Divorce and Its Effects on Children

In any given case, the developmental stage of the child, the parental attitude, the financial situation, the custody battle, the visitation policies, the interactions between parents prior to and after divorce and the openness with which the subject is approached will interact to produce some effect, positive or negative, on the child. The question is, as professionals, what can we do to reduce the negative effects for this population at risk? It is comforting to note that the suffering caused by family disruptions, in general, are temporary. But there is no reason why school personnel, armed with appropriate information and understanding, cannot help to make the transition a little easier for the children. "For the sake of the children" should not be just a phrase associated with keeping unhappy marriages intact.     

Prostatic neoplasia in transgenic mice with prostate-directed overexpression of the c-myc oncoprotein

BACKGROUND: Promoter elements within the 5' DNA region of the rat C(3)1 gene have been shown to direct prostate-specific expression of gene products when they are fused through recombinant DNA procedures and used to produce transgenic mice. In order to test the in vivo effects of chronic overexpression of the mouse c-myc protooncogene on the prostate glands of transgenic mice, we created several lines of C(3)1-c-myc transgenic mice and then examined the phenotype of males with this genetic alteration. METHODS: The modified promoter and 5' region of the rat C(3)1 gene was fused to the coding region of the mouse c-myc gene using recombinant DNA techniques. This DNA was used to create three different founder lines of transgenic mice. Tissues from males and females heterozygous for the transgene were examined for expression of the recombinant mouse c-myc mRNA by an RNase protection assay. Prostates from males were examined for expression of recombinant c-myc mRNA by in situ hybridization. Thin sections of fixed ventral prostates from males were analyzed by microscopy for histological abnormalities. RESULTS: Three different lines of transgenic mice were obtained from these procedures. These mice demonstrated expression of recombinant mouse c-myc mRNA in the testis and ventral prostates of males and in the uterus of females. In situ hybridization demonstrated that the epithelial cells were the source of recombinant c-myc expression in the ventral prostates of the transgenic lines. Microscopic analysis of the ventral prostates from these mice demonstrated abnormalities in epithelial cell morphology seemingly typical of an intraepithelial neoplasia-like phenotype. However, none of the males of any of the lines developed overt prostatic adenocarcinoma over their lifetimes. CONCLUSIONS: Chronic overexpression of c-myc in the ventral prostate epithelial cells of C3(1)-c-myc transgenic mice leads to the development of epithelial cell abnormalities similar to those seen in low-grade prostatic intraepithelial neoplasia in humans. These abnormalities were not found to progress to adenocarcinoma over the lifetimes of the transgenic mice, suggesting the need for additional oncogenic changes in the pathway to prostatic adenocarcinomas. Furthermore, our cumulative experience with the use of the C3(1) gene promoter in the generation of transgenic mice suggests that the probasin promoter element provides a much more specific and effective means to target transgenes to the prostate glands of mice.     

Epothilones: mechanism of action and biologic activity.

Drugs that target microtubules are among the most commonly prescribed anticancer therapies. Although the mechanisms by which perturbation of microtubule function leads to selective death of cancer cells remain unclear, several new microtubule-targeting compounds are undergoing clinical testing. In part, these efforts focus on overcoming some of the problems associated with taxane-based therapies, including formulation and administration difficulties and susceptibility to resistance conferred by P-glycoprotein. Epothilones have emerged from these efforts as a promising new class of anticancer drugs. Preclinical studies indicate that epothilones bind to and stabilize microtubules in a manner similar but not identical to that of paclitaxel and that epothilones are effective in paclitaxel-resistant tumor models. Clinical phase I and early phase II data are available for BMS-247550, BMS-310705, EPO906, and KOS-862. The results suggest that these compounds have a broad range of antitumor activity at doses and schedules associated with tolerable side effects.     

Abrogation of head and neck squamous cell carcinoma growth by epidermal growth factor receptor ligand fused to pseudomonas exotoxin transforming growth factor alpha-PE38.

PURPOSE: This study was undertaken to determine whether low intratumoral doses of the epidermal growth factor receptor ligand-transforming growth factor alpha (TGF-alpha) fused to Pseudomonas exotoxin (TGF-alpha-PE38)-abrogated head and neck squamous cell carcinoma (HNSCC) tumor growth in vitro and in vivo. EXPERIMENTAL DESIGN: In vitro cytotoxicity assays were carried out to determine the sensitivity of HNSCC cells to TGF-alpha-PE38. TGF-alpha-PE38-treated HNSCC cells were examined by immunoblotting for cleaved poly(ADP-ribose) polymerase to evaluate apoptosis. Nude mice bearing established HNSCC xenografts were treated with several doses of TGF-alpha-PE38 to evaluate the antitumor efficacy in vivo. Tumor sections were stained with terminal deoxynucleotidyl transferase-mediated nick end labeling for apoptosis. To determine the effect of oral administration of TGF-alpha-PE38, gavage injections of TGF-alpha-PE38 were administered, and the esophagus and surrounding soft tissue were then stained for apoptotic cells. RESULTS: HNSCC cell lines examined were sensitive to low doses of TGF-alpha-PE38 (EC(50) in the range of 1.6 to 10 ng/mL). HNSCC cells treated with TGF-alpha-PE38 undergo apoptosis. Antitumor effects were observed using 0.1 and 0.03 microg of TGF-alpha-PE38 administered intratumorally. At these doses, the treatment was well tolerated. Tumors treated with the toxin had a higher number of apoptotic cells compared with the control tumors. No apoptotic cells were observed in the pharyngoesophageal tissues of the mice after gavage administration of the toxin suggesting that the toxin could be orally administered without toxicity. CONCLUSIONS: These results indicate that topical or intratumoral administration of low doses of TGF-alpha-PE38 may demonstrate antitumor effects in HNSCC without associated systemic toxicity.     

Relationship and significance of greatest percentage of tumor and perineural invasion on needle biopsy in prostatic adenocarcinoma

Serum prostate-specific antigen (PSA) levels and the biopsy Gleason sum are used along with clinical staging to predict prostatectomy pathology results for men with localized prostate cancer. The additional predictive value of perineural invasion (PNI) in pretreatment prostate needle biopsies for evaluating tumor stage in this setting is controversial. The current study evaluates the independent predictive value of PNI for tumor staging in a cohort of 632 men who underwent radical retropubic prostatectomies for clinically localized adenocarcinoma of the prostate between the years 1994 and 1998. None of these men received hormonal or radiation therapy before surgery. In addition to the Gleason sum, biopsy results contained detailed information regarding tumor burden: 1) total number of biopsy cores involved by adenocarcinoma, 2) greatest percentage of any single biopsy involved by prostate carcinoma (GPC), and 3) total percentage of cancer added over all cores (TPC). The presence or absence of any PNI was recorded. Pretreatment factors were analyzed in a univariate and multivariate fashion to determine their predictive value using the TNM tumor stage (pT2 vs pT3) and the modified tumor staging system, which includes surgical margin status (pT2 vs pT3 or positive surgical margin) as end points. Univariate analysis revealed a significant association between pT3 disease and several preoperative factors including age, Gleason sum, serum PSA, digital rectal examination, PNI, GPC, TPC, and the total number of positive cores (p <0.01). Multivariate analysis indicated that serum PSA, Gleason sum, age, and GPC contributed significantly to predicting pT3 disease with odds ratios of 2.7 (95% CI, 1.7-4.3), 2.3 (95% CI, 1.7-3.1), 1.7 (95% CI, 1.1-2.7), and 1.7 (95% CI, 1.4-2.1) respectively. PNI was significant in multivariate analysis only when GPC and TPC were not considered, due to a significant interaction between GPC and PNI (p <0.0001, Wilcoxon's rank sum test). These predictive factors showed a similar relationship to adverse pathology when an alternative definition of adverse pathology was used that included positive surgical margins (pT3 or any positive margin). In the interaction between GPC and PNI, GPC was more significant than PNI in predicting pT3 disease. However, PNI added additional information when adverse pathology was defined more broadly as pT3 or any positive margin.     

Bladder neck-sparing modification of radical prostatectomy adversely affects surgical margins in pathologic T3a prostate cancer

OBJECTIVES: To determine whether the bladder neck-sparing (BNS) modification of radical retropubic prostatectomy (RRP) alters the likelihood of positive surgical margins and postsurgical prostate cancer recurrence. METHODS: Surgical outcomes, as measured by pathologic margin status and progression-free survival, were evaluated in 751 consecutive RRP cases, among whom 222 underwent BNS technique. To reduce selection bias, comparison of positive margin rates between BNS and standard RRP was stratified by pathologic stage. Differences in surgical margin rates were assessed using the chi-square test, and effects of bladder neck preservation on prostate-specific antigen (PSA)-free survival were assessed, using multivariable Cox proportional hazards analysis. RESULTS: The clinical stage, Gleason score, and preoperative serum PSA profiles were similarly distributed between patients undergoing standard RRP and those undergoing the BNS modification. Surgical margins in the unstratified entire cohort were positive at rates similar to prior reports (28% BNS, 27% standard RRP). However, stratification by pathologic stage revealed that among pT3a cancers, BNS surgery was associated with significantly higher rates of positive surgical margins than was standard RRP (47% versus 20%; chi- square = 6.32, P = 0.01). Differences in positive margin rates were not seen between the two groups at other pathologic stages. The adverse effect of BNS technique on pT3a surgical margins was associated with a trend toward an adverse effect on PSA-free survival (Cox proportional hazards P = 0.016). CONCLUSIONS: The BNS modification of RRP can be associated with an increased rate of positive surgical margins specifically in cancers that have focally penetrated through the prostatic capsule (pT3a), with an associated trend toward decreased PSA-free survival in this group. BNS surgery may, therefore, compromise the ability to completely remove a subset of cancers focally penetrating the prostatic capsule.