Prognostic impact of baseline tumour immune infiltrate on disease-free survival in patients with completely resected, BRAFv600 mutation-positive melanoma receiving adjuvant vemurafenib.

BACKGROUND: We conducted a retrospective exploratory analysis to evaluate the effects of baseline tumour immune infiltrate on disease-free survival (DFS) outcomes in patients with fully resected stage IIC-IIIC melanoma receiving adjuvant vemurafenib monotherapy or placebo in the BRIM8 study. PATIENTS AND METHODS: BRIM8 was a phase III, international, double-blind, randomised, placebo-controlled study. Eligible patients with BRAFV600 mutation-positive, completely resected melanoma were randomly assigned to oral vemurafenib (960 mg twice daily) or matching placebo for 52 weeks. The primary end point was DFS. The association of CD8+ T-cell infiltration and programmed death ligand 1 (PD-L1) expression with DFS, as measured by immunohistochemistry, was explored retrospectively. RESULTS: Four hundred ninety-eight patients were randomly assigned to receive adjuvant vemurafenib (n = 250) or placebo (n = 248); tumour samples were available for biomarker analysis for approximately 60% of patients. In the pooled biomarker population, placebo-treated patients with <1% CD8+ T cells in the tumour centre had shorter median DFS than those with ≥1% CD8+ T cells (7.7 versus 47.8 months). DFS benefit from vemurafenib versus placebo was greater in patients with <1% CD8+ T cells [hazard ratio (HR) 0.56; 95% confidence interval (CI) 0.34-0.92) than in patients with ≥1% CD8+ T cells (HR 0.77; 95% CI 0.48-1.22). Likewise, median DFS was shorter among placebo-treated patients with <5% versus ≥5% PD-L1+ immune cells (IC) in the tumour (7.2 versus 47.8 months). A greater DFS benefit with vemurafenib versus placebo was observed in patients with <5% PD-L1+IC (HR 0.36; 95% CI 0.24-0.56) than in patients with ≥5% PD-L1+IC (HR 0.99; 95% CI 0.58-1.69). CONCLUSIONS: The presence of CD8+ T cells and PD-L1+IC are favourable prognostic factors for DFS. Treatment with adjuvant vemurafenib may overcome the poor DFS prognosis associated with low CD8+ T-cell count or PD-L1 expression. CLINICALTRIALS. GOV IDENTIFIER: NCT01667419.

Measures of body fatness and height in early and mid-to-late adulthood and prostate cancer: risk and mortality in The Pooling Project of Prospective Studies of Diet and Cancer.

BACKGROUND: Advanced prostate cancer etiology is poorly understood. Few studies have examined associations of anthropometric factors (e.g. early adulthood obesity) with advanced prostate cancer risk. PATIENTS AND METHODS: We carried out pooled analyses to examine associations between body fatness, height, and prostate cancer risk. Among 830 772 men, 51 734 incident prostate cancer cases were identified, including 4762 advanced (T4/N1/M1 or prostate cancer deaths) cases, 2915 advanced restricted (same as advanced, but excluding localized cancers that resulted in death) cases, 9489 high-grade cases, and 3027 prostate cancer deaths. Cox proportional hazards models were used to calculate study-specific hazard ratios (HR) and 95% confidence intervals (CI); results were pooled using random effects models. RESULTS: No statistically significant associations were observed for body mass index (BMI) in early adulthood for advanced, advanced restricted, and high-grade prostate cancer, and prostate cancer mortality. Positive associations were shown for BMI at baseline with advanced prostate cancer (HR = 1.30, 95% CI = 0.95-1.78) and prostate cancer mortality (HR = 1.52, 95% CI = 1.12-2.07) comparing BMI ≥35.0 kg/m2 with 21-22.9 kg/m2. When considering early adulthood and baseline BMI together, a 27% higher prostate cancer mortality risk (95% CI = 9% to 49%) was observed for men with BMI <25.0 kg/m2 in early adulthood and BMI ≥30.0 kg/m2 at baseline compared with BMI <25.0 kg/m2 in early adulthood and BMI <30.0 kg/m2 at baseline. Baseline waist circumference, comparing ≥110 cm with <90 cm, and waist-to-hip ratio, comparing ≥1.00 with <0.90, were associated with significant 14%-16% increases in high-grade prostate cancer risk and suggestive or significant 20%-39% increases in prostate cancer mortality risk. Height was associated with suggestive or significant 33%-56% risks of advanced or advanced restricted prostate cancer and prostate cancer mortality, comparing ≥1.90 m with <1.65 m. CONCLUSION: Our findings suggest that height and total and central adiposity in mid-to-later adulthood, but not early adulthood adiposity, are associated with risk of advanced forms of prostate cancer. Thus, maintenance of healthy weight may help prevent advanced prostate cancer.

The Two-Brains Hypothesis: Towards a guide for brain-brain and brain-machine interfaces.

Great advances have been made in signaling information on brain activity in individuals, or passing between an individual and a computer or robot. These include recording of natural activity using implants under the scalp or by external means or the reverse feeding of such data into the brain. In one recent example, noninvasive transcranial magnetic stimulation (TMS) allowed feeding of digitalized information into the central nervous system (CNS). Thus, noninvasive electroencephalography (EEG) recordings of motor signals at the scalp, representing specific motor intention of hand moving in individual humans, were fed as repetitive transcranial magnetic stimulation (rTMS) at a maximum intensity of 2.0[Formula: see text]T through a circular magnetic coil placed flush on each of the heads of subjects present at a different location. The TMS was said to induce an electric current influencing axons of the motor cortex causing the intended hand movement: the first example of the transfer of motor intention and its expression, between the brains of two remote humans. However, to date the mechanisms involved, not least that relating to the participation of magnetic induction, remain unclear. In general, in animal biology, magnetic fields are usually the poor relation of neuronal current: generally "unseen" and if apparent, disregarded or just given a nod. Niels Bohr searched for a biological parallel to complementary phenomena of physics. Pertinently, the two-brains hypothesis (TBH) proposed recently that advanced animals, especially man, have two brains i.e., the animal CNS evolved as two fundamentally different though interdependent, complementary organs: one electro-ionic (tangible, known and accessible), and the other, electromagnetic (intangible and difficult to access) - a stable, structured and functional 3D compendium of variously induced interacting electro-magnetic (EM) fields. Research on the CNS in health and disease progresses including that on brain-brain, brain-computer and brain-robot engineering. As they grow even closer, these disciplines involve their own unique complexities, including direction by the laws of inductive physics. So the novel TBH hypothesis has wide fundamental implications, including those related to TMS. These require rethinking and renewed research engaging the fully complementary equivalence of mutual magnetic and electric field induction in the CNS and, within this context, a new mathematics of the brain to decipher higher cognitive operations not possible with current brain-brain and brain-machine interfaces. Bohr may now rest.

Electromagnetic induction between axons and their schwann cell myelin-protein sheaths.

Two concepts have long dominated vertebrate nerve electrophysiology: (a) Schwann cell-formed myelin sheaths separated by minute non-myelinated nodal gaps and spiraling around axons of peripheral motor nerves reduce current leakage during propagation of trains of axon action potentials; (b) "jumping" by action potentials between successive nodes greatly increases signal conduction velocity. Long-held and more recent assumptions and issues underlying those concepts have been obscured by research emphasis on axon-sheath biochemical symbiosis and nerve regeneration. We hypothesize: mutual electromagnetic induction in the axon-glial sheath association, is fundamental in signal conduction in peripheral and central myelinated axons, explains the g-ratio and is relevant to animal navigation.

Media and technology usage and attitudes in emergency department patients.

Introduction: Digital health technologies are increasingly being used in emergency medicine, many of which utilize smartphones and computers. Patient willingness to use these modalities is an important factor in successful implementation. Therefore, this study aimed to assess emergency department (ED) patients' use of and attitudes towards technology. Methods: This was a pooled sub-analysis of ED patients (≥18 years old) that were enrolled in two studies evaluating the ED patient experience in response to novel technological interventions. Participants completed the Media and Technology Usage and Attitudes Scale (MTUAS) that assessed computer and smartphone ownership; frequency of use of phone calls, texting, email, and smartphones; and anxiety and dependence attitudes on these technologies. Results: One hundred and forty-four participants completed the survey. Mean age was 47.2 years (SD 17.94); 61.8% were female; and 61.1% were white. There was high usage of smartphones (93.1%) and computers (74.3%). Participants most frequently used phone calling and texting and least commonly used email. Participants had a positive attitude (mean 3.9/5, SD 0.68) towards the use of these technologies. Discussion: ED patients reported high ownership of smartphones and computers, had a positive attitude towards their use, and had varying frequency with which they used different technologies. Future studies can use this information to inform the development of digital health interventions that utilize technologies that patients find most acceptable.

Endotoxin protein: a B-cell mitogen and polyclonal activator of C3H/HeJ lymphocytes.

A cell wall protein that is ordinarily complexed to the lipopolysaccharide endotoxin in gram-negative bacteria has been separated by the use of aqueous phenol. The protein is active as a B-cell mitogen and polyclonal activator of murine lymphocytes including the C3H/HeJ strain which is a nonresponder to lipoplysaccharide or lipid A.

Endotoxin protein is a mitogen and polyclonal activator of human B lymphocytes.

Endotoxin protein (EP) has been shown to be a mitogen and polyclonal activator of human peripheral blood lymphocytes. EP stimulates proliferation of B lymphoyctes in the absence of T cells, and this activation is nonspecific by a number of parameters. Additionally, EP mitogenesis, but not polyclonal activation, is inhibited in the presence of human serum, suggesting that these events are dissociable. In these studies, EP appears to be equivalent to or better than pokeweed mitogen in stimulating nonspecific antibody production in vitro.

Micronutrient assay for cancer prevention clinical trials: serum retinol, retinyl palmitate, alpha-carotene, and beta-carotene with the use of high-performance liquid chromatography.

Assay of serum levels of retinol, retinyl palmitate, alpha-carotene, and beta-carotene to assess nutritional status, to trials of retinol and/or beta-carotene to assess nutritional status, to monitor compliance with medication schedules, and to conduct toxicity surveillance. The optimal assay method for clinical trial use represents a balance between analytical power and speed/simplicity. Three such methods were evaluated by means of shared samples between two laboratories. Each method required less than 15 minutes per assay and detected all of the analytes of interest. Careful evaluation of calibration materials and procedures permitted different laboratories using different methods to produce results with an interlaboratory variability smaller than the within-laboratory variability for each separate method. Typical precisions for the analytes in serum samples are: retinol, 0.06 relative standard deviation (RSD; standard deviation divided by mean value); retinyl palmitate, 0.08 RSD; alpha-carotene, 0.15 RSD; and beta-carotene, 0.11 RSD. Application of these methods to several hundred samples indicated that retinyl palmitate and beta-carotene levels were indicative of administered retinol and beta-carotene, whereas retinol itself was not. Population variability in pretreatment serum levels of these micronutrients expressed as RSD (retinol, 0.24; alpha-carotene, 1.11; and beta-carotene, 0.98) far exceeded the analytical imprecision in these determinations, confirming that the present assays could meet the needs of current clinical intervention trials.

Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial.

BACKGROUND: Evidence has accumulated from observational studies that people eating more fruits and vegetables, which are rich in beta-carotene (a violet to yellow plant pigment that acts as an antioxidant and can be converted to vitamin A by enzymes in the intestinal wall and liver) and retinol (an alcohol chemical form of vitamin A), and people having higher serum beta-carotene concentrations had lower rates of lung cancer. The Beta-Carotene and Retinol Efficacy Trial (CARET) tested the combination of 30 mg beta-carotene and 25,000 IU retinyl palmitate (vitamin A) taken daily against placebo in 18314 men and women at high risk of developing lung cancer. The CARET intervention was stopped 21 months early because of clear evidence of no benefit and substantial evidence of possible harm; there were 28% more lung cancers and 17% more deaths in the active intervention group (active = the daily combination of 30 mg beta-carotene and 25,000 IU retinyl palmitate). Promptly after the January 18, 1996, announcement that the CARET active intervention had been stopped, we published preliminary findings from CARET regarding cancer, heart disease, and total mortality. PURPOSE: We present for the first time results based on the pre-specified analytic method, details about risk factors for lung cancer, and analyses of subgroups and of factors that possibly influence response to the intervention. METHODS: CARET was a randomized, double-blinded, placebo-controlled chemoprevention trial, initiated with a pilot phase and then expanded 10-fold at six study centers. Cigarette smoking history and status and alcohol intake were assessed through participant self-report. Serum was collected from the participants at base line and periodically after randomization and was analyzed for beta-carotene concentration. An Endpoints Review Committee evaluated endpoint reports, including pathologic review of tissue specimens. The primary analysis is a stratified logrank test for intervention arm differences in lung cancer incidence, with weighting linearly to hypothesized full effect at 24 months after randomization. Relative risks (RRs) were estimated by use of Cox regression models; tests were performed for quantitative and qualitative interactions between the intervention and smoking status or alcohol intake. O'Brien-Fleming boundaries were used for stopping criteria at interim analyses. Statistical significance was set at the .05 alpha value, and all P values were derived from two-sided statistical tests. RESULTS: According to CARET's pre-specified analysis, there was an RR of 1.36 (95% confidence interval [CI] = 1.07-1.73; P = .01) for weighted lung cancer incidence for the active intervention group compared with the placebo group, and RR = 1.59 (95% CI = 1.13-2.23; P = .01) for weighted lung cancer mortality. All subgroups, except former smokers, had a point estimate of RR of 1.10 or greater for lung cancer. There are suggestions of associations of the excess lung cancer incidence with the highest quartile of alcohol intake (RR = 1.99; 95% CI = 1.28-3.09; test for heterogeneity of RR among quartiles of alcohol intake has P = .01, unadjusted for multiple comparisons) and with large-cell histology (RR = 1.89; 95% CI = 1.09-3.26; test for heterogeneity among histologic categories has P = .35), but not with base-line serum beta-carotene concentrations. CONCLUSIONS: CARET participants receiving the combination of beta-carotene and vitamin A had no chemopreventive benefit and had excess lung cancer incidence and mortality. The results are highly consistent with those found for beta-carotene in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study in 29133 male smokers in Finland.

Randomized phase III intergroup trial of isotretinoin to prevent second primary tumors in stage I non-small-cell lung cancer.

BACKGROUND: Promising data have suggested that retinoid chemoprevention may help to control second primary tumors (SPTs), recurrence, and mortality of stage I non-small-cell lung cancer (NSCLC) patients. METHODS: We carried out a National Cancer Institute (NCI) Intergroup phase III trial (NCI #I91-0001) with 1166 patients with pathologic stage I NSCLC (6 weeks to 3 years from definitive resection and no prior radiotherapy or chemotherapy). Patients were randomly assigned to receive a placebo or the retinoid isotretinoin (30 mg/day) for 3 years in a double-blind fashion. Patients were stratified at randomization by tumor stage, histology, and smoking status. The primary endpoint (time to SPT) and the secondary endpoints (times to recurrence and death) were analyzed by log-rank test and the Cox proportional hazards model. All statistical tests were two-sided. RESULTS: After a median follow-up of 3.5 years, there were no statistically significant differences between the placebo and isotretinoin arms with respect to the time to SPTs, recurrences, or mortality. The unadjusted hazard ratio (HR) of isotretinoin versus placebo was 1.08 (95% confidence interval [CI] = 0.78 to 1.49) for SPTs, 0.99 (95% CI = 0.76 to 1.29) for recurrence, and 1.07 (95% CI = 0.84 to 1.35) for mortality. Multivariate analyses showed that the rate of SPTs was not affected by any stratification factor. Rate of recurrence was affected by tumor stage (HR for T(2) versus T(1) = 1.77 [95% CI = 1.35 to 2.31]) and a treatment-by-smoking interaction (HR for treatment-by-current-versus-never-smoking status = 3.11 [95% CI = 1.00 to 9.71]). Mortality was affected by tumor stage (HR for T(2) versus T(1) = 1.39 [95% CI = 1.10 to 1.77]), histology (HR for squamous versus nonsquamous = 1.31 [95% CI = 1.03 to 1.68]), and a treatment-by-smoking interaction (HR for treatment-by-current-versus-never-smoking = 4.39 [95% CI = 1.11 to 17.29]). Mucocutaneous toxicity (P<.001) and noncompliance (40% versus 25% at 3 years) were higher in the isotretinoin arm than in the placebo arm. CONCLUSIONS: Isotretinoin treatment did not improve the overall rates of SPTs, recurrences, or mortality in stage I NSCLC. Secondary multivariate and subset analyses suggested that isotretinoin was harmful in current smokers and beneficial in never smokers.

The clinical evaluation of cancer chemoprevention agents: defining and contrasting phase I, II, and III objectives.

A number of potential chemoprevention agents are now in clinical trials to evaluate their efficacy. A larger number of compounds await clinical investigation. The design of phase I and phase II trials for cancer chemoprevention agents requires a different approach than for cytotoxic agents. The unique nature of the target populations, the scope of side effect evaluation, and the potential duration of treatment must be considered in the design of these trials. This article will discuss the effect these variables have on the evaluation of a chemoprevention agent and propose models for the phase I and phase II trials of chemoprevention agents.

Overexpression of HER-2 in ovarian carcinomas.

The transmembrane receptor encoded by the HER-2 cellular oncogene is amplified in several types of human carcinomas and provides an attractive therapeutic target. Shown by immunohistology, <25% of newly diagnosed ovarian carcinomas express the HER-2 protein. However, now we report that this protein was expressed in all 20 tumor cell lines derived from stage III and IV ovarian cancers as well as in tumor cells harvested from patients with malignant ascites and in tumor samples taken at a second surgery, suggesting that cells with excess expression may have a selective growth advantage. HER-2-positive ovarian carcinoma cells were shown to be sensitive to antibody-dependent cellular cytotoxicity, and their in vitro proliferation was inhibited by anti-HER-2 MAb Herceptin. We postulate, therefore, that therapy which targets HER-2 may be more efficacious in patients with ovarian carcinoma than indicated by the commonly low expression of HER-2 in tumors removed at the time of primary surgery.

Effect of verapamil on in vitro cytotoxicity of adriamycin and vinblastine in human tumor cells.

Verapamil has been shown to reverse acquired drug resistance to Adriamycin (ADR) and vinblastine in the P388 leukemia and Ehrlich ascites carcinoma model systems. Because of its potential clinical application, we evaluated the ability of verapamil to modulate the effect of ADR and vinblastine on the in vitro cloning of fresh human tumor cells. Fifty-three tumors were cloned in a soft agar system. Continuous exposure to verapamil at concentrations of 1.0, 5.0, and 10.0 micrograms/ml, did not significantly modulate the overall inhibitory activity of ADR and vinblastine (P greater than 0.05). There was no evidence of an effect when results were analyzed by tumor type or previous treatment except in the subgroup of 13 tumors obtained from patients who previously had a clinical response to ADR but were relapsing at the time the tumor specimen was obtained. In this population, at three concentrations of ADR, there was a significant modulation of drug effect (P = 0.10, 0.03, 0.03, respectively). In each subgroup, some tumors showed marked modulation of drug effect by verapamil. These results suggest that the mechanisms of acquired in vivo resistance to ADR may be similar to those occurring in cell lines. However, the effect on human tumors was minor as compared to the results with cell lines. The in vivo significance of this finding remains to be determined.

The beta-carotene and retinol efficacy trial (CARET) for chemoprevention of lung cancer in high risk populations: smokers and asbestos-exposed workers.

CARET is a multicenter, two-armed, double-masked randomized chemoprevention trial in Seattle, Portland, San Francisco, Baltimore, Connecticut, and Irvine, to test whether oral administration of beta-carotene (30 mg/day) plus retinyl palmitate (25,000 IU/day) can decrease the incidence of lung cancer in high risk populations, namely, heavy smokers and asbestos-exposed workers. The intervention combines the antioxidant action of beta-carotene and the tumor suppressor mechanism of vitamin A. As of April 30, 1993, CARET had randomized 1,845 participants in the 1985-1988 pilot phase plus 13,260 "efficacy" participants since 1989; of these, 4,000 are asbestos-exposed males and 11,105 are smokers and former smokers (44% female). Accrual is complete everywhere except Irvine, which was the last center added (1991), and the safety profile of the regimen to date has been excellent. With 14,420 smokers, 4,010 asbestos-exposed participants, and 114,100 person-years through February 1998, we expect CARET to be capable of detecting a 23% reduction in lung cancer incidence in the two populations combined and 27, 49, 32, and 35% reductions in the smokers, female smokers, male smokers, and asbestos-exposed subgroups, respectively. CARET is highly complementary to the alpha-tocopherol-beta-carotene study in Finland and the Harvard Physicians Health Study (beta-carotene alone) in the National Cancer Institute portfolio of major cancer chemoprevention trials.

Pharmacokinetics of 13-cis-retinoic acid in patients with advanced cancer.

13-cis-Retinoic acid (13-CRA) is a synthetic analog of vitamin A effective reversing preneoplastic lesions in both humans and animals. To study its physiochemical properties and disposition kinetics, we developed a rapid, sensitive, and precise high-performance liquid chromatography assay for 13-CRA in biological samples. This assay system resulted in a clear separation of 13-CRA from all-trans-retinoic acid and retinol and had a detection limit of 20 ng/ml plasma. Recovery was 89 +/- 6% (S.D.) at equivalent physiological concentrations with a precision of 8%. To study the disposition kinetics in humans, 13 patients received a p.o. bolus of 13-CRA and had blood samples collected at timed intervals. For the 10 patients studied on the first day of 13-CRA administration, the mean time to peak plasma concentration was 222 +/- 102 min. Interpatient peak 13-CRA plasma concentrations were found to be variable, suggesting irregular gastrointestinal absorption. Beta-Phase t 1/2 was approximately 25 hr. The prolonged terminal-phase plasma half-life may represent biliary excretion and enterohepatic circulation.

The custom triflange cup: build it and they will come.

The custom triflange is a patient-specific implant for the treatment of severe bone loss in revision total hip arthroplasty (THA). Through a process of three-dimensional modelling and prototyping, a hydroxyapatite-coated component is created for acetabular reconstruction. There are seven level IV studies describing the clinical results of triflange components. The most common complications include dislocation and infection, although the rates of implant removal are low. Clinical results are promising given the challenging problem. We describe the design, manufacture and implantation process and review the clinical results, contrasting them to other methods of acetabular reconstruction in revision THA.

The distance between cytochromes a and a3 in the azide compound of bovine-heart cytochrome oxidase.

The electron-spin relaxation rates of the two species of cytochrome a3(3+)-azide found in the azide compound of bovine-heart cytochrome oxidase were measured by progressive microwave saturation at T = 10 K. It has been shown previously that Cyt a3(3+)-azide gives rise to two distinct EPR resonances, depending upon the oxidation state of Cyt a. When Cyt a is ferrous, Cyt a3(3+)-azide has g = 2.88, 2.19 and 1.64; upon oxidation of Cyt a, the a3(3+)-azide g-values become g = 2.77, 2.18, and 1.74 (Goodman, G. (1984) J Biol. Chem. 259, 15094-15099). The relaxation effect of Cyt a on Cyt a3 could be measured as the difference in microwave field saturation parameter H1/2 between the g = 2.77 and g = 2.88 species. For each signal the spin-lattice relaxation time T1 was determined from H1/2 using the transverse relaxation time T2. The value of T2 at 10 K was extrapolated from a plot of line-width vs. temperature at higher temperature. The dipolar contribution to T1 was related to the Cyt a-Cyt a3 spin-spin distance utilizing available information on the relative orientation of Cyt a3-azide and Cyt a (Erecinska, M., Wilson, D.F. and Blasie, J.K. (1979) Biochim. Biophys. Acta 545, 352-364). By taking into account the relaxation parameters for both gx and gz components of the Cyt a3-azide g-tensor, the angle between the gz components of the Cyt a and Cyt a3 g-tensors was determined to be between 0 and 18 degrees, and the Cyt a-Cyt a3 spin-spin distance was found to be 19 +/- 8 A.

Phase I trial of retinol in cancer patients.

Vitamin A (all-trans-retinol) and its analogues are undergoing evaluation as antineoplastic and chemoprevention agents. Because its toxicity and activity are poorly defined, we have completed a phase I trial of retinol. Retinol was administered to 13 cancer patients in daily doses ranging from 100,000 units/m2 to 350,000 units/m2. Neuropsychiatric changes were the earliest dose-limiting symptomatic toxicities, noted in 3 of 5 patients receiving more than 240,000 U/m2 for 3-4 months. Two patients receiving more than 270,000 U/m2 developed hepatomegaly after 3 and 4 months. Liver biopsies were consistent with vitamin A toxicity. Three patients receiving 200,000 U/m2 developed an increase in serum triglycerides concentration. Mild skin and mucous membrane dryness occurred in most patients receiving more than 150,000 U/m2. A mixed response was seen in one patient with melanoma. Because of neuropsychiatric and hepatic toxicity a retinol dose of 200,000 U/m2/day is recommended for future phase II trials.