Organic mercury compounds: human exposure and its relevance to public health

Humans may be exposed to organic forms of mercury by either inhalation, oral, or dermal routes, and the effects of such exposure depend upon both the type of mercury to which exposed and the magnitude of the exposure. In general, the effects of exposure to organic mercury are primarily neurologic, while a host of other organ systems may also be involved, including gastrointestinal, respiratory, hepatic, immune, dermal, and renal. While the primary source of exposure to organic mercury for most populations is the consumption of methylmercury-contaminated fish and shellfish, there are a number of other organomercurials to which humans might be exposed. The antibacterial and antifungal properties of organomercurials have resulted in their long use as topical disinfectants (thimerosal and merbromin) and preservatives in medical preparations (thimerosal) and grain products (both methyl and ethyl mercurials). Phenylmercury has been used in the past in paints, and dialkyl mercurials are still used in some industrial processes and in the calibration of certain analytical laboratory equipment. The effects of exposure to different organic mercurials by different routes of exposure are summarized in this article.     

Nerve growth factor and enhancement of proliferation,invasion, and tumorigenicity of pancreatic cancer cells

Nerve growth factor (NGF) exerts both stimulatory and inhibitory effects on neuronal and certain non-neuronal tumors. In pancreatic cancer NGF is overexpressed, and this overexpression is associated with increased perineural invasion. NGF has the potential to stimulate the growth of some pancreatic cancer cell lines, and this effect is mediated by the phosphorylation of tyrosine kinase receptor A and mitogen-activated protein kinase activation; it is dependent on the expression levels of tyrosine kinase receptor A and p75 receptors. To determine whether cancer cell-derived NGF can participate in the regulation of pancreatic cancer cell proliferation, PANC-1 human pancreatic cancer cells were stably transfected with a full-length human beta-NGF expression vector. In vitro and in vivo growth characteristics were analyzed by proliferation assays and invasion assays and in a nude mouse tumor model. Stable transfection of NGF in PANC-1 cells resulted in enhanced anchorage-dependent growth, with a decrease in doubling times of up to 50%, and in an approximately twofold increase in anchorage-independent cell growth and cell invasion. Furthermore, stably transfected PANC-1 cells showed enhanced tumorigenicity in nude mice. These results suggest that NGF has the capacity to act in a paracrine and/or an autocrine manner in pancreatic cancer and that it enhances cancer cell growth and invasion in vivo, thereby contributing to the aggressiveness and poor prognosis of this disease.     

Association of early life factors and acute lymphoblastic leukaemia in childhood: historical cohort study

In a historical cohort study of all singleton live births in Northern Ireland from 1971-86 (n=434,933) associations between early life factors and childhood acute lymphoblastic leukaemia were investigated. Multivariable analyses showed a positive association between high paternal age (> or =35 years) and acute lymphoblastic leukaemia (relative risk=1.49; 95% confidence interval (CI)=0.96--2.31) but no association with maternal age. High birth weight (> or =3500 g) was positively associated with acute lymphoblastic leukaemia (relative risk=1.66; 95% CI=1.18--2.33). Children of mothers with a previous miscarriage or increased gestation (> or =40 weeks) had reduced risks of ALL (respective relative risks=0.49; 95% CI=0.29--0.80, and 0.67; 95% CI=0.48--0.94). Children born into more crowded households (> or =1 person per room) had substantially lower risks than children born into less crowded homes with also some evidence of a lower risk for children born into homes with three adults (relative risks=0.56; 95% CI=0.35-0.91 and 0.58; 95% CI=0.21-1.61 respectively). These findings indicate that several early life factors, including living conditions in childhood and maternal miscarriage history, influence risk of acute lymphoblastic leukaemia in childhood.     

Cancer statistics for African Americans

The American Cancer Society provides estimates on the number of new cancer cases and deaths, and compiles health statistics on African Americans in a biennial publication, Cancer Facts and Figures for African Americans. The compiled statistics include cancer incidence, mortality, survival, and lifestyle behaviors using the most recent data on incidence and survival from the National Cancer Institute's (NCI) Surveillance, Epidemiology, and End Results (SEER) program, mortality data from the National Center for Health Statistics (NCHS), and behavioral information from the Behavior Risk Factor Surveillance System (BRFSS), Youth Risk Behavior Surveillance System (YRBSS), and National Health Interview Survey (NHIS). It is estimated that 132,700 new cases of cancer and 63,100 deaths will occur among African Americans in the year 2003. Although African Americans have experienced higher incidence and mortality rates of cancer than whites for many years, incidence rates have declined by 2.7 percent per year in African-American males since 1992, while stabilizing in African-American females. During the same period, death rates declined by 2.1 percent and 0.4 percent per year among African-American males and females, respectively. The decrease in both incidence and death rates from cancer among African-American males was the largest of any racial or ethnic group. Nonetheless, African Americans still carry the highest cancer burden among US racial and ethnic groups. Most cancers detectable by screening are diagnosed at a later stage and survival rates are lower within each stage of disease in African Americans than in whites. The extent to which these disparities reflect unequal access to health care versus other factors is an active area of research.     

Sequence-dependent synergistic cytotoxicity of ecteinascidin-743 and paclitaxel in human breast cancer cell lines in vitro and in vivo

Ecteinascidin 743 (ET-743) is a potent antitumor agent from the Caribbean tunicate Ecteinascidia turbinata and is presently in clinical trials for human cancers. The aim of this study was to assess the nature of the interaction between ET-743 and other antineoplastic agents using the combination index method of Chou and Talalay to better understand how ET-743 might be used clinically. We examined the cytotoxic effect of ET-743 combined with six other antineoplastic agents on human breast cancer cell lines, MX-1, MCF7, and P-glycoprotein overexpressing MCF7/DXR to different schedules. Pretreatment with paclitaxel for 24 h before ET-743 was the most effective combination regimen in all three breast cancer cell lines. Furthermore, sequential treatment with paclitaxel followed by ET-743 increased the antitumor effects in nude mice bearing MX-1 mammary carcinoma xenografts without increasing toxicity. These results suggest that the combination of ET-743 and paclitaxel should be assessed in clinical trials for the treatment of breast cancer.     

Posttreatment visual acuity in patients treated with episcleral plaque therapy for choroidal melanomas: dose and dose rate effects

PURPOSE: To determine the relationship between the long-term visual function and the dose and dose rates delivered to critical ocular structures in patients with choroidal melanoma treated with 125I episcleral plaque radiotherapy. MATERIALS AND METHODS: From 1987 to 1994, 63 patients underwent 125I episcleral plaque (Collaborative Ocular Melanoma Study [COMS] design) application for the treatment of choroidal melanoma. The mean tumor height was 4.5 mm (range 1.7-8.3). Doses and dose rates at the tumor apex, macula, and optic disc were calculated. Forty-three records were scored to assess whether a decrease in visual acuity of >2 lines on a standard Snellen eye chart had occurred. Patient age and the presence of hypertension or diabetes were noted. Statistical analysis was performed to assess both the rate at which visual decline had occurred and the presence of significant factors that had contributed to this decline. RESULTS: With a median follow-up of 36 months, the 3-year actuarial survival rate was 93.6%. The 3-year actuarial local control rate was 86.9%. The median time to visual loss after therapy was 18.7 months. The 3-year actuarial rate of visual preservation was 40.5%. Multivariate analysis demonstrated higher macula dose rates (p = 0.003) to forecast visual decline. Macula dose rates of 111 +/- 11.1 cGy/h were associated with a 50% risk of significant visual loss. CONCLUSION: Patients in our series treated with 125I plaque brachytherapy for choroidal melanoma experienced favorable tumor control, but with a measurable incidence of visual decline. Higher dose rates to the macula correlated strongly with poorer posttreatment visual outcome. This information may be valuable in selecting the optimal dose rates to treat choroidal melanomas and to predict the risk of visual decline.     

Soft tissue sarcoma brain metastases. Prevalence in a cohort of 3829 patients

BACKGROUND: Brain metastases from soft tissue sarcoma (STS) are uncommon. To the authors' knowledge limited information is available regarding the influence of the initial STS site, the significance of parenchymal versus leptomeningeal metastases, and the role of surgical resection. METHODS: STS patients evaluated between July 1982 and March 1999 who presented with or developed brain metastases were identified from a prospective database. Association between factors was determined using the Fisher exact test. Survival was estimated using the Kaplan-Meier method. The influence of factors on the endpoint (disease specific survival [DSS]) was analyzed using the log-rank test. Significance was defined at P < or = 0.05. RESULTS: A total of 3829 STS patients were evaluated during the study interval; 21 patients presented with and 19 patients subsequently developed brain metastases, accounting for < 1% (40 of 3829 patients) of the total patient group. The STS presentation status for this group of patients (n = 40) included 15 patients with primary STS, 1 patient with local recurrence, and 24 patients with metastatic disease. The most frequent types of STS metastasizing to the brain were leiomyosarcoma (eight patients), liposarcoma (five patients), rhabdomyosarcoma (four patients), and malignant fibrous histiocytoma (MFH) (four patients). Fourteen other sarcoma types were determined in the remaining 19 patients. Of the 19 patients who developed subsequent brain metastases, 18 had lung metastases as the immediate prior site of disease. The median overall follow-up for the 40 patients was 14 months (range, 1-128 months); for survivors (n = 5), the median overall follow-up was 18 months. During follow-up, 34 patients died of disease and 1 patient died of other causes. Brain metastasectomy was performed in 27 of the 40 patients and was highly associated with the initial site of STS; 20 of the 27 patients who underwent resection versus 2 of the 13 patients who did not undergo resection initially had extremity or trunk STS (P < 0.001). No association was observed between parenchymal versus leptomeningeal site of metastases and any outcome factor. The 1-year and 2-year overall DSS for the 40 patients was 55% and 25%, respectively, with a median survival of 15 months. The 1-year and 2-year postmetastasis survival rates were 34% and 20%, respectively, with a median survival of 7 months. Metastasectomy (n = 27) was associated with an improved median postmetastasis survival (9.6 months vs. 2.7 months for unresected patients; P < 0.01). The 2-year postmetastasis survival was 27% for those patients who underwent resection and 0% for the unresected patients. CONCLUSIONS: Although brain metastases from STS are rare, vigilance is warranted. Symptomatic patients should be examined neurologically and investigated thoroughly for metastases. Surgical resection may be an appropriate treatment for selected patients; however, survival is dismal.     

A randomized,placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma

BACKGROUND: Bone metastases are a common cause of morbidity in patients with prostate carcinoma. We studied the effect of a new bisphosphonate, zoledronic acid, which blocks bone destruction, on skeletal complications in prostate cancer patients with bone metastases. METHODS: Patients with hormone-refractory prostate cancer and a history of bone metastases were randomly assigned to a double-blind treatment regimen of intravenous zoledronic acid at 4 mg (N = 214), zoledronic acid at 8 mg (subsequently reduced to 4 mg; 8/4) (N = 221), or placebo (N = 208) every 3 weeks for 15 months. Proportions of patients with skeletal-related events, time to the first skeletal-related event, skeletal morbidity rate, pain and analgesic scores, disease progression, and safety were assessed. All statistical tests were two-sided. RESULTS: Approximately 38% of patients who received zoledronic acid at 4 mg, 28% who received zoledronic acid at 8/4 mg, and 31% who received placebo completed the study. A greater proportion of patients who received placebo had skeletal-related events than those who received zoledronic acid at 4 mg (44.2% versus 33.2%; difference = -11.0%, 95% confidence interval [CI] = -20.3% to -1.8%; P =.021) or those who received zoledronic acid at 8/4 mg (38.5%; difference versus placebo = -5.8%, 95% CI = -15.1% to 3.6%; P =.222). Median time to first skeletal-related event was 321 days for patients who received placebo, was not reached for patients who received zoledronic acid at 4 mg (P =.011 versus placebo), and was 363 days for those who received zoledronic acid at 8/4 mg (P =.491 versus placebo). Compared with urinary markers in patients who received placebo, urinary markers of bone resorption were statistically significantly decreased in patients who received zoledronic acid at either dose (P =.001). Pain and analgesic scores increased more in patients who received placebo than in patients who received zoledronic acid, but there were no differences in disease progression, performance status, or quality-of-life scores among the groups. Zoledronic acid at 4 mg given as a 15-minute infusion was well tolerated, but the 8-mg dose was associated with renal function deterioration. CONCLUSION: Zoledronic acid at 4 mg reduced skeletal-related events in prostate cancer patients with bone metastases.     

Phase I study of vinorelbine and docetaxel with granulocyte colony-stimulating factor support in the treatment of metastatic breast cancer

Purpose: Vinorelbine and docetaxel are two active agents in the treatment of metastatic breast cancer. When given together, these drugs exhibit synergistic antitumor activity without significant pharmacokinetic interaction. The dose-limiting toxicities of this combination are neutropenic fever and mucositis. Adding granulocyte colony-stimulating factor (G-CSF) might lessen the toxicity and increase the maximum tolerated dose (MTD) of this combination. The aim of this study was to determine the MTD of vinorelbine and docetaxel given in combination with G-CSF. Patients and methods: Between August 1997 and December 1998, 14 patients with metastatic breast cancer were enrolled in this study. All patients had received doxorubicin-based therapy, and 46% had received paclitaxel in the adjuvant or neoadjuvant setting. Patients were treated with vinorelbine at a starting dose of 20 mg/m ² intravenously over 10 min on days 1 and 5 and docetaxel at a starting dose of 85 mg/m ² intravenously over 1 hr on day 1, following the vinorelbine. Treatments were repeated every 21 days. Prophylactic G-CSF 5 mcg/kg was given subcutaneously on days 3-10. Toxicity was graded according to the National Cancer Institute's grading system. Results: A total of 65 cycles was administered at dose levels 0, -1, -2, and -3. The median absolute granulocyte count nadir for all courses was 200 mm^{- 3} (range, 0.1-7700 mm^{- 3}), and the median time to this nadir was 9 days (range, 7-30). The median platelet nadir was 163 (range, 27-401k), and the median time to this nadir was 8 days (range, 7-30). The most common grade 3 nonhematologic toxicities for all courses were fatigue and myalgia, which occurred in 32 and 10 cycles, respectively. Neutropenic fever was encountered in 11 cycles. Three patients developed colitis-like pictures, two of whom died as a result. Consequently, the protocol was closed to accrual before a MTD was reached. Conclusion: The combination of vinorelbine, docetaxel, and G-CSF in our hands has proven to be a toxic regimen, even when relatively low doses of vinorelbine and docetaxel are given. Meticulous observation of patients receiving this combination is warranted since the combination resulted in two deaths in this study.     

Gabapentin versus lamotrigine monotherapy: a double-blind comparison in newly diagnosed epilepsy

PURPOSE: This randomised, double-blind study compared the newer antiepileptic drugs (AEDs) gabapentin (GBP) and lamotrigine (LTG) as monotherapy in newly diagnosed epilepsy. METHODS: Patients with partial seizures with and/or without secondary generalization or primary generalized tonic-clonic seizures were randomized to either GBP or LTG. During 2- and 6-week titration periods, respectively, GBP dosage reached 1,800 mg/day, and LTG, 150 mg/day. In the subsequent 24-week maintenance phase, the dose could be adjusted based on seizure control or adverse events between 1,200 and 3,600 mg/day for GBP and 100 and 300 mg/day for LTG. The primary end point was time to exit, a composite of efficacy and tolerability. Evaluable patients were used for the primary efficacy analysis, whereas tolerability was examined on an intent-to-treat basis. RESULTS: A total of 309 patients was randomized, and 291 (148 GBP, 143 LTG) were included in the evaluable population. Nineteen patients in each group had an exit event. The median time to exit was 69 days for GBP and 48 days for LTG. The hazard ratio was estimated as 1.043 (90% confidence intervals, 0.602-1.809). Overall, 106 (71.6% of the evaluable population) GBP-treated and 96 (67.1%) LTG-treated patients completed the study. Of those, 80 (75.5%) patients taking GBP and 73 (76.0%) taking LTG remained seizure free during the final 12 weeks of treatment. Only 14 (8.9%) GBP-treated patients and 15 (9.9%) LTG-treated patients withdrew because of study drug-related adverse events. CONCLUSIONS: GBP and LTG monotherapy were similarly effective and well tolerated in patients with newly diagnosed epilepsy.