Follow-up schedules after treatment for malignant melanoma.

BACKGROUND: Existing follow-up guidelines after treatment for melanoma are based largely on dated literature and historical precedent. This study aimed to calculate recurrence rates and establish prognostic factors for recurrence to help redesign a follow-up schedule. METHODS: Data were retrieved from the Sydney Melanoma Unit database for all patients with a single primary melanoma and American Joint Committee on Cancer (AJCC) stage I-II disease, who had received their first treatment between 1959 and 2002. Recurrence rates, timing and survival were recorded by substage, and predictive factors were analysed. RESULTS: Recurrence occurred in 18.9 per cent (895 of 4748) of patients overall, 5.2 per cent (95 of 1822) of those with stage IA disease, 18.4 per cent (264 of 1436) with IB, 28.7 per cent (215 of 750) with IIA, 40.6 per cent (213 of 524) with IIB and 44.3 per cent (86 of 194) with IIC disease. Overall, the median disease-free survival time was 2.6 years, but there were marked differences between AJCC subgroups. Primary tumour thickness, ulceration and tumour mitotic rate were important predictors of recurrence. CONCLUSION: A new follow-up schedule was proposed: stage I annually, stage IIA 6-monthly for 2 years and then annually, stage IIB-IIC 4-monthly for 2 years, 6-monthly in the third year and annually thereafter.

Ultrastructural and morphometric study of diethylstilbestrol-associated lesions diagnosed as cervical intraepithelial neoplasia III.

Investigations were carried out to characterize diethylstilbestrol (DES)-associated squamous lesions and to assess their biological significance. Five DES-associated cervical lesions displayed architectural features which were diagnosed as cervical intraepithelial neoplasia (CIN) III, such as full-thickness replacement by atypical squamous cells with vertical orientation and absence of normal polarity. Electron microscopic examination revealed only one of the five to be consistent with the generally recognized ultrastructural picture of non-DES CIN III. In the remaining four lesions, the moderate-to-large numbers of tonofibrils and well-developed desmosomes distinguished them from the true CIN III lesions. Morphometric studies indicate the five DES-associated lesions in this study as a group to be significantly different from normal squamous epithelium, from maturing metaplasia, and from non-DES-related CIN III in the parameters of differentiation studied. Their intermediary position between maturing metaplasia and non-DES CIN III suggests that they are more differentiated than CIN III and less differentiated than maturing metaplasia. Nuclear area measurements indicate the increased nuclear-cytoplasmic ratio observed in the DES-associated CIN III lesions of this study is due to a decrease in cytoplasmic volume, as opposed to an increased nuclear size.

PIP: 5 diethylstilbestrol (DES)-associated squamous lesions, all of which had been diagnosed as cervical intraepithelial neoplasia 3 (CIN 3), were investigate to assess the biological significance of these lesions among women exposed in utero to DES. The diagnoses were based on characteristics such as full-thickness replacement by atypical squamous cells with vertical orientation and absence of normal polarity. However, by electron microscopic techniqeus it was found that only 1 of the 5 lesions was consistent with the generally recognized ultrastructural look of non-DES-associated CIN 3. The remaining 4 leasions had in architecture moderate-to-large numbers of tonofibrils and well-developed desmosomes which distinguished these lesions from true CIN 3 lesions. A morphometric study indicated that the 5 DES-associated lesions studied here are significantly different from normal squamous epithelium, from maturing metaplasia, and from non-DES-related CIN 3, suggesting that they are more differentiated than CIN 3 and less differentiated than maturing metaplasia. When nuclear areas were measured in these lesions, increased nuclear-cytoplasmic ratio was observed in the DES-associated CIN 3 lesions, caused by decreased cytoplasmic volume rather than increased nuclear size.

Relationship between dihydropyrimidine dehydrogenase activity and plasma 5-fluorouracil levels with evidence for circadian variation of enzyme activity and plasma drug levels in cancer patients receiving 5-fluorouracil by protracted continuous infusion.

The activity of dihydropyrimidine dehydrogenase (DPD) in peripheral blood mononuclear cells and plasma concentration of 5-fluorouracil (FUra) were simultaneously determined in cancer patients receiving FUra by protracted continuous infusion (300 mg/m2/day). Blood samples were drawn every 3 h over 24-h period and the resulting DPD and FUra values analyzed for circadian periodicity. In the seven patients studied, a circadian rhythm of DPD activity was observed (P less than 0.00001, Cosinor analysis) with the peak of activity at 1 a.m. (0.197 +/- 0.007 nmol/min/mg) and the trough at a 1 p.m. (0.113 +/- 0.007 nmol/min/mg). In addition, a circadian rhythm was observed for the plasma concentrations of FUra obtained over a 24-h period (P less than 0.00001, Cosinor analysis) with peak values (27.4 +/- 1.3 ng/ml) occurring at 11 a.m. and trough values (5.6 +/- 1.3 ng/ml) occurring at 11 p.m. The ratio of the maximum concentration of FUra to the minimum concentration observed was almost 5-fold. This study demonstrates a circadian variation of DPD activity in human peripheral blood mononuclear cells and a circadian variation of FUra plasma levels in patients receiving FUra by protracted continuous infusion. An inverse relationship between the circadian patterns of DPD activity and FUra plasma levels was also noted, suggesting that an association may exist between DPD activity and FUra plasma concentration. Further evidence of an association between DPD activity in peripheral blood mononuclear cells and plasma FUra concentration was demonstrated by a linear relationship between the two parameters in all patients (r = -0.627) and within individual patients (-0.978 less than r less than -0.742). With the recent advent of programmable pumps, information on the circadian pattern of FUra and/or DPD may be useful in planning continuous infusion schedules in order that optimal plasma drug concentration may be maintained over a 24-h cycle, thereby enhancing the therapeutic efficacy of FUra administered by continuous infusion.

Relationship between circadian-dependent toxicity of 5-fluorodeoxyuridine and circadian rhythms of pyrimidine enzymes: possible relevance to fluoropyrimidine chemotherapy.

Previous studies in experimental animals and patients have suggested a circadian variation in host toxicity following administration of 5-fluorodeoxyuridine (FdUrd) although the biochemical mechanisms are not fully understood. Thymidine kinase (TK; EC 2.7.1.21), the initial enzyme in the thymidine-phosphorylation pathway, is the first enzyme in the anabolism of FdUrd. Dihydropyrimidine dehydrogenase (DPD; EC 1.3.1.2), is the rate-limiting enzyme in the pyrimidine catabolic pathway and has been shown to be the key enzyme in FdUrd catabolism. The present study examined the relationship between the suggested circadian variation in FdUrd toxicity and potential circadian variations in the activity of these enzymes. Initial studies in Sprague-Dawley rats confirmed that the time of FdUrd administration affected death rate and other drug-related toxicities including loss of body weight, diarrhea, and bone marrow suppression, with the least toxicity and highest survival rate being observed in rats receiving FdUrd at 12:00 noon and 4:00 p.m. and the greatest toxicity and lowest survival rate at 12:00 midnight and 4:00 a.m. Statistical analysis revealed a circadian pattern in FdUrd toxicity (Cosinor analysis, P < 0.001). In subsequent studies with the same species, we simultaneously measured TK and DPD activities in several tissues at various times over 24 h. Under standardized light conditions (lights on, 6:00 a.m. to 6:00 p.m.; lights off, 6:00 p.m. to 6:00 a.m.), with sampling at 4-h intervals (4:00 and 8:00 a.m.; 12:00 noon; 4:00 and 8:00 p.m., and 12:00 midnight), a circadian variation in TK activity was observed (P < 0.0001, Cosinor analysis) in bone marrow, intestinal mucosa, liver, and spleen. In the same group of animals, a circadian pattern of DPD activity in liver and bone marrow was also observed (Cosinor analysis, P < 0.0001) that was inverse compared to the circadian variation in TK activity (Pearson correlation analysis, P < 0.05). Further statistical analysis indicated that the observed circadian variation in FdUrd toxicity was correlated with the circadian variation of TK activity and inversely correlated with DPD activity (Pearson correlation analysis, P < 0.05). Based on the above data, we conclude that the circadian pattern of TK and DPD activity may explain the observed circadian variation in toxicity as the time of FdUrd administration is varied. These results may be useful in the design of improved chemotherapeutic regimens using time-modified administration of FdUrd.

An experimental approach to relate a tumor-associated enzyme marker to tumor cell numbers.

Alkaline phosphatase was monitored in 17 mice with s.c.-implanted tumors to relate the total circulating alkaline phosphatase to the total number of tumor cells in each mouse. There was a semilogarithmic relationship between the alkaline phosphatase units and the number of tumor cells. A time-independent standard plot of alkaline phosphatase and the number of tumor cells was used to estimate the size of disseminated and localized tumors. In animals treated with cyclophosphamide, the alkaline phosphatase marker was used to monitor the regression and recurrence of the neoplasm in vivo.

Circadian variation of 5-fluorouracil catabolism in isolated perfused rat liver.

The catabolism of 5-fluorouracil (FUra) was measured in isolated perfused rat liver (IPRL) at various times of the day. IPRLs were prepared from rats sacrificed at 3-h intervals and the elimination rate of FUra and FUra catabolites (i.e., rate leaving the IPRL in the effluent perfusate) following infusion of [3H]FUra was analyzed for circadian periodicity. Animals were housed under standardized conditions of light and dark and divided into two groups of 24 animals each. The first group was housed under "normal" light conditions (lights on from 6:00 a.m. to 6:00 p.m.; off from 6:00 p.m. to 6:00 a.m.), while the second group was housed under "reverse" light conditions (lights on from 10:00 p.m. to 10:00 a.m.; off from 10:00 a.m. to 10:00 p.m.). A circadian rhythm was observed in the elimination rate of FUra and FUra catabolites by both groups (P less than 0.0001, Cosinor analysis). Under "normal" light conditions, peak and trough elimination rate of FUra was at 19 h after light onset (HALO; 183.8 +/- 3.4 nmol/min/g liver) and 7 HALO (123.8 +/- 3.4 nmol/min/g liver), respectively. There was a reciprocal relationship between the elimination rates of FUra and FUra catabolites with peak and trough values for FUra catabolites at 7 HALO (70.5 +/- 3.6 nmol/min/g liver) and 19 HALO (17.5 +/- 3.6 nmol/min/g liver), respectively. Animals housed under the "reverse" conditions of light and dark also exhibited a circadian pattern. Under the "reverse" conditions, the peak and trough elimination rate of FUra was at 18.5 HALO (170.0 +/- 1.7 nmol/min/g liver) and 6.5 HALO (130.0 +/- 1.7 nmol/min/g liver), respectively. The peak and trough elimination rate of FUra catabolites under these conditions occurred at 6.5 HALO (64.3 +/- 2.2 nmol/min/g liver) and 18.5 HALO (29.7 +/- 2.2 nmol/min/g liver), respectively. These results demonstrate that the elimination rate of FUra and FUra catabolites by IPRL varies over a 24-h period with a circadian rhythm in association with the light/dark cycle. Such a variation in the hepatic elimination rate of FUra in humans could result in a variation in the systemic level of drug during chemotherapy thus affecting the therapeutic efficacy of FUra. This study suggests that a circadian pattern in the hepatic catabolism of FUra needs to be considered when planning chemotherapeutic regimens with FUra.

Conditioning: a new approach to immunotherapy.

It has been demonstrated by Parmiani et al. (Int. J. Cancer, 29: 323-332, 1982) that a significant protective effect can be obtained against the transplanted syngeneic YC8 lymphoma by prior immunization of BALB/c mice with normal allogeneic DBA/2 spleen cells. Using this well established tumor model, we investigated a novel approach, conditioning of specific immunotherapeutic activity. For this purpose, we used the odor of camphor as the conditioning stimulus and allogeneic DBA/2 spleen cells as unconditioning stimulus. We associated the conditioning and unconditioning stimuli two, three, and four times. Following this the conditioned animals were reexposed to the odor of camphor only. In each case, we observed a delay in tumor growth and in some instances the conditioned group performed better than the immunotherapy control group. These results indicate that a limited number of treatments with the antigen is better than the continuous treatment in maintaining the immunity and the homeostasis of the system.

Increase of HLA-DR4 in melanoma patients from Alabama.

This report describes the association of HLA-DR phenotypes in a population of 91 Caucasian melanoma patients compared with 106 Caucasian controls from the Sunbelt region of the United States. Over 75% of both patients and controls were born in Alabama or a surrounding state. There was a significant increase in the frequency of HLA-DR4 (chi 2 = 12.8; rho = 0.0003). This was present in 38.5% of the patients compared to a 16.0% frequency in the controls, producing a relative risk of 3.3. The difference in DR4 distribution remained significant after correcting for the number of antigens (rho c = 0.0018). The patients were then grouped into two categories, "low risk" and "high risk," based on their clinically assessed risk at presentation for metastatic involvement. The decrease of DR3 in the high-risk group (chi 2 = 5.2; rho = 0.02) suggested that it may represent a marker for long-term survival. Thus, it appears that susceptibility to developing melanoma may be associated with DR4 while survival may be associated with DR3.

A multifactorial analysis of prognostic factors in patients with liver metastases from colorectal carcinoma.

A multifactorial analysis was used to identify the dominant prognostic variables predicting survival rates of 175 patients with hepatic metastases from colorectal carcinoma. Seven of 22 parameters examined simultaneously were found to independently influence the median survival rate in these patients: (1) elevated alkaline phosphatase (p = 0.0004), (2) elevated serum bilirubin level (p = 0.0005), (3) location of hepatic metastases (unilateral or bilateral, p = 0.0022), (4) number of metastatic nodes involved (0, 1-5, greater than 5; p = 0.0148), (5) depressed serum albumin (p = 0.0217), (6) whether or not the primary colorectal tumor was resected (p = 0.0013), and (7) chemotherapy (given or withheld, p = 0.0439). The prothrombin time, serum lactic dehydrogenase, and the number of hepatic metastases also correlated with survival, but they did not independently predict survival rates after other more dominant factors were accounted for. A mathematical equation for predicting an individual patient's clinical course once they developed hepatic metastases was derived from this statistical analysis. In addition, a simple and clinically useful guide for predicting outcome was developed that integrated the two most important risk factors, alkaline phosphatase and bilirubin.

Adjuvant therapy of stage III and IV malignant melanoma using granulocyte-macrophage colony-stimulating factor.

PURPOSE: To evaluate granulocyte-macrophage colony-stimulating factor (GM-CSF) as surgical adjuvant therapy in patients with malignant melanoma who are at high risk of recurrence. PATIENTS AND METHODS: Forty-eight assessable patients with stage III or IV melanoma were treated in a phase II trial with long-term, chronic, intermittent GM-CSF after surgical resection of disease. Patients with stage III disease were required to have more than four positive nodes or a more than 3-cm mass. All patients were rendered clinically disease-free by surgery before enrollment. The GM-CSF was administered subcutaneously in 28-day cycles, such that a dose of 125 microg/m(2) was delivered daily for 14 days followed by 14 days of rest. Treatment cycles continued for 1 year or until disease recurrence. Patients were evaluated for toxicity and disease-free and overall survival. RESULTS: Overall and disease-free survival were significantly prolonged in patients who received GM-CSF compared with matched historical controls. The median survival duration was 37.5 months in the study patients versus 12.2 months in the matched controls (P <.001). GM-CSF was well tolerated; only one subject discontinued drug due to an adverse event (grade 2 injection site reaction). CONCLUSION: GM-CSF may provide an antitumor effect that prolongs survival and disease-free survival in patients with stage III and IV melanoma who are clinically disease-free. These results support institution of a prospective, randomized clinical trial to definitively determine the value of surgical adjuvant therapy with GM-CSF in such patients.

A multifactorial analysis of melanoma. IV. Prognostic factors in 200 melanoma patients with distant metastases (stage III).

A multifactorial analysis of 200 cutaneous melanoma patients with distant metastasis (stage III) was performed on 13 clinical and pathological factors using the Cox regression analysis. There were only three dominant prognostic variables that independently predicted the patient's clinical course: (1) number of metastatic sites (1 vs. 2 vs. greater than or equal to 3, p less than 0.00001), (2) remission duration (less than 12 mo vs. greater than or equal to 12 mo, p = 0.0186), and (3) the location of the metastases (visceral vs. nonvisceral vs. combined, p = 0.0192). Factors that were not significant in the multifactorial analysis included the patients' age and sex, the site of the primary melanoma, the sequence of metastases, and all histopathological features of the primary melanoma (thickness, level of invasion, ulceration, growth pattern, pigmentation, and lymphocyte infiltration). For a single metastatic site, the 1-yr survival rate was 36%, while it was only 13% for 2 sites, and 0% for greater than or equal to 3 sites (p less than 0.00001). The 1-yr survival for patients was 40% for nonvisceral sites (skin, subcutaneous, distant lymph nodes) compared to only 11% for visceral metastases and 8% for combined sites (p less than 0.00001). Pulmonary metastases were associated with a significantly higher survival rate than metastatic melanoma in any other visceral site. The most common first site of distant metastases (either alone or in combination) was skin (38%), lung (36%), liver (20%), and brain (20%). The skin, subcutaneous and distant lymph node group was the first site of metastases in 59% of patients. This finding emphasizes the importance of careful physical exams in routine metastatic evaluations. Only a minority (25%) of stage I patients progressed to stage III disease after a median interval of 2.8 years. In contrast, the majority (75%) of melanoma patients with nodal metastases (stage II) progressed to stage III disease after a median duration of only 11 mo. Of the patients who eventually developed stage III disease, 95% of those who initially presented with stage II disease progressed within 3 yr, while stage I patients who progressed to stage III did not reach a 95% cumulative incidence until 8 yr.

Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system.

PURPOSE: The American Joint Committee on Cancer (AJCC) recently proposed major revisions of the tumor-node-metastases (TNM) categories and stage groupings for cutaneous melanoma. Thirteen cancer centers and cancer cooperative groups contributed staging and survival data from a total of 30,450 melanoma patients from their databases in order to validate this staging proposal. PATIENTS AND METHODS: There were 17,600 melanoma patients with complete clinical, pathologic, and follow-up information. Factors predicting melanoma-specific survival rates were analyzed using the Cox proportional hazards regression model. Follow-up survival data for 5 years or longer were available for 73% of the patients. RESULTS: This analysis demonstrated that (1) in the T category, tumor thickness and ulceration were the most powerful predictors of survival, and the level of invasion had a significant impact only within the subgroup of thin (< or = 1 mm) melanomas; (2) in the N category, the following three independent factors were identified: the number of metastatic nodes, whether nodal metastases were clinically occult or clinically apparent, and the presence or absence of primary tumor ulceration; and (3) in the M category, nonvisceral metastases was associated with a better survival compared with visceral metastases. A marked diversity in the natural history of pathologic stage III melanoma was demonstrated by five-fold differences in 5-year survival rates for defined subgroups. This analysis also demonstrated that large and complex data sets could be used effectively to examine prognosis and survival outcome in melanoma patients. CONCLUSION: The results of this evidence-based methodology were incorporated into the AJCC melanoma staging as described in the companion publication.

Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma.

PURPOSE: To revise the staging system for cutaneous melanoma under the auspices of the American Joint Committee on Cancer (AJCC). MATERIALS AND METHODS: The prognostic factors analysis described in the companion publication (this issue), as well as evidence from the published literature, was used to assemble the tumor-node-metastasis criteria and stage grouping for the melanoma staging system. RESULTS: Major changes include (1) melanoma thickness and ulceration but not level of invasion to be used in the T category (except for T1 melanomas); (2) the number of metastatic lymph nodes rather than their gross dimensions and the delineation of clinically occult (ie, microscopic) versus clinically apparent (ie, macroscopic) nodal metastases to be used in the N category; (3) the site of distant metastases and the presence of elevated serum lactic dehydrogenase to be used in the M category; (4) an upstaging of all patients with stage I, II, and III disease when a primary melanoma is ulcerated; (5) a merging of satellite metastases around a primary melanoma and in-transit metastases into a single staging entity that is grouped into stage III disease; and (6) a new convention for defining clinical and pathologic staging so as to take into account the staging information gained from intraoperative lymphatic mapping and sentinel node biopsy. CONCLUSION: This revision will become official with publication of the sixth edition of the AJCC Cancer Staging Manual in the year 2002.

A randomized trial to improve self-management practices of adults with asthma.

The prevalence and impact of adult asthma are substantial, and poor self-management practices, especially failures to adhere to treatment regimens, appear to be a significant problem. Desirable characteristics of an intervention program to improve self-management were identified through needs assessment and review of existing patient education resources. A comprehensive program was developed that integrated a workbook with one-to-one counseling and adherence-enhancing strategies. A longitudinal 1-year study compared patients receiving this self-management program with "usual care" patients receiving standard asthma pamphlets. Patients were randomly assigned to conditions. Baseline score and asthma severity were statistically controlled. Self-management patients had substantially better adherence than usual care patients, as well as improved functional status, at follow-up. Hospital and emergency department visits decreased in both groups but did not differ between groups.

Evaluation of the deoxyuridine suppression test by using whole blood samples from folic acid-supplemented subjects.

We performed the deoxyuridine suppression test (dUST) along with assessment of folate and vitamin B-12 status in blood specimens from 136 normal women and 109 women with cervical dysplasia. All tests were repeated at 2, 4, and 6 mo in subjects with dysplasia during a randomized, double-blind intervention trial in which 50 received a 10-mg daily oral folic acid supplement (F group) and 59 received a placebo (P group). Median folate concentration increased fivefold in plasma and threefold in erythrocytes of F group beginning at the second months and remained elevated whereas concentrations of the P group remained unchanged. Vitamin B-12 values did not vary significantly in either group. The dUST value decreased from 10.4 +/- 4.6% (means +/- SD) pretreatment to 4.5 +/- 4.7% in F group after 2 mo (p less than 0.001). The dUST values had significant negative correlation with plasma and erythrocyte folate concentrations. However, erythrocyte folate had the greatest power to distinguish P group from F group.

Zinc concentration in plasma and erythrocytes of subjects receiving folic acid supplementation.

It has been suggested that oral supplements of folic acid interfere with the intestinal absorption of zinc and may have toxic side effects. The concentrations of Zn and folate in blood were monitored in a group of women with cervical dysplasia randomly assigned to receive 10 mg/d of either folic acid (pteroylglutamic acid) or ascorbate. Fifty subjects were evaluated after 2 mo; 21 of the same subjects were evaluated again after 4 mo. No untoward clinical effects were observed. Significant elevation of erythrocyte folate above the baseline value was observed in the supplemented group but not in the placebo group (p less than 0.001). The concentration of Zn in plasma and erythrocytes did not change significantly in either the folate-treated or placebo groups after 2 and 4 mo. It is concluded that carefully controlled clinical intervention trials of this type do not impose a risk of depleting the concentration of Zn in erythrocytes and plasma.

A longitudinal analysis of human papillomavirus 16 infection, nutritional status, and cervical dysplasia progression.

To evaluate the effect of potential risk factors, especially human papillomavirus type 16 (HPV-16) infection and nutritional status on the course of cervical dysplasia, we analyzed data from an intervention trial conducted from 1985 to 1990, in Birmingham, Alabama. With the use of data of four repeated evaluations of dysplasia at an interval of 2 months, specific relationships between HPV-16 infection, plasma retinol and zinc levels, and dysplasia progression were evaluated through longitudinal data analysis of generalized estimating equations. Repeated assessments of nutritional status from blood samples, HPV-16 infection, and dysplasia diagnosis were available from 206 women. Dysplasia diagnosis was confirmed by both Papanicolaou smear and colposcopy examinations and was classified as normal, low, or high grade squamous intraepithelial lesions according to the Bethesda system and assigned a score of 0, 1, or 2, respectively. Generalized estimating equation analyses were performed with assumptions of variance of Poisson and link of logarithm. Separate analyses were also conducted for HPV-16-positive and HPV-16-negative women. By multivariate modeling with adjustment for age, race, smoking, oral contraceptive use, and plasma levels of nutrients, HPV-16 infection was found to be related to the progression of cervical dysplasia, with a relative risk of 1.19 and a 95% confidence interval of 1.03-1.38. High plasma levels of retinol were related to the regression of cervical dysplasia, especially in HPV-16-positive women. A protective effect was also observed for high levels of zinc.(ABSTRACT TRUNCATED AT 250 WORDS)

A case control study of nutritional factors and cervical dysplasia.

The association of nutritional factors with cervical dysplasia was examined through a case-control study. Analysis was conducted in 257 cases and 133 controls confirmed both by cytological examination and colposcopic findings. A 24-h dietary recall questionnaire was used to assess nutritional intake. Various risk factors (including age at first intercourse, number of sexual partners, parity, cigarette smoking, oral contraceptive use, human papillomavirus type 16 infection, and age and race) were adjusted for their potential confounding effects. While analyses were also performed to adjust for total calories, results were not changed significantly. Among the nutrients examined, vitamin A intake showed a significantly increased risk at the lowest quartile compared to the highest quartile, with an odds ratio of 2.2 (95% confidence interval, 1.2-4.2). A significant trend of increasing risk was also observed with lower intake of vitamin A (P = 0.05). Riboflavin showed increased risk at the two lower quartiles of intake with a trend test P value of 0.04. Increased risk was also found for lower intakes of vitamin C compared to the highest intake level. For folate, increased risk was found in the second highest quartile compared with the highest quartile with an odds ratio of 2.0 (95% confidence interval, 1.0-3.8). The calcium:phosphorus ratio showed an increased risk at the lowest level (odds ratio, 2.0; 95% confidence interval, 1.0-4.3). Insufficient intake of vitamin A, riboflavin, ascorbate, and folate is associated with an increased risk of cervical dysplasia.

Effect of thymic hormone treatment on several immune functions of nude mice.

Studies of the effect of short-term, intense treatment with thymic hormone on mitogen response, cytotoxicity to EL-4 lymphoma and natural killer cell (NK) activity was investigated Balb/c nude mice (about 12-16-week-old) were treated 5 times per week for 3 weeks with: Facteur Thymic Serique (FTS) and Thymopentin (TP5, Thymopoietin 32-36) at 1 microgram and 10 ng; TM4 1 ng (an enzyme resistant variant of FTS); Thymosin Fraction V (TF5), 10 and 1 microgram; and 0.1 ml saline, and killed 2 days after the last treatment. The animals were monitored for changes in weight, hematocrit, peripheral blood lymphocyte (PBL) and spleen mitogen response. Additional groups of nude mice were immunized with 1 x 10(7) 5000 R irradiated EL-4 cells 10 days before sacrifice and tested for the presence of cytotoxic T-lymphocytes (CTL). The results show that weight and hematocrit were similar among the groups. Treatment with FTS significantly elevated the number of PBL. Spleen stimulation in mice treated with 1 microgram TP5 was depressed to mitogen concanavalin A (ConA) and lipopolysaccharide (LPS) stimulation. The phytohemagglutinin (PHA) response was not different among the treatment groups. The PBL mitogen response to ConA and LPS was generally increased over saline control in the hormone treated groups but was not statistically significant. The PHA response was only slightly elevated. No CTL was generated in nude mice in any of the groups. However, there was a statistically significant general depression of NK activity in all of the hormone treated animals compared with saline. The results indicate that the basic differentiation defect of the T-cells of nude mice cannot be restored to full functional activity by short-term treatment.

Steroid-induced weakness in patients with primary brain tumors.

Clinically significant steroid myopathy (SM) occurred in 23 (10.6%) of 216 adult patients with primary brain tumors who received 2 or more continuous weeks of daily dexamethasone therapy. SM occurred over a wide range of peak and cumulative doses of dexamethasone as well as a wide range of periods of continuous treatment. This was not an entirely random event, however, as two-thirds of the patients developed their weakness during the 9th through the 12th week of continuous dexamethasone treatment. The risk of developing SM was significantly lower in patients taking phenytoin than in patients who were not taking anticonvulsants. The only other patient or treatment factor associated with SM was a possible direct correlation with the appearance of a cushingoid body habitus. In this retrospective review, the occurrence of SM had a significant negative impact on the quality of life of all affected individuals. As expected, patients who tolerated a reduction in their steroid dose improved, while other patients suffered the combined effects of tumor progression and worsening myopathy. Substituting a nonfluorinated glucocorticoid for dexamethasone is probably advisable if neuro-oncology patients affected by SM cannot be weaned from the steroids.