Novel staging tool for localized prostate cancer: a pilot study using genetic adaptive neural networks

PURPOSE: An estimated $1.5 billion is spent annually for direct medical expenses and an additional $2.5 billion for indirect costs for the management of prostate cancer. Today there are several procedures for staging prostate cancer, including lymph node dissection. Despite these procedures, the accuracy of predicting extracapsular disease remains low (range 37 to 63, mean 45%). Use of multiple staging procedures adds significantly to the costs of managing prostate cancer. Recently artificial intelligence based neural networks have become available for medical applications. Unlike traditional statistical methods, these networks do not assume linearity or homogeneity of variance and, thus, they are more accurate for clinical data. We applied this concept to staging localized prostate cancer and devised an algorithm that can be used for prostate cancer staging. MATERIALS AND METHODS: Our study comprised 1,200 men with clinically organ confined prostate cancer who underwent preoperative staging using serum prostate specific antigen, systematic biopsy and Gleason scoring before radical prostatectomy and lymphadenectomy. The performance of the neural network was validated for a subset of patients and network predictions were compared with actual pathological stage. Mean patient age was 62.9 years, mean serum prostate specific antigen 8.1 ng./ml. and mean biopsy Gleason 6. Of the patients 55% had organ confined disease, 27% positive margins, 8% seminal vesicle involvement and 7% lymph node disease. Of margin positive patients 30% also had seminal vesicle involvement, while of seminal vesicle positive patients 50% also had positive margins. RESULTS: The sensitivity of the network was 81 to 100%, and specificity was 72 to 75% for various predictions of margin, seminal vesicle and lymph node involvement. The negative predictive values tended to be relatively high for all 3 features (range 92 to 100%). The neural network missed only 8% of patients with margin positive disease, and 2% with lymph node and 0% with seminal vesicle involvement. CONCLUSIONS: Our study suggests that neural networks may be useful as an initial staging tool for detection of extracapsular extension in patients with clinically organ confined prostate cancer. These networks preclude unnecessary staging tests for 63% of patients with clinically organ confined prostate cancer.     

Rapid screening for psychologic distress in men with prostate carcinoma: a pilot study

BACKGROUND: As more oncology care is moved to the outpatient setting, the need for a rapid means for oncologists to identify patients with significant distress has increased. Concurrent with this move has been the pressure to reduce time spent with each patient, adding to the likelihood that a distressed patient will not be recognized and will remain untreated in the current health care environment. METHODS: A pilot program was conducted in a prostate carcinoma oncology clinic to test the feasibility of a two-stage approach that identifies patients in significant distress and refers them for treatment. Two pencil and paper self-report measures were used to detect psychologic distress in patients over the previous week: 1) The Hospital Anxiety and Depression Scale (HADS) and 2) "The Distress Thermometer." Patients who scored above an agreed upon cutoff score on either measure (HADS = 15+; Thermometer = 5+) were referred to the psychiatric liaison in the clinic for evaluation. RESULTS: Compliance in filling out the measures was excellent; only 8 of 121 patients (6.6%) refused. Thirty-one percent of evaluable patients were referred based on elevated scores. Seventeen of 29 patients actually were evaluated. Eight of 17 patients met Diagnostic and Statistical Manual (of Mental Disorders)-IV criteria for a psychiatric disorder. CONCLUSIONS: This approach for rapid screening for distress was acceptable in prostate carcinoma patients, although these older men were reluctant to agree to evaluation and treatment. This simple screening method needs further testing and the identification of barriers on the part of the patient and oncologist that impede the identification of the most distressed patients.     

Apoptosis and other mechanisms in androgen ablation treatment and androgen independent progression of prostate cancer: a review

Patients with advanced prostate cancer commonly present with disseminated disease. For these patients, androgen ablation is a first-line treatment. This mode of therapy usually has an initially palliative effect on tumor-related symptoms and slows growth, although virtually all tumors eventually relapse to an androgen-independent, more aggressively growing phenotype. However, surprisingly little is known about the actions mediating the initial palliative effect as well as the initiation of androgen-independent tumor growth. In this review, some current concepts on mechanisms of androgen ablation treatment and androgen-independent progression of prostate cancer is highlighted. Special attention is given to the involvement of apoptosis in these processes.     

A case of fulminant hepatitis caused by antiandrogen, flutamide in a patient with prostate cancer

Preincubation of rat liver nuclei with tocopherol decreased inhibition of RNA-polymerase activity of isolated rat liver nuclei by A23187, verapamil, and phorbol myristate acetate (PMA). In nuclei of vitamin E-deficient rats, A23187, verapamil, and PMA did not inhibit label incorporation into RNA with and without tocopherol. A23187, verapamil, and PMA did not inhibit the activity of nuclei treated with 1% Triton X-100; tocopherol activated RNA synthesis but co-administration of A23187 or verapamil and tocopherol had no effect and the combination of tocopherol and PMA inhibited RNA-polymerase activity by 25%. The effect of the combination of verapamil and PMA in the presence of free tocopherol was different from the effect of these compounds assayed in the presence of the complex of tocopherol with tocopherol-binding protein.     

Neural network analysis of combined conventional and experimental prognostic markers in prostate cancer: a pilot study

Radiolabeling permits the detection of trace amounts of zwitterionic detergent remaining in extracted hydrophobic or membrane proteins. To develop a sensitive and specific assay for its presence, the commonly used zwitterionic membrane protein detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (Chaps) was synthesized in a tritiated form. Synthesis via 7-ketodeoxycholic acid gave [7-3H]Chaps in 53% yield with a specific activity of 0.85 mCi/mmol. A novel solvent extraction system for cholic acid obviated the need for chromatographic isolation of this intermediate. The protocol can be readily modified to yield [7-3H]Chaps of higher specific activity. [7-3H]Chaps was used to monitor the efficiency of various strategies for detergent removal from concentrated bacterial culture supernatants containing 0.2% (w/v) Chaps. Dialysis removed 95% of Chaps and the addition of detergent-affinity beads to the dialysis buffer resulted in 97% removal of Chaps. Gel-filtration chromatography removed 99.9% of Chaps, while a detergent-affinity bead chromatography column removed 99.99%. Overall, gel-filtration chromatography was the most convenient and economical method for the one-step removal of the zwittergent from complex biological mixtures.     

Development of an androgen receptor-null model for identifying the initiation site for androgen stimulation of proliferation and suppression of programmed (apoptotic) death of PC-82 human prostate cancer cells

Whether androgen regulates the proliferation and survival of androgen-responsive prostate cancer cells directly or indirectly via a paracrine pathway initiated in androgen receptor (AR)-expressing stromal cells is unknown. To resolve this issue, female mice heterozygous for the testicular feminized male loss of function mutation in their X-linked AR genes were cross-bred to T cell-defective homozygous male nude mice. Using a PCR-based restriction enzyme digestion method, the resulting AR/tfm, Nu/nu F1 hybrid females were identified and back-crossed to homozygous male nude mice to produce AR-null male nude mice lacking both AR and T-cell function. Androgen-responsive PC-82 human prostate cancers were xenografted into these AR-null versus AR-wild-type male nude mice. In both backgrounds, the cancer cells did not grow in nonandrogenized hosts. In contrast, PC-82 prostate cancer cells grew with identical characteristics (i.e., take rate, morphology, PSA expression, growth rate, and percentage of cell proliferating or dying) in androgenized hosts of both backgrounds. Likewise, in both backgrounds, androgen ablation of mice bearing growing PC-82 cancers resulted in the inhibition of proliferation and activation of programmed (apoptotic) cell death of the cancer cells. These results demonstrate that both the androgen-stimulated proliferation and the suppression of programmed cell death of PC-82 human prostate cancer cells are initiated by the AR pathway directly within these cancer cells themselves and do not involve initiation by AR-expressing stromal cells in a paracrine manner.     

Lung cancer: intermittent irradiation synchronized with respiratory motion--results of a pilot study

Pyothorax-associated lymphoma (PAL) is a newly-described entity developing several decades after artificial pneumothorax treatment for pulmonary or pleural tuberculosis. It is known to be associated with Epstein-Barr virus (EBV) with constant expression of the two latent membrane proteins: latent membrane protein (LMP)-1 and EBV-associated nuclear antigen (EBNA)-2. We are reporting three new cases of PAL. All of the tumours were of B-cell lineage and classified as large-cell diffuse lymphomas according to the International Working Formulation for the Classification of Lymphomas. The EBV genome was detected in two of the cases with LMP-1 and EBNA-2 expression. No EBV could be detected in the third case suggesting that different mechanisms may be involved in the pathogenesis of the disease. Body cavity-based high grade lymphomas (BCBL) represent a new disease, developing mainly in human immunodeficiency virus (HIV) infected patients: the tumoural cells often contain both human herpes virus (HHV)-8 (or Kaposi's sarcoma herpes virus) and EBV genomes, suggesting that these viruses might co-operate in the pathogenesis of the disease. The pleural location and the association of EBV have led to speculation that PAL could also be related to HHV-8 infection. However, no HHV-8 genome could be detected in any of the 14 tested cases already reported in the literature nor in the two cases we studied (one EBV-positive and one EBV-negative), suggesting that PAL and BCBL are two different entities.     

Antiandrogen suppression syndrome in patients with hormone-resistant cancer of the prostate

OBJECTIVE: To analyze the evolution of serum prostate specific antigen (PSA) levels and the clinical response following the suppression of the antiandrogen in patients with metastatic prostate cancer who undergo complete androgen blockade in a hormone refractory status. MATERIAL AND METHODS: 19 patients were evaluated. Following flutamide suppression, their PSA serum levels were measured monthly and the subjective clinical response assessed. Additionally, the objective clinical response was also assessed at three months. RESULTS: In 11 patients (57.9%), PSA serum concentration continued to increase and no clinical response was seen in any of them. In the 8 remaining cases (42.1%) there was a decrease in PSA serum levels ranging between 2.1 and 84.5%; this decrease was greater than 50% in 5 patients (26.3%). Mean duration of the biochemical response was 4.5 months (2-11). Subjective clinical responses were reported in 5 patients (26.2%), while an objective clinical response was seen in 2 (10.5%) cases who had PSA reductions greater than 50% and were maintained for periods of over 6 months. CONCLUSIONS: Antiandrogen suppression in patients with hormone refractory prostate cancer with complete hormone blockade, can result in considerable albeit short biochemical and clinical responses. For this reason, this should be considered as the first therapeutical approach, whereas in responder patients any other second line treatment could be delayed until a new PSA increase or symptomatic worsening is detected.     

Chlormadinone acetate withdrawal syndrome under combined androgen blockade for advanced prostate cancer

Between July 1991 and December 1994 at Tsukuba Gakuen Hospital, we treated 19 consecutive men with advanced adenocarcinoma of the prostate (five at stage C, four at stage D1 and 10 at stage D2). Of these, 14 patients underwent castration (two patients) or received LH-RH analogue (12 patients) plus chlormadinone acetate for combined androgen blockade. We report three representative cases of sequential prostate specific antigen (PSA) elevation following initial response to this combined androgen blockade. Discontinuation of chlormadinone acetate resulted in decline of the serum PSA level. This suggests that trial chlormadinone acetate withdrawal in patients showing increasing levels of PSA during combined androgen blockade should be considered before initiation of alternative treatment.     

Serial sectioning of sentinel nodes in patients with breast cancer: a pilot study

Bone morphogenetic protein (BMP) has the ability to induce ectopic bone, while the action of transforming growth factor beta (TGF beta) is to stimulate proliferation of osteoblasts and chondrocytes as well as the production of extracellular matrix. The aim of the present study was to study their synergistic actions in bone formation. Three kinds of complexes, recombinant human BMP2 (rhBMP2), TGF beta and rhBMP2/TGF beta in ceramic bovine bone (CBB), were made and then implanted into the thigh muscle pouches of mice. The histological reactions of the implanted areas were studied at intervals of 3, 5, 7, 14 and 21 days. The results showed that, except for the implants with TGF beta alone, both rhBMP2 and rhBMP2/TGF beta implants exhibited new ectopic bone formation. The morphometric study revealed that the quantity of newly formed bone induced by rhBMP2/TGF beta was obviously greater than by rhBMP2 alone. These results indicate that TGF beta in combination with BMP may enhance formation of ectopic bone.     

Aneuploidy index in blood: a potential marker for early onset, androgen response, and metastasis in human prostate cancer

OBJECTIVES: To investigate whether the frequency of chromosome abnormalities in peripheral blood lymphocytes defined as the aneuploidy index in blood (AnIB) can be used as a clinical marker of early age onset, androgen response, and metastasis in human prostate cancer. METHODS: Peripheral blood samples were collected from 80 patients with prostate cancer, and chromosome preparations were made from 72-hour cultures after mitotic block. The AnIB of 59 informative cases was compared with several parameters, including age at disease onset, Gleason grade of tumor, clinical stage of tumor, metastasis, and prostate-specific antigen (PSA) level. RESULTS: Patients with AnIB levels greater than 3 had a significantly higher incidence of metastasis (P = 0.022), androgen-independent disease (P = 0.002), and early age at disease onset (age at diagnosis less than 65 years) (P = 0.002) compared with the patients with lower AnIB (less than 3) levels. In addition, patients with AnIB levels greater than 5 had higher PSA levels (greater than 20 ng/mL) (P = 0.029) than patients with AnIB levels less than 5. CONCLUSIONS: Chromosome abnormalities can be detected in the peripheral lymphocytes of patients with prostate cancer, and AnIB can be used as an early diagnostic and predictive marker for prostate cancer metastasis and androgen-independent disease.     

Pathological staging and biochemical recurrence after neoadjuvant androgen deprivation therapy in combination with radical prostatectomy in clinically localized prostate cancer: results of a phase II study

OBJECTIVES: To assess the pathological staging and biochemical progression-free survival (assessed using serum prostate-specific antigen level) of patients with clinically localized prostate cancer using neoadjuvant androgen deprivation therapy (ADT) in combination with radical retropubic prostatectomy (RRP). PATIENTS AND METHODS: A prospective study was carried out on 69 patients with localized prostate cancer who were enrolled in a trial of 3 months of ADT followed by RRP (group 1). These patients were compared with 72 patients matched for age and clinical stage who declined ADT therapy and had RRP concurrently (group 2). Assignment to the individual treatment groups was thus determined by the patient's preference and not the physician's selection. Pathological staging and biochemical progression-free recurrence were compared between the groups. RESULTS: The rate of organ-confined (pT2) tumours was 74% in group 1 and 49% in group 2 (P < 0.01), and the rate of margin-negative tumours was 87% in group 1 and 64% in group 2 (P < 0.01). Within a median follow-up of 35 months, there was no significant difference in biochemical failure between the groups (P = 0.37). Patients with pT2 disease, regardless of treatment, had similar biochemical failure rates. In the patients with margin-positive disease, there was a significantly higher biochemical failure rate in group 1 (P = 0.02). CONCLUSIONS: The rates of organ- and specimen-confined disease were higher among the patients treated with ADT. The preliminary follow-up suggested that patients with pT2 disease after ADT have a biochemical progression-free recurrence rate similar to pT2 patients treated with RRP alone. Additionally, high biochemical failure rates in patients with margin-positive disease after ADT may identify a subset of more biologically aggressive tumours in need of early adjuvant treatment.     

Antitumor activity of suramin in hormone-refractory prostate cancer controlling for hydrocortisone treatment and flutamide withdrawal as potentially confounding variables

BACKGROUND: A prospective Phase II clinical trial was conducted to assess the clinical activity of a pharmacokinetically guided suramin regimen in patients who had documented progression of metastatic prostate cancer after hydrocortisone plus antecedent or simultaneous withdrawal of flutamide. METHODS: Fifty-four patients whose disease had progressed after castration and flutamide administration were enrolled on this trial. The study was divided into two parts. Initially, 52 patients received hydrocortisone (30 mg/day) and for those patients receiving flutamide, at study entry (34 patients) flutamide was simultaneously discontinued. Forty-three patients whose disease progressed on hydrocortisone received suramin for 6-8 weeks. Six patients who progressed on hydrocortisone became ineligible for suramin due to clinical deterioration, four patients are still responding to hydrocortisone at more than 1 year, and one patient elected to postpone initiation of suramin. Suramin was given as intermittent infusions at fixed doses on days 1-5 and thereafter dosing was guided by adaptive control with feedback to maintain plasma suramin concentrations between 300-175 micrograms/ml. Antitumor activity was assessed by prostate specific antigen (PSA) decline and soft-tissue disease response. RESULTS: Ten patients (19%; 95% CI, 9.6%-32.5%) responded to hydrocortisone therapy with either a 50% or greater PSA decline for at least 4 weeks (9 patients) and/or a partial response of measurable soft-tissue disease (2 patients). Five of these patients (10%) demonstrated a 80% or greater PSA decline. All responders to hydrocortisone had simultaneous flutamide withdrawal, and had been receiving flutamide as part of initial combined androgen blockade. Seven of 37 evaluable patients (19%; 95% CI, 8.0%-35.2%) responded to suramin with a 50% or greater decline in PSA for 4 weeks or longer. One patient (3%) had a 80% or greater decline in PSA. There were no soft-tissue disease responses to suramin. The median time to progression was 1.9 months for hydrocortisone therapy and 2.6 months for suramin therapy. The median survival for all patients was 14.6 months. CONCLUSION: Suramin has antitumor activity in metastatic prostate carcinoma independent of the therapeutic effect of hydrocortisone administration or flutamide withdrawal. The role of prior flutamide withdrawal and hydrocortisone replacement should be taken into account in future studies of suramin.     

Predictors of improved outcome for patients with localized prostate cancer treated with neoadjuvant androgen ablation therapy and three-dimensional conformal radiotherapy

PURPOSE: To identify prognostic variables that predict for improved biochemical and local control outcome in patients with localized prostatic cancer treated with neoadjuvant androgen deprivation (NAAD) and three-dimensional conformal radiotherapy (3D-CRT). MATERIALS AND METHODS: Between 1989 and 1995, 213 patients with localized prostate cancer were treated with a 3-month course of NAAD that consisted of leuprolide acetate and flutamide before 3D-CRT. The purpose of NAAD in these patients was to reduce the preradiotherapy target volume so as to decrease the dose delivered to adjacent normal tissues and thereby minimize the risk of morbidity from high-dose radiotherapy. The median pretreatment prostate-specific antigen (PSA) level was 15.3 ng/mL (range, 1 to 560 ng/mL). The median 3D-CRT dose was 75.6 Gy (range, 64.8 to 81 Gy), and the median follow-up time was 3 years (range, 1 to 7 years). RESULTS: The significant predictors for improved outcome as identified in a multivariate analysis included pretreatment PSA level < or = 10.0 ng/mL(P < .00), NAAD-induced preradiotherapy PSA nadir < or = 0.5 ng/mL (P < .001), and clinical stage < or = T2c (P < .04). The 5-year PSA relapse-free survival rates were 93%, 60%, and 40% for patients with pretreatment PSA levels < or = 10 ng/mL, 10 to 20 ng/mL, and greater than 20 ng/mL, respectively (P < .001). Patients with preradiotherapy nadir levels < or = 0.5 ng/mL after 3 months of NAAD experienced a 5-year PSA relapse-free survival rate of 74%, as compared with 40% for patients with higher nadir levels (P < .001). The incidence of a positive biopsy among 34 patients pretreated with androgen ablation was 12%, as compared with 39% for 117 patients treated with 3D-CRT alone who underwent a biopsy (P < .001). CONCLUSION: For patients treated with NAAD and high-dose 3D-CRT, pretreatment PSA, preradiotherapy PSA nadir response, and clinical stage are important predictors of biochemical outcome. Patients with NAAD-induced PSA nadir levels greater than 0.5 ng/mL before radiotherapy are more likely to develop biochemical failure and may benefit from more aggressive therapies.     

Finasteride and flutamide as potency-sparing androgen-ablative therapy for advanced adenocarcinoma of the prostate

OBJECTIVES: Androgen ablation with luteinizing hormone-releasing hormone (LHRH) agonists, orchiectomy, or oral estrogens has significant untoward sexual side effects. We evaluated a combination of finasteride and flutamide as potency-sparing androgen ablative therapy (AAT) for advanced adenocarcinoma of the prostate. In addition, we evaluated whether finasteride provided additional intraprostatic androgen blockade to flutamide. METHODS: Twenty men with advanced prostate cancer were given flutamide, 250 mg orally three times daily. Serum prostate-specific antigen (PSA) values were measured weekly. At a nadir PSA value, finasteride, 5 mg orally every day, was added. PSA values were then measured weekly until a second nadir PSA value was achieved. Sexual function was evaluated at baseline, at the second nadir PSA value, and every 3 months thereafter. Testosterone, dihydrotestosterone (DHT), and dehydroepiandrostenedione (DHEA) levels were measured at baseline and at the first and second nadir PSA values. RESULTS: The median follow-up period was 16.9 months. Therapy failed in 1 patient with Stage D2 disease at 12 months, but an additional response to subsequent LHRH agonist therapy was observed. One patient developed National Cancer Institute grade 3 diarrhea and was withdrawn from the study. Seven of 20 men developed mild gynecomastia, and 3 of 20 developed mild transient liver function test elevations. Mean PSA levels were 94.6 +/- 38.2 ng/mL at baseline and 7.8 +/- 2.7 and 4.7 +/- 2.2 ng/mL at the first and second PSA nadir values, respectively (P = 0.034). Mean percent decline in PSA value from baseline was 87.0 +/- 3.1% with flutamide alone and 94.0 +/- 1.9% with both flutamide and finasteride (P = 0.001). Eleven of 20 men were potent at baseline. At the second nadir PSA value, 9 (82%) of 11 were potent, whereas 2 (18%) of 11 were impotent. With longer follow-up (median 16.4 months), 6 (55%) of 11 men were potent, 2 (18%) of 11 were partially potent, and 3 (27%) of 11 were impotent. With flutamide alone, testosterone rose a mean of 77 +/- 14.7% of baseline (P = 0.0001), DHEA fell a mean of 32.4 +/- 4.6% (P = 0.0001), and DHT was unchanged. With the addition of finasteride, testosterone rose another 14 +/- 6% (P = 0.06, not significant), DHEA was unchanged, and DHT fell a mean of 34.8 +/- 4.7% (P = 0.0009). CONCLUSIONS: Finasteride and flutamide were safe and well tolerated as AAT for advanced prostate cancer. Finasteride provided additional intraprostatic androgen blockade to flutamide, as measured by additional PSA suppression. Sexual potency was preserved initially in most patients, although there was a reduction in potency and libido in some patients on longer follow-up. Further evaluation of this therapy is needed.     

Lifestyle factors and prostate cancer risk: a case-control study in Sweden

We examined associations between lifestyle factors and subsequent risk of prostate cancer in a population-based case-control study. Information on smoking and alcohol habits, socioeconomic factors, marital status, family history, and sexual habits were obtained from a questionnaire and a face-to-face interview with 256 (74.6%) eligible patients and 252 (76.6%) selected controls, frequency matched by age and screened for prostate cancer with negative findings. Unconditional logistic regression was used to estimate the odds ratios (ORs). Risk was elevated among current smokers of cigarettes (OR, 1.8) and current users of hard liquor (OR, 1.4); however, the lack of dose-response trend for both of these exposures argues against a causal association. We found tentative evidence that early first intercourse, a larger number of sexual partners, and other indices of high sexual activity are associated with increased risk. Similarly, adult height, an indicator of nutrition during childhood and adolescence, was weakly positively associated with risk, although larger studies are needed to establish this link. Unmarried men had a lower risk than married men (OR, 0.3), and socioeconomic status did not appear to be strongly associated with prostate cancer. Men with a father who had prostate cancer had a more than 2-fold increased risk of prostate cancer, whereas those with a brother affected had about a 5-folk risk.     

The effects of LH-RH agonist alone or with flutamide in the treatment of stage D2 prostate cancer]

We compared the clinical efficacy of treatment with a luteinizing hormone-releasing hormone (LH-RH) agonist alone to combined androgen blockade (CAB) with a LH-RH agonist and fiutamide. A total of 66 stage D2 prostate cancer patients were enrolled from Nov. 1992 to Mar. 1996 (n = 30: LH-RH agonist alone, n = 36 CAB). Serum PSA levels after 3 months of treatment and progression-free survival rates (Kaplan-Meier curves) were compared. Results were statistically evaluated by Wilcoxon's text. There were no differences in PSA levels between LH-RH agonist alone and CAB. Progression-free survival rates were longer in the patients treated CAB compared to LH-RH agonist alone (P = 0.041). Furthermore, in patients with poorly differentiated prostate cancers, longer survival rates were also observed with CAB (P = 0.030). However, there were no differences in high EOD (> or = 2) patients between the two treatments (P = 0.652).     

MDA-assisted psychotherapy with neurotic outpatients: a pilot study

Ten neurotic patients (five males and five females) were treated over a period of 2 to 6 months (mean, 4.1) as outpatients. The study allowed for a maximum of 75 hours of psychotherapy (mean, 51.55 hours). During the course of treatment, two to four (mean, 3.5) administrations of MDA (3,4-methylenedioxyamphetamine) were employed as adjunctive aids in an effort to enhance the psychotherapeutic process. The mean duration of the drug sessions was 8 hours (range, 6 to 14 hours). The first administration of MDA took place when, in the therapist's judgment, sufficient rapport had been established with the patient. All patients received an initial dose of 75 mg of MDA; subsequent dosage was allowed to range up to 200 mg. On these occasions, the drug appeared to be well tolerated with no serious side effects or complications observed. Psychometric assessments were obtained pre- and post-treatment, employing the Minnesota Multiphasic Personality Inventory (MMPI), Wittenborn Psychiatric Rating Scales (WPRS), and Brief Psychiatric Rating Scale (BPRS). In addition, follow-up evaluations were obtained 6 months after the termination of therapy by the use of the MMPI, WPRS, BPRS, and a Social History Questionnaire (SHQ) which had also been administered before treatment was initiated. Clinically, the impression was obtained that psychotherapy and the adjunctive use of MDA appeared to facilitate improvement in these patients. This impression was substantiated by significant reductions in scores on the psychometric assessments measuring depression, anxiety, and obsessive-compulsive traits. The meaures evaluating the sense of well-being and self-actualization also were encouraging. Although some of the patients were not as responsive as others, there were no observations to suggest that the condition of any of these patients had become worse.