Phase I trial and pharmacokinetics of trimelamol (N2,N4,N6-trihydroxymethyl-N2,N4,N6-trimethylmelamine).

Trimelamol is an analogue of hexamethylmelamine and pentamethylmelamine which does not require metabolic activation and is sufficiently soluble to allow parenteral administration. A Phase I trial has been performed at the Royal Marsden Hospital in which two schedules of administration have been evaluated, a single i.v. infusion repeated every 3 weeks and 3 daily doses repeated every 3 weeks. Pharmacokinetic analysis was performed at all dose levels on both schedules and a linear correlation was demonstrated between dose and area under the curve. Myelosuppression was dose limiting for single dose administration with a maximum tolerated dose of 2400 mg/m2. Median leukocyte nadirs at 1800, 2100, and 2400 mg/m2 were 3.2, 2.6, and 1.5 x 10(9)/liter. Thrombocytopenia and anemia also occurred but were not dose limiting. Doses greater than 1500 mg/m2 caused WHO grade 3 nausea and vomiting but no acute sedation. Three day administration appeared to be less myelosuppressive, giving a maximum tolerated dose of 1000 mg/m2. Median leukocyte nadirs at 800, 900, and 1000 mg/m2 daily for 3 days were 3.0, 2.3, and 1.5 x 10(9)/liter. Nonhematological toxicities were also less marked on the fractionated schedule. Antitumor effects were observed including 1 complete and 9 partial responses. Demonstration of activity in ovarian cancer has led to further evaluation in this disease using the 3-day schedule at a dose of 800 mg/m2 daily for 3 days.

Carbon monoxide diffusing capacity is a poor predictor of clinically significant bleomycin lung. New Zealand Clinical Oncology Group.

In a retrospective analysis, serial lung function tests from 81 patients receiving bleomycin were studied to determine the accuracy of carbon monoxide diffusing capacity (DLCO) as a predictor of clinically significant bleomycin lung. Six of 81 patients developed clinically significant bleomycin lung, and the DLCO predicted its development in only one patient (sensitivity, one of six patients; 16.7%). Respiratory symptoms and chest x-ray abnormalities were the earliest manifestations in the other five patients. Seventy-five of 81 patients did not develop clinically significant bleomycin lung, and 12 of these had major falls (greater than or equal to 35% pretreatment level) in DLCO (specificity, 63 of 75 patients; 84.0%). In eight patients, bleomycin was continued after a major fall in DLCO, and none developed clinically significant lung toxicity. In this study, the DLCO failed to predict the development of serious bleomycin lung toxicity in all but one case. Furthermore, in some patients, it would appear that bleomycin may be stopped inappropriately after low DLCO measurements. It is important to monitor for respiratory symptoms and chest x-ray abnormalities during bleomycin treatment as these will be the earliest signs of lung toxicity in most cases.

A randomized comparison of single-agent doxorubicin and epirubicin as first-line cytotoxic therapy in advanced breast cancer.

One hundred forty-one patients with advanced breast cancer who had not received prior chemotherapy were randomly assigned to receive doxorubicin 60 mg/m2 or epirubicin 90 mg/m2 every 3 weeks. These doses were selected to produce equivalent toxicities. All patients were assessed for toxicity, and 138 patients were assessable for response. After a median of five treatment cycles, 47% (32 of 68) of doxorubicin-treated patients achieved a partial or complete response. Response duration and survival were 10 and 12 months for doxorubicin and 8 and 10 months for epirubicin, respectively. Noncardiac toxicities were similar for both drugs. Of 41 patients receiving doxorubicin who had serial left ventricular ejection fraction assessments, seven sustained a fall of 10% or more, and one patient developed congestive cardiac failure at a cumulative doxorubicin dose of 489 mg/m2. Of 39 patients receiving epirubicin who had serial cardiac assessments, five sustained left ventricular ejection fraction falls of 10% or more and two patients developed congestive cardiac failure at cumulative doses of 178 mg/m2 and 833 mg/m2. These data indicate that an epirubicin dose of 90 mg/m2 produces toxicity equivalent to doxorubicin 60 mg/m2 but does not improve response rates, response duration, or survival in advanced breast cancer.

Carboplatin (Paraplatin; JM8) and etoposide (VP-16) as first-line combination therapy for small-cell lung cancer.

Fifty-two previously untreated patients with small-cell lung carcinoma (SCLC) were treated with a combination of carboplatin 300 mg/m2 intravenously (IV) on day 1 and etoposide 100 mg/m2 IV on days 1 through 3 every 28 days for four courses. Patients with limited disease (LD) subsequently received thoracic radiotherapy; no prophylactic cranial radiotherapy was used. Forty-four patients (85%) achieved an objective response, including 82% (29% complete remissions) of LD patients and 88% (13% complete remissions) of extensive-disease (ED) patients. Median response duration for LD patients was 7 months and 5.5 months for ED patients. Median survival for both LD and ED patients was 9.5 months. Myelosuppression was the main toxicity, with World Health Organization (WHO) grade 3/4 leucopenia occurring in 44% of patients. There was one (2%) treatment-related neutropenic death. Treatment was otherwise well tolerated, and in particular no renal toxicity, neurotoxicity, or ototoxicity was seen. This new combination is highly active in terms of response rate, but response duration and survival is disappointing, and might be improved by prolonged treatment or by the use of additional drugs in combination.

Effect of zinc on lysis of sheep erythrocytes by guinea pig C4-deficient serum.

The divalent cation Zn2+ enhanced the lysis of sheep erythrocytes (ShE) by guinea pig C4-deficient (C4D) serum. Enhancement by Zn2+ (0.1 mM) was demonstrated in the presence of cobra venom factor (CoVF, 2 units/ml) and optimal Mg2+ (1.0 mM). Moreover, Zn2+ (0.1 mM) in the presence of Mg2+ (1.0 mM) caused the lysis of ShE by C4D serum without the addition of CoVF. Further studies were therefore performed in the absence of CoVF. Although addition of Zn2+ or Mg2+ alone to some pools of C4D serum caused lysis of ShE, the greatest extent of lysis occurred when Zn2+ and Mg2+ were both added to the reaction mixtures. When C4D serum was resin-treated, both Mg2+ and Zn2+ were required for lysis. Addition of Ca2+ had no effect. This pathway required high concns of serum and was inhibited by pretreating the serum with zymosan (2 mg/ml serum, 37 degrees C, 1 hr) or by heating the serum at 56 degrees C for 20 min. K76-COOH monocarboxylic acid also inhibited this pathway. These results suggest that Zn2+ together with Mg2+ activates the alternative pathway on the nonactivator surface (ShE).

Interaction of Zn2+ with guinea-pig C5 convertase and guinea-pig C5.

A comparison of two methods of C5 activation, the standard method (EAC14 + C2, C3, C5, C6, and C7) and the washed-cell intermediate method (EAC1423 + C5 and washed), demonstrated that formation of hemolytically competent SAC14235 was reduced in the washed-cell method. Addition of Zn2+ in this method increased the formation of competent SAC14235 to the approximate level of the standard method. The optimum concn range of Zn2+ was 0.006-0.025 mM. In the standard method Zn2+ had no significant enhancing effect on the formation of competent SAC14235. Zn2+ had a greater affinity for EAC1423 than for fluid-phase C5 when reacted with each separately. Maximum enhancement, however, was obtained when Zn2+ was present during the reaction of C5 with EAC1423. The effect of Zn2+ on C5 activity was not related to the stabilizing property of C6 on cell-bound C5. In the washed-cell method there was an inverse relationship between the concn of C2 or C3 and the concn of C5 required to generate one competent SAC14235/cell. Over a 10-fold range of C2 or C3 concn there was an approximate four-fold increase in the number of competent SAC14235/cell formed in the presence of Zn2+. Zn2+ enhances formation of competent SAC14235 on cells that have a limited ability to activate C5 even though the C2 and C3 on the convertase are present in excess.

The effect of ethylenedinitrilotetraacetic acid (EDTA) on the reaction between the guinea-pig C5 convertase and guinea-pig C5.

Guinea-pig C5 was reacted with EAC1423 in the washed-cell intermediate assay in the presence of glucose gelatin veronal buffer (GGVB), Zn2+-GGVB (0.025 mM), GGVB2+ containing Ca2+ and/or Mg2+ or EDTA (0.013 M)-GGVB. The EDTA inhibited the formation of competent SAC14235, while Ca2+ and/or Mg2+ had a slight enhancing effect compared to GGVB alone and Zn2+ gave a four-fold increase. Similar results were obtained by using human C5 with guinea-pig C5 convertase and functionally pure guinea-pig C6, C7, C8 and C9. When guinea-pig C6 was incorporated into these various reaction mixtures with guinea-pig C5, its addition markedly reduced the inhibition by EDTA, while Zn2+ still showed an enhancing effect. These results demonstrate that EDTA inhibited formation of competent SAC14235 by preventing activation of C5. The association of C6 with C5 can partially overcome the inhibition of C5 conversion by EDTA and may account for C5 activity in reaction mixtures containing C-EDTA.

Carboplatin (JM8) as a single agent and in combination in the treatment of small cell lung cancer.

Carboplatin, a cisplatin analogue without significant nephrotoxicity, was used as a single agent in the treatment of 56 patients with small cell lung carcinoma at a dose of 300-400 mg/m2 i.v. monthly. Twenty-three patients (41%) achieved a response including 5 (9%) complete remissions. Eighteen (60%) of 30 previously untreated patients achieved a response. The drug was well tolerated with nausea or vomiting in only 43% of patients and no nephrotoxicity was seen. Myelosuppression was dose limiting and 39% of patients developed leukopenia. In a subsequent study carboplatin in a dose of 300 mg/m2 was used in combination with etoposide 100 mg/m2 i.v. days 1-3, repeating monthly for 4 courses. So far 32 (89%) of 36 evaluable patients have achieved a response. In patients with limited disease 20/23 patients (87%) have responded including 7 (30%) complete remissions. Leukopenia was dose limiting and occurred in 83% of patients. Carboplatin is a highly active new drug in the treatment of small cell lung cancer.

Phase II trial of procarbazine, vincristine and lomustine (POC) chemotherapy in metastatic cutaneous malignant melanoma.

40 patients with symptomatic metastatic melanoma were treated with procarbazine, vincristine and lomustine (POC). 4 patients had received chemotherapy previously. Responses were seen in 8 patients (20%), 4 of whom had a complete remission. All responding patients had some tumour shrinkage after one cycle. The median duration of response was 27 weeks, with 2 patients remaining in complete remission at 6 and 6.5 years. The median survival for the whole group was 22 weeks, whilst that of the responding patients was 35 weeks. Using conventional anti-emetics, the principal toxicities were nausea and vomiting, severe in 15% of cycles. Other nonhaematological toxicity was uncommon. Neutropenia (WHO grade 3 or 4) occurred in 11% of cycles and thrombocytopenia in 8%. The response rate of metastatic melanoma to POC chemotherapy was similar to other cytotoxic regimens though toxicity, other than nausea and vomiting, was minimal. The rapid response allows patients with unresponsive disease to be identified early, avoiding continuing toxicity.

Risk factors for early hospital readmission after cardiac operations.

OBJECTIVE: Early hospital readmissions after cardiac procedures are both costly and harmful to patients. We investigated the factors that predispose to readmission to develop strategies to minimize this problem. METHODS: As part of a prospective data collection, patients having cardiac procedures at our institution are routinely tracked for 30 days after their discharge from the hospital. We reviewed 2650 patients in our cardiac database who underwent operations over the past 5 years. We used univariate and multivariate statistical techniques to identify risks for readmission. RESULTS: Of 2574 discharged patients, 252 (9.8%) required readmission. The most common causes of readmission are cardiac (42%), pulmonary (19%), gastrointestinal (10%), extremity complications (6.7%; deep vein thrombophlebitis, peripheral arterial vascular disease, and saphenous vein harvest site problems), sternal wound problems (7.5%), and metabolic problems (4%). Of more than 70 variables studied, only 6 are significant multivariate predictors of readmission: female sex (P =.002); diabetes (P =.001); chronic lung problems (P =.011); increased distance between home and hospital (P >.001); preoperative atrial fibrillation (P =.002); and preoperative chronic renal insufficiency (P =.002). Type of operation, redo procedures, and other intraoperative and postoperative variables are not important multivariate predictors of readmission. Prolonged hospital length of stay for the initial procedure did not cause more frequent readmission. The costs of initial hospitalization (operating room costs combined with postoperative in-hospital costs) were not significantly increased in those patients who required readmission. CONCLUSIONS: The high-risk patient for readmission is a woman with diabetes, chronic lung disease, renal insufficiency, and preoperative atrial fibrillation who lives at a distance from the hospital. Readmission does not depend on periprocedural variables (eg, cardiopulmonary bypass time) or on postoperative complications. High procedural costs from the initial hospitalization do not predispose to readmission. These results suggest interventions that may reduce readmission.

Identification of RFamide neuropeptides in the medicinal leech.

Using a four-step reverse phase HPLC separation and RIA, five RFamide peptides were purified from CNS extracts of the leech Hirudo medicinalis. YMRFamide, FMRFamide, YLRFamide, FLRFamide, and GGKYMRFamide were identified by a combination of antiserum specificity in RIA, Edman degradation, and mass spectrometry. At least three of these five endogenous peptides can modulate neuromuscular interactions in the leech (38). FMRFamide-like immunoreactivity was selectively released from neural processes on isolated heart tubes in the presence of calcium and depolarizing levels of potassium.

High-dose cyclophosphamide with autologous bone marrow rescue after conventional chemotherapy in the treatment of small cell lung carcinoma.

Within an original consecutive series of 94 patients, 36 eligible patients with small cell lung carcinoma were treated with high-dose cyclophosphamide 7 g/m2 after conventional chemotherapy with VP16, adriamycin, and vincristine. The first 17 also underwent autologous bone marrow rescue. Treatment was well tolerated apart from one treatment-related death. Measurable tumour was still present in 15 patients before high-dose cyclophosphamide, and although 12 (80%) of these achieved further tumour response, these responses were all short-lived, with a median duration of 9 weeks. In 14 limited-disease patients already in complete remission before high-dose therapy the initial result was better, but 11 (79%) have now relapsed following overall median response duration of 10 months. High-dose cyclophosphamide after conventional chemotherapy is feasible and achieves a high response rate, but it does not appear to be associated with significant survival benefit either overall or in patient subgroup.

Phase I study of the cytotoxic agent N-[2-(dimethylamino)ethyl]acridine-4-carboxamide.

N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide (DACA) is a new DNA-intercalating drug with a dual mode of cytotoxic action that is thought to involve topoisomerases I and II. On the basis of novelty of action and promising preclinical activity against solid tumours in mice, DACA was selected for clinical trial under the auspices of the Cancer Research Campaign, United Kingdom. We report the phase I findings of a 3-h infusion regimen, repeated 3-weekly, of escalating doses through 18-1000 mg/m2 given to 31 patients with solid malignancies. A maximum tolerated dose (MTD) of 750 mg/m2 was identified, with 3 of 6 cycles being abandoned at 1000 mg/m2. Dose-limiting toxicity took the form of infusional arm pain, in some cases associated with facial discomfort, that was of rapid onset and subsided quickly on the cessation of infusion. The mechanism is unclear but is modulated to some extent by the rate of drug delivery, and it was unaffected in this study by concurrent anti-inflammatory or opiate medication. No host or tumour anti-proliferative activity was observed at these doses, and only minimal toxicity of any other kind was evident. Animal data suggest that the MTD achieved with this schedule may be sub-therapeutic in humans. It is therefore important that efforts be continued to explore methods of giving higher doses of DACA.

Plasma pharmacokinetics of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide in a phase I trial.

DACA [N-[2-(dimethylamino)ethyl]acridine-4-carboxamide] is an acridine derivative with high activity against solid tumours in mice and a dual mode of cytotoxic action involving topoisomerases I and II. The plasma pharmacokinetics of DACA were studied in 28 patients with solid tumours in a phase I trial. A single dose was given every 3 weeks, being escalated from a starting dose of 18 mg/m2 (as the dihydrochloride trihydrate salt) to a maximal dose, limited by severe pain in the infusion arm, of 1000 mg/m2. Drug was given by constant intravenous infusion with a target delivery period of 3 h. Blood samples were taken from the contralateral arm before, during and for up to 72 h after the infusion. DACA was separated from plasma by solid-phase extraction and was analysed by reversed-phase high-performance liquid chromatography (C18 column) using fluorescence detection. A two-compartment pharmacokinetic model provided the best fit for the concentration-time profiles obtained for most patients showing clearance of 1.00+/-0.36 l h(-1) kg(-1), a volume of distribution of the central compartment of 0.72+/-0.55 l/kg, an initial half-life of 0.28+/-0.19 h and a terminal half-life of 2.04+/-0.94 h. All pharmacokinetic parameters were independent of dose, indicating first-order kinetics. As DACA binds strongly to alpha1-acid glycoprotein, plasma concentrations of this protein were determined and used to estimate free-drug fractions in plasma. Estimated values for the free fraction varied from 0.9% to 3.3% and were lower than those determined by equilibrium dialysis for mice and rats (15% and 16%, respectively). At the maximum tolerated dose (MTD) of 750 mg/m2, the area under the drug concentration-time curve (AUC) was 46.2+/-4.4 microM h, exceeding that obtained in mice treated at the MTD (23.4 microM h). On the other hand, the corresponding free-drug AUC was 0.92+/-0.03 microM h, much lower than the corresponding value (3.5 microM h) determined for mice. These results suggest that free-drug rather than total drug concentrations are more appropriate for interspecies dose comparisons when significant differences exist in the free plasma fraction.

Metabolism of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide in cancer patients undergoing a phase I clinical trial.

N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide (DACA) is an experimental antitumour agent that has just completed phase I clinical trials in New Zealand and the United Kingdom. Urine (0-72 h) was analysed from 20 patients receiving DACA infused over 3 h (dose range 60-1000 mg/m2, the latter being the highest dose achieved in the trial). Aliquots were analysed for DACA and its metabolites by high-performance liquid chromatography (HPLC). Over 72 h, 44+/-5% (range 20-60%) of the dose was recovered in the urine, with 0.8+/-0.3% (range 0-3.1%) occurring as DACA. The major urinary metabolite was DACA-N-oxide-9(10H)acridone, accounting for 34+/-3% of the dose. Minor metabolites were identified as N-monomethyl-DACA-9(10H)acridone (2.0+/-0.5%), DACA-9(10H)acridone (3.3+/-0.5%), N-monomethyl-DACA (0.2+/-0.1%) and DACA-N-oxide (0.5+/-0.1%). No ring-hydroxylated metabolite was detected. The urinary excretion of metabolites was greatest over 0-6 h in most patients. The composition of urinary metabolites was also independent of the delivered dose. Plasma was sampled at intervals throughout the infusion and at time points up to 48 h post-administration. The major plasma metabolites observed were DACA-9(10H)acridone and DACA-N-oxide-9(10H)acridone. These results indicate that, based on urinary excreted metabolites, the major biotransformation reactions for DACA in humans involve N-oxidation of the tertiary amine side chain and acridone formation, both of which appear to be detoxication reactions.

Predictors of favorable outcome following naltrexone treatment.

In order to determine the type of patient most likely to benefit from opiate antagonist therapy, a series of multivariate regression analyses were performed on a sample of male veterans who completed induction on naltrexone. Patient background characteristics, demographic factors and during-treatment variables were used to predict outcome measured at 1-month follow-up. Employment at the start of naltrexone and length of naltrexone therapy were significantly related to better outcome at 1-month follow-up. Treatment duration was clearly the best outcome predictor. The finding that at least 30 days of naltrexone therapy was necessary for significant improvement at 1-month follow-up but that longer periods of treatment were not necessarily associated with greater gains suggests that treatment can be limited and still be relatively successful. A second set of analyses attempted to discover patient characteristics predictive of longer treatment duration. Results showed that patients who were employed and/or married at the start of naltrexone therapy were more likely to stay in treatment longer. Similar results have been obtained by others suggesting that these patients have the best family and social supports to sustain a positive treatment outcome. In addition, they may also be more 'motivated' since they have the most to lose personally and financially by readdiction.

Paraneoplastic cerebellar degeneration in a patient with chemotherapy-responsive ovarian cancer.

A 54-year-old female with small volume residual stage III ovarian cancer had received two courses of carboplatin chemotherapy with obvious response, when she developed rapidly progressive neurological symptoms. Over a period of 48 h, an incapacitating syndrome of ataxia, nystagmus and dysarthria evolved. Central nervous system metastases were excluded by computed tomography scanning and cerebrospinal fluid cytology. Anti-Purkinje cell antibodies ('anti-Yo') detected in the serum confirmed the diagnosis of paraneoplastic cerebellar degeneration. Isolated reports have suggested that the clinical course of this condition can be ameliorated with high dose steroids and plasmapheresis. However, in this case the very early introduction of both these did not bring about any improvement in the patient's symptoms. She remained severely incapacitated and unable to care for herself for the remaining 15 months of her life. The patient died of progressive ovarian cancer that had become clinically evident 10 months after the onset of neurological symptoms. This case illustrates many of the classical features of this rare condition, and the world literature is reviewed.

Survival of patients with primary fallopian tube carcinoma.

Vaughan MM, Evans BD, Weitzer MJ. Survival of patients with primary fallopian tube carcinoma. Int J Gynecol Cancer 1998; 8: 16-22. Thirty-seven patients with primary fallopian tube carcinoma (PFTC) presenting between 1952 and 1995 were studied. The mean age was 57 years. Seven patients had stage I disease, 20 stage II, 8 stage III, and 2 stage IV. Actuarial 5-year survivals were 73% for stage I, 33% for stage II and 0% for stage III. Stage was a significant predictor of survival at 5 years (Stage I vs. III, P = 0.0006; stage II vs. III, P = 0.0001), however, the majority of patients, even with early stage disease, died of progressive PFTC within 10 years. Grade appeared highly significant at 5 and 10 years (Grades 1 & 2 vs. 3, P = 0. 0023). Neither age nor lymphocytic infiltrate appeared definitely predictive of survival. Eleven of 22 stage II patients received adjuvant treatment. While their median and 5-year survivals were superior to those not receiving adjuvant treatment (51 vs. 30 months, 47% vs. 22%), the difference was not statistically significant. This retrospective analysis confirms the poor prognosis of patients with PFTC. The majority of patients, even with early stage tumors, eventually succumb to their disease. Larger studies may identify a group of patients potentially curable with surgery alone, and clarify the role of adjuvant therapy.

Carboplatin and chlorambucil combination chemotherapy as treatment for patients with ovarian cancer.

Fifty-six patients with ovarian cancer (three stage IC, nine stage II, 33 stage III and II stage IV) were treated with carboplatin 350 mg m-2 i.v. day 1 and chlorambucil orally 0.15 mg kgm-1 days 1-7 inclusive, repeated every 28 days for eight courses. The regimen was well tolerated and was virtually free of nephro- and neurotoxicity. Grade III or IV hematology toxicity occurred in 18 patients but only 31 or 330 courses administered were delayed. Of 40 assessable patients eight achieved a clinical/radiologic complete response and 17 a clinical/radiologic partial response. Actuarial survival at 50 months was 65% for stage II patients, 27% for stage III patients and no stage IV patients survived beyond 20 months. Forty-two per cent of patients with residual disease less 2 cm survived 50 months, compared with 44% of patients with moderate volume (2-5 cm) residual disease and 6% of patients with bulk residual disease. This is an active, well tolerated regimen. However, only patients with small volume residual disease have a significant chance of prolonged survival.

Ductography is a useful technique in evaluation of abnormal nipple discharge.

The purpose of this study was to evaluate the utility of ductography, or galactography, in identifying ductal abnormalities in patients presenting with abnormal nipple discharge and to correlate these findings with pathologic results. Abnormal nipple discharge was defined as either bloody or testing positive for occult blood. Milky discharge (galactorrhea) was not evaluated. From July 1992 to June 1994, a total of 43 women presented to the UCLA Breast Center with complaints of abnormal nipple discharge. Mean age of the patients was 54.9 years. All patients underwent technically adequate ductography. A total of 25 patients then underwent 26 excisional biopsies for abnormal ductographic findings. Surgery was usually simplified by the appropriate ductal injection of methylene blue immediately preoperatively. No complications from the procedure were identified. Pathologic entities were correlated with ductographic findings. Ductography identified ductal abnormalities in 33/45 (73%) of ductograms. Filling defects were noted in 19/45 (42%) of ductograms, ductal dilatation in 3/45 (7%), both filling defects and dilatation were noted in 11/45 (24%) of ductograms, and 12/45 (27%) were normal ductograms. Pathologically, ductographic anomalies correlated well with histologic findings. We conclude that ductography is an effective and safe means of identifying ductal abnormalities in patients with abnormal breast discharge. A high incidence of benign intraductal papilloma and a moderate risk of cancer and precancerous lesions were identified. We believe that patients with abnormal nipple discharge should undergo routine ductography and dye localization before surgery.