patients with localized resectable neuroblastoma without regional lymph node involvement when no therapy beyond surgical resection was administered. One hundred one patients observed for 3 to 60 months had a 2-year disease-free survival of 89% (SE = 5%). Of the nine patients experiencing relapse, only three have died. There were no apparent distinguishing characteristics of the nine failures. Due to the favorable prognosis of the subset of neuroblastoma patients, prognostic factor analysis had very limited power and lacked clinical importance. Complete gross removal of the localized tumors is adequate therapy to ensure the survival of the majority of these patients.

Multifocal ganglioneuroblastoma coexistent with total colonic aganglionosis.

Neuroblastoma and Hirschsprung's disease are considered aberrations of neural crest cell growth, migration, or differentiation. Their coexistence, however, is rare. We present the case of an only child with total colon Hirschsprung's disease diagnosed shortly after birth, who was found to have noncontiguous ganglioneuroblastomas without metastases at age 16 months. The spectrum of neural crest anomalies, long segment Hirschsprung's disease and multifocal neuroblastoma, in this child is unique and previously unreported.