Aberrant patterns of cellular communication in diabetes-induced embryopathy I. Membrane signalling

Objective: Our purpose was to investigate the role of membrane signalling in the mechanism of diabetes-induced embryopathy. Methods: Three groups of 70-90-day-old Sprague-Dawley rats were employed in our study: group 1 was normal control rats receiving a normal diet; group 2 represented experimentally induced diabetic rats with malformed offspring (intravenous injection of 65 mg/kg streptozotocin on pregnancy day 6) and group 3 included streptozotocin-induced diabetic rats with normal offspring. Embryos were examined on day 12 under light microscopy, categorized as morphologically normal or defective, and yolk sac cells were harvested from each group. Activities of ERK1 and 2, Raf-1, JNK 1 and 2 in yolk sac cells were analyzed by Western blot with primary antibodies specific to the phosphorylated kinases, respectively. Results: A strong link between hyperglycemia and congenital malformations was confirmed. Key mitogen-activated protein kinases serve as syllabic intermediates: increased activities of Jun-amino-terminal kinase (JNK1 and 2) and decreased activities of extracellular signal-regulated kinase (ERK1 and 2) were observed during hyperglycemia-induced embryopathy. Conclusions: Poorly controlled maternal diabetes results in embryopathy which is mediated via a pattern of aberrant cellular communication manifested by both macroscopic and microscopic membrane injury.     

Ultra-structural changes and apoptotic activity in cerebellum of post-menopausal-diabetic rats: a histochemical and ultra-structural study

Diabetes mellitus (DM) is one of the most common and chronic diseases, especially in post-menopausal periods. Neuro-degeneration occurs more frequently in post-menopausal diabetics. Therefore, we investigated ovariectomized rats cerebellar cortex response to the estradiol deficiency and hyperglycemia. For the ovariectomy, the rats were bilaterally ovariectomized, and then DM induced by a single dose of Alloxan monohydrate injection in ovariectomy or/and diabetic groups. During light and electron microscopic examination, degenerated Purkinje cells membrane, swollen organelles, degenerated mitochondria, edema formation and vacuolization were seen in the ovariectomy and ovariectomy-diabetic groups sections. In addition, increased apoptotic activity was observed in the ovariectomy and ovariectomy-diabetic groups compared to the control group. We demonstrated that estradiol and insulin deficiency can affect the cerebellar cortex, which support the hypothesis that the execution of neuronal damages in post-menopausal diabetics. Also, diabetes and menopause are major risks factors for many disorders including nervous system and the number of post-menopausal-diabetics are increasing world-wide.     

Apoptosis in epithelial ovarian tumours Prognostic significance of clinical and histopathologic factors and its association with the immunohistochemical expression of apoptotic regulatory proteins (p53, bcl-2 and bax)

OBJECTIVE: The objective was to establish the importance of apoptosis-related genes and the apoptotic index (AI) as prognostic factors in patients with epithelial ovarian tumours. MATERIAL AND METHODS: Tumour specimens from 130 epithelial ovarian tumours were examined for expression of p53, bcl-2 and bax proteins. The apoptotic index was evaluated by modified terminal deoxynucleotide-transferase-mediated digoxigenin triphosphate-biotin nick end-labelling (TUNEL) methods and by haematoxylin-eosin (H-E) staining. Other clinical and histopathological variables were also analysed. Statistical analyses were performed using the SPSS 10.0 package. RESULTS: The apoptotic index detected by H-E and enzymatic assay was high in the majority of carcinomas (serous, endometrioid and clear cell (p=0.001). In the univariate survival analysis, high apoptotic index, high p53 and low bcl-2 expression, significantly correlated with shorter survival and shorter disease-free periods (p<0.01). In multivariate analysis the age (p=0.026; CI: 1.035-1.066 and p=0.011; CI: 1.835-2.077), FIGO stage (p=0.017; CI: 1.385-4.514 and p=0.024; CI: 1.217-1.940), p53 expression (p=0.03; CI: 1.017-1.627 and p=0.02; CI: 1.050-2.350) and apoptotic index (p=0.019; CI: 1.375-1.750 and p=0.019; CI: 1.442-2.085) were revealed to be independent prognostic factors for survival and recurrence, respectively. CONCLUSIONS: Our results indicate that the apoptotic index and p53 nuclear accumulation are independent predictive factors of recurrence and short survival. Our data also suggest different patterns of alterations for the various tumour types.     

60%氧暴露对新生大鼠肺组织细胞凋亡相关基因表达的影响

目的探讨中浓度高氧(60%O2)暴露新生大鼠肺损伤模型中细胞凋亡相关基因Bax和Bcl-XL的效应。方法新生足月大鼠随机分为实验组和对照组,每组8只,制备中浓度氧致新生鼠BPD模型,应用HE染色、免疫组织化学和RT-PCR技术,观察生后1、4、7、11和14d肺组织病理改变、Bax及Bcl-XL基因的蛋白和mRNA表达水平。结果高氧组自4d开始出现肺泡发育障碍,至14d单位面积肺泡数明显减少,平均肺泡面积显著增大。高氧组与空气组比较,Bax基因表达1d开始增加,其mRNA水平于11d开始降低至1·0216±0·2597,蛋白表达于14d降低至0·3950±0·0138;Bcl-XL基因mRNA水平1d至14d表达增加,其蛋白表达1d降低至0·3690±0·0399,随后增加,差异有统计学意义。随氧暴露时间延长,高氧组Bax的mRNA及蛋白和Bcl-XL的mRNA表达水平均呈降低趋势,Bcl-XL蛋白表达呈上升趋势。空气组的Bax mRNA水平从11d开始增加,蛋白水平从14d开始增加。空气组Bcl-XLmRNA和蛋白水平1d表达最丰。结论中浓度高氧暴露诱导新生鼠肺细胞凋亡的调节可能和Bax/Bcl-XL基因表达异常有关。在高氧暴露早期,Bax表达增加,促进肺细胞凋亡。肺上皮细胞和血管内皮细胞的凋亡损伤了正常的肺发育。随着氧暴露时间延长,Bax的表达降低,Bcl-XL表达增加。这种变化促进肺修复,新生鼠对高氧形成耐受。本文亦初步揭示了凋亡和氧暴露的时相关系,即高氧暴露早期时肺细胞凋亡效应显著,后期减弱。     

Patterns of expression of Bax, Bcl-2 and Bcl-x(L) in the implantation site in rat during pregnancy

The uterine endometrium responds to blastocyst implantation with extensive proliferation and differentiation of stromal cells into decidual cells, forming the antimesometrial and mesometrial decidua. These undergo regression by apoptosis but as this process occurs at different time periods suggest that there is spatially dependent temporal control of apoptosis in these specific regions. To elucidate the role of the mitochondrion-dependent signalling pathway in tissue regression, we investigated the spatial and temporal pattern of expression of the Bcl-2 family members in uterine tissues of the implantation site, from the post-implantation period to parturition. Furthermore, the activities of the initiator caspases-8 and -9, and of the executioner caspase-3 were determined. Overall Bax and Bcl-2 were expressed from day 8 till day 19, whilst Bcl-x(L) was extinguished by day 16. In the antimesometrial and in the mesometrial decidua both Bcl-2 and Bax declined from days 10 to 12. In the latter Bcl-2 immunoreactivity decreased till the end of pregnancy, whilst for Bax a constant level remained thereafter. The pattern of variation of enzymatic activities throughout pregnancy for all the enzymes was similar, increasing from days 10 to 14 and decreasing towards the end of pregnancy. The increased levels of active caspase-9 correlated with Bax/Bcl-2 and Bcl-x(L) expression suggesting that the apoptotic mitochondrion-dependent pathway is involved in decidual regression during pregnancy progression.     

Prolonged inhibition of nitric oxide synthesis in pregnant rats: effects on blood pressure,fetal growth and litter size

Methods In order to investigate the effect of chronic inhibition of nitric oxide synthesis along pregnancy, pregnant rats were given drinking water alone (control group) or drinking water containing nonselective nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME; 15 mg/day/rat equivalent to 50 mg/kg/day; treated group), from postmating days 1 to 18 of pregnancy. On days 1 to 17 of pregnancy, urinary volume, urinary sodium and potassium excretion, and urine protein concentration were measured. Systolic blood pressure (SBP) was recorded daily. On days 6, 11 and 18 of pregnancy the number of sites of implantation, number of embryos, litter size, fetal and placenta weight were determined.Results Systolic blood pressure (mmHg) increased (p<0.001) on the 2nd day of administration of L-NAME and remained high throughout the experiment. This treatment increased urinary protein excretion and urine volume (p<0.01), with changes in the sodium and potassium excretion rate along the study. On day 6 of gestation in treated group, the number of implantation sites (0.14±0.10) significantly decreased (p<0.05) compared with the control group (1.45±0.58), but on day 11 of pregnancy the number of embryos was similar in both groups. By day 18 of pregnancy, L-NAME caused a substantial decrease (p<0.001) in litter weight (6.30±0.77 to 12.00±0.92 g), weight of placenta (3.17±0.22 to 4.74±0.21 g) (p<0.001) and litter size (7.95±0.59 to 11.95±0.45 fetus/litter; p<0.001). Also, treatment with L-NAME caused an important number of fetal resorptions (2.93±0.42 No./litter to 0 in control group).Conclusion Thus, treatment of pregnant rats with L-NAME, has an important effect on systolic blood pressure and on the physiology of reproduction, mainly in the third stage of pregnancy.     

Effects of strontium ranelate,raloxifene and misoprostol on bone mineral density in ovariectomized rats

Objectives

To investigate the effects of strontium ranelate, raloxifene and misoprostol on bone mineral density (BMD) in ovariectomized rats to contribute to the individualization of the treatment of postmenopausal osteoporosis.

Study design

Sixty sexually mature female Sprague–Dawley rats weighing 250 g were used. The 60 rats were divided into six groups of 10 rats each: SR, MISO, RAL, SHAM, DW and OVX. All except the SHAM rats were subjected to bilateral ovariectomy. Three days after surgery, rats were administered strontium ranelate (Protelos^®, 2 g, Servier, Istanbul), 1800 mg/kg/day; misoprostol (Cytotec^®, 200 mcg, Ali Raif, Istanbul), 200 mcg/kg/day; raloxifene (Evista^®, 60 mg, Lily and Company, Istanbul), 3 mg/kg/day and 1 cc of distilled water by gavage for 8 weeks. Bone mineral density measurements were then performed.

Results

The strontium ranelate (SR) group had significantly higher vertebral BMD than all other groups. Femoral density in the SR group was also significantly higher than in other groups and there was no difference between femoral density in the strontium ranelate and sham groups.

Conclusions

Strontium ranelate, raloxifene and misoprostol can prevent bone loss in the vertebrae, whereas strontium ranelate can also prevent bone loss in the femur of ovariectomized rats. Strontium ranelate increases greater than raloxifene and misoprostol BMD in the vertebrae.

Condensation

Strontium ranelate may increase both vertebral and femur BMD in ovariectomized rats while raloxifene and misoprostol may only increase lumbar spine BMD.     

Clinical and pathological characteristics,pathological reevaluation and recurrence patterns of cellular leiomyomas: a retrospective study in 76 patients

Objectives

To analyze clinical and pathologic features as well as recurrence patterns of cellular leiomyomas (CL) in women who underwent surgical therapy for symptomatic disease.

Study design

This retrospective study was conducted at the Department of Obstetrics and Gynecology, University Women's Clinic, Tuebingen, Germany. We identified all women who had CL on final diagnosis after surgery between January 1, 2000, and December 31, 2010.

Results

Our study sample comprised 76 women with a diagnosis of CL. A single uterine mass was present in 51.3% of the cases; in uteri with both CL and uterine leiomyomas (UL), the CL constituted the largest uterine mass in 20 of 21 (95.2%) cases. Additionally, in 98% of the uteri, CL were either the largest or the only uterine mass. Five women (6.6%; 5/76) had reported surgical procedures for symptomatic leiomyoma before the index surgery in our analysis. Three women underwent hysteroscopic resection of the leiomyomas and 2 women underwent abdominal myomectomy. Mean time to recurrence was 14.0 months (median 6.0; range, 4.0–52.0). Over the follow-up period, 6 women who underwent uterus-conserving surgery (12.0%; 6/50) with CL had leiomyoma recurrence. Five women underwent abdominal myomectomy and one underwent hysteroscopic resection of the CL. One patient had recurrence of a CL 43 months after abdominal myomectomy and underwent vaginal hysterectomy; the other five women had recurrences of UL. Mean time to recurrence was 28.6 months (median 12.5; range, 4.0–83.0).

Conclusions

Recurrence rates of CL in our study group resemble recurrence rates of UL.     

The in vitro perifused rat ovary: II. Role of oxygen tension in the whole and quartered ovary

In vitro perifusion of whole ovaries raises questions about tissue viability and its effects on the observed ovarian steroid secretion. To assess effects of tissue degeneration, whole and quartered ovaries from pregnant mare serum gonadotropin (PMSG-) treated immature rats were perifused for 8 h, employing various levels of pO₂. Histological examination of both the whole and quartered ovary showed signs of degeneration in centrally located follicles but not in follicles located near the surface. However, basal and gonadotropin-stimulated (luteinizing hormone plus follicle stimulating hormone) secretion of estradiol, testosterone and progesterone were not significantly different in the whole ovary whether in the presence of high or low PO₂ (n=8; p > 0.05). Similarly, although the quartered ovary secreted greater amounts of steroids than did the whole ovaries (p < 0.05, n=8), pO₂ levels did not affect the steroid output. We conclude that during in vitro perifusion, minimal oxygen supply is sufficient for ovarian steroidogenesis to proceed. In addition, although quartered ovaries displayed some evidence of tissue degeneration, they were more responsive in terms of steroid output per mg ovary than were whole ovaries.     

Effect of human interferon-alpha-2b on experimental endometriosis in rats: comparison between short and long series of treatment

Objective

A randomised and controlled experimental study was carried out to determine the effect of short and long series of treatment with recombinant human interferon-alpha-2b on surgically induced endometriosis in rats.

Study design

Ninety-six Wistar adult female rats, which had undergone an autotransplant into the peritoneal cavity of four endometrial fragments measuring 4.5 mm at the side, were randomly divided into three groups. One third of the animals were manipulated like the treated animals but were not given treatment and served as control (group C). Another third (group S) were treated with three doses (one every 48 h, 100,000 U per dose) of recombinant human interferon-alpha-2b (subcutaneous route), and the last third (group L) were treated with fifteen doses of interferon (100,000 U every 48 h).

Results

Before interferon was administered, there were no differences between groups in the average growth of experimental endometriosis per animal (17.3 ± 6.7, 18.1 ± 9.2, 16.4 ± 5.6 mm in groups C, S and L respectively). After the treatment, experimental endometriosis per animal was significantly smaller in the groups treated with interferon than in the control non-treated group (p < 0.001), and in the group treated with 15 doses versus the group treated with 3 doses (p < 0.05), (17.6 ± 7.5, 14.0 ± 9.5, 9.4 ± 6.0 mm in groups C, S, and L respectively). While the implants of the animals in the control group showed no change in size throughout the study (120 days) (+1.96% of variation), the mean size of the implants in the treated rats decreased, (22.7% with the short and 42.8% with the long series of treatment with interferon). Only one implant in group C (0.8%) disappeared, while this occurred in 27 cases (22.5%) in group S (p < 0.001) and in 45 (37.5%) in group L (p < 0.001 versus group C and p < 0.05 versus group S).

Conclusion

The long series of treatment with human interferon-alpha-2b was more effective than the short one in reducing the size of surgically induced endometriosis in the peritoneal cavity of the rat.     

Induction of labor with RU 486 (mifepristone) in relaxin-deficient rats: antepartum administration of relaxin facilitates delivery and increases pup survival

OBJECTIVE: This study was conducted to determine whether antepartum administration of relaxin improves RU 486-induced delivery at term in rats that lack circulating endogenous relaxin. STUDY DESIGN: Pregnant rats were modified two ways to obtain circulating levels of relaxin and progesterone that resemble those of pregnant humans: relaxin was immunoneutralized throughout the second half of the 23-day pregnancy and high progesterone levels were sustained until term by inserting progesterone implants on day 20. Porcine relaxin was administered subcutaneously from 8 AM on day 20 until delivery. Labor was induced by administering RU 486 subcutaneously at 4 AM on day 22. RESULTS: After induction of labor with RU 486, labor and delivery were faster, and the incidence of live births was higher when rats were also administered relaxin during the antepartum period. CONCLUSION: Antepartum administration of relaxin in combination with RU 486 has beneficial effects on delivery in relaxin-deficient rats.     

Bcl-2, BAX, and apoptosis in endometrial hyperplasia after high dose gestagen therapy: a comparison of responses in patients treated with intrauterine levonorgestrel and systemic medroxyprogesterone

OBJECTIVES: The aim of the study was to investigate apoptosis as a growth regulatory mechanism of gestagen in endometrial precancers and to compare differences in the apoptotic cascade after high and low dose gestagen regimens. METHOD: Pre- and post-treatment paraffin-embedded endometrial hyperplasia specimens from women treated with levonorgestrel intrauterine device (n = 26) and women treated with 10 mg medroxyprogesterone for 10 days per cycle (n = 31) were examined for changes in the expression of Bcl-2 and BAX and the extent of apoptosis after 3 months of treatment. Immunohistochemical expression in tissue specimens for Bcl-2 and BAX was evaluated by H-score. Average number of apoptotic cells per hundred cells within ten different high power field (40 x) was evaluated for each section after in situ apoptosis detection (TUNEL method). A second group of patients with endometrial hyperplasia was examined after 1 week treatment with levonorgestrel IUD (n = 6) or medroxyprogesterone (n = 5) to determine early effects on expression of Bcl-2 and BAX and the extent of apoptosis. RESULTS: All the patients in the IUD group (n = 31) but only about half of the patients in per oral group (16 of 26) responded to treatment. The glandular reduction in Bcl-2 expression was markedly greater for the IUD patients than for the patients who received oral gestagen. The decrease in BAX expression after IUD treatment was less than the reduction of Bcl-2. Decrease in glandular Bcl-2 after 3 months of treatment was coincident with a significant increase in the measurable amount of apoptosis. In stromal cells, the increase in expression of Bcl-2 and BAX was found after gestagen treatment, the response being much more marked for the IUD group. The non- responders to per oral gestagen had no Bcl-2 expression in stroma after 3 months of therapy whereas an increase was observed for the responders. After 1 week, glandular Bcl-2 expression was significantly reduced after treatment in the IUD group. As for the rest, no changes were detected in either of the groups. CONCLUSION: Our results indicate that proteins in the apoptotic cascade are regulated by gestagen therapy in human endometrial precancers. Expression of these proteins is shown to be dependent on administration form and/or type of gestagen. Stromal Bcl-2 expression appears to be a potential biomarker which can separate responders of gestagen treatment from non-responders after oral administration.     

Endometrial cancer in the oldest old: Tumor characteristics, patterns of care, and outcome

Objective

Despite the fact that endometrial cancer commonly occurs in elderly women, little is known about the outcome of the oldest old, those > 80 years of age. We examined the patterns of care and outcome of the oldest old women with endometrial cancer.

Methods

An analysis of women > 65 years of age with endometrioid adenocarcinoma of the uterus diagnosed between 1988 and 2006 and registered in the Surveillance, Epidemiology, and End Results database was performed. Patients were stratified by age into the following groups: 65-69, 70-74, 75-79, 80-84, and ≥ 85 years of age. Multivariable logistic regression models were constructed to examine treatment while adjusting for other confounders. Cancer-specific survival was examined using Cox proportional hazards models.

Results

A total of 37,718 women including 5289 aged 80-84 and 3446 ≥ 85 years of age were identified. Older women had higher grade tumors (p < 0.0001) and more advanced stage disease (p < 0.0001). After adjusting for tumor characteristics, patients ≥ 85 years of age were less likely to undergo hysterectomy (OR = 0.14; 95% CI = 0.12-0.16) and lymphadenectomy (OR = 0.48; 95% CI = 0.44-0.54) and less likely to receive radiation (OR = 0.41; 95% CI = 0.36-0.46). After adjustment for treatment and prognostic factors, cancer-specific mortality was 53% (HR = 1.53; 95% CI = 1.39-1.67) greater in women 80-84 and 89% (HR = 1.89; 95% CI = 1.71-2.08) greater in those ≥ 85 years of age than in women 65-69 years old.

Conclusion

Women > 80 years of age receive less aggressive care than younger women. Even after adjusting for treatment differences, cancer-specific mortality is higher in the oldest old women.     

The role of Sep (O-phosphoserine) tRNA: Sec (selenocysteine) synthase (SEPSECS) in proliferation,apoptosis and hormone secretion of trophoblast cells

Objectives

To investigate whether Sep (O-phosphoserine) tRNA: Sec (selenocysteine) synthase (SEPSECS), which plays an essential role in the synthesis of selenoprotein, affects proliferation, apoptosis and hormone secretion of human trophoblast cells.

Methods

Human trophoblast JEG-3 cells were divided into four groups: control group, SEPSECS silenced-expression group, empty vector group and SEPSECS over-expression group. Over-expression and silenced-expression were achieved by transfection with plasmid DNA or RNA oligonucleotide, respectively. 3-[4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium bromide (MTT) and colony formation assays were performed to investigate cell proliferation, while apoptosis was tested by annexin V-FITC, PI double staining and caspases-3 activation assays, enzyme-linked immunosorbent assay (ELISA) was used to determine the level of progesterone (PG) and human chorionic gonadotropin (hCG).

Results

SEPSECS silenced-expression clearly inhibited proliferation of JEG-3 cells (p < 0.05), significantly induced cell apoptosis (p < 0.01) and reduced the production of PG and hCG (p < 0.05). On the contrary, SEPSECS over-expression significantly promoted both cell proliferation (p < 0.01) and secretion of PG and hCG (p < 0.05).

Conclusions

SEPSECS significantly affects proliferation, apoptosis and hormone secretion of human trophoblast cells, suggesting that a potential relationship exists among SEPSECS, cell proliferation, apoptosis and hormone production of human placental trophoblast cells. Furthermore, this may provide a clue to uncover the relationship between selenium and human placental in association with an emphasis on the importance of selenium adequacy during pregnancy.     

Glucose metabolism and angiogenesis in granulosa cell tumors of the ovary: activation of Akt, expression of M2PK, TKTL1 and VEGF

OBJECTIVES: Very little is known about the biology of granulosa cell tumors of the ovary. A hallmark of granulosa cell tumors of the ovary is extensive growth, distant metastases however, are rarely found. We hypothesise that granulosa cell tumors of the ovary on the one hand need to stimulate vascularisation; on the other hand glucose metabolism has to be altered to ensure the supply of nutrients and metabolites. Increased glycolysis, the main source of energy supply, is considered to be important during malignant transformation. Thus, we focussed on a selection of key factors in angiogenesis and tumor glycolysis to study metabolic characteristics of granulosa cell tumors of the ovary. STUDY DESIGN: We analysed 32 tumor specimens for immunohistochemical expression of vascular endothelial growth factor, phosphorylated Akt, M2 pyruvate kinase isoenzyme, and transketolase-like enzyme 1. As controls, we stained 10 samples of normal ovaries. RESULTS: We found expression of vascular endothelial growth factor in 94%, transketolase-like enzyme 1 in 81%, and phosphorylated Akt as well as M2 pyruvate kinase isoenzyme in 53% of the specimens. There were no significant differences between the expression levels in primary and those in recurrent tumors. Temporal analysis of marker expression in primary tumors and recurrences in the same patients revealed no increase or decrease of marker expression overtime. In contrast to granulosa cell tumors, normal ovaries showed no expression of the markers analysed in granulosa cells. CONCLUSION: Our results show that granulosa cell tumors of the ovary express vascular endothelial growth factor as an important stimulator of tumor angiogenesis as well as several molecular markers for glycolysis. The dependence of granulosa cell tumors of the ovary on the glycolytic pathway may provide a biochemical basis for therapeutic strategies involving glycolytic inhibitors.     

Cancer of the uterine corpus among Hispanic women living in the United States: patterns of staging, diagnosis, and primary treatment

OBJECTIVES: To evaluate the demographic characteristics, clinico-pathological features, and patterns of care of uterine cancer among Hispanic women living in the United States. METHODS: The National Cancer Institute (NCI)'s Surveillance, Epidemiology, and End Results Program (SEER), was used to identify 1618 Hispanic, 17,814 non-Hispanic white (NHW), and 1477 non-Hispanic black (NHB) women diagnosed with primary carcinoma of the uterus during 1996-2000. Data derived from hospital registries was analyzed, for differences in case presentation, staging, and primary treatment by race/ethnicity and age. Statistical analysis was performed using the IBM PC packages, Stata, and the SAS system. RESULTS: Hispanic women were statistically significantly more likely to present with uterine cancer at a younger age compared to non-Hispanic groups. Hispanic women with early stage disease (stage I-II) were also statistically significantly more likely to be younger than 55 years at the time of diagnosis (NHW: OR=0.40, 95% CI: 0.35-0.45; P = 0.0000, NHB: OR=0.45, 95% CI: 0.38-0.55; P=0.0000). Hispanics were statistically significant less likely than NHB to present with advanced stage disease, high tumor grade, and receive radiation therapy for uterine cancer. CONCLUSIONS: Hispanic women are more likely to be diagnosed with uterine cancer at a younger age than other ethnic groups. The etiologic factors related to this presentation have yet to be precisely defined. Additional epidemiological and demographic studies, addressing such factors as body mass index and other medical co-morbidities, are needed to identify opportunities for improved cancer prevention and control in this population of women.     

Phase II study of mitomycin,doxorubicin, and cisplatin in the treatment of advanced uterine leiomyosarcoma: a Gynecologic Oncology Group study

OBJECTIVE: Because of preliminary observations favoring the use of mitomycin, doxorubicin, and cisplatin (MAP) chemotherapy in leiomyosarcomas, the Gynecologic Oncology Group (GOG) decided to conduct a phase II clinical trial of this combination regimen in patients with advanced disease. METHODS: Patients with histologically confirmed uterine leiomyosarcoma who had not previously received cytotoxic drugs were considered for participation in this clinical trial. Eligible patients had measurable disease, GOG performance status 0-2, and adequate bone marrow, renal, and hepatic function according to standard criteria. Mitomycin 8 mg/m(2) and doxorubicin 40 mg/m(2) were each given by iv injection followed immediately by cisplatin 60 mg/m(2) in 1 liter of 0.45% saline plus mannitol 25 g. Patients who remained free from tumor progression or intolerable toxicity received at least three, to a maximum of six, cycles of MAP. RESULTS: Forty-one patients were registered, of whom 4 were determined ineligible (wrong cell type, 2; wrong site of origin, 1; inadequate pathology material, 1). Thirty-five of the 37 were evaluable for response after receiving from one to six (median three) cycles of MAP. Three patients (9%) achieved a complete response and 5 (14%) exhibited a partial response. The most common adverse effects were leukopenia (33 patients) and thrombocytopenia (30 patients). Pulmonary toxicity was seen in 10 patients and was a factor in the clinical deterioration and death of 2. CONCLUSION: MAP is active against advanced uterine leiomyosarcomas, but not remarkably so. Despite its low therapeutic index, this novel, possibly interactive, combination may serve as a forerunner to regimens that more efficiently exploit the enhancement of sarcoma cell kill under hypoxic conditions.