Ann M. Dnistrian

Serum folate, homocysteine and colorectal cancer risk in women: a nested case–control study

SummaryAccumulating evidence suggests that folate, which is plentiful in vegetables and fruits, may be protective against colorectal cancer. The authors have studied the relationship of baseline levels of serum folate and homocysteine to the subsequent risk of colorectal cancer in a nested case–control study including 105 cases and 523 matched controls from the New York University Women’s Health Study cohort. In univariate analyses, the cases had lower serum folate and higher serum homocysteine levels than controls. The difference was more significant for folate (P < 0.001) than for homocysteine (P = 0.04). After adjusting for potential confounders, the risk of colorectal cancer in the subjects in the highest quartile of serum folate was half that of those in the lowest quartile (odds ratio, OR = 0.52, 95% confidence interval, CI = 0.27–0.97, P-value for trend = 0.04). The OR for the highest quartile of homocysteine, relative to the lowest quartile, was 1.72 (95% CI = 0.83–3.65, P-value for trend = 0.09). In addition, the risk of colorectal cancer was almost twice as high in subjects with below-median serum folate and above-median total alcohol intake compared with those with above-median serum folate and below-median alcohol consumption (OR = 1.99, 95% CI = 0.92–4.29). The potentially protective effects of folate need to be confirmed in clinical trials.

Ovarian cancer antigen CA125 is encoded by the MUC16 mucin gene

Serum assays based on the CA125 antigen are widely used in the monitoring of patients with ovarian cancer; however very little is known about the molecular nature of the CA125 antigen. We recently cloned a partial cDNA (designated MUC16) that codes for a new mucin that is a strong candidate for being the CA125 antigen. This assignment has now been confirmed by transfecting a partial MUC16 cDNA into 2 CA125‐negative cell lines and demonstrating the synthesis of CA125 by 3 different assays. Of the 3 antibodies (OC125, M11 and VK‐8) tested on the transfected cells, only the first 2 were strongly positive, indicating the differential expression of the CA125 epitopes in these cells. The cloning and expression of CA125 antigen opens the way to an understanding of its function in normal and malignant cells.

Thiopental and propofol affect different regions of the brain at similar pharmacologic effects.

In this study, we examined the onset and duration of local analgesic effects of bupivacaine incorporated into biodegradable microcapsules (extended-duration local anesthetic; EDLA) administered as subcutaneous infiltrations in different doses in humans. In 18 volunteers, the skin on the medial calf was infiltrated with 10 mL of EDLA, and the opposite calf was infiltrated with 10 mL of aqueous bupivacaine (5.0 mg/mL) in a double-blinded, randomized manner. Three different concentrations of EDLA were tested (6.25, 12.5, and 25 mg/mL), with 6 subjects in each group. Pain responses to mechanical and heat stimuli and sensory thresholds (touch, warm, and cold detection thresholds) were examined by von Frey hairs and contact thermodes. Assessments were made before and 2, 4, 6, 8, 24, 48, 72, 96, and 168 h after the injections. Safety evaluations were performed daily for the first week and at 2 wk, 6 wk, and 6 mo after the injections. The time to maximum effects was significantly shorter for aqueous bupivacaine (2–6 h) than for EDLA (4–24 h), but there were no significant differences between the maximum effects of EDLA and aqueous bupivacaine. From 24 to 96 h after the injections, EDLA was significantly more efficient than aqueous bupivacaine for all variables, and significant effects of EDLA were demonstrated for at least 96 h for all variables. In general, a dose-response gradient was seen in the EDLA group for 5 of 7 variables when the curves expressing effect over time for the different concentrations were evaluated. No serious side effects were observed for up to 6 mo after administration. In conclusion, bupivacaine incorporated in microcapsules provided analgesia for 96 h after subcutaneous infiltration.Propofol has a greater amnesic effect than thiopental. In this study we tested whether different brain regions were affected by propofol and thiopental at similar drug effects. Changes in regional cerebral blood flow (rCBF) were identified by using SPM99 analysis of images obtained with positron emission tomography with (15)O water. Ten right-handed male volunteers (age, 35 +/- 10 yr; weight, 74.1 +/- 7.5 kg; mean +/- sd) were randomized to receive thiopental (n = 4) or propofol (n = 6) to target sedative and hypnotic concentrations with bispectral index (BIS) monitoring. Four positron emission tomography images were obtained during various tasks at baseline and with sedative and hypnotic effects. Two participants receiving propofol were unresponsive at sedative concentrations and were not included in the final analyses. Median serum concentrations were 1.2 and 2.7 microg/mL for sedative and hypnotic propofol effects, respectively. Similarly, thiopental concentrations were 4.8 and 10.6 microg/mL. BIS decreased similarly in both groups. The pattern of rCBF change was markedly different for propofol and thiopental. Propofol decreased rCBF in the anterior (right-sided during sedation) brain regions, whereas thiopental decreased rCBF primarily in the cerebellar and posterior brain regions. At similar levels of drug effect, propofol and thiopental affect different regions of the brain. These differences may help to identify the loci of action for the nonsedative effects of propofol, such as amnesia.

Iron intake, body iron stores and colorectal cancer risk in women: a nested case-control study

Accumulated evidence suggests that increased body iron stores may increase the risk of colorectal cancer, possibly via catalyzing oxidation reactions. We examined the relationship between iron status and colorectal cancer in a case‐control study nested within the New York University Womens Health Study cohort. For 105 incident cases of colorectal cancer with an average follow‐up of 4.7 years and 523 individually matched controls, baseline levels of serum iron, ferritin, total iron binding capacity (TIBC) and transferrin saturation were determined as indicators of body iron stores, and total iron intake was assessed based on their diet and supplement intake. Overall, there were no associations between the risk of colorectal cancer and any of these indices except for serum ferritin, which showed a significant inverse association. When analyzed by subsite, there was an increasing trend in risk of cancer of the proximal colon with increasing total iron intake (p‐value for trend = 0.04). In addition, a significantly increased risk of colorectal cancer associated with higher total iron intake [odds ratio (OR) = 2.50; 95% confidence interval (CI): 1.06–5.87] was observed among subjects with higher intake of total fat. Our results do not support a role of increased body iron stores in the development of colorectal cancer, but suggest that luminal exposure to excessive iron may possibly increase the risk in combination with a high fat diet. Int. J. Cancer 80:693–698, 1999.

Clinical events in prostate cancer lifestyle trial: results from two years of follow-up.

OBJECTIVES Previous research has demonstrated that patients with prostate cancer participating in the Prostate Cancer Lifestyle Trial had a reduction in prostate-specific antigen (PSA) levels, inhibition of LNCaP cell growth, and fewer prostate cancer-related clinical events at the end of 1 year compared with controls. The aim of this study was to examine the clinical events in this trial during a 2-year period. METHODS The Prostate Cancer Lifestyle Trial was a 1-year randomized controlled clinical trial of 93 patients with early-stage prostate cancer (Gleason score <7, PSA 4-10 ng/mL) undergoing active surveillance. The patients in the experimental arm were encouraged to adopt a low-fat, plant-based diet, to exercise and practice stress management, and to attend group support sessions. The control patients received the usual care. RESULTS By 2 years of follow-up, 13 of 49 (27%) control patients and 2 of 43 (5%) experimental patients had undergone conventional prostate cancer treatment (radical prostatectomy, radiotherapy, or androgen deprivation, P < .05). No differences were found between the groups in other clinical events (eg, cardiac), and no deaths occurred. Three of the treated control patients but none of the treated experimental patients had a PSA level of >or=10 ng/mL, and 1 treated control patient but no treated experimental patients had a PSA velocity of >2 ng/mL/y before treatment. No significant differences were found between the untreated experimental and untreated control patients in PSA change or velocity at the end of 2 years. CONCLUSIONS Patients with early-stage prostate cancer choosing active surveillance might be able to avoid or delay conventional treatment for at least 2 years by making changes in their diet and lifestyle.

Multiple Markers for Lung Cancer Diagnosis: Validation of Models for Advanced Lung Cancer

Sera from 171 patients with advanced lung cancer, from 110 normals, and from 123 subjects with benign respiratory diseases were analyzed for 10 substances to detect lung cancer: ferritin, lipid-bound sialic acid, total sialic acid, beta 2-microglobulin, lipotropin, the alpha and beta subunits of human chorionic gonadotropin, calcitonin (two assays), parathyroid hormone, and carcinoembryonic antigen. Individual markers were studied, and optimal combinations of markers were sought for discriminating lung cancer patients from normals and from patients with benign lung disease. Numerous methods for combining the markers were examined, but the methods of logistic regression and recursive partitioning were finally adopted. The best discrimination rules we could find used only carcinoembryonic antigen (CEA) and total sialic acid (TSA). The performance of these rules was validated on an independent serum panel containing sera from 68 patients with advanced lung cancer, from 40 normals, and from 52 patients with benign respiratory disease. The combination rules based on TSA and CEA performed better than a rule based on CEA alone. Logistic discrimination rules with TSA and CEA that were designed to have 95% specificity achieved 54% sensitivity for discriminating advanced lung cancer from normal controls and 52% sensitivity for discriminating advanced lung cancer from controls with benign disease. Some aspects of clinical applicability are discussed, including planned studies for localized lung cancer and the requirement for further testing in specific clinical settings.

A neuroanatomical construct for the amnesic effects of propofol.

Background This study was designed to identify neuroanatomical locations of propofols effects on episodic memory by producing minimal and maximal memory impairment during conscious sedation. Drug-related changes in regional cerebral blood flow (rCBF) were located in comparison with rCBF increases during a simple word memory task. Methods Regional cerebral blood flow changes were assessed in 11 healthy volunteers using H215O positron emission tomography (PET) and statistical parametric mapping (SPM99) at 600 and 1,000 ng/ml propofol target concentrations. Study groups were based on final recognition scores of auditory words memorized during PET scanning. rCBF changes during propofol administration were compared with those during the word memory task at baseline. Results Nonoverlapping memory effects were evident: low (n = 4; propofol concentration 523 ± 138 ng/ml; 44 ± 13% decrement from baseline memory) and high (n = 7; 829 ± 246 ng/ml; 87 ± 6% decrement from baseline) groups differed in rCBF reductions primarily in right-sided prefrontal and parietal regions, close to areas activated in the baseline memory task, particularly R dorsolateral prefrontal cortex (Brodmann area 46; x, y, z = 51, 38, 22). The medial temporal lobe region exhibited relative rCBF increases. Conclusions As amnesia becomes maximal, rCBF reductions induced by propofol occur in brain regions identified with working memory processes. In contrast, medial temporal lobe structures were resistant to the global CBF decrease associated with propofol sedation. The authors postulate that the episodic memory effect of propofol is produced by interference with distributed cortical processes necessary for normal memory function rather than specific effects on medial temporal lobe structures.

Endocrine consequences of CMF adjuvant therapy in premenopausal and postmenopausal breast cancer patients

The effect of CMF adjuvant therapy (cyclophosphamide, methotrexate, and 5‐fluorouracil) on endocrine function was investigated in breast cancer patients. CMF therapy resulted in suppression of ovarian function in some premenopausal patients but pituitary function and adrenal function were unaffected. There was an inverse relation between age and duration of treatment required to induce ovarian suppression. Although amenorrhea was achieved within 2–4 months in patients aged 40 years or older, younger women required larger cumulative doses of cytotoxic drugs to induce ovarian dysfunction. Patients younger than 30 years of age continued to menstruate with no major alteration in hormonal levels resulting from the cytotoxic drugs. CMF therapy had no significant effect on hormonal levels in postmenopausal patients indicating that in this group therapeutic response is not mediated via the endocrine system.

Serum lipid‐bound sialic acid as a marker in breast cancer

The reliability of lipid‐bound sialic acid (LSA) as a marker in breast cancer was evaluated in 78 normal subjects, 106 patients with benign breast disease, 64 patients with primary operable breast cancer, and 61 patients with recurrent metastatic breast cancer. LSA levels were determined before and after mastectomy and during chemotherapy in selected patients to determine the value of LSA in monitoring therapy and predicting response. LSA levels greater than 20 mg/dl were not seen in normal subjects but were present in patients with benign breast disease (13%), primary breast cancer (47%) and recurrent metastatic breast cancer (62%). LSA levels decreased after initiation of chemotherapy and remained low in patients clinically disease‐free. Recurrences were associated with elevated LSA in patients failing chemotherapy or endocrine ablative surgery. LSA measurements appeared to be of limited value in the detection of breast cancer but serial measurements may be useful in assessing disease progression and identifying patients resistant to therapy. Cancer 50:1815‐1819, 1982.

Dietary intake and blood levels of lycopene: association with cervical dysplasia among non-Hispanic, black women.

We examined whether elevated levels of retinoids, carotenoids, folate, and vitamin E protected against cervical dysplasia among non-Hispanic, black women. We enrolled 32 women with incident cervical dysplasia, including cervical intraepithelial neoplasia (CIN) I, CIN II, and CIN III/carcinoma in situ, and 113 control women with normal cervical cytology in case-control study. Micronutrient levels were estimated from a food-frequency questionnaire (FFQ) and measured from blood samples. Information on risk factors for cervical neoplasia was elicited by interview. Hybrid capture was used to determine infection with human papillomavirus. After adjustment for potential confounders, analysis of micronutrient levels estimated from the FFQ suggested that women in the upper tertile of lycopene and vitamin A intake were one-third (odds ratio = 0.32, 95% confidence interval = 0.8-1.3) and one-fourth (odds ratio = 0.24, 95% confidence interval = 0.05-1.2) as likely, respectively, to have dysplasia as women in the lower tertile. Borderline protective trends (p < or = 0.10) were apparent. Elevated levels of serum lycopene also suggested some protection against dysplasia. Results were not significant at alpha = 0.05 because of the small number of case women enrolled. Overall, correlations between estimates from the FFQ and serum levels were poor. This study indicates that, among black women, lycopene and perhaps vitamin A may play a protective role in the early stages of cervical carcinogenesis.