Mercury induces inflammatory mediator release from human mast cells

Background  

Mercury is known to be neurotoxic, but its effects on the immune system are less well known. Mast cells are involved in allergic reactions, but also in innate and acquired immunity, as well as in inflammation. Many patients with Autism Spectrum Disorders (ASD) have "allergic" symptoms; moreover, the prevalence of ASD in patients with mastocytosis, characterized by numerous hyperactive mast cells in most tissues, is 10-fold higher than the general population suggesting mast cell involvement. We, therefore, investigated the effect of mercuric chloride (HgCl₂) on human mast cell activation.     

Phase II pilot study of combined chemohormonal therapy with doxorubicin and estramustine in metastatic prostate cancer

Twenty-nine patients with progressive hormone-refractory metastatic adenocarcinoma of the prostate were treated with daily estramustine phosphate at 10 mg/kg, and I.V. doxorubicin 50 mg/m2 every 3 weeks. Twenty-six patients were evaluable. Four of seven patients with nonosseous measurable disease had partial responses lasting 3 to 10 months. Eleven of 19 patients with osseous metastases had stable disease or improvement on bone scan, 6 of these for 7 months or longer. Median time to progression was 20 weeks, and the median survival was 43 weeks.     

Absence of a correlation of androgen receptor gene CAG repeat length and prostate cancer risk in an African-American population

Shorter androgen receptor gene CAG repeat length has been associated with an increased risk of prostate cancer, an earlier age of onset, and more advanced stage of disease. Studies comparing the distribution of CAG repeat lengths within different populations have reported that racial groups with higher prostate cancer incidence also have shorter CAG repeat lengths. We evaluated CAG repeat length in 685 black men in Louisiana, South Carolina, and the District of Columbia who were participating in prostate cancer screening, comparing the 118 who were diagnosed with prostate cancer with 567 who had normal serum prostate-specific antigen levels and no evidence of cancer on digital rectal examination. The median CAG repeat length was 21 among cases and 19 among controls (P = 0.11). Cases were significantly older than controls, with a median age of 68 years compared with 54 years (P < 0.0001). After adjusting for age, we found no association between prostate cancer risk and CAG repeat length (odds ratio, 1.05; 95% CI, 0.98-1.13; P = 0.16). Dividing CAG repeat lengths into septiles and calculating the odds ratio for each revealed no specific repeat-length range with a significantly elevated or depressed risk of prostate cancer, but a trend test showed a significant association between longer CAG repeat lengths and an elevated risk of prostate cancer (P = 0.02). Neither grade nor stage was associated with CAG repeat length. This study confirms earlier reports that black men have shorter CAG repeat lengths than reported white and Asian populations. We did not find an increased risk of prostate cancer among black men with fewer CAG repeats.     

Phase II study of carboxyamidotriazole in patients with advanced renal cell carcinoma refractory to immunotherapy: E4896, an Eastern Cooperative Oncology Group Study

BACKGROUND: The current study evaluated the response rate and 6-month time to disease progression of the antiangiogenesis agent carboxyamidotriazole (CAI) in patients with metastatic renal cell carcinoma (RCC). METHODS: Fifty-seven patients with histologically confirmed metastatic RCC that progressed after biologic therapy (interferon or interleukin-2) were enrolled. Four patients were ineligible. CAI was administered orally as a 28-day cycle. Response and time to disease progression were evaluated. RESULTS: Fifteen of 53 eligible patients received > 5 cycles, but 13 patients eventually discontinued treatment because of progressive disease. The majority of toxicities were Grade 1. However, Grade 3/4 toxicities did occur, the majority of which were gastrointestinal in nature. One of 47 patients evaluable achieved a partial response (1.9%) lasting 172 days. Six of 53 patients were alive and disease progression free at 6 months from the start of treatment (11.3%). The median overall survival was 12.5 months. The survival periods in the low-risk, intermediate-risk, and poor-risk groups were 16.2 months, 20.9 months, and 5.8 months, respectively. CONCLUSIONS: Patients in trials of second-line therapy appear to have a better prognosis than previously considered, in part because they are eligible for another clinical trial. CAI was found to have little to no effect on the natural history of progressive RCC.     

Phase II trial of gemcitabine and docetaxel in patients with advanced carcinoma of the urothelium: a trial of the Eastern Cooperative Oncology Group

BACKGROUND: Gemcitabine and docetaxel are active agents in advanced urothelial carcinoma. A Phase II trial of this combination was performed to determine the activity and toxicity of these agents in a multiinstitutional setting in patients previously treated with one prior chemotherapy regimen. METHODS: Twenty-nine eligible patients with advanced urothelial carcinoma were treated with docetaxel at a dose of 40 mg/m(2) over 1 hour followed by gemcitabine, 800 mg/m(2), over 30 minutes, both intravenously (i.v.) on Days 1 and 8. Cycles were repeated every 21 days until disease progression or a maximum of 6 cycles. RESULTS: Five patients obtained an objective response for an overall response rate of 17% (90% confidence interval, 7-33%). One patient achieved a complete clinical response. The median overall survival of the group was 7.7 months. Toxicity was moderate with granulocytopenia, anorexia, and fatigue being the most commonly noted side effects. CONCLUSIONS: Gemcitabine and docetaxel is an active second-line combination in patients with advanced urothelial carcinoma. Responses in visceral, lymph node, and soft tissues sites were observed. Granulocytopenia without fever, fatigue, and anorexia was common. Thromboembolic symptoms were reported and are of concern. The combination of gemcitabine and docetaxel has the potential to palliate a subset of previously treated patients with an adequate performance status.     

Mutations in ribonuclease L gene do not occur at a greater frequency in patients with familial prostate cancer compared with patients with sporadic prostate cancer

Several genetic loci are suspected to be involved in hereditary prostate cancer, including the hereditary prostate cancer 1 (HPC1) locus at chromosome 1q24-25. The ribonuclease L (RNase L) gene has been reported as the putative hereditary prostate cancer gene located at HPC1. If this is the case, mutations of RNase L should be found at a greater frequency in familial cancers than in sporadic prostate cancers. Examination of familial and sporadic cases of prostate cancer by polymerase chain reaction and DNA sequencing resulted in a mutational frequency rate that was not statistically different between the 2 forms of the disease. These results suggest that the mutations examined within this study are rare and may contribute to very few familial prostate cancers.     

Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer

BACKGROUND: Because the optimal timing of the institution of antiandrogen therapy for prostate cancer is controversial, we compared immediate and delayed treatment in patients who had minimal residual disease after radical prostatectomy. METHODS: Ninety-eight men who underwent radical prostatectomy and pelvic lymphadenectomy and who were found to have nodal metastases were randomly assigned to receive immediate antiandrogen therapy, with either goserelin, a synthetic agonist of gonadotropin-releasing hormone, or bilateral orchiectomy, or to be followed until disease progression. The patients were assessed quarterly during the first year and then semiannually. RESULTS: After a median of 7.1 years of follow-up, 7 of 47 men who received immediate antiandrogen treatment had died, as compared with 18 of 51 men in the observation group (P=0.02). The cause of death was prostate cancer in 3 men in the immediate-treatment group and in 16 men in the observation group (P<0.01). At the time of the last follow-up, 36 men in the immediate-treatment group (77 percent) and 9 men in the observation group (18 percent) were alive and had no evidence of recurrent disease, including undetectable serum prostate-specific antigen levels (P<0.001). In the observation group, the disease recurred in 42 men; 13 of the 36 who were treated had a complete response to local treatment or hormonal therapy (or both), 16 died of prostate cancer, and 1 died of another disease. The remaining men in this group were alive with progressive disease at the time of the last follow-up or had had a recent relapse. Except for the treatment group (immediate therapy or observation), no clinical or histologic characteristic significantly influenced the outcome. CONCLUSIONS: Immediate antiandrogen therapy after radical prostatectomy and pelvic lymphadenectomy improves survival and reduces the risk of recurrence in patients with node-positive prostate cancer.     

Leukemic recombinations involving heterochromatin in myeloproliferative disorders with t(1;9)

The unbalanced t(1;9) is a rare, recurrent rearrangement in polycythemia vera (PV) resulting in trisomy of both 1q and 9p arms, whereas a balanced t(1;9)(q12;q12), to our knowledge, has never been reported before. We studied two patients with PV and one with idiopathic myelofibrosis bearing an unbalanced t(1;9) and one patient with essential thrombocythemia with a balanced t(1;9). In all cases fluorescence in situ hybridization showed that the breakpoints were located within the satellite II family of heterochromatin of chromosome 1 and the satellite III of chromosome 9. Heterochromatin breakage and reunion produce the unbalanced t(1;9) and may contribute to a gene dosage effect due to gains of 1q and 9p. Case 4 with the balanced t(1;9), however, suggests that translocation of heterochromatin close to critical genes could interfere with their function. The molecular event underlying juxtaposition of satellite II of chromosome 1 and the satellite III of chromosome 9 remains to be elucidated.     

Patient-reported acute gastrointestinal toxicity in men receiving 3-dimensional conformal radiation therapy for prostate cancer with or without neoadjuvant androgen suppression therapy

OBJECTIVE: To investigate the impact of 2 months of neoadjuvant and 2 months of concurrent hormonal therapy on the acute gastrointestinal (GI) toxicities associated with 3-dimensional conformal radiation therapy (3D-CRT) for prostate adenocarcinoma. METHODS: The study cohort consisted of 80 men who underwent 3D-CRT with (n=40) or without (n=40) neoadjuvant and concurrent hormonal therapy. Computerized tomography-based planning occurred after neoadjuvant hormonal therapy. All patients completed a previously validated, quality-of-life self-assessment tool on 7 GI symptoms, including diarrhea, urgency, pain, rectal bleeding, cramping, mucus, and tenesmus, at baseline and weekly during radiation therapy. RESULTS: Patients who received hormonal therapy were more likely to have T2b, T2c, T3a, or T3b (P<0.001) or Gleason score 7, 8, or 9 (P=0.02) disease compared to those that did not. The dose delivered to the planning target volume was 70 Gy for both groups. Median radiation treatment volume was numerically smaller for the hormone group but not to a statistically significant degree (949 vs. 1043 cc, P=0.30). Patients who received hormonal therapy had less rectal pain (P<0.01) and tenesmus (P=0.02) but more rectal mucus (P=0.03) compared to those who did not. CONCLUSIONS: Prostate gland volume reduction after androgen suppression therapy may reduce patient-reported acute GI toxicities associated with 3D-CRT for prostate cancer.