Multi-domain neurocognitive impairment following definitive intensity-modulated radiotherapy for nasopharyngeal cancer: A cross-sectional study.

INTRODUCTION: Neurocognitive impairment from inadvertent brain irradiation is common following intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC). This study aimed to determine the prevalence, pattern, and radiation dose-toxicity relationship of this late complication. MATERIALS AND METHODS: We undertook a cross-sectional study of 190 post-IMRT NPC survivors. Neurocognitive function was screened using the Montreal Cognitive Assessment-Hong Kong (HK-MoCA). Detailed assessments of eight distinct neurocognitive domains were conducted: intellectual capacity (WAIS-IV), attention span (Digit Span and Visual Spatial Span), visual memory (Visual Reproduction Span), verbal memory (Auditory Verbal Learning Test), processing speed (Color Trail Test), executive function (Stroop Test), motor dexterity (Grooved Pegboard Test) and language ability (Verbal Fluency Test). The mean percentiles and Z-scores were compared with normative population data. Associations between radiation dose and brain substructures were explored using multivariable logistic regression. RESULTS: The median post-IMRT interval was 7.0 years. The prevalence of impaired HK-MoCA was 25.3 % (48/190). Among the participants, 151 (79.4 %) exhibited impairments in at least one neurocognitive domain. The predominantly impaired domains included verbal memory (short-term: mean Z-score, -0.56, p < 0.001; long-term: mean Z-score, -0.70, p < 0.001), processing speed (basic: mean Z-score, -1.04, p < 0.001; advanced: mean Z-score, -0.38, p < 0.001), executive function (mean Z-score, -1.90, p < 0.001), and motor dexterity (dominant hand: mean Z-score, -0.97, p < 0.001). Radiation dose to the whole brain, hippocampus, and temporal lobe was associated with impairments in executive function, verbal memory, processing speed, and motor dexterity. CONCLUSIONS: Neurocognitive impairment is prevalent and profound in post-IMRT NPC survivors. Cognitive assessment and rehabilitation should be considered part of survivorship care.

Eligibility Criteria for Active Ulcerative Pyoderma Gangrenosum in Clinical Trials: A Delphi Consensus on Behalf of the UPGRADE (Understanding Pyoderma Gangrenosum: Review and Assessment of Disease Effects) Group.

At present, there are no standardized guidelines for determining patient eligibility for pyoderma gangrenosum (PG) clinical trials. Thus, we aim to determine which clinical features, histopathological features, or laboratory features should be included in active ulcerative PG clinical trial eligibility criteria for treatment-naïve patients and patients already treated with immunomodulating medications (treatment-exposed patients). This study employed 4 rounds of the Delphi technique. Electronic surveys were administered to 21 international board-certified dermatologists and plastic surgeon PG experts (June 2022-December 2022). Our results demonstrated that for a patient to be eligible for a PG trial, they must meet the following criteria: (i) presence of ulcer(s) with erythematous/violaceous undermining wound borders, (ii) presence of a painful or tender ulcer, (iii) history/presence of rapidly progressing disease, (iv) exclusion of infection and other causes of cutaneous ulceration, (v) biopsy for H&E staining, and (vi) a presence/history of pathergy. These criteria vary in importance for treatment-naïve versus treatment-exposed patients. Given the international cohort, we were unable to facilitate live discussions between rounds. This Delphi consensus study provides a set of specific, standardized eligibility criteria for PG clinical trials, thus addressing one of the main issues hampering progress toward Food and Drug Administration approval of medications for PG.

Development and Validation of a Simple Model to Predict the Risk of Nonmelanoma Skin Cancer on Screening Total Body Skin Examination.

Objective: There is insufficient evidence to generate skin cancer screening guidelines at the population level, resulting in arbitrary variation in patient selection for screening skin examinations. This study was aimed at developing an easy-to-use predictive model of nonmelanoma skin cancer (NMSC) risk on screening total body skin examination (TBSE). Methods: This epidemiologic assessment utilized data from a prospective, multicenter international study from primarily academic outpatient dermatology clinics. Potential predictors of NMSC on screening TBSE were identified and used to generate a multivariable model that was converted into a point-based scoring system. The performance characteristics of the model were validated in a second data set from two healthcare institutions in the United States. Results: 8,501 patients were included. Statistically significant predictors of NMSC on screening TBSE included age, skin phototype, and history of NMSC. A multivariable model and point-based scoring system using these predictors exhibited high discrimination (AUC = 0.82). Conclusion: A simple three-variable model, abbreviated as CAP (cancer history, age, phototype) can accurately predict the risk of NMSC on screening TBSE by dermatology. This tool may be used in clinical decision making to enhance the yield of screening TBSE.

Consensus-Based Recommendations on the Prevention of Squamous Cell Carcinoma in Solid Organ Transplant Recipients: A Delphi Consensus Statement.

IMPORTANCE: There is a paucity of evidence to guide physicians regarding prevention strategies for cutaneous squamous cell carcinoma (CSCC) in solid organ transplant recipients (SOTRs). OBJECTIVE: To examine the development and results of a Delphi process initiated to identify consensus-based medical management recommendations for prevention of CSCC in SOTRs. EVIDENCE REVIEW: Dermatologists with more than 5 years' experience treating SOTRs were invited to participate. A novel actinic damage and skin cancer index (AD-SCI), consisting of 6 ordinal stages corresponding to an increasing burden of actinic damage and CSCC, was used to guide survey design. Three sequential web-based surveys were administered from January 1, 2019, to December 31, 2020. Pursuant to Delphi principles, respondents thoroughly reviewed all peer responses between rounds. Supplemental questions were also asked to better understand panelists' rationale for their responses. FINDINGS: The Delphi panel comprised 48 dermatologists. Respondents represented 13 countries, with 27 (56%) from the US. Twenty-nine respondents (60%) were Mohs surgeons. Consensus was reached with 80% or higher concordance among respondents when presented with a statement, question, or management strategy pertaining to prevention of CSCC in SOTRs. A near-consensus category of 70% to less than 80% concordance was also defined. The AD-SCI stage-based recommendations were established if consensus or near-consensus was achieved. The panel was able to make recommendations for 5 of 6 AD-SCI stages. Key recommendations include the following: cryotherapy for scattered actinic keratosis (AK); field therapy for AK when grouped in 1 anatomical area, unless AKs are thick in which case field therapy and cryotherapy were recommended; combination lesion directed and field therapy with fluorouracil for field cancerized skin; and initiation of acitretin therapy and discussion of immunosuppression reduction or modification for patients who develop multiple skin cancers at a high rate (10 CSCCs per year) or develop high-risk CSCC (defined by a tumor with approximately ≥20% risk of nodal metastasis). No consensus recommendation was achieved for SOTRs with a first low risk CSCC. CONCLUSIONS AND RELEVANCE: Physicians may consider implementation of panel recommendations for prevention of CSCC in SOTRs while awaiting high-level-of-evidence data. Additional clinical trials are needed in areas where consensus was not reached.

Creation and Validation of Classification Criteria for Discoid Lupus Erythematosus.

Importance: Classification criteria are the standardized definitions that are used to enroll uniform cohorts for research studies. They emphasize high specificity and are distinct from diagnostic criteria. No universally recognized classification criteria currently exist for discoid lupus erythematosus (DLE), which has led to problematic heterogeneity in observational and interventional clinical studies across the field. Objective: To create and validate classification criteria for DLE using 12 previously defined candidate criteria items. Design, Setting, and Participants: For this diagnostic study, candidate criteria items were prospectively applied by dermatologists and dermatopathologists at clinical visits of patients with DLE or a condition that could be confused for DLE, termed a DLE mimicker, at academic dermatology practices across the United States, Poland, Japan, and South Korea. Data were collected from December 1, 2017, to February 1, 2019, and analyzed from March 1 to September 19, 2019. Main Outcomes and Measures: Clinical features among these 2 groups were calculated and compared with χ2 or Fisher exact tests. Candidate models were identified using best subsets logistic regression analysis. Improvement tests, fit statistics, and discrimination were considered to choose a final model. Results: Nine sites contributed 215 patients, 15 of whom had missing or incomplete data. The final model for DLE classification criteria includes only clinical variables: atrophic scarring (3 points), location in the conchal bowl (2 points), preference for the head and neck (2 points), dyspigmentation (1 point), follicular hyperkeratosis and/or plugging (1 point), and erythematous to violaceous in color (1 point), with an area under the receiving operating characteristic curve of 0.91 (95% CI, 0.87-0.95). A score of at least 5 points yields a sensitivity of 84.1% and a specificity of 75.9% in the classification of DLE, with increasing scores yielding higher specificity. Conclusions and Relevance: These findings provide the initial validation of classification criteria for DLE for use in observational and clinical trials.

Patient Perspectives on the Use of Artificial Intelligence for Skin Cancer Screening: A Qualitative Study.

Importance: The use of artificial intelligence (AI) is expanding throughout the field of medicine. In dermatology, researchers are evaluating the potential for direct-to-patient and clinician decision-support AI tools to classify skin lesions. Although AI is poised to change how patients engage in health care, patient perspectives remain poorly understood. Objective: To explore how patients conceptualize AI and perceive the use of AI for skin cancer screening. Design, Setting, and Participants: A qualitative study using a grounded theory approach to semistructured interview analysis was conducted in general dermatology clinics at the Brigham and Women's Hospital and melanoma clinics at the Dana-Farber Cancer Institute. Forty-eight patients were enrolled. Each interview was independently coded by 2 researchers with interrater reliability measurement; reconciled codes were used to assess code frequency. The study was conducted from May 6 to July 8, 2019. Main Outcomes and Measures: Artificial intelligence concept, perceived benefits and risks of AI, strengths and weaknesses of AI, AI implementation, response to conflict between human and AI clinical decision-making, and recommendation for or against AI. Results: Of 48 patients enrolled, 26 participants (54%) were women; mean (SD) age was 53.3 (21.7) years. Sixteen patients (33%) had a history of melanoma, 16 patients (33%) had a history of nonmelanoma skin cancer only, and 16 patients (33%) had no history of skin cancer. Twenty-four patients were interviewed about a direct-to-patient AI tool and 24 patients were interviewed about a clinician decision-support AI tool. Interrater reliability ratings for the 2 coding teams were κ = 0.94 and κ = 0.89. Patients primarily conceptualized AI in terms of cognition. Increased diagnostic speed (29 participants [60%]) and health care access (29 [60%]) were the most commonly perceived benefits of AI for skin cancer screening; increased patient anxiety was the most commonly perceived risk (19 [40%]). Patients perceived both more accurate diagnosis (33 [69%]) and less accurate diagnosis (41 [85%]) to be the greatest strength and weakness of AI, respectively. The dominant theme that emerged was the importance of symbiosis between humans and AI (45 [94%]). Seeking biopsy was the most common response to conflict between human and AI clinical decision-making (32 [67%]). Overall, 36 patients (75%) would recommend AI to family members and friends. Conclusions and Relevance: In this qualitative study, patients appeared to be receptive to the use of AI for skin cancer screening if implemented in a manner that preserves the integrity of the human physician-patient relationship.

TNF Inhibitor-Induced Psoriasis: Proposed Algorithm for Treatment and Management.

Tumor necrosis factor a (TNF-α)-targeted therapies have expanded the therapeutic options for patients with inflammatory bowel disease (IBD), rheumatoid arthritis (RA), psoriasis, and psoriatic arthritis (PsA) and have significantly improved patients' quality of life. Paradoxically, anti-TNF-α agents may induce psoriatic eruptions or worsen preexisting psoriatic skin disease. Currently, there is no standard approach for the management of TNF inhibitor-induced psoriasis. Here, we conduct a literature review on TNF inhibitor-induced psoriasis and introduce a novel treatment algorithm for maintaining otherwise effective anti-TNF therapy versus switching to a different class as appropriate in the management of patients with IBD, RA, psoriasis, or PsA.

Estrogen-induced aurora kinase-A (AURKA) gene expression is activated by GATA-3 in estrogen receptor-positive breast cancer cells.

Aurora-A is a proto-oncogenic mitotic kinase that is frequently overexpressed in human epithelial malignancies including in breast and ovarian cancers. The mechanism of transcriptional upregulation of Aurora-A in human breast cancer is not yet elucidated. We report herein that Aurora-A transcription is positively regulated by GATA-3 in response to estrogen in estrogen receptor α (ERα)-positive cells. Transient expression of aurora-A promoter deletion mutants in luciferase constructs identified a GATA binding sequence motif as a functional regulatory element in ERα-positive breast cancer cells. Electrophoretic mobility shift assay identified the binding of regulatory proteins to the GATA element. Anti-GATA-3 antibody generated a supershifted complex. Recruitment of GATA-3 to the aurora-A promoter was verified by chromatin immunoprecipitation analysis with GATA-3 antibody. Ectopic expression of GATA-3 resulted in elevated expression of Aurora-A in both ERα-positive and negative cells while siRNA-mediated silencing led to downregulation of endogenous Aurora-A in ERα-positive cells. Estrogen treatment of ERα-positive cells induced increased Aurora-A expression with enhanced recruitment of GATA-3 to the aurora-A promoter. Finally, in the ACI rat model of estrogen-induced breast cancer, known to be associated with elevated Aurora-A expression, we observed increased expression of GATA-3 in preinvasive and invasive mammary epithelial cells exposed to prolonged estrogen treatment and in developing breast tumors. These results demonstrate a direct positive role of estrogen in regulating Aurora-A expression through activation of the ERα-GATA-3 signaling cascade and suggest that this pathway may be critical in the origin of estrogen-stimulated sporadic breast cancer.

Specific overexpression of cyclin E·CDK2 in early preinvasive and primary breast tumors in female ACI rats induced by estrogen.

Overexpressed Aurora A, amplified centrosomes, and aneuploidy are salient features of estrogen-induced mammary preinvasive lesions and tumors in female August--Copenhagen Irish (ACI) rats. Intimately involved in these events are cyclins and their associated cyclin-dependent kinase (CDK) partners. Cyclin E1·CDK2 overexpression plays an important dual role in late G1/S phase of the cell cycle in cancer cells. It increases DNA replication providing growth advantage to cancer cells and facilitates aberrant centrosome duplication, generating chromosomal instability and aneuploidy leading to tumor development. Presented herein, a 24.0- and 45.0-fold elevation in cyclin E1 and CDK2 was found in 17ß-estradiol (E(2))-induced ACI rat mammary tumors (MTs), respectively. Cyclin E·CDK2 positive staining was confined to the large round cells found within focal dysplasias, ductal carcinomas in situ, and invasive MTs. Co-immunoprecipitation and in vitro kinase activity of these tumors revealed that these cell cycle entities are functional. When mammary tissue derived from untreated normal, E(2)-induced hyperplasia and primary tumors were normalized to cyclin E1 levels, low molecular weight (LMW) cyclin E1 forms (33- and 45-kDa) were detected in all of these tissue groups. Moreover, increasing concentrations of protease inhibitor in tissue lysates resulted in a marked reduction of LMW forms, indicating that the presence of cyclin E1 LMW forms can be markedly reduced. Significant increases in cyclin E1 mRNA (2.1-fold) were detected in primary ACI rat E(2)-induced breast tumors, and quantitative real-time polymerase chain reaction revealed a 20% amplification of the cyclin E1 gene (CCNE1). Collectively, these results support the involvement of cyclin E1·CDK2 in centrosome overduplication during each stage of E(2)-induced mammary tumorigenesis.

Expression of selected Aurora A kinase substrates in solely estrogen-induced ectopic uterine stem cell tumors in the Syrian hamster kidney.

Sustained over-expression of Aurora A (AurA), centrosome amplification, chromosomal instability, and aneuploidy are salient features that occur in high frequency in human breast premalignant stages and in primary ductal breast cancer (BC), as well as in 17beta-estradiol (E2)-induced oncogenesis in animal models. We have reported that AurA/B protein expression increases 8.7- and 4.6-fold, respectively, in primary E2-induced male Syrian hamster uterine stem cell-like tumors of the kidney (EUTK) when compared with cholesterol-treated control kidneys. Upon a 10-day E2-withdrawal or coadministration of tamoxifen citrate, a 78-79% and 81-64% reduction in AurA/B protein expression, respectively, were observed in primary tumors when compared with tumors from animals continuously exposed to E2. These data indicate that AurA/B expression is regulated by estrogens via estrogen receptor alpha. To determine whether this E2-induced over-expression of the Aur kinases may contribute to the alterations observed during oncogenesis via their phosphorylation of specific substrates, we analyzed the protein expression of histone H3 and targeting protein for Xklp2 (TPX2). Histone H3 and TPX2 were significantly over-expressed 3.7- and 1.6-fold, respectively, in E2-induced tumors when compared with cholesterol-treated control kidney samples. Immunohistochemistry revealed that TPX2 protein expression was essentially confined to tumor foci cells. Collectively, these data indicate that over-expression of AurA/B is under estrogen control and that the deregulation of Aur kinase protein substrates is implicated in eliciting the alterations observed during oncogenesis.

Aurora a and B overexpression and centrosome amplification in early estrogen-induced tumor foci in the Syrian hamster kidney: implications for chromosomal instability, aneuploidy, and neoplasia.

Estrogen-induced Syrian hamster tumors in the kidney represent a useful model to gain insight into the role of estrogens in oncogenic processes. We provided evidence that early tumor foci in the kidney arise from interstitial ectopic uterine-like germinal stem cells, and that early tumor foci and well-established tumors are highly aneuploid (92-94%). The molecular mechanisms whereby estrogens mediate this process are unclear. Here, we report that estrogen treatment induced significant increases in Aurora A protein expression (8.7-fold), activity (2.6-fold), mRNA (6.0-fold), and Aurora B protein expression (4.6-fold) in tumors, compared with age-matched cholesterol-treated kidneys. Immunohistochemistry revealed that this increase in Aurora A and B protein expression was essentially confined to cells within early and large tumor foci at 3.5 and 6 months of estrogen treatment, respectively. Upon estrogen withdrawal or coadministration of tamoxifen for 10 days, a 78% to 79% and 81% to 64% reduction in Aurora A and B expression, respectively, were observed in primary tumors compared with tumors continuously exposed to estrogens. These data indicate that overexpressed Aurora A and B in these tumors are under estrogen control via estrogen receptor alpha. Aurora A coenriched with the centrosome fraction isolated from tumors in the kidney. Centrosome amplification (number and area/cell) was detected in early tumor foci and large tumors but not in adjacent uninvolved or age-matched control kidneys. Taken together, these data indicate that persistent overexpression of Aurora A and B is under estrogen control, and is coincident with centrosome amplification, chromosomal instability, and aneuploidy, and represent an important mechanism driving tumorigenesis.

Mitotic kinases: the key to duplication, segregation, and cytokinesis errors, chromosomal instability, and oncogenesis.

Chromosomal instability (CIN) and aneuploidy are commonly observed in the vast majority of human solid tumors and in many hematological malignancies. These features are considered defining characteristics of human breast, bladder and kidney cancers since they markedly exceed a 50% aneuploidy frequency. The detection of persistent mitotic kinase over-expression, particularly the Aurora family, and centrosome amplification in precursor/pre-malignant stages, strongly implicate these molecular changes in precipitating the aneuploidy seen in many human neoplasms. Mitotic spindle checkpoint defects may also lead to aneuploid tumors. However, the sustained over-expression and activity of various members of the mitotic kinase families, including Aurora (Aur) (A, B, C), Polo-like (Plk1-4), and Nek (NIMA1-11) in diverse human tumors strongly indicate that these entities are intimately involved in the development of errors in centrosome duplication, chromosome segregation, and cytokinesis. Mitotic kinases have also been implicated in regulating the centrosome cycle, spindle checkpoint and microtubule-kinetochore attachment, spindle assembly, and chromosome condensation. These mitotic kinases are modulated by de-novo synthesis, stability factors, phosphorylation, and ubiquitin-dependent proteolysis. They, in turn, phosphorylate a myriad of centrosomal/mitotic protein substrates, and have the ability to behave as oncogenes (i.e. Aur-A, Plk-1), providing a compelling link between errors in mitosis and oncogenic processes. The recent development of selective small molecule inhibitors of Aurora kinases, in particular, will provide useful tools to ascertain more precisely their role in cancer development. Potent inhibitors of mitotic kinases, when fully developed, have the promise to be effective agents against tumor growth, and possibly, tumor prevention as well.

Overexpression of cyclins D1 and D3 during estrogen-induced breast oncogenesis in female ACI rats.

A common feature of human breast oncogenesis is cell cycle deregulation. The expression of cyclins D1 and D3 was examined during estradiol-17beta (E(2))-induced mammary tumorigenesis in female August Copenhagen Irish (ACI) rats. Low serum E(2) levels ( approximately 60-120 pg/ml) were sufficient to induce mammary gland tumors (MGTs) that remarkably resemble human ductal breast cancer (BC) at the histopathologic and molecular levels. Western blot analysis of the E(2)-induced MGTs revealed a marked rise in cyclins D1 (24-fold), D3 (9-fold) and cdk4 (3-fold) expression compared with age-matched untreated controls. Small focal dysplasias with large, pale staining nuclei were commonly seen at 3-3.6 months, large focal dysplasias, including atypical ductal hyperplasia at 3.6-4.3 months, ductal carcinoma in-situ (DCISs) at 4.3-5.0 months, and 100% incidence of invasive ductal BC/frank tumors at 5-6 months were detected after E(2) treatment. Immunohistochemical analysis of serial sections of focal dysplasias, DCISs and invasive ductal carcinomas showed overexpression of cyclins D1, D3, estrogen receptor-alpha (ERalpha) and progesterone receptor (PR). However, cyclin D3 expression, unlike D1, was confined essentially to early pre-malignant lesions (focal dysplasias and DCISs) and primary MGTs with <1-5% of resting and normal hyperplastic breast cells staining positive. The kinase activity for cyclins D1 and D3, using retinoblastoma (Rb) as a substrate, in E(2)-induced MGTs and their binding to cdk4 was significantly elevated. Semi-quantitative reverse transcriptase PCR analysis of the E(2)-induced MGTs exhibited increased expression of cyclins D1 (2.9-fold) and D3 (1.4-fold) mRNA, indicating that their elevated protein expression was due in part to an increase in mRNA transcription. However, when analyzed by quantitative real-time Q-PCR, these genes were not amplified. These data indicate that in female ACI rat mammary glands, E(2)-induced pre-malignant lesions differentially and selectively express cyclins D1 and D3, thus contributing to a distinct growth advantage of these pre-neoplasias relative to E(2)-elicited normal hyperplasia.

Estrogen mediates Aurora-A overexpression, centrosome amplification, chromosomal instability, and breast cancer in female ACI rats.

Estrogens play a crucial role in the causation and development of sporadic human breast cancer (BC). Chromosomal instability (CIN) is a defining trait of early human ductal carcinoma in situ (DCIS) and is believed to precipitate breast oncogenesis. We reported earlier that 100% of female ACI (August/Copenhagen/Irish) rats treated with essentially physiological serum levels of 17beta-estradiol lead to mammary gland tumors with histopathologic, cellular, molecular, and ploidy changes remarkably similar to those seen in human DCIS and invasive sporadic ductal BC. Aurora-A (Aur-A), a centrosome kinase, and centrosome amplification have been implicated in the origin of aneuploidy via CIN. After 4 mo of estradiol treatment, levels of Aur-A and centrosomal proteins, gamma-tubulin and centrin, rose significantly in female ACI rat mammary glands and remained elevated in mammary tumors at 5-6 mo of estrogen treatment. Centrosome amplification was initially detected at 3 mo of treatment in focal dysplasias, before DCIS. At 5-6 mo, 90% of the mammary tumor centrosomes were amplified. Comparative genomic hybridization revealed nonrandom amplified chromosome regions in seven chromosomes with a frequency of 55-82% in 11 primary tumors each from individual rats. Thus, we report that estrogen is causally linked via estrogen receptor alpha to Aur-A overexpression, centrosome amplification, CIN, and aneuploidy leading to BC in susceptible mammary gland cells.

Comparative genomic hybridization of estrogen-induced ectopic uterine-like stem cell neoplasms in the hamster kidney: nonrandom chromosomal alterations.

Karyotype and comparative genomic hybridization (CGH) analyses were performed to identify nonrandom/consistent chromosomal alterations in solely estrogen (E)-induced primary ectopic uterine-like stem cell tumors in the kidney (EULTK) of the Syrian hamster, using a criterion of >/=20% frequency for nonrandom occurrence. Employing this criterion, EULTK karyotype analysis showed consistent gains in chromosomes 3, 6, 11, 14, 16, 20, and 21. Consistent trisomies were seen in all of these nonrandomly gained chromosomes. Only chromosomes 3 and 6 exhibited appreciable tetrasomies. Chromosome losses were observed consistently in chromosomes 7, 12, 17, and 19. Employing the same criterion, CGH analysis of primary EULTKs showed nonrandom amplified sequences at 1pa1-a4, 2cen-pter, 3pa1-a4, 6qb2-b4, 20qa1-a4, 21qa1-a2, Xqa3-qter and regional consistent losses at 1qc1-qter, 2qb1-c1, 3qa2-a7, 11qb5-qter, 15qa2-a5, 18qa2-a4, and 21pa. Moreover, 88% of the EULTKs examined exhibited amplification of the 6qb2-b4 region, where c-myc resides. The data presented lend credence to the supposition that chromosomal instability (CIN) is elicited by the upstream overexpression and subsequent amplification of c-myc by Es in multipotential interstitial uterine stem cells present in the kidney, thus leading to neoplastic development.

Causation and prevention of solely estrogen-induced oncogenesis: similarities to human ductal breast cancer.

Estrogens are intimately involved in the causation of some of the most prevalent cancers afflicting women, particularly, breast, endometrial, cervico-vaginal, and possibly ovarian. Therefore, it has become particularly pertinent to elucidate the molecular changes and mechanisms whereby estrogens elicit their oncogenic actions so that better prevention strategies can be developed. The estrogen-induced Syrian hamster tumors of the kidney have emerged as one of the most intensively studied in-vivo models in solely estrogen-induced oncogenesis. An advantage of this model is that the tumors occur in the absence of any intervening morphologic changes, but rather they are the result of the continuous progression of a subset of interstitial stem cells in the kidney leading to tumor formation. Evidence is presented that the origin of these tumors is derived from ectopic "uterine" stem cells, which are responsive to estrogenic hormones. The other animal tumor model studied is the highly sensitive estrogen-induced mammary tumors of female ACI rats. Their steroid receptor and other gene alterations have been delineated. Importantly, a crucial early event in this solely estrogen-induced oncogenic process, common to both animal tumor models, is the overexpression and amplification of c-myc and its protein product. Chromosomal instability, in both early and large well-established frank tumors, is another important characteristic found during early E-induced oncogenesis. These features have been shown to be characteristic of human ductal carcinomas in-situ and in primary invasive ductal breast carcinomas. The molecular alterations seen are considered crucial in eliciting estrogen-induced oncogenesis and have established for the first time a direct causal link between estrogen and the induction of chromosomal instability and aneuploidy in these estrogen-associated neoplasms.

Catechol estrogen formation in liver microsomes from female ACI and Sprague-Dawley rats: comparison of 2- and 4-hydroxylation revisited.

Estradiol (E(2))-hydroxylation was studied in liver microsomes from ACI and Sprague-Dawley female rats, which differ markedly in their susceptibility to E(2)-induced formation of mammary tumors. NADPH-dependent oxidation of E(2) by liver microsomes from ACI and Sprague-Dawley rats produced several metabolites of which 2-hydroxyestradiol (2-OH-E(2)), estrone (E(1)), and 2-hydroxyestrone (2-OH-E(1)) were predominant. Incubations with either low (9 nM) or high (50 microM) concentrations of radiolabeled E(2) and with varying amounts of microsomal protein indicated the formation of only small amounts of 4-hydroxyestradiol (4-OH-E(2)). The ratio of 2-OH-E(2) to 4-OH-E(2) formed with the low concentration of E(2) was about 10:1 regardless of the amount of microsomal protein used, and about 20:1 using a high concentration of E(2). Thus, oxidation of E(2) by liver microsomes from female ACI and Sprague-Dawley rats occurs primarily via 2-hydroxylation, and 4-hydroxylation is only a minor pathway. These results are in disagreement with a recent report indicating substantial 4-hydroxylation of E(2) by liver microsomes from female ACI rats.