Preventative effect of celecoxib in dimethylbenz[a]anthracene-induced ovarian cancer in rats.

PURPOSE: The present study investigated the preventive effect of the cyclooxygenase (COX)-2 inhibitor, celecoxib, in 7,12-dimethylbenz[a]anthracene (DMBA)-induced ovarian cancer in a rat model. METHODS: A diet containing celecoxib (1500 ppm) was started 2 weeks before the introduction of DMBA. DMBA-soaked cotton threads were surgically applied to induce ovarian cancer in female Wistar rats. Tumor growth and survival were observed for 24 weeks. RESULTS: During the study period, an overall tumor incidence of 97.5% was observed and 65% of tumors were ovarian adenocarcinoma. The celecoxib diet significantly reduced the incidence and size of DMBA-induced ovarian cancers and significantly improved survival of tumor-bearing rats. The preventive effect of celecoxib was associated with increased apoptosis. CONCLUSION: DMBA-induced ovarian cancer in rats recapitulates many pathophysiological features of the human counterpart. Our results provide supportive evidence that celecoxib has a preventive effect on development of ovarian cancer in a rat model.

High Incidence of Carcinosarcoma among Patients Previously Treated with Tamoxifen.

BACKGROUND: Tamoxifen acts as an estrogen antagonist within the breast tissue. In the uterus, tamoxifen is an agonist for some estrogen receptors and therefore can cause hyperplasia or neoplasia in the endometrium. OBJECTIVES: To compare characteristics of patients with uterine sarcoma who were and were not previously treated with tamoxifen. METHODS: The medical records of all women with uterine sarcoma who had been treated at the Carmel Medical Center in Haifa, Israel, during 2000-2013 were retrospectively reviewed. Disease characteristics, histological type of sarcoma, patient demographics, treatments and final outcomes were compared between patients who had and those who had not been exposed to tamoxifen. RESULTS: Of the 66 patients identified, 14 (21%) had been exposed to tamoxifen, one of them for 3 years and 13 for at least 5 years. Mean ages were 69 ± 8 and 66 ± 12 years for those exposed and those not exposed to the drug, respectively. Rates of uterine carcinosarcoma were 86% (12/14) and 44% (23/52), respectively (P < 0.006). Patients with carcinosarcoma were older than other sarcoma patients (73 ± 7 vs. 59 ± 11 P < 0.005).There were no statistically significant differences between the two groups in rates of diabetes mellitus, hypertension, dyslipidemia or heart disease. The mean time from diagnosis to death was 7.37 ± 0.42 years. The overall survival rates of carcinosarcoma patients were not statistically different from that of other sarcoma patients. Tamoxifen exposure was not associated with overall survival among all sarcoma patients, nor among the subgroup of carcinosarcoma patients. CONCLUSIONS: Tamoxifen treatment was associated with elevated incidence of carcinosarcoma among women with uterine sarcoma, but was not found to be associated with prognosis or with co-morbidities.

Tumor characteristics and survival outcomes of women with tamoxifen-related uterine carcinosarcoma.

OBJECTIVE: To examine tumor characteristics and survival outcome of women with uterine carcinosarcoma who had a history of tamoxifen use. METHODS: This is a multicenter retrospective study examining stage I-IV uterine carcinosarcoma cases based on history of tamoxifen use. Patient demographics, tumor characteristics, treatment pattern, and survival outcomes were compared between tamoxifen users and non-users. RESULTS: Sixty-six cases of tamoxifen-related uterine carcinosarcoma were compared to 1009 cases with no history of tamoxifen use. Tamoxifen users were more likely to be older (mean age, 69 versus 64, P<0.001) and had a past history of malignancy (100% versus 12.7%, P<0.001). Tamoxifen-related uterine carcinosarcoma was significantly associated with a higher proportion of stage IA disease (48.4% versus 29.9%) and a lower risk of stage IVB disease (7.8% versus 16.0%) compared to tamoxifen-unrelated carcinosarcoma (P=0.034). Deep myometrial tumor invasion was less common in uterine carcinosarcoma related to tamoxifen use (28.3% versus 48.8%, P=0.002). On univariate analysis, tamoxifen use was not associated with progression-free survival (5-year rates 44.5% versus 46.8%, P=0.48) and disease-specific survival (64.0% versus 59.1%, P=0.39). After adjusting for age, past history of malignancy, stage, residual disease status at surgery, and postoperative treatment patterns, tamoxifen use was not associated with progression-free survival (adjusted-hazard ratio 0.86, 95% confidence interval 0.50 to 1.50, P=0.60) and disease-specific survival (adjusted-hazard ratio 0.68, 95% confidence interval 0.36 to 1.29, P=0.24). CONCLUSION: Our study suggests that tamoxifen-related uterine carcinosarcoma may have favorable tumor characteristics but have comparable stage-specific survival outcomes compared to tamoxifen-unrelated uterine carcinosarcoma.

Immunohistochemical characterization of N-methyl-N-nitrosourea-induced mammary tumours of Sprague-Dawley rats.

BACKGROUND: Single dose of N-methyl-N-nitrosourea (MNU) was shown to induce malignant tumours in susceptible rat strains. However, such tumours are not well-characterized. MATERIAL AND METHODS: We characterized MNU-induced tumours in Sprague-Dawley rats using ultrasonographic, radiographic and immunohistochemical (IHC) methods. RESULTS: In 27 rats, 41 tumours developed, appearing ultrasonographically as hypodense, non-homogenic areas with signal enhancement at their periphery. Out of these, 39 were of malignant epithelial origin, with an IHC phenotype closely-resembling that of human invasive ductal breast carcinoma. One case was diagnosed as carcinosarcoma. IHC analysis revealed that Ki-67 antigen expression correlated positively with tumour volume (r=0.40, p=0.0079). Moreover, tumours with α-smooth muscle actin in the tumour stroma were characterized by a higher proliferative rate as compared to those without its expression (p<0.05). CONCLUSION: This rat model of chemical carcinogenesis may be suitable for examining breast cancer development and progression.

Clinico-pathologic comparison of type II endometrial cancers based on tamoxifen exposure.

OBJECTIVE: To compare clinico-pathologic variables and protein expression of potential regulatory components in patients who develop type II endometrial cancer with and without antecedent tamoxifen. METHODS: Clinico-pathologic variables were compared for all surgically staged patients (2000-2008) with grade 3 endometrioid, papillary serous, clear cell, and carcinosarcoma of the uterus based on tamoxifen exposure [Tam (+) vs. Tam (-)]. Overall survival was analyzed using a multivariable Cox regression model and Kaplan-Meier estimates. Protein expression of ERα, PR, mTOR, p-mTOR, IGF-1R, EGFR, VEGF and HER-2/neu was compared by immunohistochemistry using a semiquantitative scoring system. RESULTS: Of 115 patients with high grade endometrial cancers, 15 received tamoxifen. These patients were older at diagnosis than Tam (-) patients. A higher percentage of Tam (+) patients had carcinosarcoma compared to Tam (-) patients (60% vs. 30%, P=0.038). Overall survival for Tam (+) patients was shorter than Tam (-) patients (16.6 vs. 32.2 months, P=0.004). The hazard ratio for death for Tam (+) patients was 2.53 (P=0.014), controlling for age and stage. Intensity and extent of staining were similar for ERα, PR, VEGF, EGFR, p-mTOR and HER-2/neu. The average expression score for IGF-1R and mTOR in the Tam (+) group was significantly higher than the Tam (-) group: 10.3 vs 7.0, P=0.001 and 6.0 vs 3.1, P=0.029, respectively. CONCLUSION: There are differences in the biology of type II endometrial cancers that develop in women with prior tamoxifen exposure. Tamoxifen associated cancers show higher expression of IGF-1R and mTOR, which should be further investigated.

Prognostic impact of the history of breast cancer and of hormone therapy in uterine carcinosarcoma.

OBJECTIVE: Recent studies reveal an association between hormone therapy for breast cancer (BC), such as tamoxifen (TAM) and toremifene (TOR), and uterine carcinosarcoma (UCS). The aim of this study was to investigate the characteristics and prognosis of patients with UCS after BC and hormone therapy. METHODS: Between January 1997 and December 2007, we treated 51 patients with UCS. The medical records of these patients were reviewed, and factors that influenced their survival were retrospectively analyzed using univariate and multivariate analyses. RESULTS: Ten (19.6%) of the 51 patients had a history of BC; 6 (11.8%) had received hormone therapy with TAM or TOR. The characteristics of the patients with UCS were similar regardless of whether they had a history of BC or hormone therapy. On univariate analysis, age greater than 56 years, elevated serum lactate dehydrogenase levels, residual tumors, FIGO (International Federation of Gynecology and Obstetrics) stage higher than stage IIIa, and non-endometrioid carcinomatous components were identified as prognostic factors. On multivariate analysis, in addition to residual tumors, FIGO stage higher than stage IIIa, and non-endometrioid carcinomatous components, a history of BC (relative risk, 0.14), a history of TAM use (relative risk, 15.9), and a history of TOR use (relative risk, 16.9) were also identified as independently significant prognostic factors. CONCLUSIONS: Our data suggest that a history of BC and hormone therapy for BC is a risk factor for developing UCS without obvious impacts on the characteristics of UCS. Both of these factors had statistically significant impacts on the prognosis of patients with UCS. Further studies are necessary to clarify and validate these associations.

Progression of aggressive metastatic carcinosarcoma after treatment of epithelioid osteosarcoma.

Osteosarcoma is the most common primary malignant osseous neoplasm, constituting approximately 35% of skeletal malignancies. The different subtypes of osteosarcoma are differentiated based on clinical, histologic, and radiographic data, as well as the variable amount of osteoid produced by malignant cells. The epithelioid osteosarcoma subtype accounts for only 5.7% of all osteosarcomas and portends an extremely poor prognosis. The 5-year survival rate for patients with epithelioid osteosarcoma treated with surgery (with or without chemotherapy) is 13.5%. This is in direct contrast to the >70% ten-year survival rate of conventional osteosarcoma treated with surgery and chemotherapy. This article presents a fatal case of epithelioid osteosarcoma in an 11-year-old girl with right knee pain of 6 months' duration. Biopsy demonstrated morphologic findings consistent with high-grade osteosarcoma with epithelioid features. The epithelioid component was positive for vimentin and CD99; however, fluorescent in situ hybridization for the (11;22) translocation was negative. In this case, the epithelioid cells failed to respond to conventional or subsequent experimental chemotherapy for osteosarcoma and eventual metastasized to the lymph nodes and lungs despite multiple ablative surgeries. This case report supports the concept of carcinosarcoma with malignant cells lines arising from 2 different cellular lineages or a common cellular precursor. The epithelial component was more aggressive than the cells of mesenchymal origin, highlighting the need for continued research and a more favorable outcome for this rare subset of osteosarcoma.

Carcinosarcoma arising in uterine didelphys after tamoxifen therapy for breast cancer: a case report.

The occurrence of uterine cancer in breast cancer patients who received tamoxifen treatment, is well described. 72 our knowledge, an association between uterine anomaly and uterine carcinosarcoma in these patients had not been reported. We present a case of uterine carcinosarcoma occurring in uterine didelphys of a 72-year-old breast cancer patient, who had been treated with tamoxifen for 5 years. The patient presented with large pelvic mass. The uterine anomaly was not recognized preoperatively. The patient died of disease 5 months after diagnosis. Postmenopausal women taking tamoxifen should be closely monitored for symptoms of endometrial lesions.

Ovarian carcinosarcomas associated with prolonged use of tamoxifen: case reports.

BACKGROUND: Recent studies have indicated that the risk associated with tamoxifen may be substantially higher for uterine malignant mixed müllerian tumors and uterine sarcomas. CASE: We present 2 cases of ovarian carcinosarcomas in patients with a personal history of breast carcinoma who were treated for a prolonged period with tamoxifen. CONCLUSIONS: To our knowledge, these 2 cases are the first to describe the possible association between ovarian carcinosarcomas and previous personal and familial history of breast carcinoma and\or prolonged use of tamoxifen. These cases may suggest that like in the uterus, tamoxifen has a possible delayed effect, which might be responsible for the formation of aggressive tumors of unclear pathogenesis in the ovaries.

[Uterine carcinosarcomas associated with tamoxifen therapy. Report of two cases and review of the literature]. / Carcinosarcomes utérins associés au traitement par le tamoxifène. A propos de deux cas et revue de la littérature.

Carcinosarcomas are rare uterine cancers and carry poor prognosis. Although these tumours usually arise de novo, some cases developed under tamoxifen therapy have been reported. We report two more cases of uterine carcinosarcoma occurring in two postmenopausal patients benefiting from tamoxifen therapy as adjuvant treatment of breast cancer. A review of the literature is undertaken.

Influence of diets varying in lipid and protein content on the histopathologic variety of murine salivary gland tumors induced by 9,10-dimethyl-1,2-benzanthracene (DMBA).

The purpose of this study was to analyze the influence of diets varying in lipids and proteins on the histopathologic variety of murine salivary tumors induced by DMBA. 117 BALB/c mice were assigned to experiments one (E1: lipids, males) and two (E2: proteins, males and females), E1 comprising Soy oil (SO); Corn oil (CO, control); Fish oil (FO) and Olein (O) groups and E2, soy protein (SP) and casein (C) groups. Tumors were induced by DMBA and the animals were sacrificed at week 13- post-induction. Tumor volume was calculated. Tumor sections were stained with H-E for histopathologic evaluation. No significant association was found between tumor volume and dietary condition (p > 0.05). In E1, FO animals developed mainly carcinomas (C) (58.8%), the sarcomas (S) and carcinosarcomas (CS) being especially of high-grade type (tumors < 600 mm3). In E2, SP animals developed mainly C (55.6%). Although no significantly different (p > 0.05), S and C were more frequent in female and male mice, respectively. In both E1 and E2, the biggest tumors (> 600 mm3) were mainly high-grade S (87.5%-80%). Dietary fat and soy protein appear to influence the tumor histopathology and thus its prognosis.

Influence of diets varying in lipid and protein content on the histopathologic variety of murine salivary gland tumors induced by 9, 10-dimethyl-1, 2-benzanthracene (DMBA) / Influencia de dietas de diferente contenido lipídico y proteico sobre variantes histopatológicas de tumores de glándulas salivares murinos inducidos con 9, 10-dimethyl-1, 2-benzathraceno (DMBA)

The purpose of this study was to analyze the influence of diets varying in lipids and proteins on the histopathologic variety of murine salivary tumors induced by DMBA. 117 BALB/c mice were assigned to experiments one (E1: lipids, males) and two (E2: proteins, males and females), E1 comprising Soy oil (SO); Corn oil (CO, control); Fish oil (FO) and Olein (O) groups and E2, soy protein (SP) and casein (C) groups. Tumors were induced by DMBA and the animals were sacrificed at week 13- post-induction. Tumor volume was calculated. Tumor sections were stained with H-E for histopathologic evaluation. No significant association was found between tumor volume and dietary condition (p > 0.05). In E1, FO animals developed mainly carcinomas (C) (58.8%), the sarcomas (S) and carcinosarcomas (CS) being especially of high-grade type (tumors < 600 mm3). In E2, SP animals developed mainly C (55.6%). Although no significantly different (p > 0.05), S and C were more frequent in female and male mice, respectively. In both E1 and E2, the biggest tumors (> 600 mm3) were mainly high-grade S (87.5%-80%). Dietary fat and soy protein appear to influence the tumor histopathology and thus its prognosis.

El objetivo de este estudio fue analizar la influencia de dietas con diferente contenido de lípidos y proteínas sobre la variedad histopatológica de tumores salivares murinos inducidos por DMBA. Se asignaron 117 ratones BALB/c a los experimentos uno (E1: lípidos, machos) y dos (E2: proteínas, machos y hembras). E1 comprendió a los grupos aceite de soja (AS), aceite de maíz (AM, control), aceite de pescado (AP) y oleína (O), en tanto E2 incluyó a los grupos preteína de soja (PS) y caseína (C). Los tumores fueron inducidos por DMBA y los animales fueron sacrificados a la 13ª semana post-inducción. Se calculó el volumen tumoral. Los cortes de tumor fueron coloreados con Hematoxilina-Eosina para su evaluación histopatológica. No se encontró asociación entre volumen tumoral y condición dietaria (p>0.05). En E1, los animales del grupo AP desarrollaron principales carcinomas (C) (58,8%), en tanto que los sarcomas (S) y carcinosarcomas (CS) fueron de alto grado (tumores<600 mm³). En el E2, los animales del grupo PS desarrollaron principalmente C (55.6%). Aunque la diferencia no fue significativa (p>0.05), S y C fueron más frecuentes en ratones hembras y machos, respectivamente. Tanto el E1 com en E2, los tumores más voluminosos (> 600 mm³) fueron principalmente de alto grado (87.5%-80%) Los lípidos y la proteína de soja de la dieta parecen influenciar la histopatología de los tumores y, en consecuencia, su pronóstico.

Carcinogênese quimicamente induzida por DMBA em glândulas salivares submandibulares de ratos (rattus norvegicus) / Chemical carcinogenesis in rat (rattus norvegicus) submandibular gland using DMBA

A carcinogênese consiste em um processo de alterações genéticas após contato celular com agentes físicos, químicos ou biológicos. Esta interação pode culminar em manifestações de fenótipos malignos celulares. No estudo experimental da carcinogênese em glândulas salivares animais, os autores são unânimes em apontar os hidrocarbonetos policíclicos aromáticos (HPA) como potentes agentes carcinogênicos. O 7,12 û dimetilbenzantraceno (DMBA), pertencente ao grupo dos HPA, é considerado o carcinógeno químico de eleição para a tumorigênese de glândulas salivares animais. Este trabalho visou o estudo de DMBA injetado em glândulas salivares submandibulares de ratos. Foram utilizados 28 ratos (Rattus norvegicus), com três meses de idade e peso aproximado de 300g. Os animais foram divididos em quatro grupos de sete indivíduos. Após anestesia, tricotomia e anti-sepsia as glândulas submandibulares esquerdas de todos os animais foram expostas por incisão cervical anterior. Utilizando-se seringa de 1,0 ml injetou-se 0,1 ml de solução de DMBA/acetona à 2% naquelas glândulas. O plano epitelial foi suturado com seda preta 3-Ø. Ao final da 5ª, 10ª, 15ª, e 20ª semanas os animais foram sacrificados utilizando-se doses letais da solução anestésica/relaxante. Os resultados revelaram, na 5ª semana, sete casos de sialadenite crônica. Na 10ª semana, um caso com atipia celular ductal, dois casos de carcinoma epidermóide e quatro de sialadenite crônica. Entre a 15ª e 20ª semanas, foram observados três casos de hiperemia, três casos de carcinoma epidermóide, um caso de sarcoma e sete casos de carcinossarcoma. A análise dos dados, em porcentagem, revelou: 3,6% de atipia celular, 3,6% de sarcoma, 10,7% de hiperemia, 17,9% de carcinoma epidermóide, 25% de carcinossarcoma e 39,4% de sialadenite crônica. Conclusão: Os dados obtidos permitiram o estudo da história natural da carcinogênese glandular por DMBA desde os processos inflamatórios iniciais até à formação de neoplasias mesenquimais, epiteliais e mistas.

Uterine sarcomas in breast cancer patients treated with tamoxifen.

Tamoxifen (TMX) has been related with the development of uterine sarcomas. Since the first reported case in 1988, 65 TMX-related cases have been referred to. Here we present three new cases of uterine sarcomas in patients with breast cancer treated with TMX and we comment on the outcome of the cases described in the literature. In the past 25 years, 60 uterine sarcomas have been diagnosed and treated in Hospital Clínic. Three patients have previously received TMX 20 mg/day for 3, 5, and 7 years for breast cancer. Uterine sarcoma appeared 5, 5, and 7 years, respectively, after the start of TMX treatment, and all of them had stage I (FIGO) disease. Two patients had a carcinosarcoma and one patient had an adenosarcoma. After treatment, the disease progressed in two patients and the third patient is alive having a follow-up of 42 months. The low incidence of uterine sarcomas makes it difficult to establish a relationship with TMX. Nevertheless, looking at the literature data, 20 mg/day of TMX over 1 year could be enough to develop uterine sarcoma; the sarcoma appears mainly during the first 8 years and seem to behave more aggressively. Although only 65 cases have been reported in the past 14 years, a strict follow-up is necessary in patients with breast cancer receiving TMX therapy.

Expression of estrogen receptors alpha and beta in two uterine mesenchymal tumors after prolonged tamoxifen therapy. Report of two cases.

INTRODUCTION: Tamoxifen therapy is associated with an increased risk of endometrial carcinoma, and possibly uterine sarcomas. Little is known about hormone receptor expression in mesenchymal tumors of the uterus after tamoxifen therapy. CASES: The cases of two patients with uterine mesenchymal tumors after prolonged tamoxifen therapy due to breast cancer are presented. The expression of estrogen receptors alpha (ERalpha) and beta (ERbeta) and progesterone receptors (PR) was studied immunohistochemically in both cases. Both tumors were negative for ERalpha and positive for ERbeta. In the first case the tumor was negative for PR, while in the second only 20% of nuclei were PR-positive. CONCLUSIONS: Consistent with previous studies, uterine mesenchymal tumors after tamoxifen therapy do not express ERalpha. The results of the present report provide for the first time evidence that tamoxifen might exert a stimulatory effect on the uterus, at least during tumor progression, through ERbeta but not through ERalpha.

Carcinosarcoma of the urinary bladder following cyclophosphamide therapy: evidence for monoclonal origin and chromosome 9p allelic loss.

We report a case involving a 45-year-old man with a 12-year history of Wegener granulomatosis, who developed a carcinosarcoma of the urinary bladder after long-term cyclophosphamide therapy. Cyclophosphamide is well recognized as an etiologic agent for urothelial carcinoma of the urinary bladder. However, only 5 cases of carcinosarcoma of the urinary bladder following cyclophosphamide therapy have been reported. We used loss of heterozygosity studies and microsatellite markers to define the molecular basis of this rare neoplasm. These studies revealed evidence supporting a monoclonal origin for the 2 components of this tumor. We also demonstrated allelic loss of chromosome 9p. This loss associated with carcinosarcoma of the urinary bladder is in agreement with previous studies, suggesting a possible role for the tumor suppressor gene p16 in the pathogenesis of this tumor.

Tamoxifen-related uterine carcinosarcomas occur under/after prolonged treatment: report of five cases and review of the literature.

The risk of tamoxifen-related endometrial adenocarcinoma is well established with daily dose and treatment duration of adjuvant tamoxifen as risk factors. There have also been in the past years, a few descriptions of uterine nonepithelial malignancies occurring after tamoxifen. We describe five recent cases of uterine carcinosarcomas occurring under/after tamoxifen administered in an adjuvant setting. None of these patients had received prior pelvic radiation therapy. Their median age at the diagnosis of breast cancer was 58 years (41-68), and 69 years (50-84) at the diagnosis of uterine carcinosarcoma. The median length of exposure to tamoxifen was 9 years (5-20), and the median time from the initiation of tamoxifen to the diagnosis of the uterine malignancy (latency period) 9 years (7-20). All patients presented with an advanced stage (IIA-IVA). Our data, together with those of the literature, plead for a causal role of a prolonged exposure to tamoxifen on the subsequent development of uterine carcinosarcoma. The long latency period observed even in patients receiving only 5 years of treatment leads us also to consider a prolonged gynecologic follow-up of the patients.

Chronic toxicity and oncogenicity bioassay in rats with the chloro-s-triazine herbicide cyanazine.

Cyanazine is a member of the chloro-s-triazine class of herbicides. Other triazine herbicides have been shown to induce mammary-gland tumors in rats, although the response is unique to the Sprague-Dawley strain. Cyanazine is nongenotoxic. The present study was conducted to evaluate the chronic toxicity and oncogenic potential of cyanazine. Groups of 62 male and female rats were fed diets containing cyanazine at concentrations of 1, 5, 25, or 50 ppm for up to 2 yr. Mean body weight and body weight gain of male and female rats of the 25- and 50-ppm groups were significantly reduced over the course of the study. Food consumption and food efficiency were also reduced in these groups. Survival was not adversely affected in the treatment groups compared to controls. A significant increase in the incidence of masses of the inguinal region was noted among female rats of the 50-ppm group. These masses were correlated with a significant increase in the incidence of female rats with mammary-gland adenocarcinomas and carcinosarcomas. The incidence of rats with malignant mammary-gland tumors was elevated in the 5-, 25-, and 50-ppm groups, although the incidence within the 5-ppm group was within historical controls. There were no other toxicologically significant observations with respect to ophthalmological, clinical laboratory, or pathological evaluations. Under the conditions of this study, the no-observed-adverse-effect level was 5 ppm. Research into the mechanism of action suggests these mammary tumors are mediated through a prolactin mechanism that is thought to be of low relevance to humans.