The Long-Term Benefit of Liver Transplantation for Hepatic Metastases From Neuroendocrine Tumors.

Selection criteria and benefit of liver transplantation for hepatic metastases from neuroendocrine tumors (NETs) remain uncertain. Eighty-eight consecutive patients with metastatic NETs eligible for liver transplantation according to Milan-NET criteria were offered transplant (n = 42) versus nontransplant options (n = 46) depending on list dynamics, patient disposition, and age. Tumor burden between groups did not differ. Transplant patients were younger (40.5 vs. 55.5 years; p < 0.001). Long-term outcomes were compared after matching between groups made on multiple Cox models adjusted for propensity score built on logistic models. Survival benefit was the difference in mean survival between transplant versus nontransplant options. No patients were lost or died without recurrence. Median follow-up was 122 months. The transplant group showed a significant advantage over nontransplant strategies at 5 and 10 years in survival (97.2% and 88.8% vs. 50.9% and 22.4%, respectively; p < 0.001) and time-to-progression (13.1% and 13.1% vs. 83.5% and 89%; p < 0.001). After adjustment for propensity score, survival advantage of the transplant group was significant (hazard ratio = 7.4; 95% confidence interval (CI): 2.4-23.0; p = 0.001). Adjusted transplant-related survival benefit was 6.82 months (95% CI: 1.10-12.54; p = 0.019) and 38.43 months (95% CI: 21.41-55.45; p < 0.001) at 5 and 10 years, respectively. Liver transplantation for metastatic NETs under restrictive criteria provides excellent long-term outcome. Transplant-related survival benefit increases over time and maximizes after 10 years.

Radioembolization of hepatocarcinoma with (90)Y glass microspheres: development of an individualized treatment planning strategy based on dosimetry and radiobiology.

PURPOSE: The aim of this study was to optimize the dosimetric approach and to review the absorbed doses delivered, taking into account radiobiology, in order to identify the optimal methodology for an individualized treatment planning strategy based on (99m)Tc-macroaggregated albumin (MAA) single photon emission computed tomography (SPECT) images. METHODS: We performed retrospective dosimetry of the standard TheraSphere® treatment on 52 intermediate (n = 17) and advanced (i.e. portal vein thrombosis, n = 35) hepatocarcinoma patients with tumour burden < 50% and without obstruction of the main portal vein trunk. Response was monitored with the densitometric radiological criterion (European Association for the Study of the Liver) and treatment-related liver decompensation was defined ad hoc with a time cut-off of 6 months. Adverse events clearly attributable to disease progression or other causes were not attributed to treatment. Voxel dosimetry was performed with the local deposition method on (99m)Tc-MAA SPECT images. The reconstruction protocol was optimized. Concordance of (99m)Tc-MAA and (90)Y bremsstrahlung microsphere biodistributions was studied in 35 sequential patients. Two segmentation methods were used, based on SPECT alone (home-made code) or on coregistered SPECT/CT images (IMALYTICS™ by Philips). STRATOS™ absorbed dose calculation was validated for (90)Y with a single time point. Radiobiology was used introducing other dosimetric variables besides the mean absorbed dose D: equivalent uniform dose (EUD), biologically effective dose averaged over voxel values (BEDave) and equivalent uniform biologically effective dose (EUBED). Two sets of radiobiological parameters, the first derived from microsphere irradiation and the second from external beam radiotherapy (EBRT), were used. A total of 16 possible methodologies were compared. Tumour control probability (TCP) and normal tissue complication probability (NTCP) were derived. The area under the curve (AUC) of the receiver-operating characteristic (ROC) curve was used as a figure of merit to identify the methodology which gave the best separation in terms of dosimetry between responding and non-responding lesions and liver decompensated vs non-decompensated liver treatment. RESULTS: MAA and (90)Y biodistributions were not different (71% of cases), different in 23% and uncertain in 6%. Response correlated with absorbed dose (Spearman's r from 0.48 to 0.69). Responding vs non-responding lesion absorbed doses were well separated, regardless of the methodology adopted (p = 0.0001, AUC from 0.75 to 0.87). EUBED gave significantly better separation with respect to mean dose (AUC = 0.87 vs 0.80, z = 2.07). Segmentation on SPECT gave better separation than on SPECT/CT. TCP(50%) was at 250 Gy for small lesion volumes (<10 cc) and higher than 1,000 Gy for large lesions (>10 cc). Apparent radiosensitivity values from TCP were around 0.003/Gy, a factor of 3-5 lower than in EBRT, as found by other authors. The dose-rate effect was negligible: a purely linear model can be applied. Toxicity incidence was significantly larger for Child B7 patients (89 vs 14%, p < 0.0001), who were therefore excluded from dose-toxicity analysis. Child A toxic vs non-toxic treatments were significantly separated in terms of dose averaged on whole non-tumoural parenchyma (including non-irradiated regions) with AUC from 0.73 to 0.94. TD50 was ≈ 100 Gy. No methodology was superior to parenchyma mean dose, which therefore can be used for planning, with a limit of TD15 ≈ 75 Gy. CONCLUSION: A dosimetric treatment planning criterion for Child A patients without complete obstruction of the portal vein was developed.

A dosimetric treatment planning strategy in radioembolization of hepatocarcinoma with 90Y glass microspheres.

AIM: Our goal was to limit liver toxicity and to obtain good efficacy by developing a dosimetric treatment planning strategy. While several dosimetric evaluations are reported in literature, the main problem of the safety of the treatment is rarely addressed. Our work is the first proposal of a treatment planning method for glass spheres, including both liver toxicity and efficacy issues. METHODS: Fifty-two patients (series 1) had been treated for intermediated/advanced hepatocellular carcinoma (HCC) with glass spheres, according to the Therasphere® prescription of 120 Gy averaged on the injected lobe. They were retrospectively evaluated with voxel dosimetry, adopting the local deposition hypothesis. Regions of interest on tumor and non tumor parenchyma were drawn to determine the parenchyma absorbed dose, averaged also on non irradiated voxels, excluding tumor voxels. The relationship between the mean non tumoral parenchyma absorbed dose D and observed liver decompensation was analyzed. RESULTS: Basal Child-Pugh strongly affected the toxicity incidence, which was 22% for A5, 57% for A6, 89% for B7 patients. Restricting the analysis to our numerically richest class (basal Child-Pugh A5 patients), D median values were significantly different between toxic (median 90 Gy) and non toxic treatments (median 58 Gy) at a Mann-Withney test, (P=0.033). Using D as a marker for toxicity, the separation of the two populations in terms of area under ROC curve was 0.75, with 95% C.I. of [0.55-0.95]. The experimental Normal Tissue Complication Probability (NTCP) curve as a function of D resulted in the following values: 0%, 14%, 40%, 67% for D interval of [0-35] Gy, [35-70] Gy, [70-105] Gy, [105-140] Gy. DISCUSSION: A limit of about 70 Gy for the mean absorbed dose to parenchyma was assumed for A5 patients, corresponding to a 14% risk of liver decompensation. This result is applicable only to our administration conditions: glass spheres after a decay interval of 3.75 days. Different safety limit (40 Gy) are published for resin spheres, characterized by higher number of particle per GBq (more uniform irradiation, bigger biological effect for the same absorbed dose). CONCLUSION: As result of this study we suggest a constraint of about 70 Gy mean absorbed dose to liver non tumoral parenchyma, corresponding to about 15% probability of radioinduced liver decompensation while still aiming at achieving an absorbed of several hundreds of Gy to lesions.

Need, feasibility and convenience of dosimetric treatment planning in liver selective internal radiation therapy with (90)Y microspheres: the experience of the National Tumor Institute of Milan.

In most centres, the choice of the optimal activity to be administered in selective intra-arterial radioembolization with microspheres is nowadays based on empirical models which do not take into account the evaluation of tumour and non tumour individual absorbed dose, despite plenty of published data which showed that local efficacy is correlated to tumour absorbed dose, and that the mean absorbed dose is a toxicity risk factor. A pitfall of the crudest, empirical tumour involvement method are 20 deaths in a single centre which adopted it to administer the whole liver, or the need of systematic 25% subjective reduction of activity prescribed with body surface area method. In order to develop a possibly safer and more effective strategy based on real individual dosimetry, we examine first external beam liver radiation therapy results. The half century experience has something to be borrowed: the volume effect, according to which the smaller the fraction of the irradiated liver volume, the higher the tolerated dose. Different tolerance for different underlying disease or previous non radiation treatment is to be expected. Radiobiological models experience also has to be inherited, but not their dose reference values. Then we report the published dosimetric experience about (90)Y microsphere radioembolization of primary and metastatic liver tumours. In addition we also present original data from our growing preliminary experience of more refined (99m)Tc MAA SPECT based calculations in hepatocarcinoma patients. This overcame the mean dose approach in favour of the evaluation of dose distribution at voxel level. An insight into dosimetry issues at microscopic level (lobule level) is also provided, from which the different radiobiological behaviour between resin and glass spheres can be understood. For tumour treatment, an attenuation corrected (99m)Tc- SPECT based treatment planning strategy can be proposed, although quantitative efficacy thresholds should be differentiated according to the kind of pathology and previous treatment. For non tumour liver parenchyma, data in favour of a relationship between absorbed dose and dangerous effects are encouraging. Unfortunately in hepato-cellular carcinoma, some confounding factors may hamper the adequate estimation of the risk of toxicity. First there is a lack of consensus about the exact definition of toxicity after (90)Y microsphere radioembolization. Second, for HCC patients, progression of both cancer and cirrhosis can simulate a radioinduced toxicity, making the analysis more complex.

Biology, prognosis and response to therapy of breast carcinomas according to HER2 score.

BACKGROUND: The standardization of the HER2 score and recent changes in therapeutic modalities points to the need for a reevaluation of the role of HER2 in recently diagnosed breast carcinoma. PATIENTS AND METHODS: A multicenter, retrospective study of 1794 primary breast carcinomas diagnosed in Italy in 2000/2001 and scored in HER2 four categories according to immunohistochemistry was conducted. RESULTS: Ductal histotype, vascular invasion, grade, MIB1 positivity, estrogen and progesterone receptor expression differed significantly in HER2 3+ tumors compared with the other categories. HER2 2+ tumors almost showed values intermediate between those of the negative and the 3+ subgroups. The characteristics of HER2 1+ tumors were found to be in between those of HER2 0 and 2+ tumors. With a median follow-up of 54 months, HER2 3+ status was associated with higher relapse rates in node-positive and node-negative subgroups, while HER2 2+ only in node positive. Analysis of relapses according to type of therapy provided evidence of responsiveness of HER2-positive tumors to chemotherapy, especially taxanes. CONCLUSIONS: The present prognostic significance of HER2 is correlated to receptor expression level and points to the need to consider HER2 2+ and HER2 3+ tumors as distinct diseases with different outcomes and specific features.

Fifteen-year results of a randomized phase III trial of fenretinide to prevent second breast cancer.

PURPOSE: The synthetic retinoid fenretinide administered for 5 years for prevention of second breast cancer showed no difference after a median of 8 years, but a possible reduction in premenopausal women. We conducted a long-term analysis in a subgroup of women who were regularly followed up in a single center. PATIENTS AND METHODS: We analyzed data after a median follow-up of 14.6 years (IQ range, 12.3-16.3 years) from 1739 women aged 30-70 (872 in the fenretinide arm and 867 in the observation arm), representing 60% of the initial cohort of 2867 women. The main efficacy endpoint was second primary breast cancer (contralateral or ipsilateral). RESULTS: The number of second breast cancers was 168 in the fenretinide arm and 190 in the control arm (hazard ratio = 0.83, 95% CI, 0.67-1.03). There were 83 events in the fenretinide arm and 126 in the observation arm in premenopausal women (HR = 0.62, 95% CI, 0.46-0.83), and 85 and 64 events in postmenopausal women (HR = 1.23, 95% CI, 0.63-2.40). The younger were the women, the greater was the risk reduction associated with fenretinide, which attained 50% in women aged 40 years or younger and disappeared after age 55 (P-age*treatment interaction = 0.023). There was no difference in cancers in other organs, distant metastases or survival. CONCLUSIONS: Fenretinide induces a significant risk reduction of second breast cancer in premenopausal women, which is remarkable at younger ages, and persists several years after treatment cessation. Since adverse events are limited, a trial in young women at high-risk is warranted.

Clinical and dermatoscopic diagnosis of early amelanotic melanoma.

Amelanotic cutaneous melanoma (ACM) often defies clinical diagnosis because of the lack of pigmentation. In an attempt to find diagnostic clues, we retrospectively studied the clinical features of 15 thin (< 1 mm thick or Clark level I) ACM lesions. The clinical features of early ACMs are identified and illustrated to enable early diagnosis and cure of these lesions. The typical early lesion presents as an asymmetric macula, which may be uniformly pinkish or reddish or, more often, has faint light pigmentation (tan, brown or grey) at the periphery; it has borders that may be well- or ill-defined. In our study, these features suggested the correct clinical diagnosis in only a minority (40%) of cases. Nine cases in this series were also subjected to dermatoscopy. By this technique we identified, as constant feature, the presence of small red dots, evenly distributed or grouped on a whitish or pink-red background. Our results show the importance of dermatoscopy in the evaluation of equivocal pink or reddish lesions. Red dots seen with this technique can be an important sign for the diagnosis of thin ACM. Since this sign does not appear to be pathognomonic, the presence of an associated pigmentary network can be decisive in the differential diagnosis.

Long-term effects of fenretinide, a retinoic acid derivative, on the insulin-like growth factor system in women with early breast cancer.

High insulin-like growth factor-I (IGF-I) levels are associated with an increased risk of breast cancer in premenopausal women. Because the synthetic retinoid fenretinide showed a beneficial effect on second breast cancers in premenopausal women in a Phase III trial, we studied its long-term effects on IGF-I levels. We measured, at yearly intervals for up to 5 years, the circulating levels of IGF-I, IGF binding protein (BP)-3, and their molar ratio in 60 subjects < or = 50 years of age and 60 subjects > 50 years of age allocated either to fenretinide or no treatment. In women < or = 50 years of age, measurements of IGF-II, IGFBP-1, and IGFBP-2 were also performed. The associations between biomarkers and drug or metabolite plasma concentrations were also investigated. All biomarkers were relatively stable over 5 years in the control group. Compared with controls and after adjustment for baseline, treatment with fenretinide for 1 year induced the following changes: IGF-I, -13% [95% confidence interval (CI), -25 to 1%] in women < or = 50 years of age and -3% (95% CI, -16 to 13%) in women > 50 years of age; IGFBP-3, -4% (95% CI, -12 to 6%) in both age groups; IGF-I:IGFBP-3 molar ratio, -11% (95% CI, -22 to 1%) in women < or = 50 years of age and 1% (95% CI, -11 to 16%) in women > 50 years of age. These effects were apparently maintained for up to 5 years, although fewer samples were available as time progressed. No change in other IGF components was observed. Drug and metabolite concentrations were negatively correlated with IGF-I and IGF-I:IGFBP-3 molar ratio in women < or = 50 years of age. Fenretinide induces a moderate decline of IGF-I levels in women < or = 50 years of age. The association between IGF-I change and the reduction of second breast cancers in premenopausal women warrants further study.

Chemoprevention of breast cancer with fenretinide.

Chemoprevention of cancer represents a challenge for oncology during this new millennium. Substantial advances have been accomplished in the last decade, especially for primary and secondary prevention of breast cancer. In addition to tamoxifen, raloxifene and other selective estrogen receptor modulators, retinoids are among the most promising agents, given their ability to inhibit mammary carcinogenesis in preclinical models. Fenretinide, the synthetic amide of retinoic acid, inhibits cell growth mostly through the induction of apoptosis with mechanisms which may partly involve the retinoid receptors. Because it has a favourable toxicological profile, fenretinide has been extensively investigated in clinical trials. A large randomised phase III trial for secondary breast cancer prevention has been recently carried out in Italy. Results showed a reduction of second breast malignancies in premenopausal women. In addition, a significant decrease of circulating insulin-like growth factor (IGF)-1, a known risk factor for premenopausal breast cancer, was observed after 1 year of fenretinide administration in premenopausal women with breast cancer. Ongoing studies on the validation of the circulating IGF-1 as a surrogate endpoint biomarker of fenretinide activity and on the effectiveness of the combination with low dose tamoxifen may provide further insight into the future clinical application of fenretinide.

Safety of the synthetic retinoid fenretinide: long-term results from a controlled clinical trial for the prevention of contralateral breast cancer.

PURPOSE: To describe the pattern of occurrence of adverse events commonly arising during treatment with fenretinide, a synthetic retinoid under investigation for cancer prevention. PATIENTS AND METHODS: The series includes 2,867 women accrued in a trial aimed at assessing the effect of fenretinide on the prevention of second breast malignancy. Women were randomly assigned to receive no treatment (1,435 patients) or 5-year fenretinide treatment (1,432 patients). In terms of disease recurrence in the breast, the trial showed a possible beneficial effect of the compound in premenopausal women, and an opposite trend in postmenopausal women. End points considered for safety assessment were the occurrence of diminished dark adaptation, dermatologic disorders, gastrointestinal symptoms, disorders of the ocular surface, and abnormal laboratory values. RESULTS: The most common adverse events were diminished dark adaptation (cumulative incidence, 19.0%) and dermatologic disorders (18.6%). Less common events were gastrointestinal symptoms (13.0%) and disorders of the ocular surface (10.9%). In comparison, incidence figures in the control arm were 2.9% for diminished dark adaptation, 2.9% for dermatologic disorders, 5.4% for gastrointestinal symptoms, and 3.2% for disorders of the ocular surface. Symptoms occurring during fenretinide treatment tended to recover with time. No between-group difference was observed for the occurrence of laboratory data abnormalities. Overall, 63 (4.4%) treatment discontinuations were caused by adverse events. CONCLUSION: Given the number of patients involved in the study and the prolonged intake of the drug, the experience on fenretinide tolerability can be considered sufficiently reassuring to justify further testing of the retinoid.

Accrual issues for chemoprevention trials: the example of the 4-HPR study for the prevention of contralateral breast cancer.

This paper describes the accrual of the controlled clinical trial with fenretinide for the prevention of contralateral breast cancer. Accrual screened 4,030 potentially eligible patients of whom 1,815 were randomized. Two strategies of recruitment were used, i.e. retrospective and prospective. In the retrospective accrual, the medical staff reviewed the records of breast cancer patients who had received curative surgery to select those who fulfilled the eligibility criteria of the study. For the prospective recruitment operated, patients were contacted after the beginning of the trial. The study started in March 1987 and accrual closed on July 31, 1993. The planned accrual period was extended by 19 months. The yearly accrual tended to decrease with time. This was mainly due to the end of the retrospective recruitment and to the introduction of adjuvant chemotherapy, a reason for exclusion from the trial, also for patients with negative axillary nodes. The known accrual difficulties of chemoprevention studies proved also to be true for the high-risk population of this trial.

Randomized trial of fenretinide to prevent second breast malignancy in women with early breast cancer.

BACKGROUND: Fenretinide, a vitamin A analogue, has been shown to inhibit breast carcinogenesis in preclinical studies. We determined the efficacy of fenretinide in preventing a second breast malignancy in women with breast cancer. METHODS: We randomly assigned 2972 women, aged 30-70 years, with surgically removed stage I breast cancer or ductal carcinoma in situ to receive for 5 years either fenretinide orally (200 mg/day) or no treatment. The primary end point was the incidence of contralateral breast cancer or ipsilateral breast cancer 7 years after randomization. Other end points considered post hoc were the same outcomes stratified by menopausal status, incidence of distant metastases, overall mortality, and tumors in other organs. The hazards of breast cancer occurrence were determined by Cox proportional hazards regression analysis. Statistical tests were two-sided. RESULTS: At a median observation time of 97 months, there were no statistically significant differences in the occurrence of contralateral breast cancer (P =.642) or ipsilateral breast cancer (P =.177) between the two arms. However, an interaction was detected between fenretinide treatment and menopausal status in both outcomes (P for interaction in both outcomes =.045), with a possible beneficial effect in premenopausal women (contralateral breast cancer: adjusted hazard ratio [HR] = 0.66, and 95% confidence interval [CI] = 0.41-1.07; ipsilateral breast cancer: adjusted HR = 0.65, and 95% CI = 0.46-0. 92) and an opposite effect in postmenopausal women (contralateral breast cancer: adjusted HR = 1.32, and 95% CI = 0.82-2.15; ipsilateral breast cancer: adjusted HR = 1.19, and 95% CI = 0.75-1. 89). There were no statistically significant differences between the two arms in tumors in other organs, incidence of distant metastasis, and all-cause mortality. CONCLUSIONS: Fenretinide treatment of women with breast cancer for 5 years appears to have no statistically significant effect on the incidence of second breast malignancies overall, although a possible benefit was detected in premenopausal women. These studies, particularly the post hoc analyses, are considered exploratory and need to be confirmed.

Small melanomas: a clinical study on 270 consecutive cases of cutaneous melanoma.

The ABCD (asymmetry, border, colour, dimension) criteria represent a commonly used clinical guide for the diagnosis of early cutaneous melanoma (CM). This guide stipulates that CMs usually are more than 6 mm in diameter. The purpose of this retrospective study was to establish the frequency of occurrence of small (< or =6 mm) melanomas in a clinical context. Our series consisted of 270 consecutive CMs (39 in situ and 231 invasive) in 267 patients. Of these 270 lesions, 47 (17%) were small lesions, ranging from 2 to 6 mm in maximum linear extent, with a median value of 5 mm. Of these small lesions, 14 were in situ and 33 Invasive CMs. The median thickness of the 33 small invasive lesions was 0.31 mm. The clinical features of CMs were sufficiently distinctive to suggest a diagnosis of CM in half of the cases, irrespective of the invasiveness or not of the lesions. Dermatoscopy was performed on 36 of the small lesions and achieved a correct diagnosis in 72% of the cases. The combination of simple visual examination with dermatoscopy allowed a higher rate of recognition (86%) than when the two methods were considered separately. Results of our study show that small CMs represent a considerable clinical subset of all CMs. Clinicians must be aware of this fact in their diagnostic activity.

Chemoprevention trial of contralateral breast cancer with fenretinide. Rationale, design, methodology, organization, data management, statistics and accrual.

The Fenretinide (4-HPR) Breast Cancer Study is a randomized multicenter clinical trial originally designed and conducted by the investigators of the Istituto Nazionale Tumori of Milan. The study is sponsored by the National Cancer Institute of Bethesda and by the Italian National Research Council. The trial was designed to evaluate the effectiveness of the synthetic retinoid 4-HPR, at a dose of 200 mg per os every day for 5 years, in reducing the incidence of contralateral breast cancer in a population of patients previously operated on for breast cancer. Between 1987 and 1993, the Istituto Nazionale Tumori of Milan and 9 other collaborating Centers enrolled 2,972 women between the ages of 30 and 70 years who had been previously operated on for T1-T2 N- M0 breast cancer. This paper describes the rationale, design, methodology, organization, data management, statistics and accrual of the participating population.

Chemoprevention of breast cancer with fenretinide (4-HPR): study of long-term visual and ophthalmologic tolerability.

BACKGROUND: Fenretinide (4-HPR) is a synthetic retinoid being clinically tested in the chemoprevention of different tumors and precancerous lesions. Though safer than many other retinoids in experimental models, in humans 4-HPR may induce adverse effects that mainly affect the eye and visual function. Such effects are thought to be caused by the reduction of plasma retinol levels, which occurs after administration of the retinoid. METHODS: A series of 826 women treated with 4-HPR was studied to quantify the incidence and temporal pattern of occurrence of visual (dark adaptation) and ophthalmologic complaints (ocular dryness, lacrimation, conjunctivitis or photophobia) and to investigate the possible association between their occurrence and plasma retinol levels. RESULTS: The cumulative incidence of visual complaints reached nearly 20% at 5 years. The occurrence of these symptoms was more frequent at the start of treatment. The probability of developing visual complaints was significantly higher in patients with lower plasma retinol concentrations following 4-HPR treatment. The cumulative incidence of ophthalmologic complaints was 8% at 5 years. The occurrence of these complaints was evenly distributed during treatment. Ophthalmologic complaints were not associated with a greater degree of reduction of plasma retinol concentrations, but rather with the patient's age, since symptomatic patients were generally older than asymptomatic patients. CONCLUSIONS: Visual and ophthalmologic complaints are common during 4-HPR treatment; their estimated 5-year cumulative incidence is close to 20% and 8%, respectively. However, the pattern of occurrence over time and the underlying mechanisms of these two types of complaints seem different.

Controlled clinical trials with fenretinide in breast cancer, basal cell carcinoma and oral leukoplakia.

We are conducting three randomized studies (breast cancer, basal cell carcinoma, oral leukoplakia) and report our methodological approach and accrual here. The aim of the breast cancer study is prevention of a contralateral primary lesion in women already treated for breast cancer; the aim of the basal cell carcinoma study is prevention of recurrences or new occurrence after surgical resection; and the aim of the oral leukoplakia study is prevention of recurrences and new occurrence after CO2 laser resection. The studies were planned according to a randomized design with an intervention arm vs a no-treatment arm. Patients in the intervention group receive 4-HPR at a dose of 200 mg po. The duration of treatment is five years in the breast cancer study, and one year in the basal cell carcinoma and oral leukoplakia studies. The breast cancer study started in March 1987, closing accrual on July 31, 1993. A total of 2,972 patients entered the study; 2,849 were evaluable (1,422 in the 4-HPR group and 1,427 in the control group). Of 2,849 evaluable patients, 867 completed the first five years, 1,142 are still ongoing, and 840 patients have interrupted the study for various reasons. Follow-up is ongoing. The basal cell carcinoma study started in January 1990. As of January 1994, a total of 786 patients had entered the study; 760 were evaluable (363 in the 4-HPR group and 367 in the control group). Of 760 patients in the study, 568 completed the first year, 62 are ongoing and 130 discontinued for various reasons. The study is ongoing.(ABSTRACT TRUNCATED AT 250 WORDS)

Behavior of some steroids in endometrial adenomatous and atypical hyperplasia.

Endometrial adenomatous and atypical hyperplasia are the histopathological pictures that more frequently may develop into an adenocarcinoma. It is believed that a hormonal action may favour the genesis of endometrial cancer. We studied the plasmatic levels of some steroids, considered to be responsible for neoplastic changes, in patients with adenomatous and atypical hyperplasia. With this object we measured plasmatic levels of estrone, estradiol, androstenedione, DHEA-S and testosterone in postmenopausal patients with adenomatous and atypical hyperplasia and in fertile women, both in proliferative and secretory phases. We didn't find any difference in the steroid pattern in the two groups.