Lymphocyte blastogenesis. Post-transcriptional controls of protein synthesis.

To better understand the regulation of macromolecular synthesis in the response of lymphocytes to a mitogen, we have used two-dimensional electrophoresis to search for specificity in the early increase seen in protein synthesis in human lymphocytes treated with phytohemagglutinin and examined the role of new RNA synthesis in this response. Our results confirm a major increase in overall protein synthesis after 4 h of phytohemagglutinin treatment. A further disproportionate increase in the synthetic rates of certain polypeptides was observed using two-dimensional polyacrylamide gel electrophoresis. While actinomycin-D reduced protein synthesis to a level below that of untreated cells, phytohemagglutinin nonetheless enhanced total protein synthesis even in the presence of actinomycin. Some, but not all, of the disproportionate increases in synthesis seen for certain polypeptides are blocked by actinomycin. These results imply the existence of multiple mechanisms controlling protein synthesis early in the course of lymphocyte stimulation. At least some of these do not require new RNA synthesis and thus operate at a post-transcriptional level.

Heterogeneity of human alpha-fetoprotein as revealed by isoelectric focusing in urea-containing gels.

The heterogeneity of human alpha-fetoprotein has been studied by analytical isoelectric focusing in polyacrylamide gel slabs in the presence of 8 M urea. Six major isoelectric variants could be identified over a pH range of 6.0--6.2. Verification of their identity was achieved by crossed immunoelectrophoresis into agarose gel containing monospecific antiserum to human alpha-fetoprotein. Complete desialylation of the protein did not abolish the heterogeneity; a complex pattern of major alpha-fetoprotein bands persisted over a more alkaline pH range. We have been able to correlate the pattern of alpha-fetoprotein heterogeneity seen following extended agarose gel electrophoresis with that obtained during isoelectric focusing in the presence of urea. The quantity of certain alpha-fetoprotein charge isomers in various alpha-fetoprotein isolates may be important in considering certain biological functions of this protein.

Cisplatin and fluorouracil chemotherapy does not yield long-term benefit in locally advanced head and neck cancer: results from a single institution.

Fifty-one patients with locally advanced head and neck cancer were treated with three cycles of cisplatin at 100 mg/m2 followed by 5-day continuous infusion fluorouracil (5-FU) at 1,000 mg/m2/d as induction chemotherapy. Subsequent local therapy consisted of surgery for patients with resectable disease and/or radiotherapy. Three cycles of adjuvant chemotherapy were administered to patients with partial response (PR) or complete response (CR) to induction chemotherapy. Twenty-two patients (43%) had a clinical CR that was pathologically confirmed in 12 patients (24%), and 24 patients (47%) had a PR for an overall response rate of 90%. Local therapy included surgery in 24 patients (47%) and radiotherapy alone in 22 patients (43%). Adjuvant chemotherapy was administered to 32 patients (63%) frequently at great dose reduction. At a median follow-up of 90 months, the median survival is 22 months (95% confidence interval, 15 to 36 months), and the 5-year survival is 25%, with only five patients known to be alive and disease-free at this time. The median time to progression is 14 months, with 29 patients (57%) having documented progression of their head and neck cancer and eight (16%) having progression of a second neoplasm. Seven patients died of intervening medical events. This high incidence of second malignancies supports the continued investigation of chemoprevention for patients in CR. Despite the known high response rates achieved with cisplatin and 5-FU induction chemotherapy, the overall poor survival data reported here should lead to a thorough reexamination of the frequent administration of this regimen in the community.

GR 38032F (GR-C507/75): a novel compound effective in the prevention of acute cisplatin-induced emesis.

We evaluated, in a multi-center trial, the safety and efficacy of GR 38032F (GR-C507/75), a novel and selective serotonin antagonist, in preventing acute emesis in chemotherapy-naive patients receiving treatment with regimens containing high-dose cisplatin (greater than or equal to 100 mg/m2). Eighty-five patients were randomized to receive GR 38032F, 0.18 mg/kg, either every six or every eight hours for three doses, beginning 30 minutes before cisplatin. Patients were evaluated for emetic episodes (vomiting or retching) over a 24-hour period following cisplatin. All patients were evaluable for toxicity and 83 were evaluable for efficacy. The overall antiemetic response rate was 75% (55% complete response [CR], 20% major response). No difference in antiemetic control between the two administration schedules was noted. Patients with histories of heavy ethanol use had significantly better antiemetic control (74% CR) than modest or non-drinkers (33% CR). Toxicity of GR 38032F was modest and independent of administration schedule. The most common adverse events included mild hepatic transaminase elevations, self-limited diarrhea, dry mouth, headache, and mild sedation. Our data indicate that GR 38032F is a safe and effective agent in the control of acute cisplatin-induced nausea and vomiting. Additional trials exploring dosing, schedule, and comparison to standard antiemetic agents are indicated.

Stratified, randomized, double-blind comparison of intravenous ondansetron administered as a multiple-dose regimen versus two single-dose regimens in the prevention of cisplatin-induced nausea and vomiting.

PURPOSE: This study compares the efficacy and safety of two single-dose regimens with the approved three-dose regimen of ondansetron in the prevention of cisplatin-induced emesis. PATIENTS AND METHODS: This multicenter study was a stratified, randomized, double-blind, and parallel group design. Chemotherapy-naive inpatients were randomized to receive intravenous (IV) ondansetron (Zofran; Glaxo Inc, Research Triangle Park, NC) 0.15 mg/kg times three doses, every 4 hours or a single 8-mg or 32-mg dose followed by two saline doses that began 30 minutes before cisplatin administration. Cisplatin (high-dose > or = 100 mg/m2 or medium-dose 50 to 70 mg/m2) was given as a single infusion (< or = 3 hours). Patients were monitored for emetic episodes, adverse events, and laboratory safety parameters for 24 hours after cisplatin administration. RESULTS: A total of 699 patients (359 high-dose, 340 medium-dose) were enrolled. Of these, 618 were assessable for efficacy (15 ineligible, 66 protocol deviations). The 32-mg dose was superior to the 8-mg single dose with regard to total number of emetic episodes (high-dose, P = .015; medium-dose, P < .001), complete response (no emetic episodes: high-dose, 48% v 35%; P = .048; medium-dose, 73% v 50%; P = .001) and failure rate (> 5 emetic episodes, withdrawn or rescued: high-dose, 20% v 34%; P = .018; medium-dose, 9% v 23%; P = .005). The 32-mg single dose was also superior to the 0.15 mg/kg times three dose regimen with regard to total number of emetic episodes (medium-dose, P = .033) and failure rate (high-dose, 20% v 36%; P = .009; medium-dose, 9% v 22%; P = .011). Ondansetron was well tolerated. The most common adverse event was headache. An approximate 10-fold increase in the incidence of clinically significant transaminase elevations was observed in the high-dose versus medium-dose cisplatin strata (aspartate aminotransferase [AST], 6.5% v 0.7%; serum alanine aminotransferase [ALT], 5.0% v 0.3%). CONCLUSION: A 32-mg single dose of ondansetron is more effective than a single 8-mg dose and is at least as effective as the standard regimen of 0.15 mg/kg times three doses in the prevention of cisplatin-induced acute emesis.

Diffuse large-cell lymphoma of B-cell origin and deficient T-cell function in a patient with rheumatoid arthritis.

An increased incidence of non-Hodgkin's lymphoma has been described in patients with rheumatoid arthritis. Mechanisms related to abnormal immune regulation have been postulated, but no patients with rheumatoid arthritis and lymphoma have been previously well characterized immunologically. We describe here a patient with long-standing rheumatoid arthritis in whom a B-cell diffuse large-cell lymphoma developed. He was found to have a severe T-cell immunodeficiency and evidence of persistent Epstein-Barr virus infection. Epstein-Barr nuclear antigen was not found to be present within lymphoma cells. The combination of defective T-cell function and persistent Epstein-Barr virus infection may have predisposed this patient with rheumatoid arthritis to the development of a malignant clone of B lymphocytes.

Necrotizing myelopathy complicating Hodgkin's disease.

A case of necrotizing myelopathy is presented as a complication of Hodgkin's disease. The distinctive pathologic feature of this case was severe acute vasculitis involving only the vessels of the spinal cord that was considered to have been the cause of the segmental necrosis.

Two simple translocations in a primary squamous cell carcinoma of the head and neck.

A 59-year-old white man was diagnosed with primary squamous cell carcinoma at the base of the tongue (clinical stage T4N3aM0). Cytogenetic analysis of the metaphase spreads obtained from primary cultures of the tumor tissue revealed a clonal abnormality with a 46,XY,t(2;6) (p23;q21),t(18;19)(q21;q13) karyotype.

Randomized double-blind comparison of three dose levels of intravenous ondansetron in the prevention of cisplatin-induced emesis.

The selective 5-hydroxytryptamine3 (5HT3) antagonist ondansetron has been shown to be an effective antiemetic in patients receiving cisplatin chemotherapy. This double-blind study compared the efficacy and safety of three doses of intravenous ondansetron in the prevention of nausea and vomiting associated with high-dose (> or = 100 mg/m2) cisplatin chemotherapy. A total of 125 patients were randomized (1:1:1) to receive 0.015, 0.15, or 0.30 mg/kg every 4 h for a total of 3 doses. All patients were monitored for emetic episodes, adverse events, and laboratory safety parameters for 24 h following cisplatin administration. The 0.15-mg/kg dose was superior to the 0.015-mg/kg dose with respect to the median number of emetic episodes (P = 0.033) and complete response (no emetic episodes, P = 0.005). No statistically significant difference was found between the 0.15 and the 0.30-mg/kg groups. The most common adverse event was headache. Three 0.15-mg/kg doses of intravenous ondansetron are safe, effective, and adequate for the control of cisplatin-induced emesis.

Concomitant cisplatin and hyperfractionated external beam irradiation for advanced malignancy of the head and neck.

The combination of cisplatin and hyperfractionated external beam irradiation (HEBI), followed by salvage surgery when indicated, was evaluated in patients with advanced stage squamous cell carcinoma of the head and neck. Thirty patients with stage III (n = 5) or IV (n = 25) disease received intravenous cisplatin 100 mg/m2 by 6-hour continuous infusion on days 1, 21, and 42 of HEBI. Radiation fractions of 110 cGy were given twice daily, separated by 4 to 6 hours, beginning within 12 hours after cisplatin delivery. Doses to the primary site ranged from 60 to 76.35 Gy (median: 72.3 Gy), with 60 to 74 Gy to nodal sites. Follow-up ranged from 4 to 28 months (median: 19 months). Clinical complete response of the primary site was seen in 27 of 29 patients (93%), and complete clinical clearance of adenopathy in 20 of 26 (76%). A second biopsy 6 to 8 weeks after completion of treatment showed residual disease in both the primary and nodal sites in three patients, and in only the primary site in one patient. Four patients with persistent adenopathy had pathologic confirmation at surgery. Four patients had recurrence after negative biopsy results 6 to 9 months after treatment biopsy. At present, with median follow-up of 19 months, eight patients (26%) have died secondary to uncontrolled primary or nodal disease. Two patients have died of nonrelated causes. Overall, 10 of 30 patients (66%) remain alive with no evidence of disease. Mucositis and weight loss were the most common side effects of treatment. Seven patients developed significant xerostomia, and four have cisplatin-related hearing loss requiring amplification. The early evidence of excellent response (89% pathologic complete response of primary sites; 78% complete response of nodal sites), coupled with acceptable treatment morbidity, warrants further study of this approach.

Sequential combination chemotherapy for advanced squamous cell carcinoma of the head and neck.

Thirty-four patients with advanced squamous cell carcinoma of the head and neck have been treated with sequential combination chemotherapy consisting of Cytoxan, methotrexate, oncovin, bleomycin and adriamycin, followed by Leucovorin (COMBAL). All patients had undergone extensive prior radiation and/or surgery. All the patients had recurrent cancer. Toxicity included two deaths from drug induced pancytophenia and one from sepsis. Treatment was well tolerated and could be given in the outpatient clinic. No bleomycin pulmonary or adriamycin cardiac toxicity was seen. Results include 4 patients who achieved complete remission, objective improvement in measurable lesions in 6 others, stabilization of disease for 1 to 3 mo. in 5, and progression of disease in 13. Survival has ranged from 1 to 19+ months with a median of 10.7 mo. for patients that were evaluated. We conclude that COMBAL produces objective evidence of improvement in approximately 45% of patients with far advanced, previously treated squamous cell carcinoma of the head and neck.

Disseminated intravascular coagulation in pregnancy.

The DIC syndrome is the most common cause of an abnormal hemorrhage tendency during pregnancy and the puerperium and reflects systemic activation of the coagulation cascade by circulating thromboplastic material, with secondary activation of the fibrinolytic system. Its presence in a pregnant patient almost invariably is evidence of an underlying obstetric disorder such as abruptio placentae, eclampsia, retention of a dead fetus, amniotic fluid embolism, placental retention or bacterial sepsis. Diagnosis of the DIC syndrome rests on the demonstration of reduced levels of fibrinogen and platelets, prolongation of the thrombin, prothrombin and partial thromboplastin times, and the presence of fibrin/fibrinogen degradation products (FDP) in the serum. Therapy consists of prompt removal of the source of procoagulant material, replacement of depleted clotting factors and, in some cases, anti-coagulation with heparin.

Separation-individuation and cognition.

Through direct observation of infants and mothers in an "experimental" nursery, Mahler and her associates have accumulated data which when analyzed point to distinct phases (stages) during the long process of the development of the concepts of self and object. These phases, autism, symbiosis, and separation-individuation (itself subdivided into four subphases, differentiation, practicing, rapprochement, and consolidation of individuation) correspond well with the stages described by Piaget as constituting the period of cognitive growth described as sensorimotor intelligence. The intercorrelation of the phasic development along these two separate lines (objectal-affective and cognitive), expectable as it may be, is of considerable interest as it underlines the intrinsic strength of the psychoanalytic concept of the object. Furthermore, this intercorrelation enhances and enlarges our understanding of the process of consolidation of self and object during the first years of life.

Gender and identity issues in the analytic process.

The influence of gender--of analyst and analysand--in the unfolding of the analytic process is being addressed. A brief discussion of the reasons why such influence was either dismissed or denied in the analytic literature until recently, is followed by an overview of possible analyst-analysand interactions in the four gender-related dyads. Finally two specific developments, not uncommon in the transference of female patients in analysis with female analysts (and their countertransference implications) are presented. The first refers to the issues around closeness and distance with the maternal object (usually expressed as issues over control and as a sado-masochistic struggle with the analyst in the transference), while the second to the erotization of the transference.

The female analyst and the erotized transference.

The concept of erotized transference is discussed from Freud's original writings on the subject to those of recent contributors. It is noted that there exists an almost complete absence of reports in the literature of male patients developing an erotized transference to their female analysts. The question of how significant the gender of the analyst is in the unfolding of the transference and its vicissitudes is raised. It is maintained that the four possible analyst/analysand dyads differ qualitatively in that resistance and identification in the transference may be enhanced or inhibited by the gender of the analyst and/or the homosexual or heterosexual nature of the dyad. The erotized transference to the female analyst is focused upon as a vehicle to the study of such qualitative differences. It is hypothesized that the expression of strong erotic urges to the female analyst by the male patient is somewhat inhibited by the fantasy of the overwhelming pre-oedipal mother. In contrast, such erotic feelings are freely expressed by the female patient. Two cases, a male and a female, are described to support the above hypothesis.

A surrogate carries a fertilised ovum: multiple crossings in ego boundaries.

Recent advances in reproductive technologies have created situations in which early psychoanalytic thinking with regard to the procreative wish, infertility, and the significance of pregnancy in mothering, calls for reconsideration. The paper addresses briefly issues related to psychological infertility; it focuses specifically on possible psychological implications during full surrogacy, as this procedure is now practised in many fertility clinics in North America. The analysis of a young woman whose infertility was related to her exposure, during intra-uterinary life, to her mother's hormonal treatment (DES), presented us with the opportunity to observe the many psychological issues developing during in vitro fertilisation (IVF) and other similar procedures and, ultimately, to address the far more complex interpersonal states evolving between the biological (genetic) mother and the surrogate during full surrogacy. Analytic material provides the opportunity to discuss, specifically, questions of boundaries and boundary confusion in the relationship between the surrogate (who carried the couple's fertilised ovum to the birth of a healthy child) and the genetic mother.

Imagery and transference in the analytic process.

The structural and formal aspects of free association have not received adequate attention in the psychoanalytic literature partly because of the methodological problems involved in their objective study. Visual imagery aroused considerable interest during Freud's concentration technique but, following this, interest in imagery has declined and has remained low despite the "primacy" retained by the dreams in the analytic practice and theory. Visual imagery, an integral part of conscious thought, is enhanced during free association by the regression, the altered states of consciousness, the suspension of censorship and the shift in figure ground relationships of ordinary awareness of the analytic setting as the analysis progresses and, despite the deepening of regression, the development of transference and the establishment of the analyst as the focal figure of the patient's experience produce a shift from the visual to the verbal and a decrease in the sensory elements of free association. The predominantly verbal nature of the analytic exchange once transference is established is underscored by the analyst's interpretations which, by their emphasis on ordered verbal thought, reinforce the dialectical elements of analysis. The above shift from the visual to the verbal during free association was well illustrated in a case where the development of transference signalled the decrease of the abundant visual element present at the beginning in the material of the patient. Interestingly, the patient's dreams became equally more verbal as the analysis progressed, a phenomenon which was also observed by Anzieu in Freud's dreams in his study of the latter's self-analysis. The possible mechanism for this shift and its significance are discussed.

Pregnancy, developmental crisis and object relations: psychoanalytic considerations.

The psychoanalytic literature until recently was focused on the task of understanding and conceptualizing motherhood as 'not secondary' (to the girl's wish for the penis) but the central organizer of the woman's sexual drive. Pregnancy was viewed as a developmental crisis but little had been written on the internal shifts and realignments in the mental organization of the woman during pregnancy. Material from the analyses of three women during their first pregnancy is discussed and some theoretical conclusions are offered.

Narcissism and the personal myth.

Kris (1956) described the concept of the personal myth as an autobiographical story built around a family romance fantasy seen specifically in obsessive characters and serving a defensive function. In this paper the concept of the personal myth was expanded to include similar defensive constellations originating from within the grandiose self, built around omnipotent and omniscient fantasies and occurring in character formations with pregenital, narcissistic pathology. The case of a known author and poet, Nikos Kazantzakis, was used to illustrate the thesis of the paper. The available biographical material and the work of the author offer evidence to support the claim that the author's personal myth was a protective shield against anxiety originating in early narcissistic traumata.

Early sexual abuse and nightmares in the analysis of adults.

An examination of the nightmares of four adults in analysis who had been sexually abused as children revealed a characteristic distortion of the body representation as it appeared in the manifest content of the dream. The authors believe that childhood sexual trauma has profound and pervasive effects on the development and consolidation of the body image. Experienced as a grave assault on body integrity and function, it mobilizes primitive anxieties and specific genital anxieties, resulting in distortion, fragmentation, or disintegration of the body representation. The frequently observed multiple somatization of victims of sexual abuse is attributable to such a damaged and persecutory body representation.