INT2 and ERBB2 amplification and ERBB2 expression in breast tumors from patients with different outcomes

Summary The relationships of INT2 and ERBB2 amplification and of ERBB2 overexpression in primary breast tumors to prognostic factors, recurrence, and survival have generated considerable controversy. The rationale for this study is that long-term, recurrence-free survival is a more direct criterion for testing the validity of a tumor marker than correlation either with prognostic factors or with short-term recurrence and survival. We examined the association of recurrence with INT2 and ERBB2 amplification and ERBB2 expression by comparing primary breast tumors from patients surviving without recurrence for 8.5 years after diagnosis. the LTS group, to tumors from patients recurring within two years, the RR group. The RR (N = 63) and LTS (N = 61) samples were coded and examined for amplification by Southern blotting and for expression by immunohistochemistry. Comparison between the RR and LTS groups demonstrated that INT2 amplification was associated with a significantly (P = 0.018) higher (5.6-fold) risk of recurrence, an association that remained significant after controlling for lymph node (LN), tumor size (TS), and histograde (HG) status. ERBB2 amplification and expression were not associated with a higher recurrence risk. Survival analyses within the RR group, however, demonstrated significantly shorter survival time among cases with than without ERBB2 amplification (P = 0.018, median survival 16 vs 25 months), or ERBB2 expression (P = 0.019, median survival 15 vs 25 months), but not INT2 amplification. Univariate Cox proportional hazards regression models also demonstrated significantly shorter survival among cases with ERBB2 amplification (P = 0.016) or expression (P = 0.049), that remained significant in multivariate analyses (P = 0.022) for ERBB2 amplification. These results indicate a significant positive association between INT2 amplification and risk for tumor recurrence in the RR as compared to the LTS group. The relationship of ERBB2 amplification or overexpression to patient outcome is more complex. ERBB2 amplification and expression have a significant relationship with shorter survival among patients recurrent within two years, but their occurrence in tumors from women surviving without recurrence for 8.5 years suggests that ERBB2 status is not predictive of shorter survival for all breast cancers.     

Electroconvulsive Therapy in Adolescents

Because of the limited number of case reports on the use of electroconvulsive therapy (ECT) in adolescent psychiatric patients, we retrospectively reviewed the medical records of 20 young patients who underwent ECT. They constituted all the patients 相似文献   

Development of fluridil,a topical suppressor of the androgen receptor in androgenetic alopecia

Nonsteroidal antiandrogens (AA) cannot be topically used for androgenetic alopecia (AGA) because of systemic resorption. A new class of androgen receptor (AR) suppressors designed for safe topical treatment of AGA was synthesized from (3‐amino‐2‐hydroxy‐2‐methyl‐N‐(4‐nitro‐3‐trifluoromethyl)phenyl) propanamide (BP‐34), to contain perfluoroalkyl moieties. The trifluoromethyl derivative (fluridil) at 10 μM decreased expression of the AR in LNCaP human cells by 95%, its serum half‐life was 6 h; it decomposes hydrolytically to BP‐34 and trifluoroacetic acid. Acute intraperitoneal maximum tolerated dose (MTD) of fluridil in mice is 270–300 mg/kg/d and the subacute MTD is 450 mg/kg/d. The oral LD₅₀ in mice was 2,872 mg/kg in males, 2,232 mg/kg in females, and >2,500 mg/kg in rats. Fluridil solution in isopropanol was not cutaneously absorbed in rabbits, did not sensitize or show any phototoxic or photoallergic effects on guinea pig skin, and demonstrated no skin irritation potential in rabbits and humans. Fluridil solid induced only slight and reversible eye irritancy in rabbits and displayed no cytotoxicity to rabbit corneal fibroblasts in vitro. Fluridil demonstrated no significant mutagenicity potential by Ames method. In a double‐blind study, 43 males with AGA, Norwood grade II to Va, used topical 2% fluridil in isopropanol or the vehicle daily for 12 months. Anagens (growing hairs) increased in the fluridil group from 76% to 89%. All hematological and biochemistry values remained within normal range, including testosterone, which varied but seasonally. No fluridil or its decomposition product (BP‐34) was detected in serum. No adverse side effects were reported. Drug Dev. Res. 59:292–306, 2003. © 2003 Wiley‐Liss, Inc.     

Bioactive suture: a novel immunotherapy for head and neck cancer.

PURPOSE: We have proposed to characterize the mechanism through which bioactive surgical sutures generate a T(H)1 immune response and to define the immune-stimulating half-life of the sutures. EXPERIMENTAL DESIGN: Bioactive sutures of interferon gamma (IFNgamma), interleukin 2 (IL-2), anti-CD3/CD28, anti-CD3/CD28 + IL-2, or anti-CD3/CD28 + IFNgamma sutures were used to stimulate lymphocytes from normal donors and from head and neck cancer patients in vitro over a 24-day period. Cell supernatants were analyzed by ELISA, and T cells were phenotyped to characterize the immune response generated. Intracellular cytokine staining was performed to measure the expansion of flu-specific T cells. Electromobility shift assay and supershift assay were used to measure the intranuclear DNA binding activity of nuclear factor kappaB and its p65 subunit in T cells activated by sutures in the presence and absence of a proteasome inhibitor, MG-132. RESULTS: Anti-CD3/CD28, anti-CD3/CD28 + IL-2, or anti-CD3/CD28 + IFNgamma generated a prolonged T(H)1 immune response for 18 days in vitro. Anti-CD3/CD28 expanded flu-specific T cells. Activated T cells demonstrated enhanced CD40 ligand (CD40L) expression within 72 hours of stimulation, which stimulated other cells to secrete IL-12. Stimulated T cells demonstrated increased intranuclear expression of nuclear factor-kappaB, which was blocked by MG-132, and also reduced CD40L and IL-12 expression. CONCLUSIONS: This is the first report to demonstrate that bioactive surgical sutures can generate a prolonged T(H)1 immune response and expand flu-specific T cells. Bioactive sutures, which are primarily a T-cell stimulant, also stimulated other cells to secrete IL-12 and prolonged the immune response. Sutures may provide a novel in situ stimulating strategy for enhancing the immune system of cancer patients.     

Phase II trial of gefitinib in recurrent glioblastoma.

PURPOSE: To evaluate the efficacy and tolerability of gefitinib (ZD1839, Iressa; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. PATIENTS AND METHODS: This was an open-label, single-center phase II trial. Fifty-seven patients with first recurrence of a glioblastoma who were previously treated with surgical resection, radiation, and usually chemotherapy underwent an open biopsy or resection at evaluation for confirmation of tumor recurrence. Each patient initially received 500 mg of gefitinib orally once daily; dose escalation to 750 mg then 1,000 mg, if a patient received enzyme-inducing antiepileptic drugs or dexamethasone, was allowed within each patient. RESULTS: Although no objective tumor responses were seen among the 53 assessable patients, only 21% of patients (11 of 53 patients) had measurable disease at treatment initiation. Seventeen percent of patients (nine of 53 patients) underwent at least six 4-week cycles, and the 6-month event-free survival (EFS) was 13% (seven of 53 patients). The median EFS time was 8.1 weeks, and the median overall survival (OS) time from treatment initiation was 39.4 weeks. Adverse events were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent at higher doses. Withdrawal caused by drug-related adverse events occurred in 6% of patients (three of 53 patients). Although the presence of diarrhea positively predicted favorable OS from treatment initiation, epidermal growth factor receptor expression did not correlate with either EFS or OS. CONCLUSION: Gefitinib is well tolerated and has activity in patients with recurrent glioblastoma. Further study of this agent at higher doses is warranted.     

Nonsteroidal anti-inflammatory drug use associated with reduced incidence of adenocarcinomas of the esophagus and gastric cardia that overexpress cyclin D1: a population-based study.

This study was undertaken to determine whether selected risk factors for esophageal and gastric cancer are associated with tumors that overexpress cyclin D1. Archived tumor tissue was available for 630 esophageal and gastric cancer patients who participated in a population-based case-control study. Patients were categorized into case groups based on whether protein overexpression of the cyclin D1 gene, as assessed by immunohistochemistry, was present (cyclin D1+, n = 285) or not (cyclin D1-, n = 345) in the tumor. The distribution of risk factors in each of these case groups was then compared with the distribution among the 695 controls. Multivariate-adjusted odds ratios (OR) for esophageal adenocarcinoma were reduced in relation to use of aspirin and other nonsteroidal anti-inflammatory drug (NSAID) use but only among patients with cyclin D1+ tumors (0.45, 95% confidence interval [CI] = 0.26, 0.79) and not among those with cyclin D1- tumors (1.12, 95% CI = 0.67, 1.86). A similar pattern was observed for gastric cardia adenocarcinomas. In contrast, ORs for esophageal squamous cell carcinoma and noncardia gastric adenocarcinomas in relation to NSAID use were reduced, regardless of cyclin D1 status. ORs did not vary with cyclin D1 status in relation to alcohol, body size, or cigarette smoking, with the following exception; for noncardia gastric adenocarcinomas the cyclin D1- tumors showed a 2-fold elevation in the OR with ever smoking. These data suggest that the reduction in risk associated with NSAID use may be restricted to those esophageal and gastric cardia adenocarcinomas that overexpress cyclin D1.     

Colorectal cancer screening knowledge, attitudes, and beliefs among veterans: does literacy make a difference?

PURPOSE: To evaluate whether lower literacy is associated with poorer knowledge and more negative attitudes and beliefs toward colorectal cancer screening among veterans without recent colorectal cancer screening. PATIENTS AND METHODS: Three hundred seventy-seven male veterans, age 50 years and older, who had not undergone recent colorectal cancer screening, were surveyed about their knowledge, attitudes, and beliefs regarding colorectal cancer screening. Patients' literacy was assessed with the Rapid Estimate of Adult Literacy in Medicine, an individually administered screening test for reading. RESULTS: Thirty-six percent of the 377 men had an eighth grade literacy level or higher. Men with lower literacy were 3.5 times as likely not to have heard about colorectal cancer (8.8% v 2.5%; P =.006), 1.5 times as likely not to know about screening tests (58.4% v 40.9%; P =.0001), and were more likely to have negative attitudes about fecal occult blood testing (FOBT), but not about flexible sigmoidoscopy. Specifically, men with lower literacy skills were two times as likely to be worried that FOBT was messy (26.7% v 13.3%; P =.008), 1.5 times as likely to feel that FOBT was inconvenient (28.7% v 18%; P =.05), and four times as likely to state they would not use an FOBT kit even if their physician recommended it (17.9% v 4.0%; P =.02). CONCLUSION: Limited literacy may be an overlooked barrier in colorectal cancer screening among veterans.     

A phase II study of carboplatin and paclitaxel in esophageal cancer.

BACKGROUND: This study was conducted to evaluate the efficacy and toxicity of combination carboplatin and paclitaxel in patients with esophageal cancer. MATERIALS AND METHODS: Thirty-five patients were enrolled. Patients were treated with paclitaxel 200 mg/m(2) intravenously (i.v.) over 3 h and carboplatin i.v. at an AUC of 5 mg/h/ml. Thirty-three patients were assessable for toxicity and objective response. RESULTS: A total of 166 treatment courses were administered with a median of five courses per patient. The objective response rate was 43% [90% confidence interval (CI) 0.3-0.58] by the intention-to-treat analysis. The median response duration was 2.8 months (90% CI 2.1-5.4). The median survival time was 9 months (90% CI 7-13.8) and the 1-year survival rate was 43% (90% CI 0.29-0.57). The major grade 3-4 toxicity observed was neutropenia, occurring in 17 patients (52%). There were no treatment-related deaths. CONCLUSIONS: The combination of carboplatin and paclitaxel is an moderately active and tolerable regimen in advanced esophageal cancer.