Science.gov

Sample records for high-grade endometrial carcinomas

  1. Concurrent primary peritoneal low-grade serous carcinoma and endometrial high-grade serous carcinoma.

    PubMed

    Lockyer, Megan G; Deavers, Michael T; Zarrin-Khameh, Neda

    2015-05-01

    A 64-yr-old postmenopausal woman with high-grade squamous intraepithelial lesion and atypical glandular cell of undetermined significance on her Pap test was found to have endometrial serous carcinoma (high grade) involving a polyp in a subsequent endometrial biopsy. She underwent hysterectomy and bilateral salpingo-oophorectomy with multiple biopsies of the peritoneum. Microscopic examination of the entirely submitted uterus showed no residual serous carcinoma. Multiple foci of low-grade serous tumor with extensive calcifications and psammoma bodies were identified on the surfaces of the left fallopian tube, ovaries, and biopsies of the peritoneum, consistent with peritoneal primary low-grade serous carcinoma. To our knowledge, this is the first reported case of low-grade serous carcinoma of the peritoneum with a concurrent (high-grade) serous carcinoma of the endometrium arising from an endometrial polyp.

  2. Poor interobserver reproducibility in the diagnosis of high-grade endometrial carcinoma.

    PubMed

    Gilks, C Blake; Oliva, Esther; Soslow, Robert A

    2013-06-01

    Patients with high-grade subtypes of endometrial carcinoma (grade 3 endometrioid, serous, clear cell, or carcinosarcoma) have a relatively poor prognosis. The specific subtype may be used to guide patient management, but there is little information on the reproducibility of subtype diagnosis in cases of high-grade endometrial carcinoma. Fifty-six cases diagnosed as a high-grade subtype of endometrial carcinoma were identified from the pathology archives of Vancouver General Hospital. All slides for each case were reviewed independently by 3 pathologists, who diagnosed the specific tumor subtype(s) and assigned the percentage of each subtype for mixed tumors. Agreement between observers was categorized as follows: major disagreement: (A) no consensus for low-grade endometrioid versus high-grade carcinoma (any subtype), or (B) no consensus with respect to the predominant high-grade subtype present; minor disagreement: consensus was reached about the cell type of the predominant component of a mixed tumor, but there was disagreement about the subtype of the minor component. A tissue microarray was constructed from these cases and immunostained for p16, ER, PR, PTEN, and p53. In 35 of 56 (62.5%) cases, there was agreement between all 3 reviewers regarding the subtype diagnosis of the exclusive (in pure tumors) or predominant (in mixed tumors) high-grade component. Of these cases, there was a minor disagreement (ie, disagreement about the minor high-grade component subtype in a mixed tumor) in 4 cases (4/56, 7.1%). In 20 of 56 (35.8%) cases there was a major disagreement; in 17 (30.4%) of these cases there was no consensus about the major subtype diagnosis, whereas in 3 (5.4%) cases there was disagreement about whether a component of high-grade endometrial carcinoma was present. In the final case, all 3 reviewers diagnosed the case as low-grade endometrioid carcinoma, disagreeing with the original diagnosis of high-grade carcinoma. The most frequent areas of

  3. Serous versus high-grade endometrioid endometrial carcinoma: immunohistochemistry of RFP is not useful for differentiation.

    PubMed

    Ussakli, Cigdem; Usubutun, Alp; Dincer, Nazmiye; Dolgun, Anil; Bülbül, Diilek; Isikdogan, Zuhal; Haberal, Nihan; Ozen, Ozlem; Tezel, Gaye Guler

    2016-01-01

    We evaluated the immunohistochemical expression of ret finger protein (RFP) along with conventional immunohistochemical markers in endometrioid and serous carcinomas of the endometrium. A total of 124 endometrial carcinoma cases (24 grade 1 endometrioid, 60 grade 3 endometrioid, 40 serous) were retrieved from pathology archives. Tissue microarrays were constructed. The expression of RFP, WT1, ER, PR, p53 and p16 was examined immunohistochemically. Sensitivity, specificity, area under the receiver operating characteristic (ROC) curve,  statistic for interobserver reproducibility, Kruskal-Wallis test, Mann-Whitney U test and Fisher's exact tests were performed for statistical analyses. The mean RFP score was 1.54 in grade 1 endometrioid, 4.31 in grade 3 endometrioid, and 6.31 in serous carcinomas (p < 0.001). Overall, RFP scores were higher both in serous and grade 3 endometrioid carcinoma (p > 0.05), and significantly lower in grade 1 endometrioid carcinoma (p < 0.05). p16 and p53 staining patterns were able to differentiate between high-grade endometrioid and serous carcinoma (p < 0.001). ER, PR and WT-1 did not reach statistical significance for subtyping. The  values of the general agreement between the observers were 0.737 and 0.727 for endometrioid and serous carcinomas respectively (p < 0.001). Diffuse p53 and p16 staining provides the most sensitive and specific immunomarkers for differentiating high-grade endometrioid and serous carcinomas.

  4. Immunohistochemical Profiling of Endometrial Serous Carcinoma.

    PubMed

    Chen, Wenqian; Husain, Arjumand; Nelson, Gregg S; Rambau, Peter F; Liu, Shuhong; Lee, Cheng-Han; Lee, Sandra; Duggan, Máire A; Köbel, Martin

    2017-03-01

    Endometrial serous carcinoma (ESC) is an aggressive neoplasm mainly seen in older women. The objective of this study was to refine immunohistochemical (IHC) panels for the differential diagnoses against endometrial endometrioid grade 3 (EC3), endometrial clear cell, and ovarian high-grade serous carcinoma as well as exploring the prognostic role of selected IHC markers. Fifty-two ESC from a single institution were assessed for 20 IHC markers, including ARID1A, CCNE1, CDKN2A, ERBB2, ESR1, HNF1B, FBXW7, IGF2BP3, MLH1, MSH2, MSH6, NAPSA, PAX8, PGR, PMS2, PTEN, TFF3, TP53, VIM, and WT1. ERBB2 chromogenic in situ hybridization was evaluated on tissue microarrays. Statistical analysis was performed. All ESC showed aberrant TP53, normal mismatch repair protein, and retained ARID1A and PTEN expression. ESR1 expression was present in 80% of ESC. A combination of TP53, PTEN, and CDKN2A had a sensitivity of 93.6% [95% confidence interval (CI), 84%-98%] and specificity of 87.8% (95% CI, 75%-95%) for ESC versus EC3. A combination of NAPSA and ESR1 had a sensitivity of 97.9% (95% CI, 89%-99%) and specificity of 72.2% (95% CI, 46%-90%) for ESC versus clear cell carcinoma. Absence of WT1 alone had a sensitivity of 66.0% (95% CI, 51%-79%) and specificity of 98.0% (95% CI, 94%-99%) for ESC versus ovarian high-grade serous carcinoma. Among all 52 ESCs, ERBB2 amplification was present in 23%, FBXW7 expression was absent in 10%, and CCNE1 was overexpressed in 59%, however, none were associated with prognosis. Our data support the value of IHC marker panels for histotyping of high-grade endometrial carcinomas.

  5. Integrated Genomic Characterization of Endometrial Carcinoma

    PubMed Central

    2013-01-01

    Summary We performed an integrated genomic, transcriptomic, and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumors and ~25% of high-grade endometrioid tumors have extensive copy number alterations, few DNA methylation changes, low ER/PR levels, and frequent TP53 mutations. Most endometrioid tumors have few copy number alterations or TP53 mutations but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A, KRAS and novel mutations in the SWI/SNF gene ARID5B. A subset of endometrioid tumors we identified had a dramatically increased transversion mutation frequency, and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy number low, and copy number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may impact post-surgical adjuvant treatment for women with aggressive tumors. PMID:23636398

  6. Robotic surgery compared with laparotomy for high-grade endometrial cancer.

    PubMed

    Pant, Alok; Schink, Julian; Lurain, John

    2014-06-01

    High-grade endometrial cancer often presents with occult metastatic disease and this presentation pattern can be considered a contraindication to minimally invasive surgery. We sought to compare the surgical and oncologic outcomes of patients with high-grade endometrial cancer who underwent surgical management/staging via the robotic approach versus the traditional open approach. A retrospective analysis was performed of patients with high-grade endometrial cancer who were treated at a single institution from January 2008 through December 2011. High-grade endometrial histology was defined as FIGO grade 2 or 3 endometrioid, serous, clear cell or uterine carcinosarcoma. Pre-operatively, all patients had clinical stage I disease based on a combination of physical examination and imaging studies. Baseline patient demographics, operative results, complications and oncologic outcomes were analyzed. Eighty consecutive patients were included. Forty-seven patients underwent surgical management using the robotic approach and 33 patients underwent a traditional operation via laparotomy. The groups were well matched in terms of age, body mass index, medical co-morbidities, stage and histology. The average hospital stay for patients who underwent open surgery was significantly longer than for those who underwent a robotic approach [5.6 versus 1.4 days (p = 0.0001)]. Of the patients who underwent robotic surgery, 7/47 (15 %) experienced an operative complication versus 18/33 (55 %) in the open surgery cohort (p = 0.002). The average number of pelvic lymph nodes retrieved in each cohort was 12. The average number of para-aortic lymph nodes retrieved in each group was 4. On final pathologic analysis, 20 patients in the robotic surgery arm were found to have disease that had spread beyond the uterus (43 %), compared to 14 in the traditional surgery group (42 %). There were 11/47 (23 %) recurrences in the robotic surgery group during the study period, compared to 8/33 (24

  7. HER2 over-expressing high grade endometrial cancer expresses high levels of p95HER2 variant

    PubMed Central

    Growdon, Whitfield B.; Groeneweg, Jolijn; Byron, Virginia; DiGloria, Celeste; Borger, Darrell R.; Tambouret, Rosemary; Foster, Rosemary; Chenna, Ahmed; Sperinde, Jeff; Winslow, John; Rueda, Bo R.

    2015-01-01

    Background Subsets of high grade endometrial cancer (EnCa) over-express HER2 (ERBB2), yet clinical trials have failed to demonstrate any anti-tumor activity utilizing trastuzumab, an approved platform for HER2 positive breast cancer (BrCa). A truncated p95HER2 variant lacking the trastuzumab binding site may confer resistance. The objective of this investigation was to characterize the expression of the p95HER2 truncated variant in EnCa. Materials and Methods With institutional approval, 86 high grade EnCa tumors were identified with tumor specimens from surgeries performed between 2000-2011. Clinical data were collected and all specimens underwent tumor genotyping, HER2 immunohistochemistry (IHC, HercepTest®), HER2 fluorescent in situ hybridization (FISH), along with total HER2 (H2T) and p95HER2 assessment with VeraTag® testing. Regression models were used to compare a cohort of 86 breast tumors selected for equivalent HER2 protein expression. Results We identified 44 high grade endometrioid and 42 uterine serous carcinomas (USC). IHC identified high HER2 expression (2+ or 3+) in 59% of the tumors. HER2 gene amplification was observed in 16 tumors (12 USC, 4 endometrioid). Both HER2 gene amplification and protein expression correlated with H2T values. High p95HER2 expression above 2.8 RF/mm2 was observed in 53% (n = 54) with significant correlation with H2T levels. When matched to a cohort of 107 breast tumors based on HercepTest HER2 expression, high grade EnCa presented with higher p95 levels (p < 0.001). Conclusions: These data demonstrate that compared to BrCa, high grade EnCa expresses higher levels of p95HER2 possibly providing rationale for the trastuzumab resistance observed in EnCa. PMID:25602714

  8. STAR and AKR1B10 are down-regulated in high-grade endometrial cancer.

    PubMed

    Sinreih, Maša; Štupar, Saša; Čemažar, Luka; Verdenik, Ivan; Frković Grazio, Snježana; Smrkolj, Špela; Rižner, Tea Lanišnik

    2017-02-21

    Endometrial cancer is the most frequent gynecological malignancy in the developed world. The majority of cases are estrogen dependent, and are associated with diminished protective effects of progesterone. Endometrial cancer is also related to enhanced inflammation and decreased differentiation. In our previous studies, we examined the expression of genes involved in estrogen and progesterone actions in inflammation and tumor differentiation, in tissue samples from endometrial cancer and adjacent control endometrium. The aims of the current study were to examine correlations between gene expression and several demographic characteristics, and to evaluate changes in gene expression with regard to histopathological and clinical characteristics of 51 patients. We studied correlations and differences in expression of 38 genes involved in five pathophysiological processes: (i) estrogen-stimulated proliferation; (ii) estrogen-dependent carcinogenesis; (iii) diminished biosynthesis of progesterone: (iv) enhanced formation of progesterone metabolites; and (v) increased inflammation and decreased differentiation. Spearman correlation coefficient analysis shows that expression of PAQR7 correlates with age, expression of SRD5A1, AKR1B1 and AKR1B10 correlate with body mass, while expression of SRD5A1 and AKR1B10 correlate with body mass index. When patients with endometrial cancer were stratified based on menopausal status, histological grade, myometrial invasion, lymphovascular invasion, and FIGO stage, Mann-Whitney U tests revealed significantly decreased expression of STAR (4.4-fold; adjusted p=0.009) and AKR1B10 (9-fold; adjusted p=0.003) in high grade versus low grade tumors. Lower levels of STAR might lead to decreased de-novo steroid hormone synthesis and tumor differentiation, and lower levels of AKR1B10 to diminished elimination of toxic electrophilic carbonyl compounds in high-grade endometrial cancer. These data thus reveal the potential of STAR and AKR1B10 as

  9. Thalidomide in Treating Patients With Recurrent or Persistent Endometrial Cancer

    ClinicalTrials.gov

    2013-01-23

    Endometrial Adenoacanthoma; Endometrial Adenocarcinoma; Endometrial Adenosquamous Cell Carcinoma; Endometrial Clear Cell Carcinoma; Endometrial Papillary Serous Carcinoma; Recurrent Endometrial Carcinoma

  10. Megestrol Acetate or Levonorgestrel-Releasing Intrauterine System in Treating Patients With Atypical Endometrial Hyperplasia or Endometrial Cancer

    ClinicalTrials.gov

    2014-09-09

    Atypical Endometrial Hyperplasia; Endometrial Adenocarcinoma; Recurrent Endometrial Carcinoma; Stage IA Endometrial Carcinoma; Stage IB Endometrial Carcinoma; Stage II Endometrial Carcinoma; Stage IIIA Endometrial Carcinoma; Stage IIIB Endometrial Carcinoma; Stage IIIC Endometrial Carcinoma; Stage IVA Endometrial Carcinoma; Stage IVB Endometrial Carcinoma

  11. ZEB1 overexpression associated with E-cadherin and microRNA-200 downregulation is characteristic of undifferentiated endometrial carcinoma.

    PubMed

    Romero-Pérez, Laura; López-García, M Ángeles; Díaz-Martín, Juan; Biscuola, Michele; Castilla, M Ángeles; Tafe, Laura J; Garg, Karuna; Oliva, Esther; Matias-Guiu, Xavier; Soslow, Robert A; Palacios, José

    2013-11-01

    Undifferentiated endometrial carcinomas are very aggressive high-grade endometrial carcinomas that are frequently under-recognized. This study aimed to analyze the molecular alterations underlying the development of these endometrial carcinomas, focusing on those related to dedifferentiation. We assessed a series of 120 tumors: 57 grade 1 and 2 endometrioid endometrial carcinomas, 15 grade 3 endometrioid endometrial carcinomas, 27 endometrial serous carcinomas, and 21 undifferentiated endometrial carcinomas. We found a high frequency of DNA mismatch repair deficiency (38%) and moderate rate of p53 overexpression (∼33%) in undifferentiated carcinomas. In contrast to the characteristic endometrioid phenotype, there was a dramatic downregulation of E-cadherin expression in the undifferentiated subtype. Quantitative methylation studies dismissed CDH1 promoter hypermethylation as the mechanism responsible for this change in gene expression, while immunohistochemistry revealed that the E-cadherin repressor ZEB1 was frequently overexpressed (62%) in undifferentiated endometrial carcinomas. This finding was accompanied by a sharp downregulation in the expression of the miR-200 family of microRNAs, well-known targets of ZEB1. Furthermore, there was enhanced expression of epithelial-to-mesenchymal transition markers in undifferentiated endometrial carcinomas, such as N-cadherin, cytoplasmic p120, and osteonectin. In addition, HMGA2, a regulator of epithelial-to-mesenchymal transition that is expressed in aggressive endometrial tumors, such as endometrial serous carcinomas and carcinosarcomas, was expressed in >20% of undifferentiated carcinomas. These results suggest that ZEB1 overexpression, associated with E-cadherin and miR-200s downregulation, and the expression of mesenchymal markers might enhance the metastatic potential of undifferentiated endometrial carcinomas, leading to a poor prognosis. In addition, our observations suggest that the immnohistochemical analysis

  12. [Radiotherapy of cervix and endometrial carcinoma].

    PubMed

    Barillot, I; Haie-Méder, C; Charra Brunaud, C; Peignaux, K; Kerr, C; Thomas, L

    2016-09-01

    External irradiation and brachytherapy still have a major place in the treatment of cervix and endometrial carcinoma. This review presents the French guidelines in terms of preparation and choice of irradiation techniques of these gynecological malignancies.

  13. Endometrium is not the primary site of origin of pelvic high-grade serous carcinoma in BRCA1 or BRCA2 mutation carriers.

    PubMed

    Reitsma, Welmoed; Mourits, Marian J E; de Bock, Geertruida H; Hollema, Harry

    2013-04-01

    Serous endometrial intraepithelial carcinoma has been proposed to be a potential precursor lesion of pelvic high-grade serous carcinoma. If true, an increased incidence of uterine papillary serous carcinomas would be expected in BRCA1 and BRCA2 mutation carriers, who are at high-risk of developing pelvic high-grade serous carcinoma. This study explored particularly the occurrence of uterine papillary serous carcinoma, as well as other endometrial cancers, following risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 germline mutation attending a tertiary multidisciplinary clinic. A consecutive series of women with a BRCA1 or BRCA2 mutation who had undergone risk-reducing salpingo-oophorectomy without hysterectomy at the University Medical Center Groningen from January 1996 until March 2012 were followed prospectively. They were crossed with the histopathology list of endometrial cancer diagnoses reported by the Dutch nationwide pathology database PALGA. To assess the risk of endometrial cancer, a standardized incidence ratio was calculated comparing the observed with the expected number of endometrial cancer cases. Overall, 201 BRCA1 and 144 BRCA2 mutation carriers at a median age of 50 years (range, 32-78) were analyzed. After a median follow-up period of 6 years, after risk-reducing salpingo-oophorectomy, two cases of endometrial cancer were diagnosed, whereas the expected number was 0.94 cases (standardized incidence ratio 2.13; 95% confidence interval 0.24-7.69; P=0.27). Both endometrial cancer cases were of the endometrioid histological subtype. We showed that the incidence of endometrial cancer following risk-reducing salpingo-oophorectomy, especially uterine papillary serous carcinoma, in women at high-risk of developing pelvic high-grade serous carcinoma is not increased. On the basis of our data, the hypothesis of serous endometrial intraepithelial carcinoma being an important precursor lesion of pelvic high-grade serous carcinoma seems

  14. Isolated Abdominal Wall Metastasis of Endometrial Carcinoma

    PubMed Central

    Simões, Jorge; Gonçalves, Matilde; Matos, Isabel

    2014-01-01

    A woman in her mid-60s presented with a bulky mass on the anterior abdominal wall. She had a previous incidental diagnosis of endometrial adenocarcinoma FIGO stage IB following a vaginal hysterectomy. Physical exam and imaging revealed a well circumscribed bulging tumour at the umbilical region, measuring 10 × 9 × 9 cm, with overlying intact skin and subcutaneous tissue. Surgical resection was undertaken, and histological examination showed features of endometrial carcinoma. She began chemotherapy and is alive with no signs of recurrent disease one year after surgery. This case brings up to light an atypical location of a solitary metastasis of endometrial carcinoma. PMID:25349753

  15. Expression of Ki-67 as proliferation biomarker in imprint smears of endometrial carcinoma.

    PubMed

    Konstantinos, Kosmas; Marios, Stamoulas; Anna, Marouga; Nikolaos, Kavantzas; Efstratios, Patsouris; Paulina, Athanassiadou

    2013-03-01

    The aims of this study were to determine the expression of Ki-67 in type I and type II endometrial adenocarcinomas as well as normal endometrium in imprint smears and to correlate the results with clinicopathologic parameters of primary untreated endometrial cancer patients. During a 29-month period, 255 patients were evaluated with entometrial imprint cytology. Endometrial samples freshly resected from women who underwent total abdominal hysterectomy were studied. One hundred twenty-six patients had endometrial carcinoma and 129 cases were diagnosed as normal endometrium. The expression of Ki-67 was assessed by immunocytochemistry. Positive staining was correlated with increased stage, grade and lymph node metastases. High expression was more frequent in type II than type I endometrial adenocarcinoma and high-grade endometrial carcinoma had higher proportions of Ki-67 positive immunostaining compared with low-grade carcinoma. Proliferative endometrium showed high Ki-67 expression level, even higher than those of grade 1 and type I. On the other hand, secretory endometrium Ki-67 positive cells were markedly diminished and even disappeared. Completely negative staining was found to be related to atrophic endometrium. Immunocytochemical findings from Ki-67 stain, in addition to cytomorphologic features, appeared to be useful for the diagnosis of endometrial carcinoma in endometrial cytology with imprint smears. High Ki-67 expression correlates with morphologic features of aggressiveness and the expression pattern of Ki-67 correspond to the expected cyclic/atrophic pattern in normal endometrium.

  16. Molecular genetic heterogeneity in undifferentiated endometrial carcinomas.

    PubMed

    Rosa-Rosa, Juan M; Leskelä, Susanna; Cristóbal-Lana, Eva; Santón, Almudena; López-García, Ma Ángeles; Muñoz, Gloria; Pérez-Mies, Belen; Biscuola, Michele; Prat, Jaime; Esther, Oliva E; Soslow, Robert A; Matias-Guiu, Xavier; Palacios, Jose

    2016-11-01

    Undifferentiated and dedifferentiated endometrial carcinomas are rare and highly aggressive subtypes of uterine cancer, not well characterized at a molecular level. To investigate whether dedifferentiated carcinomas carry molecular genetic alterations similar to those of pure undifferentiated carcinomas, and to gain insight into the pathogenesis of these tumors, we selected a cohort of 18 undifferentiated endometrial carcinomas, 8 of them with a well-differentiated endometrioid carcinoma component (dedifferentiated endometrioid carcinomas), and studied them by immunohistochemistry and massive parallel and Sanger sequencing. Whole-exome sequencing of the endometrioid and undifferentiated components, as well as normal myometrium, was also carried out in one case. According to The Cancer Genome Atlas classification, we distributed 95% of the undifferentiated carcinomas in this series as follows: (a) hypermutated tumors with loss of any mismatch repair protein expression and microsatellite instability (eight cases, 45%); (b) ultramutated carcinomas carrying mutations in the exonuclease domain of POLE (two cases, 11%); (c) high copy number alterations (copy-number high) tumors group exhibiting only TP53 mutations and high number of alterations detected by FISH (two cases, 11%); and (d) low copy number alterations (copy-number low) tumors with molecular alterations typical of endometrioid endometrial carcinomas (five cases, 28%). Two of the latter cases, however, also had TP53 mutations and higher number of alterations detected by FISH and could have progressed to a copy-number high phenotype. Most dedifferentiated carcinomas belonged to the hypermutated group, whereas pure undifferentiated carcinomas shared molecular genetic alterations with copy-number low or copy-number high tumors. These results indicate that undifferentiated and dedifferentiated endometrial carcinomas are molecularly heterogeneous tumors, which may have prognostic value.

  17. Temsirolimus in Treating Patients With Metastatic or Locally Advanced Recurrent Endometrial Cancer

    ClinicalTrials.gov

    2015-02-05

    Endometrial Adenocarcinoma; Endometrial Adenosquamous Cell Carcinoma; Endometrial Clear Cell Carcinoma; Endometrial Papillary Serous Carcinoma; Recurrent Endometrial Carcinoma; Stage IIIA Endometrial Carcinoma; Stage IIIB Endometrial Carcinoma; Stage IIIC Endometrial Carcinoma; Stage IVA Endometrial Carcinoma; Stage IVB Endometrial Carcinoma

  18. Risk-scoring models for individualized prediction of overall survival in low-grade and high-grade endometrial cancer

    PubMed Central

    AlHilli, Mariam M.; Mariani, Andrea; Bakkum-Gamez, Jamie N.; Dowdy, Sean C.; Weaver, Amy L.; Peethambaram, Preema P.; Keeney, Gary L.; Cliby, William A.; Podratz, Karl C.

    2015-01-01

    Objective Overall survival (OS) in endometrial cancer (EC) is dependent on patient-, disease-, and treatment-specific risk factors. Comprehensive risk-scoring models were developed to estimate OS in low-grade and high-grade EC. Methods Patients undergoing primary surgery for EC from 1999 through 2008 were stratified histologically according to the International Federation of Gynecology and Obstetrics (FIGO) as either (i) low grade: grades 1 and 2 endometrioid EC or (ii) high grade: grade 3, including non-endometrioid EC. Associations between patient-, pathological-, and treatment-specific risk factors and OS starting on postoperative day 30 were assessed using multivariable Cox regression models. Factors independently associated with OS were used to construct nomograms and risk-scoring models. Results Eligible patients (N= 1281) included 925 low-grade and 356 high-grade patients; estimated 5-year OSs were 87.0% and 51.5%, respectively. Among patients alive at last follow-up, median follow-up was 5.0 (low grade) and 4.6 years (high grade), respectively. In low-grade patients, independent factors predictive of compromised OS included age, cardiovascular disease, pulmonary dysfunction, stage, tumor diameter, pelvic lymph node status, and grade 2 or higher 30-day postoperative complications. Among high-grade patients, age, American Society of Anesthesiologists score, stage, lymphovascular space invasion, adjuvant therapy, para-aortic nodal status, and cervical stromal invasion were independent predictors of compromised OS. The two risk-scoring models/nomograms had excellent calibration and discrimination (unbiased c-indices = 0.803 and 0.759). Conclusion Patients with low-grade and high-grade EC can be counseled regarding their predicted OS using the proposed risk-scoring models. This may facilitate institution of personalized treatment algorithms, surveillance strategies, and lifestyle interventions. PMID:24690476

  19. Oncocytoma-Like Renal Tumor With Transformation Toward High-Grade Oncocytic Carcinoma

    PubMed Central

    Sirintrapun, Sahussapont J.; Geisinger, Kim R.; Cimic, Adela; Snow, Anthony; Hagenkord, Jill; Monzon, Federico; Legendre, Benjamin L.; Ghazalpour, Anatole; Bender, Ryan P.; Gatalica, Zoran

    2014-01-01

    Abstract Renal oncocytoma is a benign tumor with characteristic histologic findings. We describe an oncocytoma-like renal tumor with progression to high-grade oncocytic carcinoma and metastasis. A 74-year-old man with no family history of cancer presented with hematuria. Computed tomography showed an 11 cm heterogeneous multilobulated mass in the right kidney lower pole, enlarged aortocaval lymph nodes, and multiple lung nodules. In the nephrectomy specimen, approximately one third of the renal tumor histologically showed regions classic for benign oncocytoma transitioning to regions of high-grade carcinoma without sharp demarcation. With extensive genomic investigation using single nucleotide polymorphism-based array virtual karyotyping, multiregion sequencing, and expression array analysis, we were able to show a common lineage between the benign oncocytoma and high-grade oncocytic carcinoma regions in the tumor. We were also able to show karyotypic differences underlying this progression. The benign oncocytoma showed no chromosomal aberrations, whereas the high-grade oncocytic carcinoma showed loss of the 17p region housing FLCN (folliculin [Birt–Hogg–Dubé protein]), loss of 8p, and gain of 8q. Gene expression patterns supported dysregulation and activation of phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (Akt), mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK), and mechanistic target of rapamycin (serine/threonine kinase) (mTOR) pathways in the high-grade oncocytic carcinoma regions. This was partly attributable to FLCN underexpression but further accentuated by overexpression of numerous genes on 8q. In the high-grade oncocytic carcinoma region, vascular endothelial growth factor A along with metalloproteinases matrix metallopeptidase 9 and matrix metallopeptidase 12 were overexpressed, facilitating angiogenesis and invasiveness. Genetic molecular testing provided evidence for the

  20. Isolated humeral recurrence in endometrial carcinoma

    PubMed Central

    Devdas, Santosh Kumar; Digumarti, Leela; Digumarti, Raghunadharao; Patro, Kunha Charan; Nutakki, Ramakoteswararao

    2016-01-01

    Isolated skeletal metastasis in endometrial carcinoma at recurrence is very rare. We report a 52-year-old woman diagnosed to have FIGO Stage 1b, Grade 1 endometrioid adenocarcinoma, presenting with isolated distal humerus metastasis, 2 years after surgery and adjuvant radiotherapy for primary disease. Imaging, bone scintigraphy, and cytology confirmed the diagnosis of poorly differentiated metastatic adenocarcinoma. She was treated with local radiotherapy followed by six cycles of paclitaxel and carboplatin chemotherapy along with zoledronic acid, monthly. She is symptom-free after the treatment and at a first follow-up visit after 3 months. PMID:27688615

  1. Prevention of Ovarian High-Grade Serous Carcinoma by Elucidating Its Early Changes

    DTIC Science & Technology

    2014-10-01

    that i) reproductive hormone signaling is altered in HGSC, that ii) reproductive hormone receptor status (ERα/PR) may be an important indicator of...microenvironment ovulatory stresses, which may include altered reproductive hormone levels and the ovulatory inflammatory response. The...inflammatory response and altered reproductive hormone physiology. Keywords: BRCA, fallopian tube epithelium, high-grade serous carcinoma INTRODUCTION In 2013

  2. Nrf2 expression in endometrial serous carcinomas and its precancers.

    PubMed

    Chen, Ning; Yi, Xiaofang; Abushahin, Nisreen; Pang, Shujie; Zhang, Donna; Kong, Beihua; Zheng, Wenxin

    2010-12-24

    Endometrial serous carcinoma (ESC) is the most aggressive subtype of endometrial cancer. Its aggressive behavior and poor clinical outcome may be partially attributed to lack of early diagnostic markers and unclear patho-genesis. The transcription factor Erythroid-E2-related factor 2 (Nrf2) is a recently identified protein marker, which plays a role in carcinogenesis as well as responsible for poor prognosis of many human cancers. The aim of this study is to determine the Nrf2 expression in benign endometrium (n=28), endometrial cancers (n=122) as well as their precursor lesions (n=81) trying to see whether Nrf2 has any diagnostic usage and is potentially involved in endometrial carcinogenesis. The level of Nrf2 was evaluated by immunohistochemical (IHC) and verified by using Western blots. Among the malignant cases, Nrf2 was positive in 28 (68%) of 50 ESCs, which was significantly more than in 3 (6%) of 50 endometrioid carcinomas (p < 0.001) and 2 (13%) of 15 clear cell carcinomas (p = 0.001) and other histologic types of endometrial cancers. Among endometrial precursor lesions, both serous endometrial glandular dysplasia (EmGD, 40%) and serous endometrial intraepithelial carcinoma (EIC, 44%) showed a significantly higher Nrf2 expression than that in atypical endometrial hyperplasia or endometrial intraepithelial neoplasia (0%), clear cell EmGD (10%), and clear cell EIC (25%), respectively. We conclude that Nrf2 overexpression is closely associated with endometrial neoplasms with serous differentiation. Alteration of Nrf2 expression may represent one of the early molecular events in ESC carcinogenesis and overexpression of Nrf2 may used as a diagnostic marker in surgical pathology.

  3. Dicer1 dysfunction promotes stemness and aggression in endometrial carcinoma.

    PubMed

    Wang, Xiao-Jun; Jiang, Fei-Zhou; Tong, Huan; Ke, Jie-Qi; Li, Yi-Ran; Zhang, Hui-Lin; Yan, Xiao-Fang; Wang, Fang-Yuan; Wan, Xiao-Ping

    2017-04-01

    Endometrial carcinoma is one of the most common gynecological malignancies, but the molecular events involved in the development and progression of endometrial carcinoma remain unclear. Dicer1 and cancer stem cells play important roles in cell motility and survival. This study investigated the role of the let-7 family and Dicer1 in the stemness of endometrial carcinoma cells. We profiled Dicer1 expression in clinical samples and explored its relationship with stem cell-associated markers and clinical parameters. We showed that Dicer1 dysfunction leads to the enrichment of tumor stemness features and tumor aggression both in vitro and in vivo. We also identified the mechanism related to this potential tumor-predisposing phenotype: loss of Dicer1 induced abnormal expression of the let-7 family, which comprises well-known tumor suppressors, thus regulating stemness in endometrial carcinoma cells.

  4. Stromal p16 expression is significantly increased in endometrial carcinoma.

    PubMed

    Yoon, Gun; Koh, Chang Won; Yoon, Nara; Kim, Ji-Ye; Kim, Hyun-Soo

    2017-01-17

    p16 is a negative regulator of cell proliferation and is considered a tumor suppressor protein. Alterations in p16 protein expression are associated with tumor development and progression. However, the p16 expression status in the peritumoral stroma has not been investigated in the endometrium. Therefore, we evaluated stromal p16 expression in different types of endometrial lesions using immunohistochemistry. Differences in the p16 expression status according to the degree of malignancy and histological type were analyzed. This study included 62, 26, and 36 cases of benign, precancerous, and malignant endometrial lesions, respectively. Most benign lesions showed negative or weak expression, whereas precancerous lesions showed a variable degree of staining proportion and intensity. Atypical hyperplasia/endometrial intraepithelial neoplasia (AH/EIN) and serous endometrial intraepithelial carcinoma (SEIC) had significantly higher stromal p16 expression levels than benign lesions. Endometrioid carcinoma (EC), serous carcinoma (SC), and carcinosarcoma showed significantly elevated stromal p16 expression levels compared with benign and precancerous lesions. In addition, there were significant differences in stromal p16 expression between AH/EIN and SEIC and between EC and SC. In contrast, differences in stromal p16 expression among nonpathological endometrium, atrophic endometrium, endometrial polyp, and hyperplasia without atypia were not statistically significant. Our observations suggest that stromal p16 expression is involved in the development and progression of endometrial carcinoma, and raise the possibility that p16 overexpression in the peritumoral stroma is associated with aggressive oncogenic behavior of endometrial SC.

  5. Association of Ulex europaeus agglutinin I binding with invasion in endometrial carcinoma.

    PubMed

    Ambros, R A; Kurman, R J

    1993-10-01

    Ulex europaeus agglutinin I (UEA-I), a lectin which specifically binds L-fucose, has been shown to extensively bind endometrial carcinoma cells but not benign endometrial glands. Patterns of UEA-I binding were examined in five cases of uteri containing proliferative endometrium, five cases of endometrial hyperplasia, and 54 cases of endometrioid (typical) carcinoma of the endometrium and correlated with the histologic features of the tumor and its behavior. Whereas proliferative endometrium showed luminal staining only, diffuse cytoplasmic staining was frequently seen in hyperplasia and carcinoma. Carcinomas with a high percentage of tumor cells staining with UEA-I tended to be high-grade with a greater tendency to deep myometrial and vascular invasion than tumors with little or no staining. By univariate survival analysis, the extent of UEA-I binding was found to correlate with patient survival. By multivariate analysis, however, survival correlated most closely with the presence of deep myometrial and vascular invasion, and UEA-I binding was not found to be an independent prognostic indicator. This study suggests that increased fucosylation of proteins in endometrioid cancer cells may play a role in myometrial and vascular invasion.

  6. Persistence of endometrial activity after radiation therapy for cervical carcinoma

    SciTech Connect

    Barnhill, D.; Heller, P.; Dames, J.; Hoskins, W.; Gallup, D.; Park, R.

    1985-12-01

    Radiation therapy is a proved treatment for cervical carcinoma; however, it destroys ovarian function and has been thought to ablate the endometrium. Estrogen replacement therapy is often prescribed for patients with cervical carcinoma after radiation therapy. A review of records of six teaching hospitals revealed 16 patients who had endometrial sampling for uterine bleeding after standard radiation therapy for cervical carcinoma. Fifteen patients underwent dilatation and curettage, and one patient underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy when a dilatation and curettage was unsuccessful. Six patients had fibrosis and inflammation of the endometrial cavity, seven had proliferative endometrium, one had cystic hyperplasia, one had atypical adenomatous hyperplasia, and one had adenocarcinoma. Although the number of patients who have an active endometrium after radiation therapy for cervical carcinoma is not known, this report demonstrates that proliferative endometrium may persist, and these patients may develop endometrial hyperplasia or adenocarcinoma. Studies have indicated that patients with normal endometrial glands have an increased risk of developing endometrial adenocarcinoma if they are treated with unopposed estrogen. Patients who have had radiation therapy for cervical carcinoma should be treated with estrogen and a progestational agent to avoid endometrial stimulation from unopposed estrogen therapy.

  7. A spontaneous high-grade undifferentiated mammary carcinoma in a seven-week-old female rat.

    PubMed

    Faustino-Rocha, Ana I; Gama, Adelina; Oliveira, Paula A; Alvarado, Antonieta; Ferreira, Rita; Ginja, Mário

    2017-02-01

    The present work describes a rare case of a spontaneous high-grade carcinoma in a seven-week-old Sprague-Dawley female rat that had been included in the control group of an assay of mammary carcinogenesis. The mass was detected at 50days of age, it grown quickly and the animal was humanely sacrificed eight days later. The tumor was located in the left cervical region, in the vicinity of the left submandibular and sublingual glands. It was soft and reddish and had several dens with a bloody content. The tumor was PAS negative and exhibited immunostaining for ER-α. The histopathologic and immunohistochemical data are suggestive of a high-grade carcinoma from mammary gland. It was the first report of a spontaneous mammary tumor in such a young rat.

  8. Trametinib With or Without GSK2141795 in Treating Patients With Recurrent or Persistent Endometrial Cancer

    ClinicalTrials.gov

    2017-01-31

    Endometrial Adenocarcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Mixed Adenocarcinoma; Endometrial Serous Adenocarcinoma; Endometrial Undifferentiated Carcinoma; Recurrent Uterine Corpus Carcinoma

  9. PTEN sequence analysis in endometrial hyperplasia and endometrial carcinoma in Slovak women.

    PubMed

    Gbelcová, H; Bakeš, P; Priščáková, P; Šišovský, V; Hojsíková, I; Straka, Ľ; Konečný, M; Markus, J; D'Acunto, C W; Ruml, T; Böhmer, D; Danihel, Ľ; Repiská, V

    2015-01-01

    Phosphatase and tensin homolog (PTEN) is a protein that acts as a tumor suppressor by dephosphorylating the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate. Loss of PTEN function has been implicated in the pathogenesis of a number of different tumors, particularly endometrial carcinoma (ECa). ECa is the most common neoplasia of the female genital tract. Our study evaluates an association between the morphological appearance of endometrial hyperplasia and endometrial carcinoma and the degree of PTEN alterations. A total of 45 endometrial biopsies from Slovak women were included in present study. Formalin-fixed and paraffin-embedded tissue samples with simple hyperplasia (3), complex hyperplasia (5), atypical complex hyperplasia (7), endometrioid carcinomas G1 (20) and G3 (5), and serous carcinoma (5) were evaluated for the presence of mutations in coding regions of PTEN gene, the most frequently mutated tumor suppressor gene in endometrial carcinoma. 75% of the detected mutations were clustered in exons 5 and 8. Out of the 39 mutations detected in 24 cases, 20 were frameshifts and 19 were nonsense, missense, or silent mutations. Some specimens harboured more than one mutation. The results of current study on Slovak women were compared to a previous study performed on Polish population. The two sets of results were similar.

  10. Incidental nonuterine high-grade serous carcinomas arise in the fallopian tube in most cases: further evidence for the tubal origin of high-grade serous carcinomas.

    PubMed

    Gilks, C Blake; Irving, Julie; Köbel, Martin; Lee, Chenghan; Singh, Naveena; Wilkinson, Nafisa; McCluggage, W Glenn

    2015-03-01

    Most nonuterine high-grade serous carcinomas (HGSCs) in women with hereditary breast and ovarian cancer syndrome, due to germline BRCA1/2 mutation, arise in the fimbria of the fallopian tube. However, the site of origin of sporadic HGSC, which is usually widely disseminated at presentation, is not well established. We sought to characterize cases of HGSC discovered incidentally in patients not known to be at high risk, in order to determine the site distribution and possible origin of sporadic HGSC. Incidental microscopic, non-mass-forming cases of serous tubal intraepithelial carcinoma or HGSC in salpingo-oophorectomy specimens in which the tubes and ovaries had been extensively examined were identified. No patients were known or suspected BRCA1/2 mutation carriers. Twenty-one cases were identified (mean age: 57 y). Surgery was for benign disease (n=15), uterine endometrioid adenocarcinoma or atypical hyperplasia (n=3), bladder carcinoma (n=1), or ovarian serous borderline tumor (n=2). In 16 of 21 cases, the lesion was confined to the fallopian tube (unilateral in 14 cases, bilateral in 2). There was serous tubal intraepithelial carcinoma in all cases and invasive HGSC into the underlying lamina propria in 8 of these 16 cases; the invasive focus measured 1.3 cm or less in every case. In the remaining 5 cases, there was fallopian tube mucosal and ovarian involvement; in 2 of these cases, there was also microscopic peritoneal involvement. Sporadic cases of nonuterine HGSC arise in the fallopian tube fimbria in a large majority of cases, providing further evidence for the tubal origin of these neoplasms.

  11. CEUS in the differentiation between low and high-grade bladder carcinoma

    PubMed Central

    Drudi, F.M.; Di Leo, N.; Malpassini, F.; Antonini, F.; Corongiu, E.; Iori, F.

    2012-01-01

    Introduction Bladder cancer ranks 4th overall in the number of newly diagnosed cancers and 10th in causes of cancer deaths. More than 90% of all cases of bladder cancer are transitional cell carcinoma (TCC). The goal of this study is to confirm the usefulness of low mechanical index contrast-enhanced ultrasonography (CEUS), also in association with time–intensity curves, in the differentiation between high- and low-grade bladder malignant lesions. Materials and methods From February 2006 to February 2012 we recruited 144 patients. All patients underwent grayscale ultrasonography (US), color-Doppler ultrasonography (CDUS) and contrast-enhanced ultrasonography (CEUS). Subsequently all patients underwent cystoscopy and TURB. Results Histological diagnoses were: 88 high-grade carcinomas (61.1%), and 56 low-grade carcinomas (38.9%). Sensitivity and specificity of CDUS were 87.5% (126/144) and 60%, respectively. Sensitivity and specificity of CEUS were 90.9% and 85.7%, respectively. Sensitivity and specificity of TIC were 91.6% (132/144) and 85.7%, respectively. Discussion and conclusions CEUS is a reliable noninvasive method for differentiating low- and high-grade bladder carcinomas since it provides typical enhancement patterns as well as specific contrast-sonographic perfusion curves. PMID:23730389

  12. Correlation between NDRG1 and PTEN expression in endometrial carcinoma.

    PubMed

    Chen, Jiawei; Li, Shuxia; Yang, Zhaorui; Lu, Guangzhong; Hu, Honghui

    2008-04-01

    N-myc Downstream-Regulated Gene 1 (NDRG1) is known as a differentiation-related gene that plays important roles in cell differentiation, organ formation, and embryonic development. NDRG1 has recently been shown to be associated with carcinogenesis and tumor progression in a wide variety of tumors. Phosphatase and tensin homolog deleted from chromosome (PTEN), a phosphatase and tensin homolog located on chromosome 10, is shown to be a tumor suppressor and is often mutated or deleted in various tumor cells, particularly in endometrial carcinoma. Using an immunohistochemical approach, we investigated the expression of NDRG1 and PTEN in normal endometrium, atypical hyperplasia, and endometrial carcinoma. All tumor tissues harvested in this study were derived from endometrioid carcinoma Type I, that were estrogen-related. Our results demonstrate that the expression of NDRG1 was up-regulated in 5/40 (12.5%), 18/34 (52.94%), and 86/103 (83.5%) normal endometrium, atypical hyperplasia, and endometrial carcinoma cases, respectively (P < 0.01), while in 6/40 (15%), 20/34 (58.82%), and 89/103 (86.41%) normal endometrium, atypical hyperplasia, and endometrial carcinoma cases, respectively. PTEN expression was significantly decreased (P < 0.01). Statistical analyzes demonstrated a positive correlation between NDRG1 up-regulation and PTEN down-regulation (P < 0.01). The expression of NDRG1 had no correlation with the differentiation degree of the tumor cells, lymph-node metastasis, and/or abdominal cavity implantation (P > 0.05). Our results indicated that development of endometrial carcinoma is associated with an overexpression of NDRG1 and the loss of PTEN expression. Identification of changes in the NDRG1 and PTEN expression may be a significant diagnostic tool for the early detection of endometrial carcinoma.

  13. CCNE1 amplification and centrosome number abnormality in serous tubal intraepithelial carcinoma: further evidence supporting its role as a precursor of ovarian high-grade serous carcinoma.

    PubMed

    Kuhn, Elisabetta; Wang, Tian-Li; Doberstein, Kai; Bahadirli-Talbott, Asli; Ayhan, Ayse; Sehdev, Ann Smith; Drapkin, Ronny; Kurman, Robert J; Shih, Ie-Ming

    2016-10-01

    Aberration in chromosomal structure characterizes almost all cancers and has profound biological significance in tumor development. It can be facilitated by various mechanisms including overexpression of cyclin E1 and centrosome amplification. As ovarian high-grade serous carcinoma has pronounced chromosomal instability, in this study we sought to determine whether increased copy number of CCNE1 which encodes cyclin E1 and centrosome amplification (>2 copies) occurs in its putative precursor, serous tubal intraepithelial carcinoma. We found CCNE1 copy number gain/amplification in 8 (22%) of 37 serous tubal intraepithelial carcinomas and 12 (28%) of 43 high-grade serous carcinomas. There was a correlation in CCNE1 copy number between serous tubal intraepithelial carcinoma and high-grade serous carcinoma in the same patients (P<0.001). There was no significant difference in the percentage of CCNE1 gain/amplification between serous tubal intraepithelial carcinoma and high-grade serous carcinoma (P=0.61). Centrosome amplification was recorded in only 5 (14%) of 37 serous tubal intraepithelial carcinomas, and in 10 (40%) of 25 high-grade serous carcinomas. The percentage of cells with centrosome amplification was higher in high-grade serous carcinoma than in serous tubal intraepithelial carcinoma (P<0.001). Induced expression of cyclin E1 increased the percentage of fallopian tube epithelial cells showing centrosome amplification. Our findings suggest that gain/amplification of CCNE1 copy number occurs early in tumor progression and precedes centrosome amplification. The more prevalent centrosome amplification in high-grade serous carcinoma than in serous tubal intraepithelial carcinoma supports the view that serous tubal intraepithelial carcinoma precedes the development of many high-grade serous carcinomas.

  14. Architectural patterns of ovarian/pelvic high-grade serous carcinoma.

    PubMed

    Bromley, Amy B; Altman, Alon D; Chu, Pamela; Nation, Jill G; Nelson, Gregg S; Ghatage, Praful; Kalloger, Steve E; Han, Guangming; Köbel, Martin

    2012-09-01

    We describe the architectural patterns of advanced ovarian/pelvic high-grade serous carcinomas that have been treated with upfront surgery, followed by adjuvant chemotherapy or neoadjuvant chemotherapy, followed by interval debulking to explore the association with the chemotherapeutic response. For 70 cases of advanced (i.e. stage III/IV) high-grade serous carcinomas (33 platinum resistant/intermediate, 37 platinum sensitive; 24 neoadjuvantly treated, 44 primary surgery), all tumor-containing histologic slides were reviewed by 1 of 3 pathologists. Histologic type was confirmed and the following features were assessed: major architectural pattern and the presence of any of 8 predefined minor architectural patterns (papillary, transitional cell carcinoma-like, micropapillary, microcystic, nested papillary, slit-like, glandular, solid). A semiquantitative assessment of psammoma bodies, histiocytic response, necrosis, nuclear atypia, and single-cell invasion was performed. Mitotic count was performed in 10 HPF and 1 HPF was counted for intraepithelial lymphocytes. The morphologic features were tested for an association with previous neoadjuvant chemotherapy and response to chemotherapy (resistant/intermediate versus chemotherapy-sensitive cases stratified by neoadjuvant chemotherapy), which was carried out using χ tests for categorical variables and analysis of variance for continuous data. Combinations of features were analyzed using unsupervised clustering (Wald). Although 8 of 18 features were significantly different when samples from neoadjuvantly treated patients were compared with those not previously treated, no individual histomorphologic feature or a combination of features was associated with response to chemotherapy. Further subtyping of high-grade serous carcinomas will likely need ancillary molecular markers that may have a greater potential to identify cases that will not respond to platinum-based chemotherapy.

  15. Copanlisib in Treating Patients With Persistent or Recurrent Endometrial Cancer

    ClinicalTrials.gov

    2017-01-20

    Endometrial Endometrioid Adenocarcinoma; Endometrial Mixed Adenocarcinoma; Endometrial Serous Adenocarcinoma; Endometrial Undifferentiated Carcinoma; Metastatic Endometrioid Adenocarcinoma; Recurrent Uterine Corpus Carcinoma

  16. Tubal Pregnancy Associated with Endometrial Carcinoma after In Vitro Fertilization Attempts

    PubMed Central

    Bayoglu Tekin, Yesim; Guvendag Guven, Emine Seda; Sehitoglu, Ibrahim; Guven, Suleyman

    2014-01-01

    Endometrial carcinoma is rarely seen during reproductive ages and commonly related to infertility, polycystic ovarian syndrome (PCOS), and obesity. Pregnancy associated endometrial carcinoma is even rarer and this is the second case reported in the literature concerning tubal pregnancy associated endometrial carcinoma. We present a case of a 36-year-old woman with a history of PCOS, infertility, and several attempts of ovulation induction and in vitro fertilization, who was diagnosed with tubal pregnancy and a well differentiated endometrial carcinoma. We also review the literature about pregnancy associated endometrial carcinoma in the first trimester. PMID:25614844

  17. Ovarian low and high grade serous carcinomas: hidden divergent features in the tumor microenvironment

    PubMed Central

    Buttarelli, Marianna; Martinelli, Enrica; Mascilini, Floriana; Petrillo, Marco; Ferrandina, Gabriella; Scambia, Giovanni; Gallo, Daniela

    2016-01-01

    Only recently low-grade serous carcinoma (LGSOC) of the ovary has been recognized as a disease entity distinct from the more common high-grade serous carcinoma (HGSOC), with significant differences in pathogenesis and clinical and pathologic features. The present study aimed at evaluating whether the different natural histories and patterns of response to therapy demonstrated for LGSOC and HGSOC, along with a diverse genomic landscape, may also reside in the supporting tumor stroma, specifically in the state of differentiation and activation of tumor associated macrophages (TAMs). TAMs play complex roles in tumorigenesis since they are believed to possess both tumor rejecting (M1 macrophages) and tumor promoting (M2 macrophages) activities. Here we showed that, when compared to HGSOC (n = 55), LGSOC patients (n = 25) exhibited lower density of tumor-infiltrating CD68+ macrophage, along with an attenuated M2-skewed (CD163+) phenotype. Accordingly, assessment of intratumoral vascularization and of matrix metalloproteinase 9 expression (a key protein involved in tumor invasion and metastasis) revealed lower expression in LGSOC compared to HGSOC patients, in line with emerging evidence supporting a role for TAMs in all aspects of tumor initiation, growth, and development. In conclusion, results from the present study demonstrate that microenvironmental factors contribute greatly to determine clinical and pathological features that differentiate low and high grade serous ovarian carcinomas. This understanding may increase possibilities and opportunities to improve disease control and design new therapeutic strategies. PMID:27462782

  18. Current Issues in the Diagnosis and Treatment of Endometrial Carcinoma.

    PubMed

    Stubert, J; Gerber, B

    2016-02-01

    Endometrial carcinoma is the most common carcinoma of the female genital tract. Its most important clinical sign is postmenopausal bleeding. An endometrial biopsy is essential for diagnosis. Treatment decisions are governed by tumour risk assessment and patient comorbidity, which is often present. Pelvic and paraaortic lymph node dissection is unnecessary in low risk cases (definition: pT1 a, G1/2) and adjuvant radiotherapy and systemic treatments are usually avoidable. Treatment of high-risk patients (G3 and/or pT1b) and palliative cases is difficult and not well standardised. New molecular-based subtype classification may help treatment decision making in future.

  19. Lower Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Promotes the Proliferation and Migration of Endometrial Carcinoma

    PubMed Central

    Xia, Xian; Wang, Jie; Liu, Yuan; Yue, Ming

    2017-01-01

    Background The incidence and death rates of endometrial cancer are alarmingly increasing. The diagnosis and treatment of endometrial cancer is crucial to decreasing mortality. Cystic fibrosis transmembrane conductance regulator (CFTR) belongs to the adenosine triphosphate (ATP)-binding cassette transporter family and plays an essential role in anion regulation and tissue homeostasis of various epithelia. This study explored the expression of CFTR in endometrial carcinoma and the role of CFTR in proliferation and migration of endometrial carcinoma cells. Material/Methods Immunohistochemistry and real-time (RT)-PCR were used to test the expression of CFTR in normal endometrium and endometrial carcinoma. CFTR inhibitor was used to restrain the expression of CFTR on the endometrial carcinoma, the effects on the proliferation and migration of endometrial carcinoma cells were also studied. RT-PCR was performed to test the expression of mir-125b after restraining CFTR. Proliferation and migration capability of endometrial carcinoma cells were detected after transfection of endometrial carcinoma cells with mir-125b mimic. Results Compared with cells from normal endometrium, the expression of CFTR was significantly upregulated in endometrial carcinoma cells. After adding CFTR(inh)172, the capability for proliferation and transfer of endometrial carcinoma cells was strengthened, the expression of mir-125b was reduced, and after transfection with mir-125b mimics entering the endometrial carcinoma cells, the ability of the proliferation and transfer of endometrial carcinoma cells was also reduced. Conclusions The high expression of CFTR in the endometrial carcinoma cells played a pivotal role in restraining the proliferation and transfer of endometrial carcinoma cells. PMID:28225751

  20. Lower Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Promotes the Proliferation and Migration of Endometrial Carcinoma.

    PubMed

    Xia, Xian; Wang, Jie; Liu, Yuan; Yue, Ming

    2017-02-22

    BACKGROUND The incidence and death rates of endometrial cancer are alarmingly increasing. The diagnosis and treatment of endometrial cancer is crucial to decreasing mortality. Cystic fibrosis transmembrane conductance regulator (CFTR) belongs to the adenosine triphosphate (ATP)-binding cassette transporter family and plays an essential role in anion regulation and tissue homeostasis of various epithelia. This study explored the expression of CFTR in endometrial carcinoma and the role of CFTR in proliferation and migration of endometrial carcinoma cells. MATERIAL AND METHODS Immunohistochemistry and real-time (RT)-PCR were used to test the expression of CFTR in normal endometrium and endometrial carcinoma. CFTR inhibitor was used to restrain the expression of CFTR on the endometrial carcinoma, the effects on the proliferation and migration of endometrial carcinoma cells were also studied. RT-PCR was performed to test the expression of mir-125b after restraining CFTR. Proliferation and migration capability of endometrial carcinoma cells were detected after transfection of endometrial carcinoma cells with mir-125b mimic. RESULTS Compared with cells from normal endometrium, the expression of CFTR was significantly upregulated in endometrial carcinoma cells. After adding CFTR(inh)172, the capability for proliferation and transfer of endometrial carcinoma cells was strengthened, the expression of mir-125b was reduced, and after transfection with mir-125b mimics entering the endometrial carcinoma cells, the ability of the proliferation and transfer of endometrial carcinoma cells was also reduced. CONCLUSIONS The high expression of CFTR in the endometrial carcinoma cells played a pivotal role in restraining the proliferation and transfer of endometrial carcinoma cells.

  1. Frequent CCNE1 amplification in endometrial intraepithelial carcinoma and uterine serous carcinoma.

    PubMed

    Kuhn, Elisabetta; Bahadirli-Talbott, Asli; Shih, Ie-Ming

    2014-07-01

    Uterine serous carcinoma accounts for only 10% of all uterine epithelial cancers, but is the leading cause of death among them. The pathogenesis of this aggressive neoplasm has been largely elusive until recently, when comprehensive genome-wide analyses of uterine serous carcinoma have been performed. Among amplified cancer-related genes, CCNE1, encoding for cyclin E1, is frequently amplified in uterine serous carcinoma. In the current study we applied fluorescence in situ hybridization (FISH) to determine CCNE1 copy number in uterine serous carcinoma and concurrent endometrial intraepithelial carcinoma, the noninvasive component of uterine serous carcinoma, and the results were correlated with clinicopathological and molecular features. We found that 20 (45%) of 44 uterine serous carcinomas and 11 (41%) of 27 endometrial intraepithelial carcinomas showed CCNE1 amplification. Overall, we found high concordance in CCNE1 copy number in concurrent uterine serous carcinoma and endometrial intraepithelial carcinoma pairs (P-value=0.0003). No correlation was observed between CCNE1 copy number and clinicopathological features, as well as common mutations previously reported in uterine serous carcinoma. In summary, we confirm that amplification of CCNE1 is a frequent molecular genetic change in uterine serous carcinoma. Moreover, the identification of CCNE1 amplification in many endometrial intraepithelial carcinomas suggests that this genetic event occurs early during tumor progression.

  2. Utility of immunohistochemistry in predicting microsatellite instability in endometrial carcinoma.

    PubMed

    Modica, Ippolito; Soslow, Robert A; Black, Destin; Tornos, Carmen; Kauff, Noah; Shia, Jinru

    2007-05-01

    Identification of the microsatellite instability (MSI) phenotype in endometrial carcinoma is important given that such tumors are the most common noncolorectal tumors to occur in hereditary nonpolyposis colorectal cancer syndrome, and may bear prognostic relevance. The objective of this study was to assess the utility of immunohistochemistry (IHC), a simple and fast technique, in detecting MSI in endometrial carcinoma. The study subjects consisted of 90 endometrial carcinoma patients with equal representation of MSI-high (MSI-H) and non-MSI-H tumors. MSI was tested using the standard polymerase chain reaction-based method and the 5 NCI-recommended markers. Overall, IHC with MLH1 and MSH2 antibodies detected 69% of MSI-H tumors with a specificity of 100%. Adding PMS2 and MSH6 to the antibody panel increased the sensitivity to 91% but decreased the specificity to 83%. The most common IHC abnormality in MSI tumors was concurrent loss of MLH1/PMS2. Assessment of staining was straightforward in most cases but not in all. Staining inadequacies existed. Five stains (4 MLH1 and 1 MSH6) were not interpretable because of the lack of any internal positive control. Two percent to 10% of the cases (depending on the antibody assessed) had only focal weak staining; the highest frequency (10%) occurred with MLH1 antibody. PMS2 staining detected 7 MLH1-staining present MSI-H cases, thus partly accounting for the increased sensitivity with the 4-antibody panel. MSH6 staining identified 9 cases with loss of MSH6 alone, 6 of 9 were non-MSI-H, thus partly accounting for the decreased specificity with the 4-antibody panel. In conclusion, our results suggest that IHC is useful in detecting MSI in endometrial carcinoma. Although IHC has a lower sensitivity with more apparent staining inadequacies in detecting MSI in endometrial carcinoma than it does in colorectal carcinoma, its use in endometrial carcinoma may be an important adjunct when screening for hereditary cases. In the future, as

  3. Pathophysiology and management of endometrial hyperplasia and carcinoma.

    PubMed Central

    Fu, Y. S.; Gambone, J. C.; Berek, J. S.

    1990-01-01

    Endometrial cancer is currently the commonest pelvic malignancy affecting American women, most of whom share the same pathophysiologic basis, that is, unopposed estrogenic stimulation. The initial result of hyperestrogenism is the development of endometrial hyperplasia, which is reversible in most cases by appropriate hormonal therapy. Persistent stimulation eventually leads to atypical hyperplasia with nuclear atypia and invasive carcinoma. Because there is no cost-effective screening method for the detection of endometrial hyperplasia and carcinoma, it is essential to survey the high-risk population with appropriate diagnostic techniques. After diagnosis, therapy should be individualized based on pathologic findings (cell type and histologic grade) and extent of disease (International Federation of Gynaecologists and Obstetricians stage, depth of myometrial invasion, and pelvic and para-aortic lymph node status). Recent studies suggest that sex hormone receptors and nuclear DNA ploidy patterns provide useful prognostic information independent of histologic grade. Images PMID:2202159

  4. Minor serous and clear cell components adversely affect prognosis in ''mixed-type'' endometrial carcinomas: a clinicopathologic study of 36 stage-I cases.

    PubMed

    Quddus, M Ruhul; Sung, C James; Zhang, Cunxian; Lawrence, W Dwayne

    2010-07-01

    Most endometrial carcinomas contain only 1 Müllerian cell type although the presence of 2 or more cell types within 1 tumor, for example a predominantly low-grade endometrioid carcinoma with a minor component (arbitrarily defined as 30% or less) of high-grade serous and/or clear cell carcinoma, is not uncommon. The current study attempts to evaluate whether the presence of minor serous or clear cell components exerts an adverse effect on the prognosis in stage-I endometrial carcinomas of ''mixed-type.'' The study cases include 22 cases of stage-I endometrioid carcinoma with a minor component of serous carcinoma and 14 cases of endometrioid carcinoma with a minor component of clear cell carcinoma. Minor components were arbitrarily defined as representing anywhere between 5% and 30% of the total tumor. The study cases were compared with 56 cases of histologically pure age-matched and stage-matched endometrioid carcinomas, 6 pure serous carcinomas, and 13 pure clear cell carcinomas. All study and control cases were fully staged. Treatment history and outcome status were obtained and follow-up ranged from 56 to 140 months. Our study suggests that the presence of minor components of serous and clear cell carcinoma, defined as between 5% and 30%, within a mixed-type endometrial carcinoma appears to adversely influence the long-term survival of stage-I tumors, although a larger study is needed to corroborate our findings.

  5. OVARIAN LOW-GRADE AND HIGH-GRADE SEROUS CARCINOMA: Pathogenesis, Clinicopathologic and Molecular Biologic Features, and Diagnostic Problems

    PubMed Central

    Vang, Russell; Shih, Ie-Ming; Kurman, Robert J.

    2009-01-01

    Ovarian serous carcinomas have been graded using various systems. Recently, a 2-tier system in which tumors are subdivided into low-grade and high-grade has been proposed. This approach is simplistic, reproducible, and based on biologic evidence indicating that both tumors develop via different pathways. Low-grade serous carcinomas exhibit low-grade nuclei with infrequent mitotic figures. They evolve from adenofibromas or borderline tumors, have frequent mutations of the KRAS, BRAF, or ERBB2 genes, and lack TP53 mutations (Type I pathway). The progression to invasive carcinoma is a slow step-wise process. Low-grade tumors are indolent and have better outcome than high-grade tumors. In contrast, high-grade serous carcinomas have high-grade nuclei and numerous mitotic figures. Identification of a precursor lesion in the ovary has been elusive and therefore the origin of ovarian carcinoma has been described as de novo. More recently, studies have suggested that a proportion appear to originate from intraepithelial carcinoma in the fallopian tube. The development of these tumors is rapid (Type II pathway). The vast majority are characterized by TP53 mutations and lack mutations of KRAS, BRAF, or ERBB2. Although both types of serous carcinomas evolve along different pathways, rare high-grade serous carcinomas seem to arise through the Type I pathway. Immunohistochemical stains for p53, p16, and Ki-67 for distinction of low- from high-grade tumors are of limited value but can be helpful in selected instances. This review provides an update on the pathogenesis and clinicopathologic features of these two types of serous carcinomas and addresses some of the diagnostic problems that are encountered in routine practice. PMID:19700937

  6. A survival analysis comparing women with ovarian low-grade serous carcinoma to those with high-grade histology.

    PubMed

    Chen, Ming; Jin, Ying; Bi, Yalan; Yin, Jie; Wang, Yongxue; Pan, Lingya

    2014-01-01

    Ovarian low-grade serous carcinoma (LGSC) and high-grade serous carcinoma have distinct molecular profiles, clinical behaviors, and treatment responses. The survival advantage for patients with low-grade carcinoma compared with patients with high-grade histology remains controversial. We retrospectively reviewed the medical charts of 381 patients with ovarian serous carcinoma at Peking Union Medical College Hospital from 2007 to 2010. Patients were classified into two groups according to MD Anderson two-tier system: 35 (9.2%) cases with LGSC and 346 with high-grade serous carcinoma. Patients with low-grade serous ovarian cancer had a significantly younger age at diagnosis (46 versus 56 years, P=0.046), and their median progression-free survival (PFS) and overall survival values were 35.0 and 54.0 months, respectively. A multivariate analysis showed that, for serous ovarian cancer, the histological grade was a significant prognostic factor for PFS but not for overall survival (P=0.022 and P=0.0566, respectively). When stratified by the existence of a residual disease, patients with low-grade disease who underwent cytoreductive surgery without macroscopic residual disease (>1 cm) had a significantly improved median PFS time (36.0 months) compared with that of patients with high-grade carcinoma who received optimal cytoreductive surgery (16.0 months, P=0.017). Conversely, patients with low-grade and high-grade carcinoma who were left with macroscopic residue (>1 cm) experienced a similarly shorter median PFS (10.0 and 13.0 months, respectively, P=0.871). The International Federation of Gynecology and Obstetrics stage and residual disease were significant prognostic factors of low-grade carcinoma, while positive ascites was associated with a worse PFS value. Our data showed that LGSC is a different entity from high-grade carcinoma and that LGSC was associated with improved PFS after optimal cytoreductive surgery but not suboptimal operation.

  7. Intensity-Modulated Radiation Therapy, Cisplatin, and Bevacizumab Followed by Carboplatin and Paclitaxel in Treating Patients Who Have Undergone Surgery for Endometrial Cancer

    ClinicalTrials.gov

    2014-10-09

    Endometrial Adenocarcinoma; Endometrial Adenosquamous Cell Carcinoma; Endometrial Clear Cell Carcinoma; Endometrial Papillary Serous Carcinoma; Stage I Endometrial Carcinoma; Stage II Endometrial Carcinoma; Stage III Endometrial Carcinoma; Stage IV Endometrial Carcinoma

  8. Fine-needle aspiration diagnosis of high grade adenoid cystic carcinoma metastatic to the pancreas.

    PubMed

    David, Doina; Masineni, Sreeharsha N; Giorgadze, Tamar

    2015-02-01

    Pancreatic tumors are mostly primary tumors, with only rare metastatic tumors described in the literature. Here we report an unusual case of fine-needle aspiration (FNA) diagnosis of high grade adenoid cystic carcinoma of the parotid gland metastatic to the pancreas. The aspirate smears were moderately cellular and revealed numerous basaloid neoplastic cells. The cytomorphologic differential diagnosis included primary pancreatic tumor with small cell morphology as well as metastatic tumors. By immunocytochemistry, the tumor cells were positive for cytokeratins (AE1/AE3, CAM5.2, and CK7), and CD117 (C-KIT), and negative for CD45, WT1, synaptophysin, chromogranin, CD56, TTF-1, and CK20. The cytomorphologic features and immunoprofile in our case were consistent with high-grade carcinoma metastases from patient's known salivary gland primary. To the best of our knowledge, this case is the first reported encounter of FNA diagnosis of pancreatic metastasis with small cell morphology from a salivary gland neoplasm as primary site.

  9. A Case of High-grade Transitional Cell Carcinoma of the Bladder in a Pediatric Patient With Turner Syndrome.

    PubMed

    Aguiar, Liza; Danialan, Richard; Kim, Christina

    2015-06-01

    Transitional cell carcinoma is a rare entity in children, especially in the first decade of life. The majority of these tumors are of low grade and noninvasive. We report an interesting case of a high-grade superficial transitional cell carcinoma in a 3-year-old girl with Turner syndrome.

  10. Prophylactic salpingectomy and prophylactic salpingoophorectomy for adnexal high-grade serous epithelial carcinoma: A reappraisal.

    PubMed

    Oliver Perez, M Reyes; Magriñá, Javier; García, Alvaro Tejerizo; Jiménez Lopez, Jesus Salvador

    2015-12-01

    At present, there is no effective screening of ovarian cancer. Primary prevention may be the only strategy to decrease the mortality from ovarian cancer, not only in women at high risk but also at low risk. Several recent studies have identified the distal fimbriae end of the fallopian tubes as primary precursor of High-grade serous carcinoma. Serous tubal intraepithelial carcinomas and occult invasive serous carcinomas have been identified in 2-17% of the fallopian tubes of BRCA1/2 positive women undergoing risk-reducing salpingo-oophorectomy. Removal of the fallopian tubes with ovarian preservation has been suggested as a reasonable strategy that could reduce the risk of developing ovarian carcinoma in both low and high-risk women. It has been proposed after childbearing in women at high risk to be followed by bilateral oophorectomy at a later date. Bilateral salpingectomy is also suggested for low risk women, at the time of other benign gynaecologic surgery as a primary preventive strategy. Some studies have shown a risk reduction of ovarian cancer in women with bilateral prophylactic salpingectomy. Current research regarding bilateral salpingoophorectomy as primary prevention approach of ovarian cancer is reviewed here. In addition, the potential use of bilateral salpingectomy as prevention approach of ovarian cancer is discussed.

  11. A Rare Collision Tumour of Uterus- Squamous Cell Carcinoma and Endometrial Stromal Sarcoma

    PubMed Central

    Gupta, Bindiya; Pathre, Abhishek; Rajaram, Shalini; Goyal, Neerja

    2017-01-01

    Collision tumours are defined by co-existence of two tumours in the same or adjacent organs which are topographically and histologically distinct with minimal or no histological admixture. Collision tumours have been described in many organs notably thyroid, brain, adrenal gland, stomach and rarely uterus. Most of the collision tumours reported in uterus have two components; an adenocarcinoma and a sarcoma. We report a case of a 60-year-old lady who presented with complaints of post-menopausal bleeding. A cervical biopsy was performed which showed a non-keratinizing squamous cell carcinoma of cervix. Intra-operatively the uterus was bulky with a 6 cm x 5 cm polypoidal mass in the endometrial canal along with a 2 cm friable cervical growth. The fleshy uterine cavity mass was a spindle cell tumour with moderate pleomorphism and frequent mitosis. It was immunopositive for CD10 and negative for smooth muscle actin and cytokeratin 5/6. The other growth showed non-keratinizing squamous cell carcinoma which was positive for cytokeratin 5/6. Based on the distinct topographical location and limited areas of tumour admixture of the two tumours, a diagnosis of collision tumour of uterus comprising of endometrial stromal sarcoma (high grade) uterus and squamous cell carcinoma cervix was made. PMID:28384878

  12. Nintedanib in Treating Patients With Recurrent or Persistent Endometrial Cancer

    ClinicalTrials.gov

    2016-10-26

    Endometrial Adenocarcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Mucinous Adenocarcinoma; Endometrial Serous Adenocarcinoma; Endometrial Squamous Cell Carcinoma; Endometrial Transitional Cell Carcinoma; Endometrial Undifferentiated Carcinoma; Malignant Uterine Corpus Mixed Epithelial and Mesenchymal Neoplasm; Recurrent Uterine Corpus Carcinoma

  13. Ovarian high-grade serous carcinoma with a noninvasive growth pattern simulating a serous borderline tumor.

    PubMed

    Imamura, Hiroko; Ohishi, Yoshihiro; Aman, Murasaki; Shida, Kaai; Shinozaki, Tomoko; Yasutake, Nobuko; Sonoda, Kenzo; Kato, Kiyoko; Oda, Yoshinao

    2015-10-01

    Ovarian serous borderline tumors (SBTs) being a precursor of low-grade serous carcinomas are morphologically characterized by noninvasive growth and low-grade cytology. On the other hand, many pathologists regard cytologically high-grade, noninvasive (HG-noninv) ovarian serous tumors resembling SBTs in low magnification as conventional high-grade serous carcinomas (HGSCs) by personal experiences. Nonetheless, there are no established molecular characteristic of such tumors. In this study, therefore, we attempted to provide the molecular evidence. We selected 37 ovarian serous tumors that exhibited a cytologically HG-noninv growth pattern, including 36 tumors that coexisted with conventional invasive HGSC components (HG-inv) and a single tumor exclusively composed of pure HG-noninv. Histologically, all HG-noninv showed many mitotic figures, and serous tubal intraepithelial carcinomas were identified in 3 tumors with HG-noninv. Immunohistochemically, most HG-noninv showed aberrant p53 expression, frequent IMP3 positivity, p16 overexpression, a high MIB-1 labeling index, and infrequent PAX2. By molecular analysis, the pure HG-noninv and 13 HGSCs with HG-noninv showed TP53 mutations, but KRAS/BRAF mutations were not detected in any of them. In 1 tumor, we detected an identical TP53 mutation in both HG-noninv and HG-inv components by using laser capture microdissection. These immunohistochemical and molecular features of HG-noninv were similar to those of conventional invasive HGSCs but different from those of SBTs. In conclusion, our results showed that a cytologically HG-noninv growth pattern simulating an SBT is a morphological spectrum of HGSC, but not a true SBT.

  14. Serous carcinoma arising in endometrial polyps: clinicopathologic study of 4 cases.

    PubMed

    Idrees, Romana; Din, Nasir Ud; Fatima, Saira; Kayani, Naila

    2013-06-01

    Uterine serous carcinoma (USC) is a rare variant of endometrial cancer that is not related to increased estrogen level; rather, it arises in a background of atrophic endometrium. Our aim was to describe clinicopathologic features of 4 cases of USC arising in endometrial polyps (EPs). The mean age of the patients at presentation was 53 years (range, 50-61 years). All patients presented with postmenopausal bleeding. In 3 patients, endometrial curretings were done before surgery, which was reported as EP with superficial foci of USC, EP with few clusters of atypical cells, and high-grade serous carcinoma, respectively. All patients underwent hysterectomy with bilateral salpingo-oophorectomy and omental sampling. The uterine cavity showed an EP in all cases ranging in size from 2 to 3.5 cm (mean, 3 cm). The hysterectomy specimens revealed USC in EP as well as the adjacent endometrium in 3 patients. The nonneoplastic endometrium was atrophic in all cases. Residual tumor was not found in the endometrium in 1 case. Omental metastatic deposits were found in all cases. Tumor deposits were also seen in the serosa of uterus, fallopian tubes, and parametrium in 1 case. Two patients died of disease 2 years after diagnosis. The remaining 2 patients are alive after a follow-up of 3 years, respectively. In conclusion, USC is a rare aggressive tumor, and to establish the diagnosis, it is important to look for the small foci of the tumor in the atrophic endometrium and on the surface of the polyps as these patients are likely to harbor additional disease in the uterus or extrauterine sites. The postmenopausal group is at high risk for developing these tumors; therefore, all the endometrial biopsies/curettings and the EPs in this age group should be thoroughly sampled.

  15. Adenovirus mediated homozygous endometrial epithelial Pten deletion results in aggressive endometrial carcinoma

    SciTech Connect

    Joshi, Ayesha; Ellenson, Lora Hedrick

    2011-07-01

    Pten is the most frequently mutated gene in uterine endometriod carcinoma (UEC) and its precursor complex atypical hyperplasia (CAH). Because the mutation frequency is similar in CAH and UEC, Pten mutations are thought to occur relatively early in endometrial tumorigenesis. Previous work from our laboratory using the Pten{sup +/-} mouse model has demonstrated somatic inactivation of the wild type allele of Pten in both CAH and UEC. In the present study, we injected adenoviruses expressing Cre into the uterine lumen of adult Pten floxed mice in an attempt to somatically delete both alleles of Pten specifically in the endometrium. Our results demonstrate that biallelic inactivation of Pten results in an increased incidence of carcinoma as compared to the Pten{sup +/-} mouse model. In addition, the carcinomas were more aggressive with extension beyond the uterus into adjacent tissues and were associated with decreased expression of nuclear ER{alpha} as compared to associated CAH. Primary cultures of epithelial and stromal cells were prepared from uteri of Pten floxed mice and Pten was deleted in vitro using Cre expressing adenovirus. Pten deletion was evident in both the epithelial and stromal cells and the treatment of the primary cultures with estrogen had different effects on Akt activation as well as Cyclin D3 expression in the two purified components. This study demonstrates that somatic biallelic inactivation of Pten in endometrial epithelium in vivo results in an increased incidence and aggressiveness of endometrial carcinoma compared to mice carrying a germline deletion of one allele and provides an important in vivo and in vitro model system for understanding the genetic underpinnings of endometrial carcinoma.

  16. Candidate genes and pathways downstream of PAX8 involved in ovarian high-grade serous carcinoma

    PubMed Central

    Soriano, Amata Amy; Monticelli, Antonella; Affinito, Ornella; Cocozza, Sergio; Zannini, Mariastella

    2016-01-01

    Understanding the biology and molecular pathogenesis of ovarian epithelial cancer (EOC) is key to developing improved diagnostic and prognostic indicators and effective therapies. Although research has traditionally focused on the hypothesis that high-grade serous carcinoma (HGSC) arises from the ovarian surface epithelium (OSE), recent studies suggest that additional sites of origin exist and a substantial proportion of cases may arise from precursor lesions located in the Fallopian tubal epithelium (FTE). In FTE cells, the transcription factor PAX8 is a marker of the secretory cell lineage and its expression is retained in 96% of EOC. We have recently reported that PAX8 is involved in the tumorigenic phenotype of ovarian cancer cells. In this study, to uncover genes and pathways downstream of PAX8 involved in ovarian carcinoma we have determined the molecular profiles of ovarian cancer cells and in parallel of Fallopian tube epithelial cells by means of a silencing approach followed by an RNA-seq analysis. Interestingly, we highlighted the involvement of pathways like WNT signaling, epithelial-mesenchymal transition, p53 and apoptosis. We believe that our analysis has led to the identification of candidate genes and pathways regulated by PAX8 that could be additional targets for the therapy of ovarian carcinoma. PMID:27259239

  17. Endometrial and ovarian carcinomas with undifferentiated components: clinically aggressive and frequently underrecognized neoplasms.

    PubMed

    Tafe, Laura J; Garg, Karuna; Chew, Ivy; Tornos, Carmen; Soslow, Robert A

    2010-06-01

    Carcinomas of the endometrium and ovary with undifferentiated components are uncommon neoplasms that are likely underdiagnosed. They are important to recognize as they have been shown to be clinically aggressive. We identified 32 carcinomas with undifferentiated components as defined by Silva and co-workers, 26 endometrial and 6 of ovarian origin. The patient age ranged from 21 to 76 years (median 55); 40% of patients were endometrial and 83% of ovarian carcinomas with undifferentiated components) presented at advanced stages (FIGO III-IV). Pelvic and para-aortic lymph nodes were the most frequent sites of metastases. Twenty tumors, entirely undifferentiated, consisted of sheets of dyshesive, ovoid cells with uniform, large vesicular nuclei, whereas 12 tumors contained combinations of differentiated endometrioid adenocarcinoma with undifferentiated components. Although most undifferentiated tumors had a monotonous cytologic appearance without prominent stroma, six showed focal nuclear pleomorphism and eight cases had variably sized zones of rhabdoid cells in a background of myxoid stroma. The tumors were frequently misdiagnosed; they received a wide range of diagnoses, including FIGO grade 2 or 3 endometrioid carcinoma, carcinosarcoma, high-grade sarcoma including endometrial stromal sarcoma, neuroendocrine carcinoma, lymphoma, granulosa cell tumor and epithelioid sarcoma. Up to 86% of the cases showed focal, but strong keratin and/or epithelial membrane antigen staining, with CK18 being the most frequently positive keratin stain. They were predominantly negative for neuroendocrine markers, smooth muscle markers and estrogen receptor/progesterone receptor. Mismatch repair protein expression by immunohistochemistry was evaluated in 17 cases, and 8 (47%) were abnormal (7 with loss of MLH1/PMS2 and 1 with MSH6 loss). Follow-up was available for 27 patients, although it was very short in many cases, ranging from 0.5 to 89

  18. Brivanib Alaninate in Treating Patients With Recurrent or Persistent Endometrial Cancer

    ClinicalTrials.gov

    2016-03-16

    Endometrial Adenocarcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Mixed Adenocarcinoma; Endometrial Mucinous Adenocarcinoma; Endometrial Serous Adenocarcinoma; Endometrial Squamous Cell Carcinoma; Endometrial Transitional Cell Carcinoma; Endometrial Undifferentiated Carcinoma; Recurrent Uterine Corpus Carcinoma

  19. Origin and molecular pathogenesis of ovarian high-grade serous carcinoma.

    PubMed

    Kurman, R J

    2013-12-01

    A new paradigm for the pathogenesis of ovarian cancer has recently been proposed which helps to explain persistent problems in describing the development and diverse morphology of these neoplasms. The paradigm incorporates recent advances in our understanding of the molecular pathogenesis of epithelial 'ovarian' cancer with new insights into the origin of these tumors. Correlated clinicopathologic and molecular genetic studies led to the development of a dualistic model that divides all the various histologic types of epithelial ovarian carcinomas into two broad categories designated 'type I' and 'type II'. The prototypic type I tumor is low-grade serous carcinoma and the prototypic type II tumor is high-grade serous carcinomas (HGSCs). As the serous tumors comprise ∼70% of all epithelial ovarian tumors and account for the majority of deaths, the serous tumors will be the subject of this review. There are marked differences between the low-grade and high-grade serous tumors. Briefly, the former are indolent, present in stage I (tumor confined to the ovary) and develop from well-established precursors, so-called 'atypical proliferative (borderline) tumors,' which are characterized by specific mutations, including KRAS, BRAF and ERBB2; they are relatively genetically stable. In contrast, HGSCs are aggressive, present in the advanced stage, and develop from intraepithelial carcinomas in the fallopian tube. They harbor TP53 mutations in over 95% of cases, but rarely harbor the mutations detected in the low-grade serous tumors. At the time of diagnosis they demonstrate marked chromosomal aberrations but over the course of the disease these changes remain relatively stable. Along with the recent advances in understanding the molecular pathogenesis of these tumors, studies have demonstrated that the long sought for precursor of ovarian HGSC appears to develop from an occult intraepithelial carcinoma in the fimbrial region of the fallopian tube designated 'serous tubal

  20. Widespread chromosomal abnormalities in high-grade ductal carcinoma in situ of the breast. Comparative genomic hybridization study of pure high-grade DCIS.

    PubMed

    Moore, E; Magee, H; Coyne, J; Gorey, T; Dervan, P A

    1999-03-01

    For a variety of technical reasons it is rarely possible to study cytogenetic abnormalities in ductal carcinoma in situ (DCIS) using traditional techniques. However, by combining molecular biology and computerized image analysis it is possible to carry out cytogenetic analyses on formalin-fixed, paraffin-embedded tissue, using comparative genomic hybridization (CGH). The purpose of this study was to identify the prevalence of chromosomal amplifications and deletions in high-grade DCIS and to look specifically for unique or consistent abnormalities in this pre-invasive cancer. Twenty-three cases of asymptomatic, non-palpable, screen-detected, high-grade DCIS were examined using CGH on tumour cells obtained from histology slides. All cases showed chromosomal abnormalities. A wide variety of amplifications and deletions were spread across the genome. The most frequent changes were gains of chromosomes 17 (13 of 23), 16p (13 of 23), and 20q (9 of 23) and amplifications of 11q13 (22 of 23), 12q 24.1-24.2 (12 of 23), 6p21.3 (11 of 23), and 1q31-qter (6 of 23). The most frequent deletions were on 13q 21.3-q33 (7 of 23), 9p21 (4 of 23), and 6q16.1 (4 of 23). These findings indicate that high-grade DCIS is, from a cytogenetic viewpoint, an advanced lesion. There was no absolutely consistent finding in every case, but amplification of 11q13 was found in 22 of the 23 cases. The precise significance of this is unknown at present. This region of chromosome 11q harbours a number of known oncogenes, including cyclin D1 andINT2. It is likely that many of these findings are the result of accumulated chromosomal abnormalities, reflecting an unstable genome in established malignancy.

  1. Current Issues in the Diagnosis and Treatment of Endometrial Carcinoma

    PubMed Central

    Stubert, J.; Gerber, B.

    2016-01-01

    Endometrial carcinoma is the most common carcinoma of the female genital tract. Its most important clinical sign is postmenopausal bleeding. An endometrial biopsy is essential for diagnosis. Treatment decisions are governed by tumour risk assessment and patient comorbidity, which is often present. Pelvic and paraaortic lymph node dissection is unnecessary in low risk cases (definition: pT1 a, G1/2) and adjuvant radiotherapy and systemic treatments are usually avoidable. Treatment of high-risk patients (G3 and/or pT1b) and palliative cases is difficult and not well standardised. New molecular-based subtype classification may help treatment decision making in future. PMID:26941450

  2. Trebananib in Treating Patients With Persistent or Recurrent Endometrial Cancer

    ClinicalTrials.gov

    2016-02-10

    Endometrial Adenocarcinoma; Endometrial Adenosquamous Carcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Endometrioid Adenocarcinoma, Variant With Squamous Differentiation; Endometrial Serous Adenocarcinoma; Endometrioid Stromal Sarcoma; Recurrent Uterine Corpus Carcinoma

  3. Early hepatocellular carcinoma with high-grade atypia in small vaguely nodular lesions.

    PubMed

    Ojima, Hidenori; Masugi, Yohei; Tsujikawa, Hanako; Emoto, Katsura; Fujii-Nishimura, Yoko; Hatano, Mami; Kawaida, Miho; Itano, Osamu; Kitagawa, Yuko; Sakamoto, Michiie

    2016-04-01

    Multistep hepatocarcinogenesis progresses from dysplastic nodules to early hepatocellular carcinoma (eHCC) and to advanced HCC. The aim of the present study was to investigate the detailed histopathological features of eHCC. We investigated 66 small vaguely nodular lesions resected from 40 patients. The degree of cellular and structural atypia and stromal invasion were assessed. The immunohistochemical expression of HCC-related markers adenylate cyclase-associated protein 2 (CAP2), heat shock protein 70 (HSP70), Bmi-1, CD34 and h-caldesmon were evaluated. Of the 66 nodules, 10 were diagnosed as low-grade dysplastic nodules (LGDN), 10 as high-grade dysplastic nodules (HGDN) and 46 as eHCC. Among the 46 eHCC, 18 nodules (39.1%) showed marked stromal invasion and/or the presence of the scirrhous component and were subclassified as high-grade eHCC (HGeHCC). The remaining 28 eHCC, which lacked these features, were subclassified as low-grade eHCC (LGeHCC) and were examined further. HGeHCC showed high levels of cellular and structural atypia and large tumor size. The immunohistochemical expression of CAP2 and the area of sinusoidal vascularization showed increases from LGDN to HGeHCC. The density of arterial tumor vessels was high in HGeHCC compared with other nodule types. Cluster analysis of these parameters subclassified 65 nodules into HGeHCC-dominant, LGeHCC and HGDN-dominant, and LGDN-dominant groups. These results indicate the increased malignant potential of HGeHCC and suggest that it is already a transitional stage to advanced HCC. We consider that our grading classification system may be valuable for considering treatment strategies for eHCC around 2 cm in diameter.

  4. Extracorporeal spread and its prognostic impact in stages I and II (FIGO) endometrial carcinoma.

    PubMed

    Sakuragi, N; Tanaka, T; Satoh, C; Nishiya, M; Ohkouchi, T; Tsumura, N; Takeda, N; Hirahatake, K; Sagawa, T; Ohkubo, H

    1991-09-01

    Prognostic risk factors were statistically analyzed from the histopathologic data obtained from 90 Japanese women with stages I and II endometrial carcinoma treated surgically, including systemic retroperitoneal lymph node dissection, between June 1979 and June 1989. In stage Ia endometrial carcinoma, pelvic and paraaortic nodes metastasis were seen in 13.8(4/29)% and 0.0(0/19)% of patients, respectively. In stage Ib, the incidence of pelvic and paraaortic node metastasis was 25.6(11/43)% and 9.7(3/31)%, respectively. In stage II, the incidence was 38.9(7/18)% and 13.3(2/15)%, respectively. Prognosis of patients even with deep myometrial invasion (greater than or equal to 2/3) or G3 tumor was fairly good (5-year survival rate: 87.5% and 85.7%, respectively) if the disease was histologically confined to the uterine corpus. Once the tumor spread outside the corpus uteri, the survival rate of patients was strongly affected by the grade of the tumor, moderate to marked lymph-vascular space invasion of tumor cells, or tumor invading middle or outer third of myometrium (P less than 0.05 for each factor). In summary, endometrial cancer frequently metastasize to pelvic and paraaortic lymph nodes even in the early stages, and lymph node metastasis and other extracorporeal spread of disease have a serious impact on patient survival. Prognosis of patients with extracorporeal spread of disease seems to be determined by the high grade of tumor and lymph-vascular space invasion. These results suggest that surgical exploration including paraaortic lymph node dissection to accurately evaluate the extent of the disease is essential to estimate the patient's prognostic risk and to individualize the treatment schedule.

  5. Primary high-grade serous carcinoma arising in the urethra or urethral diverticulum: a report of 2 cases of an extremely rare phenomenon.

    PubMed

    Flynn, Ciaran; Oxley, Jon; McCullagh, Paul; McCluggage, W Glenn

    2013-01-01

    Serous carcinomas most commonly arise within the uterine corpus or ovary/fallopian tube, but there are 2 prior case reports of primary vaginal serous carcinoma. We report 2 examples of high-grade serous carcinoma arising within the urethra or a urethral diverticulum (1 case each). Both neoplasms exhibited the classic morphologic features of high-grade serous carcinoma, and a combination of clinical, radiologic, and pathologic examination excluded other possible sites of primary neoplasm.

  6. Utility of p16 expression for distinction of uterine serous carcinomas from endometrial endometrioid and endocervical adenocarcinomas: immunohistochemical analysis of 201 cases.

    PubMed

    Yemelyanova, Anna; Ji, Hongxiu; Shih, Ie-Ming; Wang, Tian-Li; Wu, Lee-Shu-Fune; Ronnett, Brigitte M

    2009-10-01

    Uterine serous carcinomas typically have a characteristic morphology (papillary architecture, high-grade nuclei) and immunoprofile (diffuse/strong p53 expression, loss of hormone receptor expression) that distinguish them from most endometrial endometrioid carcinomas. However, glandular variants of serous carcinoma can simulate Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) grade 2 endometrioid carcinomas, and some serous carcinomas lack p53 expression and retain hormone receptor expression, making classification difficult. P16 expression patterns distinguish endometrioid carcinomas (patchy) from human papillomavirus (HPV)-related endocervical adenocarcinomas (diffuse/strong) but utility for distinction of serous carcinomas from endometrioid carcinomas and endocervical adenocarcinomas has not been evaluated in a large series. Immunohistochemical analysis of p16 expression was performed on 201 uterine and endocervical adenocarcinomas in hysterectomy specimens, including 49 serous carcinomas, 101 endometrial endometrioid carcinomas (44 FIGO grade 1, 40 FIGO grade 2, and 17 FIGO grade 3), and 51 HPV-related endocervical adenocarcinomas. All serous carcinomas demonstrated diffuse/moderate-strong p16 expression, with percentage of positive tumor cells ranging from 90% to 100% (mean/median: 95%/100%). In contrast, endometrial endometrioid carcinomas exhibited less diffuse and less intense expression, with percent of positive tumor cells ranging from 10% to 90% (mean/median: 38%/30%; staining intensity: variable). Similar to serous carcinomas, all endocervical adenocarcinomas exhibited diffuse/moderate-strong p16 expression, with percentage of positive tumor cells ranging from 90% to 100% (mean/median: 94%/90%). P16 can serve as an additional diagnostic marker, used as part of an immunohistochemical panel, including p53 and hormone receptors, for distinction of uterine serous carcinomas from endometrioid carcinomas. Distinction of serous carcinomas

  7. A Molecular Portrait of High-Grade Ductal Carcinoma In Situ

    PubMed Central

    Abba, Martin C.; Gong, Ting; Lu, Yue; Lee, Jaeho; Zhong, Yi; Lacunza, Ezequiel; Butti, Matias; Takata, Yoko; Gaddis, Sally; Shen, Jianjun; Estecio, Marcos R.; Sahin, Aysegul A.; Aldaz, C. Marcelo

    2016-01-01

    Ductal carcinoma in situ (DCIS) is a noninvasive precursor lesion to invasive breast carcinoma. We still have no understanding on why only some DCIS lesions evolve to invasive cancer whereas others appear not to do so during the life span of the patient. Here, we performed full exome (tumor vs. matching normal), transcriptome, and methylome analysis of 30 pure high-grade DCIS (HG-DCIS) and 10 normal breast epithelial samples. Sixty-two percent of HG-DCIS cases displayed mutations affecting cancer driver genes or potential drivers. Mutations were observed affecting PIK3CA (21% of cases), TP53 (17%), GATA3 (7%), MLL3 (7%) and single cases of mutations affecting CDH1, MAP2K4, TBX3, NF1, ATM, and ARID1A. Significantly, 83% of lesions displayed numerous large chromosomal copy number alterations, suggesting they might precede selection of cancer driver mutations. Integrated pathway-based modeling analysis of RNA-seq data allowed us to identify two DCIS subgroups (DCIS-C1 and DCIS-C2) based on their tumor-intrinsic subtypes, proliferative, immune scores, and in the activity of specific signaling pathways. The more aggressive DCIS-C1 (highly proliferative, basal-like, or ERBB2+) displayed signatures characteristic of activated Treg cells (CD4+/CD25+/FOXP3+) and CTLA4+/CD86+ complexes indicative of a tumor-associated immunosuppressive phenotype. Strikingly, all lesions showed evidence of TP53 pathway inactivation. Similarly, ncRNA and methylation profiles reproduce changes observed postinvasion. Among the most significant findings, we observed upregulation of lncRNA HOTAIR in DCIS-C1 lesions and hypermethylation of HOXA5 and SOX genes. We conclude that most HG-DCIS lesions, in spite of representing a preinvasive stage of tumor progression, displayed molecular profiles indistinguishable from invasive breast cancer. PMID:26249178

  8. ERBB2 mutations associated with solid variant of high-grade invasive lobular breast carcinomas

    PubMed Central

    Bidard, François-Clément; Vacher, Sophie; Schnitzler, Anne; Chemlali, Walid; Trémoulet, Laurence; Fuhrmann, Laetitia; Cottu, Paul; Rouzier, Roman; Bièche, Ivan; Vincent-Salomon, Anne

    2016-01-01

    ERBB2 and ERBB3 somatic gain-of-function mutations, which may be targeted by anti-ERBB2 therapies, were reported by high-throughput sequencing studies in 1% and 2% of invasive breast cancers respectively. Our study aims to determine ERBB2 and ERBB3 mutations frequencies in grade 3 and/or ERBB2-positive invasive lobular breast carcinomas (ILC). All the 529 ILC surgically-excised registered at Institut Curie in the years 2005 to 2008 were reviewed. Thirty-nine grade 3 ERBB2-negative ILC and 16 ERBB2-positive ILC were retrieved and subjected to Sanger sequencing of the ERBB2 and ERBB3 activation mutation hotspots (ERBB2: exons 8, 17, 19, 20, 21; ERBB3: exons 3, 6, 7, 8). Among the 39 grade 3 ERBB2-negative ILC, six tumors were found to have at least one detectable ERBB2 activating mutation (incidence rate: 15%, 95%CI [4%-27%]). No ERBB2 mutation was found among the 16 ERBB2-positive ILC. No ERBB3 mutation was found in any of the 55 ILC. ERBB2 mutations were statistically associated with solid ILC features (p=0.01). Survival analyses showed no significant prognostic impact of ERBB2 mutations. Our study demonstrates that high grade ERBB2-negative ILC display a high frequency of ERBB2 mutations, and should be subjected to systematic genetic screening. PMID:27602491

  9. YAP Induces High-Grade Serous Carcinoma in Fallopian Tube Secretory Epithelial Cells

    PubMed Central

    Hua, Guohua; Lv, Xiangmin; He, Chunbo; Remmenga, Steven W.; Rodabough, Kerry J.; Dong, Jixin; Yang, Liguo; Lele, Subodh M.; Yang, Peixin; Zhou, Jin; Karst, Alison; Drapkin, Ronny I.; Davis, John S.; Wang, Cheng

    2015-01-01

    Accumulating evidence indicates that ovarian high-grade serous carcinoma (HGSC) originates from Fallopian tube secretory epithelial cells (FTSECs). However, the molecular mechanisms underlying the initiation and progression of HGSC derived from FTSECs remains unclear. In the present study, we found that the Hippo/YAP signaling pathway plays a critical role in the initiation and progression of Fallopian tube and ovarian HGSC. Importantly, YAP was overexpressed in inflammatory and cancerous Fallopian tube tissues. Further, overexpression of wild-type YAP, or constitutively active YAP in immortalized FTSECs, induced cell proliferation, migration, colony formation, and tumorigenesis. Moreover, the Hippo/YAP and the fibroblast growth factor (FGF) signaling pathways formed an autocrine/paracrine positive feedback loop to drive the progression of the FTSECs-derived HGSC. Evidence in this study strongly suggests that combined therapy with inhibitors of YAP (such as verteporfin) and FGFRs (such as BGJ398) can provide a novel therapeutic strategy to treat Fallopian tube and ovarian HGSC. PMID:26364602

  10. Clonal evolution of high-grade serous ovarian carcinoma from primary to recurrent disease.

    PubMed

    Castellarin, Mauro; Milne, Katy; Zeng, Thomas; Tse, Kane; Mayo, Michael; Zhao, Yongjun; Webb, John R; Watson, Peter H; Nelson, Brad H; Holt, Robert A

    2013-03-01

    High-grade serous carcinoma (HGSC) is the most common and fatal form of ovarian cancer. While most tumours are highly sensitive to cytoreductive surgery and platinum- and taxane-based chemotherapy, the majority of patients experience recurrence of treatment-resistant tumours. The clonal origin and mutational adaptations associated with recurrent disease are poorly understood. We performed whole exome sequencing on tumour cells harvested from ascites at three time points (primary, first recurrence, and second recurrence) for three HGSC patients receiving standard treatment. Somatic point mutations and small insertions and deletions were identified by comparison to constitutional DNA. The clonal structure and evolution of tumours were inferred from patterns of mutant allele frequencies. TP53 mutations were predominant in all patients at all time points, consistent with the known founder role of this gene. Tumours from all three patients also harboured mutations associated with cell cycle checkpoint function and Golgi vesicle trafficking. There was convergence of germline and somatic variants within the DNA repair, ECM, cell cycle control, and Golgi vesicle pathways. The vast majority of somatic variants found in recurrent tumours were present in primary tumours. Our findings highlight both known and novel pathways that are commonly mutated in HGSC. Moreover, they provide the first evidence at single nucleotide resolution that recurrent HGSC arises from multiple clones present in the primary tumour with negligible accumulation of new mutations during standard treatment.

  11. Independent prognostic value of peritoneal immunocytodiagnosis in endometrial carcinoma.

    PubMed

    Benevolo, M; Mariani, L; Vocaturo, G; Vasselli, S; Natali, P G; Mottolese, M

    2000-02-01

    Among the clinical parameters that play a pivotal role in predicting the outcome of patients with endometrial carcinoma, intraperitoneal microscopic dissemination represents an important cause of recurrences. To date, peritoneal cytology has been incorporated into the current surgical staging system (International Federation of Gynecology and Obstetrics 88), although its predictive value remains a controversial issue. In this study the authors investigated the possibility of applying immunocytochemistry (ICC) to the diagnosis of peritoneal washing (PW) aimed at improving conventional cytology and verifying the prognostic value of peritoneal malignant cells. The authors analyzed 182 PWs sampled from endometrial cancer patients. The ICC analysis was performed using two monoclonal antibodies (MAbs)--AR-3 and B72.3--that in combination recognize more than 95% of endometrial carcinomas. The presence of peritoneal-free cancer cells was identified morphologically in 27 of 182 lavages (14.8%) and ICC in 50 of 182 (27.5%), with a significant improvement (p <0.0001). Five-year survival analysis, comparing results of ICC and cytodiagnosis, demonstrated a significant decrease of disease-free survival in patients with peritoneal microscopic disease. Furthermore, multivariate analysis showed that ICC diagnosis of PWs is an independent prognostic factor. Data indicate that the use of selected MAbs allows one to identify cytologically false-negative cases, providing results that are highly predictive of a worse clinical outcome.

  12. Primary sources of pelvic serous cancer in patients with endometrial intraepithelial carcinoma.

    PubMed

    Jia, Lin; Yuan, Zeng; Wang, Yiying; Cragun, Janiel M; Kong, Beihua; Zheng, Wenxin

    2015-01-01

    Serous endometrial intraepithelial carcinoma is often associated with extrauterine disease. It is currently unclear where does the extrauterine disease come from. This study addressed this issue. A total of 135 samples from 21 serous endometrial intraepithelial carcinoma patients were studied. Cellular lineage relationships between intrauterine and extrauterine serous carcinomas were determined by TP53-mutation analysis and correlated to the clinicopathologic features. There were three conditions contributing the extrauterine disease: metastasis from serous endometrial intraepithelial carcinoma (n=10) showed identical TP53 mutation between intrauterine lesions and extrauterine disease, cases of adnexal origin (n=5) had discordant TP53 mutations, and the mixed cellular origin cases (n=6) with both identical and discordant mutation status. Patients with extrauterine disease from serous endometrial intraepithelial carcinoma metastasis typically had small tumor masses (<2 cm) in extrauterine sites and without finding of serous tubal intraepithelial carcinoma, while extrauterine disease with adnexal or tubal origin commonly had larger tumor masses in extrauterine sites including ovary and omentum and serous tubal intraepithelial carcinoma. The majority of extrauterine diseases associated with serous endometrial intraepithelial carcinoma are metastasized from the endometrium. Serous endometrial intraepithelial carcinoma is frequently associated with serous cancers of adnexal or tubal origin, indicating that endometrial and adnexal or tubal serous cancers may share similar etiologies. TP53-mutation analysis provides a strong linkage for cellular lineage analysis. Tumor size in extrauterine disease and presence of serous tubal intraepithelial carcinoma or not are useful clinicopathologic features to determine primary cancer site, which helps in clinical management.

  13. High-grade fimbrial-ovarian carcinomas are unified by altered p53, PTEN and PAX2 expression.

    PubMed

    Roh, Michael H; Yassin, Yosuf; Miron, Alexander; Mehra, Karishma K; Mehrad, Mitra; Monte, Nicolas M; Mutter, George L; Nucci, Marisa R; Ning, Geng; Mckeon, Frank D; Hirsch, Michelle S; Wa, Xian; Crum, Christopher P

    2010-10-01

    High-grade endometrioid and serous carcinomas of the ovary and fallopian tube are responsible for the majority of cancer deaths and comprise a spectrum that includes early or localized (tubal intraepithelial carcinoma) and advanced (invasive or metastatic) disease. We subdivided a series of these tumors into three groups, (1) classic serous, (2) mixed serous and endometrioid and (3) endometrioid carcinomas and determined: (1) the frequencies of coexisting tubal intraepithelial carcinoma, (2) frequency of a dominant ovarian mass suggesting an ovarian origin and (3) immuno-localization of WT-1, p53, PTEN, PAX2 and p16(ink4). All tumors were analyzed for p53 mutations. Thirty six, 25 and 8% of groups 1-3 were associated with tubal intraepithelial carcinoma (P=0.09) and 34, 45 and 62% predominated in one ovary (P=0.028), respectively. Differences in frequencies of diffuse p53 immunostaining (85-93%), WT-1 (70-98%) and p16(ink4) positivity (69-75%) were not significant for all groups. Greater than 95% reduction in PAX2 and PTEN occurred in 67-75 and 5-12%, respectively; however, PAX2 and PTEN staining intensity, when present, was often heterogeneous, highlighting different tumor populations. PAX2 and PTEN expression were markedly reduced or absent in 12 of 12 and 4 of 12 tubal intraepithelial carcinomas. In summary, high-grade müllerian carcinomas share identical frequencies of altered or reduced expression of p53, PTEN and PAX2, all of which can be appreciated in tubal intraepithelial carcinomas. Because only a subset of these tumors appears to arise in the fallopian tube, attention to expression of these biomarkers in the ovary and other müllerian sites might facilitate the identification of other carcinogenic pathways. PAX2 and PTEN, in addition to p53 and p16(ink4), comprise a potentially important gene combination in high-grade pelvic carcinogenesis.

  14. Post-Ablation Endometrial Carcinoma (PAEC) Following Radiofrequency Endometrial Ablation: A Case Report and Its Implications for Management of Endometrial Ablation Failures.

    PubMed

    Wortman, Morris; Dawkins, Josette C

    2016-10-26

    Endometrial ablation (EA) has become one of the most commonly performed gynecologic procedures in the United States and other developed countries. Global endometrial ablation (GEA) devices have supplanted resectoscopic ablation primarily because they have brought with them technical simplicity and unprecedented safety. These devices, all of which received FDA approval between 1997 and 2001, are typically used to treat abnormal uterine bleeding (AUB) in premenopausal women. Several million women in the US who have undergone a previous EA procedure are about to enter the risk pool for the development of endometrial cancer (EC). Ours is the 18th reported case of post-ablation endometrial carcinoma (PAEC) in the English literature. This case underscores the diagnostic challenges faced in evaluating women with a history of a previous EA who cannot be properly evaluated with conventional techniques such as endometrial biopsy and sonohysterography.

  15. Significance of a minor high-grade component in a low-grade noninvasive papillary urothelial carcinoma of bladder.

    PubMed

    Reis, Leonardo O; Taheri, Diana; Chaux, Alcides; Guner, Gunes; Mendoza Rodriguez, Maria A; Bivalacqua, Trinity J; Schoenberg, Mark P; Epstein, Jonathan I; Netto, George J

    2016-01-01

    To assess the clinicopathological features and prognostic significance of the presence of 5% or less high-grade component in otherwise low-grade noninvasive bladder urothelial carcinoma, referred to as mixed-grade (MG) urothelial carcinoma, we reviewed all archival cases with such diagnosis between 2005 and 2014. Clinicopathological and outcome parameters were compared to those in our previously reported low- and high-grade noninvasive bladder urothelial carcinoma cohorts (LGUC and HGUC, respectively). The study included 31 MG urothelial carcinomas. Mean patient age was 67.6 years, and mean follow-up was 39.7 months. Intravesical treatment was administered in 15 patients (48.4%). Recurrence occurred in 14 cases (45.2%): 10 as LGUC and 4 as HGUC; there was no stage progression. Mean time to progression was 9 months (5-17 months), and there was no death of disease. MG urothelial carcinoma stage progression and dead of disease rates were comparable to that of LGUC. MG urothelial carcinoma stage progression was significantly lower than that of HGUC, P = .002, using Pearson χ(2) test. MG urothelial carcinoma patients with no intravesical treatment had higher incidence rate of grade progression (25%) compared to LGUC patients (7.9%); however, the difference was not statistically significant. MG urothelial carcinoma had a prognosis closer to "pure" LGUC than "pure" HGUC. Untreated MG urothelial carcinoma may have a higher rate of grade progression than LGUC, although more data are needed before this issue can be definitively addressed. Until such data are available, it is reasonable to keep MG urothelial carcinoma as a distinct grade category with potential management implications.

  16. Evidence for a dualistic model of high-grade serous carcinoma: BRCA mutation status, histology, and tubal intraepithelial carcinoma.

    PubMed

    Howitt, Brooke E; Hanamornroongruang, Suchanan; Lin, Douglas I; Conner, James E; Schulte, Stephanie; Horowitz, Neil; Crum, Christopher P; Meserve, Emily E

    2015-03-01

    Most early adnexal carcinomas detected in asymptomatic women with germline BRCA mutations (BRCA) present as serous tubal intraepithelial carcinomas (STIC). However, STICs are found in only ∼40% of symptomatic high-grade serous carcinomas (HGSCs) and less frequently in pseudoendometrioid variants of HGSC. Consecutive cases of untreated HGSC from BRCA and BRCA women with detailed fallopian tube examination (SEE-FIM protocol) were compared. STIC status (+/-) was determined, and tumors were classified morphologically as SET ("SET", >50% solid, pseudoendometrioid, or transitional) or classic predominate ("Classic"). SET tumors trended toward a higher frequency in BRCA versus BRCA women (50% vs. 28%, P=0.11), had a significantly younger mean age than those with classic HGSC in BRCA women (mean 56.2 vs. 64.8 y, P=0.04), and displayed a better clinical outcome in both groups combined (P=0.024). STIC was significantly more frequent in tumors from the BRCA cohort (66% vs. 31%, P=0.017) and specifically the BRCA tumors with classic morphology (83%) versus those with SET morphology (22%, P=0.003). Overall, several covariables-histology, BRCA status, age, coexisting STIC, and response to therapy-define 2 categories of HGSC with differences in precursor (STIC) frequency, morphology, and outcome. We introduce a dualistic HGSC model that could shed light on the differences in frequency of STIC between symptomatic and asymptomatic women with HGSC. This model emphasizes the need for further study of HGSC precursors to determine their relevance to the prevention of this lethal malignancy.

  17. High-grade neuroendocrine carcinomas of the lung highly express enhancer of zeste homolog 2, but carcinoids do not.

    PubMed

    Findeis-Hosey, Jennifer J; Huang, Jiaoti; Li, Faqian; Yang, Qi; McMahon, Loralee A; Xu, Haodong

    2011-06-01

    Enhancer of zeste homolog 2, the catalytic subunit of polycomb repressive complex 2, is a histone methyltransferase and plays an important role in cell proliferation and cell cycle regulation. It has been shown to be overexpressed in a number of malignant neoplasms. This study aimed to determine the expression pattern of enhancer of zeste homolog 2 in neuroendocrine tumors of the lung and the potential of enhancer of zeste homolog 2 to serve as a biomarker to segregate carcinoids from high-grade neuroendocrine carcinomas. Fifty-four cases, including 25 typical carcinoids, 7 atypical carcinoids, 9 large-cell neuroendocrine carcinomas, and 13 small-cell lung carcinomas, were immunohistochemically studied using a monoclonal antibody against enhancer of zeste homolog 2. All 13 small-cell lung carcinomas demonstrated moderate to strong nuclear staining with 12 exhibiting more than 90% of tumor cells staining. All 9 large-cell neuroendocrine carcinomas were moderately to strongly positive for enhancer of zeste homolog 2, with 6 cases having staining in more than 80% of tumor cells. In contrast, all 25 typical carcinoids and 6 atypical carcinoids showed only rare scattered enhancer of zeste homolog 2-positive tumor cells, with 1 case of atypical carcinoid exhibiting moderate staining in 40% of tumor cells. A subsequent validation study of the 14 specimens of lung or mediastinal lymph node biopsy and fine-needle aspiration, including 6 small-cell lung carcinomas, 2 large-cell neuroendocrine carcinomas, 5 typical carcinoids, and 1 atypical carcinoid, was performed. Enhancer of zeste homolog 2 was diffusely and strongly positive in all small-cell lung carcinomas and large-cell neuroendocrine carcinomas, even with severe crush artifact, whereas it was only positive in rare tumor cells in carcinoids. These findings support the formulation that enhancer of zeste homolog 2 may play an important role in the regulation of biologic behavior of high-grade neuroendocrine carcinomas

  18. The Expression of the Zonula Adhaerens Protein PLEKHA7 Is Strongly Decreased in High Grade Ductal and Lobular Breast Carcinomas

    PubMed Central

    Tille, Jean-Christophe; Ho, Liza; Shah, Jimit; Seyde, Olivia; McKee, Thomas A.; Citi, Sandra

    2015-01-01

    PLEKHA7 is a junctional protein, which participates in a complex that stabilizes E-cadherin at the zonula adhaerens. Since E-cadherin is involved in epithelial morphogenesis, signaling, and tumor progression, we explored PLEKHA7 expression in cancer. PLEKHA7 expression was assessed in invasive ductal and lobular carcinomas of the breast by immunohistochemistry, immunofluorescence and quantitative RT-PCR. PLEKHA7 was detected at epithelial junctions of normal mammary ducts and lobules, and of tubular and micropapillary structures within G1 and G2 ductal carcinomas. At these junctions, the localization of PLEKHA7 was along the circumferential belt (zonula adhaerens), and only partially overlapping with that of E-cadherin, p120ctn and ZO-1, as shown previously in rodent tissues. PLEKHA7 immunolabeling was strongly decreased in G3 ductal carcinomas and undetectable in lobular carcinomas. PLEKHA7 mRNA was detected in both ductal and lobular carcinomas, with no observed correlation between mRNA levels and tumor type or grade. In summary, PLEKHA7 is a junctional marker of epithelial cells within tubular structures both in normal breast tissue and ductal carcinomas, and since PLEKHA7 protein but not mRNA expression is strongly decreased or lost in high grade ductal carcinomas and in lobular carcinomas, loss of PLEKHA7 is a newly characterized feature of these carcinomas. PMID:26270346

  19. Photoaffinity labeling of the progesterone receptor from human endometrial carcinoma

    SciTech Connect

    Clarke, C.L.; Satyaswaroop, P.G.

    1985-11-01

    A nude mouse model for the growth of human endometrial carcinoma and hormonal modulation of the progesterone receptor (PR) was established previously. This study describes the effect of 17 beta-estradiol and tamoxifen (TAM) on growth rate and PR concentration in a hormonally responsive human endometrial tumor (EnCa 101) grown in this experimental system and presents the first characterization of human endometrial carcinoma PR. EnCa 101 was transplanted subcutaneously into ovariectomized, BALB/c, nu/nu athymic mice and grown under 17 beta-estradiol-stimulated, TAM-stimulated, and control conditions. Both 17 beta-estradiol and TAM increased the growth rate of EnCa 101 in nude mice, and a parallel increase in the cytosol PR concentration was observed. PR was partially purified by phosphocellulose and DEAE cellulose chromatography, and the DEAE eluate was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and photoaffinity labeling with (17 alpha-methyl-TH)promegestone ((TH)R5020). Two PR-negative tumors (EnCa K and EnCa V) were also examined in parallel. Photolabeling and sodium dodecyl sulfate-polyacrylamide gel electrophoresis of EnCa 101 grown in the presence of 17 beta-estradiol or TAM revealed incorporation of (3H)R5020 into proteins of molecular weight approximately 116,000 and 85,000. Labeled proteins of molecular weight 66,000, 45,000, and 35,000 were also observed. No incorporation of (TH)R5020 was observed in EnCa 101 grown in the absence of estrogen, nor was any observed in EnCa K or EnCa V.

  20. Radiation Therapy With or Without Cisplatin in Treating Patients With Recurrent Endometrial Cancer

    ClinicalTrials.gov

    2016-10-26

    Endometrial Adenocarcinoma; Endometrial Adenosquamous Carcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Endometrioid Adenocarcinoma, Variant With Squamous Differentiation; Endometrial Serous Adenocarcinoma; Recurrent Uterine Corpus Carcinoma

  1. Association of the Apolipoprotein E 2 Allele with Concurrent Occurrence of Endometrial Hyperplasia and Endometrial Carcinoma

    PubMed Central

    Ivanova, Tatiana I.; Krikunova, Ludmila I.; Ryabchenko, Nikolay I.; Mkrtchyan, Liana S.; Khorokhorina, Vera A.; Salnikova, Lyubov E.

    2015-01-01

    Genes encoding proteins with antioxidant properties may influence susceptibility to endometrial hyperplasia (EH) and endometrial carcinoma (ECa). Patients with EH (n = 89), EH concurrent with ECa (n = 76), ECa (n = 186), and healthy controls (n = 1110) were genotyped for five polymorphic variants in the genes involved in metabolism of lipoproteins (APOE Cys112Arg and Arg158Cys), iron (HFE Cys282Tyr and His63Asp), and catecholamines (COMT Val158Met). Patients and controls were matched by ethnicity (all Caucasians), age, body mass index (BMI), and incidence of hypertension and diabetes. The frequency of the APOE E 2 allele (158Cys) was higher in patients with EH + ECa than in controls (P = 0.0012, PBonferroni = 0.018, OR = 2.58, 95% CI 1.49–4.45). The APOE E 4 allele (112Arg) was more frequently found in patients with EH than in controls and HFE minor allele G (63Asp) had a protective effect in the ECa group, though these results appeared to be nonsignificant after correction for multiple comparisons. The results of the study indicate that E 2 allele might be associated with concurrent occurrence of EH and ECa. PMID:25741405

  2. The oncofetal protein IMP3: a novel biomarker for endometrial serous carcinoma.

    PubMed

    Zheng, Wenxin; Yi, Xiaofang; Fadare, Oluwole; Liang, Sharon X; Martel, Maritza; Schwartz, Peter E; Jiang, Zhong

    2008-02-01

    Insulin-like growth factor II mRNA-binding protein 3 (IMP3) is an oncofetal protein highly expressed in fetal tissue and malignant tumors but rarely found in adult benign tissues. The aim of this study is to determine the expression of IMP3 in benign endometrium, endometrial cancer, and its precursor lesions, trying to see whether IMP3 has any diagnostic usage. Two hundred ninety-eight endometrial samples were examined for IMP3 expression by immunohistochemistry. These included benign endometrium (n=68), atypical hyperplasia or endometrial intraepithelial neoplasia (n=35), endometrial glandular dysplasia (n=21), endometrial intraepithelial carcinoma (n=18), endometrioid carcinoma (n=70), mucinous carcinoma (n=8), serous carcinoma (n=51), clear cell carcinoma (n=12), and other malignancies (n=15). Maturational patterns in the 68 benign endometrial samples included atrophic (n=12), proliferative (n=18), secretory (n=14), menstrual (n=8), and gestational (n=16). Most of the carcinomas were histologically pure; where mixed, the second component constituted <10% of the total tumor volume. The extent and intensity of IMP3 expression was semiquantitatively determined and scored for all samples. A renal cell carcinoma with known IMP3 expression was used as positive control for each immunohistochemistry run. Among the malignant cases, IMP3 expression was predominantly found in endometrial serous carcinoma and its putative precursor lesions, with 3 (14%) of 21 endometrial glandular dysplasia, 16 (89%) of 18 serous endometrial intraepithelial carcinoma, and 48 (94%) of 51 serous carcinomas (P<0.001). In contrast, the frequency of IMP3 expression was significantly lesser in nonserous malignancies with 0 (0%) of 35, 5 (7%) of 70, 0 (0%) of 8, 3 (25%) of 12, and 5 (33%) of 15 positive expression rates in atypical hyperplasia or endometrial intraepithelial neoplasia, endometrioid, mucinous, clear cell carcinomas, and other malignancies, respectively. The IMP3 staining was

  3. Assessing endometrial hyperplasia and carcinoma treated with progestin therapy.

    PubMed

    Mentrikoski, Mark J; Shah, Akeesha A; Hanley, Krisztina Z; Atkins, Kristen A

    2012-10-01

    The effects of increased amounts of progesterone on the endometrium, including such features as eosinophilic cytoplasmic metaplasia, glandular atrophy, and decidualized stroma, are well-known among surgical pathologists. These changes are typically seen as secondary effects of pregnancy or exogenous hormone therapy for birth control purposes or abnormal bleeding. Treatment with progesterone has become a viable alternative to hysterectomy in some patients with complex atypical hyperplasia (CAH) and well-differentiated endometrial carcinoma (WDC), especially those who are poor surgical candidates or those wishing to preserve fertility. To date, only 1 study has specifically examined the effects of progestin therapy on patients with a previous diagnosis of CAH or WDC. That study proposed a classification scheme for the assessment of treated CAH and WDC. The authors concluded that after 6 months of treatment, endometrial biopsy findings of persistent cytologic atypia and architectural abnormalities were associated with treatment failure. This current study aims to assess the previously proposed criteria in a cohort of 30 patients (18 with a diagnosis of CAH and 12 with a diagnosis of WDC), and determine the usefulness of these criteria in clinical practice. Our study confirms that cytologic atypia after 6 months of therapy is strongly associated with treatment failure, and should be an indication to pursue definitive surgical treatment in these patients.

  4. Calvarial metastasis from endometrial carcinoma: Case report and review of the literature

    PubMed Central

    Cecchi, Paolo C.; Kluge, Reinhard; Schwarz, Andreas

    2014-01-01

    Hematogenous bone metastases from endometrial carcinoma are not frequent and their treatment is a matter of debate. We describe an extremely rare case of calvarial metastasis from endometrial carcinoma in an 80-year-old woman treated by means of one-step surgical radical resection and heterologous cranioplasty, along with a review of the literature regarding epidemiology, clinico-radiological features, prognosis, and management of skull metastases. PMID:25685234

  5. No strong association between HER-2/neu protein overexpression and gene amplification in high-grade invasive urothelial carcinomas.

    PubMed

    Caner, Vildan; Turk, Nilay Sen; Duzcan, Fusun; Tufan, N Lale Satiroglu; Kelten, E Canan; Zencir, Sevil; Dodurga, Yavuz; Bagci, Huseyin; Duzcan, S Ender

    2008-09-01

    The generation of urothelial carcinoma is caused by the accumulation of various molecular changes, as in most malignancies. There are conflicting data about the status of HER-2/neu oncogene in urothelial carcinomas. The aim of this study was to determine the status of HER-2/neu oncogene in high-grade invasive urothelial carcinoma of urinary bladder both in protein and DNA level. We evaluated HER-2/neu protein overexpression by immunohistochemistry (IHC) and gene amplification by fluorescent in situ hybridization (FISH) and real-time quantitative PCR in paraffin-embedded samples of high-grade invasive urothelial carcinoma obtained from 36 patients. Polysomy 17 was also assessed by FISH. Immunohistochemically, HER-2/neu protein overexpression was observed in 22 (61.1%) tumors (ten tumors with score 3+ and 12 with score 2+). Fourteen of 36 tumors (38.9%) were evaluated as negative (score 0 or 1+). Complete concordance between FISH and the PCR was seen in all of the samples scored as 0 and 1+ by IHC. HER-2/neu gene amplification was observed in three of 27 (11.1%) tumors by FISH (nine samples were non-informative) and in eight of 36 (22.2%) tumors by the PCR. The complete concordance between HER2-2/neu protein overexpression and gene amplification was seen only in three of 27 tumors. Polysomy 17 was seen in nine tumors (33.3%). The results indicated that, in contrast to breast cancer, there was no strong association between HER-2/neu overexpression and gene amplification in invasive urothelial carcinomas, and polysomy 17 was higher in tumors showing HER-2/neu overexpression.

  6. Immunohistochemical analysis of ras oncogene product p21 in human endometrial carcinoma.

    PubMed

    Yaginuma, Y; Fujita, M; Saitoh, S; Hayakawa, K; Kuzumaki, N; Ishikawa, M

    1993-09-01

    Monoclonal antibody rp-28 directed against the ras gene product p21 has been used to evaluate ras p21 expression in endometrial lesions. Endometrial cancer showed a variable reactivity according to histological type: in well differentiated adenocarcinoma 63% were positive (12/19); in moderately differentiated adenocarcinoma 53% were positive (8/15); in poorly differentiated adenocarcinoma 40% were positive (2/5). The staining intensity of ras p21 seemed to be stronger in the more differentiated types of endometrial carcinoma. In endometrial carcinoma with premenopausal women, 27% were positive (3/11), and with postmenopausal women 71% were positive (20/28). The difference between premenopausal and postmenopausal groups was statistically significant (Mantel-Haenszel procedure, M-H chi 2 = 6.765, P < 0.01). The results suggest the existence of different carcinogenetic mechanisms in these two groups of endometrial cancer.

  7. The frequency and significance of WT-1 expression in serous endometrial carcinoma.

    PubMed

    Hedley, Catherine; Sriraksa, Ruethairat; Showeil, Rania; Van Noorden, Susan; El-Bahrawy, Mona

    2014-09-01

    Serous endometrial carcinoma is an aggressive type of endometrial carcinoma. Wilms tumor gene 1 (WT-1) is commonly expressed in ovarian serous carcinomas and considered a diagnostic marker of these tumors. However, it is generally believed that WT-1 is rarely expressed by endometrial serous carcinoma. The aim of this study was to evaluate the frequency and significance of WT-1 expression in endometrial serous carcinoma. We studied the expression of WT-1 in formalin-fixed, paraffin-embedded tumor sections from 77 cases of endometrial serous carcinoma. Thirty-four tumors showed positive expression for WT-1 (44%). There was a statistically significant association between the presence of WT-1 expression and disease-free survival (DFS), where patients with tumors expressing WT-1 had a shorter DFS compared with those with no WT-1 expression (P = .031; median DFS, 15 and 38 months, respectively). By multivariate Cox regression analysis, DFS was independent from other clinicopathological data (tumor stage, presence of lymphovascular space invasion, cervical involvement, and extrauterine spread), indicating that WT-1 expression is independently associated with DFS. Our study shows that WT-1 is expressed in a considerable percentage of endometrial serous carcinomas, suggesting a role for WT-1 in the pathology of these tumors. This has therapeutic significance, as WT-1 is an emerging target for immunotherapy. Moreover, our results show that WT-1 has prognostic value, being predictive of DFS. As a potential prognostic marker and therapeutic target, we recommend that WT-1 expression should be included in histopathologic reports of endometrial serous carcinoma.

  8. High-Grade Acute Organ Toxicity as a Positive Prognostic Factor in Primary Radiochemotherapy for Anal Carcinoma

    SciTech Connect

    Wolff, Hendrik Andreas; Raus, Ismene; Jung, Klaus; Schueler, Phillip; Herrmann, Markus Karl; Hennies, Steffen; Vorwerk, Hilke; Hille, Andrea; Hess, Clemens Friedrich; Christiansen, Hans

    2011-04-01

    Purpose: To test for a possible correlation between high-grade acute organ toxicity during primary radiochemotherapy and treatment outcome for patients with anal carcinoma. Methods and Materials: From 1991 to 2009, 72 patients with anal carcinoma were treated at our department (10 patients had stage I, 28 patients had stage II, 11 patients had stage IIIA, and 13 patients had stage IIIB cancer [Union Internationale Contre le Cancer criteria]). All patients received normofractionated (1.8 Gy/day, five times/week) whole-pelvis irradiation including iliac and inguinal lymph nodes with a cumulative dose of 50.4 Gy. Concomitant chemotherapy regimen consisted of two cycles of 5-fluorouracil (1,000 mg/m{sup 2}total body surface area (TBSA)/day as continuous intravenous infusion on days 1-4 and 29-32) and mitomycin C (10 mg/m{sup 2}/TBSA, intravenously on days 1 and 29). Toxicity during treatment was monitored weekly, and any incidence of Common Toxicity Criteria (CTC) grade of {>=}3 for skin reaction, cystitis, proctitis, or enteritis was assessed as high-grade acute organ toxicity for later analysis. Results: We found significant correlation between high-grade acute organ toxicity and overall survival, locoregional control, and stoma-free survival, which was independent in multivariate analysis from other possible prognostic factors: patients with a CTC acute organ toxicity grade of {>=}3 had a 5-year overall survival rate of 97% compared to 30% in patients without (p < 0.01, multivariate analysis; 97% vs. 48%, p = 0.03 for locoregional control, and 95% vs. 59%, p = 0.05 for stoma-free survival). Conclusions: Our data indicate that normal tissue and tumor tissue may behave similarly with respect to treatment response, since high-grade acute organ toxicity during radiochemotherapy showed itself to be an independent prognostic marker in our patient population. This hypothesis should be further analyzed by using biomolecular and clinical levels in future clinical trials.

  9. High-Grade Mixed Adenoneuroendocrine Carcinoma in the Cecum: A Case Report

    PubMed Central

    Shin, Sang Ho; Jung, Sung Hee; Jang, Ji Woong; Kang, Min Seok; Kim, Sang Il; Kim, Ji Hye; Lee, Jun Ho

    2017-01-01

    Gastrointestinal neoplasms with an exocrine and a neuroendocrine component are rare. Such neoplasms are called “mixed adenoneuroendocrine carcinomas” (MANECs) according to the most recent World Health Organization classification of gastrointestinal tract neoplasms. MANECs have no specific findings that distinguish them from pure adenocarcinomas. In addition, the optimal management strategy of MANECs is largely unknown. We describe the case of a 32-year-old man with dizziness and abdominal bloating. A cecal mass was suspected based on an image study done at a local clinic. We evaluated the cecal mass by using colonoscopy, contrast enhanced computed tomography of the abdomen, positron emission tomography-computed tomography, and laboratory studies. The patient underwent a right hemicolectomy and adjuvant chemotherapy. The final histopathological diagnosis was a high-grade MANEC of the ascending colon, tumor stage T3N2M0. PMID:28289663

  10. Genetic events in the progression of adenoid cystic carcinoma of the breast to high-grade triple-negative breast cancer

    PubMed Central

    Fusco, Nicola; Geyer, Felipe C; De Filippo, Maria R; Martelotto, Luciano G; Ng, Charlotte K Y; Piscuoglio, Salvatore; Guerini-Rocco, Elena; Schultheis, Anne M; Fuhrmann, Laetitia; Wang, Lu; Jungbluth, Achim A; Burke, Kathleen A; Lim, Raymond S; Vincent-Salomon, Anne; Bamba, Masamichi; Moritani, Suzuko; Badve, Sunil S; Ichihara, Shu; Ellis, Ian O; Reis-Filho, Jorge S; Weigelt, Britta

    2016-01-01

    Adenoid cystic carcinoma of the breast is a rare histologic type of triple-negative breast cancer with an indolent clinical behavior, often driven by the MYB-NFIB fusion gene. Here we sought to define the repertoire of somatic genetic alterations in two adenoid cystic carcinomas associated with high-grade triple-negative breast cancer. The different components of each case were subjected to copy number profiling and massively parallel sequencing targeting all exons and selected regulatory and intronic regions of 488 genes. Reverse transcription PCR and fluorescence in situ hybridization were employed to investigate the presence of the MYB-NFIB translocation. The MYB-NFIB fusion gene was detected in both adenoid cystic carcinomas and their associated high-grade triple-negative breast cancer components. Whilst the distinct components of both cases displayed similar patterns of gene copy number alterations, massively parallel sequencing analysis revealed intra-tumor genetic heterogeneity. In case 1, progression from the trabecular adenoid cystic carcinoma to the high-grade triple-negative breast cancer was found to involve clonal shifts with enrichment of mutations affecting EP300, NOTCH1, ERBB2 and FGFR1 in the high-grade triple-negative breast cancer. In case 2, a clonal KMT2C mutation was present in the cribriform adenoid cystic carcinoma, solid adenoid cystic carcinoma and high-grade triple-negative breast cancer components, whereas a mutation affecting MYB was present only in the solid and high-grade triple-negative breast cancer areas and additional three mutations targeting STAG2, KDM6A and CDK12 were restricted to the high-grade triple-negative breast cancer. In conclusion, adenoid cystic carcinomas of the breast with high-grade transformation are underpinned by MYB-NFIB fusion gene, and, akin to other forms of cancer, may be constituted by a mosaic of cancer cell clones at diagnosis. The progression from adenoid cystic carcinoma to high-grade triple

  11. Genetic events in the progression of adenoid cystic carcinoma of the breast to high-grade triple-negative breast cancer.

    PubMed

    Fusco, Nicola; Geyer, Felipe C; De Filippo, Maria R; Martelotto, Luciano G; Ng, Charlotte K Y; Piscuoglio, Salvatore; Guerini-Rocco, Elena; Schultheis, Anne M; Fuhrmann, Laetitia; Wang, Lu; Jungbluth, Achim A; Burke, Kathleen A; Lim, Raymond S; Vincent-Salomon, Anne; Bamba, Masamichi; Moritani, Suzuko; Badve, Sunil S; Ichihara, Shu; Ellis, Ian O; Reis-Filho, Jorge S; Weigelt, Britta

    2016-11-01

    Adenoid cystic carcinoma of the breast is a rare histological type of triple-negative breast cancer with an indolent clinical behavior, often driven by the MYB-NFIB fusion gene. Here we sought to define the repertoire of somatic genetic alterations in two adenoid cystic carcinomas associated with high-grade triple-negative breast cancer. The different components of each case were subjected to copy number profiling and massively parallel sequencing targeting all exons and selected regulatory and intronic regions of 488 genes. Reverse transcription PCR and fluorescence in situ hybridization were employed to investigate the presence of the MYB-NFIB translocation. The MYB-NFIB fusion gene was detected in both adenoid cystic carcinomas and their associated high-grade triple-negative breast cancer components. Although the distinct components of both cases displayed similar patterns of gene copy number alterations, massively parallel sequencing analysis revealed intratumor genetic heterogeneity. In case 1, progression from the trabecular adenoid cystic carcinoma to the high-grade triple-negative breast cancer was found to involve clonal shifts with enrichment of mutations affecting EP300, NOTCH1, ERBB2 and FGFR1 in the high-grade triple-negative breast cancer. In case 2, a clonal KMT2C mutation was present in the cribriform adenoid cystic carcinoma, solid adenoid cystic carcinoma and high-grade triple-negative breast cancer components, whereas a mutation affecting MYB was present only in the solid and high-grade triple-negative breast cancer areas and additional three mutations targeting STAG2, KDM6A and CDK12 were restricted to the high-grade triple-negative breast cancer. In conclusion, adenoid cystic carcinomas of the breast with high-grade transformation are underpinned by the MYB-NFIB fusion gene and, akin to other forms of cancer, may be constituted by a mosaic of cancer cell clones at diagnosis. The progression from adenoid cystic carcinoma to high-grade triple

  12. The heterogeneous Gleason 7 carcinoma of the prostate: analyses of low and high grade (risk) carcinomas with criteria of the International Society of Urological Pathology (ISUP).

    PubMed

    Helpap, Burkhard; Ringli, Daniel; Shaikhibrahim, Zaki; Wernert, Nicolas; Kristiansen, Glen

    2013-03-01

    Prostate carcinoma (PCa) with Gleason score (GS) 7 has to be examined differentially regarding its prognosis. Using the criteria of ISUP and supplementations, we attempted to analyze the heterogeneity of PCa with GS 7 of biopsy and corresponding specimens of radical prostatectomies (RP). PCa of 530 patients were graded according to Gleason under additional consideration of the state of the nucleoli. Investigating the biopsy specimens, we determined the pattern of Gleason 4 of GS 7, the extension of the tumors in percent, and the number of biopsies containing tumor. In the corresponding specimens of RP, the grading and the state of TNM with margins were assessed. Carcinomas with GS 7 (4+3) in biopsy and RP specimens were unequivocally assigned to the group of high-grade tumors. Carcinomas with GS 7 (3+4) were significantly different from carcinomas with GS 6 when only few and small nucleoli in GS 6 were present (low grade type, p≤0.0001), but were similar to the GS 6 group when nucleoli were prominent (intermediary type, p=0.71). The intermediary group showed an upgrading rate of 36% from GS 6 to GS 7. Furthermore the correlation between organ-confined and non-organ-confined growth showed differences of 63% and 37% in the intermediary group (p=0.0001). The values of grading, staging, margins and metastases indicate that carcinomas of the prostate with the Gleason 3+4 pattern correspond to an intermediary group of carcinomas in contrast to high-grade (high risk) carcinomas with GS 7 and pattern 4+3.

  13. Fertility-preserving treatment in young women with well-differentiated endometrial carcinoma and severe atypical hyperplasia of endometrium.

    PubMed

    Yu, Mei; Yang, Jia-xin; Wu, Ming; Lang, Jing-he; Huo, Zhen; Shen, Keng

    2009-12-01

    A retrospective study on 25 women (8 with endometrial carcinoma, 17 with severe endometrial atypical hyperplasia) under 35 years treated with progestin showed that six cases (75%) in the endometrial carcinoma (EC) group and 17 (100%) in the atypical hyperplasia (AH) group responded to the treatment, and among the 14 complete responders, 4 (40%) patients with AH had 7 pregnancies and 3 healthy deliveries. Given accurate pretreatment assessment, progestin therapy is a feasible management option to preserve fertility for young women with well-differentiated endometrial carcinoma or severe atypical hyperplasia of endometrium.

  14. Salivary adenoid cystic carcinoma with an early phase of high-grade transformation: case report with an immunohistochemical analysis

    PubMed Central

    2013-01-01

    Background The early phase of salivary gland carcinomas with high-grade transformation (HGT) is extremely rare. We reported one case of adenoid cystic carcinoma (AdCC) with early HGT, herein. Case presentation The patient was a 27-year-old Japanese woman who suffered from swelling of the left parotid region. Most of this tumor consisted of typical AdCC histology, whereas the central area of this tumor was composed of solid growth component by atypical cells with clear cytoplasm and marked nuclear atypia. Immunohistochemically, this area was strongly and diffusely positive for epithelial membrane antigen, p53, p16, Her-2, cyclin A and cyclin B1. The Ki-67 labeling index of this area was high, entirely different from that of AdCC area. Conclusion Overall, this area was an early phase of AdCC-HGT. This case is the second case of early AdCC-HGT. We discuss the development of salivary gland carcinoma with HGT. Virtual Slides http://www.diagnosticpatology.diagnomx.eu/vx/1598278104895730 PMID:23819679

  15. Molecular analysis of mixed endometrial carcinomas shows clonality in most cases

    PubMed Central

    Hoang, Lien N.; Almadani, Noorah; Li, Xiaodong; Soslow, Robert A; Gilks, C. Blake; Lee, Cheng-Han

    2016-01-01

    Mixed endometrial carcinoma refers to a tumor that is comprised of two or more distinct histotypes. We studied 18 mixed-type endometrial carcinomas - 11 mixed serous and low-grade endometrioid carcinomas (SC/EC), 5 mixed clear cell and low-grade endometrioid carcinomas (CCC/EC), and 2 mixed clear cell and serous carcinoma (CCC/SC), using targeted next generation sequencing and immunohistochemistry to compare the molecular profiles of the different histotypes present in each case. In 16 of 18 cases there was molecular evidence that both components shared a clonal origin. Eight cases (6 EC/SC, 1 EC/CCC and 1 SC/CCC) showed a serous carcinoma molecular profile that was the same in both components. Five cases (3 CCC/EC and 2 SC/EC) showed a shared endometrioid molecular profile and identical mismatch repair protein (MMR) deficiency in both components. A single SC/EC case harbored the same POLE exonuclease domain mutation in both components. One SC/CCC and one EC/CCC case showed both shared and unique molecular features in the two histotype components, suggesting early molecular divergence from a common clonal origin. In two cases, there were no shared molecular features and these appear to be biologically unrelated synchronous tumors. Overall, these results show that the different histologic components in mixed endometrial carcinomas typically share the same molecular aberrations. Mixed endometrial carcinomas most commonly occur through morphological mimicry, whereby tumors with serous-type molecular profile show morphological features of endometrioid or clear cell carcinoma, or through underlying deficiency in DNA nucleotide repair, with resulting rapid accrual of mutations and intratumoral phenotypic heterogeneity. Less commonly, mixed endometrial carcinomas are the result of early molecular divergence from a common progenitor clone or are synchronous biologically unrelated tumors (collision tumors). PMID:26492180

  16. Cancer stem cells, epithelial-mesenchymal transition, and drug resistance in high-grade ovarian serous carcinoma.

    PubMed

    Chen, Xiaoxiang; Zhang, Jing; Zhang, Zhihong; Li, Hongxia; Cheng, Wenjun; Liu, Jinsong

    2013-11-01

    Although epithelial ovarian cancer cells are eliminated by debulking surgery and chemotherapy during initial treatment, it is believed that only a subset of cancer cells, that is, cancer stem cells, may be an important source of tumor recurrence and drug resistance. This review highlights our current understanding of high-grade serous carcinoma, ovarian cancer stem cells, common methods for enrichment of ovarian cancer stem cells, mechanisms involved in drug resistance, and potential strategies for overcoming drug resistance, with associated potential controversies and pitfalls. We also review the potential relationship between epithelial-to-mesenchymal transition and cancer stem cells and how we can induce cancer cells to differentiate into benign stromal fibroblasts in response to certain chemotherapy drugs.

  17. Uterine superficial serous carcinomas and extensive serous endometrial intraepithelial carcinomas: clinicopathological analysis of 6 patients.

    PubMed

    Ono, Kyoko; Hayashi, Hiroyuki; Tateno, Masatoshi; Tanaka, Reiko; Suzuki, Rie; Maruyama, Yasuyo; Miyagi, Yohei; Furuya, Mitsuko

    2014-01-01

    Uterine superficial serous carcinoma (SSC) and serous endometrial intraepithelial carcinoma (SEIC) are unique malignancies found primarily in postmenopausal women. SSC and SEIC lesions measuring 1 cm or less are categorized as minimal uterine serous carcinoma (MUSC). Less well understood, however, the clinical behavior of SSC and SEIC lesions measuring more than 1 cm. We investigated 6 postmenopausal patients, aged 69-83 years, with SSC or SEIC and without hyperestrogenism. All but 1 patient had tumors originating from the surface of polyps, including 3 patients who each had an enormous polyp occupying the entire uterine cavity. Two patients had extensive SEICs measuring more than 1 cm; the others had SSCs, including 1 MUSC. The mesenchymal cells of the cancer-bearing polyps lacked the morphologic characteristics of endometrial stroma, and the cancer glands often immunostained negatively for estrogen receptors and progesterone receptors. Diffuse immunostaining for human epidermal growth factor receptor 2 was detected in 3 patients, and p53 was detected in all. Cyclin E, a downstream molecule of the F-box and WD repeat domain-containing 7 (FBXW7), was detected in all patients. Microdissected cancer glands showed p53 mutations in 2 patients and a FBXW7 mutation in 1 patient. These findings suggest that mutations of FBXW7 and p53 may contribute to the carcinogenesis of less invasive tumor subtypes. Pathologists and physicians should carefully evaluate SSC and SEIC lesions involving large polyps but lacking myometrial invasion.

  18. Prognostic impact of HER3 based on protein and mRNA expression in high-grade serous ovarian carcinoma.

    PubMed

    Unger, Ulrike; Denkert, Carsten; Braicu, Ioana; Sehouli, Jalid; Dietel, Manfred; Loibl, Sibylle; Darb-Esfahani, Silvia

    2017-02-01

    HER3 is a member of the epidermal growth factor family and was predominantly described as a negative prognostic factor in various solid tumors as well as in ovarian cancer. In this study, we investigated HER3 on protein and mRNA expression in histologically defined subtypes of ovarian cancer looking for an influence on patient's survival. Altogether, we examined HER3 in ovarian high-grade serous (HGSC, n = 320), low-grade serous (LGSC, n = 55), endometrioid (EC, n = 33), and clear cell (CCC, n = 48) carcinomas using immunohistochemistry (IHC) and quantitative real-time reverse transcription PCR (qRT-PCR). Univariate and multivariate analyses were performed to explore the association between HER3 and overall survival (OS) as well as progression-free survival (PFS). In HGSC, high HER3 mRNA expression was a favorable prognostic factor for PFS (P = 0.008) and OS (P = 0.052), while for high HER3 protein expression, a trend towards better survival was seen (OS P = 0.064; PFS P = 0.099). A subgroup of HGSC with negative HER3 staining and negative HER3 mRNA levels showed most unfavorable OS and PFS (P = 0.002 and P = 0.004, respectively). Using the multivariate Cox regression model, HER3 was predictive for prolonged PFS (HR, 0.48; 95% CI, 0.26-0.88; P = 0.018). All in all, we cannot confirm the reported negative prognostic impact of HER3 expression in high-grade serous ovarian carcinoma and moreover find a rather positive prognostic implication of HER3 in this major ovarian cancer histological subtype.

  19. DNMT1 regulates human endometrial carcinoma cell proliferation

    PubMed Central

    Wang, Xinjing; Li, Bilan

    2017-01-01

    Endometrial carcinoma (EC) is the most common gynecologic malignancy, but the molecular events involved in the development and progression of EC remain unclear. This study aimed to investigate the role of DNA methyltransferase 1 (DNMT1), a member of DNA methyltransferases, in EC. AN3CA cells were transfected with DNMT1 siRNA. The proliferation, cell cycle, and apoptosis of AN3CA cells were evaluated by Cell Counting Kit-8 (CCK-8) assay and flow cytometry. The expression of related genes was detected by polymerase chain reaction and Western blot analysis. Knockdown of DNMT1 inhibited the proliferation, induced apoptosis, and G0/G1 phase arrest of AN3CA cells. Furthermore, knockdown of DNMT1 upregulated the expression of nuclear factor kappa-B-inhibitor alpha (NF-κBIA) and Bax and downregulated the expression of Bcl-2 and CCND1/2 in AN3CA cells. In conclusion, this study provides the first evidence that knockdown of DNMT1 affects the expression of cell cycle- and apoptosis-associated proteins in EC cells, suggesting the potential of DNMT1 in EC therapy.

  20. Endoscopic mucosal resection for high-grade dysplasia and intramucosal carcinoma: a Canadian experience

    PubMed Central

    Yamashita, Denise Tami; Li, Chao; Bethune, Drew; Henteleff, Harry; Ellsmere, James

    2017-01-01

    Background Endoscopic mucosal resection (EMR) is increasingly being used as a first-line treatment for Barrett esophagus (BE) with high-grade dysplasia (HGD) and intramucosal adenocarcinoma (IMC). We reviewed our experience with endoscopic treatment of BE with HGD and IMC at our institution with respect to eradication rates, complications and long-term recurrence. Methods We performed a single-centre retrospective review of all patients referred between October 2010 and August 2014 for EMR with dysplastic BE or IMC. We performed EMR using a cap-fitted endoscope, and the procedure was repeated every 3 months until eradication or progression of disease. Results A total of 28 patients were identified: 16 with dysplastic BE (14 HGD, 1 low-grade dysplasia, 1 intermediate dysplasia) and 12 with IMC. Complete eradication of HGD was achieved in 11 of 14 (79%) patients. Three of 12 (25%) patients initially referred with suspected IMC were found to have invasive adenocarcinoma on EMR. Eradication was successful in 8 of 9 (89%) patients with true IMC, with 1 patient progressing to salvage esophagectomy. Complications occurred in 2 of 28 (7%) patients; both had esophageal strictures managed with dilatation. Median duration of follow-up was 371 days. Conclusion Our experience supports the safety of EMR as a first-line treatment for patients with BE with dysplasia and IMC in early short-term follow-up. PMID:28338468

  1. Serous tubal intraepithelial carcinoma localizes to the tubal-peritoneal junction: a pivotal clue to the site of origin of extrauterine high-grade serous carcinoma (ovarian cancer).

    PubMed

    Seidman, Jeffrey D

    2015-03-01

    Recent data suggest that intraepithelial carcinoma of the fallopian tube [serous tubal intraepithelial carcinoma (STIC)] is the precursor of high-grade extrauterine serous carcinoma. A more specific location for the origin of this lesion is suggested by the recently described junction between the fallopian tubal epithelium and the peritoneum [tubal-peritoneal junction (TPJ)]. Fallopian tubes from 202 patients with advanced-stage high-grade extrauterine serous carcinoma or carcinosarcoma were evaluated histologically as were 124 prophylactic salpingo-oophorectomy specimens. These included 54 patients with BRCA or other high-risk mutation or a family history of BRCA mutation and 70 with a personal or family history of breast carcinoma. STIC was found in 81 of 202 patients with serous carcinoma (40.1%). STIC was present in 73 of 141 (52%) cases in which the fimbriae were present and in 62 of 100 (62%) cases in which the TPJ was present (P not significant). In comparison with these groups, when fimbriae and TPJ were absent, STIC was found in 8 of 61 (13%) cases (P<0.0001). None of the prophylactic specimens contained STIC. The mean size of STIC was 1.7 mm. In 32 cases (39.5%), the lesion was flat and in 49 (60.5%), papillary. The mean size of flat STICs was 0.8 mm as compared with 2.3 mm for papillary STICs (P=0.00005). STIC was identified in the same tissue fragment as the junction in 48 cases. The mean distance of STIC to the junction was 1.8 mm. In 11 cases, STIC was flanked by peritoneal mesothelium on one side and tubal epithelium on the opposite side. In 51 patients, the mean distance of invasive carcinoma from the TPJ was 1.8 mm. This distance was 1.9 mm when STIC was present (37 cases) in comparison with 1.5 mm when STIC was absent (14 cases) (P not significant). In 27 of 42 cases (64%), STIC was contiguous with invasive carcinoma. Lamina propria invasion was present in 71% of cases in which STIC was present as compared with 26% of cases in which STIC was

  2. Glucocorticoid Receptor Activation Inhibits Chemotherapy-induced Cell Death in High-grade Serous Ovarian Carcinoma

    PubMed Central

    Stringer-Reasor, Erica M.; Baker, Gabrielle M.; Skor, Maxwell N.; Kocherginsky, Masha; Lengyel, Ernst; Fleming, Gini F.; Conzen, Suzanne D.

    2015-01-01

    Objectives To test the hypothesis that glucocorticoid receptor (GR) activation increases resistance to chemotherapy in high-grade serous ovarian cancer (HGS-OvCa) and that treatment with a GR antagonist will improve sensitivity to chemotherapy. Methods GR expression was assessed in OvCa cell lines by qRT-PCR and Western blot analysis and in xenografts and primary human tumors using immunohistochemistry (IHC). We also examined the effect of GR activation versus inhibition on chemotherapy-induced cytotoxicity in OvCa cell lines and in a xenograft model. Results With the exception of IGROV-1 cells, all OvCa cell lines tested had detectable GR expression by Western blot and qRT-PCR analysis. Twenty-five out of the 27 human primary HGS-OvCas examined expressed GR by IHC. No cell line expressed detectable progesterone receptor (PR) or androgen receptor (AR) by Western blot analysis. In vitro assays showed that in GR-positive HeyA8 and SKOV3 cells, dexamethasone (100 nM) treatment upregulated the pro-survival genes SGK1 and MKP1/DUSP1 and inhibited carboplatin/gemcitabine-induced cell death. Concurrent treatment with two GR antagonists, either mifepristone (100 nM) or CORT125134 (100 nM), partially reversed these effects. There was no anti-apoptotic effect of dexamethasone on chemotherapy-induced cell death in IGROV-1 cells, which did not have detectable GR protein. Mifepristone treatment alone was not cytotoxic in any cell line. HeyA8 OvCa xenograft studies demonstrated that adding mifepristone to carboplatin/gemcitabine increased tumor shrinkage by 48% compared to carboplatin/gemcitabine treatment alone (P=0.0004). Conclusions These results suggest that GR antagonism sensitizes GR+ OvCa to chemotherapy-induced cell death through inhibition of GR-mediated cell survival pathways. PMID:26115975

  3. Prevention of Ovarian High Grade Serous Carcinoma by Elucidating Its Early Changes

    DTIC Science & Technology

    2015-10-01

    in the female reproductive tract (Fig. 1A). The tumor weight was measured in 6 to 12 weeks of age which shows statistical difference in 12 weeks of...compared to FTE from normal control specimens and use an in vitro system and a mouse model to generate a molecularly defined carcinoma resembling HGSC from...normal FTE from high-risk women compared to FTE from normal control specimens and use an in vitro system and a mouse model to generate a molecularly

  4. Do HOXB13 and P63 have a role in differentiating poorly differentiated prostatic carcinoma from urothelial high-grade carcinoma?

    PubMed

    Alshenawy, Hanan AlSaeid; Saied, Eman

    2015-09-01

    Poorly differentiated prostatic carcinoma may overlap with high-grade urothelial carcinoma; a distinction is a must as treatments differ. This study aims to evaluate traditional (PSA and HMWCK) and relatively novel (P63 and HOXB13) markers in distinguishing them; and to evaluate their role in the diagnosis of challenging cases. Sections from: diagnosed group includes 65 prostatic and urothelial carcinoma cases were stained with PSA, HMWCK, P63, and HOXB13. Sensitivity, specificity, and accuracy were evaluated. The second group includes 25 challenging cases which were stained first by PSA and HMWCK, then solved the problematic cases with P63 and HOXB13. PSA and HMWCK were sensitive and specific for prostatic and urothelial carcinomas, respectively, but the sensitivity and accuracy were higher for P63 and HOXB13. By using the traditional markers, 17 cases were diagnosed in the second group while the remaining eight cases need the novel markers to be diagnosed. A confident diagnosis can be established in the majority of cases of poorly differentiated carcinoma in either prostatic or urothelial by using a panel of PSA and HMWCK. In some problematic cases, an extended panel including P63 and HOXB13 is helpful in resolving the diagnosis.

  5. Locally Advanced Stage High-Grade Mucoepidermoid Carcinoma of Salivary Gland in a 9-Year-Old Girl: The Controversy of Adjuvant Therapy.

    PubMed

    Martínez, Olga Micol; Dorado, Elena Daghoum; García, María Dolores Amorós; Ramírez, María Isabel Oviedo; de la Fuente Muñoz, Isabel; Soler, Jose Luis Fuster

    2016-09-05

    Malignant salivary gland tumors are rare in children, mostly represented by low-grade mucoepidermoid carcinomas. For these patients, long-term survival rates above 95% are reported after surgical resection. Here we report a case of a 9-year-old girl with a high grade locally advanced mucoepidermoid carcinoma undergoing adjuvant radiotherapy and chemotherapy after surgery. We emphasize the controversy and lack of evidence-based indication for these highly toxic adjuvant therapy modalities in children.

  6. Locally Advanced Stage High-Grade Mucoepidermoid Carcinoma of Salivary Gland in a 9-Year-Old Girl: The Controversy of Adjuvant Therapy

    PubMed Central

    Martínez, Olga Micol; Dorado, Elena Daghoum; García, María Dolores Amorós; Ramírez, María Isabel Oviedo; de la Fuente Muñoz, Isabel; Soler, Jose Luis Fuster

    2016-01-01

    Malignant salivary gland tumors are rare in children, mostly represented by low-grade mucoepidermoid carcinomas. For these patients, long-term survival rates above 95% are reported after surgical resection. Here we report a case of a 9-year-old girl with a high grade locally advanced mucoepidermoid carcinoma undergoing adjuvant radiotherapy and chemotherapy after surgery. We emphasize the controversy and lack of evidence-based indication for these highly toxic adjuvant therapy modalities in children. PMID:27746885

  7. Regulation of PD-L1 expression in a high-grade invasive human oral squamous cell carcinoma microenvironment.

    PubMed

    Hirai, Mariko; Kitahara, Hiroko; Kobayashi, Yutaka; Kato, Koroku; Bou-Gharios, George; Nakamura, Hiroyuki; Kawashiri, Shuichi

    2017-01-01

    Blockade of the programmed-death 1 receptor (PD-1)/programmed-death ligand (PD-L1) pathway efficiently reduces tumour growth and improves survival. Durable tumour regression with blockade of the PD-1/PD-L1 checkpoint has been demonstrated in recent clinical studies. Oral squamous cell carcinoma (OSCC) is highly immunosuppressive, and PD-L1 expression has been proposed as a potential mechanism responsible for this phenotype. Despite the fact that anti-PD-1 treatment can produce durable responses, such therapy appears to benefit only a subset of patients. Thus, it is important to understand the mechanisms underlying regulation of PD-L1 expression in the OSCC microenvironment. In this study, we showed that PD-L1 expression in high-grade invasive OSCC cell lines was lower than that in a low-grade invasive OSCC line and found a close correlation between PD-L1 expression and the epithelial-mesenchymal transition (EMT). PD-L1 expression was upregulated in macrophages and dendritic cells (DCs) in high-grade invasive human OSCC tissues or co-cultured with mesenchymal-phenotype OSCC cells in vitro. TLR4-inhibitory peptide successfully suppressed PD-L1 upregulation on macrophages and DCs co-cultured with mesenchymal-phenotype OSCC cells, suggesting that some EMT-induced tumour antigen is critical for PD-L1 induction on tumour-associated macrophages and DCs. Further studies are necessary to explore the impact of EMT on the tumour immune microenvironment and to identify potential biomarkers for selecting patients who might preferentially benefit from PD-1/PD-L1 blockade or immunotherapies more broadly.

  8. Regulation of PD-L1 expression in a high-grade invasive human oral squamous cell carcinoma microenvironment

    PubMed Central

    Hirai, Mariko; Kitahara, Hiroko; Kobayashi, Yutaka; Kato, Koroku; Bou-Gharios, George; Nakamura, Hiroyuki; Kawashiri, Shuichi

    2017-01-01

    Blockade of the programmed-death 1 receptor (PD-1)/programmed-death ligand (PD-L1) pathway efficiently reduces tumour growth and improves survival. Durable tumour regression with blockade of the PD-1/PD-L1 checkpoint has been demonstrated in recent clinical studies. Oral squamous cell carcinoma (OSCC) is highly immunosuppressive, and PD-L1 expression has been proposed as a potential mechanism responsible for this phenotype. Despite the fact that anti-PD-1 treatment can produce durable responses, such therapy appears to benefit only a subset of patients. Thus, it is important to understand the mechanisms underlying regulation of PD-L1 expression in the OSCC microenvironment. In this study, we showed that PD-L1 expression in high-grade invasive OSCC cell lines was lower than that in a low-grade invasive OSCC line and found a close correlation between PD-L1 expression and the epithelial-mesenchymal transition (EMT). PD-L1 expression was upregulated in macrophages and dendritic cells (DCs) in high-grade invasive human OSCC tissues or co-cultured with mesenchymal-phenotype OSCC cells in vitro. TLR4-inhibitory peptide successfully suppressed PD-L1 upregulation on macrophages and DCs co-cultured with mesenchymal-phenotype OSCC cells, suggesting that some EMT-induced tumour antigen is critical for PD-L1 induction on tumour-associated macrophages and DCs. Further studies are necessary to explore the impact of EMT on the tumour immune microenvironment and to identify potential biomarkers for selecting patients who might preferentially benefit from PD-1/PD-L1 blockade or immunotherapies more broadly. PMID:27922697

  9. Diffuse reflectance spectroscopy can differentiate high grade and low grade prostatic carcinoma.

    PubMed

    Werahera, Priya N; Jasion, Edward A; David Crawford, E; Lucia, M Scott; van Bokhoven, Adrie; Sullivan, Holly T; Kim, Fernando J; Maroni, Paul D; David Port, J; Daily, John W; Rosa, Francisco G La; Werahera, Priya N; Jasion, Edward A; Crawford, E David; Lucia, M Scott; van Bokhoven, Adrie; Sullivan, Holly T; Kim, Fernando J; Maroni, Paul D; Port, J David; Daily, John W; La Rosa, Francisco G; Daily, John W; Van Bokhoven, Adrie; Crawford, E David; Port, J David; Werahera, Priya N; Lucia, M Scott; Sullivan, Holly T; Maroni, Paul D; Jasion, Edward A; La Rosa, Francisco G; Kim, Fernando J

    2016-08-01

    Prostate tumors are graded by the revised Gleason Score (GS) which is the sum of the two predominant Gleason grades present ranging from 6-10. GS 6 cancer exclusively with Gleason grade 3 is designated as low grade (LG) and correlates with better clinical prognosis for patients. GS >7 cancer with at least one of the Gleason grades 4 and 5 is designated as HG indicate worse prognosis for patients. Current transrectal ultrasound guided prostate biopsies often fail to correctly diagnose HG prostate cancer due to sampling errors. Diffuse reflectance spectra (DRS) of biological tissue depend on tissue morphology and architecture. Thus, DRS could potentially differentiate between HG and LG prostatic carcinoma. A 15-gauge optical biopsy needle was prototyped to take prostate biopsies after measuring DRS with a laboratory fluorometer. This needle has an optical sensor that utilizes 8×100 μm optical fibers for tissue excitation and a single 200 μm central optical fiber to measure DRS. Tissue biopsy cores were obtained from 20 surgically excised prostates using this needle after measuring DRS at 5 nm intervals between 500-700 nm wavelengths. Tissue within a measurement window was histopathologically classified as either benign, LG, or HG and correlated with DRS. Partial least square analysis of DRS identified principal components (PC) as potential classifiers. Statistically significant PCs (p<;0.05) were tested for their ability to classify biopsy tissue using support vector machine and leave-one-out cross validation method. There were 29 HG and 49 LG cancers among 187 biopsy cores included in the study. Study results show 76% sensitivity, 80% specificity, 93% negative predictive value, and 50% positive predictive value for HG versus benign, and 76%, 73%, 84%, and 63%, for HG versus LG prostate tissue classification. DRS failed to diagnose 7/29 (24%) HG cancers. This study demonstrated that an optical biopsy needle guided by DRS has sufficient accuracy to differentiate HG

  10. [Environmental and genetic risk factors for endometrial carcinoma].

    PubMed

    Sénéchal, Claire; Cottereau, Edouard; de Pauw, Antoine; Elan, Camille; Dagousset, Isabelle; Fourchotte, Virginie; Gauthier-Villars, Marion; Lae, Marick; Stoppa-Lyonnet, Dominique; Buecher, Bruno

    2015-03-01

    In France, endometrial cancer is at the first rank of gynecological cancers for cancer incidence, before ovarian and cervical cancers. In fact, the number of incident cases has been estimated to 7275 for the year 2012; the number of death due to endometrial cancer to 2025. This cancer is hormone-dependent and endogenous (reproductive factors) or exogenous (oral combined contraceptives, hormone replacement therapy) causes of exposition to estrogens are the major environmental risk factors for both types of endometrial cancers: type I or well-differentiated endometrioid adenocarcinomas; and type II including all other histological types: papillary serous adenocarcinomas, clear cell adenocarcinomas and carcinosarcomas, also known as malignant mixed Mullerian tumor, MMMT. Obesity, diabetes mellitus and adjuvant treatment of breast cancer with tamoxifen are also associated with an increased risk of endometrial cancer. Genetic factors may also be implicated in the pathogenesis of endometrial cancer either as "minor genetic factors" (susceptibility factors), which remain largely unknown and are responsible for the increased observed risk in relatives of women affected with endometrial cancer; or as major genetic factors responsible for hereditary forms and namely for Lynch syndrome whose genetic transmission is of autosomic dominant type. The appropriate recognition of Lynch syndrome is of critical importance because affected patients and their relatives should benefit from specific care. The aims of this review is to describe major environmental and genetic risk factors for endometrial cancer with specific attention to most recent advances in this field and to describe recommendations for care of at-risk women.

  11. Upregulation of MICA on high-grade invasive operable breast carcinoma.

    PubMed

    Madjd, Zahra; Spendlove, Ian; Moss, Robert; Bevin, Shaun; Pinder, Sarah E; Watson, Nicholas F S; Ellis, Ian; Durrant, Lindy G

    2007-10-22

    The MHC class I chain-related gene A (MICA) is frequently expressed on the surface of intestinal epithelium and by many epithelial tumours. MICA is a stress-induced antigen which was identified as an activator of natural killer cells via interaction with the NKG2D receptor. We have raised a rabbit polyclonal antibody against a synthetic peptide that recognises denatured MICA on both Western blots and in formalin-fixed paraffin-embedded sections. In the present study this antibody was used to undertake a definitive study of 530 breast cancer cases with mean follow up of 7 years to determine the prognostic significance of MICA expression. To detect any association between MICA expression and NK infiltration, whole sections of 50 tumours were also analysed for CD56 staining. Univariate analysis showed significant relationships between MICA expression and histological grade (P = 0.006), lymph node stage (P = 0.013), Nottingham Prognostic Index (NPI, P = 0.002), the presence of vascular invasion (P = 0.045) and tumour type (P = 0.023). Upregulation of MICA was more often found in histological grade 3, poor prognosis (NPI >5.4) tumours. Association of high MICA expression with NK cell infiltration was not demonstrated, as very few NK cells were present in whole breast sections. Our results suggest that induced expression of MICA may be an indicator of poor prognosis in breast carcinoma and is indicative of a tumour environment that has undergone stresses such as apoptosis, necrosis, or hypoxia.

  12. Perioperative and long-term outcomes of laparoscopy and laparotomy for endometrial carcinoma

    PubMed Central

    Yin, Xianghua; Shi, Min; Xu, Jianbo; Guo, Qinhao; Wu, Huan

    2015-01-01

    Objective: To compare the efficacy and the clinical value of laparoscopic surgery and traditional abdominal surgery for the treatment of endometrial carcinoma. Meanwhile, assessing the value of preoperative MRI in the depth of myometrial invasion of endometrial carcinoma. Methods: we retrospectively analyzed 32 patients with endometrial carcinoma who underwent laparoscopic surgery in Department of Obstetrics and Gynecology in the Subei People’s Hospital from September 2008 to March 2015, comparing data using the same surgeons’ traditional laparotomy cases during the same period. Data collected includes patient demography, intraoperative and postoperative clinical parameters and follow-up data. Result: All laparoscopic and laparotomy surgery were successful. laparoscopic surgery was better than traditional surgery with less blood loss, more early postoperative anal exhaust time, less postoperative hospital stay, and no seriously complications, there were significant differences (all P<0.05). The average operative time, in the laparoscopy group, was a little longer than the laparotomy group with no statistical significance (P>0.05). There were no differences in the two groups in terms of the number of excised lymph nodes and the recurrence and mortality rate (P>0.05). The sensitivity and specificity of the MRI imaging in assessment of deep myometrial invasion of endometrial carcinoma were 89.3% and 96.2%, respectively. Conclusion: Compared to conventional approaches, laparoscopic surgery showed favorable short-term outcomes with comparable survival. People with endometrial cancer can, therefore, be as safely managed using laparoscopy as laparotomy. MRI is of high value in assessing deep myometrial invasion in patients with endometrial carcinoma. PMID:26770538

  13. Loss of ALDH1A1 expression is an early event in the pathogenesis of ovarian high-grade serous carcinoma.

    PubMed

    Chui, M Herman; Wang, Yihong; Wu, Ren-Chin; Seidman, Jeffrey; Kurman, Robert J; Wang, Tian-Li; Shih, Ie-Ming

    2015-03-01

    Tumor-initiating cells are thought to share features with normal somatic stem cells. In mice, stem cells at the ovarian hilum have been shown to express the stem cell marker, aldehyde dehydrogenase isoform 1A1 (ALDH1A1), and are prone to malignant transformation. The potential relevance of this finding to humans has not been established. In this study, we used immunohistochemistry to assess the distribution of ALDH1A1 staining in the epithelium of human fallopian tubes, with particular reference to the transition of tubal epithelium to mesothelium (ie, tubal-mesothelial junction), ovarian surface epithelium, as well as putative precursors of ovarian high-grade serous carcinoma, namely, serous tubal intraepithelial carcinoma and 'p53 signatures,' and overt serous carcinoma. Expression of ALDH1A1 was detected in both secretory and ciliated tubal epithelial cells, tubal-mesothelial junctions and ovarian surface epithelium, but was absent in serous tubal intraepithelial carcinoma and p53 signatures. Positive staining in high-grade serous carcinoma, when present, was typically limited to rare tumor cells. In silico analyses of the mRNA expression data set from The Cancer Genome Atlas revealed downregulation of ALDH1A1 transcripts in high-grade serous carcinoma relative to normal tubal epithelium, and no association between ALDH1A1 expression levels and overall survival. Our results do not support ALDH1A1 as a specific marker of stem cells in human fallopian tube and demonstrate that its loss of expression is an early event in the development of high-grade serous carcinoma.

  14. Utility of PTEN and ERG immunostaining for distinguishing high-grade PIN from intraductal carcinoma of the prostate on needle biopsy.

    PubMed

    Morais, Carlos L; Han, Jeong S; Gordetsky, Jennifer; Nagar, Michael S; Anderson, Ann E; Lee, Stephen; Hicks, Jessica L; Zhou, Ming; Magi-Galluzzi, Cristina; Shah, Rajal B; Epstein, Jonathan I; De Marzo, Angelo M; Lotan, Tamara L

    2015-02-01

    Intraductal carcinoma of the prostate and high-grade prostatic intraepithelial neoplasia (PIN) have markedly different implications for patient care but can be difficult to distinguish in needle biopsies. In radical prostatectomies, we demonstrated that PTEN and ERG immunostaining may be helpful to resolve this differential diagnosis. Here, we tested whether these markers are diagnostically useful in the needle biopsy setting. Separate or combined immunostains were applied to biopsies containing morphologically identified intraductal carcinoma, PIN, or borderline intraductal proliferations more concerning than PIN but falling short of morphologic criteria for intraductal carcinoma. Intraductal carcinoma occurring with concurrent invasive tumor showed the highest rate of PTEN loss, with 76% (38/50) lacking PTEN and 58% (29/50) expressing ERG. Of biopsies containing isolated intraductal carcinoma, 61% (20/33) showed PTEN loss and 30% (10/33) expressed ERG. Of the borderline intraductal proliferations, 52% (11/21) showed PTEN loss and 27% (4/15) expressed ERG. Of the borderline cases with PTEN loss, 64% (7/11) had carcinoma in a subsequent needle biopsy specimen, compared with 50% (5/10) of PTEN-intact cases. In contrast, none of the PIN cases showed PTEN loss or ERG expression (0/19). On needle biopsy, PTEN loss is common in morphologically identified intraductal carcinoma yet is very rare in high-grade PIN. Borderline intraductal proliferations, especially those with PTEN loss, have a high rate of carcinoma on resampling. If confirmed in larger prospective studies, these results suggest that PTEN and ERG immunostaining may provide a useful ancillary assay to distinguish intraductal carcinoma from high-grade PIN in this setting.

  15. High-grade invasive urothelial carcinoma of the ureter with systematic lymph node metastasis successfully treated by nephroureterectomy followed by chemotherapy

    PubMed Central

    Liu, Zhu-Qing; Zhang, Xi; Xu, Qing

    2015-01-01

    We report a case of high-grade invasive urothelial carcinoma with squamous differentiation of the urinary tract. A 72-year-old woman was referred to our hospital because of asymptomatic gross hematuria. A right-sided laparoscopic radical nephroureterectomy with bladder cuff removal and right-sided pelvic lymphadenectomy were performed at our institution. Postoperative pathological examination showed high-grade urothelial carcinoma with squamous differentiation. Five months later, CT scan of the neck diagnosed it as lymph nodes metastasis. Following the laparoscopic radical nephroureterectomy, chemotherapy with gemcitabine and cisplatin or nedaplatin was carried out. After several cycles’ chemotherapy, nearly all the enlarged lymph node disappeared. Seven years and five years passed, urothelial carcinoma has not recurred after the surgery and all the lymph node disappeared respectively. PMID:25932275

  16. MiR-218 inhibits HMGB1-mediated autophagy in endometrial carcinoma cells during chemotherapy.

    PubMed

    Ran, Xiaomin; Yang, Juan; Liu, Chaoxia; Zhou, Ping; Xiao, Linzhi; Zhang, Keqiang

    2015-01-01

    Endometrial carcinoma is the most common gynecological malignancy among women worldwide. Although treatment for EC has improved with the introduction of Paclitaxel (Tax) chemotherapy, the majority of patients will develop resistance to the treatment, leading to poor prognosis. One of the causes of chemoresistance is the increased ability to undergo autophagy. In this study, we identified that miR-218 was significantly down-regulated in Tax-resistant EC cells compared to the non-drug resistant cell lines, and overexpression of miR-218 sensitized paclitaxel resistant EC cells to paclitaxel. Moreover, we demonstrated that miR-218 directly binds to the 3'-UTR of HMGB1 gene. HMGB1 was upregulated in paclitaxel resistant EC cells, it mediated autophagy and contributed to chemotherapy resistance in endometrial carcinoma in vitro. HMGB1-mediated autophagy could be suppressed by miR-218 overexpression in Tax resistant EC cells. In summary, we determined the targeting role of miR-218 to HMGB1 and the regulation of miR-218 on the HMGB1-mediated cell autophagy during chemotherapy resistance in endometrial carcinoma cells. These results reveal novel potential role of miR-218 against chemotherapy resistance during the treatment of endometrial carcinoma.

  17. [Endometrial adenocarcinoma and clear cell carcinoma in a young woman with polycystic ovarian syndrome: a case report].

    PubMed

    Niu, Jing; Liu, Nan; Liu, Guo-Bing

    2016-05-01

    A 26-year-old unmarried woman with irregular menstruation for 4 years was admitted for an intrauterine space-occupying mass. Pathological examination before surgery showed moderately to poorly differentiated endometrial adenocarcinoma. The patient underwent laparoscopically assisted epifascial panhysterectomy with bilateral salpingo-oophorectomy. Pathological examination of the surgical specimens reported moderately to poorly differentiated endometrial adenocarcinoma and stage II clear cell carcinoma. The patient then received chemotherapy and remained alive without evidence of recurrence. Young women with polycystic ovarian syndrome are at high risk of developing endometrial carcinoma, but concurrent clear cell carcinoma is rare. Careful evaluation before and after treatment are essential to improve the patients prognosis.

  18. Mammary analog secretory carcinoma of salivary gland with high-grade histology arising in hard palate, report of a case and review of literature

    PubMed Central

    Luo, Wenyi; Lindley, Sarah W; Lindley, Peter H; Krempl, Gregory A; Seethala, Raja R; Fung, Kar-Ming

    2014-01-01

    Mammary gland analog secretary carcinoma (MASC) of salivary gland is typically a tumor of low histologic grade and behaves as a low-grade malignancy with relatively benign course. This tumor shares histologic features, immunohistochemical profile, and a highly specific genetic translocation, ETV6-NTRK3, with secretory carcinoma of breast. Histologically, it is often mistaken as acinic cell carcinoma, adenocarcinoma not otherwise specified, and other primary salivary gland tumors. Here we report a case of MASC with high-grade transformation and cervical lymph node metastases confirmed with ETV6-NTRK3 translocation arising in the hard palate of a 41 year-old adult. Interestingly, the metastatic carcinoma has lower grade than the original tumor which strongly support malignant transformation of the original tumor. Most commonly, MASC arises from the parotid gland and less often in minor salivary glands. Metastasis is relatively uncommon and high-grade histology has only been reported in four cases with three of them arising from the parotid gland and the location of the fourth one has not been reported. This is the first case with high grade histology that arise from minor salivary gland and it emphasizes the importance of molecular screening of salivary gland tumor with high-grade histology for ETV6-NTRK3 translocation. In our literature of 115 cases that includes the current case, MASC occurred predominantly in adult with only a few cases under 18 years of age and a male to female ratio of 1.2:1. Parotid gland is more commonly affected but there is also significant occurrence in minor salivary glands. Except for the cases with high grade histology, the overall prognosis is good. PMID:25674280

  19. Leptin receptor expression during the progression of endometrial carcinoma is correlated with estrogen and progesterone receptors

    PubMed Central

    Méndez-López, Luis Fernando; Zavala-Pompa, Angel; Cortés-Gutiérrez, Elva I.; Cerda-Flores, Ricardo M.

    2016-01-01

    Introduction The hormone leptin, which is produced in the adipose tissue, may influence tumorigenesis directly via its receptor (Ob-R). Thus, a role for Ob-R in endometrial carcinogenesis has been proposed. However, most studies neither included samples of the entire histological progression of endometrial carcinoma nor examined Ob-R jointly with the estrogen and progesterone receptors (ER and PR, respectively). Material and methods To determine the fluctuations of Ob-R, ER, and PR during the histological progression of endometrial carcinoma, we assessed their expression via immunohistochemistry (IHC) in six histological types of endometrium (proliferative, secretory, nonatypical and atypical hyperplasia, and endometrioid and nonendometrioid endometrial carcinoma), in which we performed histopathological and digital scoring for the quantification of receptors. Results We found that Ob-R expression was positively correlated with that of ER and PR (r = 1, p < 0.001; r = 0.943, p < 0.005, respectively), and there was a significant difference in Ob-R expression among proliferative normal endometrium, hyperplasias, and carcinomas, according to their relative digitally scored Ob-R expression (p < 0.001). In addition, we observed that Ob-R expression in the secretory endometrium was more similar to that of carcinomas than to its proliferative counterpart. Conclusions These results indicate that Ob-R expression fluctuates during endometrial carcinogenesis in correlation with ER and PR, suggesting that Ob-R expression in vivo is highly dependent on estrogen and progesterone activities in the endometrium and on its ER and PR status, as suggested previously by in vitro studies. PMID:28144276

  20. Comparison of Two Combination Chemotherapy Regimens Plus Radiation Therapy in Treating Patients With Stage III or Stage IV Endometrial Cancer

    ClinicalTrials.gov

    2015-04-30

    Endometrial Adenocarcinoma; Endometrial Adenosquamous Carcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Endometrioid Adenocarcinoma, Variant With Squamous Differentiation; Endometrial Serous Adenocarcinoma; Stage III Uterine Corpus Cancer

  1. Serous endometrial intraepithelial carcinoma arising in adenomyosis: a report of 5 cases.

    PubMed

    Abushahin, Nisreen; Zhang, Tingguo; Chiang, Sarah; Zhang, Xiangsheng; Hatch, Kenneth; Zheng, Wenxin

    2011-05-01

    Serous endometrial intraepithelial carcinoma (serous EIC) arising in adenomyosis is rare. It may be underrecognized because of its deceiving morphology when embedded in the foci of adenomyosis. Although there is no connection to peritoneal cavity, some cases may be associated with extrauterine disease. It is currently unknown what the etiology for such a disease is. More studies are in need to elucidate the pathogenesis of such a grave malady. We report a series of 5 cases of serous EIC, which may arise in adenomyosis. The 5 cases are in 5 different patients or whom on histopathological examination of their hysterectomy specimens, the finding of adenomyosis involved with serous intraepithelial neoplasia was identified. The finding of interest was the presence of multifoci of adenomyosis; some of those foci were involved in serous EIC. In addition to EIC, lesions of endometrial glandular dysplasia were present in the foci of adenomyosis. To rule out the possibility of endometrial serous carcinoma (ESC) invading into the areas of the adenomyosis, all of the 5 uteri were extensively examined. Among the 5 uteri, the eutopic endometirum showed 1 invasive ESC, 2 serous EIC, and 2 benign resting endometrium without any cancer or precancerous lesions. In 1 uterus with ESC, we did not see any direct spatial connection between the invasive component of ESC and the areas of EIC in the foci of adenomyosis. In 2 uteri with serous EIC within the endometrial cavity, there was a distance of at least 0.5 cm between the lesions within the endometrial cavity and the serous EIC in adenomyosis. The remaining 2 uteri showed no evidence of endometrial malignancy in the endometrial cavity, whereas serous EIC was present only in areas of adenomyosis. Clinicopathologic data including characterized immunohistochemical stainings and p53 gene sequence analysis are presented and clinical significance is discussed.

  2. An early-screening biomarker of endometrial carcinoma: NGAL is associated with epithelio-mesenchymal transition

    PubMed Central

    Li, Ting; Yu, Li; Wen, Jia

    2016-01-01

    neutrophilgelatinase-associated lipocalin is currently one of the most interesting and enigmatic proteins involved in the development of malignancies. In this study, we found that the expression of neutrophilgelatinase-associated lipocalin was up-regulated in endometrial cancer tissues and cell lines, significantly increased in early-grade ones, suggesting it may serve as a biomarker for early-stage screening for endometrial carcinoma. Moreover, neutrophilgelatinase-associated lipocalin was up-regulated in Ishikawa cells under going epithelio-mesenchymal transition induced by epidermal growth factor (5 ng/ml). Up-regulation of neutrophilgelatinase-associated lipocalin may correlate with the down-regulation of E-cadherin expression, up-regulation of Vimentin expression, enhanced cell migration, invasion and proliferation, which are the typical hallmarks of epithelio-mesenchymal transition processes. neutrophilgelatinase-associated lipocalin may play a dual role during tumorigenetic and developmental processes of endometrial carcinoma. These results suggested neutrophilgelatinase-associated lipocalin to be a potential molecular target in the early diagnosis and treatment of endometrial carcinoma. Further studies are warranted to clarify the molecular mechanisms behind the expression and function of neutrophilgelatinase-associated lipocalin and epithelio-mesenchymal transition. PMID:27863382

  3. Invasion Patterns of Metastatic Extrauterine High-grade Serous Carcinoma With BRCA Germline Mutation and Correlation With Clinical Outcomes.

    PubMed

    Hussein, Yaser R; Ducie, Jennifer A; Arnold, Angela G; Kauff, Noah D; Vargas-Alvarez, Hebert A; Sala, Evis; Levine, Douglas A; Soslow, Robert A

    2016-03-01

    Characteristic histopathologic features have been described in high-grade serous carcinoma associated with BRCA abnormalities (HGSC-BRCA), which are known to have relatively favorable clinical outcomes. The aim of this study was to evaluate the clinical significance of invasion patterns in metastatic HGSC-BRCA cases. Of the 37 cases of advanced-stage HGSC with known BRCA1 or BRCA2 germline mutation retrieved from our institutional files, 23 patients had a germline mutation of BRCA1 and 14 had a BRCA2 mutation. The pattern of invasion at metastatic sites was recorded and classified as a pushing pattern (either predominantly or exclusively), an exclusively micropapillary infiltrative pattern, or an infiltrative pattern composed of papillae, micropapillae, glands, and nests (mixed infiltrative pattern). Histologic evaluation of metastases was performed without knowledge of genotype or clinical outcome. Clinical data were abstracted from medical records. Median age was 56 years (range, 31 to 73 y). All patients presented at stage IIIC or IV and underwent complete surgical staging followed by chemotherapy. All 37 HGSC-BRCA cases showed either pushing pattern metastases (30; 81%) or infiltrative micropapillary metastases (7; 19%). No HGSC-BRCA case exhibited metastases composed solely of mixed infiltrative patterns. Among the 7 infiltrative micropapillary cases, 6 had a BRCA1 germline mutation versus 1 with a BRCA2 mutation. The median time of follow-up was 26 months (range, 13 to 49 mo). All 7 patients with infiltrative micropapillary metastases either experienced recurrence or died of disease (5 recurrences and 2 deaths), which was significantly worse than what was seen in patients with predominantly pushing pattern metastases, of whom 16 of 30 (53%) experienced recurrence (n=14) or died of disease (n=2) (P=0.03). In conclusion, the recognition of different invasion patterns of metastatic extrauterine HGSC-BRCA has prognostic implications. The infiltrative

  4. Aurora Kinase A expression predicts platinum-resistance and adverse outcome in high-grade serous ovarian carcinoma patients.

    PubMed

    Mignogna, Chiara; Staropoli, Nicoletta; Botta, Cirino; De Marco, Carmela; Rizzuto, Antonia; Morelli, Michele; Di Cello, Annalisa; Franco, Renato; Camastra, Caterina; Presta, Ivan; Malara, Natalia; Salvino, Angela; Tassone, Pierfrancesco; Tagliaferri, Pierosandro; Barni, Tullio; Donato, Giuseppe; Di Vito, Anna

    2016-05-21

    High-Grade Serous Ovarian Carcinoma (HGSOC) is the predominant histotype of epithelial ovarian cancer (EOC), characterized by advanced stage at diagnosis, frequent TP53 mutation, rapid progression, and high responsiveness to platinum-based-chemotherapy. To date, standard first-line-chemotherapy in advanced EOC includes platinum salts and paclitaxel with or without bevacizumab. The major prognostic factor is the response duration from the end of the platinum-based treatment (platinum-free interval) and about 10-0 % of EOC patients bear a platinum-refractory disease or develop early resistance (platinum-free interval shorter than 6 months). On these bases, a careful selection of patients who could benefit from chemotherapy is recommended to avoid unnecessary side effects and for a better disease outcome. In this retrospective study, an immunohistochemical evaluation of Aurora Kinase A (AURKA) was performed on 41 cases of HGSOC according to platinum-status. Taking into account the number and intensity of AURKA positive cells we built a predictive score able to discriminate with high accuracy platinum-sensitive patients from platinum-resistant patients (p < 0.001). Furthermore, we observed that AURKA overexpression correlates to worse overall survival (p = 0.001; HR 0.14). We here suggest AURKA as new effective tool to predict the biological behavior of HGSOC. Particularly, our results indicate that AURKA has a role both as predictor of platinum-resistance and as prognostic factor, that deserves further investigation in prospective clinical trials. Indeed, in the era of personalized medicine, AURKA could assist the clinicians in selecting the best treatment and represent, at the same time, a promising new therapeutic target in EOC treatment.

  5. ADAM12 is a prognostic factor associated with an aggressive molecular subtype of high-grade serous ovarian carcinoma.

    PubMed

    Cheon, Dong-Joo; Li, Andrew J; Beach, Jessica A; Walts, Ann E; Tran, Hang; Lester, Jenny; Karlan, Beth Y; Orsulic, Sandra

    2015-07-01

    ADAM metallopeptidase domain 12 (ADAM12) is a promising biomarker because of its low expression in normal tissues and high expression in a variety of human cancers. However, ADAM12 levels in ovarian cancer have not been well characterized. We previously identified ADAM12 as one of the signature genes associated with poor survival in high-grade serous ovarian carcinoma (HGSOC). Here, we sought to determine if high levels of the ADAM12 protein and/or messenger RNA (mRNA) are associated with clinical variables in HGSOC. We show that high protein levels of ADAM12 in banked preoperative sera are associated with shorter progression-free and overall survival. Tumor levels of ADAM12 mRNA were also associated with shorter progression-free and overall survival as well as with lymphatic and vascular invasion, and residual tumor volume following cytoreductive surgery. The majority of genes co-expressed with ADAM12 in HGSOC were transforming growth factor (TGF)β signaling targets that function in collagen remodeling and cell-matrix adhesion. In tumor sections, the ADAM12 protein and mRNA were expressed in epithelial cancer cells and surrounding stromal cells. In vitro data showed that ADAM12 mRNA levels can be increased by TGFβ signaling and direct contact between epithelial and stromal cells. High tumor levels of ADAM12 mRNA were characteristic of the mesenchymal/desmoplastic molecular subtype of HGSOC, which is known to have the poorest prognosis. Thus, ADAM12 may be a useful biomarker of aggressive ovarian cancer for which standard treatment is not effective.

  6. Novel targeted therapies in uterine serous carcinoma, an aggressive variant of endometrial cancer.

    PubMed

    Menderes, Gulden; Clark, Mitchell; Santin, Alessandro D

    2016-04-01

    Uterine serous carcinoma (USC) is a rare but aggressive subtype of endometrial cancer. Although it represents only 10% of all endometrial cancer cases, USC accounts for up to 40% of all endometrial cancer-related recurrences and subsequent deaths. With such a dismal prognosis, there is an expanding role for novel targeted approaches in the treatment of USC. Recent whole-exome sequencing studies have demonstrated gain of function of the HER2/NEU gene, as well as driver mutations in the PIK3CA/AKT/mTOR and cyclin E/FBXW7 oncogenic pathways in a large number of USCs. The results emphasize the relevance of these novel therapeutic targets for biologic therapy of USC, which will be reviewed in this article.

  7. Molecular profile of grade 3 endometrioid endometrial carcinoma: is it a type I or type II endometrial carcinoma?

    PubMed

    Alvarez, Teresa; Miller, Ezra; Duska, Linda; Oliva, Esther

    2012-05-01

    Two types of endometrial carcinoma (EC) have been delineated on the basis of clinicopathologic studies. Low-grade endometrioid carcinoma (EEC) is the prototype of type I EC and is characterized by microsatellite instability and PTEN, K-ras, and/or β-catenin gene mutations, whereas type II EC is typically represented by serous and clear cell carcinomas (SCs/CCCs), the former frequently showing p53 mutations and c-erb-2 overexpression; however, the molecular profile of grade 3 EEC has not yet been well characterized. The goal of this study was to define the immunohistochemical and molecular profile of grade 3 EEC. We studied 25 patients with grade 3 EEC ranging in age from 35 to 87 (mean 61) years. At the time of initial diagnosis, 16 patients had stage I tumors, whereas 3, 5, and 1 had stages II, III, and IV tumors, respectively. Only 1 patient with stage IV tumor had disease in the peritoneum because of direct extend of tumor through the uterine wall. Two tissue microarrays were constructed from paraffin-embedded blocks and stained for MLH-1, MSH-2, p16, cyclin D1, C-erb-B2, WT-1, and p53. Loss of MLH-1 and MSH-2 was seen in 3 of 25 and 1 of 24 tumors, respectively; none showed loss of both. Diffuse p16 nuclear expression was found in 7 of 23 cases; diffuse and strong nuclear immunostaining for p53, cyclin D1, and Her-2 was seen in 9 of 24 neoplasms, 9 of 25, and 3 of 25 carcinomas, respectively. WT-1 was negative in all 25 tumors. One of the 3 grade 3 EECs with Her-2 overexpression showed gene amplification by fluorescence in situ hybridization analysis. No gene amplification for cyclin D1 was found. Follow-up information was available for all patients. Sixteen had stage I tumors. Of these patients, 11 were alive and well (AW), 3 died of disease (DOD), and 2 died of unrelated causes (DUC), with a mean follow-up time of 56 months (range, 24 to 96 mo); 2 of 3 patients with stage II tumors DOD, and 1 was AW with a mean follow-up time of 81 months (range, 6 to 66 mo

  8. Papillary syncytial metaplasia associated with endometrial breakdown exhibits an immunophenotype that overlaps with uterine serous carcinoma.

    PubMed

    McCluggage, W Glenn; McBride, Hilary A

    2012-05-01

    Uterine serous carcinoma (USC) is an aggressive variant of Type 2 endometrial carcinoma, which in most cases exhibits, at least focally, a papillary architecture. Occasionally, especially in small biopsy specimens, it may be difficult to distinguish between USC and a variety of metaplastic or reactive processes. In particular, papillary syncytial metaplasia (PSM), as a result of endometrial breakdown, may be confused with USC or its precursor serous endometrial intraepithelial carcinoma. In such cases, immunohistochemistry is often undertaken, the panel of markers usually including estrogen receptor (ER), p53, p16, and MIB1. The expected immunoprofile of USC is ER negative, p53 and p16 positive, and a high MIB1 proliferation index, although studies have shown that significant numbers of cases deviate from this immunophenotype. With regard to the aforementioned markers, PSM has not been studied extensively, but intuitively, the expected immunophenotype would be ER positive, p53 and p16 negative, and a low MIB1 proliferation index. After 2 index cases in which breaking down menstrual endometrium with florid PSM was misdiagnosed on an endometrial biopsy as USC or suspected USC, in part due to the observed immunophenotype, we studied the expression of ER, p53, p16, MIB1, and HMGA2 (a recently described useful marker of USC) in 10 further cases of PSM associated with endometrial breakdown. We illustrate that compared with a nonbreaking down endometrium, PSM is characterized by a decreased expression of ER and an increased expression of p53 (although still wild-type staining) and p16, the latter marker typically being diffusely positive. HMGA2 is negative, and there is a low MIB1 proliferation index. In cases of PSM, which are morphologically problematic, the immunophenotype may further heighten the suspicion of serous malignancy and potentially result in a misdiagnosis.

  9. Body mass index, conversion rate and complications among patients undergoing robotic surgery for endometrial carcinoma.

    PubMed

    Cunningham, Mary J; Dorzin, Esther; Nguyen, Loan; Anderson, Elizabeth; Bunn, W Douglas

    2015-12-01

    A retrospective cohort study was performed to evaluate the relationship of BMI to conversion rate in patients undergoing robotic surgery for endometrial cancer. Secondary outcomes were operative times, number of lymph nodes retrieved, and complications. Women with endometrial cancer scheduled for robotic surgery from September 2008 to September 2012 were included. Women were divided into three groups based on BMI, and conversion rates to laparotomy were compared. Descriptive and comparative analyses were performed among non-obese, obese, and morbidly obese women who completed robotic surgery. 298 women were scheduled for robotic surgery for endometrial carcinoma: 87 non-obese (BMI 19-29, μ 25.23), 110 obese (BMI 30-39, μ 34.21), and 101 morbidly obese (BMI 40-71, μ 47.38). Conversion to laparotomy occurred in 18 patients (6%), with no difference in conversion rate between BMI categories. Direct comparison between converted and completed robotic patients showed no significant differences in preoperative characteristics, except that patients who required conversion had a higher number of previous abdominal surgeries. Patients completing robotic surgery underwent node dissections at similar rates in all three BMI categories. Operating room time, but not surgical time, was increased in morbidly obese patients. There were no significant differences in complications, performance of lymphadenectomy, or lymph node yields between BMI categories. Increase in BMI was not associated with an increase in rate of conversion to laparotomy or complication rate in patients undergoing robotic surgery for endometrial carcinoma. Node dissections were pathologically equivalent between BMI categories.

  10. IMP3 expression in lesions of the biliary tract: a marker for high-grade dysplasia and an independent prognostic factor in bile duct carcinomas.

    PubMed

    Riener, Marc-Oliver; Fritzsche, Florian R; Clavien, Pierre-Alain; Pestalozzi, Bernhard C; Probst-Hensch, Nicole; Jochum, Wolfram; Kristiansen, Glen

    2009-10-01

    The oncofetal protein IMP3 (insulin-like growth factor II mRNA binding protein 3) is expressed during embryogenesis and carcinogenesis. Various tumor types have been analyzed for IMP3 expression, which was exclusively found in tumor cells and correlated with increased tumor aggressiveness and reduced overall survival. To our knowledge, IMP3 expression has not been investigated in bile duct carcinomas. Using large tissue sections from resection specimens of the extrahepatic biliary tract, we analyzed IMP3 in normal bile ducts (n = 36), bile ducts with acute inflammation and reactive epithelial changes (n = 26), low-grade dysplasia (n = 9), and high-grade dysplasia (n = 11). Furthermore, IMP3 expression was assessed in bile duct carcinoma (n = 115) using clinically well-characterized tissue microarrays. The findings were correlated with clinical-pathologic parameters including survival. High-grade dysplasia was strongly positive for IMP3 in all cases studied compared with no or weak expression in normal, inflamed, and low-grade dysplastic bile ducts. Of the bile duct carcinomas 58.3% (67/115) were strongly positive for IMP3, which was associated with a higher proliferation rate (P = .004) and p53 positivity (P = .022). Patients with strong IMP3 expression had significantly reduced overall survival (P = .037) similarly to the subgroup of pT3 carcinomas (P = .007). In multivariate analysis, IMP3 expression was an independent prognostic factor for overall survival (P = .040, RR = 1.809). This comprehensive study shows that IMP3 is an independent prognostic biomarker in bile duct carcinoma. In addition, it may be a marker for high-grade dysplasia in the extrahepatic biliary tract.

  11. Ovarian stromal tumor with minor sex cord elements with coexistent endometrial carcinoma.

    PubMed

    Kumar, Sunesh; Mathur, Sandeep; Subbaiah, Murali; Singh, Lavleen

    2013-01-01

    Ovarian stromal tumor with minor sex cord elements is a rare tumor. It is composed of predominantly fibrothecomatous tumor with scattered minor sex cord elements in less than 10% of the tumor area. These tumors may be hormonally active and predispose to carcinoma endometrium. A case of ovarian fibroma-thecoma with minor sex cord elements in which coexistent endometrial carcinoma was also discovered is being reported. Though thecoma may be a predisposing factor for endometrial cancer, meticulous histopathological examination of the ovary may reveal additional sources of estrogen like granulosa cell aggregates as in our patient. Such patients would require long-term follow-up to detect any recurrence of granulosa cell tumor.

  12. Evidence for a latent precursor (p53 signature) that may precede serous endometrial intraepithelial carcinoma.

    PubMed

    Jarboe, Elke A; Pizer, Ellen S; Miron, Alexander; Monte, Nick; Mutter, George L; Crum, Christopher P

    2009-03-01

    Both serous intraepithelial carcinoma and endometrial glandular dysplasia are associated with uterine serous carcinoma. Recently a candidate serous cancer precursor containing p53 mutations (p53 signature) was described in the fallopian tube. We analyzed normal and neoplastic endometrium for a similar entity. In total 10 endometrial polyps involved by intraepithelial and/or invasive carcinoma and 137 benign polyps were studied. All were stained for p53 and MIB-1. A subset of p53 signatures and carcinomas were analyzed for gamma-H2AX and p53 mutations. p53 signatures were identified in 7 of 10 cases intraepithelial carcinoma and were multicentric in 2. In one case, the signature was in continuity with intraepithelial carcinoma. Of 137 benign polyps (4%), 6 contained p53 signatures. The MIB-1 fraction in most signatures was less than 5%, and ranged from 50 to 90% in carcinomas. DNA damage (gamma-H2AX) was demonstrated in both p53 signatures and adjacent carcinomas but not in benign polyps. Shared identical p53 mutations were found in paired signatures and carcinomas in two of three cases analyzed, including one case with multiple signatures. In one, a coexistent invasive serous cancer was not found to contain a p53 mutation. In a third, a p53 signature and an invasive cancer harbored two different p53 mutations. This is the first description of p53 signatures adjacent to carcinoma, suggesting a role for this entity in the genesis of serous malignancy. The significance of p53 signatures in benign conditions (polyps) remains to be determined. The role of the p53 signature in early serous neoplasia is discussed.

  13. Marked heterogeneity of HER2/NEU gene amplification in endometrial serous carcinoma.

    PubMed

    Buza, Natalia; Hui, Pei

    2013-12-01

    Significant heterogeneity of HER2 protein expression has been recently observed in HER2 positive endometrial serous carcinomas. Tumor cells with HER2 overexpression and/or gene amplification in a heterogeneous tumor may represent a biologically more aggressive subclone that is clinically relevant to prognosis and potential targeted therapy. To correlate with HER2 protein heterogeneity, we investigated the heterogeneity of HER2/NEU gene amplification in endometrial serous carcinoma. A total of 17 endometrial serous carcinomas with heterogeneous HER2 protein expression were selected for the study, including nine cases with a 3+ and eight cases with a 2+ immunohistochemical score. Initial reflex HER2 FISH was available for seven of the eight 2+ cases, five of which showed HER2/NEU gene amplification. All 17 cases underwent repeat FISH targeting larger tumor tissue areas. Ten cases (72%) displayed striking heterogeneity of HER2/NEU gene copy number in the form of cluster amplification. Diffuse HER2 amplification was observed in four cases, no amplification was seen in three tumors. In cases with cluster amplification, HER2 protein overexpression by immunohistochemistry closely correlated at the cellular level with HER2/NEU gene amplification. In conclusion, the significant percentage of cases with heterogeneous HER2/NEU gene amplification indicates that the existing HER2 testing guidelines designed for breast cancer may not be applicable to endometrial serous carcinoma. Clinical testing on multiple different tumor samples or large tumor tissue sections is recommended for both immunohistochemistry and FISH assessment of HER2 status. Direct comparison with the HER2 immunostaining pattern may be helpful in detecting HER2 amplified areas in a heterogeneous tumor.

  14. Anal and perianal squamous carcinomas and high-grade intraepithelial lesions exclusively associated with "low-risk" HPV genotypes 6 and 11.

    PubMed

    Cornall, Alyssa M; Roberts, Jennifer M; Garland, Suzanne M; Hillman, Richard J; Grulich, Andrew E; Tabrizi, Sepehr N

    2013-11-01

    Anal squamous cell carcinomas are predominantly associated with high-risk human papillomaviruses (HPVs), particularly HPV 16, similar to cervical, vaginal and vulvar cancers. Although the presence of "low-risk" HPVs, in particular genotypes 6 and 11, have occasionally been reported in various HPV-related anogenital cancers, the overall distribution of these genotypes in the anal canal and perianal tissue may differ to that in the cervix. In addition, although the majority of anal and perianal cancers are associated with HPV, some are not; hence, confirmation of direct association of the virus within a lesion is important. Using laser capture microdissection, anal and perianal invasive carcinomas and high-grade squamous intraepithelial lesions (HSILs) in biopsies previously associated with HPV 6 or 11 alone were isolated from tissue sections and HPV genotype tested. Of seven cases tested, four invasive carcinomas were positive for HPV 6 only, one invasive carcinoma was negative for HPV and two HSILs were positive for HPV 11 only. All samples were confirmed as HPV 16/18 negative using two different DNA targets (E6 and L1). From these results, we confirm that HPV 6 and 11 can occasionally be associated with high-grade lesion and anal cancer.

  15. ERCC1 and XRCC1 but not XPA single nucleotide polymorphisms correlate with response to chemotherapy in endometrial carcinoma

    PubMed Central

    Chen, Liang; Liu, Mei-Mei; Liu, Hui; Lu, Dan; Zhao, Xiao-Dan; Yang, Xue-Jing

    2016-01-01

    Our study aimed to investigate the correlation between single nucleotide polymorphisms of ERCC1/XRCC1/XPA genes and postoperative chemotherapy efficacy and prognosis of endometrial carcinoma. Our study included 108 patients with endometrial carcinoma and 100 healthy participants. ERCC1 rs11615/XRCC1 rs25487/XPA rs1800975 gene polymorphisms were detected by polymerase chain reaction–restriction fragment length polymorphism. Then the chemotherapy efficacy and toxic effects of the patients were assessed. The genotype and allele frequency of ERCC1 rs11615/XRCC1 rs25487 in the case group were significantly different from that in the control group (all P<0.05). The patients with AA + GA in ERCC1 rs11615 had an increased risk of endometrial carcinoma than those with GG, and the risk of endometrial carcinoma for patients with AA + GA was also higher in comparison with patients with GG genotype in XRCC1 rs25487 (all P<0.05). GG on both ERCC1 rs11615/XRCC1 rs25487 had a higher effective rate of chemotherapy than GA + AA (all P<0.05). ERCC1 rs11615/XRCC1 rs25487 gene polymorphisms were linked with toxic effects in liver, kidney, and nervous system. ERCC1 rs11615/XRCC1 rs25487, muscular invasion, and tumor stage were independent risk factors for the prognosis of endometrial carcinoma (all P<0.05). However, no significant associations were observed between XPA rs1800975 polymorphism and chemotherapy efficacy and prognosis of endometrial carcinoma (all P>0.05). These results indicated that ERCC1 and XRCC1 but not XPA polymorphisms correlate with response to chemotherapy in endometrial carcinoma. PMID:27895494

  16. Recent advances in the understanding of the pathogenesis of serous carcinoma: the concept of low- and high-grade disease and the role of the fallopian tube

    PubMed Central

    Carlson, Joseph; Roh, Michael H.; Chang, Martin C.; Crum, Christopher P.

    2008-01-01

    Summary In the past 50 years, the concept of serous ovarian cancer has been progressively refined, with the distinction of the borderline serous tumour, identification of a smaller subset of well-differentiated serous malignancies and, recently, closer attention to the pathogenesis of high-grade serous malignancies. High-grade serous carcinoma, traditionally presumed to arise within Müllerian inclusion cysts of the ovarian surface, cortex and peritoneum, has recently been linked to the distal fallopian tube. This review addresses the disparate forms of serous neoplasia, which reflect both different genetic abnormalities and stages of differentiation of Müllerian epithelium. The significance of these different origins is addressed in the context of ovarian cancer prevention. PMID:20953242

  17. Analysis of DNA Copy Number Alterations in Ovarian Serous Tumors Identifies New Molecular Genetic Changes in Low-grade and High-grade Carcinomas

    PubMed Central

    Kuo, Kuan-Ting; Guan, Bin; Feng, Yuanjian; Mao, Tsui-Lien; Chen, Xu; Jinawath, Natini; Wang, Yue; Kurman, Robert J.; Shih, Ie-Ming; Wang, Tian-Li

    2009-01-01

    Ovarian serous carcinoma, the most common and lethal type of ovarian cancer, was thought to develop from two distinct molecular pathways. High-grade (HG) serous carcinomas contain frequent TP53 mutations while low-grade (LG) carcinomas arise from serous borderline tumors (SBT) and harbor mutations in KRAS/BRAF/ERBB2 pathway. However, the molecular alterations involved in the progression from SBT to LG carcinoma remain largely unknown. As well, the extent of deletion of tumor suppressors in ovarian serous carcinomas has not been well-studied. To further address these two issues, we assessed DNA copy number changes among affinity-purified tumor cells from 37 ovarian serous neoplasms including SBT, LG and HG tumors using high density 250K SNP arrays. Chromosomal instability index as measured by changes in DNA copy number was significantly higher in HG than in LG serous carcinomas. Hemizygous ch1p36 deletion was common in LG serous carcinomas but was rarely seen in SBT. This region contains several candidate tumor suppressors including miR-34a. In contrast, in HG serous carcinomas, significant numbers of amplifications and deletions including homozygous deletions were identified. Among homozygous deletions, loci containing Rb1, CDKN2A/B, CSMD1, and DOCK4 were most common, being present in 10.6%, 6.4%, 6.4% and 4.3%, respectively, in independent 47 affinity-purified HG serous carcinomas. Except the CDKN2A/B region, these homozygous deletions were not present in either SBT or LG tumors. Our study provides a genome-wide homozygous deletion profiles in HG serous carcinomas, serving as a molecular foundation to study tumor suppressors in ovarian cancer. PMID:19383911

  18. Chromatin remodelling and DNA repair genes are frequently mutated in endometrioid endometrial carcinoma.

    PubMed

    García-Sanz, Pablo; Triviño, Juan Carlos; Mota, Alba; Pérez López, María; Colás, Eva; Rojo-Sebastián, Alejandro; García, Ángel; Gatius, Sonia; Ruiz, María; Prat, Jaime; López-López, Rafael; Abal, Miguel; Gil-Moreno, Antonio; Reventós, Jaume; Matias-Guiu, Xavier; Moreno-Bueno, Gema

    2017-04-01

    In developed countries, endometrial carcinoma is the most common cancer that affects the female genital tract. Endometrial carcinoma is divided into two main histological types, type I or endometrioid and type II or non-endometrioid, each of which have characteristic, although not exclusive, molecular alterations and mutational profiles. Nevertheless, information about the implication and relevance of some of these genes in this disease is lacking. We sought here to identify new recurrently mutated genes in endometrioid cancers that play a role in tumourigenesis and that influence the clinical outcome. We focused on low-grade, non-ultramutated tumours as these tumours have a worse prognosis than the ultramutated POLE-positive endometrioid endometrial carcinomas (EECs). We performed exome-sequencing of 11 EECs with matched normal tissue and subsequently validated 15 candidate genes in 76 samples. For the first time, we show that mutations in chromatin remodelling-related genes (KMT2D, KMT2C, SETD1B and BCOR) and in DNA-repair-related genes (BRCA1, BRCA2, RAD50 and CHD4) are frequent in this subtype of endometrial cancer. The alterations to these genes occurred with frequencies ranging from 35.5% for KMT2D to 10.5% for BRCA1 and BCOR, with some showing a tendency toward co-occurrence (RAD50-KMT2D and RAD50-SETD1B). All these genes harboured specific mutational hotspots. In addition, the mutational status of KMT2C, KMT2D and SETD1B helps to predict the degree of myometrial invasion, a critical prognostic feature. These results highlight the possible implication of these genes in this disease, creating opportunities for new therapeutic approaches.

  19. Tumor progression, metastasis, and modulators of epithelial-mesenchymal transition in endometrioid endometrial carcinoma: an update.

    PubMed

    Makker, Annu; Goel, Madhu Mati

    2016-02-01

    Endometrioid endometrial carcinoma (EEC), also known as type 1 endometrial cancer (EC), accounts for over 70-80% of all cases that are usually associated with estrogen stimulation and often develops in a background of atypical endometrial hyperplasia. The increased incidence of EC is mainly confined to this type of cancer. Most EEC patients present at an early stage and generally have a favorable prognosis; however, up to 30% of EEC present as high risk tumors, which have invaded deep into the myometrium at diagnosis and progressively lead to local or extra pelvic metastasis. The poor survival of advanced EC is related to the lack of effective therapies, which can be attributed to poor understanding of the molecular mechanisms underlying the progression of disease toward invasion and metastasis. Multiple lines of evidence illustrate that epithelial-mesenchymal transition (EMT)-like events are central to tumor progression and malignant transformation, endowing the incipient cancer cell with invasive and metastatic properties. The aim of this review is to summarize the current knowledge on molecular events associated with EMT in progression, invasion, and metastasis of EEC. Further, the role of epigenetic modifications and microRNA regulation, tumor microenvironment, and microcystic elongated and fragmented glands like invasion pattern have been discussed. We believe this article may perhaps stimulate further research in this field that may aid in identifying high risk patients within this clinically challenging patient group and also lead to the recognition of novel targets for the prevention of metastasis - the most fatal consequence of endometrial carcinogenesis.

  20. Incidence of positive peritoneal cytology in patients with endometrial carcinoma after hysteroscopy vs. dilatation and curettage

    PubMed Central

    Crnobrnja, Bojana; Zegura, Branka; Takac, Iztok; Pakiz, Maja

    2017-01-01

    Abstract Background The aim of the study was to compare the frequency of positive peritoneal washings in endometrial cancer patients after either hysteroscopy (HSC) or dilatation and curettage (D&C). Patients and methods We performed a retrospective analysis of 227 patients who underwent either HSC (N = 144) or D&C (N = 83) and were diagnosed with endometrial carcinoma at the University Medical Centre Maribor between January 2008 and December 2014. The incidence of positive peritoneal cytology was evaluated in each group. Results There was no overall difference in the incidence of positive peritoneal washings after HSC or D&C (HSC = 13.2%; D&C = 12.0%; p = 0.803). However, a detailed analysis of stage I disease revealed significantly higher rates of positive peritoneal washings in the HSC group (HSC = 12.8%; D&C = 3.4%; p = 0.046). Among these patients, there was no difference between both groups considering histologic type (chi-square = 0.059; p = 0.807), tumour differentiation (chi-square = 3.709; p = 0.156), the time between diagnosis and operation (t = 0.930; p = 0.357), and myometrial invasion (chi-square = 5.073; p = 0.079). Conclusions Although the diagnostic procedure did not influence the overall incidence of positive peritoneal washings, HSC was associated with a significantly higher rate of positive peritoneal cytology in stage I endometrial carcinoma compared to D&C. PMID:28265237

  1. Establishment and characterization of a human uterine endometrial undifferentiated carcinoma cell line, TMG-L.

    PubMed

    Hasegawa, Kiyoshi; Suzuki, Machiko; Ishikawa, Kunimi; Yasue, Akira; Kato, Rina; Nakamura, Azumi; Kuroki, Jun; Udagawa, Yasuhiro

    2003-03-01

    A new cell line of human uterine endometrial undifferentiated carcinoma, designated as TMG-L, was established from the metastatic lymph node of 56-year-old patient TMG-L cells have been cultured with Ham's F-12 medium supplemented with 10% FCS and grew as a loosely adherent monolayer with polygonal or spindle-shaped cells exhibiting poor cell-cell contact and piled up against each other, showing a tendency to grow as floating cells. The doubling time of this cell line was about 48 hours, and chromosomal analysis revealed aneuploidy at passage 25. The cells formed tumors in SCID mouse, the histology of which was similar to that of undifferentiated carcinoma component of primary tumor. TMG-L cells showed the loss of expression and membranous localization of either E-cadherin or alpha-catenin, implied corresponding loss of their adhesive function. And this dysfunction implicated the biological aggressive behavior of uterine endometrial undifferentiated carcinoma. This cell line appears to provide a useful system for studying uterine undifferentiated carcinoma in vivo and in vitro.

  2. Clinical outcomes of stage I endometrial carcinoma patients treated with surgery alone: Siriraj Hospital experiences

    PubMed Central

    2016-01-01

    Objective To evaluate the recurrence rates and patterns of failure in patients with stage I endometrial carcinoma after surgical staging without adjuvant therapy. Methods Medical records of 229 patients with stage I endometrial carcinoma, treated with surgery alone between 2002 and 2010 at Siriraj Hospital were retrospectively reviewed. The primary objective of this study was recurrence rates. The secondary objectives were patterns of failure, disease-free survival, overall survival, and prognostic factors related to outcomes. Results During median follow-up time of 53.3 months, 11 recurrences (4.8%) occurred with a median time to recurrence of 21.2 months (range, 7.7 to 77.8 months). Vaginal recurrence was the most common pattern of failure (8/11 patients, 72.7%). Other recurrences were pelvic, abdominal and multiple metastases. Factors that appeared to be prognostic factors on univariate analyses were age and having high intermediate risk (HIR) (Gynecologic Oncology Group [GOG] 99 criteria), none of which showed significance in multivariate analysis. The recurrence rates were higher in the patients with HIR criteria (22.2% vs. 4.1%, p=0.013) or patients with stage IB, grade 2 endometrioid carcinoma (9.4% vs. 4.3%, p=0.199). Five-year disease-free survival and 5-year overall survival were 93.9% (95% CI, 89.9 to 5.86) and 99.5% (95% CI, 97.0 to 99.9), respectively. Conclusion The patients with low risk stage I endometrial carcinoma had excellent outcomes with surgery alone. Our study showed that no single factor was demonstrated to be an independent predictor for recurrence. PMID:27329196

  3. Targeted therapy in uterine serous carcinoma: an aggressive variant of endometrial cancer.

    PubMed

    Black, Jonathan D; English, Diana P; Roque, Dana M; Santin, Alessandro D

    2014-01-01

    Uterine serous carcinoma (USC) is a highly aggressive variant of endometrial cancer. Although it only represents less than 10% of all cases, it accounts for a disproportionate number of deaths from endometrial cancer. Comprehensive surgical staging followed by carboplatin and paclitaxel chemotherapy represents the mainstay of USC therapy. Vaginal cuff brachytherapy is also of potential benefit in USC. Recent whole-exome sequencing studies have demonstrated gain of function of the HER2/NEU gene, as well as driver mutations in the PIK3CA/AKT/mTOR and cyclin E/FBXW7 oncogenic pathways in a large number of USCs. These results emphasize the relevance of these novel therapeutic targets for biologic therapy of chemotherapy-resistant recurrent USC.

  4. Development of targeted therapy in uterine serous carcinoma, a biologically aggressive variant of endometrial cancer.

    PubMed

    El-Sahwi, Karim S; Schwartz, Peter E; Santin, Alessandro D

    2012-01-01

    Endometrial cancer (EC) is the most common female genital malignancy in the USA. Most carcinomas arising from the uterus are estrogen dependent and are associated with obesity and hypertension. They are designated type I ECs and typically, due to their early diagnosis secondary to postmenopausal bleeding, have a good prognosis. By contrast, type II ECs develop in older patients, are not hormone dependent and are responsible for most recurrences and deaths from EC. Uterine serous cancer constitutes up to 10% of all endometrial tumors, and represents the most biologically aggressive variant of type II EC. This article will describe the most salient molecular markers that have been identified in uterine serous cancer, thus far with emphasis on the use of erbB2 (HER2/neu) as the first of a series of therapeutic markers for the treatment of this highly-aggressive subset of ECs.

  5. Triple Synchronous Malignancies in Genital Tract; Primary Endometrial, Ovarian and Fallopian Tube Carcinoma: A Case Report

    PubMed Central

    Alkilic, Aysegul; Turgay, Batuhan; Gemici, Ali; Atabekoglu, Cem Somer

    2017-01-01

    Synchronous malignancies, including three or more tumours, are extremely rare. Herein, we present a case of a woman with a concurrent simultaneous endometrial, ovarian and fallopian tubal carcinoma with different histopathological characteristics. A 55-year-old postmenopausal woman with a diagnosis of endometrial adenocarcinoma by pipelle biopsy, underwent surgical staging. Final pathology result was reported as synchronous stage IA grade 2 endometrioid adenocarcinoma of the uterus, stage IA grade 2 mucinous adenocarcinoma of the right ovary and in situ serous cystadenocarcinoma of the right fallopian tube. In the postoperative period, patient followed without adjuvant therapy. To our knowledge, this a very rare case report in the literature of sychronous triple gynaecologic cancers including fallopian tube cancer and with the longest disease free survival time with over 39 months due to better prognosis than metastatic or advanced primitive diseases. PMID:28274004

  6. Endoglin, VEGF, and its receptors in predicting metastases in endometrial carcinoma.

    PubMed

    Saarelainen, Sami K; Staff, Synnöve; Peltonen, Nina; Lehtimäki, Terho; Isola, Jorma; Kujala, Paula M; Vuento, Maarit H; Mäenpää, Johanna U

    2014-05-01

    Preoperative evaluation of the risk for metastases in endometrial carcinoma is challenging. The growth of new vessels, angiogenesis, is important for tumor growth and purported to be involved in the metastatic process. The aim of this study was to evaluate the significance of preoperative serum levels and immunohistochemical expression of angiogenic markers in predicting a metastasized disease. Preoperative sera from 98 consecutive women presenting with endometrial carcinoma were collected. Serum concentrations of VEGF, sFLT1, and CD105 were assessed by enzyme-linked immunosorbent assay (ELISA). Immunohistochemistry was used to assess the expression of CD105, VEGF, FLT1, and KDR. The results were correlated to the presence of metastases, presence of deep (≥50%) myometrial invasion, and the histological grade of the tumor. Tumors with other than endometrioid histology were excluded. Of the 80 evaluable patients, 11 had a metastasized disease. The serum concentration of VEGF was higher in the group with metastases than in the group without metastases (median [range], 743 pg/mL [546-1,183 pg/mL] vs. 383 pg/mL [31-1,524 pg/mL], p < 0.001, respectively). In the multivariable analysis, the concentration of VEGF was the sole independent, albeit weak predictive factor for the presence of metastases (odds ratio, 1.004, 95% confidence interval, 1.002-1.007; p = 0.001). The immunohistochemical expression of the markers was not associated with any of the clinicopathological features of the tumors. The results of the present study suggest that preoperative serum VEGF concentration correlates with the presence of metastases in endometrioid endometrial carcinoma.

  7. Validation of endogenous control reference genes for normalizing gene expression studies in endometrial carcinoma.

    PubMed

    Ayakannu, Thangesweran; Taylor, Anthony H; Willets, Jonathon M; Brown, Laurence; Lambert, David G; McDonald, John; Davies, Quentin; Moss, Esther L; Konje, Justin C

    2015-09-01

    Real-time quantitative RT-PCR (qRT-PCR) is a powerful technique used for the relative quantification of target genes, using reference (housekeeping) genes for normalization to ensure the generation of accurate and robust data. A systematic examination of the suitability of endogenous reference genes for gene expression studies in endometrial cancer tissues is absent. The aims of this study were therefore to identify and evaluate from the thirty-two possible reference genes from a TaqMan(®) array panel their suitability as an internal control gene. The mathematical software packages geNorm qBasePLUS identified Pumilio homolog 1 (Drosophila) (PUM1), ubiquitin C (UBC), phosphoglycerate kinase (PGK1), mitochondrial ribosomal protein L19 (MRPL19) and peptidylpropyl isomerase A (cyclophilin A) (PPIA) as the best reference gene combination, whilst NormFinder identified MRPL19 as the best single reference gene, with importin 8 (IPO8) and PPIA being the best combination of two reference genes. BestKeeper ranked MRPL19 as the most stably expressed gene. In addition, the study was validated by examining the relative expression of a test gene, which encodes the cannabinoid receptor 1 (CB1). A significant difference in CB1 mRNA expression between malignant and normal endometrium using MRPL19, PPIA, and IP08 in combination was observed. The use of MRPL19, IPO8 and PPIA was identified as the best reference gene combination for the normalization of gene expression levels in endometrial carcinoma. This study demonstrates that the arbitrary selection of endogenous control reference genes for normalization in qRT-PCR studies of endometrial carcinoma, without validation, risks the production of inaccurate data and should therefore be discouraged.

  8. Folate receptor α expression and significance in endometrioid endometrium carcinoma and endometrial hyperplasia.

    PubMed

    Senol, Serkan; Ceyran, Ayse Bahar; Aydin, Abdullah; Zemheri, Ebru; Ozkanli, Seyma; Kösemetin, Duygu; Sehitoglu, Ibrahim; Akalin, Ibrahim

    2015-01-01

    Endometrioid-type endometrial carcinoma (EEC) developing on the ground of endometrial hyperplasia (EH) is amongst the most commonly observed type of cancer in the world. Folate receptor α (FRα) is a vitamin molecule that has a role in cell proliferation. The fact that FRα, which is known to be needed extremely by the cells of malignancies that proliferate rapidly, is present in limited amounts in normal tissues while it is overexpressed in malignant cells of the same tissues makes folate a candidate for target molecular therapy. In our study, FRα expression in 214 cases, with 95 diagnosed within EEC and 119 with EH, was studied immunohistochemically. FRα expression in EEC was found significantly high compared to EH and normal endometrium (P<0.01). Similarly, FRα expression in EH cases with complex atypia were significantly high compared to other hyperplasia subgroups (P<0.01). The findings of our results make us think that FRα overexpression may play a role in the EEC carcinogenesis and carcinoma progression from EH. Furthermore, we suggest that it can be helpful in the treatment of EEC and/or transition from hyperplasia stage to EEC as a molecular therapy targeting receptors labeled with antibody-based props containing FRα. Finally, we suggest that FRα may be used, based on the expression intensity, as a supplemental option to determine the patients that shall be directed to radical therapy amongst patients with complex atypical EH.

  9. Treatment results in women with clinical stage I and pathologic stage II endometrial carcinoma.

    PubMed

    Jobsen, J J; Schutter, E M; Meerwaldt, J H; Van Der Palen, J; Van Der Sijde, R; Ten Cate, L N

    2001-01-01

    The aim of this study is to report survival and results of therapy and possible prognostic factors in women with pathologic stage II endometrial carcinoma. Forty-two patients with pathologic stage II endometrial carcinoma were treated at the department of Radiation Oncology of the Medisch Spectrum Twente between 1987 and 1998. All patients received external radiotherapy following standard surgical procedures and no adjuvant systemic therapy was given. From the 42 patients 21 had a pathologic stage IIA and 21 stage IIB. The median follow-up was 62 months. The overall recurrence rate was 21.5% (9/42). Seven patients had distant metastasis, of which three also had locoregional recurrence, vaginal vault and/or pelvic. The presence of myometrial invasion (> (1/2)) and/or lymph-angioinvasion showed a significant relation with distant metastasis (P = 0.017). Stage IIB showed more recurrences, 33% (7/21). There was a significant different 5-year disease specific survival for stage IIA and IIB, respectively, 95% and 74% (P = 0.0311). Patients with a differentiation grade 3 and stage IIB showed a significantly poorer (P = 0.003) 5-year survival of 48.6% (P = 0.003). Results obtained in the present series of patients are in accordance with the literature. The present treatment policy seems justified, except for patients with pathologic stage IIB and grade 3, in which a more aggressive treatment should be considered.

  10. Predictive and prognostic factors in definition of risk groups in endometrial carcinoma.

    PubMed

    Sorbe, Bengt

    2012-01-01

    Background. The aim was to evaluate predictive and prognostic factors in a large consecutive series of endometrial carcinomas and to discuss pre- and postoperative risk groups based on these factors. Material and Methods. In a consecutive series of 4,543 endometrial carcinomas predictive and prognostic factors were analyzed with regard to recurrence rate and survival. The patients were treated with primary surgery and adjuvant radiotherapy. Two preoperative and three postoperative risk groups were defined. DNA ploidy was included in the definitions. Eight predictive or prognostic factors were used in multivariate analyses. Results. The overall recurrence rate of the complete series was 11.4%. Median time to relapse was 19.7 months. In a multivariate logistic regression analysis, FIGO grade, myometrial infiltration, and DNA ploidy were independent and statistically predictive factors with regard to recurrence rate. The 5-year overall survival rate was 73%. Tumor stage was the single most important factor with FIGO grade on the second place. DNA ploidy was also a significant prognostic factor. In the preoperative risk group definitions three factors were used: histology, FIGO grade, and DNA ploidy. Conclusions. DNA ploidy was an important and significant predictive and prognostic factor and should be used both in preoperative and postoperative risk group definitions.

  11. Amplification of the bromodomain-containing protein 4 gene in ovarian high-grade serous carcinoma is associated with worse prognosis and survival

    PubMed Central

    UCAR, DUYGU; LIN, DOUGLAS I.

    2015-01-01

    High-grade serous carcinoma (HGSC) of the ovary is an aggressive and devastating neoplasm and the identification of novel therapeutic targets may result in a significant decrease in patient morbidity and mortality. Over the last few years, chromatin regulators have become attractive targets for cancer therapy. More specifically, bromodomain-containing protein 4 (BRD4), a protein that is associated with acetylated chromatin and transcriptional activation, has been shown to selectively regulate the transcription of key oncogenic drivers, such as CMYC, in several tumor types. The Cancer Genome Atlas (TCGA) Project has molecularly characterized the genome of ovarian serous carcinomas, which enabled us to study the association of genomic alterations of BRD4 with patient survival and clinicopathological characteristics. Our analysis using clinical and genomic data from the TCGA ovarian carcinoma samples revealed that somatic amplification of BRD4 (observed in 12% of the cases) was correlated with increased BRD4 mRNA levels and is significantly associated with worse overall and progression-free survival compared to wild-type cases. These findings support the hypothesis that future studies and trials investigating newly developed BRD4 inhibitors are required in a subset of patients with ovarian HGSC. PMID:26807235

  12. Loss of Sprouty2 in human high-grade serous ovarian carcinomas promotes EGF-induced E-cadherin down-regulation and cell invasion.

    PubMed

    So, Wai-Kin; Cheng, Jung-Chien; Fan, Qianlan; Wong, Alice S T; Huntsman, David G; Gilks, C Blake; Leung, Peter C K

    2015-01-30

    Sprouty (SPRY) proteins are well-characterized factors that inhibit receptor tyrosine kinase signaling. Our Human Exonic Evidence-Based Oligonucleotide (HEEBO) microarray results showed that the mRNA levels of SPRY2, but not of SPRY1 or SPRY4, are down-regulated in high-grade serous ovarian carcinoma (HGSC) tissues and epithelial ovarian cancer (EOC) cell lines. Molecular inversion probe (MIP) copy number analysis showed the deletion of the SPRY2 locus in HGSC. Overexpression of SPRY2 reduced EGF-induced cell invasion by attenuating EGF-induced E-cadherin down-regulation. Moreover, a positive correlation between SPRY2 and E-cadherin protein levels was observed in HGSC tissues. This study reveals the loss of SPRY2 in HGSC and indicates an important tumor-suppressive role for SPRY2 in mediating the stimulatory effect of EGF on human EOC progression.

  13. Matricellular protein CCN1 (CYR61) expression is associated with high-grade ductal carcinoma in situ.

    PubMed

    Saglam, Ozlen; Dai, Feng; Husain, Seema; Zhan, Yilei; Toruner, Gokce; Haines, G Kenneth

    2014-06-01

    Cysteine-rich protein 61, connective tissue growth factor, and nephroblastoma overexpressed gene (CCN) comprise a family of matricellular proteins that have multiple physiologic functions including development, tissue repair, cell adhesion, migration, and proliferation. The expression of CCN1, cyclin D1, β-catenin, and p53 was explored by immunohistochemistry in different grades of ductal carcinoma in situ (DCIS) cases. These cases did not contain any infiltrating carcinoma components. In addition, all cysteine-rich protein 61 gene exons (encoding the CCN1 protein) were sequenced in 30 samples. Allred and H-scores were calculated for expression in both DCIS and the surrounding benign breast tissue. All cases of DCIS showed degrees of cytoplasmic CCN1 staining with median H-scores of 170, 160, and 60 in grades 3, 2, and 1, respectively (P = .043). Twelve of 28 DCIS 3, 1 of 15 DCIS 2, and 0 of 18 DCIS 1 also showed nuclear staining for CCN1. The cytoplasmic staining difference was preserved when the cases were divided into estrogen receptor (ER)+/DCIS grade 1, ER+/DCIS 2 and 3, and ER-/DCIS 2 and 3 by the H-score (P = .037). Cyclin D1 expression was positively correlated with the CCN1 cytoplasmic H-score in all DCIS samples (P = .038). Membranous β-catenin expression correlated with the grade of intraepithelial carcinoma by both H-score (P = .047) and Allred score (P = .026). Our results suggest that CCN1 has a role in the development of intraepithelial carcinoma. CCN1 expression correlates with grade of DCIS independent of ER status. It can induce cell cycle progression through cyclin D1. It is warranted to study high expression of CCN1 in DCIS as an independent risk factor in a larger cohort.

  14. Accumulated metabolites of hydroxybutyric acid serve as diagnostic and prognostic biomarkers of ovarian high-grade serous carcinomas

    PubMed Central

    Hilvo, Mika; de Santiago, Ines; Gopalacharyulu, Peddinti; Schmitt, Wolfgang D.; Budczies, Jan; Kuhberg, Marc; Dietel, Manfred; Aittokallio, Tero; Markowetz, Florian; Denkert, Carsten; Sehouli, Jalid; Frezza, Christian

    2016-01-01

    Ovarian cancer is a heterogeneous disease of low prevalence, but poor survival. Early diagnosis is critical for survival, but is often challenging because the symptoms of ovarian cancer are subtle and become apparent only during advanced stages of the disease. Therefore, the identification of robust biomarkers of early disease is a clinical priority. Metabolomic profiling is an emerging diagnostic tool enabling the detection of biomarkers reflecting alterations in tumor metabolism, a hallmark of cancer. In this study, we performed metabolomic profiling of serum and tumor tissue from 158 patients with high-grade serous ovarian cancer (HGSOC) and 100 control patients with benign or non-neoplastic lesions. We report metabolites of hydroxybutyric acid (HBA) as novel diagnostic and prognostic biomarkers associated with tumor burden and patient survival. The accumulation of HBA metabolites caused by HGSOC was also associated with reduced expression of succinic semialdehyde dehydrogenase (encoded by ALDH5A1), and with the presence of an epithelial-to-mesenchymal transition (EMT) gene signature, implying a role for these metabolic alterations in cancer cell migration and invasion. In conclusion, our findings represent the first comprehensive metabolomics analysis in HGSOC and propose a new set of metabolites as biomarkers of disease with diagnostic and prognostic capabilities. PMID:26685161

  15. Reversing Platinum Resistance in High-Grade Serous Ovarian Carcinoma: Targeting BRCA and the Homologous Recombination System.

    PubMed

    Wiedemeyer, W Ruprecht; Beach, Jessica A; Karlan, Beth Y

    2014-01-01

    Resistance to platinum chemotherapy is one of the main factors driving ovarian cancer mortality, and overcoming platinum resistance is considered one of the greatest challenges in ovarian cancer research. Genetic and functional evidence points to the homologous recombination (HR) DNA repair system, and BRCA1 and BRCA2 in particular, as main determinants of response to platinum therapy. BRCA-mutant ovarian cancers are especially sensitive to platinum, associated with better survival, and amenable to poly ADP ribose polymerase inhibitor treatment. Here, we discuss a therapeutic concept that seeks to disrupt HR capacity via targeting of BRCA1 and BRCA2 functionality in order to reverse platinum resistance in BRCA-proficient high-grade serous ovarian cancers (HGSOC). We review the molecular signaling pathways that converge on BRCA1 and BRCA2, their activation status in ovarian cancer, and therapeutic options to modulate BRCA function. Several recent publications demonstrate efficient chemosensitization of BRCA-proficient cancers by combining targeted therapy with standard platinum-based agents. Due to its inherent genomic heterogeneity, molecularly defined subgroups of HGSOC may require different approaches. We seek to provide an overview of available agents and their potential use to reverse platinum resistance by inhibiting the HR system, either directly or indirectly, by targeting oncogenic activators of HR.

  16. Intraperitoneal Paclitaxel, Doxorubicin Hydrochloride, and Cisplatin in Treating Patients With Stage III-IV Endometrial Cancer

    ClinicalTrials.gov

    2016-10-26

    Endometrial Adenosquamous Carcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Mixed Adenocarcinoma; Endometrial Serous Adenocarcinoma; Endometrial Squamous Cell Carcinoma; Endometrial Undifferentiated Carcinoma; Recurrent Uterine Corpus Carcinoma; Stage IIIA Uterine Corpus Cancer; Stage IIIC Uterine Corpus Cancer; Stage IVA Uterine Corpus Cancer; Stage IVB Uterine Corpus Cancer

  17. Trop-2 protein overexpression is an independent marker for predicting disease recurrence in endometrioid endometrial carcinoma

    PubMed Central

    2012-01-01

    Background Endometrial cancer is the most common gynecologic malignancy in developed countries. Trop-2 is a glycoprotein involved in cellular signal transduction and is differentially overexpressed relative to normal tissue in a variety of human adenocarcinomas, including endometrioid endometrial carcinomas (EEC). Trop-2 overexpression has been proposed as a marker for biologically aggressive tumor phenotypes. Methods Trop-2 protein expression was quantified using tissue microarrays consisting of formalin-fixed paraffin-embedded specimens from 118 patients who underwent surgical staging from 2001–9 by laparotomy for EEC. Clinicopathologic characteristics including age, stage, grade, lymphovascular space invasion, and medical comorbidities were correlated with immunostaining score. Univariate and multivariate analyses were performed for overall survival, disease-free survival, and progression-free survival in relation to clinical parameters and Trop-2 protein expression. Results Clinical outcome data were available for 103 patients. Strong Trop-2 immunostaining was significantly associated with higher tumor grade (p=0.02) and cervical involvement (p<0.01). Univariate analyses showed a significant association with reduced disease-free survival (DFS) (p=0.01), and a trend towards significance for overall and progression-free survival (p=0.06 and p=0.05, respectively). Multivariate analyses revealed Trop-2 overexpression and advanced FIGO stage to be independent prognostic factors for poor DFS (p=0.04 and p <0.001, respectively). Conclusions Trop-2 protein overexpression is significantly associated with higher tumor grade and serves as an independent prognostic factor for DFS in endometrioid endometrial cancer. PMID:23151048

  18. The Fallopian Tube Origin and Primary Site Assignment in Extrauterine High-grade Serous Carcinoma: Findings of a Survey of Pathologists and Clinicians.

    PubMed

    McCluggage, W Glenn; Hirschowitz, Lynn; Gilks, C Blake; Wilkinson, Nafisa; Singh, Naveena

    2016-10-31

    Accumulating recent evidence suggests that the majority of extrauterine high-grade serous carcinomas (HGSCs) do not arise from the ovary as historically accepted but from the distal, fimbrial end of the fallopian tube from a precursor known as serous tubal intraepithelial carcinoma. There has been variable acceptance of this evidence among pathologists and clinicians dealing with "ovarian" cancer and this has resulted in wide variation in the assignment of primary site between different institutions when HGSC involves >1 anatomic site. This has obvious implications for cancer epidemiology, registration, and entry into clinical trials. We undertook a survey of members of several national and international gynecologic pathology and clinical cancer societies with a view to ascertaining the degree of acceptance of the fallopian tube origin of extrauterine HGSC and to explore various aspects regarding site assignment, pathologic sampling, diagnosis, FIGO staging, and reporting of these neoplasms. The results indicate wide acceptance among both pathologists and clinicians of the fallopian tube theory of origin of HGSC (86% pathologists, 92% clinicians), although there is significant variation regarding the perceived importance of assigning a primary site given the limited prognostic and therapeutic significance. Interestingly, clinicians feel it is more important to assign a primary site than pathologists (71% vs. 49%). The survey also indicates widespread acceptance of recently proposed criteria for site assignment in extrauterine HGSC.

  19. Prognostic significance of differential expression of angiogenic genes in women with high-grade serous ovarian carcinoma

    PubMed Central

    Siamakpour-Reihani, Sharareh; Owzar, Kouros; Jiang, Chen; Turner, Taylor; Deng, Yiwen; Bean, Sarah M.; Horton, Janet K.; Berchuck, Andrew; Marks, Jeffrey R.; Dewhirst, Mark W.; Secord, Angeles Alvarez

    2015-01-01

    Objectives To identify angiogenic biomarkers associated with tumor angiogenesis and clinical outcome in high-grade serous ovarian cancer (HGSC). Methods 51 HGSC samples were analyzed using Affymetrix HG-U133A microarray. Microvessel density (MVD) counts were determined using CD31and CD105. Association between mRNA expression levels and overall survival were assessed using rank score statistic. Effect size was estimated as a hazard ratio (HR) under a proportional hazards model. The Storey q-value method was used to account for multiple testing within the false-discovery rate (FDR) framework. Publicly available databases including TCGA and GSE were used for external confirmation. Results Thirty-one angiogenic-related genes were significantly associated with survival (q ≤ 0.05). Of these 31 genes, 4 were also associated with outcome in the TCGA data: AKT1 (q=0.02; TCGA p= 0.01, HR=0.8), CD44 (q= 0.003; TCGA p=0.05, HR=0.9), EPHB2 (q= 0.01; TCGA p=0.05, HR=1.2), and ERBB2 (q= 0.02; TCGA p= 0.05, HR=1.2). While 5 were associated with outcome in the GSE database: FLT1 (q= 0.03; GSE26712 p=0.01, HR=3.1); PF4 (q= 0.02; GSE26712 p=0.01, HR=3.0), NRP1 (q= 0.02; GSE26712 p < 0.04, HR>1.4), COL4A3 (q= 0.04; GSE26712 p= 0.03, HR=1.3), ANGPTL3 (q= 0.02; GSE14764 p=0.02, HR=1.5). High AKT1 and CD44 were associated with longer survival. In contrast, high expression of EPHB2, ERBB2, FLT1; PF4, NRP1, COL4A3, and ANGPTL3 were associated with shorter survival. CD105-MVD and CD31-MVD were not significantly associated with angiogenic gene expression. Conclusions Thirty-one angiogenic-related genes were associated with survival in advanced HGSC and nine of these genes were confirmed in independent publicly available databases. PMID:26260910

  20. Utility of α-methylacyl-coenzyme-A racemase (p504s) immunohistochemistry in distinguishing endometrial clear cell carcinomas from serous and endometrioid carcinomas.

    PubMed

    Fadare, Oluwole; Parkash, Vinita; Gwin, Katja; Hanley, Krisztina Z; Jarboe, Elke A; Liang, Sharon X; Quick, Charles M; Zheng, Wenxin; Rawish, Kojo R; Hecht, Jonathan L; Desouki, Mohamed M

    2013-12-01

    The expression of α-methylacyl-coenzyme-A racemase (AMACR) has previously been reported in 75% to 100% of urethral/bladder clear cell carcinomas, tumors that are known to display broad phenotypic overlap with their identically named müllerian counterparts. Herein, we assess the utility of AMACR in distinguishing endometrial clear cell carcinomas (CCCs) from endometrial serous carcinomas (ESCs) and endometrial endometrioid carcinomas (EECs). A total of 111 endometrial carcinomas in a tissue microarray, including 49 CCCs, 13 ESCs, and 49 EECs, were assessed for AMACR immunoreactivity, with results scored semiquantitatively (scores 0, 1+, 2+, 3+ for 0%, 1%-5%, 6%-50%, >50% immunoreactive cells, respectively). Fifty (45%) of the 111 carcinomas were AMACR positive, with the following score distribution: CCC: 0 (n = 12), 1+ (n = 12), 2+ (n = 3), 3+ (n = 22); EEC: 0 (n = 38), 1+ (n = 4), 2+ (n = 4), 3+ (n = 3); ESC: 0 (n = 11), 1+ (n = 1), 2+ (n = 0), 3+ (n = 1). AMACR expression was significantly more frequent in CCC (75%) than in ESC (15%) or EEC (22%); P < .0001. The sensitivity and specificity of AMACR expression in classifying a carcinoma as CCC were 0.75 (95% confidence interval [CI], 0.61-0.86) and 0.79 (95% CI, 0.66-0.88), respectively, with an odds ratio of 11.62 (95% CI, 5-28; P < .001) and an area under the curve of 0.79 (95% CI, 0.68-0.88). These findings indicate that AMACR expression is strongly associated with CCC and displays a relatively robust diagnostic test performance. However, its practical utility may be limited by the focal nature of its expression in 32% of the AMACR-positive CCC cases as well as its expression in 15% to 22% of the non-CCC histotypes.

  1. FGFR3b Extracellular Loop Mutation Lacks Tumorigenicity In Vivo but Collaborates with p53/pRB Deficiency to Induce High-grade Papillary Urothelial Carcinoma

    PubMed Central

    Zhou, Haiping; He, Feng; Mendelsohn, Cathy L.; Tang, Moon-shong; Huang, Chuanshu; Wu, Xue-Ru

    2016-01-01

    Missense mutations of fibroblast growth factor receptor 3 (FGFR3) occur in up to 80% of low-grade papillary urothelial carcinoma of the bladder (LGP-UCB) suggesting that these mutations are tumor drivers, although direct experimental evidence is lacking. Here we show that forced expression of FGFR3b-S249C, the most prevalent FGFR3 mutation in human LGP-UCB, in cultured urothelial cells resulted in slightly reduced surface translocation than wild-type FGFR3b, but nearly twice as much proliferation. When we expressed a mouse equivalent of this mutant (FGFR3b-S243C) in urothelia of adult transgenic mice in a tissue-specific and inducible manner, we observed significant activation of AKT and MAPK pathways. This was, however, not accompanied by urothelial proliferation or tumorigenesis over 12 months, due to compensatory tumor barriers in p16-pRB and p19-p53-p21 axes. Indeed, expressing FGFR3b-S249C in cultured human urothelial cells expressing SV40T, which functionally inactivates pRB/p53, markedly accelerated proliferation and cell-cycle progression. Furthermore, expressing FGFR3b-S243C in transgenic mouse urothelium expressing SV40T converted carcinoma-in-situ to high-grade papillary urothelial carcinoma. Together, our study provides new experimental evidence indicating that the FGFR3 mutations have very limited urothelial tumorigenicity and that these mutations must collaborate with other genetic events to drive urothelial tumorigenesis. PMID:27157475

  2. Analysis of residual disease following preoperative radiotherapy versus initial surgery in endometrial carcinoma

    SciTech Connect

    Chung, C.K.; Stryker, J.A.; Nahhas, W.A.; Cunningham, D.E.; Mortel, R.

    1982-02-01

    A clinicopathologic study of residual disease following pre-operative radiotherapy (RT) in 67 patients and initial surgery in 40 patients with early invasive endometrial carcinoma is presented. In 10%, extrauterine spread was found at operation. In 10% of patients, the histologic type, and in 19% the grade of tumor, differed between the curettage and hysterectomy specimens. Pre-op RT altered the depth of myometrial invasion and frequency of vascular invasion, but there was no evidence that irradiation itself affected the histologic type or grade of tumor. The patients with residual tumor after pre-op RT had significantly more cancer-related deaths than those without residual disease. The high risk factors were deep myometrial invasion and residual disease outside the uterus. Vascular invasion did not affect the prognosis in this series. The importance of surgical-pathologic staging by initial surgery is discussed.

  3. Immunolocalization of Corticotropin-Releasing Hormone (CRH) and Its Receptors (CRHR1 and CRHR2) in Human Endometrial Carcinoma

    PubMed Central

    Sato, Naoko; Takagi, Kiyoshi; Suzuki, Takashi; Miki, Yasuhiro; Tanaka, Sota; Nagase, Satoru; Warita, Hitoshi; Fukudo, Shin; Sato, Fumiko; Sasano, Hironobu; Ito, Kiyoshi

    2014-01-01

    Objective Corticotropin-releasing hormone (CRH), a major regulator of the stress response, regulates various biological functions through its interaction with CRH receptors 1 (CRHR1) and 2 (CRHR2). CRH, CRHR1, and CRHR2 have recently been reported in several types of carcinoma, but the significance of these proteins has remained largely unknown in human endometrial carcinoma. Materials and Methods A total of 87 endometrial carcinoma specimens were obtained from Japanese female patients who underwent surgical treatment, fixed in 10% formalin, and embedded in paraffin wax. Immunohistochemistry for CRH, CRHR1, and CRHR2 was performed, and clinical data were obtained from the medical records. Results Immunopositivity of CRH, CRHR1, and CRHR2 in the specimens was 26%, 15%, and 10%, respectively. Univariate analysis revealed that immunohistochemical CRH status was positively associated with CRHR1 and CRHR2 status and that CRHR1 status was significantly associated with the risk of recurrence and poorer clinical outcome, whereas CRHR2 status was marginally associated with better prognosis for overall survival. Multivariate analysis demonstrated CRHR1 status as an independent prognostic factor for both disease-free and overall survival. Conclusions These results suggest that intratumoral CRH-CRHR1 signaling plays an important role in the progression of endometrial carcinoma and that CRHR1 is a potent prognostic factor in patients with this disease. PMID:25254562

  4. Prediction of coexistent carcinomas risks by subjective EIN diagnosis and comparison with WHO classification in endometrial hyperplasias.

    PubMed

    Yang, Yu-Feng; Liao, Ying-Yang; Peng, Ning-Fu; Li, Le-Qun; Xie, Shu-Rui; Wang, Run-Bang

    2012-12-15

    Endometrial intraepithelial neoplasia (EIN) classification is proposed as a new diagnostic system to resolve the limitations of the World Health Organization (WHO) classification in routine practice. Our aim was to find out whether EIN classification excels the WHO classification regarding the accurate prediction of coexisting endometrial carcinomas (EC) in biopsy specimens. We retrospectively re-classified 139 WHO-classified endometrial hyperplasia (EH) cases by subjective EIN diagnosis and compared the incidence of coexisting carcinomas using two classification systems by re-evaluating biopsy and corresponding hysterectomy specimens. Of 139 WHO-classified hyperplasia cases, 36 and 103 were classified as benign and EIN cases, respectively. Forty of 93 cases with atypical EH had EC at hysterectomy as compared with 2/46 cases without atypical EH, while EC was detected in 42/103 cases with EIN, and in 0 of 36 cases without EIN. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for atypical EH vs. non-atypical EH in biopsy specimen was 95.2%, 45.4%, 43.0% and 95.7%, respectively. For EIN vs. benign, the sensitivity was 100% and the specificity was 37.1%. The incidence of coexisting carcinomas in EIN cases was similar to that in atypical EH cases. However, regarding the exclusion of coexisting carcinomas, EIN criteria of benign lesions excelled the WHO criteria of non-atypical EH/CH.

  5. Cabozantinib-S-Malate in Treating Patients With Recurrent or Metastatic Endometrial Cancer

    ClinicalTrials.gov

    2017-03-20

    Endometrial Adenosquamous Carcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Mixed Adenocarcinoma; Endometrial Serous Adenocarcinoma; Metastatic Endometrioid Adenocarcinoma; Recurrent Uterine Corpus Carcinoma; Stage IV Uterine Corpus Cancer; Stage IVA Uterine Corpus Cancer; Stage IVB Uterine Corpus Cancer

  6. External hemipelvectomy as treatment for solitary coxofemoral metastasis from endometrial carcinoma: case report and review of the literature.

    PubMed

    Vizzielli, Giuseppe; Fanfani, Francesco; Costantini, Barbara; Gallotta, Valerio; Scambia, Giovanni; Fagotti, Anna

    2012-05-01

    The best treatment for bone metastasis from endometrial cancer as a presenting feature is unclear. We report the first case in the literature of coxofemoral metastases from endometrial cancer treated by surgical approach. Then, after a careful review of the literature, we discuss the best therapeutic option for this subset of patients. A 62-year-old woman with pain, erythema and swelling of the left leg and no history of postmenopausal bleeding underwent biopsy of the leg, which revealed a moderately differentiated endometrial carcinoma, infiltrating muscle and adipose tissues. There were no other sites of distal spread. A literature review was conducted by searching the items 'endometrial cancer' and 'bone metastasis' in MEDLINE and EnBase up to September 2010. The patient was treated with neoadjuvant chemotherapy, but she did not show a clinical response. By considering her prognosis and quality of life, we decided to perform for the first time a total abdominal hysterectomy with bilateral salpingo-oophorectomy in addition to an external hemipelvectomy with a limb amputation and partial ilium and pubic preservation. Thirty months after the procedure the patient is still alive. No other similar results are present in the literature. Patients in good clinical condition with a single bone metastasis of endometrial cancer should be treated aggressively with surgery, as survival can be extended with an acceptable quality of life.

  7. Elucidation of Molecular Alterations in Precursor Lesions of Ovarian Serous Carcinoma

    DTIC Science & Technology

    2012-07-01

    was discussed. Dr. Soslow asked how to evaluate endometrial serous cancers if there is a lesion in the tubes and if peritoneal carcinoma was...received by all participants as well as from DoD OCRP staff. 15. SUBJECT TERMS prevention, p53 mutations, high grade serous ovarian cancer and STIC...ovarian cancer by characterizing the early lesions involved in the development of high-grade ovarian serous carcinoma, and 2) to provide biomarkers

  8. Sunitinib Malate in Treating Patients With Recurrent or Metastatic Endometrial Cancer

    ClinicalTrials.gov

    2017-01-31

    Endometrial Adenocarcinoma; Endometrial Endometrioid Adenocarcinoma; Endometrial Serous Adenocarcinoma; Recurrent Uterine Corpus Carcinoma; Stage IVA Uterine Corpus Cancer; Stage IVB Uterine Corpus Cancer; Uterine Carcinosarcoma; Uterine Corpus Carcinosarcoma

  9. A clinical and pathologic comparison between stage-matched endometrial intraepithelial carcinoma and uterine serous carcinoma: is there a difference?

    PubMed

    Hou, June Y; McAndrew, Thomas C; Goldberg, Gary L; Whitney, Kathleen; Shahabi, Shohreh

    2014-04-01

    Endometrial intraepithelial carcinoma (EIC) is a rare pathologic variant of uterine serous carcinoma (USC). Our aim is to distinguish patterns of clinic-pathologic outcomes in patients with EIC and USC for disease limited to the endometrium (stage 1A) as well as with distant metastasis (stage 4B). Surgically staged patients were retrospectively identified and relevant variables were extracted and compared. Kaplan-Meier was used to generate the survival data. More USC (n = 29) exhibited lymphovascular invasion (stage 4, P = .01) and expressed higher levels of estrogen receptor-α than EIC (P = .0009 and .063 for stages 1 and 4, respectively). The survival is comparable, with 1 recurrence in each group for stage 1A disease. For stage 4 EIC and USC, the progression-free survival (14 vs10 months) and overall survival (19 vs 20 months) are similar to what is previously published. In conclusion, EIC, whether limited to the endometrium, or widely metastatic, imparts similar outcomes and should be treated comparably with stage-matched USC.

  10. MAP3K8/TPL-2/COT is a potential predictive marker for MEK inhibitor treatment in high-grade serous ovarian carcinomas

    PubMed Central

    Gruosso, Tina; Garnier, Camille; Abelanet, Sophie; Kieffer, Yann; Lemesre, Vincent; Bellanger, Dorine; Bieche, Ivan; Marangoni, Elisabetta; Sastre-Garau, Xavier; Mieulet, Virginie; Mechta-Grigoriou, Fatima

    2015-01-01

    Ovarian cancer is a silent disease with a poor prognosis that urgently requires new therapeutic strategies. In low-grade ovarian tumours, mutations in the MAP3K BRAF gene constitutively activate the downstream kinase MEK. Here we demonstrate that an additional MAP3K, MAP3K8 (TPL-2/COT), accumulates in high-grade serous ovarian carcinomas (HGSCs) and is a potential prognostic marker for these tumours. By combining analyses on HGSC patient cohorts, ovarian cancer cells and patient-derived xenografts, we demonstrate that MAP3K8 controls cancer cell proliferation and migration by regulating key players in G1/S transition and adhesion dynamics. In addition, we show that the MEK pathway is the main pathway involved in mediating MAP3K8 function, and that MAP3K8 exhibits a reliable predictive value for the effectiveness of MEK inhibitor treatment. Our data highlight key roles for MAP3K8 in HGSC and indicate that MEK inhibitors could be a useful treatment strategy, in combination with conventional chemotherapy, for this disease. PMID:26456302

  11. Dasatinib, Paclitaxel, and Carboplatin in Treating Patients With Stage III-IV or Recurrent Endometrial Cancer

    ClinicalTrials.gov

    2015-12-22

    Endometrial Adenocarcinoma; Endometrial Adenosquamous Carcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Mucinous Adenocarcinoma; Endometrial Serous Adenocarcinoma; Endometrial Undifferentiated Carcinoma; Endometrioid Adenocarcinoma; Recurrent Uterine Corpus Carcinoma; Stage IIIA Uterine Corpus Cancer; Stage IIIB Uterine Corpus Cancer; Stage IIIC Uterine Corpus Cancer; Stage IVA Uterine Corpus Cancer; Stage IVB Uterine Corpus Cancer; Uterine Carcinosarcoma

  12. A case of endometrial carcinoma in a long-term Levonorgestrel Intrauterine System (LNG 52 mg-IUS) user.

    PubMed

    Thomas, Melisa; Briggs, Paula

    2017-03-01

    This report describes a 50-year-old woman who presented to a community gynaecology clinic complaining of persistent heavy vaginal bleeding with an LNG 52 mg-IUS in situ. She was subsequently found to have stage 1 grade 1a endometrioid carcinoma. From the literature, we have identified five similar cases. This case highlights the possibility of endometrial carcinoma despite treatment with an LNG 52 mg-IUS and reinforces the importance of investigating women who present with unusual persistent or heavy vaginal bleeding.

  13. An assessment of prognostic factors, adjuvant treatment and outcomes of stage IA polyp-limited versus endometrium-limited type II endometrial carcinoma

    PubMed Central

    Liang, Lusha W.; Perez, Alexendar R.; Cangemi, Nicholas A.; Zhou, Qin; Iasonos, Alexia; Abu-Rustum, Nadeem; Alektiar, Kaled M.; Makker, Vicky

    2015-01-01

    Objective To determine clinical outcomes in patients with stage IA polyp-limited versus endometrium-limited high-grade (type II) endometrial carcinoma (EC). Methods We identified all cases of stage IA polyp-limited or endometrium-limited high-grade EC (FIGO Grade 3 endometrioid, Serous, Clear Cell, or Mixed) who underwent simple hysterectomy, bilateral salpingo-oophorectomy, peritoneal washings, omental biopsy, and pelvic and paraaortic lymph node dissection and received adjuvant treatment at our institution from 10/1995–11/2012. Progression-free survival (PFS) and overall survival (OS) by histology, adjuvant therapy, and polyp-limited vs endometrium-limited disease status were determined using log-rank test. We analyzed three treatment groups: patients who received chemotherapy with or without Radiation Therapy (RT) (intravaginal or pelvic); patients who received RT (intravaginal RT or pelvic RT) alone; and patients who received no adjuvant treatment. Results In all, 85 women underwent hysterectomy/salpingo-oophorectomy; all were surgically staged with lymph node assessment and had stage IA EC with no lymphovascular or myometrial invasion. Median follow-up for survivors was 46.5 months (range, 1.98–188.8 months). Forty-nine patients (57.6%) had polyp-limited disease and 36 (42.4%) had endometrium-limited disease. There were no significant differences in clinicopathologic characteristics between patients within the three treatment groups with regards to age at diagnosis, mean BMI, ECOG performance status, polyp-limited, endometrium-limited disease, diabetes, or race. The 3-year PFS rate was 94.9% and the 3-year OS rate was 98.8%. Univariate PFS and OS analysis revealed that age was a relevant prognostic factor [(PFS:HR (95%CI):1.13(1.02–1.25); P=0.022 and OS HR (95%CI):1.19(1.02–1.38); P=0.03]. Adjuvant treatment did not impact outcomes. Conclusions Clinical outcomes of surgical stage IA, type II polyp- or endometrium-limited high-grade epithelial EC are

  14. Fifteen-Year Radiotherapy Outcomes of the Randomized PORTEC-1 Trial for Endometrial Carcinoma

    SciTech Connect

    Creutzberg, Carien L.; Nout, Remi A.; Lybeert, Marnix L.M.; Warlam-Rodenhuis, Carla C.; Jobsen, Jan J.; Mens, Jan-Willem M.; Lutgens, Ludy C.H.W.; Pras, Elisabeth; Poll-Franse, Lonneke V. van de; Putten, Wim L.J. van

    2011-11-15

    Purpose: To evaluate the very long-term results of the randomized Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC)-1 trial for patients with Stage I endometrial carcinoma (EC), focusing on the role of prognostic factors for treatment selection and the long-term risk of second cancers. Patients and Methods: The PORTEC trial (1990-1997) included 714 patients with Stage IC Grade 1-2 or Stage IB Grade 2-3 EC. After surgery, patients were randomly allocated to external-beam pelvic radiotherapy (EBRT) or no additional treatment (NAT). Analysis was by intention to treat. Results: 426 patients were alive at the date of analysis. The median follow-up time was 13.3 years. The 15-year actuarial locoregional recurrence (LRR) rates were 6% for EBRT vs. 15.5% for NAT (p < 0.0001). The 15-year overall survival was 52% vs. 60% (p = 0.14), and the failure-free survival was 50% vs. 54% (p = 0.94). For patients with high-intermediate risk criteria, the 15-year overall survival was 41% vs. 48% (p = 0.51), and the 15-year EC-related death was 14% vs. 13%. Most LRR in the NAT group were vaginal recurrences (11.0% of 15.5%). The 15-year rates of distant metastases were 9% vs. 7% (p = 0.25). Second primary cancers had been diagnosed over 15 years in 19% of all patients, 22% vs. 16% for EBRT vs. NAT (p = 0.10), with observed vs. expected ratios of 1.6 (EBRT) and 1.2 (NAT) compared with a matched population (p = NS). Multivariate analysis confirmed the prognostic significance of Grade 3 for LRR (hazard ratio [HR] 3.4, p = 0.0003) and for EC death (HR 7.3, p < 0.0001), of age >60 (HR 3.9, p = 0.002 for LRR and 2.7, p = 0.01 for EC death) and myometrial invasion >50% (HR 1.9, p = 0.03 and HR 1.9, p = 0.02). Conclusions: The 15-year outcomes of PORTEC-1 confirm the relevance of HIR criteria for treatment selection, and a trend for long-term risk of second cancers. EBRT should be avoided in patients with low- and intermediate-risk EC.

  15. The Genomic Landscape of TP53 and p53 Annotated High Grade Ovarian Serous Carcinomas from a Defined Founder Population Associated with Patient Outcome

    PubMed Central

    Wojnarowicz, Paulina M.; Oros, Kathleen Klein; Quinn, Michael C. J.; Arcand, Suzanna L.; Gambaro, Karen; Madore, Jason; Birch, Ashley H.; de Ladurantaye, Manon; Rahimi, Kurosh; Provencher, Diane M.; Mes-Masson, Anne-Marie; Greenwood, Celia M. T.; Tonin, Patricia N.

    2012-01-01

    High-grade ovarian serous carcinomas (HGSC) are characterized by TP53 mutations and non-random patterns of chromosomal anomalies, where the nature of the TP53 mutation may correlate with clinical outcome. However, the frequency of common somatic genomic events occurring in HGSCs from demographically defined populations has not been explored. Whole genome SNP array, and TP53 mutation, gene and protein expression analyses were assessed in 87 confirmed HGSC samples with clinical correlates from French Canadians, a population exhibiting strong founder effects, and results were compared with independent reports describing similar analyses from unselected populations. TP53 mutations were identified in 91% of HGSCs. Anomalies observed in more than 50% of TP53 mutation-positive HGSCs involved gains of 3q, 8q and 20q, and losses of 4q, 5q, 6q, 8p, 13q, 16q, 17p, 17q, 22q and Xp. Nearly 400 regions of non-overlapping amplification or deletion were identified, where 178 amplifications and 98 deletions involved known genes. The subgroup expressing mutant p53 protein exhibited significantly prolonged overall and disease-free survival as compared with the p53 protein null subgroup. Interestingly, a comparative analysis of genomic landscapes revealed a significant enrichment of gains involving 1q, 8q, and 12p intervals in the subgroup expressing mutant p53 protein as compared with the p53 protein null subgroup. Although the findings show that the frequency of TP53 mutations and the genomic landscapes observed in French Canadian samples were similar to those reported for samples from unselected populations, there were differences in the magnitude of global gains/losses of specific chromosomal arms and in the spectrum of amplifications and deletions involving focal regions in individual samples. The findings from our comparative genomic analyses also support the notion that there may be biological differences between HGSCs that could be related to the nature of the TP53 mutation

  16. Phase II study of the PI3K inhibitor BKM120 in patients with advanced or recurrent endometrial carcinoma: a stratified type I-type II study from the GINECO group.

    PubMed

    Heudel, P-E; Fabbro, M; Roemer-Becuwe, C; Kaminsky, M C; Arnaud, A; Joly, F; Roche-Forestier, S; Meunier, J; Foa, C; You, B; Priou, F; Tazi, Y; Floquet, A; Selle, F; Berton-Rigaud, D; Lesoin, A; Kalbacher, E; Lortholary, A; Favier, L; Treilleux, I; Ray-Coquard, I

    2017-01-01

    Backround:Patients with metastatic endometrial carcinoma have a poor prognosis and PIK3CA mutations and amplifications are common in these cancers. This study evaluated the efficacy and safety of the pure PI3K inhibitor BKM120 in advanced or recurrent endometrial carcinoma.

  17. Role of adjunctive radiotherapy for stage I endometrial carcinoma: preoperative vs postoperative irradiation

    SciTech Connect

    Chung, C.K.; Stryker, J.A.; Nahhas, W.A.; Mortel, R.

    1981-10-01

    Eighty-five patients with clinical State I endometrial carcinoma were reviewed: 81% of patients had either pre-operative or post-operative radiotherapy (RT). The incidence of deep myometrial invasion (outer 1/3 of thickness) of pre-op RT vs. post-op RT group was 6% and 28% respectively; the pre-op irradiation seemed to alter the depth of myometrial invasion. Eleven patients (13%) developed recurrences: 9 of these patients (82%) had recurrences in the extrapelvis. The incidence of extrapelvic recurrence of patients with Grade 3 tumors was 29% 4/14); those with deep myometrial invasion was 33% (4/12). The overall 5 year survival and complication rate was 89% and 4% respectively: these results were comparable between pre-op RT and post-op RT groups. However, post-op RT offers the advantage of accurate surgical-pathologic staging and optimal individualization of adjuvant therapy. In addition, those who have deep myometrial invasion and/or Grade 3 tumors may require systemic therapy in view of high incidence of distant failures.

  18. Fludeoxyglucose F 18 PET Scan, CT Scan, and Ferumoxtran-10 MRI Scan Before Chemotherapy and Radiation Therapy in Finding Lymph Node Metastasis in Patients With Locally Advanced Cervical Cancer or High-Risk Endometrial Cancer

    ClinicalTrials.gov

    2016-11-14

    Cervical Adenocarcinoma; Cervical Adenosquamous Cell Carcinoma; Cervical Small Cell Carcinoma; Cervical Squamous Cell Carcinoma; Endometrial Clear Cell Carcinoma; Endometrial Papillary Serous Carcinoma; Stage I Endometrial Carcinoma; Stage IB Cervical Cancer; Stage II Endometrial Carcinoma; Stage IIA Cervical Cancer; Stage IIB Cervical Cancer; Stage III Cervical Cancer; Stage III Endometrial Carcinoma; Stage IVA Cervical Cancer

  19. Gankyrin Is Frequently Overexpressed in Cervical High Grade Disease and Is Associated with Cervical Carcinogenesis and Metastasis

    PubMed Central

    Qian, Wenyan; Dong, Yu; Yang, Yongbin; Liu, Zhiqiang; Feng, Youji; Ma, Ding; Zhang, Zhenbo; Wu, Sufang

    2014-01-01

    Our previous studies have showed that Gankyrin expression is correlated with a malignant phenotype in endometrial carcinoma. Here, we investigated the possible role of Gankyrin in cervical disease. The increasing protein level of Gankyrin was observed in high-grade cervical intraepithelial neoplasia and carcinoma compared with benign cervical tissues and low-grade cervical intraepithelial neoplasia. In para-carcinoma tissues, it was found interestingly that there was no lymph node metastasis when nuclei Gankyrin was positively expressed, but lymph node metastasis rate was 30% (6/20) when nuclei Gankyrin was negatively expressed. In vitro, the transfection of Gankyrin resulted in markedly up-regulating of Vimentin, β-catenin and Twist2, as well as down-regulating of E-cadherin in cervical carcinoma cells. Our results suggested that Gankyrin may be functional in cervical carcinogenesis and metastasis. PMID:24751719

  20. HER-2/neu oncogene amplification and chromosome 17 aneusomy in endometrial carcinoma: correlation with oncoprotein expression and conventional pathological parameters.

    PubMed

    Cianciulli, A M; Guadagni, F; Marzano, R; Benevolo, M; Merola, R; Giannarelli, D; Marandino, F; Vocaturo, G; Mariani, L; Mottolese, M

    2003-06-01

    The objective of the present study was to evaluate the correlation between HER-2 gene amplification and HER-2 protein overexpression in endometrial carcinoma using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). We also analyzed chromosome 17 aneusomy and the association between these biological parameters and conventional clinicopathological variables. FISH analysis was performed on 73 selected paraffin-embedded sections from endometrial carcinomas which previously had HER-2 status determined immunohistochemically using monoclonal antibodies (MoAb) 300G9 and CB11. Using a ratio of more than two oncogene signals/centromere to indicate amplification, a total of 42 out of the 73 endometrial tumors included in this study resulted positive by FISH where as protein overexpression was identified in 29 out of 73 with a concordance rate of 74.3%. However, when the mean signals/centromere per nucleus increased (ratio > 4 < or = 5) a higher concordance between the two assays was seen (p = 0.007). In addition, HER-2 amplification was significantly correlated with tumor stage (p = 0.021) and myometrial invasion (p = 0.010), whereas chromosome 17 polisomy showed a positive correlation only with myometrial invasion (p = 0.004) No significant correlation was found between HER-2 gene amplification, chromosome 17 aneusomy and patient outcome. Nevertheless, the probability of a 5 year overall survival decreased from 70% to 43%, respectively, for ratio > 2 < or = 4 and ratio > 4 < or = 5 when we grouped the amplified cases on the basis of HER-2:CEP17 ratio. In conclusion, molecular characteristics provide objective data that may be useful in predicting prognosis in patients with endometrial cancer.

  1. Concomitant endometrial and gallbladder metastasis in advanced multiple metastatic invasive lobular carcinoma of the breast: A rare case report

    PubMed Central

    Bezpalko, Kseniya; Mohamed, Mohamed A.; Mercer, Leo; McCann, Michael; Elghawy, Karim; Wilson, Kenneth

    2015-01-01

    Introduction At time of presentation, fewer than 10% of patients have metastatic breast cancer. The most common sites of metastasis in order of frequency are bone, lung, pleura, soft tissue, and liver. Breast cancer metastasis to the uterus or gallbladder is rare and has infrequently been reported in the English literature. Presentation of case A 47 year old female with a recent history of thrombocytopenia presented with abnormal vaginal bleeding. Pelvic ultrasound revealed multiple uterine fibroids and endometrial curettings revealed cells consistent with lobular carcinoma of the breast. Breast examination revealed edema and induration of the lower half of the right breast. Biopsy of the right breast revealed invasive lobular carcinoma. Bone marrow aspiration obtained at a previous outpatient visit revealed extensive involvement by metastatic breast carcinoma. Shortly after discharge, the patient presented with acute cholecystitis and underwent cholecystectomy. Microscopic examination of the gallbladder revealed metastatic infiltrating lobular carcinoma. The final diagnosis was invasive lobular carcinoma of the right breast with metastasis to the bone marrow, endometrium, gallbladder, regional lymph nodes, and peritoneum. Discussion The growth pattern of invasive lobular carcinoma of the breast is unique and poses a challenge in diagnosing the cancer at an early stage. Unlike other types of breast cancer, it tends to metastasize more to the peritoneum, ovary, and gastrointestinal tract. Metastasis to the endometrium or gallbladder is rare. Conclusion Metastatic spread should be considered in the differential diagnosis of patients with invasive lobular breast carcinoma presenting with abnormal vaginal bleeding or acute cholecystitis. PMID:26275738

  2. Endometrial carcinoma--relative effectiveness of adjuvant irradiation vs therapy reserved for relapse.

    PubMed

    Ackerman, I; Malone, S; Thomas, G; Franssen, E; Balogh, J; Dembo, A

    1996-02-01

    Fifty-four patients with recurrent endometrial carcinoma were identified from a retrospective review of charts of 304 endometrial cancer patients seen between 1983 and 1989 at our center. A review was undertaken to identify the patterns of relapse, to determine the outcome of salvage treatment, to examine the factors predictive of effective salvage, and, if salvage is effective, to assess an alternative strategy to routine adjuvant postoperative pelvic radiotherapy. Forty percent of the entire recurrent population are long-term survivors. Of the 54 relapsing patients, primary therapy had been surgery alone in 32 and surgery and adjuvant radiotherapy (rt) in 22. Isolated pelvic recurrence was the predominate relapse site in those who had not received adjuvant pelvic RT as primary therapy (23 of 32 or 72%). Distant relapse predominated in those who received adjuvant RT (17 or 22 or 77%). Twenty-eight (54%) failed in the pelvis alone, and 26 (46%) had a component of distant failure. Of the 28 with isolated pelvic relapse, 16 had vaginal mucosal disease involvement only and 12 had disease in the parametrium and/or the pelvic sidewall. With a minimum follow-up for the survivors of 5 years, 21 of the 28 with isolated pelvic relapse received radical radiotherapy and 14 or 67% had maintained pelvic control until death or last follow-up. Eleven of 14 (79%) with disease confined to the mucosa had pelvic control, whereas only 3 of 7 (43%) with extramucosal disease were controlled. No patient experienced major treatment-related toxicity. Tumor size, anatomic extent of pelvic recurrence, RT dose, and disease-free interval were examined for prognostic significance for pelvic control and survival by univariate analysis. Only anatomic extent of pelvic recurrence showed a nonstatistically significant trend as a predictor for control with P = 0.08. In conclusion, a significant proportion of patients with disease recurrence confined to the pelvis can be rendered disease-free long

  3. Endometrial carcinoma located in the right septate uterus cavity: a case report

    PubMed Central

    Boubess, Ikram; Mahdi, Youssef; Ramsiss, Hanan; Filali, Adib; Alami, Mohamad Hassan; El khannoussi, Basma; Hachi, Hafid

    2015-01-01

    Endometrial cancer in patients with uterine congenital malformations is exceptional and there are only a few rare cases published in the literature. We report the case of a 67 years-old patient with an endometrial cancer located in the right cavity of a complete septate uterus. PMID:26958135

  4. Endometrial carcinoma located in the right septate uterus cavity: a case report.

    PubMed

    Boubess, Ikram; Mahdi, Youssef; Ramsiss, Hanan; Filali, Adib; Alami, Mohamad Hassan; El Khannoussi, Basma; Hachi, Hafid

    2015-01-01

    Endometrial cancer in patients with uterine congenital malformations is exceptional and there are only a few rare cases published in the literature. We report the case of a 67 years-old patient with an endometrial cancer located in the right cavity of a complete septate uterus.

  5. Management and results of endometrial carcinoma treated at Instituto Português de Oncologia de Francisco Gentil.

    PubMed

    Tavares, M A; Patricio, M B; Vilhena, M; Da Silva, J N

    1977-02-01

    The experience of 260 patients with endometrial carcinoma was reviewed. The influence of factors such as age, stage of disease, grade and degree of myometrial penetration on the survival was presented, showing that survival decreases in elderly patients, in patients with advanced stage of disease, when the tumor is undifferentiated, and when the tumor deeply penetrates the myometrium. The methods of therapy, fall into three main groups: surgery, radiotherapy, and combined therapy, the latter yielding the best 5-year survival rate, in all stages. The incidence of vaginal recurrences was low, probably due to the fact that 68.8% of the patients were treated by a combined therapeutic modality.

  6. Virilizing Adrenocortical Carcinoma Invading the Right Atrium with Histological High-Grade Malignancy and p53 Mutation in a 3-Year-Old Child: Indication of Post Operative Adjuvant Chemotherapy.

    PubMed

    Nagasaki, Keisuke; Horikawa, Reiko; Nagaishi, Jun-Ichi; Honna, Toshiro; Sekiguchi, Akihiko; Tsunematsu, Yukiko; Tanaka, Toshiaki

    2004-01-01

    We present a 3-yr-old girl with a virilizing adrenocortical carcinoma invading into the right atrium with histological high-grade malignancy and p53 mutation. Development of facial acne and pubic hair were noted at 3 yr and 2 mo. The levels of androgens were high. Diurnal variation in ACTH and cortisol were absent. Abdominal computed tomography revealed a large right suprarenal mass, with extension into the inferior vena cava and right atrium. Based on the diagnosis of a right virilizing adrenocortical tumor with Cushing syndrome, surgery was performed by a combined thoracoabdominal approach with the patient on cardiopulmonary bypass. The tumor was 7 × 5.5 × 3.5 cm in size, and weighed 95 g. The histological diagnosis was adrenocartical carcinoma with high-grade malignancy according to the category of Weiss. A heterozygous mutation of the p53 tumor-suppressor gene (codon 248 CGC→TGG) was found. We did not perform adjuvant chemotherapy because of radical resection on macroscopic observation and no metastasis in radiological findings. Five months after the surgery, her chest X ray and computed tomography revealed multiple lung metastases and a single liver metastasis. In this type of patient with histological high-grade malignancy and p53 mutations, postoperative adjuvant chemotherapy is indicated even if macroscopic total surgical removal had been performed.

  7. 3-D reconstruction and virtual ductoscopy of high-grade ductal carcinoma in situ of the breast with casting type calcifications using refraction-based X-ray CT.

    PubMed

    Ichihara, Shu; Ando, Masami; Maksimenko, Anton; Yuasa, Tetsuya; Sugiyama, Hiroshi; Hashimoto, Eiko; Yamasaki, Katsuhito; Mori, Kensaku; Arai, Yoshinori; Endo, Tokiko

    2008-01-01

    Stereomicroscopic observations of thick sections, or three-dimensional (3-D) reconstructions from serial sections, have provided insights into histopathology. However, they generally require time-consuming and laborious procedures. Recently, we have developed a new algorithm for refraction-based X-ray computed tomography (CT). The aim of this study is to apply this emerging technology to visualize the 3-D structure of a high-grade ductal carcinomas in situ (DCIS) of the breast. The high-resolution two-dimensional images of the refraction-based CT were validated by comparing them with the sequential histological sections. Without adding any contrast medium, the new CT showed strong contrast and was able to depict the non-calcified fine structures such as duct walls and intraductal carcinoma itself, both of which were barely visible in a conventional absorption-based CT. 3-D reconstruction and virtual endoscopy revealed that the high-grade DCIS was located within the dichotomatous branches of the ducts. Multiple calcifications occurred in the necrotic core of the continuous DCIS, resulting in linear and branching (casting type) calcifications, a hallmark of high-grade DCIS on mammograms. In conclusion, refraction-based X-ray CT approaches the low-power light microscopic view of the histological sections. It provides high quality slice data for 3-D reconstruction and virtual ductosocpy.

  8. Upregulation of TrkB Promotes Epithelial-Mesenchymal Transition and Anoikis Resistance in Endometrial Carcinoma

    PubMed Central

    Bao, Wei; Qiu, Haifeng; Yang, Tingting; Luo, Xin; Zhang, Huijuan; Wan, Xiaoping

    2013-01-01

    Mechanisms governing the metastasis of endometrial carcinoma (EC) are poorly defined. Recent data support a role for the cell surface receptor tyrosine kinase TrkB in the progression of several human tumors. Here we present evidence for a direct role of TrkB in human EC. Immunohistochemical analysis revealed that TrkB and its secreted ligand, brain-derived neurotrophic factor (BDNF), are more highly expressed in EC than in normal endometrium. High TrkB levels correlated with lymph node metastasis (p<0.05) and lymphovascular space involvement (p<0.05) in EC. Depletion of TrkB by stable shRNA-mediated knockdown decreased the migratory and invasive capacity of cancer cell lines in vitro and resulted in anoikis in suspended cells. Conversely, exogenous expression of TrkB increased cell migration and invasion and promoted anoikis resistance in suspension culture. Furthermore, over-expression of TrkB or stimulation by BDNF resulted in altered the expression of molecular mediators of the epithelial-to-mesenchymal transition (EMT). RNA interference (RNAi)-mediated depletion of the downstream regulator, Twist, blocked TrkB-induced EMT-like transformation. The use of in vivo models revealed decreased peritoneal dissemination in TrkB-depleted EC cells. Additionally, TrkB-depleted EC cells underwent mesenchymal-to-epithelial transition and anoikis in vivo. Our data support a novel function for TrkB in promoting EMT and resistance to anoikis. Thus, TrkB may constitute a potential therapeutic target in human EC. PMID:23936232

  9. Analysis of recurrence and survival rates in grade 3 endometrioid endometrial carcinoma

    PubMed Central

    Wang, Jieyu; Jia, Nan; Li, Qing; Wang, Chao; Tao, Xiang; Hua, Keqin; Feng, Weiwei

    2016-01-01

    The aim of the present study was to determine risk factors associated with recurrence and survival in patients with grade 3 endometrioid endometrial carcinoma (G3EEC). A retrospective analysis of 117 patients with G3EEC, who were admitted to the Obstetrics and Gynecology Hospital of Fudan University between January 2000 and December 2011, was performed. The χ2 test or Fisher's exact test were used for the comparison of categorical variables. Kaplan-Meier method was used for estimating recurrence-free survival (RFS), disease-specific survival (DSS) and overall survival (OS) rates. Univariate and multivariate Cox proportional hazards model were used to assess the prognostic significance of various patient characteristics. In 117 patients, 16 patients (13.7%) had tumor recurrence, of which 6 (37.5%) developed local-regional recurrence and 10 (62.5%) developed distant recurrence. Out of the 16 patients with tumor recurrence, 14 (87.5%) had a recurrence within 3 years of surgery. Statistically significant characteristics affecting RFS, DSS and OS rates were outer half myometrial invasion (MI ≥50%), advanced International Federation of Gynecology and Obstetrics stage, positive lymph node metastasis (PLNM), lymph vascular space invasion, adnexal involvement and characterization as a high-risk group, according to the Gynecologic Oncology Group 99 stratification algorithm. RFS was associated with the depth of cervical mucosa (stromal) involvement. Furthermore, in the multivariate Cox proportional hazards model, significant independent adverse factors for RFS and DSS included MI ≥50% and adnexal involvement. For OS, there were no statistically significant prognostic factors. In conclusion, MI ≥50% and adnexal involvement are independent prognostic factors for RFS and DSS in G3EEC patients. PMID:27698871

  10. The relationship of cerb B 2 expression with estrogen receptor and progesterone receptor and prognostic parameters in endometrial carcinomas

    PubMed Central

    2010-01-01

    Background Endometrial carcinoma (EC) is the most common malignancy of the female genital tract. Gene alterations and overexpression of various oncogenes are important in tumor development. The human HER 2 neu (c-erbB-2) gene product is a transmembrane receptor with an intracellular tyrosine kinase that plays an important role in coordinating the endometrial growth factor receptor signaling network. The aim of this study was to investigate the expression of c-erbB-2 in endometrial cancer, to study its correlation to established prognostic parameters and estrogen receptor (ER) and progesterone receptor (PR) status. Methods Immunohistochemical (IHC) analyses of ER, PR and c-erbB-2 were performed in 72 EC cases. Results We detected a positive staining with c erbB 2 in 18.1% of the cases and determined a statistically significant relation between c-erbB-2 and PR. We could not find a statistically significant relation between c-erbB-2 staining and ER. There was not a statistically significant difference between c-erbB-2 and histological grade. The highest level of c-erbB-2 was found in grade 2 cases. There was not any statistically significant relation between c-erbB-2 and menstrual status, myometrial invasion, lymph node status, stage and survival. Conclusions Although our study provides additional evidence of the potential prognostic role of c-erbB-2, further prospective and controlled studies are required to validate their clinical usefulness. PMID:20167054

  11. Differential Expression and Clinical Significance of DNA Methyltransferase 3B (DNMT3B), Phosphatase and Tensin Homolog (PTEN) and Human MutL Homologs 1 (hMLH1) in Endometrial Carcinomas.

    PubMed

    Li, Wenting; Wang, Ying; Fang, Xinzhi; Zhou, Mei; Li, Yiqun; Dong, Ying; Wang, Ruozheng

    2017-02-21

    BACKGROUND The aim of this study was to investigate the expression and the clinicopathologic significance of DNA methyltransferase 3B (DNMT3B), phosphatase and tensin homolog (PTEN) and human MutL homologs 1 (hMLH1) in endometrial carcinomas between Han and Uygur women in Xinjiang. MATERIAL AND METHODS The expression of DNMT3B, PTEN, and hMLH1 in endometrial carcinomas were assessed by immunohistochemistry, followed by an analysis of their relationship to clinical-pathological features and prognosis. RESULTS There were a 61.7% (95/154) overexpression of DNMT3B, 50.0% (77/154) loss of PTEN expression and 18.2% (28/154) loss of hMLH1 expression. The expression of DNMT3B and PTEN in endometrial carcinomas was statistically significantly different between Uygur women and Han women (p=0.001, p=0.010, respectively). DNMT3B expression was statistically significant based on the grade of endometrial carcinomas (p=0.031). PTEN loss was statistically significant between endometrioid carcinomas (ECs) and non endometrioid carcinomas (NECs) (p=0.040). DNMT3B expression was statistically significant in different myometrial invasion groups in Uygur women (p=0.010). Furthermore, the correlation of DNMT3B and PTEN expression was significant in endometrial carcinomas (p=0.021). PTEN expression was statistically significant in the overall survival (OS) rate of women with endometrial cancers (p=0.041). CONCLUSIONS Our findings suggest that PTEN and DNMT3B possess common regulation features as well as certain ethnic differences in expression between Han women and Uygur women. An interaction may exist in the pathogenesis of endometrial carcinoma. DNMT3B was expressed differently in cases of myometrial invasion and PTEN was associated with OS, which suggested that these molecular markers may be useful in the evaluation of the biological behavior of endometrial carcinomas and may be useful indicators of prognosis in women with endometrial carcinomas.

  12. Exploratory Analysis of TP53 Mutations in Circulating Tumour DNA as Biomarkers of Treatment Response for Patients with Relapsed High-Grade Serous Ovarian Carcinoma: A Retrospective Study

    PubMed Central

    Piskorz, Anna M.; Biggs, Heather; Addley, Helen; Freeman, Sue; Moyle, Penelope; Sala, Evis; Sayal, Karen; Hosking, Karen; Gounaris, Ioannis; Earl, Helena M.; Rosenfeld, Nitzan; Brenton, James D.

    2016-01-01

    Background Circulating tumour DNA (ctDNA) carrying tumour-specific sequence alterations may provide a minimally invasive means to dynamically assess tumour burden and response to treatment in cancer patients. Somatic TP53 mutations are a defining feature of high-grade serous ovarian carcinoma (HGSOC). We tested whether these mutations could be used as personalised markers to monitor tumour burden and early changes as a predictor of response and time to progression (TTP). Methods and Findings We performed a retrospective analysis of serial plasma samples collected during routine clinical visits from 40 patients with HGSOC undergoing heterogeneous standard of care treatment. Patient-specific TP53 assays were developed for 31 unique mutations identified in formalin-fixed paraffin-embedded tumour DNA from these patients. These assays were used to quantify ctDNA in 318 plasma samples using microfluidic digital PCR. The TP53 mutant allele fraction (TP53MAF) was compared to serum CA-125, the current gold-standard response marker for HGSOC in blood, as well as to disease volume on computed tomography scans by volumetric analysis. Changes after one cycle of treatment were compared with TTP. The median TP53MAF prior to treatment in 51 relapsed treatment courses was 8% (interquartile range [IQR] 1.2%–22%) compared to 0.7% (IQR 0.3%–2.0%) for seven untreated newly diagnosed stage IIIC/IV patients. TP53MAF correlated with volumetric measurements (Pearson r = 0.59, p < 0.001), and this correlation improved when patients with ascites were excluded (r = 0.82). The ratio of TP53MAF to volume of disease was higher in relapsed patients (0.04% per cm3) than in untreated patients (0.0008% per cm3, p = 0.004). In nearly all relapsed patients with disease volume > 32 cm3, ctDNA was detected at ≥20 amplifiable copies per millilitre of plasma. In 49 treatment courses for relapsed disease, pre-treatment TP53MAF concentration, but not CA-125, was associated with TTP. Response to

  13. High-grade papillary urothelial carcinoma of the urinary tract: a clinicopathologic analysis of a post-World Health Organization/International Society of Urological Pathology classification cohort from a single academic center.

    PubMed

    Chaux, Alcides; Karram, Sarah; Miller, Jeremy S; Fajardo, Daniel A; Lee, Thomas K; Miyamoto, Hiroshi; Netto, George J

    2012-01-01

    About one half of all bladder neoplasms are noninvasive, and in those, the histologic grade is a crucial prognosticator. Few single-center studies have assessed the recurrence, progression, and cancer-related mortality rates of noninvasive high-grade papillary urothelial carcinomas. With this aim, we evaluated the clinicopathologic and outcome features of 85 patients with high-grade papillary urothelial carcinoma. Median age was 68 years, and 80.5% were men. Tumor size ranged from 0.3 to 13.0 cm (median, 1.6 cm). Recurrence was found in 36.5% of the patients, whereas tumor progression, defined as invasion of lamina propria or beyond, was identified in 40% of all cases. When present, lesion reappearance involved mostly 1 to 2 episodes. Metastasis appeared in 20% of the patients, and 15% died of disseminated bladder cancer. All cancer-related deaths occurred in the group of patients with progression, whereas patients with recurrence showed similar outcomes to those with no recurrence. For patients with tumor progression, clinical stage was significantly associated with outcome (P = .002). As for prognosis, tumor size was strongly associated with progression (P < .01). In conclusion, recurrence, progression, and cancer-specific mortality rates were 36.5%, 40%, and 15%, respectively. All the patients who died of cancer had a history of tumor progression. Patients with recurrences showed similar outcomes to those with no recurrence. Tumor size was strongly associated with tumor progression and cancer-specific survival, whereas clinical stage was significantly associated with outcome in the progression group. In light of the high recurrence and progression rates of high-grade papillary urothelial carcinoma, strict clinical surveillance aimed to detect early recurrent lesions, especially in patients with larger tumors, is warranted.

  14. Endometrial ablation

    MedlinePlus

    Hysteroscopy-endometrial ablation; Laser thermal ablation; Endometrial ablation-radiofrequency; Endometrial ablation-thermal balloon ablation; Rollerball ablation; Hydrothermal ablation; Novasure ablation

  15. Interval Between Hysterectomy and Start of Radiation Treatment Is Predictive of Recurrence in Patients With Endometrial Carcinoma

    SciTech Connect

    Cattaneo, Richard; Hanna, Rabbie K.; Jacobsen, Gordon; Elshaikh, Mohamed A.

    2014-03-15

    Purpose: Adjuvant radiation therapy (RT) has been shown to improve local control in patients with endometrial carcinoma. We analyzed the impact of the time interval between hysterectomy and RT initiation in patients with endometrial carcinoma. Methods and Materials: In this institutional review board-approved study, we identified 308 patients with endometrial carcinoma who received adjuvant RT after hysterectomy. All patients had undergone hysterectomy, oophorectomy, and pelvic and para-aortic lymph node evaluation from 1988 to 2010. Patients' demographics, pathologic features, and treatments were compared. The time interval between hysterectomy and the start of RT was calculated. The effects of time interval on recurrence-free (RFS), disease-specific (DSS), and overall survival (OS) were calculated. Following univariate analysis, multivariate modeling was performed. Results: The median age and follow-up for the study cohort was 65 years and 72 months, respectively. Eighty-five percent of the patients had endometrioid carcinoma. RT was delivered with high-dose-rate brachytherapy alone (29%), pelvic RT alone (20%), or both (51%). Median time interval to start RT was 42 days (range, 21-130 days). A total of 269 patients (74%) started their RT <9 weeks after undergoing hysterectomy (group 1) and 26% started ≥9 weeks after surgery (group 2). There were a total of 43 recurrences. Tumor recurrence was significantly associated with treatment delay of ≥9 weeks, with 5-year RFS of 90% for group 1 compared to only 39% for group 2 (P<.001). On multivariate analysis, RT delay of ≥9 weeks (P<.001), presence of lymphovascular space involvement (P=.001), and higher International Federation of Gynecology and Obstetrics grade (P=.012) were independent predictors of recurrence. In addition, RT delay of ≥9 weeks was an independent significant predictor for worse DSS and OS (P=.001 and P=.01, respectively). Conclusions: Delay in administering adjuvant RT after hysterectomy was

  16. Tibial bone metastasis as an initial presentation of endometrial carcinoma diagnosed by fine-needle aspiration cytology: A case report and review of the literature

    PubMed Central

    Boukhar, Sarag Aboujafar; Kaneshiro, Ricky; Schiller, Alan; Terada, Keith; Tauchi-Nishi, Pamela

    2015-01-01

    Endometrial cancer is the most common gynecologic malignancy in the United States. However, bony metastasis is infrequent and exceptionally rare as the initial presentation. We report a case of a 77-year-old female with a clinically silent endometrial carcinoma who presented with a left tibial metastasis as the first manifestation of her disease. Ours is only the third case diagnosed by fine-needle aspiration (FNA) cytology, and the first to detail the cytomorphologic features of metastatic endometrial cancer to bone. These microscopic findings, including three-dimensional cohesive clusters with cellular overlapping and cuboidal to columnar cells exhibiting low nuclear: cytoplasmic ratios and partially vacuolated cytoplasm, differ significantly from those of endometrial carcinoma on a Papanicolaou test. The tumor bore similarity to the more commonly encountered metastatic colon cancer, but immunohistochemical staining enabled reliable distinction between these entities. A review of osseous metastases of endometrial cancer demonstrates a predilection for bones of the lower extremity and pelvis with a predominance of the endometrioid histologic subtype. In about a quarter of the cases, the bony metastasis was the first manifestation of the cancer. FNA was an effective diagnostic modality for this unusual presentation of a common malignancy. Awareness of this entity and its differential diagnosis is essential for accurate and timely diagnosis. PMID:26085835

  17. Dasatinib in Treating Patients With Recurrent or Persistent Ovarian, Fallopian Tube, Endometrial or Peritoneal Cancer

    ClinicalTrials.gov

    2017-04-05

    Endometrial Clear Cell Adenocarcinoma; Estrogen Receptor Negative; Ovarian Clear Cell Cystadenocarcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Recurrent Uterine Corpus Carcinoma

  18. Endometrial hyperplasia.

    PubMed

    Mills, Anne M; Longacre, Teri A

    2010-11-01

    Endometrial hyperplasia is a heterogeneous set of pathologic lesions that range from mild, reversible glandular proliferations to direct cancer precursors. These lesions comprise a continuum of morphologic appearances, with the earliest proliferation represented by crowded glands with simple tubular architecture lined by cells resembling proliferative endometrium, whereas advanced proliferations in this continuum are characterized by crowded glands with complex architecture, often containing cells with nuclear atypia resembling low-grade endometrioid adenocarcinoma. The former "early" proliferations may be isolated to an endometrial polyp, but advanced proliferations are generally more diffusely present throughout the endometrium. There are at least three major classification systems for endometrial carcinoma precursor lesions, each of which trend toward overlap at the complex end of the spectrum. Although some classifications are based on a series of molecular genetic alterations (which may or may not translate into biologically or clinically relevant risk lesions), each classification scheme ultimately uses a series of histologic features, usually a combination of architecture and cytology, to establish a diagnosis of hyperplasia. Because different pathologists may apply different histologic criteria for endometrial hyperplasia depending on the classification system used, this article will provide an overview of the classifications used in current daily practice, present the histologic criteria and relative merits of each classification system, and discuss common and not so common causes of misclassification.

  19. Diagnostic Accuracy of MRI, DWI MRI, FDG-PET/CT and FEC PET/CT in the Detection of Lymph Node Metastases in Surgically Staged Endometrial and Cervical Carcinoma

    ClinicalTrials.gov

    2016-01-21

    Surgically Staged Endometrial and Cervical Carcinoma; Cervical Cancer: Invasive Disease, FIGO Stage 1B1 or Higher; Endometrial Cancer:; Stage 1A With Myometrial Invasion or Any Higher Stage and Grade 3; Stage 1A With Myometrial Invasion or Any Other Higher Stage and Serous Papillary or Clear Cell Sub-types; Stage II Disease or Above and Any Histology Grade

  20. The genomic landscape and evolution of endometrial carcinoma progression and abdominopelvic metastasis

    PubMed Central

    Gibson, William J.; Hoivik, Erling A.; Halle, Mari K.; Taylor-Weiner, Amaro; Cherniack, Andrew D.; Berg, Anna; Holst, Frederik; Zack, Travis I.; Werner, Henrica M. J.; Staby, Kjersti M.; Rosenberg, Mara; Stefansson, Ingunn M.; Kusonmano, Kanthida; Chevalier, Aaron; Mauland, Karen K.; Trovik, Jone; Krakstad, Camilla; Giannakis, Marios; Hodis, Eran; Woie, Kathrine; Bjorge, Line; Vintermyr, Olav K.; Wala, Jeremiah A.; Lawrence, Michael S.; Getz, Gad; Carter, Scott L.; Beroukhim, Rameen; Salvesen, Helga B.

    2016-01-01

    Recent studies have detailed the genomic landscape of primary endometrial cancers, but their evolution into metastases has not been characterized. We performed whole-exome sequencing of 98 tumor biopsies including complex atypical hyperplasias, primary tumors, and paired abdominopelvic metastases to survey the evolutionary landscape of endometrial cancer. We expanded and reanalyzed TCGA-data, identifying novel recurrent alterations in primary tumors, including mutations in the estrogen receptor cofactor NRIP1 in 12% of patients. We found that likely driver events tended to be shared by primary and metastatic tissue-samples, with notable exceptions such as ARID1A mutations. Phylogenetic analyses indicated that the sampled metastases typically arose from a common ancestral subclone that was not detected in the primary tumor biopsy. These data demonstrate extensive genetic heterogeneity within endometrial cancers and relative homogeneity across metastatic sites. PMID:27348297

  1. A subset of high-grade pulmonary neuroendocrine carcinomas shows up-regulation of matrix metalloproteinase-7 associated with nuclear beta-catenin immunoreactivity, independent of EGFR and HER-2 gene amplification or expression.

    PubMed

    Pelosi, Giuseppe; Scarpa, Aldo; Veronesi, Giulia; Spaggiari, Lorenzo; Del Curto, Barbara; Moore, Patrick S; Maisonneuve, Patrick; Sonzogni, Angelica; Masullo, Michele; Viale, Giuseppe

    2005-12-01

    Nuclear translocation of beta-catenin has been correlated with epidermal growth factor receptor (EGFR) overexpression/activation in non-small cell lung cancer. Less is known on beta-catenin transactivation in high-grade pulmonary neuroendocrine tumors and on the status of beta-catenin activating EGFR and human epidermal growth factor receptor 2 (HER-2) or beta-catenin target genes cyclin D1 and matrix metalloproteinase-7 (MMP-7). beta-catenin immunoreactivity was evaluated in 51 large-cell neuroendocrine carcinomas (LCNEC) and 45 small-cell lung carcinomas (SCLC). Nineteen cases were assessed for beta-catenin gene exon 3 mutations, expression of MMP-7, and expression/gene amplification of EGFR, HER-2, and cyclin D1. beta-catenin was expressed in all 96 high-grade neuroendocrine tumors, the vast majority (94%) showing >50% immunopositive cells. A disarrayed immunoreactivity, however, was commonly encountered consisting in variably altered membrane-associated patterns of staining along with progressive accumulation of cytoplasmic immunoreactivity. In LCNEC, but not in SCLC, the disarrayed patterns correlated with EGFR and HER-2 protein expression. beta-catenin nuclear accumulation was found in nine tumors, including seven LCNEC and two SCLC, and was always associated with disarrayed immunoreactivity and increased MMP-7, but not cyclin D1 expression. These cases, however, did not show beta-catenin gene mutations or EGFR and HER-2 gene amplification or expression. No association was found between nuclear beta-catenin and any clinicopathological variable including patients' survival. The subcellular compartmentalization of beta-catenin is profoundly altered in high-grade pulmonary neuroendocrine tumors. A minor subset of these tumors shows beta-catenin nuclear accumulation in association with increased expression of MMP-7, but not of cyclin D1, independent of EGFR and HER-2 gene amplification or expression.

  2. Diagnostic role of circulating YKL-40 in endometrial carcinoma patients: a meta-analysis of seven related studies.

    PubMed

    Cheng, Daye; Sun, Ying; He, Hu

    2014-12-01

    In the past decade, several studies have suggested a possible link between circulating YKL-40 levels and endometrial carcinoma (EC), but have arrived at inconsistent results. Therefore, we conducted the present meta-analysis and aim to disclose a more comprehensive evaluation of the sensitivity, specificity, and diagnostic accuracy of YKL-40 in EC. We systematically searched PubMed, Embase, Web of Science, Science Direct, SpringerLink, EBSCO, Wanfang, and Chinese National Knowledge Infrastructure databases for studies that evaluated the diagnostic value of YKL-40 in endometrial cancer. The STATA software 12.0 and Meta-Disc software were used to test the heterogeneity and to evaluate the overall test performance. A total of seven studies including 234 EC cases and 300 controls were included in our meta-analysis. The summary estimates of YKL-40 for EC diagnosis indicated a moderately high diagnostic accuracy for circulating YKL-40, with a sensitivity of 0.74, a specificity of 0.87, a PLR of 5.74, a NLR of 0.30, a DOR of 19.14, and an AUC of 0.80. On the basis of our meta-analysis, therefore, circulating YKL-40 could be promising and meaningful in the diagnosis of EC.

  3. Molecular Alterations of TP53 are a Defining Feature of Ovarian High-Grade Serous Carcinoma: A Rereview of Cases Lacking TP53 Mutations in The Cancer Genome Atlas Ovarian Study.

    PubMed

    Vang, Russell; Levine, Douglas A; Soslow, Robert A; Zaloudek, Charles; Shih, Ie-Ming; Kurman, Robert J

    2016-01-01

    The Cancer Genome Atlas has reported that 96% of ovarian high-grade serous carcinomas (HGSCs) have TP53 somatic mutations suggesting that mutation of this gene is a defining feature of this neoplasm. In the current study, 5 gynecologic pathologists independently evaluated hematoxylin and eosin slides of 14 available cases from The Cancer Genome Atlas classified as HGSC that lacked a TP53 mutation. The histologic diagnoses rendered by these pathologists and the accompanying molecular genetic data are the subject of this report. Only 1 case (Case 5), which contained a homozygous deletion of TP53, had unanimous interobserver agreement for a diagnosis of pure HGSC. In 1 case (Case 3), all 5 observers (100%) rendered a diagnosis of HGSC; however, 3 observers (60%) noted that the histologic features were not classic for HGSC and suggested this case may have arisen from a low-grade serous carcinoma (arisen from an alternate pathway compared with the usual HGSC). In 2 cases (Cases 4 and 12), only 3 observers (60%) in each case, respectively, interpreted it as having a component of HGSC. In the remaining 10 (71%) of tumors (Cases 1, 2, 6-11, 13, and 14), the consensus diagnosis was not HGSC, with individual diagnoses including low-grade serous carcinoma, high-grade endometrioid carcinoma, HGSC, metastatic carcinoma, clear cell carcinoma, atypical proliferative (borderline) serous tumor, and adenocarcinoma, not otherwise specified. Therefore, 13 (93%) of the tumors (Cases 1-4 and 6-14) were either not a pure HGSC or represented a diagnosis other than HGSC, all with molecular results not characteristic of HGSC. Accordingly, our review of the TP53 wild-type HGSCs reported in The Cancer Genome Atlas suggests that 100% of de novo HGSCs contain TP53 somatic mutations or deletions, with the exception of the rare HGSCs that develop from a low-grade serous tumor precursor. We, therefore, propose that lack of molecular alterations of TP53 are essentially inconsistent with the

  4. AXL modulates extracellular matrix protein expression and is essential for invasion and metastasis in endometrial cancer

    PubMed Central

    Meller, Eric; Desai, Riva A.; Arif, Batool; Rankin, Erinn B.; Bligard, Katherine H.; Meyerson, Cherise; Hagemann, Ian S.; Massad, Maria; Thaker, Premal H.; Hagemann, Andrea R.; McCourt, Carolyn K.; Powell, Matt A.; Mutch, David G.; Fuh, Katherine C.

    2016-01-01

    The receptor tyrosine kinase AXL promotes migration, invasion, and metastasis. Here, we evaluated the role of AXL in endometrial cancer. High immunohistochemical expression of AXL was found in 76% (63/83) of advanced-stage, and 77% (82/107) of high-grade specimens and correlated with worse survival in uterine serous cancer patients. In vitro, genetic silencing of AXL inhibited migration and invasion but had no effect on proliferation of ARK1 endometrial cancer cells. AXL-deficient cells showed significantly decreased expression of phospho-AKT as well as uPA, MMP-1, MMP-2, MMP-3, and MMP-9. In a xenograft model of human uterine serous carcinoma with AXL-deficient ARK1 cells, there was significantly less tumor burden than xenografts with control ARK1 cells. Together, these findings underscore the therapeutic potentials of AXL as a candidate target for treatment of metastatic endometrial cancer. PMID:27764792

  5. Laparoscopy versus laparotomy for the management of endometrial carcinoma in morbidly obese patients: a prospective study

    PubMed Central

    Bige, Özgür; Demir, Ahmet; Saatli, Bahadır; Koyuncuoğlu, Meral; Saygılı, Uğur

    2015-01-01

    Objective To compare the results of total laparoscopic hysterectomy and total abdominal hysterectomy in morbidly obese women with early stage endometrial cancer. Material and Methods This prospective study was conducted on 140 morbidly obese women with body mass indices ≥35 kg/m2 and presenting with clinical stage 1 endometrial cancer. The patients underwent total laparoscopic hysterectomy (n=70) or total abdominal hysterectomy (n=70), bilateral salpingo-oophorectomy, pelvic lymphadenectomy, and peritoneal washing. Age, parity, menopausal status, weight, height, medical problems, history of previous laparotomy, surgical procedure, operative time, estimated amount of blood loss, preoperative hematocrit, postoperative hematocrit, operative complications, conversion to laparotomy, need for intraoperative or postoperative blood transfusion, intraoperative and postoperative complications, secondary surgery, tumor stage, grade, histology, number of recovered lymph nodes, and visual pain scores of the patients were recorded. Results Postoperative complications were significantly higher in the laparotomy group. Hospital stay in the laparoscopy group was significantly lower than that in the laparotomy group. The visual pain scores were significantly higher in the laparotomy group on the first, second, and third postoperative days and on the day of discharge from the hospital. Resuming activity took a significantly longer time in the laparotomy group (34.70 days) than in the laparoscopic group (17.89 days). Conclusion With the availability of skilled endoscopic surgeons, most obese women with early stage endometrial cancer can be safely managed by performing laparoscopy with an excellent surgical outcome, shorter hospitalization, less postoperative pain, and faster resumption of full activity. PMID:26401110

  6. Low-grade metastases in high-grade clear cell renal cell carcinomas: A clinicopathologic study of 4 cases with an insight into the role of mesenchymal-to-epithelial transition process.

    PubMed

    López, José I; Mosteiro, Lorena; Guarch, Rosa; Larrinaga, Gorka; Pulido, Rafael; Angulo, Javier C

    2016-02-01

    Clear cell renal cell carcinoma (CCRCC) frequently develops distant metastases. However, high-grade primary CCRCC rarely leads to low-grade metastases. Cellular changes occurring during neoplastic progression known as epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions explain this apparent contradiction. Four high-grade CCRCCs, which lead to low-grade metastases, are analyzed in this study, with the focus on epithelial-to-mesenchymal and mesenchymal-to-epithelial processes. Clinicopathologic data have been collected retrospectively and immunohistochemistry has been performed with E-cadherin, N-cadherin, vimentin, and WT-1. Three cases had organ-confined disease (2 pT2 and 1 pT1b). Three cases were G3 and 1 case was G4. Lung (3 cases), bone (2 cases), and pancreas (1 case) were the metastatic organs (2 patients developed multiple metastases). Metastases were G1 in all the cases. Average elapsed time between the primary tumor and the metastasis was 35.5 months. Three patients died of disease after 36, 120, and 180 months of follow-up, respectively. One patient is alive without disease after 75 months of follow-up. E-cadherin and N-cadherin showed concordant immunostaining patterns between primaries and metastases but inverse when correlated with Fuhrman grade. Hence, E-cadherin was positive in G3 cases and negative in G4, whereas N-cadherin was negative in G3 and positive in G4. Vimentin was positive in primaries and metastases only in 2 cases. WT-1 was consistently negative in all cases. In conclusion, pathologists must remember that high-grade CCRCC may develop low-grade metastases. Cadherin switching seems to be related to Fuhrman grade in this group of cases. This preliminary observation must be confirmed in longer studies.

  7. Urokinase-type Plasminogen Activator Resulting from Endometrial Carcinogenesis Enhances Tumor Invasion and Correlates with Poor Outcome of Endometrial Carcinoma Patients

    PubMed Central

    Huang, Chia-Yen; Chang, Ming-Cheng; Huang, Wei-Yun; Huang, Ching-Ting; Tang, Yu-Chien; Huang, Hsien-Da; Kuo, Kuan-Ting; Chen, Chi-An; Cheng, Wen-Fang

    2015-01-01

    The purpose of this study was to identify the dysregulated genes involved in the tumorigenesis and progression of endometrial endometrioid adenocarcinoma (EEC), and their possible mechanisms. Endometrial specimens including normal endometrial tissues, atypical endometrial hyperplasia, and EEC were analyzed. The expression profiles were compared using GeneChip Array. The gene expression levels were determined by real-time RT-PCR in the training and testing sets to correlate the clinico-pathological parameters of EEC. Immunoblotting, in vitro cell migration and invasion assays were performed in human endometrial cancer cell lines and their transfectants. In microarray analysis, seven dysregulated genes were identified. Only the levels of urokinase-type plasminogen activator (uPA) were higher in EEC with deep myometrial invasion, positive lympho-vascular space invasion, lymph node metastasis, and advanced stages. After multivariate analysis, uPA was the only independent poor prognostic factor for disease-free survival in the EEC patients (hazard ratio: 4.65, p = 0.03). uPA may enhance the migratory and invasive capabilities of endometrial tumor cells by the phosphorylation of ERK1/2, Akt and p38 molecules. uPA is a dysregulated gene involved in the tumorigenesis, bio-pathological features and outcomes of EEC. uPA may be a potential molecule and target for the detection and treatment of EEC. PMID:26033187

  8. Value of 18F-FDG PET/CT and MRI in diagnosing primary endometrial small cell carcinoma

    PubMed Central

    Wan, Qi; Jiao, Qian; Zhou, Jiaxuan; Zou, Qiao; Deng, Yingshi

    2014-01-01

    Primary small cell carcinoma (SCC) is a group of aggressive neoplasms that mainly arise from the lung and digestive tract. Endometrial small cell carcinoma (ESCC) is extremely rare. To our knowledge, less than 90 cases have been reported, and most of these reports were dedicated to describing the clinicopathologic or immunochemical features of ESCC. Herein, we present a new case of ESCC involving a 51-year-old woman and mainly focus on the magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT) findings. MRI showed that the uterus was significantly enlarged (11.6 cm × 11.1 cm × 14.4 cm), and a giant irregular mass (7.5 cm × 8.4 cm × 8.5 cm) was observed in the uterine cavity. The lesion demonstrated an extremely low apparent diffusion coefficient (ADC) value [(0.553±0.088)×10–3 mm2/s] and a high FDG uptake value (22.7). Multiple metastatic lymph nodes (LNs) were identified at different positions, with diameters ranging from 0.3 to 2.8 cm and a maximum standardized uptake value (SUVmax) ranging from 6.9 to 19.3. PMID:25400430

  9. Prognostic impact of programmed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor-infiltrating lymphocytes in ovarian high grade serous carcinoma

    PubMed Central

    Kulbe, Hagen; Sehouli, Jalid; Wienert, Stephan; Lindner, Judith; Budczies, Jan; Bockmayr, Michael; Dietel, Manfred; Denkert, Carsten; Braicu, Ioana; Jöhrens, Korinna

    2016-01-01

    Aims Antibodies targeting the checkpoint molecules programmed cell death 1 (PD-1) and its ligand PD-L1 are emerging cancer therapeutics. We systematically investigated PD-1 and PD-L1 expression patterns in the poor-prognosis tumor entity high-grade serous ovarian carcinoma. Methods PD-1 and PD-L1 protein expression was determined by immunohistochemistry on tissue microarrays from 215 primary cancers both in cancer cells and in tumor-infiltrating lymphocytes (TILs). mRNA expression was measured by quantitative reverse transcription PCR. An in silico validation of mRNA data was performed in The Cancer Genome Atlas (TCGA) dataset. Results PD-1 and PD-L1 expression in cancer cells, CD3+, PD-1+, and PD-L1+ TILs densities as well as PD-1 and PD-L1 mRNA levels were positive prognostic factors for progression-free (PFS) and overall survival (OS), with all factors being significant for PFS (p < 0.035 each), and most being significant for OS. Most factors also had prognostic value that was independent from age, stage, and residual tumor. Moreover, high PD-1+ TILs as well as PD-L1+ TILs densities added prognostic value to CD3+TILs (PD-1+: p = 0.002,; PD-L1+: p = 0.002). The significant positive prognostic impact of PD-1 and PD-L1 mRNA expression could be reproduced in the TCGA gene expression datasets (p = 0.02 and p < 0.0001, respectively). Conclusions Despite their reported immune-modulatory function, high PD-1 and PD-L1 levels are indicators of a favorable prognosis in ovarian cancer. Our data indicate that PD-1 and PD-L1 molecules are biologically relevant regulators of the immune response in high-grade serous ovarian carcinoma, which is an argument for the evaluation of immune checkpoint inhibiting drugs in this tumor entity. PMID:26625204

  10. High expression of SALL4 and fascin, and loss of E-cadherin expression in undifferentiated/dedifferentiated carcinomas of the endometrium

    PubMed Central

    Onder, Semen; Taskin, Orhun Cig; Sen, Fatma; Topuz, Samet; Kucucuk, Seden; Sozen, Hamdullah; Ilhan, Ridvan; Tuzlali, Sitki; Yavuz, Ekrem

    2017-01-01

    Abstract Undifferentiated/dedifferentiated endometrial carcinomas (UCE/DCEs) of the endometrium are rare tumors with poor prognosis. There are few clinicopathologic studies with detailed immunohistochemical analysis regarding UCE/DCEs. We evaluated the diagnostic value of a selected tumor stem-cell marker and epithelial-mesenchymal transition (EMT) markers, in addition to previously studied markers in identifying UCE/DCEs from other types of high-grade endometrial carcinomas. Eleven cases of UCE/DCEs with complete clinical follow-up that were diagnosed between 2006 and 2015 were included in the study. For immunohistochemical comparison, 11 clinically matched cases for each type of other high-grade endometrial carcinomas (high-grade endometrioid (F3-EC), serous [SC], and clear cell carcinoma [CCC]) were used as a control group. An immunohistochemical analysis including fascin, SALL4, E-cadherin, and β-catenin, in addition to epithelial and neuroendocrine markers was performed in each case. The majority of UCE/DCEs displayed diffuse expression of fascin (81.9%) and loss of E-cadherin expression (54.5%). SALL4 expression was detected in 36.3% of the UCE/DCE cases. SALL4 expression was significantly more frequent in UCE/DCEs than all other high-grade carcinomas (P < 0.001). Loss of E-cadherin and fascin expression was significantly more frequent in UCE/DCEs than high-grade endometrioid and clear cell adenocarcinomas (P = 0.012, 0.014 and P = 0.01, 0.003, respectively). We suggest that loss of E-cadherin expression together with fascin and SALL4 immunopositivity in addition to morphologic features have an impact in differential diagnosis of UCE/DCEs from other high-grade endometrial carcinomas. PMID:28272224

  11. EFEMP1 is repressed by estrogen and inhibits the epithelial-mesenchymal transition via Wnt/β-catenin signaling in endometrial carcinoma.

    PubMed

    Yang, Tingting; Zhang, Huilin; Qiu, Haifeng; Li, Bilan; Wang, Jingyun; Du, Guiqiang; Ren, Chune; Wan, Xiaoping

    2016-05-03

    Epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1) acted as a tumor suppressor in endometrial carcinoma (EC). However, the correlation between EFEMP1 and estrogen is unknown. Here, we reported that the expression of EFEMP1 was conversely associated with ERα in endometrial carcinoma tissues. In endometrial carcinoma cells, estrogen/ERα signaling significantly suppressed the expression of EFEMP1. Moreover, chromatin immunoprecipitation (CHIP) and dual-luciferase reporter assays demonstrate that estrogen/ERα bound to the estrogen response element (ERE) located in EFEMP1 promoter and repressed its expression. Besides, in vitro and in vivo, EFEMP1 could remarkably suppress the expression of epithelial-mesenchymal transition (EMT) markers such as Vimentin, Snail and the Wnt/β-catenin target genes like Cyclin-D1 and c-Myc, which could be restored when EFEMP1 was silenced. In addition, XAV93920 (the inhibitor of the Wnt/β-catenin pathway) blocked and LiCl (the activator of the Wnt/β-catenin pathway) enhanced the effect of EFEMP1 on EMT. In conclusion, we demonstrated that estrogen/ERα signal suppresses EFEMP1. Besides, EFEMP1 inhibits EMT via interfering the Wnt/β-catenin signaling.

  12. Treatment outcomes and prognostic factors in mexican patients with endometrial carcinoma with emphasis on patients receiving radiotherapy after surgery: an institutional perspective.

    PubMed

    Flores, Christian; Mariscal, Carlos; Celis, Alfredo; Balcázar, Nidia M; Meneses, Abelardo; Mohar, Alejandro; Mota, Aida; Trejo, Elizabeth

    2012-01-01

    Aim. To analyze the clinical characteristics and treatment outcomes in patients with endometrial carcinoma treated in a Latin American institute with emphasis in patients receiving adjuvant radiotherapy. Methods. A total of 412 patients with endometrial carcinoma admitted to our hospital between 1998 and 2008 were evaluated, retrospectively. The mean age was 55 years (28-87). Two hundred seventy patients received RT following surgery. Stage distribution was as follows: 221 patients (54%) stage I, 86 patients (21%) stage II, and 103 patients (24.5%) stage III and 2 patients (0.5%) stage IVA. Results. Overall survival rate was 95% at 2 years, 84% at 5 years, and 79% at 10 years. By the end of followup, 338 patients (82%) were disease-free, and 13 (3%) were alive with disease. Univariate and multivariate analyses identified age, grade, serosal and adnexial involvement as significant predictors for overall survival. Conclusion. The results of our study suggests that early-stage, low-grade endometrial cancer with no risk factors should not receive external beam radiotherapy, intermediate risk patients should receive only vaginal vault brachytherapy, and the use of chemotherapy with radiotherapy for patients high-risk and advanced-stage carcinoma the addition of radiotherapy is associated with a better survival being an effective therapeutic option.

  13. EFEMP1 is repressed by estrogen and inhibits the epithelial-mesenchymal transition via Wnt/β-catenin signaling in endometrial carcinoma

    PubMed Central

    Qiu, Haifeng; Li, Bilan; Wang, Jingyun; Du, Guiqiang; Ren, Chune; Wan, Xiaoping

    2016-01-01

    Epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1) acted as a tumor suppressor in endometrial carcinoma (EC). However, the correlation between EFEMP1 and estrogen is unknown. Here, we reported that the expression of EFEMP1 was conversely associated with ERα in endometrial carcinoma tissues. In endometrial carcinoma cells, estrogen/ERα signaling significantly suppressed the expression of EFEMP1. Moreover, chromatin immunoprecipitation (CHIP) and dual-luciferase reporter assays demonstrate that estrogen/ERα bound to the estrogen response element (ERE) located in EFEMP1 promoter and repressed its expression. Besides, in vitro and in vivo, EFEMP1 could remarkably suppress the expression of epithelial-mesenchymal transition (EMT) markers such as Vimentin, Snail and the Wnt/β-catenin target genes like Cyclin-D1 and c-Myc, which could be restored when EFEMP1 was silenced. In addition, XAV93920 (the inhibitor of the Wnt/β-catenin pathway) blocked and LiCl (the activator of the Wnt/β-catenin pathway) enhanced the effect of EFEMP1 on EMT. In conclusion, we demonstrated that estrogen/ERα signal suppresses EFEMP1. Besides, EFEMP1 inhibits EMT via interfering the Wnt/β-catenin signaling. PMID:27015552

  14. Toward standard HER2 testing of endometrial serous carcinoma: 4-year experience at a large academic center and recommendations for clinical practice.

    PubMed

    Buza, Natalia; English, Diana P; Santin, Alessandro D; Hui, Pei

    2013-12-01

    HER2 overexpression and/or amplification have been reported in endometrial serous carcinoma, suggesting that HER2 may be a promising therapeutic target. However, there is considerable variation in the reported rates of HER2 overexpression and amplification, likely--at least in part--resulting from variability in the testing methods, interpretation, and scoring criteria used. Unlike in breast and gastric cancer, currently there are no established guidelines for HER2 testing in endometrial carcinoma. A total of 108 endometrial carcinoma cases--85 pure serous carcinomas and 23 mixed endometrial carcinomas with serous component--were identified over a 4-year period. All H&E and HER2 immunohistochemical slides were reviewed and HER2 FISH results (available on 52 cases) were retrieved from pathology reports. HER2 immunohistochemical scores were assigned according to the FDA criteria and the current breast ASCO/CAP scoring criteria. Clinical information was retrieved from the patients' medical records. Thirty-eight cases (35%) showed HER2 overexpression and/or gene amplification, 20 of which (53%) had significant heterogeneity of protein expression by immunohistochemistry. Lack of apical membrane staining resulting in a lateral/basolateral staining pattern was observed in the majority of HER2-positive tumors. Five of the HER2-positive cases (13%) demonstrated discrepant immunohistochemical scores when using the FDA versus ASCO/CAP scoring system. The overall concordance rate between HER2 immunohistochemistry and FISH was 75% (39/52) when using the FDA criteria, compared with 81% (42/52) by the ASCO/CAP scoring system. In conclusion, in this largest comprehensive study, 35% of endometrial serous carcinoma harbors HER2 protein overexpression and/or gene amplification, over half of which demonstrate significant heterogeneity of protein expression. The current breast ASCO/CAP scoring criteria provide the highest concordance between immunohistochemistry and FISH. Assessment of

  15. Protocadherin 10 inhibits cell proliferation and induces apoptosis via regulation of DEP domain containing 1 in endometrial endometrioid carcinoma.

    PubMed

    Yang, Yihua; Jiang, Yan; Jiang, Man; Zhang, Jiamiao; Yang, Bing; She, Yuanping; Wang, Wanxue; Deng, Yan; Ye, Yuan

    2016-04-01

    Endometrial cancer is the most common gynecologic malignancy and about 80% of these cancers are endometrial endometrioid carcinoma (EEC). Previously, we have demonstrated that protocadherin 10 (PCDH10) is a tumor suppressor gene in EEC, and in this study we further explored the molecular mechanisms of PCDH10 in EEC. We first detect the PCDH10 expression in EEC tissues and then investigate the mechanism in two EEC cell lines. The mRNA and protein expression levels were measured by quantitative real time PCR (qRT-PCR) and western blot, respectively; Cell growth was determined by MTS, CCK-8 and colony formation assays; Cell cycle was determined by flow cytometry, and cell apoptosis was examined by flow cytometry and TUNEL assay. The downstream mediator of PCHD10 was confirmed by Topflash luciferase reporter assay. QRT-PCR and western blot results showed that PCDH10 was down-regulated in EEC clinical tissues. Restoration of PCDH10 suppressed cell growth and induced apoptosis in EEC cells. Dishevelled, EGL-10 and Pleckstrin domain containing 1 (DEPDC1) was a potential downstream mediator of PCDH10 as revealed by RNA-sequencing, and mechanistic studies suggested that DEPDC1 is a downstream mediator and promotes cell growth and induces apoptosis in EEC cells. Western blot further showed that PCDH10 restoration activate apoptotic signaling pathway via caspase signaling in both EEC cell lines and EEC clinical tissues. Collectively, our results suggest that PCDH10-DEPDC1-caspase signaling may be a novel regulatory axis in EEC development and it will be of great interest to explore the clinical significance of PCDH10 and DEPDC1 in the future.

  16. Differential Expression and Clinical Significance of DNA Methyltransferase 3B (DNMT3B), Phosphatase and Tensin Homolog (PTEN) and Human MutL Homologs 1 (hMLH1) in Endometrial Carcinomas

    PubMed Central

    Li, Wenting; Wang, Ying; Fang, Xinzhi; Zhou, Mei; Li, Yiqun; Dong, Ying; Wang, Ruozheng

    2017-01-01

    Background The aim of this study was to investigate the expression and the clinicopathologic significance of DNA methyltransferase 3B (DNMT3B), phosphatase and tensin homolog (PTEN) and human MutL homologs 1 (hMLH1) in endometrial carcinomas between Han and Uygur women in Xinjiang. Material/Methods The expression of DNMT3B, PTEN, and hMLH1 in endometrial carcinomas were assessed by immunohistochemistry, followed by an analysis of their relationship to clinical-pathological features and prognosis. Results There were a 61.7% (95/154) overexpression of DNMT3B, 50.0% (77/154) loss of PTEN expression and 18.2% (28/154) loss of hMLH1 expression. The expression of DNMT3B and PTEN in endometrial carcinomas was statistically significantly different between Uygur women and Han women (p=0.001, p=0.010, respectively). DNMT3B expression was statistically significant based on the grade of endometrial carcinomas (p=0.031). PTEN loss was statistically significant between endometrioid carcinomas (ECs) and non endometrioid carcinomas (NECs) (p=0.040). DNMT3B expression was statistically significant in different myometrial invasion groups in Uygur women (p=0.010). Furthermore, the correlation of DNMT3B and PTEN expression was significant in endometrial carcinomas (p=0.021). PTEN expression was statistically significant in the overall survival (OS) rate of women with endometrial cancers (p=0.041). Conclusions Our findings suggest that PTEN and DNMT3B possess common regulation features as well as certain ethnic differences in expression between Han women and Uygur women. An interaction may exist in the pathogenesis of endometrial carcinoma. DNMT3B was expressed differently in cases of myometrial invasion and PTEN was associated with OS, which suggested that these molecular markers may be useful in the evaluation of the biological behavior of endometrial carcinomas and may be useful indicators of prognosis in women with endometrial carcinomas. PMID:28220037

  17. Assessing sirtuin expression in endometrial carcinoma and non-neoplastic endometrium.

    PubMed

    Bartosch, Carla; Monteiro-Reis, Sara; Almeida-Rios, Diogo; Vieira, Renata; Castro, Armando; Moutinho, Manuel; Rodrigues, Marta; Graça, Inês; Lopes, José Manuel; Jerónimo, Carmen

    2016-01-12

    Sirtuins participate in hormone imbalance, metabolism and aging, which are important processes for endometrial cancer (EC) development. Sirtuins mRNA expression (SIRT1 to 7) was determined in 76 ECs (63 Type I, 12 Type II and one mixed EC), and 30 non-neoplastic endometria (NNE) by quantitative real-time PCR. SIRT1 and SIRT7 protein expression was evaluated by immunohistochemistry using Allred score. Compared to NNE, ECs showed SIRT7 (p < 0.001) mRNA overexpression, whereas SIRT1 (p < 0.001), SIRT2 (p < 0.001), SIRT4 (p < 0.001) and SIRT5 (p < 0.001) were underexpressed. No significant differences were observed for SIRT3 and SIRT6. Type II ECs displayed lower SIRT1 (p = 0.032) and SIRT3 (p = 0.016) transcript levels than Type I ECs. Concerning protein expression, SIRT1 immunostaining median score was higher in ECs compared to NNE epithelium (EC = 5 vs. NNE = 2, p < 0.001), while SIRT7 was lower in ECs (EC = 6 vs. NNE = 7, p < 0.001). No significant associations were found between SIRT1/7 immunoexpression and histological subtype, grade, lymphovascular invasion or stage. Our data shows that sirtuins are deregulated in EC. The diversity of expression patterns observed suggests that sirtuins may have distinctive roles in endometrial cancer similarly to what has been described in other cancer models.

  18. Cholesterol Synthetase DHCR24 Induced by Insulin Aggravates Cancer Invasion and Progesterone Resistance in Endometrial Carcinoma

    PubMed Central

    Dai, Miao; Zhu, Xiao-Lu; Liu, Fei; Xu, Qin-Yang; Ge, Qiu-Lin; Jiang, Shu-Heng; Yang, Xiao-Mei; Li, Jun; Wang, Ya-Hui; Wu, Qing-Kai; Ai, Zhi-Hong; Teng, Yin-Cheng; Zhang, Zhi-Gang

    2017-01-01

    3β-Hydroxysteroid-Δ24 reductase (DHCR24), the final enzyme of the cholesterol biosynthetic pathway, has been associated with urogenital neoplasms. However, the function of DHCR24 in endometrial cancer (EC) remains largely elusive. Here, we analyzed the expression profile of DHCR24 and the progesterone receptor (PGR) in our tissue microarray of EC (n = 258), the existing EC database in GEO (Gene Expression Omnibus), and TCGA (The Cancer Genome Atlas). We found that DHCR24 was significantly elevated in patients with EC, and that the up-regulation of DHCR24 was associated with advanced clinical stage, histological grading, vascular invasion, lymphatic metastasis, and reduced overall survival. In addition, DHCR24 expression could be induced by insulin though STAT3, which directly binds to the promoter elements of DHCR24, as demonstrated by ChIP-PCR and luciferase assays. Furthermore, genetically silencing DHCR24 inhibited the metastatic ability of endometrial cancer cells and up-regulated PGR expression, which made cells more sensitive to progestin. Taken together, we have demonstrated for the first time the crucial role of the insulin/STAT3/DHCR24/PGR axis in the progression of EC by modulating the metastasis and progesterone response, which could serve as potential therapeutic targets for the treatment of EC with progesterone receptor loss. PMID:28112250

  19. Improved Survival Endpoints With Adjuvant Radiation Treatment in Patients With High-Risk Early-Stage Endometrial Carcinoma

    SciTech Connect

    Elshaikh, Mohamed A.; Vance, Sean; Suri, Jaipreet S.; Mahan, Meredith; Munkarah, Adnan

    2014-02-01

    Purpose/Objective(s): To determine the impact of adjuvant radiation treatment (RT) on recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) in patients with high-risk 2009 International Federation of Gynecology and Obstetrics stage I-II endometrial carcinoma. Methods and Materials: We identified 382 patients with high-risk EC who underwent hysterectomy. RFS, DSS, and OS were calculated from the date of hysterectomy by use of the Kaplan-Meier method. Cox regression modeling was used to explore the risks associated with various factors on survival endpoints. Results: The median follow-up time for the study cohort was 5.4 years. The median age was 71 years. All patients underwent hysterectomy and salpingo-oophorectomy, 93% had peritoneal cytology, and 85% underwent lymphadenectomy. Patients with endometrioid histology constituted 72% of the study cohort, serous in 16%, clear cell in 7%, and mixed histology in 4%. Twenty-three percent of patients had stage II disease. Adjuvant management included RT alone in 220 patients (57%), chemotherapy alone in 25 patients (7%), and chemoradiation therapy in 27 patients (7%); 110 patients (29%) were treated with close surveillance. The 5-year RFS, DSS, and OS were 76%, 88%, and 73%, respectively. On multivariate analysis, adjuvant RT was a significant predictor of RFS (P<.001) DSS (P<.001), and OS (P=.017). Lymphovascular space involvement was a significant predictor of RFS and DSS (P<.001). High tumor grade was a significant predictor for RFS (P=.038) and DSS (P=.025). Involvement of the lower uterine segment was also a predictor of RFS (P=.049). Age at diagnosis and lymphovascular space involvement were significant predictors of OS: P<.001 and P=.002, respectively. Conclusion: In the treatment of patients with high-risk features, our study suggests that adjuvant RT significantly improves recurrence-free, disease-specific, and overall survival in patients with early-stage endometrial carcinoma

  20. Does hysteroscopy worsen prognosis in women with type II endometrial carcinoma?

    PubMed Central

    Kong, Wei-Min; Yan, Zhen; Han, Chao; Zhao, Hui; Liu, Ting-Ting; Zhang, Tong-Qing; Song, Dan; Jiao, Si-Meng; Zhou, Chunxiao

    2017-01-01

    Background Prior studies evaluating the impact of hysteroscopy on outcomes in endometrial cancer have predominantly evaluated type I tumors. We sought to evaluate whether hysteroscopy worsens prognosis in type II endometrial cancer. Methods A retrospective cohort analysis of 140 patients from two institutions with type II endometrial cancer was performed. Women who underwent either diagnostic hysteroscopy (HSC) or dilation and curettage (D&C) for cancer diagnosis from June 2001 until June 2010 were included. The clinical and pathologic characteristics, including peritoneal cytology results were reviewed. The primary endpoint was disease-specific survival (DSS). The exposure of interest was hysteroscopy. Survival curves were projected using the Kaplan-Meier method and compared using the log-rank test. Results There was no difference in age, histology, stage, depth of myometrial invasion, adnexal involvement, or nodal metastasis between HSC and D&C patients. Positive cytology was found in 16/54 (30%) patients following HSC and in 10/86 (12%) following D&C (p = 0.008). Fourteen patients with stage I and II disease had positive peritoneal cytology, with 11/40 (27.5%) patients in the HSC group and 3/59 (5%) patients in the D&C group(p = 0.002). Median DSS was clinically different for the HSC and D&C groups, but statistical significance was not reached (53 versus 63.5 months, p = 0.34). For stage I and II patients, 18/99 (18%) were dead of EC, with a median DSS of 60 months for HSC and 71 months for D&C (p = 0.82). Overall 46 (33%) patients developed a recurrence, with 18/54 (33%) in the HSC group compared to 28/86 (32%) in the D&C group (p = 0.92). There was no difference in recurrence location between groups. Conclusions Diagnostic hysteroscopy significantly increased the rate of positive peritoneal cytology at the time of surgical staging in this cohort of patients with type II EC. However, we were unable to detect a difference in prognosis as measured by DSS. PMID

  1. Spontaneous uterine perforation due to clostridial gas gangrene associated with endometrial carcinoma.

    PubMed

    Kurashina, Ryuhei; Shimada, Hiromi; Matsushima, Takashi; Doi, Daisuke; Asakura, Hirobumi; Takeshita, Toshiyuki

    2010-06-01

    Few cases of clostridial gas gangrene associated with uterine malignancy have been reported. We report on a 46-year-old woman with clostridial sepsis. On the day of admission due to severe abdominal pain, peritonitis was diagnosed, and computed tomography showed free air in the abdomen. At emergency laparotomy, perforation of the necrotic uterine wall was observed. During hysterectomy, septic shock developed, and life-saving therapy was performed in the intensive care unit after surgery. Pathological examination of the necrotic uterine wall showed grade III endometrial adenocarcinoma of the uterine endometrium (International Federation of Gynecology and Obstetrics stage IIIa) with gas gangrene due to Clostridium perfringens. This report aims to alert gynecologists to the possibility that clostridial gas gangrene of the uterus can occur in patients with peritonitis and intra-abdominal free air. Early recognition and aggressive therapy can save patients' lives.

  2. Effect of Mechanism of Action of Different ω-6/ω-3 Polyunsaturated Fatty Acids Ratio on the Growth of Endometrial Carcinoma Mice.

    PubMed

    Lu, Xiaoyuan; Ding, Xuan; Jing, Li

    2015-04-01

    To explore the effect and mechanism of action of different ω-6/ω-3 polyunsaturated fatty acids (PUFAs) ratio on the expression of AKT and mTOR in mice bearing endometrial carcinoma. Once the human endometrial carcinoma xenograft models were successfully established, 40 BALB/C mice were randomized into five groups: group A (ω-6 PUFAs), group B (10:1 ω-6/ω-3 PUFAs), group C (control group), group D (1:1 ω-6/ω-3 PUFAs), and group E (ω-3 PUFAs). Six weeks post-treatment, mice were sacrificed and the xenograft tissues were harvested for immunohistochemical SP analysis of AKT and mTOR expression. AKT and mTOR mRNA expression was determined by reverse transcription polymerase chain reaction. Group A and group B had the highest positive expression of AKT and mTOR, with increased mRNA expression. Group D and group E had the lowest positive expression of AKT and mTOR, with decreased mRNA expression. There was a positive correlation between the expression of AKT and that of mTOR (r = 0.92). Thus, ω-6/ω-3 PUFAs in different proportions are associated with the mRNA expression of AKT and mTOR in the tissues of mouse xenograft model of human endometrial cancer.

  3. Elevated MiR-222-3p promotes proliferation and invasion of endometrial carcinoma via targeting ERα.

    PubMed

    Liu, Binya; Che, Qi; Qiu, Haifeng; Bao, Wei; Chen, Xiaoyue; Lu, Wen; Li, Bilan; Wan, Xiaoping

    2014-01-01

    MicroRNAs play key roles in tumor proliferation and invasion. Here we show distinct expression of miR-222-3p between ERα-positive and ERα-negative endometrial carcinoma (EC) cell lines and primary tumors, and investigation of its relationship with ERα and other clinical parameters. In vitro, the function of miR-222-3p was examined in RL95-2 and AN3CA cell lines. MiR-222-3p expression was negatively correlated with ERα. Over-expressed miR-222-3p in RL95-2 cells promoted cell proliferation, enhanced invasiveness and induced a G1 to S phase shift in cell cycle. Furthermore, the miR-222-3p inhibitor decreased the activity of AN3CA cells to proliferate and invade. In vivo, down-regulated miR-222-3p of AN3CA cells inhibited EC tumor growth in a mouse xenograft model. Additionally, miR-222-3p increased raloxifene resistance through suppressing ERα expression in EC cells. In conclusion, miR-222-3p plays a significant role in the regulation of ERα expression and could be potential targets for restoring ERα expression and responding to antiestrogen therapy in a subset of ECs.

  4. Beside P53 and PTEN: Identification of molecular alterations of the RAS/MAPK and PI3K/AKT signaling pathways in high-grade serous ovarian carcinomas to determine potential novel therapeutic targets

    PubMed Central

    Chen, Shuhui; Cavazza, Elisa; Barlier, Catherine; Salleron, Julia; Filhine-Tresarrieu, Pierre; Gavoilles, Céline; Merlin, Jean-Louis; Harlé, Alexandre

    2016-01-01

    Despite great histological and molecular heterogeneity, the clinical management of high-grade ovarian carcinomas remains unspecialized. As a major subgroup, high-grade serous ovarian carcinomas (HGSOCs) require novel therapies. In addition to utilizing conventional histological prognostic markers and performing oncogenetic investigations, the molecular diagnostic method of next generation sequencing (NGS) was performed to identify ‘druggable’ targets that could provide access to innovative therapy. The present study was performed in 45 HGSOC patients (mean age, 59.1 years; range, 25–87 years) with histologically proven HGSOC. Breast cancer 1/2 (BRCA1/2) germline mutations were screened in 17 patients with a familial or personal history of cancer, which was justified by oncogenetic investigations. Tumor protein 53 (P53) and phosphatase and tensin homolog (PTEN) expression were assessed in formalin-fixed paraffin-embedded tissues using immunohistochemistry. Somatic mutations of Kirsten rat sarcoma viral oncogene homolog, neuroblastoma RAS viral oncogene homolog (NRAS), B-Raf proto-oncogene, serine/threonine kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) and MET proto-oncogene, receptor tyrosine kinase (MET) were screened using NGS on DNA extracts from frozen tumor specimens obtained at diagnosis. With a median follow-up of 38 months (range, 6–93 months), 20 patients are alive, 10 patients are disease-free and 14 patients progressed within 6 months following platinum-based therapy. P53 overexpression was detected in 67% of patients and PTEN loss was detected in 38% of the patients. The overexpression of mutant P53 was found to be associated with a longer progression-free and overall survival. In total, 2 NRAS (exon 3), 3 PIK3CA (exon 5 and 10) and 5 MET mutations (exons 14 and 18) were detected. In HGSOCs, in addition to P53 and PTEN alterations, somatic genetic abnormalities can be detected using NGS and provide molecular

  5. Mutation profile and clinical outcome of mixed endometrioid-serous endometrial carcinomas are different from that of pure endometrioid or serous carcinomas.

    PubMed

    Coenegrachts, L; Garcia-Dios, D A; Depreeuw, J; Santacana, M; Gatius, S; Zikan, M; Moerman, P; Verbist, L; Lambrechts, D; Matias-Guiu, Xavier; Amant, Frédéric

    2015-04-01

    Clinical outcome of 23 patients with mixed endometrioid and serous endometrial carcinomas (mixed EEC-SC) was compared to that of pure endometrioid (EEC) and pure serous (SC) carcinomas. Hotspot mutation frequencies in KRAS, PIK3CA, PTEN, and TP53 and microsatellite instability (MSI) status were determined in mixed EEC-SC, as well as in their EEC and SC microdissected components separately, and alterations were compared to frequencies in pure EEC and SC. Relapse-free (RFS) and overall survival (OS) differed significantly between mixed EEC-SC and pure EEC and SC, revealing that outcome of mixed EEC-SCs was intermediate to that of pure EEC and pure SC. PTEN mutations were absent in pure SC, but occurred in 20 % of pure EEC, and 13 % of mixed EEC-SC. In contrast, TP53 mutations were more frequent in pure SC (17 %) and mixed EEC-SC (22 %) than in pure EEC (2 %). Mutations in mixed EEC-SC were shared by the two microdissected components in 30 %, whereas in 35 %, some mutations were component-specific. Mutation analysis confirms similarities between the EEC and SC components of mixed EEC-SC with pure EEC and pure SC, respectively. However, PTEN and KRAS mutations were more frequent in the SC component of mixed EEC-SC than in pure SC, while TP53 mutations were more frequent in the EEC component of mixed EEC-SC than in pure EEC. Presence of different clonal mutation pattern between EEC and SC components of mixed EEC-SC raises the possibility of divergent tumor heterogeneity or biclonal origin in some cases.

  6. Mammary analogue secretory carcinoma of salivary glands with high-grade transformation: report of 3 cases with the ETV6-NTRK3 gene fusion and analysis of TP53, β-catenin, EGFR, and CCND1 genes.

    PubMed

    Skálová, Alena; Vanecek, Tomas; Majewska, Hanna; Laco, Jan; Grossmann, Petr; Simpson, Roderick H W; Hauer, Lukas; Andrle, Pavel; Hosticka, Lubor; Branžovský, Jindrich; Michal, Michal

    2014-01-01

    Mammary analogue secretory carcinoma of salivary gland origin (MASC) is a recently described tumor resembling secretory carcinoma of the breast characterized by strong S-100 protein, mammaglobin, and vimentin immunoexpression and which harbors a t(12;15) (p13;q25) translocation resulting in ETV6-NTRK3 fusion product. Histologically, conventional MASC displays bland histomorphology and a lobulated growth pattern and is often composed of microcystic, tubular, and solid structures with abundant eosinophilic homogenous or bubbly secretions. Colloid-like secretory material stains positively for periodic acid-Schiff with and without diastase as well as for Alcian Blue. We present for the first time, 3 patients with MASC of the parotid gland in which high-grade (HG) transformation developed in each case characterized by an accelerated clinical course and poor outcome. The HG component revealed strong membrane staining for EGFR and β-catenin, cytoplasmic/nuclear staining for S-100 protein, and nuclear staining for cyclin-D1, whereas HER-2/neu was absent. Analysis for the presence of the ETV6-NTRK3 fusion transcript revealed positivity in both HG and low-grade component of MASC in 2 of the 3 studied cases. The tumor in case 2 was negative in both its elements for the t(12;15) translocation, but ETV6 gene rearrangement was detected in both components in all 3 cases. Analysis of TP53 and CTNNB1 gene mutations in the HG component of MASCs as well as detection of copy number aberration of EGFR and CCND1 gene did not harbor any abnormalities. All 3 patients with HG-transformed MASC died of disseminated disease within 2 to 6 years after diagnosis. Recognizing HG-transformed MASC and testing for ETV6 rearrangement may be of potential value in patient treatment, because the presence of the ETV6-NTRK3 translocation may represent a therapeutic target in MASC.

  7. A Multi-Step miRNA-mRNA Regulatory Network Construction Approach Identifies Gene Signatures Associated with Endometrioid Endometrial Carcinoma

    PubMed Central

    Xiong, Hanzhen; Li, Qiulian; Chen, Ruichao; Liu, Shaoyan; Lin, Qiongyan; Xiong, Zhongtang; Jiang, Qingping; Guo, Linlang

    2016-01-01

    We aimed to identify endometrioid endometrial carcinoma (EEC)-related gene signatures using a multi-step miRNA-mRNA regulatory network construction approach. Pathway analysis showed that 61 genes were enriched on many carcinoma-related pathways. Among the 14 highest scoring gene signatures, six genes had been previously shown to be endometrial carcinoma. By qRT-PCR and next generation sequencing, we found that a gene signature (CPEB1) was significantly down-regulated in EEC tissues, which may be caused by hsa-miR-183-5p up-regulation. In addition, our literature surveys suggested that CPEB1 may play an important role in EEC pathogenesis by regulating the EMT/p53 pathway. The miRNA-mRNA network is worthy of further investigation with respect to the regulatory mechanisms of miRNAs in EEC. CPEB1 appeared to be a tumor suppressor in EEC. Our results provided valuable guidance for the functional study at the cellular level, as well as the EEC mouse models. PMID:27271671

  8. Correlations between p21 expression and clinicopathological findings, p53 gene and protein alterations, and survival in patients with endometrial carcinoma.

    PubMed

    Ito, K; Sasano, H; Matsunaga, G; Sato, S; Yajima, A; Nasim, S; Garret, C T

    1997-11-01

    The p21 protein inhibits cyclin-dependent kinases and mediates cell-cycle arrest and cell differentiation. It is induced by wild-type p53, but not by mutant p53. This study of 75 patients with endometrial carcinoma investigates the relationship between p21 expression and the functional status of p53, and the usefulness of p21 as a prognostic marker. Correlations were determined between p21 immunoreactivity, p53 overexpression as examined by immunohistochemistry, p53 DNA mutations as examined by polymerase chain reaction-single-stranded conformation polymorphism (PCR-SSCP) analysis, and clinicopathological features, including the clinical outcome. Immunoreactivity for p21 and p53 mutations were detected in 47 (62.7 per cent), 37 (49 per cent), and 23 (31 per cent) patients, respectively. There were no significant correlations between the presence or absence of p21 immunoreactivity and p53 overexpression and DNA mutations. Survival curves revealed that patients with p53 overexpression tended to have a poorer prognosis than those without p53 overexpression (P = 0.104), that patients with p53 mutations had a significantly worse prognosis than those without mutations (P = 0.035), and that patients with p21 expression tended to have a better prognosis than those without p21 expression (P = 0.074). Immunohistochemical analysis of p21 was not useful for evaluating the functional status of p53 in patients with endometrial carcinoma. Both p21 expression and p53 abnormalities were considered as prognostic indicators in patients with endometrioid endometrial carcinoma.

  9. Survival outcomes improved in contemporary cohort of patients with pelvic or abdominal recurrence after treatment for Stage I/II endometrial carcinoma

    PubMed Central

    Xu, Melody J.; Chu, Christina; Rubin, Stephen; Lin, Lilie L.

    2015-01-01

    Objectives Pelvic and abdominal recurrences in Stage I/II endometrial carcinoma are associated with poor outcomes, yet prognostic factors for survival after recurrence are not well-described. Herein we identify patients with pelvic or abdominal recurrence after surgery for Stage I/II endometrial carcinoma and describe symptoms at presentation, prognostic factors, and salvage treatment toxicity. Methods This is a retrospective cohort of 20 consecutively treated patients with recurrence after treatment for Stage I/II endometrial carcinoma followed by our Institution’s Radiation Oncology Department from 1998-2015. Results The median time to pelvic or abdominal recurrence was 18.1 months (range, 4.2-59.6 months), with 50% of recurrences at extra-nodal locations. Two year progression-free survival (PFS) was 44% and 2 year overall survival (OS) was 82%. Salvage treatments varied widely, including chemotherapy and radiation therapy (RT) (7), surgery and RT (3), and surgery, chemotherapy, and RT (3). On univariate analysis of PFS, symptoms at recurrence (p=0.04) and extra-nodal recurrences (p<0.01) were found to be statistically significant negative prognosticators for PFS. On univariate analysis of OS, increasing age at recurrence and presence of symptoms were found to have a trend toward statistically significant association with negative OS outcomes (p=0.08 and p=0.10, respectively). Conclusions Our study demonstrates long-term survival for pelvic or abdominal recurrences is possible with curative salvage therapy. The presence of symptoms is a negative prognostic factor in treatment outcome and imaging may be effective for diagnosis in symptomatic and asymptomatic patients. Larger studies need to be performed to confirm these findings. PMID:26237194

  10. Phase II Study of Everolimus and Letrozole in Patients With Recurrent Endometrial Carcinoma

    PubMed Central

    Slomovitz, Brian M.; Jiang, Yunyun; Yates, Melinda S.; Soliman, Pamela T.; Johnston, Taren; Nowakowski, Maureen; Levenback, Charles; Zhang, Qian; Ring, Kari; Munsell, Mark F.; Gershenson, David M.; Lu, Karen H.; Coleman, Robert L.

    2015-01-01

    Purpose The phosphoinositol-3 kinase (PI3K) pathway is frequently dysregulated in endometrial cancer (EC). Hormonal manipulation leads to response in some patients with EC, but resistance derived from PI3K pathway activation has been documented. Targeting mammalian target of rapamycin (mTOR) may overcome endocrine resistance. We conducted a two-institution phase II trial of everolimus and letrozole in women with recurrent EC. Patients and Methods Patients were considered incurable, had measurable disease, and were treated with up to two prior cytotoxic regimens. Everolimus was administered orally at 10 mg daily and letrozole was administered orally at 2.5 mg daily. Each cycle consisted of 4 weeks of therapy. Patients were treated until progression, toxicity, or complete response (CR). The primary end point was the clinical benefit rate (CBR), which was defined as CR, partial response, or stable disease (≥ 16 weeks) by RECIST 1.0 criteria. Translational studies were performed to correlate biomarkers with response. Results Thirty-eight patients were enrolled (median age, 62 years; range, 24 to 82 years). Thirty-five patients were evaluable for response. The CBR was 40% (14 of 35 patients); the median number of cycles among responders was 15 (range, seven to 29 cycles). The confirmed objective response rate (RR) was 32% (11 of 35 patients; nine CRs and two partial responses; median, 15 cycles; range, eight to 29 cycles). Twenty percent of patients (seven of 35 patients) were taken off treatment after a prolonged CR and at the discretion of the treating clinician. None of the patients discontinued treatment as a result of toxicity. Serous histology was the best predictor of lack of response. Patients with endometrioid histology and CTNNB1 mutations responded well to everolimus and letrozole. Conclusion Everolimus plus letrozole results in a high CBR and RR in patients with recurrent EC. Further development of this combination in recurrent endometrioid EC is under way

  11. Resection of sternal metastasis from endometrial carcinoma followed by reconstruction with sandwiched marlex and stainless steel mesh: report of a case.

    PubMed

    Haraguchi, Shuji; Hioki, Masafumi; Hisayoshi, Takao; Yamashita, Koji; Koizumi, Kiyoshi; Shimizu, Kazuo

    2006-01-01

    We report the successful resection of sternal metastasis from endometrial carcinoma, followed by reconstruction of the chest defect, in an 87-year-old woman. We performed subtotal sternectomy and concurrent resection of the ribs and overlying soft tissue. The skeletal defect was then reconstructed with sandwiched Marlex and stainless steel mesh, and soft tissue coverage was accomplished by using a pectoralis major advancement flap. The patient had an uneventful postoperative course with no sign of recurrence during 5 years of follow-up. Thus, reconstruction with Marlex and stainless steel mesh could be an effective technique for preventing paradoxical movement of the thorax and protecting the intrathoracic organs.

  12. Treatment of Advanced or Recurrent Endometrial Carcinoma with Doxorubicin in Patients Progressing after Paclitaxel/Carboplatin: Memorial Sloan-Kettering Cancer Center (MSKCC) Experience from 1995-2009

    PubMed Central

    Makker, Vicky; Hensley, Martee L.; Zhou, Qin; Iasonos, Alexia; Aghajanian, Carol. A.

    2013-01-01

    Objective Long-term survival for patients with advanced endometrial carcinoma is poor, and limited options exist for the management of recurrent disease. Our goal was to investigate the activity of doxorubicin in the second-line setting in patients who progressed after paclitaxel/carboplatin adjuvant treatment. Methods We conducted a retrospective analysis of patients with recurrent endometrial carcinoma who were treated at Memorial Sloan-Kettering Cancer Center from 1995-2009, and who received paclitaxel/carboplatin adjuvant chemotherapy followed by second-line doxorubicin therapy at time of recurrence. The median PFS and OS times following paclitaxel/carboplatin and following second-line doxorubicin therapy were estimated using the Kaplan-Meier method. Toxicity was assessed by the treating physician at each visit and graded using version 4.0 of Common Terminology Criteria for Adverse Events (CTCAE). Patient presentation, treatment, patterns of recurrence, and patient outcomes were summarized. Results Seventeen patients were included in study analyses. The median PFS from completion of paclitaxel/carboplatin was 8.0 months (95% CI: 4.5-13.6 months). At the time of recurrence, all 17 patients were treated with doxorubicin as second-line therapy. No patient achieved objective response of stable disease. The median PFS of this cohort following doxorubicin treatment was 2.1 months (95% CI: 0.95-2.7) months. Median OS was 5.8 months (95% CI: 1.0-15.0 months). There is only one patient still alive; her median follow-up time is 49.4 months. Predominant doxorubicin-related grade 2 toxicities included nausea/vomiting (18.8%), fatigue (18.8%), and neutropenia (12.5%). No grade 3 or 4 toxicities occurred. Conclusions Among patients with advanced endometrial carcinoma who had received adjuvant paclitaxel/carboplatin, treatment with doxorubicin at time of disease recurrence failed to achieve any objective responses and was associated with a very short (2 months) time to

  13. Epigenetic regulation of L1CAM in endometrial carcinoma: comparison to cancer–testis (CT-X) antigens

    PubMed Central

    2013-01-01

    Background L1CAM was originally identified as an adhesion molecule involved in neural development. In many human carcinomas L1CAM is over-expressed and is associated with a bad prognosis. We previously reported that L1CAM was absent in the vast majority of endometrioid endometrial carcinomas (ECs) (type 1) but was strongly expressed in the more aggressive serous and clear-cell ECs (termed type 2). The differential regulation of L1CAM in ECs is not well understood. Recent evidence suggests that it can be regulated by epigenetic mechanisms. Here we investigated the role of DNA-methylation of the L1CAM promoter for expression. We also studied the relationship to cancer testis (CT-X) antigens that co-localize with L1CAM on chromosome Xq28, a region that is often activated in human tumors. Methods We used EC cell lines and primary tumor tissues for our analysis. For expression analysis we employed RT-PCR and Western blotting. DNA-Methylation of the L1CAM promoter was determined after bisulfite conversation and DNA sequencing. Tumor tissues were examined by immunohistochemical (IHC) staining. Results We demonstrate that the treatment of L1CAM low/negative expressing EC cell lines with 5′-Azacytidine (5-AzaC) or knock-down of DNMT1 (DNA methyltransferase 1) as well as the HDAC (histone deacetylase) inhibitor Trichostatin A (TSA) up-regulated L1CAM at the mRNA and protein level. The L1CAM gene has two promoter regions with two distinct CpG islands. We observed that the expression of L1CAM correlated with hypermethylation in promoter 1 and 5-AzaC treatment affected the DNA-methylation pattern in this region. The CT-X antigens NY-ESO-1, MAGE-A3 and MAGE-A4 were also strongly up-regulated by 5-AzaC or knock-down of DNMT1 but did not respond to treatment with TSA. Primary EC tumor tissues showed a variable methylation pattern of the L1CAM promoter. No striking differences in promoter methylation were observed between tumor areas with L1CAM expression and those without

  14. Effects of Intermediate-Conductance Ca(2+)-Activated K(+) Channels on Human Endometrial Carcinoma Cells.

    PubMed

    Zhang, Yingli; Feng, Youji; Chen, Lu; Zhu, Jianqing

    2015-06-01

    The objective of this study was to investigate the effect of intermediate-conductance Ca(2+)-activated K(+) (KCa3.1) channels on the cell proliferation, cell cycle, apoptosis, migration, and invasion in endometrial cancer (EC) cells. Human EC cell lines HEC-1-A and Ishikawa were cultured in vitro and transfected with recombinant plasmid containing KCa3.1-targeting shRNA. RT-qPCR and Western blot were used to examine the mRNA and protein expression levels of KCa3.1 channels in transfected cells. In addition, the specific inhibitor of KCa3.1, TRAM-34, was used to examine the effect of KCa3.1 blockage on migration capacity and invasiveness of EC cells using transwell assay. Proliferation and apoptotic rates of EC cells transfected with KCa3.1 shRNA or treated with TRAM-34 were analyzed using MTT, BrdU incorporation assay, and flow cytometry. Expression of cell cycle proteins and metalloproteinase-2 (MMP-2) was evaluated by RT-qPCR and Western blotting. TRAM-34 treatment and KCa3.1 silencing using shRNA dramatically suppressed both the mRNA and protein expression of KCa3.1 channels (P < 0.01) compared with control groups. Blockage of KCa3.1 by TRAM-34 treatment and KCa3.1 shRNA transfection exerted inhibitory effect on cell growth of both EC cell lines, as demonstrated by increased cell population at G0-G1 phase and decreased cell population at S phase. However, both the treatments did not result in significant changes in the apoptotic rate (P > 0.05) compared to controls. Protein expressions of cyclin D1, cyclin E, and survivin were significantly decreased in the experimental groups comparing to control. We showed that TRAM-34 treatment led to significantly inhibited migration, invasion, and MMP-2 expression in HEC-1-A and Ishikawa cells, compared with the control group (P < 0.01). Blockage of KCa3.1 channel activity or expression inhibits cell proliferation and cell cycle progression without inducing apoptosis in EC cells. Moreover, TRAM-34 could reduce the

  15. A proposed model for endometrial serous carcinogenesis.

    PubMed

    Zheng, Wenxin; Xiang, Li; Fadare, Oluwole; Kong, Beihua

    2011-01-01

    Endometrial serous carcinomas constitute no more than 10% of endometrial adenocarcinomas, but frequently present at an advanced stage and have a significantly worse prognosis than the more common low-grade and intermediate-grade endometrioid adenocarcinomas. The neoplasm's potential for rapid tumor progression and the high mortality that is associated with advanced-stage disease underscore the importance of understanding endometrial serous carcinogenesis so that its precancers can be diagnosed and an effective therapeutic intervention can be administered. In this study, the authors summarize the current state of knowledge on endometrial serous carcinogenesis and propose a model for its development based on recent work from our group and published data from other researchers. In this model, endometrial serous carcinoma arises predominantly in the resting endometrium, manifesting first as p53 immunoreactive, morphologically normal endometrial cells (p53 signatures), evolving to endometrial glandular dysplasia (which is the first morphologically identifiable precursor lesion), then to serous endometrial intraepithelial carcinoma (a carcinoma with a noninvasive growth pattern in the uterus but which is not infrequently associated with extrauterine disease), and finally into fully developed serous carcinoma. Endometrial glandular dysplasia is a lesion, which can be diagnosed by routine microscopic evaluation, whose ablation or removal may potentially offer the opportunity to prevent the development of the associated malignancy. The diagnostic criteria, practical applicability, and evidentiary basis for the delineation of this lesion are studied.

  16. Usefulness of DWI in preoperative assessment of deep myometrial invasion in patients with endometrial carcinoma: a systematic review and meta-analysis

    PubMed Central

    2014-01-01

    Background The objective of this study was to perform a systematic review and a meta-analysis in order to estimate the diagnostic accuracy of diffusion weighted imaging (DWI) in the preoperative assessment of deep myometrial invasion in patients with endometrial carcinoma. Methods Studies evaluating DWI for the detection of deep myometrial invasion in patients with endometrial carcinoma were systematically searched for in the MEDLINE, EMBASE, and Cochrane Library from January 1995 to January 2014. Methodologic quality was assessed by using the Quality Assessment of Diagnostic Accuracy Studies tool. Bivariate random-effects meta-analytic methods were used to obtain pooled estimates of sensitivity, specificity, diagnostic odds ratio (DOR) and receiver operating characteristic (ROC) curves. The study also evaluated the clinical utility of DWI in preoperative assessment of deep myometrial invasion. Results Seven studies enrolling a total of 320 individuals met the study inclusion criteria. The summary area under the ROC curve was 0.91. There was no evidence of publication bias (P = 0.90, bias coefficient analysis). Sensitivity and specificity of DWI for detection of deep myometrial invasion across all studies were 0.90 and 0.89, respectively. Positive and negative likelihood ratios with DWI were 8 and 0.11 respectively. In patients with high pre-test probabilities, DWI enabled confirmation of deep myometrial invasion; in patients with low pre-test probabilities, DWI enabled exclusion of deep myometrial invasion. The worst case scenario (pre-test probability, 50%) post-test probabilities were 89% and 10% for positive and negative DWI results, respectively. Conclusion DWI has high sensitivity and specificity for detecting deep myometrial invasion and more importantly can reliably rule out deep myometrial invasion. Therefore, it would be worthwhile to add a DWI sequence to the standard MRI protocols in preoperative evaluation of endometrial cancer in order to detect deep

  17. PIK3CA mutations in the kinase domain (exon 20) of uterine endometrial adenocarcinomas are associated with adverse prognostic parameters.

    PubMed

    Catasus, Lluis; Gallardo, Alberto; Cuatrecasas, Miriam; Prat, Jaime

    2008-02-01

    Mutations of the oncogene PIK3CA occur frequently in endometrial carcinomas, but their prognostic significance is unclear. To determine the clinicopathological and molecular implications of these mutations, PIK3CA status was investigated in 109 endometrial (102 endometrioid and 7 mixed) carcinomas and the results were compared with clinicopathological parameters associated with prognosis. Tumors were also investigated for microsatellite instability and PTEN, beta-catenin gene (CTNNB1), K-RAS, and B-RAF mutations. We found 35 PIK3CA somatic missense mutations in 32 (29%) endometrial carcinomas. Eighteen mutations occurred in exon 20 (kinase domain), and 17 in exon 9 (helical domain). Almost all mutated tumors were pure endometrioid adenocarcinomas. All tumors with PIK3CA mutations exhibited myometrial invasion (P=0.032). Lymphovascular invasion was found more frequently in mutated (28%) than nonmutated carcinomas (18%). Histological grade varied significantly according to the location of the PIK3CA mutations whether in exon 9 or exon 20 (P=0.033). The frequency of exon 9 mutations was higher in grade 1 carcinomas (57%) than in grade 2 (29%) or grade 3 (14%) tumors. Conversely, mutations in exon 20 were more common in grade 3 (60%) than in grade 2 (20%) or grade 1 (20%) carcinomas. None of the tumors confined to the endometrium (stage IA) had PIK3CA mutations. Furthermore, whereas 64% of adenocarcinomas with exon 9 mutations had invaded < or =(1/2) of the myometrial thickness (stage IB), 73% of tumors with exon 20 mutations had either deeper myometrial invasion (stage IC) or cervical involvement (stage II) (P=0.045). PIK3CA mutations coexisted with microsatellite instability and mutations in PTEN, CTNNB1, K-RAS, and B-RAF genes. These results favor that PIK3CA mutations are associated with myometrial invasion and, moreover, that tumors harboring PIK3CA mutations in exon 20 are frequently high-grade, deeply invasive endometrial carcinomas that tend to exhibit

  18. Personal history of breast cancer as a significant risk factor for endometrial serous carcinoma in women aged 55 years old or younger.

    PubMed

    Liang, Sharon X; Pearl, Micheal; Liang, Shu; Xiang, Li; Jia, Lin; Yang, Binlie; Fadare, Oluwole; Schwartz, Peter E; Chambers, Setsuko K; Kong, Beihua; Zheng, Wenxin

    2011-02-15

    A comparative study between endometrial serous carcinoma (ESC) and endometrial endometrioid carcinoma (EEC) was performed to determine whether a personal history of breast cancer is a risk factor for ESC in women aged ≤ 55 yr. Study subjects consisted of 348 women who were diagnosed with ESC and 830 comparison subjects who had EEC. Variables studied included age at diagnosis, a history of breast cancer, tamoxifen therapy, hormonal replacement therapy and smoking history. Overall, 19.4% of women with ESC had a history of breast cancer, which was significantly higher than that of 3% in comparison subjects. Among the study subjects, the incidence of a prior breast cancer was significantly higher in patients who were 55 yr of age or younger (41.5%) than those who were older than 55 yr (16%). The statistical significance of both of the aforementioned comparisons was independent of tamoxifen usage on multivariate analyses. The mean time interval between prior breast cancer and endometrial cancer was 92.5 mo (range 7-240 mo) in the study group and 79 mo (range 7-192 mo) in the comparison group. For the whole cohort and individual subgroups (ESC, EEC, ≤ 55 yr and >55 yr), a personal history of breast cancer did not adversely affect the patient outcomes, which was largely dependent on standard clinicopathologic parameters such as International Federation of Gynecology and Obstetrics stage, as has previously been demonstrated. These findings suggest that a personal history of breast cancer may be a significant risk factor for the development of ESC in women aged ≤ 55 yr. Further studies are needed to clarify the relationship between these two cancers in this age group and whether this increased risk is reflective of a genetic predisposition.

  19. Cancer-Related Triplets of mRNA-lncRNA-miRNA Revealed by Integrative Network in Uterine Corpus Endometrial Carcinoma

    PubMed Central

    Zhang, Yu-Hang; Deng, Qinfang

    2017-01-01

    The regulation of transcriptome expression level is a complex process involving multiple-level interactions among molecules such as protein coding RNA (mRNA), long noncoding RNA (lncRNA), and microRNA (miRNA), which are essential for the transcriptome stability and maintenance and regulation of body homeostasis. The availability of multilevel expression data enables a comprehensive view of the regulatory network. In this study, we analyzed the coding and noncoding gene expression profiles of 301 patients with uterine corpus endometrial carcinoma (UCEC). A new method was proposed to construct a genome-wide integrative network based on variance inflation factor (VIF) regression method. The cross-regulation relations of mRNA, lncRNA, and miRNA were then selected based on clique-searching algorithm from the network, when any two molecules of the three were shown as interacting according to the integrative network. Such relation, which we call the mRNA-lncRNA-miRNA triplet, demonstrated the complexity in transcriptome regulation process. Finally, six UCEC-related triplets were selected in which the mRNA participates in endometrial carcinoma pathway, such as CDH1 and TP53. The multi-type RNAs are proved to be cross-regulated as to each of the six triplets according to literature. All the triplets demonstrated the association with the initiation and progression of UCEC. Our method provides a comprehensive strategy for the investigation of transcriptome regulation mechanism. PMID:28280730

  20. Germline MLH1 Mutations Are Frequently Identified in Lynch Syndrome Patients With Colorectal and Endometrial Carcinoma Demonstrating Isolated Loss of PMS2 Immunohistochemical Expression.

    PubMed

    Dudley, Beth; Brand, Randall E; Thull, Darcy; Bahary, Nathan; Nikiforova, Marina N; Pai, Reetesh K

    2015-08-01

    Current guidelines on germline mutation testing for patients suspected of having Lynch syndrome are not entirely clear in patients with tumors demonstrating isolated loss of PMS2 immunohistochemical expression. We analyzed the clinical and pathologic features of patients with tumors demonstrating isolated loss of PMS2 expression in an attempt to (1) determine the frequency of germline MLH1 and PMS2 mutations and (2) correlate mismatch-repair protein immunohistochemistry and tumor histology with germline mutation results. A total of 3213 consecutive colorectal carcinomas and 215 consecutive endometrial carcinomas were prospectively analyzed for DNA mismatch-repair protein expression by immunohistochemistry. In total, 32 tumors from 31 patients demonstrated isolated loss of PMS2 immunohistochemical expression, including 16 colorectal carcinomas and 16 endometrial carcinomas. Microsatellite instability (MSI) polymerase chain reaction was performed in 29 tumors from 28 patients with the following results: 28 tumors demonstrated high-level MSI, and 1 tumor demonstrated low-level MSI. Twenty of 31 (65%) patients in the study group had tumors demonstrating histopathology associated with high-level MSI. Seventeen patients underwent germline mutation analysis with the following results: 24% with MLH1 mutations, 35% with PMS2 mutations, 12% with PMS2 variants of undetermined significance, and 29% with no mutations in either MLH1 or PMS2. Three of the 4 patients with MLH1 germline mutations had a mutation that results in decreased stability and quantity of the MLH1 protein that compromises the MLH1-PMS2 protein complex, helping to explain the presence of immunogenic but functionally inactive MLH1 protein within the tumor. The high frequency of MLH1 germline mutations identified in our study has important implications for testing strategies in patients suspected of having Lynch syndrome and indicates that patients with tumors demonstrating isolated loss of PMS2 expression

  1. Role of miR-34a as a suppressor of L1CAM in endometrial carcinoma

    PubMed Central

    Schirmer, Uwe; Doberstein, Kai; Rupp, Anne-Kathleen; Bretz, Niko P.; Wuttig, Daniela; Kiefel, Helena; Breunig, Christian; Fiegl, Heidi; Müller-Holzner, Elisabeth; Zeillinger, Robert; Eva, Heidi; Zeimet, Alain G.; SÜltmann, Holger; Altevogt, Peter

    2014-01-01

    L1CAM promotes cell motility, invasion and metastasis formation in various human cancers and can be considered as a driver of tumor progression. Knowledge about genetic processes leading to the presence of L1CAM in cancers is of considerable importance. Experimentally, L1CAM expression can be achieved by various means. Overexpression of the transcription factor SLUG or treatment of cells with TGF-ß1 can induce or augment L1CAM levels in cancer cells. Likewise, hypomethylation of the L1CAM promoter on the X chromosome correlates with L1CAM expression. However, presently no mechanisms that might control transcriptional activity are known. Here we have identified miR-34a as a suppressor of L1CAM. We observed that L1CAM positive endometrial carcinoma (EC) cell lines HEC1B and SPAC1L lost L1CAM protein and mRNA by treatment with demethylating agents or knock-down of the DNA-methyltransferase-1 (DNMT1). Concomitantly, several miRNAs were up-regulated. Using miRNA profiling, luciferase reporter assays and mutagenesis, we identified miR-34a as a putative binder to the L1CAM-3'UTR. Overexpression of miR-34a in HEC1B cells blocked L1CAM expression and inhibited cell migration. In ECC1 cells (wildtype p53) the activation of p53 caused miR-34a up-regulation and loss of L1CAM expression that was miR-34a dependent. We observed an inverse correlation between L1CAM and miR-34a levels in EC cell lines. In primary tumor sections areas expressing high amounts of L1CAM had less miR-34a expression than those with low L1CAM levels. Our data suggest that miR-34a can regulate L1CAM expression by targeting L1CAM mRNA for degradation. These findings shed new light on the complex regulation of L1CAM in human tumors. PMID:24497324

  2. Role of miR-34a as a suppressor of L1CAM in endometrial carcinoma.

    PubMed

    Schirmer, Uwe; Doberstein, Kai; Rupp, Anne-Kathleen; Bretz, Niko P; Wuttig, Daniela; Kiefel, Helena; Breunig, Christian; Fiegl, Heidi; Müller-Holzner, Elisabeth; Zeillinger, Robert; Schuster, Eva; Zeimet, Alain G; Sültmann, Holger; Altevogt, Peter

    2014-01-30

    L1CAM promotes cell motility, invasion and metastasis formation in various human cancers and can be considered as a driver of tumor progression. Knowledge about genetic processes leading to the presence of L1CAM in cancers is of considerable importance. Experimentally, L1CAM expression can be achieved by various means. Over-expression of the transcription factor SLUG or treatment of cells with TGF-β1 can induce or augment L1CAM levels in cancer cells. Likewise, hypomethylation of the L1CAM promoter on the X chromosome correlates with L1CAM expression. However, presently no mechanisms that might control transcriptional activity are known. Here we have identified miR-34a as a suppressor of L1CAM. We observed that L1CAM positive endometrial carcinoma (EC) cell lines HEC1B and SPAC1L lost L1CAM protein and mRNA by treatment with demethylating agents or knock-down of the DNA-methyltransferase-1 (DNMT1). Concomitantly, several miRNAs were up-regulated. Using miRNA profiling, luciferase reporter assays and mutagenesis, we identified miR-34a as a putative binder to the L1CAM-3'UTR. Over-expression of miR-34a in HEC1B cells blocked L1CAM expression and inhibited cell migration. In ECC1 cells (wildtype p53) the activation of p53 caused miR-34a up-regulation and loss of L1CAM expression that was miR-34a dependent. We observed an inverse correlation between L1CAM and miR-34a levels in EC cell lines. In primary tumor sections areas expressing high amounts of L1CAM had less miR-34a expression than those with low L1CAM levels. Our data suggest that miR-34a can regulate L1CAM expression by targeting L1CAM mRNA for degradation. These findings shed new light on the complex regulation of L1CAM in human tumors.

  3. Paclitaxel and Carboplatin With or Without Metformin Hydrochloride in Treating Patients With Stage III, IV, or Recurrent Endometrial Cancer

    ClinicalTrials.gov

    2017-02-23

    Endometrial Adenocarcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Serous Adenocarcinoma; Endometrial Undifferentiated Carcinoma; Recurrent Uterine Corpus Carcinoma; Stage IIIA Uterine Corpus Cancer; Stage IIIB Uterine Corpus Cancer; Stage IIIC Uterine Corpus Cancer; Stage IVA Uterine Corpus Cancer; Stage IVB Uterine Corpus Cancer

  4. INCIDENCE OF ENDOMETRIAL HYPERPLASIA

    PubMed Central

    REED, Susan D.; NEWTON, Katherine M.; CLINTON, Walter L.; EPPLEIN, Meira; GARCIA, Rochelle; ALLISON, Kimberly; VOIGT, Lynda F.; Weiss, Noel S.

    2009-01-01

    Objective Estimate age-specific incidence of endometrial hyperplasia: simple, complex, and atypical, in order of increasing likelihood of progression to carcinoma. Study design Women ages 18–90 years with endometrial pathology specimens (1985–2003) at a large integrated health plan were identified using automated data. Incidence rates were obtained by dividing the number of cases by the estimated number of female health plan enrollees who retained a uterus. Results Endometrial hyperplasia peak incidence was: simple-142/100,000 woman-years, complex-213/100,000 woman-years, both in the early 50s; and atypical-56/100,000 woman-years in the early 60s. Age-adjusted incidence decreased over the study period, especially for atypical hyperplasia. Conclusions Endometrial hyperplasia incidence without and with atypia peaks in the early postmenopausal years and in the early 60s, respectively. Given that some cases of endometrial hyperplasia likely go undiagnosed, the figures provided should be viewed as minimum estimates of the true incidence. PMID:19393600

  5. Long-term results of high-dose-rate brachytherapy in the primary treatment of medically inoperable stage I-II endometrial carcinoma

    SciTech Connect

    Niazi, Tamim M.; Souhami, Luis . E-mail: luis.souhami@muhc.mcgill.ca; Portelance, Lorraine; Bahoric, Boris; Gilbert, Lucy; Stanimir, Gerald

    2005-11-15

    Purpose: Total-abdominal hysterectomy and bilateral salpingo-oophorectomy (TAHBSO) is the gold-standard therapy for patients with endometrial carcinoma. However, patients with high operative risks are usually treated with radiation therapy (RT) alone. The goal of this study was to update our experience of high-dose-rate brachytherapy (HDRB), with or without external-beam irradiation (EBRT), for such patients. Methods and Materials: Between 1984 and 2003, 38 patients with Stage I and Stage II adenocarcinoma of the endometrium considered high operative risk received RT as the primary treatment. The median age was 74.1 years. Before 1996, the local extent of the disease was assessed by an examination under anesthesia (EUA) and by EUA and magnetic resonance imaging (MRI) thereafter. Eight patients (21%) were treated with combined HDRB and EBRT, and 30 patients (79%) were treated with with HDRB alone. The median HDRB dose was 23.9 Gy, typically delivered in 3 fractions in a weekly schedule. The median EBRT dose was 42 Gy. Results: At a median follow-up of 57.5 months for patients at risk, 11 patients (29%) have failed: 6 patients (16%) locally, 4 patients (10.5%) distantly, and 1 patient (3%) locally and distantly. Local failure was established by biopsy, and 4 patients were salvaged by TAHBSO. Higher stage and higher grade were both associated with increased failure rate. The 15-year disease-specific survival (DSS) was 78% for all stages, 90% for Stage I, and 42% for Stage II (p < 0.0001). The 15-year DSS was 91% for Grade I and 67% for Grade II and III combined (p = 0.0254). Patients with Stage I disease established by MRI (11 patients) and who received a total HDRB dose of 30 Gy had a DSS rate of 100% at 10 years. Four patients experienced late toxicities: 1 Grade II and 3 Grade III or IV. Conclusion: Medically inoperable Stage I endometrial carcinoma may be safely and effectively treated with HDRB as the primary therapy. In selected Stage I patients, our results are

  6. Whole Genome Pathway Analysis Identifies an Association of Cadmium Response Gene Loss with Copy Number Variation in Mutant p53 Bearing Uterine Endometrial Carcinomas

    PubMed Central

    Stupack, Dwayne G

    2016-01-01

    Background Massive chromosomal aberrations are a signature of advanced cancer, although the factors promoting the pervasive incidence of these copy number alterations (CNAs) are poorly understood. Gatekeeper mutations, such as p53, contribute to aneuploidy, yet p53 mutant tumors do not always display CNAs. Uterine Corpus Endometrial Carcinoma (UCEC) offers a unique system to begin to evaluate why some cancers acquire high CNAs while others evolve another route to oncogenesis, since about half of p53 mutant UCEC tumors have a relatively flat CNA landscape and half have 20–90% of their genome altered in copy number. Methods We extracted copy number information from 68 UCEC genomes mutant in p53 by the GISTIC2 algorithm. GO term pathway analysis, via GOrilla, was used to identify suppressed pathways. Genes within these pathways were mapped for focal or wide distribution. Deletion hotspots were evaluated for temporal incidence. Results Multiple pathways contributed to the development of pervasive CNAs, including developmental, metabolic, immunological, cell adhesion and cadmium response pathways. Surprisingly, cadmium response pathway genes are predicted as the earliest loss events within these tumors: in particular, the metallothionein genes involved in heavy metal sequestration. Loss of cadmium response genes were associated with copy number changes and poorer prognosis, contrasting with 'copy number flat' tumors which instead exhibited substantive mutation. Conclusion Metallothioneins are lost early in the development of high CNA endometrial cancer, providing a potential mechanism and biological rationale for increased incidence of endometrial cancer with cadmium exposure. Developmental and metabolic pathways are altered later in tumor progression. PMID:27391266

  7. Sorafenib induces endometrial carcinoma apoptosis by inhibiting Elk-1-dependent Mcl-1 transcription and inducing Akt/GSK3β-dependent protein degradation.

    PubMed

    Sun, Nian-Kang; Huang, Shang-Lang; Chang, Ting-Chang; Chao, Chuck C-K

    2013-08-01

    Endometrial carcinoma (EC) is one of the main gynecologic malignancies affecting women, but effective treatments are currently lacking. In the present study, we investigated the effect of sorafenib, a general kinase inhibitor, on several EC cell lines (HEC1A, HEC1B, and RL95-2). Sorafenib induced cell death in EC cells with the following order of sensitivity: HEC1A > HEC1B > RL95-2. Sorafenib suppressed several anti-apoptotic proteins in HEC1A cells, including myeloid cell leukemia 1 (Mcl-1). Ectopic overexpression of Mcl-1 prevented the cell killing effect of sorafenib. Sorafenib suppressed Mcl-1 at the gene transactivation level by inactivating the ERK/Elk-1 pathway. Accordingly, the inhibitory effect of sorafenib on Mcl-1 expression decreased following knockdown of Elk-1 using short-hairpin RNA (shRNA). Elk-1 overexpression rescued both the inhibitory effect of sorafenib on Mcl-1 expression and the cell killing effect of sorafenib. Furthermore, sorafenib reduced the stability of the Mcl-1 protein by enhancing its ubiquitination and degradation by the proteasome via the AKT/GSK3β and the ERK pathways. Similar results were detected in other EC cell lines. These results indicate that sorafenib induces apoptosis in EC cells by down-regulating the anti-apoptotic protein Mcl-1 via transcriptional inhibition and protein degradation. Our results thus support the notion that sorafenib may be used in endometrial cancer therapy.

  8. Endometrial Endometrioid Carcinoma With Large Cystic Growth Configuration and Deceptive Pattern of Invasion Associated With Abundant Nodular Fasciitis-like Stroma: A Unique Hitherto Unreported Histology in Endometrioid Carcinoma.

    PubMed

    Švajdler, Marián; Michal, Michael; Dubinský, Pavol; Švajdler, Peter; Ondič, Ondrej; Michal, Michal

    2016-11-01

    We describe a case of an unusual endometrial endometrioid carcinoma occurring in a 67-year-old woman. The tumor involved uterine corpus as well as lower uterine segment and presented as polypoid tumor protruding through the cervical orifice. Microscopically, the tumor was characterized by broad zones of cytologically bland fibromyxoid stroma resembling nodular fasciitis, showing vaguely nodular architecture. Neoplastic glands were characterized by interconnected elongated slit-like and large cystic profiles, mostly lined by flattened epithelium with variable squamous differentiation, whereas typical columnar endometrioid cells were only focally present. Voluminous nodules of the stroma produced phyllodes-like appearance of the tumor. The tumor showed some resemblance to the microcystic, elongated, and fragmented (MELF) glands growth pattern, but in contrast with MELF pattern, where fibromyxoid change occurs focally, in the presented case abundant myofibroblastic proliferation was present throughout the tumor and the neoplastic glands showed anastomosing "large cystic" rather than "small cystic" profiles. Some of the neoplastic glands presented almost complete or complete squamous differentiation, with relatively bland-looking squamous cells and no hint of endometrioid differentiation, which resulted in initial misdiagnosis of Müllerian adenofibroma. We believe that nodular fasciitis-like pattern represents yet undescribed, and diagnostically challenging pattern of invasion in endometrial endometrioid carcinoma.

  9. In vitro maturation and fertilization of oocytes from an intact ovary of a surgically treated patient with endometrial carcinoma: case report.

    PubMed

    Revel, A; Safran, A; Benshushan, A; Shushan, A; Laufer, N; Simon, A

    2004-07-01

    Polycystic ovary syndrome (PCOS) with prolonged anovulation had resulted in endometrial carcinoma in a 43-year-old woman. Since she and her husband did not share common biological children, they requested fertility preservation. Due to the woman's age, high dose progesterone and postponing surgery were both considered inappropriate. We therefore proposed oocyte retrieval from the ovaries removed by staging laparotomy followed by in vitro maturation and ICSI. Surrogacy could then enable a future pregnancy. Fourteen of 17 (82%) retrieved oocytes matured in vitro. Following ICSI, eight embryos (two at the pronuclear stage and six cleaved) were cryopreserved. To the best of our knowledge, this is the first report of oocyte aspiration, maturation and fertilization from an ovary removed by laparotomy.

  10. External Pelvic and Vaginal Irradiation Versus Vaginal Irradiation Alone as Postoperative Therapy in Medium-Risk Endometrial Carcinoma-A Prospective Randomized Study

    SciTech Connect

    Sorbe, Bengt; Horvath, Gyoergy; Andersson, Hakan; Boman, Karin; Lundgren, Caroline; Pettersson, Birgitta

    2012-03-01

    Purpose: To evaluate the value of adjuvant external beam pelvic radiotherapy as adjunct to vaginal brachytherapy (VBT) in medium-risk endometrial carcinoma, with regard to locoregional tumor control, recurrences, survival, and toxicity. Methods and Materials: Consecutive series of 527 evaluable patients were included in this randomized trial. Median follow-up for patients alive was 62 months. The primary study endpoints were locoregional recurrences and overall survival. Secondary endpoints were recurrence-free survival, recurrence-free interval, cancer-specific survival, and toxicity. Results: Five-year locoregional relapse rates were 1.5% after external beam radiotherapy (EBRT) plus VBT and 5% after vaginal irradiation alone (p = 0.013), and 5-year overall survival rates were 89% and 90%, respectively (p = 0.548). Endometrial cancer-related death rates were 3.8% after EBRT plus VBT and 6.8% after VBT (p = 0.118). Pelvic recurrences (exclusively vaginal recurrence) were reduced by 93% by the addition of EBRT to VBT. Deep myometrial infiltration was a significant prognostic factor in this medium-risk group of endometrioid carcinomas but not International Federation of Gynecology and Obstetrics grade or DNA ploidy. Combined radiotherapy was well tolerated, with serious (Grade 3) late side effects of less than 2%. However, there was a significant difference in favor of VBT alone. Conclusions: Despite a significant locoregional control benefit with combined radiotherapy, no survival improvement was recorded, but increased late toxicity was noted in the intestine, bladder, and vagina. Combined RT should probably be reserved for high-risk cases with two or more high-risk factors. VBT alone should be the adjuvant treatment option for purely medium-risk cases.

  11. Paclitaxel, Carboplatin, and Bevacizumab or Paclitaxel, Carboplatin, and Temsirolimus or Ixabepilone, Carboplatin, and Bevacizumab in Treating Patients With Stage III, Stage IV, or Recurrent Endometrial Cancer

    ClinicalTrials.gov

    2017-01-31

    Endometrial Adenocarcinoma; Endometrial Adenosquamous Carcinoma; Endometrial Clear Cell Adenocarcinoma; Endometrial Serous Adenocarcinoma; Recurrent Uterine Corpus Carcinoma; Stage IIIA Uterine Corpus Cancer; Stage IIIB Uterine Corpus Cancer; Stage IIIC Uterine Corpus Cancer; Stage IVA Uterine Corpus Cancer; Stage IVB Uterine Corpus Cancer

  12. Endometrial cancer

    MedlinePlus

    ... endometrial polyps Infrequent periods Never being pregnant Obesity Polycystic ovary syndrome (PCOS) Starting menstruation at an early age (before age ... Epithelium High blood ... Hysterectomy - abdominal - discharge Hysterectomy - laparoscopic - discharge ...

  13. Endometrial polyps

    MedlinePlus

    ... cancer is higher if you are postmenopausal, on Tamoxifen, or have heavy or irregular periods. These factors may increase the risk for endometrial polyps: Obesity Tamoxifen, a treatment for breast cancer Postmenopausal hormone replacement ...

  14. Endometrial Cancer

    MedlinePlus

    Member Login Join Pay Dues Follow us: Women's Health Care Physicians Contact Us My ACOG ACOG Departments Donate ... and is best made in consultation with your health care team. What happens after treatment for endometrial cancer? ...

  15. Endometrial Ablation

    MedlinePlus

    ... a thin layer of the lining of the uterus and stops the menstrual flow in many women. ... medical conditions, including the following: • Disorders of the uterus or endometrium • Endometrial hyperplasia • Cancer of the uterus • ...

  16. From endometrial hyperplasia to endometrial cancer: insight into the biology and possible medical preventive measures.

    PubMed

    Boruban, Melih C; Altundag, Kadri; Kilic, Gokhan S; Blankstein, Josef

    2008-04-01

    Controversies are still seen in the histological differential diagnosis of hyperplasia and well-differentiated endometrial carcinoma. Prediction of endometrial cancer in patients with hyperplasia with atypia, with the available markers has not been reliable yet. Hence these patients require more attention in the clinical management. Endometrial hyperplasia is proliferation of endometrial glands resulting in a higher gland : stroma ratio. Cytological atypia, which may progress to or co-exist with endometrial cancer and other pathological changes, result from estrogen stimulation unopposed by progesterone. Biomarkers whose expression is altered in cases of endometrial hyperplasia or cancer such as progesterone receptor, insulin-like growth factor I, retinaldehyde dehydrogenase type II, and secreted frizzled-related protein 4, seem to be promising to use as early-stage tumor markers. Mutation of PTEN is present in 83% of endometrial adenocarcinoma cases, making it the most frequent early molecular genetic alteration in type 1 endometrial tumors, which are generally associated with hyperplasia. p53 gene mutation is not found in endometrial hyperplasia, but researchers have detected this mutation in 20% of cases of endometrial carcinoma and 90% of cases of serous endometrial tumors. Cyclooxygenase-2 is important in tumorogenic transformation of hyperplasia. Expression of cyclooxygenase-2 decreases apoptosis, increases angiogenesis, and is related to invasiveness. Cyclooxygenase-2 expression increases significantly in cases of well-differentiated endometrial adenocarcinoma. Prostaglandin E2 is known to regulate aromatase gene expression and is the product of cyclooxygenase-2. The data about aromatase inhibitors are promising; in breast cancer patients, treatment with tamoxifen induces uterine abnormalities as early as 3 months after the initiation of therapy. In contrast, these abnormalities are not seen in patients who receive aromatase inhibitors and switched therapy

  17. [Criteria for evaluating the effectiveness of aromatase inhibitors in the neoadjuvant treatment of patients with endometrial carcinoma].

    PubMed

    Bershteĭn, L M; Danilova, M A; Kovalevskiĭ, A Iu; Gershfel'd, E D; Poroshina, T E; Tsyrlina, T E; Meshkova, I E; Turkevich, E A; Maksimov, S Ia

    2009-01-01

    Clinical and experimental effects of neoadjuvant treatment of endometrial cancer patients with non-steroidal aromatase inhibitors: letrozole (femara, n=10, 2.5 mg/day, 14 days), anastrozole (arimidex, n=15,1 mg/day, 28 days) and exemestane (aromazine, n=13, 25 mg/day, 14 days) were compared. Administration of anastrozole was mostly frequently followed by pain relief in the lower abdomen and/or decreased rates of uterine discharge. Endometrial wall thickness (M-echo signal) decreased significantly in 60% of patients receiving anastrozole, exemestane - 58.3% and letrozole - 40%. Substantial drop in intratumoral aromatase and blood estradiol levels occurred more frequently after anastrozole and letrozole while progesterone receptor levels in tumor were markedly lower after exemestane administration. Assay of blood LH (except letrozole), FSH and cholesterol appeared to be of less relevance. On the contrary, significance of assessment of marker Ki-67 expression, which, in the case of anastrozole, dropped in 6 out of 12 patients after a 28-day course, could hardly be underestimated.

  18. Associations between etiologic factors and mortality after endometrial cancer diagnosis: The NRG Oncology/Gynecologic Oncology Group 210 Trial

    PubMed Central

    Felix, Ashley S; McMeekin, D Scott; Mutch, David; Walker, Joan L; Creasman, William T; Cohn, David E; Ali, Shamshad; Moore, Richard G; Downs, Levi S; Ioffe, Olga B; Park, Kay J; Sherman, Mark E; Brinton, Louise A

    2015-01-01

    Background Few studies have analyzed relationships between risk factors for endometrial cancer, especially with regard to aggressive (non-endometrioid) histologic subtypes, and prognosis. We examined these relationships in the prospective NRG Oncology/Gynecologic Oncology Group 210 trial. Methods Prior to surgery, participants completed a questionnaire assessing risk factors for gynecologic cancers. Pathology data were derived from clinical reports and central review. We used the Fine and Gray subdistribution hazards model to estimate subhazard ratios (HRs) and 95% confidence intervals (CIs) for associations between etiologic factors and cause-specific subhazards in the presence of competing risks. These models were stratified by tumor subtype and adjusted for stage and socioeconomic status indicators. Results Median follow-up was 60 months after enrollment (range: 1 day – 118 months). Among 4,609 participants, a total of 854 deaths occurred, of which, 582 deaths were attributed to endometrial carcinoma. Among low-grade endometrioid cases, endometrial carcinoma-specific subhazards were significantly associated with age at diagnosis (HR=1.04, 95% CI=1.01–1.06 per year, P-trend) and BMI (class II obesity vs. normal BMI: HR=2.29, 95% CI=1.06–4.98, P-trend=0.01). Among high-grade endometrioid cases, endometrial carcinoma-specific subhazards were associated with age at diagnosis (HR=1.05, 95% CI=1.02–1.07 per year, P-trend<0.001). Among non-endometrioid cases, endometrial carcinoma-specific subhazards were associated with parity relative to nulliparity among serous (HR=0.55, 95% CI=0.36–0.82) and carcinosarcoma cases (HR=2.01, 95% CI=1.00–4.05). Discussion Several endometrial carcinoma risk factors are associated with prognosis, which occurs in a tumor-subtype specific context. If confirmed, these results would suggest that factors beyond histopathologic features and stage are related to prognosis. PMID:26341710

  19. Endoscopic Ultrasound Does Not Accurately Stage Early Adenocarcinoma or High-Grade Dysplasia of the Esophagus

    DTIC Science & Technology

    2010-01-01

    MeSH search terms: " endoscopic ultrasound," "Barrett’s esophagus ," "adeno· carcinoma," "Barrett’s esophagus and high grade dyspla.c;ia...adenocarcinoma of the esophagus ; EMR, endoscopic mucosal resection; EUS, endoscopic ul- trasound; HGD, high-grade dysplasia. <D 2010 by the AGA Institute... esophagus and early adenocarcinoma found EUS examination to have perfecr accuracy for differentiating Tl CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol

  20. The Kruppel-like factor 9 (KLF9) network in HEC-1-A endometrial carcinoma cells suggests the carcinogenic potential of dys-regulated KLF9 expression

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Krüppel-like factor 9 (KLF9) is a transcriptional regulator of uterine endometrial cell proliferation, adhesion and differentiation; processes essential for pregnancy success and which are subverted during tumorigenesis. The network of endometrial genes controlled by KLF9 is largely unknown. Over-...

  1. IMP2 expression distinguishes endometrioid from serous endometrial adenocarcinomas.

    PubMed

    Zhang, Liping; Liu, Yuxin; Hao, Suyang; Woda, Bruce A; Lu, Di

    2011-06-01

    Among various endometrial adenocarcinomas, endometrioid carcinoma can be very difficult to separate from serous carcinomas. Various biomarkers have been studied with proven value, including p53, Ki-67, and p16. In this study, we present data on another biomarker, IMP2, which we believe is sensitive and specific. Using 320 endometrial biopsy cases, we demonstrate that IMP2 is normally expressed in all proliferative and inactive endometrial glandular cells. The pattern of such expression is unchanged in serous carcinomas. IMP2 expression is, however, lost in all cases of endometrioid carcinomas by at least 25% to >95% of tumor cell populations. Therefore, loss of IMP2 expression can differentiate endometrioid from serous carcinomas. Such finding of IMP2 expression remained the same in mixed endometrioid and serous carcinomas; IMP2 expression is lost in all endometrioid components by at least 25% of tumor cell population, whereas it remained diffuse and strong in all serous components of carcinomas.

  2. RNA interference-mediated targeting of DKK1 gene expression in Ishikawa endometrial carcinoma cells causes increased tumor cell invasion and migration.

    PubMed

    Yi, Nuo; Liao, Qin-Ping; Li, Zhen-Hua; Xie, Bao-Jiang; Hu, Yu-Hong; Yi, Wei; Liu, Min

    2013-09-01

    The Wnt signaling pathway plays an essential role in tumor invasion and migration. DKK1 functions as an important inhibitor of the pathway and represents a promising target for cancer therapy. The aim of the present study was to determine the role of DKK1 in endometrial carcinoma (EC) cell invasion and migration using RNA interference (RNAi) technology. Ishikawa EC cells were transfected at high efficiency with specific DKK1 siRNA. RT-PCR and western blot analysis were used to determine the mRNA and protein levels of DKK1, β-catenin and metalloproteinase 14 (MMP14) in siRNA-treated and -untreated cells. In addition, the invasion and migration of the EC cells were detected by invasion and migration assays. Transient transfection of DKK1 siRNA significantly inhibited the mRNA and protein levels of DKK1. Markedly increased cell invasion and migration was observed following treatment with DKK1 siRNA when compared with the negative control siRNA-treated and siRNA-untreated cells. The knockdown of DKK1 also elevated the mRNA and protein levels of β-catenin and MMP14 involved in the Wnt signaling pathway, indicating that targeting this gene may promote intracellular Wnt signal transduction and thus, accelerate EC cell invasion and migration in vitro. The RNAi-mediated targeting of DKK1 gene expression in Ishikawa EC cells resulted in increased tumor cell invasion and migration. DKK1 was identified as an inhibitor of EC cell invasion and migration via its novel role in the Wnt signaling pathway. Targeting DKK1 may therefore represent an effective anti-invasion and -migration strategy for the treatment of EC.

  3. Diagnostic and prognostic significance of miRNA signatures in tissues and plasma of endometrioid endometrial carcinoma patients.

    PubMed

    Torres, Anna; Torres, Kamil; Pesci, Anna; Ceccaroni, Marcello; Paszkowski, Tomasz; Cassandrini, Paola; Zamboni, Giuseppe; Maciejewski, Ryszard

    2013-04-01

    The aim of our study was to define tissue and plasma miRNA signatures, which could potentially serve as diagnostic and prognostic markers in endometrioid endometrial cancer (EEC) and to investigate miRNA profiles in regard to clinicopathological characteristics. Tissue and plasma samples were collected from 122 women (77 EEC and 45 controls). Expression profiling of 866 human miRNAs and 89 human viral miRNAs was performed in 24 samples and was followed by qPCR validation in 104 patients. Expression of 16 miRNAs was analyzed in 48 plasma samples. Microarray study revealed regulation of 21 miRNAs in EEC tissues comparing to normal endometrium. Altered expression of 17 miRNAs was confirmed by qPCR performed in 104 tissue samples. Seven miRNAs were upregulated and two were downregulated in EEC plasma samples. Expression of a number of miRNAs was associated with International Federation of Gynecology and Obstetrics stage, grade, relapse and nodal metastases. Two miRNA signatures: miR-92a/miR-410 and miR-92a/miR-205/miR-410 classified tumor tissues with higher accuracy in comparison to single miRNAs (AUC: 0.977, 95% CI: 0.927-0.996 and 0.984, 95% CI: 0.938-0.999, respectively). miRNA signature composed of miR-205 and miR-200a predicted relapse with AUC of 0.854 (95% CI: 0.691-0.951). Tissue miRNA signatures were independent prognostic markers of overall (miR-1228/miR-200c/miR-429, HR: 2.98) and progression-free survival (miR-1228/miR-429, HR: 2.453). Plasma miRNA signatures: miR-9/miR-1228 and miR-9/miR-92a, classified EEC plasma samples with high accuracy yielding AUCs of 0.909 (95% CI: 0.789-973) and 0.913 (95% CI: 0.794-0.976), respectively. We conclude that miRNA signatures hold a great promise to become noninvasive biomarkers for early EEC detection and prognosis.

  4. [Epidemiological survey on the relationship between obesity and endometrial cancer].

    PubMed

    Fujimoto, I; Hamada, T; Hasumi, K; Masubuchi, K; Sakamoto, G; Sugano, H

    1986-10-01

    Endometrial carcinoma is found more frequently in obese subjects. In this study, we evaluated the comparative risks of endometrial cancer relative to obesity indices calculated using the Brocas coefficient. From 1979 to 1983, we treated 185 patients with endometrial cancer at the Cancer Institute Hospital, Tokyo. Compared to nonobese subjects, those who exhibited an obesity index of 1.2 or more were found to have a relative risk value of 2.0 or more times that of normal subjects across all age groups. Based on these findings, it is suggested that a practical and effective preventive measure against endometrial cancer is to avoid becoming obese.

  5. Early detection of high-grade tubal serous carcinoma in women at low risk for hereditary breast and ovarian cancer syndrome by systematic examination of fallopian tubes incidentally removed during benign surgery.

    PubMed

    Rabban, Joseph T; Garg, Karuna; Crawford, Beth; Chen, Lee-may; Zaloudek, Charles J

    2014-06-01

    Early detection of sporadic pelvic serous carcinoma remains an elusive goal. In women at high risk for hereditary breast and ovarian cancer syndrome who undergo prophylactic salpingectomy, systematic pathologic examination of the fallopian tubes will detect occult tubal cancer, mostly in the fimbriae, of a minority of women. Such tubal cancers are the putative precursor to advanced-stage pelvic cancer. We hypothesized that early tubal cancer detection can also be accomplished in women at low risk using a similar approach. In this study, we performed complete and systematic examination of the fallopian tubes removed during surgery performed for benign indications. Among 522 women, 4 cases of serous tubal intraepithelial carcinoma (STIC) were identified. Three of these cases would have gone undetected using the current standard of care of sampling only a single random section of the tube. The fourth case was accompanied by occult ovarian carcinoma. The fimbriae contained STIC in 3 of the 4 cases and atypical mucosa in 1 case in which the STIC was in the nonfimbriated portion of the tube. The morphologic and immunohistochemical features (aberrant p53 and MIB-1) of these STICs were similar to those expected in high-risk women. All 4 patients with STIC underwent BRCA1 and BRCA2 gene testing; no germline mutations were identified in any patient. An additional 11 specimens contained atypical mucosal proliferations that fell short of morphologic and immunohistochemical criteria for STIC. Two of these 11 fulfilled criteria for a serous tubal intraepithelial lesion, and the remaining atypical proliferations exhibited normal p53 and MIB-1. For most specimens, the fimbriae could be completely submitted in 1 or 2 cassettes per tube. These results demonstrate that systematic examination of the tubal fimbriae can serve as a form of early detection of sporadic tubal cancer without incurring significant labor or cost. We propose that the tubal fimbriae should be completely examined

  6. Three or Four Fractions of 4-5 Gy per Week in Postoperative High-Dose-Rate Brachytherapy for Endometrial Carcinoma

    SciTech Connect

    Rovirosa, Angeles; Ascaso, Carlos; Sanchez-Reyes, Alberto; Herreros, Antonio; Abellana, Rosa; Pahisa, Jaume; Lejarcegui, Jose Antonio; Biete, Albert

    2011-10-01

    Purpose: To evaluate the results of high-dose-rate brachytherapy (HDRBT) using a schedule of three or four fractions per week, when possible, in 89 patients on local control and toxicity in postoperative treatment of endometrial carcinoma. The effect of the overall HDRBT treatment time (OTT) on toxicity was also evaluated. Patients and Methods: Federation Internationale de Gynecologie Obstetrique Stage: 24 IB, 45 IC, 4 IIA, 6 IIB, 4 IIIA, 2 IIIB, and 4 IIIC. Radiotherapy: Group 1-67 of 89 patients received external beam irradiation (EBI; 44-50 Gy) plus HDRBT (3 fractions of 4-6 Gy); Group 2-22 of 89 patients received HDRBT alone (6 fractions of 4-5 Gy). OTT: Group 1-HDRBT was completed in a median of 5 days in 32 patients and in >5 days in 35; Group 2-HDRBT was completed in <15 days in 11 patients and in {>=}16 days in 11. Toxicity was evaluated using Radiation Therapy Oncology Group scores and the bioequivalent dose (BED) study was performed in vaginal mucosa surface. Statistics included Student's t test, chi-square test, and receiving operator curves. Results: With a mean follow-up of 31 months (range, 6-70), 1 of 89 patients had vaginal relapse. Early toxicity appeared in 8 of 89 (9%) patients and was resolved. Late toxicity appeared in 13/89 (14%): vaginal nine Grade 1, three Grade 2, one Grade 4; bladder two Grade 2; rectal three Grade 1, one Grade 2. No differences were found in relation to OTT in Groups 1 and 2. Mean BED was 88.48 Gy in Group 1 and 165.28 Gy in Group 2. Cases with Grade 2 late vaginal toxicity received >75 Gy after EBI and >165 Gy in Group 2. Conclusions: Three fractions of 4-5 Gy in 3-5 days after EBI or 6 fractions in <15 days in patients receiving HDRBT alone was a safe treatment in relation to toxicity and local control. Vaginal surface BED less than 75 Gy after EBI and less than 160 Gy in HDRBT alone may be safe to avoid G2 toxicity.

  7. Aqueous Extract of Solanum nigrum Leaf Activates Autophagic Cell Death and Enhances Docetaxel-Induced Cytotoxicity in Human Endometrial Carcinoma Cells

    PubMed Central

    Tai, Cheng-Jeng; Wang, Chien-Kai; Chang, Yu-Jia; Lin, Chi-Shian; Tai, Chen-Jei

    2012-01-01

    Chemotherapy is the main approach in dealing with advanced and recurrent endometrial cancer. An effective complementary ingredient can be helpful in improving the clinical outcome. Aqueous extract of Solanum nigrum leaf (AE-SN) is a principal ingredient for treating cancer patients in traditional Chinese medicinal practice but lacks sufficient evidence to verify its tumor suppression efficacy. This study evaluated the antitumor effects of AE-SN and also assessed the synergistic effects of AE-SN with docetaxel On the human endometrial cancer cell lines, HEC1A, HEC1B, and KLE. The activation of apoptotic markers, caspase-3 and poly-ADP-ribose polymerase, and autophagic marker, microtubule-associated protein 1 light chain 3 A/B, wAS determined to clarify the cell death pathways responsible for AE-SN induced tumor cell death. Results indicated that AE-SN-treatment has significant cytotoxicity on the tested endometrial cancer cells with accumulation of LC3 A/B II and demonstrated a synergistic effect of AE-SN and docetaxel in HEC1A and HEC1B cells, but not KLE cells. In conclusion, AE-SN treatment was effective in suppressing endometrial cancer cells via the autophagic pathway and was also capable of enhancing the cytotoxicity of docetaxel in human endometrial cancer cells. Our results provide meaningful evidence for integrative cancer therapy in the future. PMID:23304219

  8. Pilot study in the treatment of endometrial carcinoma with 3D image-based high-dose-rate brachytherapy using modified Heyman packing: Clinical experience and dose-volume histogram analysis

    SciTech Connect

    Weitmann, Hajo Dirk . E-mail: dirk.weitmann@akhwien.at; Poetter, Richard; Waldhaeusl, Claudia; Nechvile, Elisabeth; Kirisits, Christian; Knocke, Tomas Hendrik

    2005-06-01

    Purpose: The aim of this study was to evaluate dose distribution within uterus (clinical target volume [CTV]) and tumor (gross tumor volume [GTV]) and the resulting clinical outcome based on systematic three-dimensional treatment planning with dose-volume adaptation. Dose-volume assessment and adaptation in organs at risk and its impact on side effects were investigated in parallel. Methods and Materials: Sixteen patients with either locally confined endometrial carcinoma (n = 15) or adenocarcinoma of uterus and ovaries after bilateral salpingo-oophorectomy (n = 1) were included. Heyman packing was performed with mean 11 Norman-Simon applicators (3-18). Three-dimensional treatment planning based on computed tomography (n = 29) or magnetic resonance imaging (n = 18) was done in all patients with contouring of CTV, GTV, and organs at risk. Dose-volume adaptation was achieved by dwell location and time variation (intensity modulation). Twelve patients treated with curative intent received five to seven fractions of high-dose-rate brachytherapy (7 Gy per fraction) corresponding to a total dose of 60 Gy (2 Gy per fraction and {alpha}/{beta} of 10 Gy) to the CTV. Four patients had additional external beam radiotherapy (range, 10-40 Gy). One patient had salvage brachytherapy and 3 patients were treated with palliative intent. A dose-volume histogram analysis was performed in all patients. On average, 68% of the CTV and 92% of the GTV were encompassed by the 60 Gy reference volume. Median minimum dose to 90% of CTV and GTV (D90) was 35.3 Gy and 74 Gy, respectively. Results: All patients treated with curative intent had complete remission (12/12). After a median follow-up of 47 months, 5 patients are alive without tumor. Seven patients died without tumor from intercurrent disease after median 22 months. The patient with salvage treatment had a second local recurrence after 27 months and died of endometrial carcinoma after 57 months. In patients treated with palliative

  9. Improvement in High-Grade Osteosarcoma Survival

    PubMed Central

    Hung, Giun-Yi; Yen, Hsiu-Ju; Yen, Chueh-Chuan; Wu, Po-Kuei; Chen, Cheng-Fong; Chen, Paul C-H; Wu, Hung-Ta H.; Chiou, Hong-Jen; Chen, Wei-Ming

    2016-01-01

    Abstract The aim of this study was to compare survival before and after 2004 and define the prognostic factors for high-grade osteosarcomas beyond those of typical young patients with localized extremity disease. Few studies have reported the long-term treatment outcomes of high-grade osteosarcoma in Taiwan. A total of 202 patients with primary high-grade osteosarcoma who received primary chemotherapy at Taipei Veterans General Hospital between January 1995 and December 2011 were retrospectively evaluated and compared by period (1995–2003 vs 2004–2011). Patients of all ages and tumor sites and those following or not following controlled protocols were included in analysis of demographic, tumor-related, and treatment-related variables and survival. Overall survival and progression-free survival at 5 years were, respectively, 67.7% and 48% for all patients (n = 202), 77.3% and 57.1% for patients without metastasis (n = 157), and 33.9% and 14.8% for patients with metastasis (n = 45). The survival rates of patients treated after 2004 were significantly higher (by 13%–16%) compared with those of patients treated before 2004, with an accompanying 30% increase in histological good response rate (P = .002). Factors significantly contributing to inferior survival in univariate and multivariate analyses were diagnosis before 2004, metastasis at diagnosis, and being a noncandidate for a controlled treatment protocol. By comparison with the regimens used at our institution before 2004, the current results support the effectiveness of the post-2004 regimens, which consisted of substantially reduced cycles of high-dose methotrexate and a higher dosage of ifosfamide per cycle, cisplatin, and doxorubicin, for treating high-grade osteosarcoma in Asian patients. PMID:27082623

  10. Expression of leptin receptor in endometrial biopsies of endometrial and ovarian cancer patients

    PubMed Central

    MÉNDEZ-LÓPEZ, LUIS FERNANDO; DÁVILA-RODRÍGUEZ, MARTHA IMELDA; ZAVALA-POMPA, ANGEL; TORRES-LÓPEZ, ERNESTO; GONZÁLEZ-MARTÍNEZ, BLANCA EDELIA; LÓPEZ-CABANILLAS-LOMELÍ, MANUEL

    2013-01-01

    The adipokine leptin plays a critical role in the regulation of reproductive function and there has been growing interest in its potential role in the development of cancers in which obesity is an established risk factor. Serum leptin levels were found to be higher in patients diagnosed with endometrial and ovarian cancer compared to those observed in healthy individuals. This study was conducted to determine the expression of the leptin receptor (Ob-R) in endometrial biopsies of patients diagnosed with endometrial and ovarian cancer. In this preliminary study, immunohistochemistry (IHC) and the color deconvolution method were used to assess the expression levels of the Ob-R protein in three groups of endometrial tissue: one from patients diagnosed with endometrioid endometrial carcinoma, one from patients diagnosed with ovarian cancer and one from individuals without any diagnosed gynecologic disease (control group). Our results demonstrated that the highest expression of Ob-R protein in endometrial biopsies was detected in the ovarian cancer group (P=0.000). This finding suggests that changes in Ob-R expression may be assessed through the measurement of the optical density of endometrial biopsies and may become a useful tool in preventive screening, particularly for ovarian cancer. PMID:24649005

  11. Molecular profiling of endometrial carcinoma precursor, primary and metastatic lesions suggests different targets for treatment in obese compared to non-obese patients

    PubMed Central

    Berg, Anna; Hoivik, Erling A.; Mjøs, Siv; Holst, Frederik; Werner, Henrica M. J.; Tangen, Ingvild L.; Taylor-Weiner, Amaro; Gibson, William J.; Kusonmano, Kanthida; Wik, Elisabeth; Trovik, Jone; Halle, Mari K.; Øyan, Anne M.; Kalland, Karl-Henning; Cherniack, Andrew D.; Beroukhim, Rameen; Stefansson, Ingunn; Mills, Gordon B.; Krakstad, Camilla; Salvesen, Helga B.

    2015-01-01

    Obesity is linked to increased incidence of endometrioid endometrial cancer (EEC) and complex atypical hyperplasia (CAH). We here explore pattern and sequence of molecular alterations characterizing endometrial carcinogenesis in general and related to body mass index (BMI), to improve diagnostic stratification and treatment strategies. We performed molecular characterization of 729 prospectively collected EEC and CAH. Candidate biomarkers were identified in frozen samples by whole-exome and Sanger sequencing, oligonucleotide gene expression and Reverse Phase Protein Arrays (investigation cohort) and further explored in formalin fixed tissues by immunohistochemistry and Fluorescent in Situ Hybridization (validation cohort). We here demonstrate that PIK3CA mutations, PTEN loss, PI3K and KRAS activation are early events in endometrial carcinogenesis. Molecular changes related to KRAS activation and inflammation are more common in obese CAH patients, suggesting different prevention and systemic treatment strategies in obese and non-obese patients. We also found that oncoprotein Stathmin might improve preoperative diagnostic distinction between premalignant and malignant endometrial lesions. PMID:25415225

  12. Coexisting atypical polypoid adenomyoma and endometrioid endometrial carcinoma in a young woman with Cowden Syndrome: Case report and implications for screening and prevention.

    PubMed

    Edwards, James M; Alsop, Skylar; Modesitt, Susan C

    2012-01-01

    ► Cowden Syndrome is a rare hereditary cancer syndrome, which confers an increased risk of breast, thyroid, endometrial and colon cancer. ► Atypical polypoid adenomyoma does not generally represent a premalignant lesion, but must be carefully screened for foci of malignancy. ► Cancer screening must be intensified for patients who meet the diagnostic criteria for Cowden Syndrome.

  13. Primary high grade sarcoma of the specialised prostatic stroma: a case report with clinico-pathological considerations.

    PubMed

    Fraggetta, F; Pepe, P; Giunta, M L; Aragona, F

    2008-12-01

    Malignant tumours of the prostate other than carcinomas are rare. One such malignant tumours arising from the specialised stromal tissue of the prostate is stromal prostatic sarcoma (namely low-grade and high-grade). Herein, we report the clinico-pathological features of a high grade stromal sarcoma of the prostate occurring in a 65-year-old man who presented for urinary obstructive symptoms. The clinical picture suggested a benign prostatic hyperplasia, and surgery consisting in a transcapsular adenomectomy was performed. Following a pathological diagnosis of high grade prostatic stromal sarcoma, a radical cystoprostatectomy and bilateral pelvic node dissection was performed showing residual high grade stromal sarcoma of the prostate and incidental in situ urothelial carcinoma of the bladder. No further medical treatments were planned. One year after surgery the patient is well with no evidence of local disease or distant metastases.

  14. Type II endometrial cancers: A case series

    PubMed Central

    Lobo, Flora D.; Thomas, Eliz

    2016-01-01

    Introduction: Endometrial carcinoma ranks 3rd in India among gynecological malignancies. Endometrial cancer (EC) can be classified into two distinct groups – type I and type II, based on histology, which differs in molecular, clinical and histopathological profiles. Type II is nonestrogen dependent, nonendometrioid, more aggressive and carries poor prognosis. Although type II cancers contribute only about 10% of EC incidence, they present at advanced age and cause approximately 50% recurrence and deaths with a low 5-year, overall survival rate. Type II EC are also characterized by genetic alterations in p53, human epidermal growth factor-2/neu, p16 and E-cadherin. Materials and Methods: Endometrial carcinomas diagnosed from endometrial biopsies and hysterectomy specimens received in the Department of Pathology, Kasturba Medical College, Mangalore, from January 2007 to June 2012 were included in the study. Clinicopathological analysis of the 84 cases of EC was done with emphasis on morphology. p53 immunostaining was performed in two cases of serous carcinoma. Results: Out of a total of 84 cases of EC, ten cases were of type II (11.9%). Out of which, eight were serous carcinoma (9.5%) and two clear cell (2.4%). p53 immunostain was strongly positive in the serous papillary carcinomas. The age of the patients ranged from 45 to 75 years. Myometrial invasion was more than half. Treatment was hysterectomy followed by aggressive chemotherapy. Conclusion: Of the type II EC, serous carcinoma is the most common type. Clinical presentation and prognosis differs in comparison to type I EC, thus the recognition of this type of EC is pivotal. PMID:27499593

  15. Upper Tract Urothelial Carcinoma in the Genetically Predisposed Patient: Role of Urinary Markers in Predicting Recurrence

    PubMed Central

    Tecle, Nahom; Whelan, Patrick; Strong, Andrea; Deane, Leslie A.

    2016-01-01

    Abstract Background: Upper tract urothelial carcinoma (UTUC) is an uncommon disease that is diagnosed clinically by the selective use of urine cytology, urine biomarkers, and imaging of the upper tract. We present a case of a patient with Lynch syndrome and high-grade UTUC that was diagnosed by an abnormal Cxbladder assay, prompting further endoscopic examination. Case Presentation: A 59-year-old Caucasian female with a history of endometrial cancer and bladder cancer with Lynch syndrome presented for evaluation of recurrent urothelial carcinoma. Her previous bladder tumors have been T1 high grade and Ta high grade and have been treated with resection and multiple cycles of intravesical Bacillus Calmette–Guerin (BCG) therapy. She had also undergone a robotic left distal ureterectomy and psoas hitch for a high-grade distal ureteral tumor. Surveillance cystoscopy 7 months after revealed a biopsy-confirmed bladder tumor, which was resected, and she was started on maintenance BCG therapy. At presentation, follow-up urine cytology and UroVysion studies were negative. Cxbladder test was also initially negative. However, during close clinical monitoring, the Cxbladder test became positive. Cystoscopy was once more performed, which was unremarkable. Bilateral ureteroscopy was performed, revealing high-grade upper tract renal papillary carcinoma (UTUC) in the left renal pelvis. The patient declined a nephroureterectomy. She was treated with two sessions of holmium laser ablation of the left renal pelvis tumor and underwent 6 weekly courses of BCG + interferon instilled into her left renal pelvis using a 5F open-ended catheter. Repeat urine cytology, UroVysion, and Cxbladder tests were negative after completion of upper tract BCG therapy. Conclusion: Cxbladder test may be useful and an adjunct to urine cytology and the UroVysion FISH assay to evaluate patients at high risk for recurrent UTUC. PMID:28078326

  16. Studies on high grade cerebral gliomas

    SciTech Connect

    Bleehen, N.M. )

    1990-04-01

    A brief review of attempts in the United Kingdom to improve the results of treatment of high grade (grade 3, 4) supra-tentorial astrocytomas is presented. The radiosensitizer misonidazole failed to improve the results of post-surgical radiotherapy, however, multivariate analysis of data from these patients has provided a prognostic index of use in defining good and poor prognosis patients. An overview study of adjuvant nitrosourea therapy trials has shown a small significant advantage for the chemotherapy. A study of chemosensitization by benznidazole of CCNU treatment of patients in relapse failed to demonstrate any effect. 13 references.

  17. Gene therapy for high-grade glioma

    PubMed Central

    Natsume, Atsushi

    2008-01-01

    The treatment of high-grade gliomas remains difficult despite recent advances in surgery, radiotherapy and chemotherapy. True advances may emerge from the increasing understanding in molecular biology and discovery of novel mechanisms for the delivery of tumoricidal agents. In an attempt to overcome this formidable neoplasm, molecular approaches using gene therapy have been investigated clinically since 1992. The clinical trials have mainly been classified into three approaches: suicide gene therapy, immune gene therapy and oncolytic viral therapy. In this article, we review these approaches, which have been studied in previous and ongoing clinical trials. PMID:19262115

  18. Temsirolimus With or Without Megestrol Acetate and Tamoxifen Citrate in Treating Patients With Advanced, Persistent, or Recurrent Endometrial Cancer

    ClinicalTrials.gov

    2017-04-11

    Endometrial Carcinoma; Recurrent Uterine Corpus Carcinoma; Stage IIIA Uterine Corpus Cancer; Stage IIIB Uterine Corpus Cancer; Stage IIIC1 Uterine Corpus Cancer; Stage IIIC2 Uterine Corpus Cancer; Stage IVA Uterine Corpus Cancer; Stage IVB Uterine Corpus Cancer

  19. Clinical characteristics of high grade foveal hypoplasia.

    PubMed

    Park, Kyung-Ah; Oh, Sei Yeul

    2013-02-01

    To report clinical characteristics of high grade foveal hypoplasia. Patients with foveal hypoplasia of grade 3 or 4 on spectral domain optical coherence tomography according to a previously published scheme were enrolled. All patients underwent a full ophthalmologic assessment including visual acuity testing, slit lamp biomicroscopy, fundus examination, and evaluation of ocular alignment. The underlying causes of foveal hypoplasia were identified as albinism in five patients and aniridia in six patients. The mean logMAR visual acuity was 0.57 ± 0.24 (range 0.22-1.00) in the right eyes and 0.58 ± 0.21 (range 0.30-1.00) in the left eyes. On fundus examination in patients with albinism, two patients showed marked transparency, one patient showed moderate transparency, and two patients showed minimal transparency. Among six patients with aniridia, five patients showed normal macular pigmentation without macular reflex and one patient showed decreased macular pigmentation with no macular reflex. Patients with high grade macular hypoplasia tended to have poor visual acuities; however, the range of visual acuity was quite variable. Other factors associated with underlying disease could be the reason of this variability. Therefore, careful consideration should be given when assessing visual prognosis in foveal hypoplasia using optical coherence tomography.

  20. 40 CFR 246.200 - High-grade paper recovery.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 24 2010-07-01 2010-07-01 false High-grade paper recovery. 246.200... SEPARATION FOR MATERIALS RECOVERY GUIDELINES Requirements and Recommended Procedures § 246.200 High-grade paper recovery....

  1. 40 CFR 246.200 - High-grade paper recovery.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 25 2011-07-01 2011-07-01 false High-grade paper recovery. 246.200... SEPARATION FOR MATERIALS RECOVERY GUIDELINES Requirements and Recommended Procedures § 246.200 High-grade paper recovery....

  2. Metformin for endometrial hyperplasia: a Cochrane protocol

    PubMed Central

    Clement, Naomi S; Oliver, Thomas R W; Shiwani, Hunain; Saner, Juliane R F; Mulvaney, Caroline A; Atiomo, William

    2016-01-01

    Introduction Endometrial hyperplasia is a precancerous lesion of the endometrium, commonly presenting with uterine bleeding. If managed expectantly, it frequently progresses to endometrial carcinoma, rates of which are increasing dramatically worldwide. However, the established treatment for endometrial hyperplasia (progestogens) involves multiple side effects and leaves the risk of recurrence. Metformin is the most commonly used oral hypoglycaemic agent in type 2 diabetes mellitus. It has also been linked to the reversal of endometrial hyperplasia and may therefore contribute to decreasing the prevalence of endometrial carcinoma without the fertility and side effect consequences of current therapies. However, the efficacy and safety of metformin being used for this therapeutic target is unclear and, therefore, this systematic review will aim to determine this. Methods and analysis We will search the following trials and databases with no language restrictions: Cochrane Gynaecology and Fertility Specialised Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; EBSCO Cumulative Index to Nursing and Allied Health Literature; PubMed; Google Scholar; ClinicalTrials.gov; the WHO International Trials Registry Platform portal; OpenGrey and the Latin American and Caribbean Health Sciences Literature (LILACS). We will include randomised controlled trials (RCTs) of use of metformin compared with a placebo or no treatment, conventional medical treatment (eg, progestogens) or any other active intervention. Two review authors will independently assess the trial eligibility, risk of bias and extract appropriate data points. Trial authors will be contacted for additional data. The primary review outcome is the regression of endometrial hyperplasia histology towards normal histology. Secondary outcomes include hysterectomy rate; abnormal uterine bleeding; quality of life scores and adverse reactions to treatments. Ethics and dissemination

  3. Coordinate patterns of estrogen receptor, progesterone receptor, and Wilms tumor 1 expression in the histopathologic distinction of ovarian from endometrial serous adenocarcinomas.

    PubMed

    Fadare, Oluwole; James, Samuel; Desouki, Mohamed M; Khabele, Dineo

    2013-10-01

    The purpose of this study is to assess whether composite or coordinate immunoexpression patterns of estrogen receptor (ER), progesterone receptor (PR), and Wilms tumor 1 (WT1) gene can significantly distinguish between endometrial serous carcinoma (ESC) and ovarian serous carcinoma (OSC). Immunohistochemical analyses were performed on whole tissue sections from 22 uterus-confined ESCs and on a tissue microarray of 140 high-grade, pan-stage OSCs, using antibodies to ER, PR, and WT-1. Estrogen receptor, PR, and WT1 expressions were present in 37%, 49%, and 81% of OSC, respectively, but these markers were also present in 18%, 27%, and 36% of ESC. The ER+/PR+/WT1+ coordinate profile was identified in 33.6% of OSC but in none of ESC (P = .0006), resulting in a calculated sensitivity and specificity of this profile for OSC of 33.6% and 100%, respectively. By contrast, the ER-/PR-/WT1- coordinate profile was identified in 41% of ESC but in only 6.4% of OSC (P = .0001), resulting in a calculated sensitivity and specificity of this profile for ESC of 50% and 94%. In summary, in the differential diagnosis between OSC and ESC, positivity for all 3 markers favors an extrauterine origin, whereas negativity for all 3 markers is supportive of an endometrial origin. The use of single markers for this purpose is not recommended, as each lacks optimal discriminatory power. Coordinate profiles, in general, have a high specificity but low sensitivity in this differential diagnosis.

  4. Hsa-microRNA-181a is a regulator of a number of cancer genes and a biomarker for endometrial carcinoma in patients: a bioinformatic and clinical study and the therapeutic implication

    PubMed Central

    He, Shuming; Zeng, Shumei; Zhou, Zhi-Wei; He, Zhi-Xu; Zhou, Shu-Feng

    2015-01-01

    The aberrant expression of human microRNA-181a-1 (hsa-miR-181a) has been implicated in the pathogenesis of various cancers, serving as an oncogene or a tumor suppressor. However, the role of hsa-miR-181a in the pathogenesis of endometrial carcinoma (EC) and its clinical significance are unclear. This study aimed to search for the molecular targets of hsa-miR-181a using bioinformatic tools and then determine the expression levels of hsa-miR-181a in normal, hyperplasia, and EC samples from humans. To predict the targets of hsa-miR-181a, ten different algorithms were used, including miRanda-mirSVR, DIANA microT v5.0, miRDB, RNA22 v2, TargetMiner, TargetScan 6.2, PicTar, MicroCosm Targets v5, and miRWALK. Two algorithms, TarBase 6.0 and miRTarBase, were used to identify the validated targets of hsa-miR-181a-5p (a mature product of hsa-miR-181a), and the web-based Database for Annotation, Visualization and Integrated Discovery (DAVID) 6.7 was used to provide biological functional interpretation of the validated targets of hsa-miR-181a-5p. A total of 78 formalin-fixed, paraffin-embedded tissue specimens from 65 patients and 13 healthy subjects were collected and examined, including normal endometrium (n=13), endometrial hyperplasia (n=18), and EC (37 type I and 10 type II EC cases). Our bioinformatic studies have showed that hsa-miR-181a might regulate a large number of target genes that are important in the regulation of critical cell processes, such as cell fate, cell survival, metabolism, and cell death. To date, 313 targets of hsa-miR-181a have been validated, and 22 of these targets are cancer genes. The precision of predictions by all the algorithms for hsa-miR-181a-1’s targets was low. Many of these genes are involved in tumorigenesis of various cancers, including EC, based on the DAVID and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. In comparison with normal endometrial tissue, the expression level of hsa-miR-181a was significantly

  5. A Phase II Study of Intensity Modulated Radiation Therapy to the Pelvis for Postoperative Patients With Endometrial Carcinoma: Radiation Therapy Oncology Group Trial 0418

    SciTech Connect

    Jhingran, Anuja; Winter, Kathryn; Portelance, Lorraine; Miller, Brigitte; Salehpour, Mohammad; Gaur, Rakesh; Souhami, Luis; Small, William; Berk, Lawrence; Gaffney, David

    2012-09-01

    Purpose: To determine the feasibility of pelvic intensity modulated radiation therapy (IMRT) for patients with endometrial cancer in a multi-institutional setting and to determine whether this treatment is associated with fewer short-term bowel adverse events than standard radiation therapy. Methods: Patients with adenocarcinoma of the endometrium treated with pelvic radiation therapy alone were eligible. Guidelines for target definition and delineation, dose prescription, and dose-volume constraints for the targets and critical normal structures were detailed in the study protocol and a web-based atlas. Results: Fifty-eight patients were accrued by 25 institutions; 43 were eligible for analysis. Forty-two patients (98%) had an acceptable IMRT plan; 1 had an unacceptable variation from the prescribed dose to the nodal planning target volume. The proportions of cases in which doses to critical normal structures exceeded protocol criteria were as follows: bladder, 67%; rectum, 76%; bowel, 17%; and femoral heads, 33%. Twelve patients (28%) developed grade {>=}2 short-term bowel adverse events. Conclusions: Pelvic IMRT for endometrial cancer is feasible across multiple institutions with use of a detailed protocol and centralized quality assurance (QA). For future trials, contouring of vaginal and nodal tissue will need continued monitoring with good QA and better definitions will be needed for organs at risk.

  6. Immunological profiling of molecularly classified high-risk endometrial cancers identifies POLE-mutant and microsatellite unstable carcinomas as candidates for checkpoint inhibition.

    PubMed

    Eggink, Florine A; Van Gool, Inge C; Leary, Alexandra; Pollock, Pamela M; Crosbie, Emma J; Mileshkin, Linda; Jordanova, Ekaterina S; Adam, Julien; Freeman-Mills, Luke; Church, David N; Creutzberg, Carien L; De Bruyn, Marco; Nijman, Hans W; Bosse, Tjalling

    2017-01-01

    High-risk endometrial cancer (EC) is an aggressive disease for which new therapeutic options are needed. Aims of this study were to validate the enhanced immune response in highly mutated ECs and to explore immune profiles in other EC subgroups. We evaluated immune infiltration in 116 high-risk ECs from the TransPORTEC consortium, previously classified into four molecular subtypes: (i) ultramutated POLE exonuclease domain-mutant ECs (POLE-mutant); (ii) hypermutated microsatellite unstable (MSI); (iii) p53-mutant; and (iv) no specific molecular profile (NSMP). Within The Cancer Genome Atlas (TCGA) EC cohort, significantly higher numbers of predicted neoantigens were demonstrated in POLE-mutant and MSI tumors compared with NSMP and p53-mutants. This was reflected by enhanced immune expression and infiltration in POLE-mutant and MSI tumors in both the TCGA cohort (mRNA expression) and the TransPORTEC cohort (immunohistochemistry) with high infiltration of CD8(+) (90% and 69%), PD-1(+) (73% and 69%) and PD-L1(+) immune cells (100% and 71%). Notably, a subset of p53-mutant and NSMP cancers was characterized by signs of an antitumor immune response (43% and 31% of tumors with high infiltration of CD8(+) cells, respectively), despite a low number of predicted neoantigens. In conclusion, the presence of enhanced immune infiltration, particularly high numbers of PD-1 and PD-L1 positive cells, in highly mutated, neoantigen-rich POLE-mutant and MSI endometrial tumors suggests sensitivity to immune checkpoint inhibitors.

  7. Hormone therapy for younger patients with endometrial cancer.

    PubMed

    Lee, Wen-Ling; Lee, Fa-Kung; Su, Wen-Hsiang; Tsui, Kuan-Hao; Kuo, Cheng-Deng; Hsieh, Shie-Liang Edmond; Wang, Peng-Hui

    2012-12-01

    The relationship between hormones and endometrial cancer is well known because disease states, such as chronic anovulation and endogenous estrogen production from hormone-secreting tumors (for example, granulosa cell tumor of the ovary), are related to excess estrogen, and unopposed estrogen use might lead to endometrial overgrowth, hyperplasia, and subsequent development of endometrial carcinoma. Therefore, the possibility of using antihormone therapy in endometrial carcinoma and/or its precancer lesions, such as simple hyperplasia with and without atypia and complex hyperplasia with and without atypia, is always supposed, as in the management of breast cancer. In addition, if women in whom endometrial cancer is diagnosed are very young, some critical issues should be considered, including the possibility of ovary preservation-partial preservation of fertility and the possibility of both ovary and uterus preservation-complete preservation of fertility. Other factors are also important to consider and include oncologic risk, appropriateness of candidates for treatment, type of hormone use, response rate of hormonal therapy, appropriate surveillance, and additional counseling for issues such as anxiety about relapse and metastasis, distress about side effects, advice of the family, advice of the medical staff, and economic burden. This review will be focused on updated information and recent knowledge of the use of hormones in the management of younger women with endometrial cancer who want fertility preservation.

  8. Cervical cytology in serous and endometrioid endometrial cancer.

    PubMed

    Roelofsen, Thijs; Geels, Yvette P; Pijnenborg, Johanna M A; van Ham, Maaike A P C; Zomer, Saskia F; van Tilburg, Johanna M Wiersma; Snijders, Marc P M L; Siebers, Albert G; Bulten, Johan; Massuger, Leon F A G

    2013-07-01

    The aim of this study was to determine the frequency of abnormal cervical cytology in preoperative cervical cytology of patients diagnosed with uterine papillary serous carcinoma (UPSC) and endometrioid endometrial carcinoma (EEC). In addition, associations between abnormal cervical cytology and clinicopathologic factors were evaluated. In this multicentre study, EEC patients diagnosed at two hospitals from 1999 to 2009 and UPSC patients diagnosed at five hospitals from 1992 to 2009, were included. Revision of the histologic slides was performed systematically and independently by 3 gynecopathologists. Cervical cytology within six months before histopathologic diagnosis of endometrial carcinoma was available for 267 EEC and 80 UPSC patients. Cervical cytology with atypical, malignant, or normal endometrial cells in postmenopausal women was considered as abnormal cytology, specific for endometrial pathology. Abnormal cervical cytology was found in 87.5% of UPSC patients, compared with 37.8% in EEC patients. In UPSC, abnormal cytology was associated with extrauterine spread of disease (P=0.043). In EEC, abnormal cytology was associated with cervical involvement (P=0.034). In both EEC and UPSC patients, abnormal cervical cytology was not associated with survival. In conclusion, abnormal cervical cytology was more frequently found in UPSC patients. It was associated with extrauterine disease in UPSC patients, and with cervical involvement in EEC patients. More prospective research should be performed to assess the true clinical value of preoperative cervical cytology in endometrial cancer patients.

  9. Endometrial pathology in postmenopausal tamoxifen treatment: comparison between gynaecologically symptomatic and asymptomatic breast cancer patients.

    PubMed Central

    Cohen, I; Perel, E; Flex, D; Tepper, R; Altaras, M M; Cordoba, M; Beyth, Y

    1999-01-01

    AIMS: To evaluate whether endometrial pathology is more likely to be diagnosed in gynaecologically symptomatic rather than in gynaecologically asymptomatic postmenopausal breast cancer patients with tamoxifen treatment; and to evaluate the possible influence of various clinical factors on the incidence of endometrial pathology. METHODS: Endometrial histological findings, transvaginal ultrasonographic endometrial thickness, demographic characteristics, health habits, and risk factors for endometrial cancer were compared between 14 gynaecologically symptomatic (group I) and 224 gynaecologically asymptomatic (group II) postmenopausal breast cancer patients with tamoxifen treatment. RESULTS: Overall, 28.6% of the study population had endometrial pathology. The incidence of overall positive endometrial histological findings was significantly higher in group I than in group II (92.9% v 24.6%, p < 0.0001). Atrophic endometrium was more common in group II than in group I (75.3% v 7.1%, p < 0.0001). Most other endometrial pathology was significantly more common in group I than in group II (endometrial hyperplasia, 35.7% v 5.6%, p < 0.0001; endometrial polyps, 35.7% v 13.4%, p < 0.0111; endometrial carcinoma, 21.5% v 0.9%, p < 0.0001). Endometrial pathology appeared considerably later in the gynaecologically asymptomatic patients than in gynaecologically symptomatic patients (p = 0.0002). Vaginal bleeding or spotting occurred exclusively in group I. The incidence of endometrial pathology in the entire study population was consistent with that reported elsewhere, and higher than that reported for healthy postmenopausal women. CONCLUSIONS: Endometrial pathology is more likely to be diagnosed in gynaecologically symptomatic postmenopausal breast cancer patients with tamoxifen treatment, and after a shorter duration of time, than in gynaecologically asymptomatic patients. PMID:10474520

  10. Sertoliform endometrioid carcinoma of the endometrium with dual immunophenotypes for epithelial membrane antigen and inhibin alpha: case report and literature review.

    PubMed

    Liang, Sharon X; Patel, Kausha; Pearl, Michael; Liu, Jingxuan; Zheng, Wenxin; Tornos, Carmen

    2007-07-01

    We report a rare case of sertoliform endometrioid carcinoma of the endometrium in a 71-year-old African American woman who presented with postmenopausal bleeding. Her medical condition was remarkable for hypertension, diabetes, and obesity. She underwent total hysterectomy, right salpingo-oophorectomy and lymph node sampling. The endometrium was occupied by a 4.5-cm solid polypoid tumor, which grossly invaded into the myometrium. Microscopically, the tumor consisted of small hollow tubules, anastomosing cords and trabeculae, and tightly packed nests. Microglandular areas mimicking adult granulosa cell tumors were also present. But true Call-Exner bodies were absent. Component of typical endometrioid carcinoma was noted only focally. The uninvolved endometrium demonstrated atypical complex hyperplasia. The tumor cells were diffusely immunoreactive for epithelial membrane antigen, estrogen receptor, and progesterone receptor (PR), and focally for vimentin. The tumor cells were also diffusely positive for inhibin alpha and CD99. Immunostains for other sex cord markers (calretinin, WT-1, and Melan-A) were also positive in approximately 30% to 40% of the tumor cells. Immunostains for CD10, smooth muscle actin, desmin, or HHF35 were negative. Two ovarian sertoliform endometrioid carcinomas from our archived tissue were, however, immunoreactive for epithelial membrane antigen but negative for inhibin alpha. Despite the prominent sertoliform features, both histologically and immunohistochemically, the tumor was of a high-grade endometrial carcinoma and will likely behave as such. As of today, dual differentiation of epithelium and sex cord by immunohistochemical staining has not been demonstrated in sertoliform endometrioid carcinomas of either endometrial or ovarian origin. Our case is the first documentation of such example and suggests that endometrial carcinoma can undergo true sex cord differentiation.

  11. Effect of steroidal and nonsteroidal antiestrogens on the growth of a tamoxifen-stimulated human endometrial carcinoma (EnCa101) in athymic mice.

    PubMed

    Gottardis, M M; Ricchio, M E; Satyaswaroop, P G; Jordan, V C

    1990-06-01

    Tamoxifen (TAM), a nonsteroidal antiestrogen, is used in the adjuvant treatment of breast cancer. Previous studies, however, have indicated that some human breast and endometrial tumors are stimulated to grow with TAM in the athymic mouse. One such TAM-stimulated tumor is the EnCa101 human endometrial adenocarcinoma. Our aim was to evaluate the ability of different doses of TAM or other nonsteroidal antiestrogens to stimulate the growth of EnCa101 tumors in athymic mice. Additionally we have evaluated less estrogenic antiestrogens (two steroidal antiestrogens, RU 39,411 and ICI 164,384, and two nonsteroidal antiestrogens, keoxifene and MER-25) for their ability to inhibit TAM-stimulated growth. All experiments were done in ovariectomized athymic mice transplanted in the axillary mammary fat with 1-mm3 pieces of EnCa101 tumor. Sustained release preparations (0.5-2.0-cm Silastic capsule or 5-mg TAM cholesterol pellet) of TAM caused similar tumor growth. The growth rate was not altered by an additional daily i.p. injection of 1 mg TAM in 0.1 ml peanut oil. A 3-mg TAM daily dose was toxic. Four weeks of treatment (100-micrograms s.c. injections, every other day) with nonsteroidal antiestrogens, trioxifene mesylate, enclomiphene, or nafoxidine stimulated tumor growth. However, keoxifene stimulated this tumor to a lesser degree than TAM and partially inhibited TAM-stimulated growth. ICI 164,384 showed no stimulatory activity (1-mg s.c. injections every other day) alone compared to controls but inhibited TAM-stimulated (0.25-cm Silastic capsule) growth. In a parallel experiment, RU 39,411 (1-mg s.c. injections every other day) stimulated EnCa101 to grow. In contrast when RU 39,411 was administered in a sustained release preparation (2.0-cm Silastic capsule) there was no stimulatory growth compared to controls. Additionally RU 39,411 inhibited TAM-stimulated growth, but the low-potency antiestrogen, MER-25, was less effective in this regard. These data suggest that less

  12. Endometrial cancer and microsatellite instability status

    PubMed Central

    Vidugiriene, Jolanta; Valuckas, Konstantinas Povilas; Smailyte, Giedre; Uleckiene, Saule; Bacher, Jeff

    2015-01-01

    Microsatellite instability (MSI) is an important factor in the development of various cancers as an identifier of a defective DNA mismatch repair system. The objective of our study was to define the association between microsatellite instability status and traditional clinicopathologic characteristics of endometrioid type adenocarcinoma. Material and methods MSI status of endometrial cancer was examined by employing the Promega MSI Analysis System. This system uses 5 mononucleotide markers to identify MSI in tumour and normal tissue DNA (BAT-25, BAT-26, NR-21, NR-24, and MONO-27), and 2 pentanucleotide markers (Penta C and Penta D) for specimen identification. In this study, we investigated MSI status in 109 endometrial carcinomas. Results and conclusions One hundred (92%) of 109 endometrial cancers showed endometrioid type histology and only 9 (8%) non-endometrioid type. MSI-high was found in 17% (17/100) of endometrioid type adenocarcinomas, in 0% (0/9) of non-endometrioid carcinomas. Selected clinicopathologic parameters for endometrioid type adenocarcinomas were compared to the MSI status which was separated into two groups – MSI-high and MSI stable. The results showed that MSI-high status was related to clinicopathologic parameters such as deep myometrial invasion and higher histologic grade in endometrioid type adenocarcinomas.

  13. Stages of Endometrial Cancer

    MedlinePlus

    ... Stage II endometrial cancer. Cancer has spread into connective tissue of the cervix, but has not spread outside ... uterus. In stage II , cancer has spread into connective tissue of the cervix , but has not spread outside ...

  14. Endometrial Cancer Prevention

    MedlinePlus

    ... is the most common invasive cancer of the female reproductive system. Endometrial cancer is diagnosed most often ... body. It helps the body develop and maintain female sex characteristics. Estrogen can affect the growth of ...

  15. Endometrial cancer following radiation therapy for cervical cancer

    SciTech Connect

    Gallion, H.H.; van Nagell, J.R. Jr.; Donaldson, E.S.; Powell, D.E.

    1987-05-01

    The clinical and histologic features of eight cases of carcinoma of the endometrium which developed following radiation therapy for squamous cell carcinoma of the cervix are described. No patient had a well-differentiated tumor and significant myometrial invasion was present in all cases. Three of the eight tumors were papillary serous adenocarcinoma. Five of the eight patients developed recurrent tumor and died of their disease. The risk of endometrial cancer in patients previously radiated for cervical cancer is evaluated.

  16. Endometrial Ablation for Menorrhagia

    PubMed Central

    Sanders, Barry H.

    1992-01-01

    Endometrial ablation is a relatively new treatment for patients with persistent menorrhagia. The procedure can be performed by either laser photocoagulation or electrocoagulation; both have a very low risk of complication. Generally, less than 24 hours of hospitalization is required and return to normal activities, including work, is almost immediate. Endometrial ablation is likely to become a mainstay of treatment for menorrhagia as the technology and training become more readily available. PMID:21229128

  17. Stratified epithelium in prostatic adenocarcinoma: a mimic of high-grade prostatic intraepithelial neoplasia.

    PubMed

    Hameed, Omar; Humphrey, Peter A

    2006-07-01

    Typically glands of prostatic adenocarcinoma have a single cell lining, although stratification can be seen in invasive carcinomas with a cribriform architecture, including ductal carcinoma. The presence and diagnostic significance of stratified cells within non-cribriform carcinomatous prostatic glands has not been well addressed. The histomorphological features and immunohistochemical profile of cases of non-cribriform prostatic adenocarcinoma with stratified malignant glandular epithelium were analyzed. These cases were identified from needle biopsy cases from the consultation files of one of the authors and from a review of 150 consecutive in-house needle biopsy cases of prostatic adenocarcinoma. Immunohistochemistry was performed utilizing antibodies reactive against high molecular weight cytokeratin (34betaE12), p63 and alpha-methylacyl-coenzyme-A racemase (AMACR). A total of 8 cases were identified, including 2 from the 150 consecutive in-house cases (1.3%). In 4 cases, the focus with glands having stratified epithelium was the sole carcinomatous component in the biopsy, while such a component represented 5-30% of the invasive carcinoma seen elsewhere in the remaining cases. The main attribute in all these foci was the presence of glandular profiles lined by several layers of epithelial cells with cytological and architectural features resembling flat or tufted high-grade prostatic intraepithelial neoplasia, but lacking basal cells as confirmed by negative 34betaE12 and/or p63 immunostains in all cases. The AMACR staining profile of the stratified foci was variable, with 4 foci showing positivity, and 3 foci being negative, including two cases that displayed AMACR positivity in adjacent non-stratified prostatic adenocarcinoma. Prostatic adenocarcinoma with stratified malignant glandular epithelium can be identified in prostate needle biopsy samples harboring non-cribriform prostatic adenocarcinoma and resembles glands with high-grade prostatic

  18. Endometrial tubal metaplasia in a young puerperal woman after breast cancer

    PubMed Central

    Di Benedetto, Luisa; Giovanale, Valentina; Caserta, Donatella

    2015-01-01

    Introduction: Tamoxifen is the usual endocrine (anti-estrogen) therapy for hormone receptor-positive breast cancer in pre and post-menopausal women. Previous studies have suggested an increased prevalence of endometrial diseases after treatment with tamoxifen. Case presentation: The authors report a case of 38-year-old woman with diagnosis of endometrial polyp and tubal metaplasia, during puerperium and after micropapillary ductal breast cancer surgery, 5 years of tamoxifen treatment, spontaneous pregnancy without complications and full-term vaginal delivery. Conclusion: Tamoxifen is a safe and reliable treatment of breast cancer, but data suggest an association with endometrial polyps, hyperplasia, metaplasia and carcinoma. One of the most common types of endometrial metaplasia is ciliated tubal metaplasia. It is generally known that endometrial tubal metaplasia is a benign disease. However studies propose endometrial tubal metaplasia to be a potential premalignant endometrial lesion and its association with endometrial hyperplasia and well-differentiated endometrioid carcinoma. We propose close monitoring of patients taking tamoxifen and prompt evaluation of any uterine bleeding or pelvic complaint or abnormal TVUS images. PMID:26261678

  19. 40 CFR 246.200 - High-grade paper recovery.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 26 2013-07-01 2013-07-01 false High-grade paper recovery. 246.200 Section 246.200 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID WASTES SOURCE... paper recovery....

  20. 40 CFR 246.200 - High-grade paper recovery.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 25 2014-07-01 2014-07-01 false High-grade paper recovery. 246.200 Section 246.200 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID WASTES SOURCE... paper recovery....

  1. 40 CFR 246.200 - High-grade paper recovery.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 26 2012-07-01 2011-07-01 true High-grade paper recovery. 246.200 Section 246.200 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID WASTES SOURCE... paper recovery....

  2. 1. Mill exterior, high grade chute partially restored on the ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    1. Mill exterior, high grade chute partially restored on the outside of mill building center of picture. Looking northeast from below bridge. - Kennecott Copper Corporation, Concentration Mill, On Copper River & Northwestern Railroad, Kennicott, Valdez-Cordova Census Area, AK

  3. [Laparoscopic hysterectomy in the management of endometrial cancer].

    PubMed

    Seracchioli, R; Fabbri, E; Guerrini, M; Mignemi, G; Venturoli, S

    2006-10-01

    Endometrial carcinoma is the most commonly reported gynaecologic malignancy in industrialized countries. Traditionally the surgical treatment of endometrial cancer is total abdominal hysterectomy, bilateral salpingo-oophorectomy, and peritoneal washing cytology. Alternative surgical procedures have been proposed compared to abdominal hysterectomy: increased number of issues about laparoscopy shows the common trend to use this technique. Literature largely described advantages of the laparoscopic procedure compared to abdominal and vaginal surgery. Long-term follow-up series are not available; further investigation into survival and recurrence rates is indicated.

  4. Cytologic characteristics and histomorphologic correlations of 21 salivary duct carcinomas.

    PubMed

    Klijanienko, J; Vielh, P

    1998-11-01

    Fine-needle samplings (FNS) of 21 salivary duct carcinomas, histologically correlated, including 19 primaries, one local recurrence, and one lymph node metastasis from 19 patients, are reported. Cytologic diagnosis of high-grade adenocarcinoma was established in 15 (71%). Five (24%) cases were misclassified as high-grade mucoepidermoid carcinomas and one (5%) as squamous-cell carcinoma. The histologic evaluation in all cases showed cytomorphologic features resembling mammary duct carcinoma with marked cytonuclear atypia and occasional oncocytic appearance. Our cytohistologic correlations indicate that irregular clusters of high-grade adenocarcinoma cells with necrotic background and oncocytic features suggest a cytologic diagnosis of either primary salivary duct carcinoma or metastatic mammary carcinoma.

  5. Overexpression and oncogenic function of HMGA2 in endometrial serous carcinogenesis.

    PubMed

    Wei, Linxuan; Liu, Xiaolin; Zhang, Wenjing; Wei, Yuyan; Li, Yingwei; Zhang, Qing; Dong, Ruifen; Kwon, Jungeun Sarah; Liu, Zhaojian; Zheng, Wenxin; Kong, Beihua

    2016-01-01

    The high-mobility group A protein 2 (HMGA2) is a non-histone chromatin factor highly expressed in fetal tissue and malignant tumors but rarely detected within normal adult tissues. The clinical implications and biological functions of HMGA2 in endometrial carcinoma are largely unknown. Here we report that HMGA2 expression was barely detected in benign endometrium samples (2 of 28 samples). However, HMGA2 expression increased significantly from precancerous lesion endometrial glandular dysplasia (7 of 17, 41.2%), to serous endometrial intraepithelial carcinoma (5 of 8, 62.5%) and to full blown endometrial serous carcinoma (39 of 59, 66.1%). Functional characterization of HMGA2 revealed that the gene has both tumor growth promotion and metastasis. In addition, HMGA2 induced epithelial-mesenchymal transition (EMT) through modulation vimentin and β-catenin. Furthermore, HMGA2 overexpression started from endometrial serous precancers, non-invasive cancers, as well as in full blown carcinomas in a p53 knockout mouse model we recently established in our laboratory. Our findings suggest that HMGA2 may serve as a useful diagnostic marker in the assessment of endometrial serous cancer and its precursor lesions.

  6. Surgical Outcomes of High-Grade Spinal Cord Gliomas

    PubMed Central

    Hida, Kazutoshi; Yano, Syunsuke; Aoyama, Takeshi; Koyanagi, Izumi; Houkin, Kiyohiro

    2015-01-01

    Study Design A retrospective study. Purpose The purpose of this study was to obtain useful information for establishing the guidelines for treating high-grade spinal cord gliomas. Overview of Literature The optimal management of high-grade spinal cord gliomas remains controversial. We report the outcomes of the surgical management of 14 high-grade spinal glioma. Methods We analyzed the outcomes of 14 patients with high-grade spinal cord gliomas who were surgically treated between 1989 and 2012. Survival was charted with the Kaplan-Meier plots and comparisons were made with the log-rank test. Results None of the patients with high-grade spinal cord gliomas underwent total resection. Subtotal resection was performed in two patients, partial resection was performed in nine patients, and open biopsy was performed in three patients. All patients underwent postoperative radiotherapy and six patients further underwent radiation cordotomy. The median survival time for patients with high-grade spinal cord gliomas was 15 months, with a 5-year survival rate of 22.2%. The median survival time for patients with World Health Organization grade III tumors was 25.5 months, whereas the median survival time for patients with glioblastoma multiforme was 12.5 months. Both univariate and multivariate Cox proportional hazards models demonstrated a significant effect only in the group that did not include cervical cord lesion as a factor associated with survival (p=0.04 and 0.03). Conclusions The surgical outcome of patients diagnosed with high-grade spinal cord gliomas remains poor. Notably, only the model which excluded cervical cord lesions as a factor significantly predicted survival. PMID:26713128

  7. Role of epigenomics in ovarian and endometrial cancers.

    PubMed

    Balch, Curtis; Matei, Daniela E; Huang, Tim H-M; Nephew, Kenneth P

    2010-06-01

    Ovarian cancer is the most lethal gynecologic malignancy and while constituting only 3% of all female cancers, it causes 14,600 deaths in the USA annually. Endometrial cancer, the most diagnosed and second-most fatal gynecologic cancer, afflicts over 40,000 US women annually, causing an estimated 7780 deaths in 2009. In both advanced ovarian and endometrial carcinomas, the majority of initially therapy-responsive tumors eventually evolve to a fully drug-resistant phenotype. In addition to genetic mutations, epigenetic anomalies are frequent in both gynecologic malignancies, including aberrant DNA methylation, atypical histone modifications and dysregulated expression of distinct microRNAs, resulting in altered gene-expression patterns favoring cell survival. In this article, we summarize the most recent hypotheses regarding the role of epigenetics in ovarian and endometrial cancers, including a possible role in tumor 'stemness' and also evaluate the possible therapeutic benefits of reversal of these oncogenic chromatin aberrations.

  8. Mutations in chromatin machinery and pediatric high-grade glioma

    PubMed Central

    Lulla, Rishi R.; Saratsis, Amanda Muhs; Hashizume, Rintaro

    2016-01-01

    Pediatric central nervous system tumors are the most common solid tumor of childhood. Of these, approximately one-third are gliomas that exhibit diverse biological behaviors in the unique context of the developing nervous system. Although low-grade gliomas predominate and have favorable outcomes, up to 20% of pediatric gliomas are high-grade. These tumors are a major contributor to cancer-related morbidity and mortality in infants, children, and adolescents, with long-term survival rates of only 10 to 15%. The recent discovery of somatic oncogenic mutations affecting chromatin regulation in pediatric high-grade glioma has markedly improved our understanding of disease pathogenesis, and these findings have stimulated the development of novel therapeutic approaches targeting epigenetic regulators for disease treatment. We review the current perspective on pediatric high-grade glioma genetics and epigenetics, and discuss the emerging and experimental therapeutics targeting the unique molecular abnormalities present in these deadly childhood brain tumors. PMID:27034984

  9. Photodynamic therapy of Cervical Intraepithelial Neoplasia (CIN) high grade

    NASA Astrophysics Data System (ADS)

    Carbinatto, Fernanda M.; Inada, Natalia M.; Lombardi, Welington; da Silva, Eduardo V.; Belotto, Renata; Kurachi, Cristina; Bagnato, Vanderlei S.

    2016-02-01

    Cervical intraepithelial neoplasia (CIN) is the precursor of invasive cervical cancer and associated with human papillomavirus (HPV) infection. Photodynamic therapy (PDT) is a technique that has been used for the treatment of tumors. PDT is based on the accumulation of a photosensitizer in target cells that will generate cytotoxic reactive oxygen species upon illumination, inducing the death of abnormal tissue and PDT with less damaging to normal tissues than surgery, radiation, or chemotherapy and seems to be a promising alternative procedure for CIN treatment. The CIN high grades (II and III) presents potential indications for PDT due the success of PDT for CIN low grade treatment. The patients with CIN high grade that were treated with new clinic protocol shows lesion regression to CIN low grade 60 days after the treatment. The new clinical protocol using for treatment of CIN high grade shows great potential to become a public health technique.

  10. Serous tubal intraepithelial carcinoma, chronic fallopian tube injury, and serous carcinoma development.

    PubMed

    Malmberg, Karin; Klynning, Charlotta; Flöter-Rådestad, Angelique; Carlson, Joseph W

    2016-06-01

    Ovarian carcinoma is the deadliest gynecological malignancy. Previous studies have suggested that the fallopian tube may be the primary site for high-grade serous carcinoma. In prophylactic salpingo-oophorectomies from women with hereditary high risk for ovarian cancer, precursors can be assessed prior to onset and studied as a model for serous cancer precursor lesions. Epidemiologic studies indicate that carcinogenesis may be a result of chronic fallopian tube injury. The aims of this study were to (1) to examine the incidence of serous tubal intraepithelial carcinoma (STIC) in relation to other clinical parameters and (2) to evaluate whether chronic fallopian tube injury was related to cancer development. This study enrolled 101 women, comprising the following three groups: hereditary (n = 60), sporadic serous cancer (n = 18; endometrial cancers were excluded), and control (n = 23). The cases were histologically examined and clinical risk factors were collected. The histological changes were compared between different patients and correlated to clinical risk factors. STICs were identified primarily on the fallopian tube fimbria. The incidence of STIC was 3 % in the hereditary patients. In sporadic serous cancer cases, 61 % were associated with STIC and tubal carcinoma (p < 0.001). No differences in tubal injury or inflammation were seen when comparing the sporadic serous cancer group and the control group or within the hereditary group. STIC and invasive cancer were seen more often in the older patients than in the younger patients (p = 0.528). This small study, no correlation with chronic tubal injury or inflammation was identified.

  11. Recent Advances in Endometrial Cancer

    PubMed Central

    Tran, Arthur-Quan; Gehrig, Paola

    2017-01-01

    Endometrial cancer is the most common gynecologic malignancy in the United States, with yearly rates continuing to increase. Most women present with early stage disease; however, advanced disease carries a grave prognosis. As a result, novel therapies are currently under investigation for the treatment of endometrial cancer. These advances include a better understanding of the genetic basis surrounding the development of endometrial cancer, novel surgical therapies, and new molecular targets for the treatment of this disease. This review explores the literature regarding these advancements in endometrial cancer. PMID:28184290

  12. Is Invasive Micropapillary Serous Carcinoma a Low-grade Carcinoma?

    PubMed

    Ohishi, Yoshihiro; Imamura, Hiroko; Aman, Murasaki; Shida, Kaai; Kaku, Tsunehisa; Kato, Kiyoko; Oda, Yoshinao

    2016-01-01

    "Invasive micropapillary serous carcinoma" has been proposed as a synonym for low-grade serous carcinoma by some expert pathologists. In contrast, Singer and colleagues reported that some serous carcinomas with conspicuous invasive micropapillary pattern (SC-IMPs) can show high-grade nuclear atypia. However, the molecular features of such tumors have not been well documented. The aim of this study was to demonstrate and emphasize the fact that high-grade serous carcinoma confirmed by immunohistochemistry and molecular analysis can show conspicuous invasive micropapillary pattern. We selected 24 "SC-IMPs" and investigated: (1) their morphologic features; (2) the immunostaining pattern of p53 protein; and (3) KRAS/BRAF/TP53 gene mutations. The 24 SC-IMPs were subdivided into low-grade and high-grade tumors based primarily on the nuclear atypia, with the mitotic rate used as a secondary feature: low grade (n=5) and high grade (n=19). Low-grade SC-IMPs were characterized by low-mitotic activity, absence of abnormal mitosis, presence of serous borderline tumor, occasional BRAF mutation, and infrequent TP53 mutation. High-grade SC-IMPs were characterized by high-mitotic activity, presence of abnormal mitosis, conventional high-grade serous carcinoma, frequent TP53 mutation, and lack of KRAS/BRAF mutation. We demonstrated that high-grade serous carcinoma confirmed by aberrant p53 immunostaining and molecular analysis can show conspicuous invasive micropapillary pattern, validating Singer and colleague's report. Serous carcinoma with conspicuous invasive micropapillary pattern should not be readily regarded as low-grade serous carcinoma. Nuclear grade is the most important diagnostic feature in the SC-IMPs.

  13. Molecular diagnostic assays for cervical neoplasia: emerging markers for the detection of high-grade cervical disease.

    PubMed

    Malinowski, Douglas P

    2005-04-01

    The accurate detection and diagnosis of cervical carcinoma and its malignant precursors (collectively referred to as high-grade cervical disease) represents one of the current challenges in clinical medicine and cytopathology. The advent of molecular diagnostics and the use of whole-genome profiling using DNA microarrays promises to yield improved understanding of the disease process with the subsequent development of more accurate diagnostic procedures based upon these discoveries. Recent reports describing a variety of experimental approaches have identified a series of candidate genes that are overexpressed in cervical carcinoma. In this article, representative examples of these markers and the resulting translational research will be reviewed within the context of improved cervical disease detection. An emerging class of markers, the minichromosome maintenance protein family of DNA licensing factors (MCM-2, MCM-6, MCM-7), shows promise for the specific detection of high-grade cervical disease using simple antibody-based immunochemistry formats. These proteins are overexpressed in cervical disease as a result of infection by oncogenic strains of human papillomavirus (HPV) and subsequent uncontrolled activation of gene transcription and aberrant S-phase induction, mediated through the E2F transcription factor pathway. This behavior appears to be a hallmark of high-grade cervical disease and provides the link between oncogenic HPV infections and the molecular behavior of cervical neoplasia (CN). The use of these molecular descriptors of CN in simple immunochemistry formats compatible with conventional cytology preparations is anticipated to improve the screening and detection of cervical disease within the healthcare system.

  14. Expression of MIF and c-erbB-2 in endometrial cancer.

    PubMed

    Xiao, Wei; Dong, Xiujuan; Zhao, Honghui; Han, Shiyu; Nie, Ruixue; Zhang, Xiahua; An, Ruifang

    2016-05-01

    The aim of the present study was to investigate the expression of c-erbB-2 and macrophage migration inhibitory factor (MIF) in endometrial cancer and to elucidate the significance of the early diagnosis and prognosis of endometrial cancer. The gene copy number of c‑erbB‑2 and MIF was characterized by reverse transcription quantitative polymerase chain reaction and the reactivity was assessed by immunohistochemistry in 70 patients using a polyclonal antibody, and evaluated semiquantitatively according to the percentage of cells demonstrating membranous or diffuse cytoplasmic staining. A correlation between age, tumor stage, grade, myometrial invasion and lymph node metastasis was observed. The mRNA expression of c‑erbB‑2 and MIF was high in endometrial carcinoma. The positive expression rate of MIF protein in normal endometrium, atypical hyperplasia and endometrial carcinoma significantly increased along with the degree of aggravation of the disease by 20 (3/15), 45 (9/20) and 70% (35/50), respectively. The positive expression of MIF and c‑erbB‑2 was highest in endometrial cancer and a significantly higher level of protein was observed in tumors at stage I, stage G1, with a depth of myometrial invasion <0.4 cm and no lymph node metastasis. The protein expression of c‑erbB‑2 in endometrial cancer was higher in tumors at the G2‑3 phase, clinical stage III‑IV, lymph node metastasis, and had no association with the depth of myometrial invasion and age. MIF and c‑erbB‑2 were correlated with the occurrence and the development of endometrial cancer, and thus can be used for the early diagnosis and prognosis of endometrial cancer. The present study laid the foundation for identifying new treatments for endometrial cancer.

  15. Whole-exome sequencing identified mutational profiles of high-grade colon adenomas

    PubMed Central

    Kim, Tae-Min; Rhee, Je-Keun; Park, Hyeon-Chun; Sung, Min Kim; Kim, Sung Soo; Hyeok, Chang An; Lee Hyung, Sug; Chung, Yeun-Jun

    2017-01-01

    Although gene-to-gene analyses identified genetic alterations such as APC, KRAS and TP53 mutations in colon adenomas, it is largely unknown whether there are any others in them. Mutational profiling of high-grade colon adenoma (HGCA) that just precedes colon carcinoma might identify not only novel adenoma-specific genes but also critical genes for its progression to carcinoma. For this, we performed whole-exome sequencing (WES) of 12 HGCAs and identified 11 non-hypermutated and one hypermutated (POLE-mutated) cases. We identified 22 genes including APC, KRAS, TP53, GNAS, NRAS, SMAD4, ARID2, and PIK3CA with non-silent mutations in the cancer Census Genes. Bi-allelic and mono-allelic APC alterations were found in nine and one HGCAs, respectively, while the other two harbored wild-type APC. Five HGCAs harbored either mono-allelic (four HGCAs) or bi-allelic (one HGCA) SMAD4 mutation or 18q loss that had been known as early carcinoma-specific changes. We identified MTOR, ACVR1B, GNAQ, ATM, CNOT1, EP300, ARID2, RET and MAP2K4 mutations for the first time in colon adenomas. Our WES data is largely matched with the earlier ‘adenoma-carcinoma model’ (APC, KRAS, NRAS and GNAS mutations), but there are newly identified SMAD4, MTOR, ACVR1B, GNAQ, ATM, CNOT1, EP300, ARID2, RET and MAP2K4 mutations in this study. Our findings provide resource for understanding colon premalignant lesions and for identifying genomic clues for differential diagnosis and therapy options for colon adenomas and carcinomas. PMID:28179590

  16. Integrated Proteogenomic Characterization of Human High-Grade Serous Ovarian Cancer.

    PubMed

    Zhang, Hui; Liu, Tao; Zhang, Zhen; Payne, Samuel H; Zhang, Bai; McDermott, Jason E; Zhou, Jian-Ying; Petyuk, Vladislav A; Chen, Li; Ray, Debjit; Sun, Shisheng; Yang, Feng; Chen, Lijun; Wang, Jing; Shah, Punit; Cha, Seong Won; Aiyetan, Paul; Woo, Sunghee; Tian, Yuan; Gritsenko, Marina A; Clauss, Therese R; Choi, Caitlin; Monroe, Matthew E; Thomas, Stefani; Nie, Song; Wu, Chaochao; Moore, Ronald J; Yu, Kun-Hsing; Tabb, David L; Fenyö, David; Bafna, Vineet; Wang, Yue; Rodriguez, Henry; Boja, Emily S; Hiltke, Tara; Rivers, Robert C; Sokoll, Lori; Zhu, Heng; Shih, Ie-Ming; Cope, Leslie; Pandey, Akhilesh; Zhang, Bing; Snyder, Michael P; Levine, Douglas A; Smith, Richard D; Chan, Daniel W; Rodland, Karin D

    2016-07-28

    To provide a detailed analysis of the molecular components and underlying mechanisms associated with ovarian cancer, we performed a comprehensive mass-spectrometry-based proteomic characterization of 174 ovarian tumors previously analyzed by The Cancer Genome Atlas (TCGA), of which 169 were high-grade serous carcinomas (HGSCs). Integrating our proteomic measurements with the genomic data yielded a number of insights into disease, such as how different copy-number alternations influence the proteome, the proteins associated with chromosomal instability, the sets of signaling pathways that diverse genome rearrangements converge on, and the ones most associated with short overall survival. Specific protein acetylations associated with homologous recombination deficiency suggest a potential means for stratifying patients for therapy. In addition to providing a valuable resource, these findings provide a view of how the somatic genome drives the cancer proteome and associations between protein and post-translational modification levels and clinical outcomes in HGSC. VIDEO ABSTRACT.

  17. High-grade serous ovarian cancer 3 years after bilateral salpingectomy: A case report

    PubMed Central

    Sato, Emi; Nakayama, Kentaro; Ishikawa, Masako; Nakamura, Kohei; Ishibashi, Tomoka; Kyo, Satoru

    2017-01-01

    Although epithelial ovarian cancer commonly originates from the ovarian surface epithelium and/or ovarian inclusion cysts, it was recently proposed that high-grade serous ovarian cancer (HGSC) develops from the Fallopian tubes. In our department, we encountered a case of HGSC that contradicts the hypothesis of a tubal origin for HGSC. A 51-year-old postmenopausal woman had undergone hysterectomy, left oophorectomy and bilateral salpingectomy for uterine myoma. Three years later, the patient was diagnosed with stage IV ovarian cancer and underwent primary debulking surgery. The pathological examination revealed HGSC, although there was no evidence of serous tubal intraepithelial carcinoma or any other type of cancer in the previously resected left ovary and bilateral Fallopian tubes. Moreover, p53 overexpression was not detected in the right ovarian cancer specimen, while paired box gene 8, a marker of Fallopian tube epithelium, was highly expressed. Therefore, HGSC may develop from an inclusion cyst with metaplasia of from the ovarian surface epithelium.

  18. Krüppel-Like factor 9 loss-of-expression in human endometrial carcinoma links altered expression of growth-regulatory genes with aberrant proliferative response to estrogen

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Endometrial cancer is the most commonly diagnosed female genital tract malignancy. Krüppel-like Factor 9 (KLF9), a member of the evolutionarily conserved Sp-family of transcription factors, is expressed in uterine stroma and glandular epithelium where it affects cellular proliferation, differenti...

  19. Endometrial metaplasias and reactive changes: a spectrum of altered differentiation.

    PubMed

    Nicolae, Alina; Preda, Ovidiu; Nogales, Francisco F

    2011-02-01

    Endometrial metaplasias and changes (EMCs) are conditions frequently overlooked and misdiagnosed. The aim of this review is to update current issues and provide a classification with a practical clinicopathological approach. Hormonal or irritative stimuli are the main inducing factors of EMCs, although some metaplasias have a mutational origin. EMCs vary from reactive, degenerative lesions to those able to associate with malignancy or those having a preneoplastic potential. The most common types of EMCs are ciliated tubal metaplasia (CTM) and mucinous metaplasia (MM), which occur in simple and complex glands, and possibly these architectural changes hold the same prognostic significance as they do in hyperplastic endometrioid lesions. Immunohistochemically, CTM is positive for LhS28, bcl-2, PAX2 and p16(INK4A). Complex CTM is likely to be a precursor of ciliated endometrioid-type carcinomas. MMs should be evaluated architecturally, taking into account that their atypicality is minimal. The differentiation between complex MM and mucinous carcinoma may be extremely difficult. Surface complex, papillary MM in endometrial polyps can be considered as benign. Intestinal-type endometrial MM is rare and its presence should prompt further investigation of associated lesions in the endocervix. Endometrial squamous metaplasia (ESS) is often linked to chronic irritative situations. It should be differentiated from secondary involvement by a human papilomavirus-related cervical lesion. Morular metaplasia is a mutational phenomenon with a distinct phenotype that helps to differentiate it from ESS. Morules are benign, hormonally inert structures that are often markers of complex endometrioid glandular architecture, and they are associated with an attenuated malignancy. Endometrial reactive changes are commonly associated with desquamation or hormonal imbalance. The frequent, p16(INK4A) positive, benign surface papillary syncytial change may be misdiagnosed, in some cases, as

  20. Successful Nonoperative Management of High-Grade Blunt Renal Injuries

    PubMed Central

    Darwish, Oussama; Dang, Brian; Monda, John J.; Adsul, Prajakta; Syed, Johar; Siddiqui, Sameer A.

    2016-01-01

    Current management of high-grade blunt renal trauma favors a nonoperative approach when possible. We performed a retrospective study of high grade blunt renal injuries at our level I trauma center to determine the indications and success of nonoperative management (NOM). 47 patients with blunt grade IV or V injuries were identified between October 2004 and December 2013. Immediate operative patients (IO) were compared to nonoperatively managed (NOM). Of the 47 patients, 3 (6.4%) were IO and 44 (95.6%) NOM. IO patients had a higher heart rate on admission, 133 versus 100 in NOM (P = 0.01). IO patients had a higher rate of injury to the renal vein or artery (100%) compared to NOM group (18%) (P = 0.01). NOM failed in 3 of 44 patients (6.8%). Two required nonemergent nephrectomy and one required emergent exploration resulting in nephrectomy. Six NOM patients had kidney-related complications (13.6%). The renal salvage rate for the entire cohort was 87.2% and 93.2% for NOM. Nonoperative management for hemodynamically stable patients with high-grade blunt renal trauma is safe with a low risk of complications. Management decisions should consider hemodynamic status and visualization of active renal bleeding as well as injury grade in determining operative management. PMID:28018427

  1. Past, present, and future of hormonal therapy in recurrent endometrial cancer

    PubMed Central

    Carlson, Matthew J; Thiel, Kristina W; Leslie, Kimberly K

    2014-01-01

    Endometrial cancer is a heterogeneous disease. Type I cancers are hormonally driven, typically present with a low grade at an early stage, and are of endometrioid histology. These cancers are often cured by surgery, and the rate of recurrence is low. Type II cancers are less differentiated, often appear at a later stage, and are of serous, clear cell, or high grade endometrioid histology. The risk of recurrence in these cancers is much higher than with type I tumors. Isolated pelvic recurrences can be treated with radiation or exenteration, but systemic disease is fatal. It is in these recurrent patients, where prolongation of progression-free survival is the goal, that hormonal therapy can have the greatest benefit. In selected patients, hormonal therapy can be as effective as cytotoxic chemotherapy, without the toxicity and at a much lower cost. Here we review the evidence for treatment of patients suffering from recurrent endometrial cancer with hormonal therapy and explore avenues for the future of hormonal treatment of endometrial cancer. Currently, progesterone is the hormonal treatment of choice in these patients. Other drugs are also used, including selective estrogen receptor modulators, aromatase inhibitors, and gonadotropin-releasing hormone antagonists. Hormonal treatment of recurrent endometrial cancer relies on expression of the hormone receptors, which act as nuclear transcription factors. Tumors that express these receptors are the most sensitive to therapy; it is for this reason that patient selection is vitally important to the successful treatment of recurrent endometrial cancer with hormonal therapy. PMID:24833920

  2. Therapeutic options for management of endometrial hyperplasia.

    PubMed

    Chandra, Vishal; Kim, Jong Joo; Benbrook, Doris Mangiaracina; Dwivedi, Anila; Rai, Rajani

    2016-01-01

    Endometrial hyperplasia (EH) comprises a spectrum of changes in the endometrium ranging from a slightly disordered pattern that exaggerates the alterations seen in the late proliferative phase of the menstrual cycle to irregular, hyperchromatic lesions that are similar to endometrioid adenocarcinoma. Generally, EH is caused by continuous exposure of estrogen unopposed by progesterone, polycystic ovary syndrome, tamoxifen, or hormone replacement therapy. Since it can progress, or often occur coincidentally with endometrial carcinoma, EH is of clinical importance, and the reversion of hyperplasia to normal endometrium represents the key conservative treatment for prevention of the development of adenocarcinoma. Presently, cyclic progestin or hysterectomy constitutes the major treatment option for EH without or with atypia, respectively. However, clinical trials of hormonal therapies and definitive standard treatments remain to be established for the management of EH. Moreover, therapeutic options for EH patients who wish to preserve fertility are challenging and require nonsurgical management. Therefore, future studies should focus on evaluation of new treatment strategies and novel compounds that could simultaneously target pathways involved in the pathogenesis of estradiol-induced EH. Novel therapeutic agents precisely targeting the inhibition of estrogen receptor, growth factor receptors, and signal transduction pathways are likely to constitute an optimal approach for treatment of EH.

  3. Therapeutic options for management of endometrial hyperplasia

    PubMed Central

    2016-01-01

    Endometrial hyperplasia (EH) comprises a spectrum of changes in the endometrium ranging from a slightly disordered pattern that exaggerates the alterations seen in the late proliferative phase of the menstrual cycle to irregular, hyperchromatic lesions that are similar to endometrioid adenocarcinoma. Generally, EH is caused by continuous exposure of estrogen unopposed by progesterone, polycystic ovary syndrome, tamoxifen, or hormone replacement therapy. Since it can progress, or often occur coincidentally with endometrial carcinoma, EH is of clinical importance, and the reversion of hyperplasia to normal endometrium represents the key conservative treatment for prevention of the development of adenocarcinoma. Presently, cyclic progestin or hysterectomy constitutes the major treatment option for EH without or with atypia, respectively. However, clinical trials of hormonal therapies and definitive standard treatments remain to be established for the management of EH. Moreover, therapeutic options for EH patients who wish to preserve fertility are challenging and require nonsurgical management. Therefore, future studies should focus on evaluation of new treatment strategies and novel compounds that could simultaneously target pathways involved in the pathogenesis of estradiol-induced EH. Novel therapeutic agents precisely targeting the inhibition of estrogen receptor, growth factor receptors, and signal transduction pathways are likely to constitute an optimal approach for treatment of EH. PMID:26463434

  4. Irradiation of Pediatric High-Grade Spinal Cord Tumors

    SciTech Connect

    Tendulkar, Rahul D.; Pai Panandiker, Atmaram S.; Wu Shengjie; Kun, Larry E.; Broniscer, Alberto; Sanford, Robert A.; Merchant, Thomas E.

    2010-12-01

    Purpose: To report the outcome using radiation therapy (RT) for pediatric patients with high-grade spinal cord tumors. Methods and Materials: A retrospective chart review was conducted that included 17 children with high-grade spinal cord tumors treated with RT at St. Jude Children's Research Hospital between 1981 and 2007. Three patients had gross total resection, 11 had subtotal resection, and 3 underwent biopsy. The tumor diagnosis was glioblastoma multiforme (n = 7), anaplastic astrocytoma (n = 8), or anaplastic oligodendroglioma (n = 2). Seven patients received craniospinal irradiation (34.2-48.6 Gy). The median dose to the primary site was 52.2 Gy (range, 38-66 Gy). Results: The median progression-free and overall survivals were 10.8 and 13.8 months, respectively. Local tumor progression at 12 months (79% vs. 30%, p = 0.02) and median survival (13.1 vs. 27.2 months, p = 0.09) were worse for patients with glioblastoma multiforme compared with anaplastic astrocytoma or oligodendroglioma. The median overall survival was shorter for patients when failure included neuraxis dissemination (n = 8) compared with local failure alone (n = 5), 9.6 vs. 13.8 months, p = 0.08. Three long-term survivors with World Health Organization Grade III tumors were alive with follow-up, ranging from 88-239 months. Conclusions: High-grade spinal cord primary tumors in children have a poor prognosis. The propensity for neuraxis metastases as a component of progression after RT suggests the need for more aggressive therapy.

  5. Radiosurgical boost for primary high-grade gliomas.

    PubMed

    Prisco, Flavio E; Weltman, Eduardo; de Hanriot, Rodrigo M; Brandt, Reynaldo A

    2002-04-01

    The purpose of this study was to retrospectively evaluate the survival of patients with high-grade gliomas treated with external beam radiotherapy with or without radiosurgical boost. From July 1993 to April 1998, 32 patients were selected, 15 of which received radiosurgery. Inclusion criteria were age > 18 years, histological confirmation of high-grade glioma, primary tumor treatment with curative intent, unifocal tumor and supratentorial location. All patients were found to be in classes III-VI, according to the recursive partitioning analysis proposed by the Radiation Therapy Oncology Group. The median interval between radiotherapy and radiosurgery was 5 weeks (range 1-13). Treatment volumes ranged from 2.9 to 70.3 cc (median 15.0 cc). Prescribed radiosurgery doses varied from 8.0 to 12.5 Gy (median 10.0 Gy). Radiosurgery and control groups were well balanced with respect to prognostic factor distributions. Median actuarial survival time in radiosurgery and control groups was 21.4 months and 11.6 months, respectively (p = 0.0254). Among patients with KPS > 80, median survival time was 11.0 months and 53.9 months in the control and radiosurgery groups, respectively (p = 0.0103). Radiosurgery was the single factor correlated with survival on Cox model analysis (p = 0.0362) and was associated with a 2.76 relative reduction in the risk of cancer death (95% confidence interval (CI) 1.07-7.13). Our results suggest that radiosurgery may confer a survival advantage for patients in RPA classes III-VI, especially for those with Karnofsky performance status >80. The definitive role of radiosurgical boost for patients with high-grade gliomas awaits the results of randomized trials.

  6. Endometrial Intraepithelial Neoplasia (EIN) in endometrial biopsy specimens categorized by the 1994 World Health Organization classification for endometrial hyperplasia.

    PubMed

    Li, Xiao-Chao; Song, Wen-Jing

    2013-01-01

    Our study is to determine the presence of endometrial intraepithelial neoplasia (EIN) in endometrial biopsy specimens classified by the 1994 World Health Organization (WHO) criteria for endometrial hyperplasia. Endometrial biopsy specimens that were stained with hematoxylin and eosin (HE) were examined and categorized by the WHO 1994 criteria and for the presence of EIN as defined by the International Endometrial Collaborative Group. β-catenin expression was examined by immunohistochemistry. A total of 474 cases of HE stained endometrial biopsy tissues were reviewed. There were 379 cases of simple endometrial hyperplasia, 16 with simple atypical endometrial hyperplasia, 48 with complex endometrial hyperplasia, and 31 with complex atypical endometrial hyperplasia. Among the 474 endometrial hyperplasia cases, there were 46 (9.7%) that were classified as EIN. Of these 46 cases, 11(2.9%) were classified as simple endometrial hyperplasia, 1 (6.3%) as simple atypical endometrial hyperplasia, 6 (12.5%) as complex endometrial hyperplasia, and 28 (90.3%) as complex atypical endometrial hyperplasia. EIN was associated with a higher rate of β-catenin positivity than endometrium classified as benign hyperplasia (72% vs. 22.5%, respectively, P < 0.001), but a lower rate than endometrial adenocarcinoma (72% vs. 96.2%, respectively, P < 0.001). In benign endometrial hyperplasia, high β-catenin expression was noted in the cell membranes, whereas in EIN and endometrial adenocarcinoma high expression was noted in the cytoplasm. In conclusion, EIN is more accurate than the WHO classification for the diagnosis of precancerous lesions of the endometrium.

  7. Interleukin 6 promotes endometrial cancer growth through an autocrine feedback loop involving ERK–NF-κB signaling pathway

    SciTech Connect

    Che, Qi; Liu, Bin-Ya; Wang, Fang-Yuan; He, Yin-Yan; Lu, Wen; Liao, Yun; Gu, Wei; Wan, Xiao-Ping

    2014-03-28

    Highlights: • IL-6 could promote endometrial cancer cells proliferation. • IL-6 promotes its own production through an autocrine feedback loop. • ERK and NF-κB pathway inhibitors inhibit IL-6 production and tumor growth. • IL-6 secretion relies on the activation of ERK–NF-κB pathway axis. • An orthotopic nude endometrial carcinoma model confirms the effect of IL-6. - Abstract: Interleukin (IL)-6 as an inflammation factor, has been proved to promote cancer proliferation in several human cancers. However, its role in endometrial cancer has not been studied clearly. Previously, we demonstrated that IL-6 promoted endometrial cancer progression through local estrogen biosynthesis. In this study, we proved that IL-6 could directly stimulate endometrial cancer cells proliferation and an autocrine feedback loop increased its production even after the withdrawal of IL-6 from the medium. Next, we analyzed the mechanism underlying IL-6 production in the feedback loop and found that its production and IL-6-stimulated cell proliferation were effectively blocked by pharmacologic inhibitors of nuclear factor-kappa B (NF-κB) and extra-cellular signal-regulated kinase (ERK). Importantly, activation of ERK was upstream of the NF-κB pathways, revealing the hierarchy of this event. Finally, we used an orthotopic nude endometrial carcinoma model to confirm the effects of IL-6 on the tumor progression. Taken together, these data indicate that IL-6 promotes endometrial carcinoma growth through an expanded autocrine regulatory loop and implicate the ERK–NF-κB pathway as a critical mediator of IL-6 production, implying IL-6 to be an important therapeutic target in endometrial carcinoma.

  8. Histopathologic Features of Prognostic Significance in High-Grade Osteosarcoma.

    PubMed

    Chui, Michael Herman; Kandel, Rita A; Wong, Marcus; Griffin, Anthony M; Bell, Robert S; Blackstein, Martin E; Wunder, Jay S; Dickson, Brendan C

    2016-08-23

    Context .- In osteosarcoma treated with neoadjuvant chemotherapy the extent of tumor necrosis on resection is considered an indicator of treatment response, and this has been shown to correlate with survival in most but not all studies. Objective .- To identify additional histologic variables of prognostic significance in high-grade osteosarcoma. Design .- Slides of pretreatment biopsy and primary postneoadjuvant chemotherapy resections from 165 patients with high-grade osteosarcoma were reviewed. Univariate (Kaplan-Meier) and multivariate (Cox regression) analyses were performed to identify clinical and histomorphologic attributes associated with overall survival. Results .- Univariate analyses confirmed the prognostic significance of metastatic status on presentation, primary tumor size, anatomic site, and histologic subtype. Additionally, the identification of lymphovascular invasion, 10% or more residual viable tumor, and 10 or more mitoses per 10 high-powered fields assessed in posttreatment resections were associated with poor survival, retaining significance in multivariate analyses. Based on results from multivariate analysis, we developed a prognostic index incorporating primary tumor size and site, and significant histologic features assessed on resection (ie, lymphovascular invasion status, mitotic rate, and extent of viable tumor). This scoring system segregates patients into 3 risk categories with significant differences in overall survival and retained significance in an independent validation set of 42 cases. Conclusions .- The integration of clinical and microscopic features improves prognostication of patients with osteosarcoma.

  9. Pre-irradiation chemotherapy for newly diagnosed high grade astrocytoma.

    PubMed

    Mathieu, N Tubiana; Genet, D; Labrousse, F; Bouillet, P; Denes, S Lavau; Martin, J; Labourey, J L; Venat, L; Clavere, P; Moreau, J J

    2004-01-01

    The purpose of this work was to determine the response rate and toxicity of a combination of Carmustine and Cisplatin administered before radiation in patients with newly diagnosed high grade astrocytoma. A good response rate has been published with this association in primary cerebral high grade tumor. This protocol was administered in a homogeneous population of 37 adult patients with measurable tumor on magnetic resonance imaging (MRI) or CT scan. After biopsy or subtotal resection, the patients received BCNU 40 mg/m2/d and CODP 40 mg/m2/d, for 3 days every 28 days for 3 cycles. Evaluation was performed before each cycle. Radiation therapy began 4 weeks after completing the chemotherapy or immediately if there was evidence of tumor progression on chemotherapy. Seven out of 37 (19%) demonstrated tumor regression with a median duration to progression of 11 months. Median survival was 6 months. Myelosuppression was the predominant but manageable toxicity. This work indicated that the first chemotherapy protocol gave poor results in a homogeneous group of patients, with bad prognosis.

  10. Drugs Approved for Endometrial Cancer

    Cancer.gov

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for endometrial cancer. The list includes generic names and brand names. The drug names link to NCI's Cancer Drug Information summaries.

  11. Treatment Option Overview (Endometrial Cancer)

    MedlinePlus

    ... Stage II endometrial cancer. Cancer has spread into connective tissue of the cervix, but has not spread outside ... uterus. In stage II , cancer has spread into connective tissue of the cervix , but has not spread outside ...

  12. General Information About Endometrial Cancer

    MedlinePlus

    ... Stage II endometrial cancer. Cancer has spread into connective tissue of the cervix, but has not spread outside ... uterus. In stage II , cancer has spread into connective tissue of the cervix , but has not spread outside ...

  13. PAR1 is selectively over expressed in high grade breast cancer patients: a cohort study

    PubMed Central

    Hernández, Norma A; Correa, Elma; Avila, Esther P; Vela, Teresa A; Pérez, Víctor M

    2009-01-01

    Background The protease-activated receptor (PAR1) expression is correlated with the degree of invasiveness in cell lines. Nevertheless it has never been directed involved in breast cancer patients progression. The aim of this study was to determine whether PAR1 expression could be used as predictor of metastases and mortality. Methods In a cohort of patients with infiltrating ductal carcinoma studied longitudinally since 1996 and until 2007, PAR1 over-expression was assessed by immunoblotting, immunohistochemistry, and flow citometry. Chi-square and log rank tests were used to determine whether there was a statistical association between PAR1 overexpression and metastases, mortality, and survival. Multivariate analysis was performed including HER1, stage, ER and nodes status to evaluate PAR1 as an independent prognostic factor. Results Follow up was 95 months (range: 2–130 months). We assayed PAR1 in a cohort of patients composed of 136 patients; we found PAR1 expression assayed by immunoblotting was selectively associated with high grade patients (50 cases of the study cohort; P = 0.001). Twenty-nine of 50 (58%) patients overexpressed PAR1, and 23 of these (46%) developed metastases. HER1, stage, ER and PAR1 overexpression were robustly correlated (Cox regression, P = 0.002, P = 0.024 and P = 0.002 respectively). Twenty-one of the 50 patients (42%) expressed both receptors (PAR1 and HER1 P = 0.0004). We also found a statistically significant correlation between PAR1 overexpression and increased mortality (P = 0.0001) and development of metastases (P = 0.0009). Conclusion Our data suggest PAR1 overexpression may be involved in the development of metastases in breast cancer patient and is associated with undifferentiated cellular progression of the tumor. Further studies are needed to understand PAR1 mechanism of action and in a near future assay its potential use as risk factor for metastasis development in high grade breast cancer patients. PMID:19538737

  14. The NER-related gene GTF2H5 predicts survival in high-grade serous ovarian cancer patients

    PubMed Central

    Kamieniak, Marta M.; Muñoz-Repeto, Ivan; Borrego, Salud; Hernando, Susana; Hernández-Agudo, Elena; Heredia Soto, Victoria; Márquez-Rodas, Ivan; Echarri, María José; Lacambra-Calvet, Carmen; Sáez, Raquel; Redondo, Andrés; Benítez, Javier

    2016-01-01

    Objective We aimed to evaluate the prognostic and predictive value of the nucleotide excision repair-related gene GTF2H5, which is localized at the 6q24.2-26 deletion previously reported by our group to predict longer survival of high-grade serous ovarian cancer patients. Methods In order to test if protein levels of GTF2H5 are associated with patients' outcome, we performed GTF2H5 immunohistochemical staining in 139 high-grade serous ovarian carcinomas included in tissue microarrays. Upon stratification of cases into high- and low-GTF2H5 staining categories (> and ≤ median staining, respectively) Kaplan-Meier and log-rank test were used to estimate patients’ survival and assess statistical differences. We also evaluated the association of GTF2H5 with survival at the transcriptional level by using the on-line Kaplan-Meier plotter tool, which includes gene expression and survival data of 855 high-grade serous ovarian cancer patients from 13 different datasets. Finally, we determined whether stable short hairpin RNA-mediated GTF2H5 downregulation modulates cisplatin sensitivity in the SKOV3 and COV504 cell lines by using cytotoxicity assays. Results Low expression of GTF2H5 was associated with longer 5-year survival of patients at the protein (hazard ratio [HR], 0.52; 95% CI, 0.29 to 0.93; p=0.024) and transcriptional level (HR, 0.80; 95% CI, 0.65 to 0.97; p=0.023) in high-grade serous ovarian cancer patients. We confirmed the association with 5-year overall survival (HR, 0.55; 95% CI, 0.38 to 0.78; p=0.0007) and also found an association with progression-free survival (HR, 0.72; 95% CI, 0.54 to 0.96; p=0.026) in a homogenous group of 388 high-stage (stages III-IV using the International Federation of Gynecology and Obstetrics staging system), optimally debulked high-grade serous ovarian cancer patients. GTF2H5-silencing induced a decrease of the half maximal inhibitory concentration upon cisplatin treatment in GTF2H5-silenced ovarian cancer cells. Conclusion Low

  15. Terahertz reflectometry imaging for low and high grade gliomas

    NASA Astrophysics Data System (ADS)

    Ji, Young Bin; Oh, Seung Jae; Kang, Seok-Gu; Heo, Jung; Kim, Sang-Hoon; Choi, Yuna; Song, Seungri; Son, Hye Young; Kim, Se Hoon; Lee, Ji Hyun; Haam, Seung Joo; Huh, Yong Min; Chang, Jong Hee; Joo, Chulmin; Suh, Jin-Suck

    2016-10-01

    Gross total resection (GTR) of glioma is critical for improving the survival rate of glioma patients. One of the greatest challenges for achieving GTR is the difficulty in discriminating low grade tumor or peritumor regions that have an intact blood brain barrier (BBB) from normal brain tissues and delineating glioma margins during surgery. Here we present a highly sensitive, label-free terahertz reflectometry imaging (TRI) that overcomes current key limitations for intraoperative detection of World Health Organization (WHO) grade II (low grade), and grade III and IV (high grade) gliomas. We demonstrate that TRI provides tumor discrimination and delineation of tumor margins in brain tissues with high sensitivity on the basis of Hematoxylin and eosin (H&E) stained image. TRI may help neurosurgeons to remove gliomas completely by providing visualization of tumor margins in WHO grade II, III, and IV gliomas without contrast agents, and hence, improve patient outcomes.

  16. Terahertz reflectometry imaging for low and high grade gliomas

    PubMed Central

    Ji, Young Bin; Oh, Seung Jae; Kang, Seok-Gu; Heo, Jung; Kim, Sang-Hoon; Choi, Yuna; Song, Seungri; Son, Hye Young; Kim, Se Hoon; Lee, Ji Hyun; Haam, Seung Joo; Huh, Yong Min; Chang, Jong Hee; Joo, Chulmin; Suh, Jin-Suck

    2016-01-01

    Gross total resection (GTR) of glioma is critical for improving the survival rate of glioma patients. One of the greatest challenges for achieving GTR is the difficulty in discriminating low grade tumor or peritumor regions that have an intact blood brain barrier (BBB) from normal brain tissues and delineating glioma margins during surgery. Here we present a highly sensitive, label-free terahertz reflectometry imaging (TRI) that overcomes current key limitations for intraoperative detection of World Health Organization (WHO) grade II (low grade), and grade III and IV (high grade) gliomas. We demonstrate that TRI provides tumor discrimination and delineation of tumor margins in brain tissues with high sensitivity on the basis of Hematoxylin and eosin (H&E) stained image. TRI may help neurosurgeons to remove gliomas completely by providing visualization of tumor margins in WHO grade II, III, and IV gliomas without contrast agents, and hence, improve patient outcomes. PMID:27782153

  17. Re-irradiation alternatives for recurrent high-grade glioma

    PubMed Central

    Dong, Yuanli; Fu, Chengrui; Guan, Hui; Zhang, Tianyi; Zhang, Zicheng; Zhou, Tao; Li, Baosheng

    2016-01-01

    Despite advances in the fields of surgery, chemotherapy and radiotherapy, the prognosis for high-grade glioma (HGG) remains unsatisfactory. The majority of HGG patients experience disease recurrence. To date, no standard treatments have been established for recurrent HGG. Repeat surgery and chemotherapy demonstrate moderate efficacy. As recurrent lesions are usually located within the previously irradiated field, a second course of irradiation was once considered controversial, as it was considered to exhibit unsatisfactory efficacy and radiation-related toxicities. However, an increasing number of studies have indicated that re-irradiation may present an efficacious treatment for recurrent HGG. Re-irradiation may be delivered via conventionally fractionated stereotactic radiotherapy, hypofractionated stereotactic radiation therapy, stereotactic radiosurgery and brachytherapy techniques. In the present review, the current literature regarding re-irradiation treatment for recurrent HGG is summarized with regard to survival outcome and side effects. PMID:27703519

  18. Optimization of MR Imaging for Pretreatment Evaluation of Endometrial and Cervical Cancer

    PubMed Central

    Rauch, Gaiane M.; Kaur, Harmeet; Choi, Haesun; Ernst, Randy D.; Klopp, Ann H.; Boonsirikamchai, Piyaporn; Westin, Shannon N.; Marcal, Leonardo P.

    2014-01-01

    Endometrial and cervical cancer are the most common gynecologic malignancies in the world. Accurate staging of cervical and endometrial cancer is essential for determining the correct treatment approach. The current FIGO (International Federation of Gynecology and Obstetrics) staging system does not include modern imaging modalities. However, magnetic resonance imaging (MRI) has proven to be the most accurate noninvasive imaging modality for staging of endometrial and cervical carcinomas and often assists in patients risk stratification and treatment decisions. Multiparametric MR imaging is increasingly being used in the evaluation of the female pelvis. This approach combines anatomic T2-weighted imaging with functional imaging, i.e. dynamic contrast enhanced MRI (DCE-MRI) and diffusion weighted imaging (DWI). In endometrial and cervical cancer MR imaging is used to guide treatment decisions through an assessment of the depth of myometrial invasion and cervical stromal involvement in endometrial cancer, and of tumor size and parametrial invasion in cervical cancer. However, the efficacy of MRI in achieving accurate local staging is dependent on technique and image quality. In this article we discuss optimization of the MR imaging protocol for endometrial and cervical cancer. The use of thin section high resolution (HR) multi-planar T2 weighted images with simple modifications such as double oblique T2 weighted images supplemented by diffusion weighted imaging and contrast enhanced MRI are reviewed. PMID:25019443

  19. Clinically Significant Endometrial Cancer Risk Following a Diagnosis of Complex Atypical Hyperplasia

    PubMed Central

    COSTALES, Anthony B.; SCHMELER, Kathleen M.; BROADDUS, Russell; SOLIMAN, Pamela T.; WESTIN, Shannon N.; RAMIREZ, Pedro T.; FRUMOVITZ, Michael

    2014-01-01

    Objectives Because of the frequent detection of carcinoma in surgical specimens after hysterectomy for endometrial complex atypical hyperplasia (CAH), it has been suggested that patients with a preoperative diagnosis of CAH be referred to gynecologic oncology for potential lymphadenectomy. However, the risk of lymph node metastasis in such patients is unknown. We sought to determine the risk of endometrial cancer and to estimate the risk of lymphatic spread in women with a preoperative diagnosis of CAH. Study Design We retrospectively reviewed the medical records of 150 consecutive patients with a preoperative diagnosis of CAH who subsequently underwent hysterectomy. Clinical characteristics and pathologic information were abstracted. Risk of lymphatic spread was modeled using previously published criteria and nomograms. Results Fifty-five of the 150 patients (36.7%) had an incidental endometrial carcinoma at the time of hysterectomy. Among patients with a preoperative office biopsy compared to dilation and curettage, the rate of an incidental finding of cancer was 43.5% and 28.1%, respectively (p=0.054). Of patients with cancer, 1 (1.8%) had a grade 3 endometrial carcinoma, 4 (7.3%) had lymphovascular space involvement, and 6 (10.9%) had deep (>50%) myometrial invasion. For the 10 patients who underwent lymphadenectomy, one (10%) had lymph node metastases. Based on multiple models, the estimated risk of lymph node spread was 1.6-2.1% for all women with a preoperative diagnosis of CAH and 4.4-6.8% for the 55 women with endometrial cancer. Conclusions Given the high rates of underlying endometrial cancer and the potential need for lymphadenectomy, care for patients with a preoperative diagnosis of CAH desiring definitive management with hysterectomy should be referred to a gynecologic oncologist. PMID:25316176

  20. Expression of GLUT1 and GLUT3 glucose transporters in endometrial and breast cancers.

    PubMed

    Krzeslak, Anna; Wojcik-Krowiranda, Katarzyna; Forma, Ewa; Jozwiak, Paweł; Romanowicz, Hanna; Bienkiewicz, Andrzej; Brys, Magdalena

    2012-07-01

    Cancer cells have accelerated metabolism and high glucose requirements. The up-regulation of specific glucose transporters may represent a key mechanism by which malignant cells may achieve increased glucose uptake to support the high rate of glycolysis. In present study we analyzed the mRNA and protein expression of GLUT1 and GLUT3 glucose transporters by quantitative real-time polymerase chain reaction (Q-PCR) and Western blotting technique in 76 cases of endometrial carcinoma and 70 cases of breast carcinoma. SLC2A1 and SLCA2A3 mRNAs expression was found, respectively in 100% and 97.4% samples of endometrial cancers and only in 50% and 40% samples of breast cancers. In endometrial cancers GLUT1 and GLUT3 protein expression was identified in 67.1% and 30.3% of cases. Analogously, in breast cancers in 48.7% and 21% of samples, respectively. The results showed that both endometrial and breast poorly differentiated tumors (grade 2 and 3) had significantly higher GLUT1 and GLUT3 expression than well-differentiated tumors (grade 1). Statistically significant association was found between SLCA2A3 mRNA expression and estrogen and progesterone receptors status in breast cancers. GLUT1 has been reported to be involved in the uptake of glucose by endometrial and breast carcinoma cells earlier and the present study determined that GLUT3 expression is also involved. GLUT1 and GLUT3 seem to be important markers in endometrial and breast tumors differentiation.

  1. Project for the National Program of Early Diagnosis of Endometrial Cancer Part II

    PubMed Central

    Bohîlțea, RE; Ancăr, V; Rădoi, V; Furtunescu, F; Bohîlțea, LC

    2015-01-01

    Rationale: Endometrial cancer recorded a peak incidence in ages 60-64 years in Romania. Since 2013, an increased trend of endometrial cancer occurrence has been registered in urban areas as compared with rural ones. Unfortunately, most of the cancer cases are diagnosed too late, in an advanced stage of the disease, resulting into diminished lifetime expectancy. The first part of the article concentrated on issues such as: the description of the study, results, and discussions regarding the study, definitions and terms, risk factors specific for endometrial carcinomas, presentation of the activities of the Program, etc. Objective: Drafting a national program that will serve as an early diagnosis method of endometrial cancer. This second part of the study continues with the presentation of the activities of the Program, analyzes the human resources and materials needed to implement the Program, presents the strategies and the indicators specific for the implementation of the project. Methods and Results: A standardization of the diagnostic steps was proposed and the focus was on 4 key elements for the early diagnosis of endometrial cancer: The first steps were approached in the first part of the study and the second part of the study investigated the proper monitoring of precursor endometrial lesions or cancer associated endometrial lesions and screening high risk populations (Lynch syndrome, Cowden syndrome). Discussion: Improving medical practice based on diagnostic algorithms and programs improves and increases the lifetime expectancy, due to the fact that endometrial cancer is early diagnosed and treated before it causes serious health problems or even death. Abbreviations: ASCCP = American Society for Colposcopy and Cervical Pathology, CT = Computerized Tomography, HNPCC = Hereditary Nonpolyposis Colorectal Cancer (Lynch syndrome), IHC = Immunohistochemistry, MSI = Microsatellites instability, MSI-H/ MSI-L = high (positive test)/ low (negative test

  2. Distribution of estrogen and progesterone receptors isoforms in endometrial cancer

    PubMed Central

    2014-01-01

    Background 70–80% of sporadic endometrial carcinomas are defined as endometrioid carcinoma (EC). Early-stage, well differentiated endometrial carcinomas usually retain expression of estrogen and progesterone receptors (ER and PR, respectively), as advanced stage, poorly differentiated tumors often lack one or both of these receptors. Well-described EC prognosis includes tumor characteristics, such as depth of myometrial invasion. Therefore, in the current study, we evaluated the expression profile of ER and PR isoforms, including ER-α, PR-A and PR–B, in correlation to EC tumor histological depth. Methods Using immunohistochemistry and image analysis software, the expression of ER-α, PR-A, PR–B and Ki67 was assessed in endometrial stroma and epithelial glands of superficial, deep and extra-tumoral sections of 15 paraffin embedded EC specimens, and compared to 5 biopsies of non-malignant endometrium. Results Expression of PR-A and ER-α was found to be lower in EC compared to nonmalignant tissue, as the stromal expression was dramatically reduced compared to epithelial cells. Expression ratios of both receptors were significantly high in superficial and deep portions of EC; in non-tumoral portion of EC were close to the ratios of nonmalignant endometrium. PR-B expression was low in epithelial glands of EC superficial and deep portions, and high in the extra-tumoral region. Elevated PR-B expression was found in stroma of EC, as well. Conclusions The ratio of ER-α and PR-A expression in the epithelial glands and the stroma of EC biopsies may serve as an additional parameter in the histological evaluation of EC tumor. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1155060506119016 PMID:24684970

  3. TP53 Mutational Spectrum in Endometrioid and Serous Endometrial Cancers.

    PubMed

    Schultheis, Anne M; Martelotto, Luciano G; De Filippo, Maria R; Piscuglio, Salvatore; Ng, Charlotte K Y; Hussein, Yaser R; Reis-Filho, Jorge S; Soslow, Robert A; Weigelt, Britta

    2016-07-01

    Endometrial carcinomas (ECs) are heterogeneous at the genetic level. Although TP53 mutations are highly recurrent in serous endometrial carcinomas (SECs), these are also present in a subset of endometrioid endometrial carcinomas (EECs). Here, we sought to define the frequency, pattern, distribution, and type of TP53 somatic mutations in ECs by performing a reanalysis of the publicly available data from The Cancer Genome Atlas (TCGA). A total of 228 EECs (n=186) and SECs (n=42) from the TCGA data set, for which an integrated genomic characterization was performed, were interrogated for the presence and type of TP53 mutations, and for mutations in genes frequently mutated in ECs. TP53 mutations were found in 15% of EECs and 88% of SECs, and in 91% of copy-number-high and 35% of polymerase (DNA directed), epsilon, catalytic subunit (POLE) integrative genomic subtypes. In addition to differences in prevalence, variations in the type and pattern of TP53 mutations were observed between histologic types and between integrative genomic subtypes. TP53 hotspot mutations were significantly more frequently found in SECs (46%) than in EECs (15%). TP53-mutant EECs significantly more frequently harbored a co-occurring PTEN mutation than TP53-mutant SECs. Finally, a subset of TP53-mutant ECs (22%) was found to harbor frameshift or nonsense mutations. Given that nonsense and frameshift TP53 mutations result in distinct p53 immunohistochemical results that require careful interpretation, and that EECs and SECs display different patterns, types, and distributions of TP53 mutations, the use of the TP53/p53 status alone for the differential diagnosis of EECs and SECs may not be sufficient.

  4. Magnetic fabric and welding processes in high-grade tuffs

    NASA Astrophysics Data System (ADS)

    Pioli, L.; Ort, M.; Lanza, R.; Rosi, M.

    2003-04-01

    The welding fabric of tuffs is generally quantified through two main parameters: porosity and fiamme aspect ratio. However, these parameters are not useful for high-grade ignimbrites that display features indicating extensive rheomorphic flow, partial to complete obliteration of primary vitroclastic textures, and syn-depositional welding rather than load-related compaction. In this case, a 3D-microstructural characterization of the rock fabric is a fundamental proxy for the assessment of the dynamics and duration of welding processes. We have investigated the relations between magnetic fabric and welding textures in a rhyolitic, high-grade ignimbrite from the Sulcis volcanic District (SW Sardinia, Italy). The ignimbrite is characterized by dense welding throughout its preserved thickness and by regular lateral and vertical variations of welding, devitrification and vesiculation facies. Field and structural data indicate that syn-depositional welding and non-particulate (NP) flow were extensive and continuous during the emplacement of the ignimbrite. Paleomagnetic measurements of AMS, NRM, and AIRM of samples from the tuff indicate that the magnetic fabric is strain-sensitive and it is not significantly affected by post-depositional, static processes such as devitrification and vapor-phase alteration; in particular, magnetic susceptibility of the rock and the welding texture correlate well in terms of shape and orientation of the anisotropy ellipsoid. The direction of the K1 axis is indicative of the flow direction in the site of measurement. The anisotropy degree (P) increases with increasing welding and foliation (F) and lineation (L) are directly related to the strain facies. Onset of welding increased the degree of anisotropy and foliation; a non particulate, laminar flow stage further deformed the fabric stretching it along the flow direction and thus increasing L. The intensity of L is strictly related to the duration and the effect of simple shear (laminar

  5. Multiphoton imaging of low grade, high grade intraepithelial neoplasia and intramucosal invasive cancer of esophagus

    NASA Astrophysics Data System (ADS)

    Xu, Jian; Jiang, Liwei; Kang, Deyong; Wu, Xuejing; Xu, Meifang; Zhuo, Shuangmu; Zhu, Xiaoqin; Lin, Jiangbo; Chen, Jianxin

    2017-04-01

    Esophageal squamous cell carcinoma (ESCC) is devastating because of its aggressive lymphatic spread and clinical course. It is believed to occur through low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia (HGIN), and intramucosal invasive cancer (IMC) before transforming to submucosal cancer. In particular, these early lesions (LGIN, HGIN and IMC), which involve no lymph node nor distant metastasis, can be cured by endoscopic treatment. Therefore, early identification of these lesions is important so as to offer a curative endoscopic resection, thus slowing down the development of ESCC. In this work, spectral information and morphological features of the normal esophageal mucosa are first studied. Then, the morphological changes of LGIN, HGIN and IMC are described. Lastly, quantitative parameters are also extracted by calculating the nuclear-to-cytoplasmic ratio of epithelial cells and the pixel density of collagen in the lamina propria. These results show that multiphoton microscopy (MPM) has the ability to identify normal esophageal mucosa, LGIN, HGIN and IMC. With the development of multiphoton endoscope systems for in vivo imaging, combined with a laser ablation system, MPM has the potential to provide immediate pathologic diagnosis and curative treatment of ESCC before the transformation to submucosal cancer in the future.

  6. Efficient molecular subtype classification of high-grade serous ovarian cancer.

    PubMed

    Leong, Huei San; Galletta, Laura; Etemadmoghadam, Dariush; George, Joshy; Köbel, Martin; Ramus, Susan J; Bowtell, David

    2015-07-01

    High-grade serous carcinomas (HGSCs) account for approximately 70% of all epithelial ovarian cancers diagnosed. Using microarray gene expression profiling, we previously identified four molecular subtypes of HGSC: C1 (mesenchymal), C2 (immunoreactive), C4 (differentiated), and C5 (proliferative), which correlate with patient survival and have distinct biological features. Here, we describe molecular classification of HGSC based on a limited number of genes to allow cost-effective and high-throughput subtype analysis. We determined a minimal signature for accurate classification, including 39 differentially expressed and nine control genes from microarray experiments. Taqman-based (low-density arrays and Fluidigm), fluorescent oligonucleotides (Nanostring), and targeted RNA sequencing (Illumina) assays were then compared for their ability to correctly classify fresh and formalin-fixed, paraffin-embedded samples. All platforms achieved > 90% classification accuracy with RNA from fresh frozen samples. The Illumina and Nanostring assays were superior with fixed material. We found that the C1, C2, and C4 molecular subtypes were largely consistent across multiple surgical deposits from individual chemo-naive patients. In contrast, we observed substantial subtype heterogeneity in patients whose primary ovarian sample was classified as C5. The development of an efficient molecular classifier of HGSC should enable further biological characterization of molecular subtypes and the development of targeted clinical trials.

  7. Locked nucleic acid-inhibitor of miR-205 decreases endometrial cancer cells proliferation in vitro and in vivo.

    PubMed

    Torres, Anna; Kozak, Joanna; Korolczuk, Agnieszka; Rycak, Dominika; Wdowiak, Paulina; Maciejewski, Ryszard; Torres, Kamil

    2016-11-08

    Pathogenesis of endometrial cancer has been connected with alterations of microRNA expression and in particular miR-205 up-regulation was consistently reported in this carcinoma. Presented study aimed to investigate if inhibition of miR-205 expression using LNA-modified-nucleotide would attenuate endometrial cancer cells proliferation in vitro and in vivo.In the course of the study we found that the proliferation of endometrial cancer cells (HEC-1-B, RL-95, KLE, Ishikawa) transfected with LNA-miR-205-inhibitor and evaluated using real time cell monitoring as well as standard cell proliferation assay, was significantly decreased. Next, LNA-miR-205-inhibitor was used to assess the in vivo effects of miR-205 inhibition of endometrial cancer growth. Cby.Cg-Foxn1/cmdb mice bearing endometrial cancer xenografts were intraperitoneally injected with nine dosages of 25mg/kg of miR-205-LNA-inhibitor or scramble control or phosphatase buffered saline and were observed for 32 days. We found that systemic administration of miR-205-LNA-inhibitor was technically possible, and exerted inhibitory effect on endometrial cancer xenograft growth in vivo with only mild toxic effects in treated animals.In conclusion our results suggest that systemic delivery of miR-205-LNA-inhibitor is feasible, devoid of significant toxicity, and could be a promising treatment strategy for endometrial cancer. Therefore it warrants further studies in other animal models.

  8. Locked nucleic acid-inhibitor of miR-205 decreases endometrial cancer cells proliferation in vitro and in vivo

    PubMed Central

    Torres, Anna; Kozak, Joanna; Korolczuk, Agnieszka; Rycak, Dominika; Wdowiak, Paulina; Maciejewski, Ryszard; Torres, Kamil

    2016-01-01

    Pathogenesis of endometrial cancer has been connected with alterations of microRNA expression and in particular miR-205 up–regulation was consistently reported in this carcinoma. Presented study aimed to investigate if inhibition of miR-205 expression using LNA-modified-nucleotide would attenuate endometrial cancer cells proliferation in vitro and in vivo. In the course of the study we found that the proliferation of endometrial cancer cells (HEC-1-B, RL-95, KLE, Ishikawa) transfected with LNA-miR-205-inhibitor and evaluated using real time cell monitoring as well as standard cell proliferation assay, was significantly decreased. Next, LNA-miR-205-inhibitor was used to assess the in vivo effects of miR-205 inhibition of endometrial cancer growth. Cby.Cg-Foxn1/cmdb mice bearing endometrial cancer xenografts were intraperitoneally injected with nine dosages of 25mg/kg of miR-205-LNA-inhibitor or scramble control or phosphatase buffered saline and were observed for 32 days. We found that systemic administration of miR-205-LNA-inhibitor was technically possible, and exerted inhibitory effect on endometrial cancer xenograft growth in vivo with only mild toxic effects in treated animals. In conclusion our results suggest that systemic delivery of miR-205-LNA-inhibitor is feasible, devoid of significant toxicity, and could be a promising treatment strategy for endometrial cancer. Therefore it warrants further studies in other animal models. PMID:27655663

  9. High-Grade Leiomyosarcoma Arising in a Previously Replanted Limb

    PubMed Central

    Pan, Tiffany J.; Pantanowitz, Liron; Weiss, Kurt R.

    2015-01-01

    Sarcoma development has been associated with genetics, irradiation, viral infections, and immunodeficiency. Reports of sarcomas arising in the setting of prior trauma, as in burn scars or fracture sites, are rare. We report a case of a leiomyosarcoma arising in an arm that had previously been replanted at the level of the elbow joint following traumatic amputation when the patient was eight years old. He presented twenty-four years later with a 10.8 cm mass in the replanted arm located on the volar forearm. The tumor was completely resected and pathology examination showed a high-grade, subfascial spindle cell sarcoma diagnosed as a grade 3 leiomyosarcoma with stage pT2bNxMx. The patient underwent treatment with brachytherapy, reconstruction with a free flap, and subsequently chemotherapy. To the best of our knowledge, this is the first case report of leiomyosarcoma developing in a replanted extremity. Development of leiomyosarcoma in this case could be related to revascularization, scar formation, or chronic injury after replantation. The patient remains healthy without signs of recurrence at three-year follow-up. PMID:26366310

  10. Concurrent thermochemoradiotherapy for brain high-grade glioma

    NASA Astrophysics Data System (ADS)

    Ryabova, A. I.; Novikov, V. A.; Choinzonov, E. L.; Gribova, O. V.; Startseva, Zh. A.; Bober, E. E.; Frolova, I. G.; Baranova, A. V.

    2016-08-01

    Despite the achievements in the current strategies for treatment, the prognosis in malignant glioma patients remains unsatisfactory. Hyperthermia is currently considered to be the most effective and universal modifier of radiotherapy and chemotherapy. Preliminary treatment outcomes for 28 patients with newly diagnosed (23) and recurrent (5) high-grade gliomas were presented. All the patients received multimodality treatment including surgery, thermoche-moradiotherapy followed by 4 cycles of adjuvant chemotherapy. All the patients endured thermochemoradiotherapy well. A complication, limited skin burn (II stage), was diagnosed in two cases and treated conservatively without treatment interruption. A month after thermochemoradiotherapy the results were as follows: complete regression was achieved in 4 cases, partial regression in 4 cases, stable disease in 14 cases and disease progression in 6 cases (one of them is pseudo-progression). After completing the adjuvant chemotherapy 2 more patients demonstrated complete response and 1 patient had disease progression. Introduction of local hyperthermia in multimodal therapy of malignant glioma does not impair the combined modality treatment tolerability of patients with malignant gliomas. A small number of studied patients and short follow-up time do not allow making reliable conclusions about the impact of local hyperthermia on the treatment outcomes; however, there is a tendency towards the increase in disease-free survival in the patients with newly diagnosed malignant gliomas.

  11. High-grade cytomegalovirus antigenemia after hematopoietic stem cell transplantation.

    PubMed

    Asano-Mori, Y; Oshima, K; Sakata-Yanagimoto, M; Nakagawa, M; Kandabashi, K; Izutsu, K; Hangaishi, A; Motokura, T; Chiba, S; Kurokawa, M; Hirai, H; Kanda, Y

    2005-11-01

    Clinical impact of high-grade (HG) cytomegalovirus (CMV) antigenemia after hematopoietic stem cell transplantation has not been clarified. Therefore, in order to investigate the risk factors and outcome for HG-CMV antigenemia, we retrospectively analyzed the records of 154 Japanese adult patients who underwent allogeneic hematopoietic stem cell transplantation for the first time from 1995 to 2002 at the University of Tokyo Hospital. Among 107 patients who developed positive CMV antigenemia at any level, 74 received risk-adapted preemptive therapy with ganciclovir (GCV), and 17 of these developed HG-antigenemia defined as > or = 50 positive cells per two slides. The use of systemic corticosteroids at > or = 0.5 mg/kg/day at the initiation of GCV was identified as an independent significant risk factor for HG-antigenemia. Seven of the 17 HG-antigenemia patients developed CMV disease, with a cumulative incidence of 49.5%, which was significantly higher than that in the low-grade antigenemia patients (4%, P<0.001). However, overall survival was almost equivalent in the two groups. In conclusion, the development of HG-antigenemia appeared to depend on the profound immune suppression of the recipient. Although CMV disease frequently developed in HG-antigenemia patients, antiviral therapy could prevent a fatal outcome.

  12. Recurrent hormone-binding domain truncated ESR1 amplifications in primary endometrial cancers suggest their implication in hormone independent growth

    PubMed Central

    Holst, Frederik; Hoivik, Erling A.; Gibson, William J.; Taylor-Weiner, Amaro; Schumacher, Steven E.; Asmann, Yan W.; Grossmann, Patrick; Trovik, Jone; Necela, Brian M.; Thompson, E. Aubrey; Meyerson, Matthew; Beroukhim, Rameen; Salvesen, Helga B.; Cherniack, Andrew D.

    2016-01-01

    The estrogen receptor alpha (ERα) is highly expressed in both endometrial and breast cancers, and represents the most prevalent therapeutic target in breast cancer. However, anti-estrogen therapy has not been shown to be effective in endometrial cancer. Recently it has been shown that hormone-binding domain alterations of ERα in breast cancer contribute to acquired resistance to anti-estrogen therapy. In analyses of genomic data from The Cancer Genome Atlas (TCGA), we observe that endometrial carcinomas manifest recurrent ESR1 gene amplifications that truncate the hormone-binding domain encoding region of ESR1 and are associated with reduced mRNA expression of exons encoding the hormone-binding domain. These findings support a role for hormone-binding alterations of ERα in primary endometrial cancer, with potentially important therapeutic implications. PMID:27160768

  13. Hysteroscopic resection in the management of early-stage endometrial cancer: report of 2 cases and review of the literature.

    PubMed

    Arendas, Kristina; Aldossary, Mona; Cipolla, Amanda; Leader, Arthur; Leyland, Nicholas A

    2015-01-01

    Although endometrial cancer, the most common gynecologic malignancy, is most often diagnosed in postmenopausal women, it affects young women who wish to preserve fertility. The purpose of this article is to describe 2 cases of stage IA endometrial cancer managed conservatively by a combination of hysteroscopic surgery and medical therapy for fertility-sparing purposes, one of which achieved successful pregnancy using assisted reproductive technology, and review the existing literature on the use of hysteroscopic resection in conservative management of endometrial cancer to preserve fertility. The addition of hysteroscopic resection to conservative management of early-stage endometrial carcinoma may be a way to improve response and recurrence rates in women wishing to preserve fertility and can offer other additional benefits, such as a shorter time period to remission and a faster return to fertility. Key factors to success with this approach include an interdisciplinary approach, thorough patient counseling, and the availability of a team experienced in hysteroscopic resection.

  14. Androgen receptors are acquired by healthy postmenopausal endometrial epithelium and their subsequent loss in endometrial cancer is associated with poor survival

    PubMed Central

    Kamal, A M; Bulmer, J N; DeCruze, S B; Stringfellow, H F; Martin-Hirsch, P; Hapangama, D K

    2016-01-01

    Background: Endometrial cancer (EC) is a hormone-driven disease, and androgen receptor (AR) expression in high-grade EC (HGEC) and metastatic EC has not yet been described. Methods: The expression pattern and prognostic value of AR in relation to oestrogen (ERα and ERβ) and progesterone (PR) receptors, and the proliferation marker Ki67 in all EC subtypes (n=85) were compared with that of healthy and hyperplastic endometrium, using immunohistochemisty and qPCR. Results: Compared with proliferative endometrium, postmenopausal endometrtial epithelium showed significantly higher expression of AR (P<0.001) and ERα (P=0.035), which persisted in hyperplastic epithelium and in low-grade EC (LGEC). High-grade EC showed a significant loss of AR (P<0.0001), PR (P<0.0001) and ERβ (P<0.035) compared with LGEC, whilst maintaining weak to moderate ERα. Unlike PR, AR expression in metastatic lesions was significantly (P=0.039) higher than that in primary tumours. Androgen receptor expression correlated with favourable clinicopathological features and a lower proliferation index. Loss of AR, with/without the loss of PR was associated with a significantly lower disease-free survival (P<0.0001, P<0.0001, respectively). Conclusions: Postmenopausal endometrial epithelium acquires AR whilst preserving other steroid hormone receptors. Loss of AR, PR with retention of ERα and ERβ may promote the unrestrained growth of HGEC. Androgen receptor may therefore be a clinically relevant prognostic indicator and a potential therapeutic target in EC. PMID:26930451

  15. Novel Oncogenic PDGFRA Mutations in Pediatric High-Grade Gliomas

    PubMed Central

    Paugh, Barbara S.; Zhu, Xiaoyan; Qu, Chunxu; Endersby, Raelene; Diaz, Alexander K.; Zhang, Junyuan; Bax, Dorine A.; Carvalho, Diana; Reis, Rui M.; Onar-Thomas, Arzu; Broniscer, Alberto; Wetmore, Cynthia; Zhang, Jinghui; Jones, Chris; Ellison, David W.; Baker, Suzanne J.

    2013-01-01

    The outcome for children with high-grade gliomas (HGG) remains dismal, with a two-year survival rate of only 10–30%. Diffuse intrinsic pontine glioma (DIPG) comprise a subset of HGG that arise in brainstem almost exclusively in children. Genome-wide analyses of copy number imbalances previously showed that platelet derived growth factor receptor alpha (PDGFRA) is the most frequent target of focal amplification in pediatric HGGs, including DIPGs. To determine whether PDGFRA is also targeted by more subtle mutations missed by copy number analysis, we sequenced all PDGFRA coding exons from a cohort of pediatric HGGs. Somatic activating mutations were identified in 14.4% (13/90) of non-brainstem pediatric HGGs and 4.7% (2/43) of DIPGs, including missense mutations and in-frame deletions and insertions not previously described. 40% of tumors with mutation showed concurrent amplification, while 60% carried heterozygous mutations. Six different mutations impacting different domains all resulted in ligand-independent receptor activation that was blocked by small molecule inhibitors of PDGFR. Expression of mutants in p53-null primary mouse astrocytes conferred a proliferative advantage in vitro, and generated HGGs in vivo with complete penetrance when implanted into brain. The gene expression signatures of these murine HGGs reflected the spectrum of human diffuse HGGs. PDGFRA intragenic deletion of exons 8 and 9 were previously shown in adult HGG, but were not detected in 83 non-brainstem pediatric HGG and 57 DIPGs. Thus, a distinct spectrum of mutations confers constitutive receptor activation and oncogenic activity to PDGFRα in childhood HGG. PMID:23970477

  16. Enhanced expression of hydroxylated ceramide in well-differentiated endometrial adenocarcinoma

    PubMed Central

    Tajima, Toshiki; Miyazawa, Masaki; Hayashi, Masaru; Asai, Satoshi; Ikeda, Masae; Shida, Masako; Hirasawa, Takeshi; Iwamori, Masao; Mikami, Mikio

    2017-01-01

    Based on our previous analysis of neutral glycolipids in the human endometrium, the present authors already reported that the concentrations of glucosylceramide, lactosylceramide and globotriaosylceramide (Gb3Cer), in which both fatty acids and sphingosines in the ceramides are hydroxylated, exhibit a marked increase during the luteal phase of the menstrual cycle. It is also well known that poorly differentiated endometrial adenocarcinoma exhibits a more rapid progression and a worse response to therapy than well-differentiated endometrial adenocarcinoma. To examine the molecular background of well-differentiated and poorly differentiated cancers, the levels of neutral glycolipids in tumor tissues from endometrial carcinoma displaying different degrees of differentiation were measured. The composition of neutral glycolipids in tumor tissues was determined, and ceramide structures that were specifically expressed in well-differentiated endometrial carcinomas were investigated using biochemical analytical methods, including lipid extraction, enzyme digestion, thin-layer chromatography (TLC), gas-liquid chromatography and mass spectrometry. Well-differentiated adenocarcinoma contained numerous structurally unknown glycolipids that exhibited slower migration than globotetraosylceramide (Gb4Cer). In the case of Gb3Cer, three bands appeared on TLC in well-differentiated cancer, but only two bands appeared in the poorly-differentiated cancer. This difference was associated with the fatty acid composition of ceramide, since non-hydroxy fatty acids with ≥20 carbon atoms were increased in well-differentiated cancer, while α-hydroxy fatty acids were increased in poorly differentiated cancer. Similarly, there were two bands on TLC of Gb4Cer from well-differentiated cancer, but only one band in poorly differentiated cancer, and the long-chain base of ceramide was observed to contain phytosphingosine in well-differentiated cancer. It was demonstrated in endometrial cancer

  17. Expression of renin–angiotensin system (RAS) components in endometrial cancer

    PubMed Central

    Delforce, Sarah J; Lumbers, Eugenie R; Corbisier de Meaultsart, Celine; Wang, Yu; Proietto, Anthony; Otton, Geoffrey; Scurry, Jim; Verrills, Nicole M; Scott, Rodney J

    2017-01-01

    A dysfunctional endometrial renin–angiotensin system (RAS) could aid the growth and spread of endometrial cancer. To determine if the RAS is altered in endometrial cancer, we measured RAS gene expression and protein levels in 30 human formalin-fixed, paraffin-embedded (FFPE) endometrioid carcinomas and their adjacent endometrium. All components of the RAS were expressed in most tumours and in adjacent endometrium; mRNA levels of (pro)renin receptor (ATP6AP2), angiotensin II type 1 receptor (AGTR1), angiotensin-converting enzyme (ACE1) and angiotensin-converting enzyme 2 (ACE2) mRNA levels were greater in tumour tissue than adjacent non-cancerous endometrium (P = 0.023, 0.008, 0.004 and 0.046, respectively). Prorenin, ATP6AP2, AGTR1, AGTR2 and ACE2 proteins were abundantly expressed in both cancerous and adjacent non-cancerous endometrium. Staining was most intense in cancerous glandular epithelium. One potential target of the endometrial RAS, transforming growth factor beta-1 (TGFB1), which is essential for epithelial-to-mesenchymal transition, was also upregulated in endometrial cancer tissue (P = 0.001). Interestingly, TGFB1 was strongly correlated with RAS expression and was upregulated in tumour tissue. This study is the first to characterise the mRNA and protein expression of all RAS components in cancerous and adjacent non-cancerous endometrium. The greater expression of ATP6AP2, AGTR1 and ACE1, key elements of the pro-angiogenic/proliferative arm of the RAS, suggests that the RAS plays a role in the growth and spread of endometrial cancer. Therefore, existing drugs that inhibit the RAS and which are used to treat hypertension may have potential as treatments for endometrial cancer. PMID:27956412

  18. Methylation profiles of endometrioid and serous endometrial cancers.

    PubMed

    Seeber, Laura M S; Zweemer, Ronald P; Marchionni, Luigi; Massuger, Leon F A G; Smit, Vincent T H B M; van Baal, W Marchien; Verheijen, René H M; van Diest, Paul J

    2010-09-01

    Promoter methylation is a gene- and cancer type-specific epigenetic event that plays an important role in tumour development. As endometrioid (endometrioid endometrial carcinoma, EEC) and serous endometrial cancers (uterine papillary serous carcinoma, UPSC) exhibit different clinical, histological and molecular genetic characteristics, we hypothesized that these differences may be reflected in epigenetic phenomena as well. Identification of a panel of methylation biomarkers could be helpful in a correct histological classification of these two subtypes, which solely on the basis of morphology is not always easy. Methylation-specific multiplex ligation-dependent probe amplification was used to assess the extent of promoter methylation of different tumour suppressor genes in EEC and UPSC. Methylation results were correlated with histology and survival. The median cumulative methylation index of all genes was significantly higher in EEC (124) than in UPSC (93) (P<0.001). Promoter methylation of CDH13 and MLH1 was more frequently present in EEC, while CDKN2B and TP73 were more frequently methylated in UPSC. Almost 90% of EEC and 70% of UPSC could be predicted by CDH13 and TP73. In EEC, methylation of MLH1 was associated with a shorter disease-free survival (DFS; P<0.0001) and overall survival (OS; P=0.005). In a multivariate model, MLH1 methylation emerged as an additional prognostic factor to stage for DFS (P=0.002). In conclusion, promoter methylation is more common in EEC than UPSC. A panel of methylation biomarkers could be useful to distinguish between the two histological subtypes of endometrial cancer. Furthermore, methylation of MLH1 may have prognostic value in EEC.

  19. Prevention of Ovarian High-Grade Serous Carcinoma by Elucidating Its Early Change

    DTIC Science & Technology

    2013-10-01

    for ovarian cancer. In addition, Project 5 will determine if these biomarkers and associated precursor lesions are modifiable by oral contraceptives ...3. Determine whether oral contraceptives (OCPs) and NSAIDs reduce the morphologic and molecular changes that are associated with early “ovarian... contraceptives (OCPs) or anti- inflammatory agents, as OCPs in particular are known to prevent ovarian cancer and impact survival. Research site: Johns

  20. Early hepatocellular carcinoma and dysplastic nodules.

    PubMed

    Kojiro, Masamichi; Roskams, Tania

    2005-01-01

    It has been established that small, equivocal nodular lesions such as dysplastic nodules (DNs) and small well-differentiated hepatocellular carcinomas (early HCCs) are frequently observed in noncancerous liver tissues resected along with HCCs and in explant cirrhotic livers. DNs are classified into low-grade DNs or high-grade DNs on the basis of cytological and architectural atypia; high-grade DNs show varying degrees of cytological or architectural atypia, or both. Early HCCs are indistinctly nodular and highly differentiated and are frequently difficult to differentiate from high-grade DNs. Although the pathological diagnosis of high-grade DNs and early HCCs is controversial, the presence of tumor cell invasion into the intratumoral portal tracts (stromal invasion) is a helpful clue for differentiating early HCC from high-grade DNs. It is highly suggested that many HCCs occurring in cirrhotic liver arise in DNs and develop to classical HCC in a multistep fashion.

  1. Endometrial thickness predicts endometrial hyperplasia in patients with polycystic ovary syndrome.

    PubMed

    McCormick, Betsy A; Wilburn, Rochelle D; Thomas, Michael A; Williams, Daniel B; Maxwell, Rose; Aubuchon, Mira

    2011-06-30

    Body mass index is predictive of sonographic endometrial stripe thickness, which in turn is predictive of endometrial hyperplasia in patients with polycystic ovary syndrome. For every 1-mm increase in endometrial stripe, the odds ratio of hyperplasia increased by 1.48 (95% confidence interval, 1.04-2.10).

  2. Can Proliferation Biomarkers Reliably Predict Recurrence in World Health Organization 2003 Defined Endometrial Stromal Sarcoma, Low Grade?

    PubMed Central

    Feng, Weiwei; Malpica, Anais; Skaland, Ivar; Gudlaugsson, Einar; Robboy, Stanley J.; Dalen, Ingvild; Hua, Keqin; Zhou, Xianrong; Baak, Jan P. A.

    2013-01-01

    An estimated 1500–3000 invasive Endometrial Stromal Sarcomas (ESS) cases annually occur worldwide. Before 2003, ESS was divided as low and high grade ESS based on mitotic activity. In 2003 the WHO changed the names, excluded mitoses and made nuclear atypia and necrosis the essential diagnostic criteria to distinguish ESS, Low Grade (ESS-LG, recurrence-free survival >90%) and Undifferentiated Endometrial Sarcoma (UES, poor prognosis). We have evaluated in WHO2003 defined ESS-LG whether proliferation biomarkers predict recurrence. Using survival analysis, the prognostic value of classical mitosis counts (Mitotic Activity Index, MAI) in haematoxyllin-eosin (H&E) sections, and immunohistochemical proliferation biomarkers (Ki-67 and PhosphoHistone-3 (PPH3)) were examined in 24 invasive endometrial stromal sarcomas. Three of 24 (12.5%) ESS-LG recurred. The MAI, PPH3 and Ki-67 were all prognostic (P = 0.001, 0.002 and 0.03). MAI values were >3 in the recurrent cases, but never exceeded 10 (the classical threshold for low and high grade). Non-recurrent cases had 0≤MAI≤3. PPH3 and Ki67 counts can be easier to perform than MAI and therefore helpful in the diagnosis of ESS, Low Grade. In conclusion, in this small study of WHO2003 defined ESS-LG, high levels of proliferation as measured by MAI, PPH3 and Ki-67 are predictive of recurrence. Larger studies are required to confirm these results. PMID:24146786

  3. Hypertriglyceridemia is Frequent in Endometrial Cancer Survivors

    PubMed Central

    Hirasawa, Akira; Makita, Kazuya; Akahane, Tomoko; Yokota, Megumi; Yamagami, Wataru; Banno, Kouji; Susumu, Nobuyuki; Aoki, Daisuke

    2013-01-01

    Objective Previous studies have reported an association between endometrial cancer and the risk of metabolic syndrome; however, the pattern of endometrial cancer-associated dyslipidemia is not well understood. The standard therapy for endometrial cancer is total abdominal hysterectomy and bilateral salpingo-oophorectomy. Premenopausal bilateral salpingo-oophorectomy may cause adverse events, including dyslipidemia. Gynecologists have to care dyslipidemia in endometrial cancer survivors at cancer follow-up clinic. Methods This study included 693 patients who had undergone bilateral salpingo-oophorectomy, and included 412 women with incident endometrial cancer and 281 controls. We divided the patients into two categories according to whether they had a premenopausal or postmenopausal bilateral oophorectomy. Serum lipid levels were measured and statistically analyzed. Results Hypertriglyceridemia was statistically more frequent in patients who had undergone bilateral salpingo-oophorectomy both before and after menopause than in the corresponding non-endometrial cancer controls. High levels of low-density lipoprotein cholesterol and a high low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio were statistically more frequent in patients who had undergone bilateral salpingo-oophorectomy before menopause than in non-endometrial cancer controls. Conclusions Our report highlights the importance of the relationship between endometrial cancer and lipid metabolism, which may aid in preventing cerebrovascular or cardiovascular diseases due to dyslipidemia and improving the quality of life in endometrial cancer survivors. PMID:23999769

  4. Endometrial aspiration cytology in gynecological disorders

    PubMed Central

    Jadhav, Meenal V.; Phatke, Anjali S.; Kadgi, Nalini Vinayak; Rane, Sharda R.; Kulkarni, Kalpana K.

    2016-01-01

    Context: Endometrial aspiration is not a popular modality for the study of the endometrium despite its simplicity and potential utility. Aim: The present study was aimed at evaluating the utility of endometrial aspiration in various gynecological disorders. Materials and Methods: In this diagnostic accuracy study, 55 prospectively registered women with various gynecological disorders were evaluated clinically and subjected to endometrial aspiration cytology and study of endometrial histology. Endometrial aspiration was performed by infant feeding tube in 10 cases and intra cath cannula in 45 cases. The slides were stained with rapid Papanicolaou (PAP) stain and Leishman stain. Results: Endometrial aspiration cytology showed 90% and 94.6% sampling adequacy with infant feeding tube and intra cath cannula, respectively. Intra cath cannula was very convenient to handle and superior to infant feeding tube in aspirating the endometrium. Of the two stains used, rapid PAP stain was less time-consuming and superior to Leishman stain in studying the nuclear details. Leishman stain was helpful in detecting cytoplasmic vacuoles of secretory endometrium. Overall diagnostic accuracy of endometrial cytology was 90.4% while that for morphological hormonal evaluation was 97.6%. It enjoyed a sensitivity of 91.66%, a specificity of 88.23%, positive predictive value of 94.28%, and negative predictive value of 83.33%. Conclusion: Intra cath cannula emerged as an inexpensive, effective, and convenient device for endometrial aspiration. Endometrial aspiration proved to be a fairly effective, simple, and informative diagnostic modality. PMID:27011435

  5. Integrated Proteogenomic Characterization of Human High-Grade Serous Ovarian Cancer

    SciTech Connect

    Zhang, Hui; Liu, Tao; Zhang, Zhen; Payne, Samuel H.; Zhang, Bai; McDermott, Jason E.; Zhou, Jian-Ying; Petyuk, Vladislav A.; Chen, Li; Ray, Debjit; Sun, Shisheng; Yang, Feng; Chen, Lijun; Wang, Jing; Shah, Punit; Cha, Seong Won; Aiyetan, Paul; Woo, Sunghee; Tian, Yuan; Gritsenko, Marina A.; Clauss, Therese R.; Choi, Caitlin; Monroe, Matthew E.; Thomas, Stefani; Nie, Song; Wu, Chaochao; Moore, Ronald J.; Yu, Kun-Hsing; Tabb, David L.; Fenyö, David; Bafna, Vineet; Wang, Yue; Rodriguez, Henry; Boja, Emily S.; Hiltke, Tara; Rivers, Robert C.; Sokoll, Lori; Zhu, Heng; Shih, Ie-Ming; Cope, Leslie; Pandey, Akhilesh; Zhang, Bing; Snyder, Michael P.; Levine, Douglas A.; Smith, Richard D.; Chan, Daniel W.; Rodland, Karin D.

    2016-07-01

    Ovarian cancer remains the most lethal gynecological malignancy in the developed world, despite recent advances in genomic information and treatment. To better understand this disease, define an integrated proteogenomic landscape, and identify factors associated with homologous repair deficiency (HRD) and overall survival, we performed a comprehensive proteomic characterization of ovarian high-grade serous carcinomas (HGSC) previously characterized by The Cancer Genome Atlas (TCGA). We observed that messenger RNA transcript abundance did not reliably predict abundance for 10,030 proteins across 174 tumors. Clustering of tumors based on protein abundance identified five subtypes, two of which correlated robustly with mesenchymal and proliferative subtypes, while tumors characterized as immunoreactive or differentiated at the transcript level were intermixed at the protein level. At the genome level, HGSC is characterized by a complex landscape of somatic copy number alterations (CNA), which individually do not correlate significantly with survival. Correlation of CNAs with protein abundances identified loci with significant trans regulatory effects mapping to pathways associated with proliferation, cell motility/invasion, and immune regulation, three known hallmarks of cancer. Using the trans regulated proteins we also created models significantly correlated with patient survival by multivariate analysis. Integrating protein abundance with specific post-translational modification data identified subnetworks correlated with HRD status; specifically, acetylation of Lys12 and Lys16 on histone H4 was associated with HRD status. Using quantitative phosphoproteomics data covering 4,420 proteins as reflective of pathway activity, we identified the PDGFR and VEGFR signaling pathways as significantly up-regulated in patients with short overall survival, independent of PDGFR and VEGFR protein levels, potentially informing the use of anti-angiogenic therapies. Components of

  6. Immunohistochemical detection of P-glycoprotein in endometrial adenocarcinoma.

    PubMed Central

    Axiotis, C. A.; Monteagudo, C.; Merino, M. J.; LaPorte, N.; Neumann, R. D.

    1991-01-01

    P-glycoprotein (Pgp) has emerged as the central mediator in classic multidrug resistance in model systems in vitro. High levels of Pgp also have been detected in many normal human tissues and tumors; and its role in clinical drug resistance is currently under investigation. Recently significant levels of Pgp were localized to gravid and secretory endometrium; and it was demonstrated that the combination of estrogen and progesterone is sufficient to induce high levels of both Pgp mRNA and Pgp in uterine secretory epithelium. These findings suggest that increased Pgp expression also may be present in hormone-responsive malignancies such as endometrial adenocarcinoma. To determine whether Pgp is expressed in endometrial adenocarcinoma, 36 endometrial adenocarcinomas (grade I [n = 17]; grade II [n = 6]; grade III [n = 13]) were investigated retrospectively by the avidin-biotin-complex immunohistochemical procedure using three murine monoclonal antibodies (MAb) MAb C219, MAb C494, and MAb JSB-1, which recognize spatially distinct cytoplasmic epitopes of Pgp. Seventy-two percent of the tumors showed positive immunostaining with at least one MAb; 67% showed immunostaining with MAb C219, 50% with MAb C494, and 62% with MAb JSB-1. Forty-six percent of tumors were immunoreactive to two and 29% to all three antibodies. Membranous and Golgi/paranuclear type staining patterns were observed. Overall the intensity of immunostaining varied from one sample to another for a given tumor type, and considerable heterogeneity of expression was commonly seen within a given tumor. Strong to moderate immunoreactivity was seen in diffusely infiltrating, adenosquamous, and serous papillary carcinomas. In general, immunoreactivity to MAb C494 was weaker than MAb C219 or MAb JSB-1. Adenomatous and non-neoplastic endometrium adjacent to the tumors displayed strong membranous immunostaining with MAb JSB-1. Endometrial capillaries showed weak-to-moderate immunostaining to all three antibodies. It

  7. MicroRNA Expression Profile Identifies High Grade, Non-Muscle-Invasive Bladder Tumors at Elevated Risk to Progress to an Invasive Phenotype

    PubMed Central

    Lenherr, Sara M.; Tsai, Sheaumei; Silva Neto, Brasil; Sullivan, Travis B.; Cimmino, Cara B.; Logvinenko, Tanya; Gee, Jason; Huang, Wei; Libertino, John A.; Summerhayes, Ian C.; Rieger-Christ, Kimberly M.

    2017-01-01

    The objective of this study was to identify a panel of microRNAs (miRNAs) differentially expressed in high-grade non-muscle invasive (NMI; TaG3–T1G3) urothelial carcinoma that progress to muscle-invasive disease compared to those that remain non-muscle invasive, whether recurrence happens or not. Eighty-nine high-grade NMI urothelial carcinoma lesions were identified and total RNA was extracted from paraffin-embedded tissue. Patients were categorized as either having a non-muscle invasive lesion with no evidence of progression over a 3-year period or as having a similar lesion showing progression to muscle invasion over the same period. In addition, comparison of miRNA expression levels between patients with and without prior intravesical therapy was performed. Total RNA was pooled for microarray analysis in each group (non-progressors and progressors), and qRT-PCR of individual samples validated differential expression between non-progressive and progressive lesions. MiR-32-5p, -224-5p, and -412-3p were associated with cancer-specific survival. Downregulation of miR-203a-3p and miR-205-5p were significantly linked to progression in non-muscle invasive bladder tumors. These miRNAs include those implicated in epithelial mesenchymal transition, previously identified as members of a panel characterizing transition from the non-invasive to invasive phenotype in bladder tumors. Furthermore, we were able to identify specific miRNAs that are linked to postoperative outcome in patients with high grade NMI urothelial carcinoma of the bladder (UCB) that progressed to muscle-invasive (MI) disease. PMID:28218662

  8. Temsirolimus and Bevacizumab in Treating Patients With Advanced Endometrial, Ovarian, Liver, Carcinoid, or Islet Cell Cancer

    ClinicalTrials.gov

    2017-03-17

    Adult Hepatocellular Carcinoma; Advanced Adult Hepatocellular Carcinoma; Endometrial Serous Adenocarcinoma; Localized Non-Resectable Adult Liver Carcinoma; Lung Carcinoid Tumor; Malignant Pancreatic Gastrinoma; Malignant Pancreatic Glucagonoma; Malignant Pancreatic Insulinoma; Malignant Pancreatic Somatostatinoma; Metastatic Digestive System Neuroendocrine Tumor G1; Ovarian Carcinosarcoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Seromucinous Carcinoma; Ovarian Serous Surface Papillary Adenocarcinoma; Pancreatic Alpha Cell Adenoma; Pancreatic Beta Cell Adenoma; Pancreatic Delta Cell Adenoma; Pancreatic G-Cell Adenoma; Pancreatic Polypeptide Tumor; Recurrent Adult Liver Carcinoma; Recurrent Digestive System Neuroendocrine Tumor G1; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Pancreatic Neuroendocrine Carcinoma; Recurrent Primary Peritoneal Carcinoma; Recurrent Uterine Corpus Carcinoma; Regional Digestive System Neuroendocrine Tumor G1; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIA Uterine Corpus Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIB Uterine Corpus Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IIIC Uterine Corpus Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer; Stage IVA Uterine Corpus Cancer; Stage IVB Uterine Corpus Cancer; Uterine Carcinosarcoma

  9. Endometrial polyps in 2 African pygmy hedgehogs.

    PubMed

    Phillips, Irene D; Taylor, Jacqueline J; Allen, Andrew L

    2005-06-01

    Reports of spontaneously occurring endometrial polyps in animals are rare and have only involved a few species. This report is intended to advise veterinarians that older African pygmy hedgehogs may develop endometrial polyps and that these lesions can be a cause of bloody vaginal discharge, sometimes interpreted as hematuria.

  10. The fallopian tube as the origin of high grade serous ovarian cancer: review of a paradigm shift.

    PubMed

    Reade, Clare J; McVey, Ruaidhrí M; Tone, Alicia A; Finlayson, Sarah J; McAlpine, Jessica N; Fung-Kee-Fung, Michael; Ferguson, Sarah E

    2014-02-01

    Research published over the past 10 years has suggested that most "ovarian cancer," and specifically the high-grade serous carcinoma (HGSC) subtype of ovarian cancer, actually originates in the fallopian tube. In this review, we examine the evidence supporting the tubal origin hypothesis for HGSC, and discuss the clinical implications of our improved understanding of the pathogenesis of ovarian cancer. We searched Medline R and Medline in-process and non-indexed citations from inception to December 15, 2012, to identify all English or French language articles discussing the origins of HGSC. Articles and findings were summarized descriptively. A step-wise transformation from normal epithelium to a lesion with the ability to invade and metastasize has been demonstrated within the fallopian tube. Intraepithelial or early invasive carcinoma of the fallopian tube is frequently identified in BRCA mutation carriers who undergo prophylactic risk-reducing salpingo-oophorectomy. In both BRCA mutation carriers and women from the general population, pre-invasive changes within the fimbriated end of the fallopian tube appear in association with early HGSC. Molecular and genetic studies, as well as in vitro and animal models, have also supported a tubal origin for HGSC. Whether the removal of fallopian tubes (salpingectomy) at the time of pelvic surgery for other reasons will lead to reductions in mortality from ovarian cancer is currently unknown, but it is an important area for future clinical research.

  11. Histopathology-like categories based on endometrial imprint cytology in dysfunctional uterine bleeding

    PubMed Central

    Baxi, Seema N.; Panchal, Nirav S.

    2015-01-01

    Background: Cytology of the endometrium is an underused technique in diagnostic pathology. It has been used in the past for endometrial hyperplasia and carcinoma. Only few studies have used cytology in the diagnosis of dysfunctional uterine bleeding (DUB). Endometrial imprint cytology has been rarely used except for application of immunocytochemistry in diagnosis of endometrial carcinoma. Aim: The present study was conducted to evaluate whether it is possible to assign histopathology-like diagnosis by imprint cytology and also to evaluate its usefulness in the assessment of patients of dysfunctional uterine bleeding of low clinical suspicion. Materials and Methods: Imprint smears were made from 93 curettage materials during a study of DUB. Blinded analysis of imprint smears was performed by using McKenzie's criteria and some criteria devised for the requirements of this study. Results of cytology were correlated with histopathology. Statistical analysis was carried out by GraphpadInStat Demo. Results: Majority of the patterns classifiable in histopathology could also be classified in this study on imprint cytology. The overall sensitivity and specificity of cytology in the detection of endometrial patterns in DUB patients were 91.23% and 83.87%, respectively, although the sensitivities and specificities differ according to the phase of endometrium. Conclusion: Histopathology-like categories can be assigned on imprint smears in the diagnosis of DUB. Endometrial imprint cytology can be helpful in centers where histopathology laboratories are not available and even in well-established institutes. It is possible to improve the sensitivity and specificity with better imprinting techniques. PMID:26229245

  12. Ca2+ channel subunit α 1D promotes proliferation and migration of endometrial cancer cells mediated by 17β-estradiol via the G protein-coupled estrogen receptor.

    PubMed

    Hao, Juan; Bao, Xiaoxia; Jin, Bo; Wang, Xiujuan; Mao, Zebin; Li, Xiaoping; Wei, Lihui; Shen, Danhua; Wang, Jian-Liu

    2015-07-01

    Calcium and calcium channels are closely related to the estrogen-induced nongenomic effect of endometrial carcinoma, but the specific role of calcium channels is unknown. This study aimed to explore the expression and the biologic effect of the L-type calcium channel in endometrial carcinoma cells and to clarify the molecular mechanism of the relationship between L-type calcium channels and estrogen. The immunohistochemical results showed that Ca(2+) channel subunit α 1D (Cav1.3) expression was high in atypical hyperplasia (1.90 ± 0.35) and endometrial carcinoma tissues (2.05 ± 0.82) but weak (0.80 ± 0.15) in benign endometrial tissues (P < 0.05). Treatment with 17β-estradiol rapidly increased Cav1.3 expression in a dose- and time-dependent manner, and 100 nM cell-impermeable β-estradiol-6-(O-carboxymethyl)oxime:bovine serum albumin also promoted Cav1.3 expression. Transfection with small interfering RNA against G protein-coupled estrogen receptor (GPER) suppressed estrogen-induced up-regulation of Cav1.3 compared with control cells and markedly reduced the estrogen-induced phosphorylation of ERK1/2 and CREB. Knocking down the Cav1.3 significantly suppressed estrogen-stimulated Ca(2+) influx, cell proliferation, and migration in endometrial cancer cells. Taken together, Cav1.3 was overexpressed in atypical hyperplasia and endometrial carcinoma, and the estrogen-induced phosphorylation of downstream molecular ERK1/2 and CREB is the result of activation of the GPER pathway. L-type channel Cav1.3 is required for estrogen-stimulated Ca(2+) influx and contributes broadly to the development of endometrial cancer. The Cav1.3 channel may be a new target for endometrial carcinoma treatment.

  13. Evaluation of endometrial cancer epidemiology in Romania.

    PubMed

    Bohîlțea, R E; Furtunescu, F; Dosius, M; Cîrstoiu, M; Radoi, V; Baroș, A; Bohîlțea, L C

    2015-01-01

    Endometrial cancer represents the most frequent gynecological malignant affection in the developed countries, in which the incidence of cervical cancer has significantly decreased due to the rigorous application of screening methods and prophylaxis. According to its frequency, endometrial cancer is situated on the fourth place in the category of women's genital-mammary malignant diseases, after breast, cervical and ovarian cancer in Romania. The incidence and mortality rates due to endometrial cancer have registered an increasing trend worldwide and also in Romania, a significant decrease of the age of appearance for the entire endometrial pathology sphere being noticed. At the national level, the maximum incidence is situated between 60 and 64 years old, the mortality rate of the women under 65 years old being high in Romania. The study evaluates endometrial cancer, from an epidemiologic point of view, at the national level compared to the international statistic data.

  14. View looking northwest toward HIghGrade Ore Bin and Concentrate Bin ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    View looking northwest toward HIgh-Grade Ore Bin and Concentrate Bin - Kennecott Copper Corporation, Concentration Mill, On Copper River & Northwestern Railroad, Kennicott, Valdez-Cordova Census Area, AK

  15. Mammary analog secretory carcinoma, low-grade salivary duct carcinoma, and mimickers: a comparative study.

    PubMed

    Stevens, Todd M; Kovalovsky, Andra O; Velosa, Claudia; Shi, Qiuying; Dai, Qian; Owen, Randall P; Bell, Walter C; Wei, Shi; Althof, Pamela A; Sanmann, Jennifer N; Sweeny, Larissa; Carroll, William R; Siegal, Gene P; Bullock, Martin J; Brandwein-Gensler, Margaret

    2015-08-01

    Mammary analog secretory carcinoma (MASC) is a recently recognized low-grade salivary carcinoma characterized by a specific ETV6 rearrangement. We describe 14 new MASCs and examine their immunophenotypic and genetic profiles in the context of look-alikes, namely, low-and high-grade salivary duct carcinoma and acinic cell carcinoma. ETV6 rearrangement, and robust expression of mammaglobin and S100, were demonstrated in 11/11, 14/14, and 12/14 MASCs, respectively. All low-grade salivary duct carcinomas coexpressed S100/mammaglobin (6/6); none harbored ETV6 rearrangements (0/5). Given that S100/mammaglobin coexpression and absence of zymogen granules are features of both MASC and low-grade salivary duct carcinoma, these two are best distinguished histologically. The former is predominantly an extraductal neoplasm with bubbly pink cytoplasm, whereas the latter is a distinct intraductal micropapillary and cribriform process. Querying ETV6 gene status may be necessary for difficult cases. No acinic cell carcinoma expressed mammaglobin (0/13) or harbored an ETV6 rearrangement (0/7); only 1/13 acinic cell carcinomas weakly expressed S100. DOG1 expression was limited or absent among all tumor types, except acinic cell carcinoma which expressed DOG1 diffusely in a canalicular pattern. Therefore, histology and immunohistochemistry (mammaglobin, S100, DOG1) suffices in distinguishing acinic cell carcinoma from both MASC and low-grade salivary duct carcinoma. HER2 (ERBB2) amplification was detected in only 1/10 acinic cell carcinomas, but none of the MASCs or low-grade salivary duct carcinomas tested. High-grade salivary duct carcinomas frequently expressed mammaglobin (11/18) and harbored HER2 amplifications (13/15); none harbored ETV6 rearrangements (0/12). High-grade salivary duct carcinomas can easily be distinguished from these other entities by histology and HER2 amplification.

  16. The utility of endometrial thickness measurement in asymptomatic postmenopausal women with endometrial fluid.

    PubMed

    Seckin, B; Ozgu-Erdinc, A S; Dogan, M; Turker, M; Cicek, M N

    2016-01-01

    The aim of this study was to assess the clinical usefulness of sonographic endometrium thickness measurement in asymptomatic postmenopausal women with endometrial fluid collection. Fifty-two asymptomatic postmenopausal women with endometrial fluid, who underwent endometrial sampling were evaluated. Histopathological findings revealed that 25 (48.1%) women had insufficient tissue, 20 (38.4%) had atrophic endometrium and 7 (13.5%) had endometrial polyps. No case of malignancy was found. There was no statistically significant difference between the various histopathological categories (insufficient tissue, atrophic endometrium and polyp) with regard to the mean single-layer endometrial thickness (1.54 ± 0.87, 2.04 ± 1.76 and 1.79 ± 0.69 mm, respectively, p = 0.436). Out of 44 patients with endometrial thickness of less than 3 mm, 38 (86.4%) had atrophic changes or insufficient tissue and 6 (13.6%) had endometrial polyps. In conclusion, if the endometrial thickness is 3 mm or less, endometrial sampling is not necessary in asymptomatic postmenopausal women with endometrial fluid.

  17. Armodafinil in Reducing Cancer-Related Fatigue in Patients With High Grade Glioma | Division of Cancer Prevention

    Cancer.gov

    This randomized phase III trial studies armodafinil to see how well it works in reducing cancer-related fatigue in patients with high grade glioma. Armodafinil may help relieve fatigue in patients with high grade glioma. |

  18. High-grade ovarian cancer secreting effective exosomes in tumor angiogenesis.

    PubMed

    Yi, Huan; Ye, Jun; Yang, Xiao-Mei; Zhang, Li-Wen; Zhang, Zhi-Gang; Chen, Ya-Ping

    2015-01-01

    Ovarian cancer, the most lethal gynecological cancer, related closely to tumor stage. High-grade ovarian cancer always results in a late diagnose and high recurrence, which reduce survival within five years. Until recently, curable therapy is still under research and anti-angiogenesis proves a promising way. Tumor-derived exosomes are essential in tumor migration and metastases such as angiogenesis is enhanced by exosomes. In our study, we have made comparison between high-grade and unlikely high-grade serous ovarian cancer cells on exosomal function of endothelial cells proliferation, migration and tube formation. Exosomes derived from high-grade ovarian cancer have a profound impact on angiogenesis with comparison to unlikely high-grade ovarian cancer. Proteomic profiles revealed some potential proteins involved in exosomal function of angiogenesis such as ATF2, MTA1, ROCK1/2 and so on. Therefore, exosomes plays an influential role in angiogenesis in ovarian serous cancer and also function more effectively in high-grade ovarian cancer cells.

  19. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo

    PubMed Central

    Saunders, Laura R.; Bankovich, Alexander J.; Anderson, Wade C.; Aujay, Monette A.; Bheddah, Sheila; Black, KristenAnn; Desai, Radhika; Escarpe, Paul A.; Hampl, Johannes; Laysang, Amy; Liu, David; Lopez-Molina, Javier; Milton, Milly; Park, Albert; Pysz, Marybeth A.; Shao, Hui; Slingerland, Brian; Torgov, Michael; Williams, Samuel A.; Foord, Orit; Howard, Philip; Jassem, Jacek; Badzio, Andrzej; Czapiewski, Piotr; Harpole, David H.; Dowlati, Afshin; Massion, Pierre P.; Travis, William D.; Pietanza, M. Catherine; Poirier, J. T.; Rudin, Charles M.; Stull, Robert A.; Dylla, Scott J.

    2016-01-01

    The high-grade pulmonary neuroendocrine tumors, small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), remain among the most deadly malignancies. Therapies that effectively target and kill tumor-initiating cells (TICs) in these cancers should translate to improved patient survival. Patient-derived xenograft (PDX) tumors serve as excellent models to study tumor biology and characterize TICs. Increased expression of delta-like 3 (DLL3) was discovered in SCLC and LCNEC PDX tumors and confirmed in primary SCLC and LCNEC tumors. DLL3 protein is expressed on the surface of tumor cells but not in normal adult tissues. A DLL3-targeted antibody-drug conjugate (ADC), SC16LD6.5, comprised of a humanized anti-DLL3 monoclonal antibody conjugated to a DNA-damaging pyrrolobenzodiazepine (PBD) dimer toxin, induced durable tumor regression in vivo across multiple PDX models. Serial transplantation experiments executed with limiting dilutions of cells provided functional evidence confirming that the lack of tumor recurrence after SC16LD6.5 exposure resulted from effective targeting of DLL3-expressing TICs. In vivo efficacy correlated with DLL3 expression, and responses were observed in PDX models initiated from patients with both limited and extensive-stage disease and were independent of their sensitivity to standard-of-care chemotherapy regimens. SC16LD6.5 effectively targets and eradicates DLL3-expressing TICs in SCLC and LCNEC PDX tumors and is a promising first-in-class ADC for the treatment of high-grade pulmonary neuroendocrine tumors. PMID:26311731

  20. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo.

    PubMed

    Saunders, Laura R; Bankovich, Alexander J; Anderson, Wade C; Aujay, Monette A; Bheddah, Sheila; Black, KristenAnn; Desai, Radhika; Escarpe, Paul A; Hampl, Johannes; Laysang, Amy; Liu, David; Lopez-Molina, Javier; Milton, Milly; Park, Albert; Pysz, Marybeth A; Shao, Hui; Slingerland, Brian; Torgov, Michael; Williams, Samuel A; Foord, Orit; Howard, Philip; Jassem, Jacek; Badzio, Andrzej; Czapiewski, Piotr; Harpole, David H; Dowlati, Afshin; Massion, Pierre P; Travis, William D; Pietanza, M Catherine; Poirier, J T; Rudin, Charles M; Stull, Robert A; Dylla, Scott J

    2015-08-26

    The high-grade pulmonary neuroendocrine tumors, small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), remain among the most deadly malignancies. Therapies that effectively target and kill tumor-initiating cells (TICs) in these cancers should translate to improved patient survival. Patient-derived xenograft (PDX) tumors serve as excellent models to study tumor biology and characterize TICs. Increased expression of delta-like 3 (DLL3) was discovered in SCLC and LCNEC PDX tumors and confirmed in primary SCLC and LCNEC tumors. DLL3 protein is expressed on the surface of tumor cells but not in normal adult tissues. A DLL3-targeted antibody-drug conjugate (ADC), SC16LD6.5, comprised of a humanized anti-DLL3 monoclonal antibody conjugated to a DNA-damaging pyrrolobenzodiazepine (PBD) dimer toxin, induced durable tumor regression in vivo across multiple PDX models. Serial transplantation experiments executed with limiting dilutions of cells provided functional evidence confirming that the lack of tumor recurrence after SC16LD6.5 exposure resulted from effective targeting of DLL3-expressing TICs. In vivo efficacy correlated with DLL3 expression, and responses were observed in PDX models initiated from patients with both limited and extensive-stage disease and were independent of their sensitivity to standard-of-care chemotherapy regimens. SC16LD6.5 effectively targets and eradicates DLL3-expressing TICs in SCLC and LCNEC PDX tumors and is a promising first-in-class ADC for the treatment of high-grade pulmonary neuroendocrine tumors.

  1. Siegesbeckia orientalis Extract Inhibits TGFβ1-Induced Migration and Invasion of Endometrial Cancer Cells.

    PubMed

    Chang, Chi-Chang; Ling, Xue-Hua; Hsu, Hsia-Fen; Wu, Jing-Mei; Wang, Chao-Ping; Yang, Jyh-Ferng; Fang, Li-Wen; Houng, Jer-Yiing

    2016-08-05

    Type II endometrial carcinoma typically exhibits aggressive metastasis and results in a poor prognosis. Siegesbeckia orientalis Linne is a traditional Chinese medicinal herb with several medicinal benefits, including the cytotoxicity against various cancers. This study investigates the inhibitory effects of S. orientalis ethanol extract (SOE) on the migration and invasion of endometrial cancer cells, which were stimulated by transforming growth factor β (TGFβ). The inhibitory effects were evaluated by determining wound healing and performing the Boyden chamber assay. This study reveals that SOE can inhibit TGFβ1-induced cell wound healing, cell migration, and cell invasion in a dose-dependent manner in RL95-2 and HEC-1A endometrial cancer cells. SOE also reversed the TGFβ1-induced epithelial-mesenchymal transition, including the loss of the cell-cell junction and the lamellipodia-like structures. Western blot analysis revealed that SOE inhibited the phosphorylation of ERK1/2, JNK1/2, and Akt, as well as the expression of MMP-9, MMP-2, and u-PA in RL95-2 cells dose-dependently. The results of this investigation suggest that SOE is a potential anti-metastatic agent against human endometrial tumors.

  2. MicroRNA-134 suppresses endometrial cancer stem cells by targeting POGLUT1 and Notch pathway proteins.

    PubMed

    Gao, Yongtao; Liu, Te; Huang, Yongyi

    2015-01-16

    We aimed to ascertain the role of microRNAs (miRNAs) in regulating human endometrial cancer stem cells (HuECSCs). The expression level of miRNA-134 (miR-134), a member of the DLK1-DIO3 genomic imprinted miRNA cluster, differed significantly between HuECSCs and human endometrial cancer cells (HuECCs). miR-134 inhibited HuECSCs proliferation and migration by targeting protein O-glucosyltransferase 1 (POGLUT1) expression. Exogenous miR-134 overexpression downregulated POGLUT1 and Notch pathway proteins in HuECSCs in vitro. miR-134 overexpression affected the G2/M phase of HuECSCs and suppressed the growth of xenograft tumours formed. Thus, endogenous miR-134 regulation in HuECSCs may suppress tumourigenesis in human endometrial carcinoma.

  3. Adenoid Cystic Carcinoma of the Uterine Cervix: A Report of 2 Cases

    PubMed Central

    Kharmoum, Jinane; Ech-Charif, Soumaya; El Khannoussi, Basma

    2017-01-01

    Adenoid cystic carcinoma is malignant tumor that exceptionally occurs in the uterine cervix. It is mostly seen in postmenopausal women and has an aggressive clinical course. We report two cases of an adenoid cystic carcinoma associated with a high grade squamous intraepithelial lesion and invasive squamous cell carcinoma of the uterine cervix and discuss briefly its clinical and pathological characteristics. PMID:28348909

  4. Endometrial receptivity array: Clinical application

    PubMed Central

    Mahajan, Nalini

    2015-01-01

    Human implantation is a complex process requiring synchrony between a healthy embryo and a functionally competent or receptive endometrium. Diagnosis of endometrial receptivity (ER) has posed a challenge and so far most available tests have been subjective and lack accuracy and a predictive value. Microarray technology has allowed identification of the transcriptomic signature of the window of receptivity window of implantation (WOI). This technology has led to the development of a molecular diagnostic tool, the ER array (ERA) for diagnosis of ER. Use of this test in patients with recurrent implantation failure (RIF) has shown that the WOI is displaced in a quarter of these patients and use of a personalized embryo transfer (pET) on the day designated by ERA improves reproductive performance. Our results in the Indian population revealed an endometrial factor in 27.5% RIF patients, which was significantly greater than the non-RIF group 15% (P = 0.04). After pET, the overall ongoing pregnancy rate was 42.4% and implantation rate was 33%, which was at par with our in-vitro fertilization results over 1-year. We also performed ERA in patients with persistently thin endometrium, and it was reassuring to find that the endometrium in 75% of these patients was receptive despite being 6 mm or less. A pregnancy rate of 66.7% was achieved in this group. Though larger studies are required to validate these results ERA has become a useful tool in our diagnostic armamentarium for ER. PMID:26538853

  5. Cytogenetic and molecular profile of endometrial stromal sarcoma.

    PubMed

    Micci, Francesca; Gorunova, Ludmila; Agostini, Antonio; Johannessen, Lene E; Brunetti, Marta; Davidson, Ben; Heim, Sverre; Panagopoulos, Ioannis

    2016-11-01

    Recent cytogenetic and molecular investigations have improved our understanding of endometrial stromal tumors, including sarcomas (ESS), and helped redefine their classification into more pathogenetically meaningful categories. Because much more can be gained through such studies, we add information on another 22 ESS examined by karyotyping, PCR analysis, expression array analysis, and transcriptome sequencing. In spite of the known preference for certain pathogenetic pathways, we found considerable genetic heterogeneity in high-grade (HG) as well as in low-grade (LG) ESS. Not all HG tumors showed a YWHAE-NUTM chimeric transcript and as many as six LGESS showed no hitherto known ESS-related fusions. Among the transcripts identified by transcriptome sequencing and verified by Sanger sequencing, new variants of ZC3H7-BCOR and its reciprocal BCOR-ZC3H7 were identified as was involvement of the CREBBP and MLLT4 genes (both well known leukemia-related genes) in two new fusions. FISH analysis identified a known EPC1-PHF1 fusion which led to the identification of a new variant at the molecular level. The fact that around 70 genes were found differentially expressed, by microarray analysis, when comparing LGESS showing ESS-related fusions with LGESS without such transcripts, underscores the biochemical importance of the observed genetic heterogeneity and hints that new subgroups/entities in LGESS still remain undiscovered. © 2016 The Authors. Genes, Chromosomes & Cancer Published by Wiley Periodicals, Inc.

  6. Treatment of Endometrial Cancer in Patient with Malignant Obesity

    PubMed Central

    Popovic, Miroslav D.; Banicevic, Arnela Ceric; Popovic, Biljana; Ceric, Amela; Banicevic, Andrija; Popadic, Danijela

    2014-01-01

    ABSTRACT Our 60-year-old patient menarche in 13-year, two delivery, last menstruation in 53-year, without uterine bleeding or any kind of symptomatology. The gynecological transvaginal ultrasound examination showed hyperplasio endometrii (20mm). After curettage, pathological examination was diagnostic polypus carcinomatoides. The patient with HTA and obesity was admitted to and operated on at the Gynecological Department due to endometrial carcinoma (FIGO stage IA1). Because of her giant obesity, BMI – 71.50 kg/m2, weight 219 kg and height 175cm, surgery by the abdominal approach was very difficult to perform, so vaginal hysterectomy was carried out. The procedure was completed within 127 minutes without any intraoperative complications. Blood loss was less than 100ml. The patient was discharged on postoperative day 7. The patient was followed up for 6 months after surgery. No complications or recurrence were reported during the 6-month follow up. PMID:24783920

  7. Predicting the risk of endometrial cancer in postmenopausal women presenting with vaginal bleeding: the Norwich DEFAB risk assessment tool

    PubMed Central

    Burbos, N; Musonda, P; Giarenis, I; Shiner, A M; Giamougiannis, P; Morris, E P; Nieto, J J

    2010-01-01

    Background: This study aimed to show the longitudinal use of routinely collected clinical data from history and ultrasound evaluation of the endometrium in developing an algorithm to predict the risk of endometrial carcinoma for postmenopausal women presenting with vaginal bleeding. Methods: This prospective study collected data from 3047 women presenting with postmenopausal bleeding. Data regarding the presence of risk factors for endometrial cancer was collected and univariate and multivariate analyses were performed. Results: Age distribution ranged from 35 to 97 years with a median of 59 years. A total of 149 women (5% of total) were diagnosed with endometrial carcinoma. Women in the endometrial cancer group were significantly more likely to be older, have higher BMI, recurrent episodes of bleeding, diabetes, hypertension, or a previous history of breast cancer. An investigator best model selection approach was used to select the best predictors of cancer, and using logistic regression analysis we created a model, ‘Norwich DEFAB', which is a clinical prediction rule for endometrial cancer. The calculated Norwich DEFAB score can vary from a value of 0 to 9. A Norwich DEFAB value equal to or greater than 3 has a positive predictive value (PPV) of 7.78% and negative predictive value (NPV) of 98.2%, whereas a score equal to or greater than 5 has a PPV of 11.9% and NPV of 97.8%. Conclusion: The combination of clinical information with our investigation tool for women with postmenopausal vaginal bleeding allows the clinician to calculate a predicted risk of endometrial malignancy and prioritise subsequent clinical investigations. PMID:20354525

  8. Prolonged survival among women with BRCA germline mutations and advanced endometrial cancer: a case series.

    PubMed

    Kwon, J S; Lenehan, J; Carey, M; Ainsworth, P

    2008-01-01

    It is unclear if BRCA mutation carriers diagnosed with advanced endometrial cancer have a better prognosis compared to sporadic cases. From a population database of BRCA1 and 2 mutation carriers in Southwestern Ontario, Canada, we identified three women with advanced-stage endometrial cancer. They were 57, 59, and 64 years of age, and of English/Scottish, Ashkenazi Jewish, and English heritage, respectively. They had different mutations in BRCA1 (Q1240X:C3837T; 68_69delAG; 1961delA). One had a sarcomatoid carcinoma and two had uterine papillary serous carcinoma. All had stage IVB disease, with surgery followed by adjuvant chemotherapy and/or radiotherapy. Follow-up has ranged from 3.3 to 14.6 years. They are still alive and well with no evidence of recurrent disease. This observation raises the question as to whether BRCA mutations may be associated with a better prognosis in patients with advanced endometrial cancer.

  9. Significance of a single CA 125 assay combined with ultrasound in the early detection of ovarian and endometrial cancer.

    PubMed

    Vuento, M H; Stenman, U H; Pirhonen, J P; Mäkinen, J I; Laippala, P J; Salmi, T A

    1997-01-01

    We evaluated the utility of a single CA 125 measurement in combination with transvaginal sonography for early detection of ovarian and endometrial cancer in asymptomatic postmenopausal women. A sample of peripheral blood was taken from 1291 apparently healthy postmenopausal women, who were examined by conventional and color Doppler ultrasound for early detection of ovarian and endometrial cancer. Serum CA 125 was determined in all samples 3 years later by the IMx CA 125 assay (Abbott Laboratories, Abbott Park, IL). The cutoff level based on the 99th percentile was 30 U/ml. Elevated values were controlled by repeat sonography and an additional determination of CA 125. Record linkage with the files of the Finnish Cancer Registry was performed 3 1/2 years after the primary sonographic screening. The mean CA 125 concentration was 8.1 U/ml (range 0-1410 U/ml). Fourteen of the 1291 women had a CA 125 level greater than 30 U/ml. None of these had signs of either endometrial or ovarian malignancy in the primary sonography screening. Among the other women three cases of endometrial carcinoma (all stage Ib) and one ovarian carcinoma (stage Ia with borderline malignancy) were detected by sonography. All these patients had a CA 125 value <30 U/ml, the mean value being 11.4 U/ml (range 7.5-16.7 U/ml). During follow-up of 3.5 years, one stage Ia ovarian carcinoma, one abdominal carcinomatosis, and two endometrial carcinomas (both stage Ib) were diagnosed. In these patients the mean value for CA 125 was 12.7 U/ml (range 2.5-30.9 U/ml) at the primary sonography screening. A single CA 125 measurement provides no advantage in the early detection of ovarian and endometrial cancer in asymptomatic postmenopausal women compared with transvaginal sonography. The vast majority of women with an elevated CA 125 value have some reason other than an ovarian or endometrial malignancy for this finding.

  10. Deubiquitinase USP9X deubiquitinates β-catenin and promotes high grade glioma cell growth

    PubMed Central

    Wang, Zhihao; Yang, Chunxu; Ouyang, Wen; Zhou, Fuxiang; Zhou, Yunfeng; Xie, Conghua

    2016-01-01

    β-catenin is a crucial signal transduction molecule in the Wnt/β-catenin signal pathway, and increased β-catenin expression has consistently been found in high grade gliomas. However, the mechanisms responsible for β-catenin overexpression have remained elusive. Here we show that the deubiquitinase USP9X stabilizes β-catenin and thereby promotes high grade glioma cell growth. USP9X binds β-catenin and removes the Lys 48-linked polyubiquitin chains that normally mark β-catenin for proteasomal degradation. Increased USP9X expression correlates with increased β-catenin protein in high grade glioma tissues. Moreover, patients with high grade glioma overexpressing USP9X have a poor prognosis. Knockdown of USP9X suppresses cell proliferation, inhibits G1/S phase conversion, and induces apoptosis in U251 and A172 cells. Interestingly, c-Myc and cyclinD1, which are important downstream target genes in the Wnt/β-catenin signal pathway, also show decreased expression in cells with siRNA-mediated down-regulation of USP9X. Down-regulation of USP9X also consistently inhibits the tumorigenicity of primary glioma cells in vivo. In summary, these results indicate that USP9X stabilizes β-catenin and activates Wnt/β-catenin signal pathway to promote glioma cell proliferation and survival. USP9X could also potentially be a novel therapeutic target for high grade gliomas. PMID:27783990

  11. Mammaglobin, a Valuable Diagnostic Marker for Metastatic Breast Carcinoma

    PubMed Central

    Wang, Zhiqiang; Spaulding, Betsy; Sienko, Anna; Liang, Yiaoming; Li, Hongbao; Nielsen, Gitte; Yub Gong, Gyung; Ro, Jae Y.; “Jim” Zhai, Qihui

    2009-01-01

    Identification of metastasis and occult micrometastases of breast cancer demands sensitive and specific diagnostic markers. In this study, we assessed the utility of a mouse monoclonal antibody to human mammaglobin for one such purpose. Immunohistochemical stains were performed on paraffin-embedded sections from a total of 284 cases, which consisted of primary breast invasive carcinomas (41 cases) with matched metastases to ipsilateral axillary lymph nodes, metastatic breast carcinoma to liver (1 case) and kidney (1 case), non-breast neoplasms (161 cases), and normal human tissues (39 cases). The results showed 31 of the 41 cases of primary breast cancer with axillary lymph node metastases were positive for mammaglobin (76%). In the meantime, we documented expression of mammaglobin in occasional cases of endometrial carcinoma (17%). Our data further validated that mammaglobin is a valuable diagnostic marker for metastatic carcinoma of breast origin, although endometrial carcinoma should be considered as a major differential diagnosis. PMID:19158935

  12. Transition between urothelial carcinoma in situ and non-invasive micropapillary carcinoma as a pivot connection between diverse morphologies of bladder carcinoma: a case report of urothelial carcinoma with villoglandular differentiation.

    PubMed

    Tajima, Shogo; Koda, Kenji

    2015-01-01

    Urothelial carcinoma has numerous histological variants, and these variants may coexist in a single case. Here, we present a case of a 70-year-old man with urothelial carcinoma of the bladder with a maximal diameter of 5 mm that involved micropapillary and plasmacytoid variants, with villoglandular differentiation. The presence of these variants was confirmed by pathological examination of a transurethral resection specimen, and high-grade urothelial carcinoma was found as a minor component. Although this bladder carcinoma was classified as pT1, cystoprostatectomy, urethrectomy, and lymphadenectomy were performed due to the presence of the micropapillary and plasmacytoid variants, which are known to be aggressive. Examination of a surgically resected specimen revealed no carcinoma. A transition between urothelial carcinoma in situ and non-invasive micropapillary carcinoma was found to be a pivot point connecting the diverse morphologies of this bladder carcinoma, from which there existed two pathways. One pathway was from urothelial carcinoma in situ to the plasmacytoid variant through invasive high-grade urothelial carcinoma, and the other was from non-invasive micropapillary carcinoma to urothelial carcinoma with villoglandular differentiation or to the micropapillary variant. This is the 16th reported case of urothelial carcinoma with villoglandular differentiation in the literature. As urothelial carcinoma with villoglandular differentiation is often associated with aggressive variants, as shown in our case, it should be reported whenever encountered in routine pathological practice.

  13. The epidemic of endometrial cancer: a commentary.

    PubMed Central

    Jick, H; Walker, A M; Rothman, K J

    1980-01-01

    Vital statistics show that a rise in incidence of endometrial cancer began in the mid-1960s on the West Coast of the United States. This rise was continuous and reached a peak in 1975. Elsewhere, incidence rates for endometrial cancer rose during the 1970s. It now seems evident that much of the rise in all areas of the country was due to replacement estrogen treatment. We estimated from data obtained from the Commission on Professional and Hospital Activities-Professional Activity Study of Ann Arbor, Michigan, that over 15,000 cases of endometrial cancer were caused by replacement estrogens during the five-year period 1971--1975 alone. This represents one of the largest epidemics of serious iatrogenic disease that has ever occurred in this country. With the substantial fall in estrogen sales starting in January 1976, there has been an associated decline in the incidence rates of endometrial cancer nationwide. PMID:7356090

  14. Treatment Options by Stage (Endometrial Cancer)

    MedlinePlus

    ... Stage II endometrial cancer. Cancer has spread into connective tissue of the cervix, but has not spread outside ... uterus. In stage II , cancer has spread into connective tissue of the cervix , but has not spread outside ...

  15. Indications and options for endometrial ablation.

    PubMed

    2008-11-01

    Endometrial ablation is an effective therapeutic option for the management of menorrhagia in properly selected patients. Hysteroscopic and non-hysteroscopic techniques offer similar rates of symptom relief and patient satisfaction.

  16. Molecular Biology and Prevention of Endometrial Cancer

    DTIC Science & Technology

    2006-07-01

    and analyzed, which would most likely take an additional 3-6 months after enrollment. Aim 2: To analyze vaginal and cervical adenocarcinomas...Endometrial Cancer PRINCIPAL INVESTIGATOR: LTC George Larry Maxwell, M.D. CONTRACTING ORGANIZATION: Henry M. Jackson Foundation for...Annual 3. DATES COVERED 117 Jun 2005 – 16 Jun 2006 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Molecular Biology and Prevention of Endometrial Cancer

  17. Revised FIGO staging system for endometrial cancer.

    PubMed

    Lewin, Sharyn N

    2011-06-01

    In 1988 the International Federation of Gynecologists and Obstetricians (FIGO) developed a surgical staging system for endometrial cancer. The FIGO staging system was recently revised in 2009 to reflect our growing understanding of the natural history of endometrial cancer. In this review, we describe the revised 2009 FIGO staging system for tumors of the uterine corpus and examine the effect of the new changes in the staging criteria.

  18. Research and development of intelligent controller for high-grade sanitary ware

    NASA Astrophysics Data System (ADS)

    Bao, Kongjun; Shen, Qingping

    2013-03-01

    With the social and economic development and people's living standards improve, more and more emphasis on modern society, people improve the quality of family life, the use of intelligent controller applications in high-grade sanitary ware physiotherapy students. Analysis of high-grade sanitary ware physiotherapy common functions pointed out in the production and use of the possible risks, proposed implementation of the system hardware and matching, given the system software implementation process. High-grade sanitary ware physiotherapy intelligent controller not only to achieve elegant and beautiful, simple, physical therapy, water power, deodorant, multi-function, intelligent control, to meet the consumers, the high-end sanitary ware market, strong demand, Accelerate the enterprise product Upgrade and improve the competitiveness of enterprises.

  19. Oral undifferentiated high-grade pleomorphic sarcoma: report of a case.

    PubMed

    Alfredo, Edson; de Pádua, Joubert Magalhães; Vicentini, Eduardo Luis; Marchesan, Melissa Andreia; Comelli Lia, Raphael Carlos; da Cruz Perez, Danyel Elias; Silva-Sousa, Yara Teresinha Corrêa

    2008-01-01

    The current World Health Organization classification considers the existence of an undifferentiated unclassifiable category of pleomorphic sarcomas, defined as a group of pleomorphic high-grade sarcomas. Undifferentiated high-grade pleomorphic sarcoma represents about 5% of all soft tissue sarcomas in adults and occurs more commonly in the extremities. In the oral cavity, undifferentiated pleomorphic sarcoma is extremely rare. We report a case of undifferentiated high-grade pleomorphic sarcoma located in the floor of the mouth in a man 56 years old. Microscopically, spindle-shaped cells with accented pleomorphism arranged in a storiform pattern, several bizarre giant cells, and frequent atypical mitoses were observed. The tumor cells were positive only for vimentin, with focal positivity for CD68. The patient was treated by surgery and postoperative radiation therapy, and after 25 months, no recurrence was observed.

  20. Incidental serous tubal intraepithelial carcinoma and early invasive serous carcinoma in the nonprophylactic setting: analysis of a case series.

    PubMed

    Morrison, Jane C; Blanco, Luis Z; Vang, Russell; Ronnett, Brigitte M

    2015-04-01

    A precursor for invasive ovarian/pelvic high-grade serous carcinoma, termed serous tubal intraepithelial carcinoma (STIC), has been identified and characterized through careful analysis of the fallopian tubes in both prophylactic salpingo-oophorectomy specimens obtained from women with either a family history of breast and/or ovarian cancer or germline mutations of BRCA1 and BRCA2 and in cases of pelvic high-grade serous carcinoma. Data on incidental STICs and clinically occult microscopic invasive high-grade serous carcinomas are limited. We analyzed the clinicopathologic features of 22 cases, including 15 pure STICs and 7 STICs associated with microscopic invasive high-grade serous carcinomas, identified incidentally in fallopian tubes removed for nonprophylactic indications. Patient age ranged from 39 to 79 years (mean: 62.7; median: 61), with only 1 patient under the age of 50. No patients were known to carry BRCA1 or BRCA2 mutations. Of the 12 pure STICs for which the location in the fallopian tube could be established, 9 were in the fimbriated portion, 1 was at the junction of the fimbria and infundibulum, and 2 were in the nonfimbriated tube. Of the 7 STICs with associated invasive high-grade serous carcinoma, 3 were located in the fimbriated portion, 2 were at the junction of the fimbria and infundibulum, and 2 were in the nonfimbriated tube. The invasive components were in the fallopian tube in 6 cases, 4 in subepithelial stroma of tubal mucosa, and 2 as an intramucosal (exophytic) luminal lesion without invasion of underlying subepithelial stroma (size range: 1 to 4 mm). The remaining case had a microscopic focus of high-grade serous carcinoma within the ipsilateral ovary (1.3 mm cortical focus) identified only on deeper sections, without an associated invasive component in the fallopian tube. The preferential finding of atypical epithelium with the cytologic features of high-grade serous carcinoma, namely STIC, in the fallopian tubes rather than the

  1. Circulating Adiponectin and Risk of Endometrial Cancer

    PubMed Central

    Zheng, Qiaoli; Wu, Haijian; Cao, Jiang

    2015-01-01

    Background Adiponectin is an insulin-sensitizing hormone produced by adipocytes. It has been suggested to be involved in endometrial tumorigenesis. Published data have shown inconsistent results for the association between circulating adiponectin levels and endometrial cancer. In this study, we conducted a meta-analysis to evaluate the predictive value of circulating adiponectin levels on the development of endometrial cancer. Methods PubMed, Embase, ISI web of knowledge, and Cochrane databases were searched for all eligible studies, and the summary relative risk (SRR) was calculated. Additionally, we performed dose-response analysis with eight eligible studies. Results A total of 1,955 cases and 3,458 controls from 12 studies were included. The SRR for the ‘highest’ vs ‘lowest’ adiponectin levels indicated high adiponectin level reduced the risk of endometrial cancer [SRR = 0.40, 95% confidence interval (CI), 0.33–0.66]. Results from the subgroup analyses were consistent with the overall analysis. The SRR for each 1 µg/ml increase of adiponectin indicated a 3% reduction in endometrial cancer risk (95% CI: 2%–4%), and a 14% reduction for each increase of 5 µg/ml (95% CI: 9%–19%). No evidence of publication bias was found. Conclusions This meta-analysis demonstrates that low level of circulating adiponectin is a risk factor for endometrial cancer. PMID:26030130

  2. Human Endometrial Adenocarcinoma Transplanted into Nude Mice: Growth Regulation by Estradiol

    NASA Astrophysics Data System (ADS)

    Satyaswaroop, P. G.; Zaino, R. J.; Mortel, R.

    1983-01-01

    A model for studying the growth of primary tumors of human endometrium and its regulation by 17β -estradiol has been developed in which ovariectomized nude mice are used as recipients. The receptors for sex steroids are maintained during serial transplantation of the tumor in this system. Although the rate of growth of receptor-negative endometrial tumors transplanted into ovariectomized nude mice is unaffected by the sustained presence or absence of estradiol, the growth of receptor-positive tumors is significantly increased by estradiol. Receptor-positive tumors treated with estradiol produced elevated concentrations of progesterone receptor. That the progesterone receptor is functional in this tumor is evident from the induction of estradiol 17β -dehydrogenase activity upon progestin administration. These findings are consistent with receptor-mediated regulation of growth of endometrial carcinoma.

  3. Genomic aberrations of BRCA1-mutated fallopian tube carcinomas.

    PubMed

    Hunter, Sally M; Ryland, Georgina L; Moss, Phillip; Gorringe, Kylie L; Campbell, Ian G

    2014-06-01

    Intraepithelial carcinomas of the fallopian tube are putative precursors to high-grade serous carcinomas of the ovary and peritoneum. Molecular characterization of these early precursors is limited but could be the key to identifying tumor biomarkers for early detection. This study presents a genome-wide copy number analysis of occult fallopian tube carcinomas identified through risk-reducing prophylactic oophorectomy from three women with germline BRCA1 mutations, demonstrating that extensive genomic aberrations are already established at this early stage. We found no indication of a difference in the level of genomic aberration observed in fallopian tube carcinomas compared with high-grade serous ovarian carcinomas. These findings suggest that spread to the peritoneal cavity may require no or very little further tumor evolution, which raises the question of what is the real window of opportunity to detect high-grade serous peritoneal carcinoma arising from the fallopian tube before it spreads. Nonetheless, the similarity of the genomic aberrations to those observed in high-grade serous ovarian carcinomas suggests that genetic biomarkers identified in late-stage disease may be relevant for early detection.

  4. TP53 mutations, tetraploidy and homologous recombination repair defects in early stage high-grade serous ovarian cancer.

    PubMed

    Chien, Jeremy; Sicotte, Hugues; Fan, Jian-Bing; Humphray, Sean; Cunningham, Julie M; Kalli, Kimberly R; Oberg, Ann L; Hart, Steven N; Li, Ying; Davila, Jaime I; Baheti, Saurabh; Wang, Chen; Dietmann, Sabine; Atkinson, Elizabeth J; Asmann, Yan W; Bell, Debra A; Ota, Takayo; Tarabishy, Yaman; Kuang, Rui; Bibikova, Marina; Cheetham, R Keira; Grocock, Russell J; Swisher, Elizabeth M; Peden, John; Bentley, David; Kocher, Jean-Pierre A; Kaufmann, Scott H; Hartmann, Lynn C; Shridhar, Viji; Goode, Ellen L

    2015-08-18

    To determine early somatic changes in high-grade serous ovarian cancer (HGSOC), we performed whole genome sequencing on a rare collection of 16 low stage HGSOCs. The majority showed extensive structural alterations (one had an ultramutated profile), exhibited high levels of p53 immunoreactivity, and harboured a TP53 mutation, deletion or inactivation. BRCA1 and BRCA2 mutations were observed in two tumors, with nine showing evidence of a homologous recombination (HR) defect. Combined Analysis with The Cancer Genome Atlas (TCGA) indicated that low and late stage HGSOCs have similar mutation and copy number profiles. We also found evidence that deleterious TP53 mutations are the earliest events, followed by deletions or loss of heterozygosity (LOH) of chromosomes carrying TP53, BRCA1 or BRCA2. Inactivation of HR appears to be an early event, as 62.5% of tumours showed a LOH pattern suggestive of HR defects. Three tumours with the highest ploidy had little genome-wide LOH, yet one of these had a homozygous somatic frame-shift BRCA2 mutation, suggesting that some carcinomas begin as tetraploid then descend into diploidy accompanied by genome-wide LOH. Lastly, we found evidence that structural variants (SV) cluster in HGSOC, but are absent in one ultramutated tumor, providing insights into the pathogenesis of low stage HGSOC.

  5. Elafin drives poor outcome in high-grade serous ovarian cancers and basal-like breast tumors.

    PubMed

    Labidi-Galy, S I; Clauss, A; Ng, V; Duraisamy, S; Elias, K M; Piao, H-Y; Bilal, E; Davidowitz, R A; Lu, Y; Badalian-Very, G; Györffy, B; Kang, U-B; Ficarro, S; Ganesan, S; Mills, G B; Marto, J A; Drapkin, R

    2015-01-15

    High-grade serous ovarian carcinoma (HGSOC) and basal-like breast cancer (BLBC) share many features including TP53 mutations, genomic instability and poor prognosis. We recently reported that Elafin is overexpressed by HGSOC and is associated with poor overall survival. Here, we confirm that Elafin overexpression is associated with shorter survival in 1000 HGSOC patients. Elafin confers a proliferative advantage to tumor cells through the activation of the MAP kinase pathway. This mitogenic effect can be neutralized by RNA interference, specific antibodies and a MEK inhibitor. Elafin expression in patient-derived samples was also associated with chemoresistance and strongly correlates with bcl-xL expression. We extended these findings into the examination of 1100 primary breast tumors and six breast cancer cell lines. We observed that Elafin is overexpressed and secreted specifically by BLBC tumors and cell lines, leading to a similar mitogenic effect through activation of the MAP kinase pathway. Here too, Elafin overexpression is associated with poor overall survival, suggesting that it may serve as a biomarker and therapeutic target in this setting.

  6. Autophagy orchestrates adaptive responses to targeted therapy in endometrial cancer.

    PubMed

    Eritja, Núria; Chen, Bo-Juen; Rodríguez-Barrueco, Ruth; Santacana, Maria; Gatius, Sònia; Vidal, August; Martí, Maria Dolores; Ponce, Jordi; Bergadà, Laura; Yeramian, Andree; Encinas, Mario; Ribera, Joan; Reventós, Jaume; Boyd, Jeff; Villanueva, Alberto; Matias-Guiu, Xavier; Dolcet, Xavier; Llobet-Navàs, David

    2017-01-05

    Targeted therapies in endometrial cancer (EC) using kinase inhibitors rarely result in complete tumor remission and are frequently challenged by the appearance of refractory cell clones, eventually resulting in disease relapse. Dissecting adaptive mechanisms is of vital importance to circumvent clinical drug resistance and improve the efficacy of targeted agents in EC. Sorafenib is an FDA-approved multitarget tyrosine and serine/threonine kinase inhibitor currently used to treat hepatocellular carcinoma, advanced renal carcinoma and radioactive iodine-resistant thyroid carcinoma. Unfortunately, sorafenib showed very modest effects in a multi-institutional phase II trial in advanced uterine carcinoma patients. Here, by leveraging RNA-sequencing data from the Cancer Cell Line Encyclopedia and cell survival studies from compound-based high-throughput screenings we have identified the lysosomal pathway as a potential compartment involved in the resistance to sorafenib. By performing additional functional biology studies we have demonstrated that this resistance could be related to macroautophagy/autophagy. Specifically, our results indicate that sorafenib triggers a mechanistic MAPK/JNK-dependent early protective autophagic response in EC cells, providing an adaptive response to therapeutic stress. By generating in vivo subcutaneous EC cell line tumors, lung metastatic assays and primary EC orthoxenografts experiments, we demonstrate that targeting autophagy enhances sorafenib cytotoxicity and suppresses tumor growth and pulmonary metastasis progression. In conclusion, sorafenib induces the activation of a protective autophagic response in EC cells. These results provide insights into the unopposed resistance of advanced EC to sorafenib and highlight a new strategy for therapeutic intervention in recurrent EC.

  7. Autophagy orchestrates adaptive responses to targeted therapy in endometrial cancer

    PubMed Central

    Eritja, Núria; Chen, Bo-Juen; Rodríguez-Barrueco, Ruth; Santacana, Maria; Gatius, Sònia; Vidal, August; Martí, Maria Dolores; Ponce, Jordi; Bergadà, Laura; Yeramian, Andree; Encinas, Mario; Ribera, Joan; Reventós, Jaume; Boyd, Jeff; Villanueva, Alberto; Matias-Guiu, Xavier; Dolcet, Xavier

    2017-01-01

    ABSTRACT Targeted therapies in endometrial cancer (EC) using kinase inhibitors rarely result in complete tumor remission and are frequently challenged by the appearance of refractory cell clones, eventually resulting in disease relapse. Dissecting adaptive mechanisms is of vital importance to circumvent clinical drug resistance and improve the efficacy of targeted agents in EC. Sorafenib is an FDA-approved multitarget tyrosine and serine/threonine kinase inhibitor currently used to treat hepatocellular carcinoma, advanced renal carcinoma and radioactive iodine-resistant thyroid carcinoma. Unfortunately, sorafenib showed very modest effects in a multi-institutional phase II trial in advanced uterine carcinoma patients. Here, by leveraging RNA-sequencing data from the Cancer Cell Line Encyclopedia and cell survival studies from compound-based high-throughput screenings we have identified the lysosomal pathway as a potential compartment involved in the resistance to sorafenib. By performing additional functional biology studies we have demonstrated that this resistance could be related to macroautophagy/autophagy. Specifically, our results indicate that sorafenib triggers a mechanistic MAPK/JNK-dependent early protective autophagic response in EC cells, providing an adaptive response to therapeutic stress. By generating in vivo subcutaneous EC cell line tumors, lung metastatic assays and primary EC orthoxenografts experiments, we demonstrate that targeting autophagy enhances sorafenib cytotoxicity and suppresses tumor growth and pulmonary metastasis progression. In conclusion, sorafenib induces the activation of a protective autophagic response in EC cells. These results provide insights into the unopposed resistance of advanced EC to sorafenib and highlight a new strategy for therapeutic intervention in recurrent EC. PMID:28055301

  8. Treatment of ductal carcinoma in situ: an uncertain harm-benefit balance.

    PubMed

    2013-12-01

    lumpectomy can both result in persistent pain, which is severe in about 13% of women. Systematic reviews of data for more than 10 000 women have shown that the following factors are statistically associated with an increased risk of recurrence after lumpectomy: age less than 50 years at diagnosis, tumours larger than 25 mm, high-grade tumours, and comedo-type necrosis. Healthy surgical margins of at least 2 mm are associated with a lower risk of recurrence. The impact of radiation therapy after lumpectomy for ductal carcinoma in situ has been evaluated in four randomised trials including a total of 3925 women. Radiation therapy reduced the risk of recurrence but did not prevent death from breast cancer. Irradiation carries a risk of skin burns and long-term cardiovascular and pulmonary toxicity. It also increases the risk of persistent post-surgical pain. In two randomised placebo-controlled trials of lumpectomy with or without radiation therapy for ductal carcinoma in situ, tamoxifen (an antiestrogen) did not affect either overall or breast cancer mortality, but it reduced the risk of recurrence by about one-quarter. Adverse effects of tamoxifen include venous thrombosis and pulmonary embolism, and endometrial cancer. In practice, women diagnosed with ductal carcinoma in situ have a number of options, none of which seems to have a clearly superior harm-benefit balance. Surgical excision reduces the risk of progression but can lead to persistent pain. Following radical mastectomy, the risk of breast cancer is similar to that of the general population. Lumpectomy is associated with a higher risk of recurrence and thus requires closer monitoring. Radiation therapy reduces the risk of recurrence in high-risk situations but has noteworthy adverse effects. Simple clinical monitoring is a valid option for asymptomatic patients: it carries a risk of progression to invasive cancer but avoids exposing many women to the adverse effects of surgery and radiation therapy.

  9. Estrogen promotes fat mass and obesity-associated protein nuclear localization and enhances endometrial cancer cell proliferation via the mTOR signaling pathway.

    PubMed

    Zhu, Yaping; Shen, Jiaqi; Gao, Liyan; Feng, Youji

    2016-04-01

    Extensive exposure to estrogen is generally acknowledged as a risk factor for endometrial cancer. Given that the accumulation of adipocytes also contributes to the increased production of estrogen, in the present study, we evaluated the expression of the fat mass and obesity-associated (FTO) gene in endometrial tumor tissues and further explored the mechanism of how estrogen facilitates FTO nuclear localization and promotes endometrial cancer cell proliferation. Immunohistochemical (IHC) staining assay was used to detect the FTO expression in endometrial tumor samples. Western blotting was performed to investigate the mechanism of estrogen-induced FTO nuclear localization. siRNA was used to knock down ERα and further explore its role in FTO nuclear localization. MTT assay was carried out to determine cell proliferation. We found that FTO was overexpressed in endometrial carcinoma tissues and served as a poor prognostic marker. Additionally, estrogen induced FTO nuclear accumulation via the mTOR signaling pathway and the nuclear localization was ERα-dependent, which contributed to enhanced proliferative activity. Therefore, the present study provides new insight into the mechanisms of estrogen-induced proliferation, implying the possibility of using FTO as a potential therapeutic target for the treatment of endometrial cancer.

  10. Study establishes basis for genomic classification of endometrial cancers

    Cancer.gov

    A comprehensive genomic analysis of nearly 400 endometrial tumors suggests that certain molecular characteristics – such as the frequency of mutations – could complement current pathology methods and help distinguish between principal types of endometrial

  11. Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology.

    PubMed

    Damrauer, Jeffrey S; Hoadley, Katherine A; Chism, David D; Fan, Cheng; Tiganelli, Christopher J; Wobker, Sara E; Yeh, Jen Jen; Milowsky, Matthew I; Iyer, Gopa; Parker, Joel S; Kim, William Y

    2014-02-25

    We sought to define whether there are intrinsic molecular subtypes of high-grade bladder cancer. Consensus clustering performed on gene expression data from a meta-dataset of high-grade, muscle-invasive bladder tumors identified two intrinsic, molecular subsets of high-grade bladder cancer, termed "luminal" and "basal-like," which have characteristics of different stages of urothelial differentiation, reflect the luminal and basal-like molecular subtypes of breast cancer, and have clinically meaningful differences in outcome. A gene set predictor, bladder cancer analysis of subtypes by gene expression (BASE47) was defined by prediction analysis of microarrays (PAM) and accurately classifies the subtypes. Our data demonstrate that there are at least two molecularly and clinically distinct subtypes of high-grade bladder cancer and validate the BASE47 as a subtype predictor. Future studies exploring the predictive value of the BASE47 subtypes for standard of care bladder cancer therapies, as well as novel subtype-specific therapies, will be of interest.

  12. [High-grade prostatic intraepithelial neoplasia: state-of-the-art].

    PubMed

    Allina, D O; Andreeva, Iu Iu; Zavalishina, L E; Kekeeva, T V; Frank, G A

    2015-01-01

    According to current views, high-grade prostatic intraepithelial neoplasia is the most likely precursor of prostate adenocarcinoma. This review gives the latest data of genetic, proteomic, and morphological analyses of this neoplasia and touches upon the probems that might arise when searching for new markers for differential diagnosis and prognosis estimation.

  13. Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer

    PubMed Central

    Moran-Jones, Kim; Gloss, Brian S.; Murali, Rajmohan; Chang, David K.; Colvin, Emily K.; Jones, Marc D.; Yuen, Samuel; Howell, Viive M.; Brown, Laura M.; Wong, Carol W.; Spong, Suzanne M.; Scarlett, Christopher J.; Hacker, Neville F.; Ghosh, Sue; Mok, Samuel C.; Birrer, Michael J.; Samimi, Goli

    2015-01-01

    Ovarian cancer is the most common cause of death among women with gynecologic cancer. We examined molecular profiles of fibroblasts from normal ovary and high-grade serous ovarian tumors to identify novel therapeutic targets involved in tumor progression. We identified 2,300 genes that are significantly differentially expressed in tumor-associated fibroblasts. Fibroblast expression of one of these genes, connective tissue growth factor (CTGF), was confirmed by immunohistochemistry. CTGF protein expression in ovarian tumor fibroblasts significantly correlated with gene expression levels. CTGF is a secreted component of the tumor microenvironment and is being pursued as a therapeutic target in pancreatic cancer. We examined its effect in in vitro and ex vivo ovarian cancer models, and examined associations between CTGF expression and clinico-pathologic characteristics in patients. CTGF promotes migration and peritoneal adhesion of ovarian cancer cells. These effects are abrogated by FG-3019, a human monoclonal antibody against CTGF, currently under clinical investigation as a therapeutic agent. Immunohistochemical analyses of high-grade serous ovarian tumors reveal that the highest level of tumor stromal CTGF expression was correlated with the poorest prognosis. Our findings identify CTGF as a promoter of peritoneal adhesion, likely to mediate metastasis, and a potential therapeutic target in high-grade serous ovarian cancer. These results warrant further studies into the therapeutic efficacy of FG-3019 in high-grade serous ovarian cancer. PMID:26575166

  14. Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer.

    PubMed

    Moran-Jones, Kim; Gloss, Brian S; Murali, Rajmohan; Chang, David K; Colvin, Emily K; Jones, Marc D; Yuen, Samuel; Howell, Viive M; Brown, Laura M; Wong, Carol W; Spong, Suzanne M; Scarlett, Christopher J; Hacker, Neville F; Ghosh, Sue; Mok, Samuel C; Birrer, Michael J; Samimi, Goli

    2015-12-29

    Ovarian cancer is the most common cause of death among women with gynecologic cancer. We examined molecular profiles of fibroblasts from normal ovary and high-grade serous ovarian tumors to identify novel therapeutic targets involved in tumor progression. We identified 2,300 genes that are significantly differentially expressed in tumor-associated fibroblasts. Fibroblast expression of one of these genes, connective tissue growth factor (CTGF), was confirmed by immunohistochemistry. CTGF protein expression in ovarian tumor fibroblasts significantly correlated with gene expression levels. CTGF is a secreted component of the tumor microenvironment and is being pursued as a therapeutic target in pancreatic cancer. We examined its effect in in vitro and ex vivo ovarian cancer models, and examined associations between CTGF expression and clinico-pathologic characteristics in patients. CTGF promotes migration and peritoneal adhesion of ovarian cancer cells. These effects are abrogated by FG-3019, a human monoclonal antibody against CTGF, currently under clinical investigation as a therapeutic agent. Immunohistochemical analyses of high-grade serous ovarian tumors reveal that the highest level of tumor stromal CTGF expression was correlated with the poorest prognosis. Our findings identify CTGF as a promoter of peritoneal adhesion, likely to mediate metastasis, and a potential therapeutic target in high-grade serous ovarian cancer. These results warrant further studies into the therapeutic efficacy of FG-3019 in high-grade serous ovarian cancer.

  15. 40 CFR 246.200-2 - Recommended procedures: High-grade paper recovery from smaller offices.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... offices. The recovery of high-grade paper generated by office facilities of less than 100 office workers... paper recovery from smaller offices. 246.200-2 Section 246.200-2 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID WASTES SOURCE SEPARATION FOR MATERIALS RECOVERY GUIDELINES...

  16. The obesity-associated polymorphisms FTO rs9939609 and MC4R rs17782313 and endometrial cancer risk in non-Hispanic white women.

    PubMed

    Lurie, Galina; Gaudet, Mia M; Spurdle, Amanda B; Carney, Michael E; Wilkens, Lynne R; Yang, Hannah P; Weiss, Noel S; Webb, Penelope M; Thompson, Pamela J; Terada, Keith; Setiawan, Veronica Wendy; Rebbeck, Timothy R; Prescott, Jennifer; Orlow, Irene; O'Mara, Tracy; Olson, Sara H; Narod, Steven A; Matsuno, Rayna K; Lissowska, Jolanta; Liang, Xiaolin; Levine, Douglas A; Le Marchand, Loic; Kolonel, Laurence N; Henderson, Brian E; Garcia-Closas, Montserrat; Doherty, Jennifer Anne; De Vivo, Immaculata; Chen, Chu; Brinton, Louise A; Akbari, Mohammad R; Goodman, Marc T

    2011-02-08

    Overweight and obesity are strongly associated with endometrial cancer. Several independent genome-wide association studies recently identified two common polymorphisms, FTO rs9939609 and MC4R rs17782313, that are linked to increased body weight and obesity. We examined the association of FTO rs9939609 and MC4R rs17782313 with endometrial cancer risk in a pooled analysis of nine case-control studies within the Epidemiology of Endometrial Cancer Consortium (E2C2). This analysis included 3601 non-Hispanic white women with histologically-confirmed endometrial carcinoma and 5275 frequency-matched controls. Unconditional logistic regression models were used to assess the relation of FTO rs9939609 and MC4R rs17782313 genotypes to the risk of endometrial cancer. Among control women, both the FTO rs9939609 A and MC4R rs17782313 C alleles were associated with a 16% increased risk of being overweight (p = 0.001 and p = 0.004, respectively). In case-control analyses, carriers of the FTO rs9939609 AA genotype were at increased risk of endometrial carcinoma compared to women with the TT genotype [odds ratio (OR)  = 1.17; 95% confidence interval (CI): 1.03-1.32, p = 0.01]. However, this association was no longer apparent after adjusting for body mass index (BMI), suggesting mediation of the gene-disease effect through body weight. The MC4R rs17782313 polymorphism was not related to endometrial cancer risk (per allele OR = 0.98; 95% CI: 0.91-1.06; p = 0.68). FTO rs9939609 is a susceptibility marker for white non-Hispanic women at higher risk of endometrial cancer. Although FTO rs9939609 alone might have limited clinical or public health significance for identifying women at high risk for endometrial cancer beyond that of excess body weight, further investigation of obesity-related genetic markers might help to identify the pathways that influence endometrial carcinogenesis.

  17. Fine-needle sampling findings in 26 carcinoma ex pleomorphic adenomas: diagnostic pitfalls and clinical considerations.

    PubMed

    Klijanienko, J; El-Naggar, A K; Vielh, P

    1999-09-01

    Preoperative fine-needle samplings (FNS) of 26 histologically proven carcinoma ex pleomorphic adenomas (24 primary tumors and 2 local recurrences in 24 patients) were retrospectively reviewed in order to evaluate their cytologic characteristics. Histologically, 17 were high-grade and 9 were low-grade carcinomas; 10 carcinomas were intratumoral (in situ), and 16 were infiltrative. A cytologic diagnosis of malignancy was established in 13 (50%) cases, 2 (7.7%) were suspicious, and 11 (42.3%) were negative for malignancy (10 pleomorphic adenomas, 1 inflammation). The majority (76.5%) of high-grade carcinomas were correctly diagnosed by FNS, regardless of invasiveness. Paradoxically, most (77.8%) negative results were encountered in low-grade carcinomas. Accurate diagnosis of malignancy on FNS is achieved in high-grade tumors and low sensitivity may cause interpretative difficulties in low-grade tumors. Diagn. Cytopathol. 1999; 21:163-166.

  18. Combined cytotoxic effect of UV-irradiation and TiO2 microbeads in normal urothelial cells, low-grade and high-grade urothelial cancer cells.

    PubMed

    Imani, Roghayeh; Veranič, Peter; Iglič, Aleš; Kreft, Mateja Erdani; Pazoki, Meysam; Hudoklin, Samo

    2015-03-01

    The differentiation of urothelial cells results in normal terminally differentiated cells or by alternative pathways in low-grade or high-grade urothelial carcinomas. Treatments with traditional surgical and chemotherapeutical approaches are still inadequate and expensive, as bladder tumours are generally highly recurrent. In such situations, alternative approaches, using irradiation of the cells and nanoparticles, are promising. The ways in which urothelial cells, at different differentiation levels, respond to UV-irradiation (photolytic treatment) or to the combination of UV-irradiation and nanoparticles (photocatalytic treatment), are unknown. Here we tested cytotoxicity of UV-irradiation on (i) normal porcine urothelial cells (NPU), (ii) human low-grade urothelial cancer cells (RT4), and (iii) human high-grade urothelial cancer cells (T24). The results have shown that 1 minute of UV-irradiation is enough to kill 90% of the cells in NPU and RT4 cultures, as determined by the live/dead viability assay. On the other hand, the majority of T24 cells survived 1 minute of UV-irradiation. Moreover, even a prolonged UV-irradiation for 30 minutes killed <50% of T24 cells. When T24 cells were pre-supplemented with mesoporous TiO2 microbeads and then UV-irradiated, the viability of these high-grade urothelial cancer cells was reduced to <10%, which points to the highly efficient cytotoxic effects of TiO2 photocatalysis. Using electron microscopy, we confirmed that the mesoporous TiO2 microbeads were internalized into T24 cells, and that the cell's ultrastructure was heavily compromised after UV-irradiation. In conclusion, our results show major differences in the sensitivity to UV-irradiation among the urothelial cells with respect to cell differentiation. To achieve an increased cytotoxicity of urothelial cancer cells, the photocatalytic approach is recommended.

  19. Does the use of the 2009 FIGO classification of endometrial cancer impact on indications of the sentinel node biopsy?

    PubMed Central

    2010-01-01

    Background Lymphadenectomy is debated in early stages endometrial cancer. Moreover, a new FIGO classification of endometrial cancer, merging stages IA and IB has been recently published. Therefore, the aims of the present study was to evaluate the relevance of the sentinel node (SN) procedure in women with endometrial cancer and to discuss whether the use of the 2009 FIGO classification could modify the indications for SN procedure. Methods Eighty-five patients with endometrial cancer underwent the SN procedure followed by pelvic lymphadenectomy. SNs were detected with a dual or single labelling method in 74 and 11 cases, respectively. All SNs were analysed by both H&E staining and immunohistochemistry. Presumed stage before surgery was assessed for all patients based on MR imaging features using the 1988 FIGO classification and the 2009 FIGO classification. Results An SN was detected in 88.2% of cases (75/85 women). Among the fourteen patients with lymph node metastases one-half were detected by serial sectioning and immunohistochemical analysis. There were no false negative case. Using the 1988 FIGO classification and the 2009 FIGO classification, the correlation between preoperative MRI staging and final histology was moderate with Kappa = 0.24 and Kappa = 0.45, respectively. None of the patients with grade 1 endometrioid carcinoma on biopsy and IA 2009 FIGO stage on MR imaging exhibited positive SN. In patients with grade 2-3 endometrioid carcinoma and stage IA on MR imaging, the rate of positive SN reached 16.6% with an incidence of micrometastases of 50%. Conclusions The present study suggests that sentinel node biopsy is an adequate technique to evaluate lymph node status. The use of the 2009 FIGO classification increases the accuracy of MR imaging to stage patients with early stages of endometrial cancer and contributes to clarify the indication of SN biopsy according to tumour grade and histological type. PMID:20804553

  20. Association between intratumoral lymphatic microvessel density (LMVD) and clinicopathologic features in endometrial cancer: a retrospective cohort study

    PubMed Central

    2010-01-01

    Background Lymph node metastasis in endometrial cancer significantly decreases survival rate. Few data on the influence of intratumoral lymphatic microvessel density (LMVD) on survival in endometrial cancer are available. Our aim was to assess the intratumoral LMVD of endometrial carcinomas and to investigate its association with classical pathological factors, lymph node metastasis and survival. Methods Fifty-seven patients with endometrial carcinoma diagnosed between 2000 and 2008 underwent complete surgical staging and evaluation of intratumoral LMVD and other histologic variables. Lymphatic microvessels were identified by immunohistochemical staining using monoclonal antibody against human podoplanin (clone D2-40) and evaluated by counting the number of immunostained lymphatic vessels in 10 hot spot areas at 400× magnification. The LMVD was expressed by the mean number of vessels in these 10 hot spot microscopic fields. We next investigated the association of LMVD with the clinicopathologic findings and prognosis. Results The mean number of lymphatic vessels counted in all cases ranged between 0 and 4.7. The median value of mean LMVD was 0.5, and defined the cut-off for low and high LMVD. We identified low intratumoral LMVD in 27 (47.4%) patients and high LMVD in 30 (52.6%) patients. High intratumoral LMVD was associated with lesser miometrial and adnaexal infiltration, lesser cervical and peritoneal involvement, and fewer fatal cases. Although there was lower lymph node involvement among cases with high LMVD, the difference did not reach significance. No association was seen between LMVD and FIGO staging, histological type, or vascular invasion. On the other hand, low intratumoral LMVD was associated with poor outcome. Seventy-five percent of deaths occurred in patients with low intratumoral LMVD. Conclusion Our results show association of high intratumoral LMVD with features related to more localized disease and better outcome. We discuss the role of

  1. Body mass index, serum total cholesterol, and risk of gastric high-grade dysplasia

    PubMed Central

    Huang, Ya-Kai; Kang, Wei-Ming; Ma, Zhi-Qiang; Liu, Yu-Qin; Zhou, Li; Yu, Jian-Chun

    2016-01-01

    Abstract Obesity is related to an increased risk of gastric cardia cancer. However, the influences of excess body weight and serum total cholesterol on the risk of gastric high-grade dysplasia have not been fully characterized. A case–control study was conducted to explore the relationships between body mass index (BMI), serum total cholesterol level, and the risk of gastric high-grade dysplasia in Chinese adults. A total of 893 consecutive patients with gastric high-grade dysplasia (537 men and 356 women) and 902 controls (543 men and 359 women) were enrolled from January 2000 to October 2015. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated, and a multivariate analysis was conducted. After adjusting for age, alcohol consumption, smoking status, family history of gastric cancer or esophageal cancer, and serum total cholesterol level, a BMI ranging from 27.5 to 29.9 was significantly related to an increased risk of gastric high-grade dysplasia in both men (adjusted OR = 1.87, 95% CI = 1.24–2.81) and women (adjusted OR = 2.72, 95% CI = 1.44–5.16). The 2 highest BMI categories (27.5–29.9 and ≥30.0) were identified as risk factors for gastric cardia high-grade dysplasia in both men (BMI = 27.5–29.9: adjusted OR = 1.78, 95% CI = 1.02–3.10; BMI ≥ 30.0: adjusted OR = 2.54, 95% CI = 1.27–5.08) and women (BMI = 27.5–29.9: adjusted OR = 2.88, 95% CI = 1.27–6.55; BMI ≥ 30.0: adjusted OR = 2.77, 95% CI = 1.36–5.64), whereas only a BMI ranging from 27.5 to 29.9 was a risk factor for gastric noncardia high-grade dysplasia in both men (adjusted OR = 1.98, 95% CI = 1.25–3.14) and women (adjusted OR = 2.88, 95% CI = 1.43–5.81). In addition, higher serum total cholesterol was associated with an increased risk of gastric noncardia high-grade dysplasia (adjusted OR = 1.83, 95% CI = 1.25–2.69) in women. Increased BMI was associated with an increased risk

  2. γH2Ax Expression as a Potential Biomarker Differentiating between Low and High Grade Cervical Squamous Intraepithelial Lesions (SIL) and High Risk HPV Related SIL

    PubMed Central

    Kefala, Maria; Kottaridi, Christine; Spathis, Aris; Gouloumi, Alina-Roxani; Pouliakis, Abraham; Pappas, Asimakis; Sioulas, Vasileios; Chrelias, Charalambos; Karakitsos, Petros; Panayiotides, Ioannis

    2017-01-01

    Background γH2AX is a protein biomarker for double-stranded DNA breakage; its expression was studied in cervical squamous intraepithelial lesions and carcinomas. Methods Immunostaining for phospho-γH2AX was performed in sections from histologically confirmed cervical SIL and carcinomas, as well as from normal cervices used as controls. In total, 275 cases were included in the study: 112 low grade SIL (LGSIL), 99 high grade SIL (HGSIL), 24 squamous cell carcinoma (SCC), 12 adenocarcinoma and 28 cervical specimens with no essential lesions. Correlation of histological grading, high risk vs. low risk HPV virus presence, activated vs. non-activated status (by high risk HPV mRNA expression) and γH2AX expression in both basal and surface segments of the squamous epithelium was performed. Results Gradual increase of both basal and surface γH2AX expression was noted up from normal cervices to LGSIL harboring a low risk HPV type, to LGSIL harboring a high risk virus at a non-activated state (p<0.05). Thereafter, both basal and surface γH2AX expression dropped in LGSIL harboring a high risk virus at an activated state and in HGSIL. Conclusions γH2AX could serve as a potential biomarker discriminating between LGSIL and HGSIL, as well as between LGSIL harboring high risk HPV at an activated state. PMID:28118377

  3. Autologous bone marrow transplantation in poor-risk high-grade non-Hodgkin's lymphoma in first complete remission. Newcastle and Northern Lymphoma Group.

    PubMed Central

    Jackson, G. H.; Lennard, A. L.; Taylor, P. R.; Carey, P.; Angus, B.; Lucraft, H.; Evans, R. G.; Proctor, S. J.

    1994-01-01

    We report the safety and efficacy of autologous bone marrow transplantation (ABMT) in 30 patients with high-grade non-Hodgkin's lymphoma (NHL) in first complete remission (CR1) following remission induction chemotherapy. Two patients relapsed prior to ABMT. All patients were conditioned with high-dose melphalan. In Addition, ten received fractionated total body irradiation, one hemi-body irradiation and four high-dose etoposide. Unmanipulated non-cryopreserved autologous marrow was reinfused within 56 h of harvesting. Engraftment occurred in all patients with a median of 11 days of neutropenia (< 0.5 x 10(9) l-1), a median requirement for platelet transfusion of 3 days and packed red cell transfusion of 2 units, with a median hospital stay of 18 days post transplant. There was no procedure-related mortality and only minor morbidity was observed. Two patients relapsed at 1 and 2 months post transplantation, and one patient died of carcinoma of the lung 33 months after transplantation. The remaining 25 patients remain alive, well and in CR1 with a median follow-up of 44 months. The event-free survival at 3 years for all patients considered for ABMT was 83%. We conclude that ABMT for high-grade NHL in CR1 with non-cryopreserved marrow results in rapid haematological recovery without growth factor support. It is safe and is associated with high survival when used as consolidation of CR in high-risk patients. PMID:7521662

  4. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities

    SciTech Connect

    Gilks, C. Blake; Press, Joshua Z.; De Luca, Alessandro; Boyd, Niki; Young, Sean; Troussard, Armelle; Ridge, Yolanda; Kaurah, Pardeep; Kalloger, Steve E.; Blood, Katherine A.; Smith, Margaret; Spellman, Paul T.; Wang, Yuker; Miller, Dianne M.; Horsman, Doug; Faham, Malek; Gilks, C. Blake; Gray, Joe; Huntsman, David G.

    2008-05-02

    Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumors were high-grade serous or undifferentiated type. None of the endometrioid (n=5), clear cell (n=4), or low grade serous (n=2) carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumors with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic), BRCA1 loss (epigenetic), and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways.

  5. Ovarian carcinomas with genetic and epigenetic BRCA1 loss havedistinct molecular abnormalities

    SciTech Connect

    Press, Joshua Z.; De Luca, Alessandro; Boyd, Niki; Young, Sean; Troussard, Armelle; Ridge, Yolanda; Kaurah, Pardeep; Kalloger, Steve E.; Blood, Katherine A.; Smith, Margaret; Spellman, Paul T.; Wang, Yuker; Miller, Dianne M.; Horsman, Doug; Faham, Malek; Gilks, C. Blake; Gray,Joe; Huntsman, David G.

    2007-07-23

    Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumors were high-grade serous or undifferentiated type. None of the endometrioid (n = 5), clear cell (n = 4), or low grade serous (n = 2) carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumors with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic), BRCA1 loss (epigenetic), and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways.

  6. Endometrial stem cells in regenerative medicine.

    PubMed

    Verdi, Javad; Tan, Aaron; Shoae-Hassani, Alireza; Seifalian, Alexander M

    2014-01-01

    First described in 2004, endometrial stem cells (EnSCs) are adult stem cells isolated from the endometrial tissue. EnSCs comprise of a population of epithelial stem cells, mesenchymal stem cells, and side population stem cells. When secreted in the menstrual blood, they are termed menstrual stem cells or endometrial regenerative cells. Mounting evidence suggests that EnSCs can be utilized in regenerative medicine. EnSCs can be used as immuno-modulatory agents to attenuate inflammation, are implicated in angiogenesis and vascularization during tissue regeneration, and can also be reprogrammed into induced pluripotent stem cells. Furthermore, EnSCs can be used in tissue engineering applications and there are several clinical trials currently in place to ascertain the therapeutic potential of EnSCs. This review highlights the progress made in EnSC research, describing their mesodermal, ectodermal, and endodermal potentials both in vitro and in vivo.

  7. Chromophobe renal cell carcinoma with sarcomatoid transformation.

    PubMed

    Abrahams, Neil A; Ayala, Alberto G; Czerniak, Bogdan

    2003-10-01

    We present a rare case of a chromophobe renal cell carcinoma that progressed to a high-grade spindle cell sarcoma. The tumor affected a 50-year-old man who had presented with right upper quadrant discomfort and hematuria and subsequently underwent a right radical nephrectomy. Microscopically, the tumor was composed of two distinct components, a chromophobe renal cell carcinoma and a sarcomatoid component. The sarcomatoid component had exhibited aggressive behavior by spreading to a regional lymph node. This case report shows that chromophobe carcinoma can develop a sarcomatoid transformation with a high propensity for invasive growth and metastasis.

  8. Vaginal brachytherapy alone is sufficient adjuvant treatment of surgical stage I endometrial cancer

    SciTech Connect

    Solhjem, Matthew C. . E-mail: petersen.ivy@mayo.edu; Petersen, Ivy A.; Haddock, Michael G.

    2005-08-01

    Purpose To determine the efficacy and complications of adjuvant vaginal high-dose-rate brachytherapy alone for patients with Stage I endometrial cancer in whom complete surgical staging had been performed. Methods and Materials Between April 1998 and March 2004, 100 patients with Stage I endometrial cancer underwent surgical staging (total abdominal hysterectomy and bilateral salpingo-oophorectomy with pelvic {+-} paraaortic nodal sampling) and postoperative vaginal high-dose-rate brachytherapy at our institution. The total dose was 2100 cGy in three fractions. Results With a median follow-up of 23 months (range 2-62), no pelvic or vaginal recurrences developed. All patients underwent pelvic dissection, and 42% underwent paraaortic nodal dissection. A median of 29.5 pelvic nodes (range 1-67) was removed (84% had >10 pelvic nodes removed). Most patients (73%) had endometrioid (or unspecified) adenocarcinoma, 16% had papillary serous carcinoma, and 11% had other histologic types. The International Federation of Gynecology and Obstetrics stage and grade was Stage IA, grade III in 5; Stage IB, grade I, II, or III in 6, 27, or 20, respectively; and Stage IC, grade I, II, or III in 13, 17, or 10, respectively. The Common Toxicity Criteria (version 2.0) complications were mild (Grade 1-2) and consisted primarily of vaginal mucosal changes, temporary urinary irritation, and temporary diarrhea. Conclusion Adjuvant vaginal high-dose-rate brachytherapy alone may be a safe and effective alternative to pelvic external beam radiotherapy for surgical Stage I endometrial cancer.

  9. Postoperative vaginal radiation in endometrial cancer using a remote afterloading technique

    SciTech Connect

    Mandell, L.; Nori, D.; Anderson, L.; Hilaris, B.

    1985-03-01

    Carcinoma of the endometrium is the most common malignancy of the female genital tract. In early stage endometrial cancer, surgery remains the primary mode of treatment while radiation therapy plays an adjuvant role. Prophylactic vaginal radiation has been shown to reduce significantly the incidence of vaginal recurrences. Between the years 1969-1976, 330 patients with FIGO Stages I and II endometrial cancer were treated according to a standard departmental policy in which 40 Gy of external radiation was given to high risk Stage I and II patients in combination with surgery and intravaginal radiation. With this regimen, the mucosal surface received a total equivalent dose of 40 Gy. These treatments were given on an outpatient basis without the need for any sedation or analgesics. The minimum follow-up was 5 years, with a median follow-up of 8.5 years. The overall pelvic and/or vaginal recurrence rate was 2.7%. The incidence of vaginal complications was 3.7%. The advantages of a remote after loading technique in delivering vaginal vault radiation in endometrial cancer are discussed.

  10. Correlation Between E-cadherin Immunoexpression and Efficacy of First Line Platinum-Based Chemotherapy in Advanced High Grade Serous Ovarian Cancer.

    PubMed

    Miše, Branka Petrić; Telesmanić, Vesna Dobrić; Tomić, Snježana; Šundov, Dinka; Čapkun, Vesna; Vrdoljak, Eduard

    2015-04-01

    To analyze correlation between immunoexpression of E-cadherin and efficacy of first line platinum-based chemotherapy in patients with advanced-stage high-grade serous ovarian carcinoma. The expression of E-cadherin was analyzed immunohistochemically in formalin-fixed, paraffin-embedded samples from 98 patients with advanced-stage high-grade serous ovarian cancer and related to clinical features (stage according to the International Federation of Gynecology and Obstetrics (FIGO) and residual tumors after initial cytoreductive surgery), response to platinum-based chemotherapy (according to Response Evaluation Criteria in Solid tumors (RECIST 1.1 criteria)), platinum sensitivity (according to platinum free interval (PFI) as platinum-refractory, platinum-resistant and platinum-sensitive) and patients progression free survival (PFS) and overall survival (OS). E-cadherin immunostaining was positive in 74 and negative in 24 serous ovarian carcinomas. E-cadherin immunoreactivity was not associated with FIGO stage, residual tumor after initial cytoreductive surgery and number of chemotherapy cycles. Positive E-cadherin expression predict significantly better response to first line platinum-based chemotherapy (p < 0.001) and platinum sensitivity (p < 0.001). Moreover, positive E-cadherin expression predict significantly longer PFS (p < 0.001) and OS (p < 0.001). The multivariate analysis for OS showed that positive E-cadherin expression is predictor to platinum sensitivity (p < 0.001) and longer OS (p = 0.01). Positive E-cadherin expression seems to be a predictor of better response to first line platinum-based chemotherapy, platinum sensitivity and favorable clinical outcome in patients with advanced-stage serous ovarian cancer. Negative E-cadherin expression was shown to be significant, independent predictor of poorer PFS and OS. E-cadherin as a marker has predictive and prognostic value.

  11. Rare earth element patterns in Archean high-grade metasediments and their tectonic significance

    NASA Technical Reports Server (NTRS)

    Taylor, Stuart Ross; Rudnick, Roberta L.; Mclennan, Scott M.; Eriksson, Kenneth A.

    1986-01-01

    REE data on metasedimentary rocks from two different types of high-grade Archean terrains are presented and analyzed. The value of REEs as indicators of crustal evolution is explained; the three geologic settings (in North America, Southern Africa, and Australia) from which the samples were obtained are described; and the data are presented in extensive tables and graphs and discussed in terms of metamorphic effects, the role of accessory phases, provenance, and tectonic implications (recycling, the previous extent of high-grade terrains, and a model of Archean crustal growth). The diversity of REE patterns in shallow-shelf metasediments is attributed to local provenance, while the Eu-depleted post-Archean patterns are associated with K-rich plutons from small, stable early Archean terrains.

  12. Immunotherapy for high-grade glioma: how to go beyond Phase I/II clinical trials.

    PubMed

    van Gool, Stefaan

    2013-10-01

    Evaluation of: Lasky JL 3rd, Panosyan EH, Plant A et al. Autologous tumor lysate-pulsed dendritic cell immunotherapy for pediatric patients with newly diagnosed or recurrent high-grade gliomas. Anticancer Res. 33, 2047-2056 (2013). Immunotherapy for children and adults with high-grade glioma (HGG) is an emerging innovative treatment approach, which aims at stimulating the body's own immune system against HGG by using autologous dendritic cells pulsed with autologous tumor lysate as a therapeutic vaccine. This is the third report on immunotherapy for HGG in children, bringing additional knowledge and experience to the scientific community. However, at the same time, this and other manuscripts urge for the next step in treatment development.

  13. Cilengitide in Treating Younger Patients With Recurrent or Progressive High-Grade Glioma That Has Not Responded to Standard Therapy

    ClinicalTrials.gov

    2014-05-05

    Childhood High-grade Cerebellar Astrocytoma; Childhood High-grade Cerebral Astrocytoma; Recurrent Childhood Anaplastic Astrocytoma; Recurrent Childhood Anaplastic Oligoastrocytoma; Recurrent Childhood Anaplastic Oligodendroglioma; Recurrent Childhood Brain Tumor; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Glioblastoma; Recurrent Childhood Visual Pathway and Hypothalamic Glioma

  14. Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer

    PubMed Central

    Bowtell, David D.; Böhm, Steffen; Ahmed, Ahmed A.; Aspuria, Paul-Joseph; Bast, Robert C.; Beral, Valerie; Berek, Jonathan S.; Birrer, Michael J.; Blagden, Sarah; Bookman, Michael A.; Brenton, James; Chiappinelli, Katherine B.; Martins, Filipe Correia; Coukos, George; Drapkin, Ronny; Edmondson, Richard; Fotopoulou, Christina; Gabra, Hani; Galon, Jérôme; Gourley, Charlie; Heong, Valerie; Huntsman, David G.; Iwanicki, Marcin; Karlan, Beth Y.; Kaye, Allyson; Lengyel, Ernst; Levine, Douglas A.; Lu, Karen H.; McNeish, Iain A.; Menon, Usha; Narod, Steve A.; Nelson, Brad H.; Nephew, Kenneth P.; Pharoah, Paul; Powell, Daniel J.; Ramos, Pilar; Romero, Iris L.; Scott, Clare L.; Sood, Anil K.; Stronach, Euan A.; Balkwill, Frances R.

    2016-01-01

    High-grade serous ovarian cancer (HGSOC) accounts for 70-80% of ovarian cancer deaths, and overall survival has not changed significantly for several decades. In this Opinion article, we outline a set of research priorities that we believe will reduce incidence and improve outcomes for women with this disease. This ‘roadmap’ for HGSOC was determined after extensive discussions at an Ovarian Cancer Action meeting in January 2015. PMID:26493647

  15. Feasibility of Using Bevacizumab With Radiation Therapy and Temozolomide in Newly Diagnosed High-Grade Glioma

    SciTech Connect

    Narayana, Ashwatha Golfinos, John G.; Fischer, Ingeborg; Raza, Shahzad; Kelly, Patrick M.D.; Parker, Erik; Knopp, Edmond A.; Medabalmi, Praveen; Zagzag, David; Eagan, Patricia; Gruber, Michael L.

    2008-10-01

    Introduction: Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), has shown promise in the treatment of patients with recurrent high-grade glioma. The purpose of this study is to test the feasibility of using bevacizumab with chemoradiation in the primary management of high-grade glioma. Methods and Materials: Fifteen patients with high-grade glioma were treated with involved field radiation therapy to a dose of 59.4 Gy at 1.8 Gy/fraction with bevacizumab 10 mg/kg on Days 14 and 28 and temozolomide 75 mg/m{sup 2}. Subsequently, bevacizumab 10 mg/kg was continued every 2 weeks with temozolomide 150 mg/m{sup 2} for 12 months. Changes in relative cerebral blood volume, perfusion-permeability index, and tumor volume measurement were measured to assess the therapeutic response. Immunohistochemistry for phosphorylated VEGF receptor 2 (pVEGFR2) was performed. Results: Thirteen patients (86.6%) completed the planned bevacizumab and chemoradiation therapy. Four Grade III/IV nonhematologic toxicities were seen. Radiographic responses were noted in 13 of 14 assessable patients (92.8%). The pVEGFR2 staining was seen in 7 of 8 patients (87.5%) at the time of initial diagnosis. Six patients have experienced relapse, 3 at the primary site and 3 as diffuse disease. One patient showed loss of pVEGFR2 expression at relapse. One-year progression-free survival and overall survival rates were 59.3% and 86.7%, respectively. Conclusion: Use of antiangiogenic therapy with radiation and temozolomide in the primary management of high-grade glioma is feasible. Perfusion imaging with relative cerebral blood volume, perfusion-permeability index, and pVEGFR2 expression may be used as a potential predictor of therapeutic response. Toxicities and patterns of relapse need to be monitored closely.

  16. Radiologic and Clinical Outcomes of Surgery in High Grade Spondylolisthesis Treated with Temporary Distraction Rod

    PubMed Central

    Hootkani, Alireza; Jarahi, Lida; Rezvan, Manizheh; Moayedpour, Amir

    2015-01-01

    Background Surgical techniques used in the treatment of patients with high grade lumbar spondylolisthesis (> 50% slippage) are usually associated with a great deal of controversies. We aim to evaluate the surgical outcomes of high grade spondylolisthesis treated with an intraoperative temporary distraction rod. Methods We retrospectively studied 21 patients (14 females and 7 males), aged 50.4 ± 9.2 years, who had high grade lumbar spondylolisthesis that was treated with intraoperative temporary distraction rods, neural decompression, pedicular screw fixation, and posterolateral fusion involving one more intact upper vertebra. The mean follow-up period was 39.2 months. Radiologic and clinical outcomes were measured by slip angle, slip percentage, correction rate, Oswestry Disability Index (ODI), visual analogue scale (VAS), patient's satisfaction rate in the pre- and postoperative period. Data were analyzed by SPSS ver. 11.5. Results Analysis of the preoperative visits and final follow-up visits indicated that surgery could improve ODI, lumbar VAS, and leg VAS from 60.5% to 8.2%, from 6.7 to 2.2, and from 6.9 to 1.3, respectively. Slip angle and slip percentage were also changed from -8° to -15° and from 59.2% to 21.4%, respectively. Mean correction rate at the final follow-up visit was 64.1%. Loss of correction was insignificant and a neurologic complication occurred in one patient due to misplacement of one screw. Excellent and good levels of satisfaction were observed in 90.5% of the patients. Conclusions In the surgical treatment of refractory high grade spondylolisthesis, the use of a temporary distraction rod to reduce the slipped vertebra in combination with neural decompression, posterolateral fusion, and longer instrumentation is associated with satisfactory clinical and radiologic outcomes. PMID:25729523

  17. Total enbloc spondylectomy for metastatic high grade spinal tumors: Early results

    PubMed Central

    Patil, Sanganagouda S; Nene, Abhay M

    2016-01-01

    Background: High grade metastatic spinal tumors are most common and are invasive. These patients can succumb to disease progression if not treated timely. Although considered as invasive and morbid, total enbloc spondylectomy (TES) in selected cases has better survival rates. The authors describe the results of TES for high grade metastatic spinal tumors. Materials and Methods: Five patients (four females and one male) underwent TES for solitary metastatic vertebral lesion between November 2012 and January 2014. These patients presented to us with spinal instability, unrelenting severe spinal pain and/or with severe progressive radiculopathy. Average age was 46.2 years (range 39–62 years). After complete investigations, computed tomography scan, magnetic resonance imaging scan and positron emission tomography (PET) scan, it was confirmed that these patients had high grade solitary vertebral metastatic tumor. Results: Average duration of followup was 18 months (range 16–20 months). The average preoperative visual analog scale score of 9.4 (range 9–10) improved to 2 (range 1–4) at last followup. Average blood loss was 1440 mL (range 1000–2000 mL). Average duration of surgery was 198 min (range 180–240 min). Significant pain relief was noticed in each patient in the immediate postoperative period and during followups. These patients attained complete functional activities of daily living with in a month. The imaging showed implants in situ, no recurrence of tumor, and no activity on PET scan at the final followup. Conclusion: The present series shows favorable short term results of TES for solitary, metastatic, high grade vertebral body tumors by a team approach. PMID:27512215

  18. Analysis of pulmonary nodules in patients with high-grade soft tissue sarcomas

    PubMed Central

    Matsumine, Akihiko; Matsusaka, Miki; Mizumoto, Keitaro; Mori, Mayuko; Yoshizaki, Tomoya; Matsubara, Takao; Asanuma, Kunihiro; Sudo, Akihiro

    2017-01-01

    Nowadays, small pulmonary nodules are easily detectable in patients with soft tissue sarcomas (STSs) because of highly improved computed tomography (CT) technologies. The purpose of this study was to determine the frequency and significance of the pulmonary nodules detected by CT in high-grade STS patients. 124 patients with high-grade STS were retrospectively reviewed. There were 72 males (57%) and 52 females (43%). Patients’ average age was 61 years (median (quartiles) 66 years (48–75), range 8–94 years). Pulmonary nodules were detected in 49 (39.5%) of 124 patients by CT scanning at first presentation. Of 49 patients with nodules at first presentation, 34 (69.4%) had benign lesions, and 13 (26.5%) had metastatic nodules. One patient (2%) had primary lung cancer and the remaining one with one nodule could not be definitively diagnosed due to a short follow-up time. 30 patients (24.1%) of 124 patients developed pulmonary nodules during their clinical progression. Seven (23.3%) had benign lesions, whereas 21 (70%) had metastatic lesions. Primary lung cancer was detected in two patients (6.7%). The size and timing of detection of a pulmonary nodule significantly affected the final clinical diagnosisby multivariate analysis. We conclude that pulmonary nodules can be detected highly frequently in patients with high-grade STSs because of improved CT technologies. Careful follow-up is needed if nodules are detected after initial treatment or during the clinical course of the disease. PMID:28182790

  19. Declining rates of high-grade cervical lesions in young women in Connecticut, 2008-2011.

    PubMed

    Niccolai, Linda M; Julian, Pamela J; Meek, James I; McBride, Vanessa; Hadler, James L; Sosa, Lynn E

    2013-08-01

    Vaccines that prevent infection with human papillomavirus (HPV) types 16 and 18 that are known to cause cervical cancer have been available in the United States since 2006. High-grade cervical lesions are important for monitoring early vaccine impact because they are strong surrogates for cancer yet can develop within years after infection as opposed to decades. Trends in high-grade cervical lesions including cervical intraepithelial neoplasia grades 2, 2/3, and 3 and adenocarcinoma in situ among women ages 21 to 39 years old were examined using a statewide surveillance registry in Connecticut from 2008 to 2011. During this time period, HPV vaccine initiation increased among adolescent females from 45% to 61%. Analyses were stratified by age, according to census tract measures of proportion of population Black, Hispanic, living in poverty, and by urban/nonurban counties. The annual rate per 100,000 females ages 21 to 24 years declined from 834 in 2008 to 688 in 2011 (P(trend) < 0.001). No significant declines were observed among women ages 25 to 39 years. Significant declining trends also occurred in census tracts with lower proportions of the population being Black, Hispanic, or living below the federal poverty level. Declines in high-grade cervical lesions have occurred among young women during 2008 to 2011. This is the first report of declines in cervical neoplasia in the United States since HPV vaccines became available. Continued surveillance is needed to measure vaccine impact and monitor health disparities.

  20. High-grade squamous intraepithelial lesion arising adjacent to vulvar lymphangioma circumscriptum: a tertiary institutional experience

    PubMed Central

    Bae, Go Eun; Yoon, Gun; Song, Yong Jung; Kim, Hyun-Soo

    2016-01-01

    Lymphangioma circumscriptum of the vulva occurs in patients who have undergone radical hysterectomy, lymph node dissection, or radiation therapy for management of advanced uterine cancer. Since vulvar lymphangioma circumscriptum typically presents as multiple, grossly verrucous vesicles of various sizes, it may be impossible to clinically distinguish vulvar lymphangioma circumscriptum from other vulvoperineal cutaneous diseases. In the present study, 16 (1.6%) out of the 1,024 vulvar biopsy or excision specimens were diagnosed as lymphangioma circumscriptum. In two (12.5%) out of the 16 cases, unusual histopathological findings were observed. Both patients had previously undergone radical hysterectomy with lymph node dissection and postoperative radiation therapy or concurrent chemoradiation therapy for advanced cervical cancer. Microscopic examination revealed high-grade squamous intraepithelial lesions, which were located immediately adjacent to the normal squamous epithelium covering the dilated subepithelial lymphatic vessels. Further, human papillomavirus genotyping confirmed that both patients were infected with high-risk human papillomavirus. High-grade squamous intraepithelial lesion cannot be grossly distinguished from vulvar lymphangioma circumscriptum because the multiple, verrucous vesicles that constitute the characteristic gross appearance of vulvar lymphangioma circumscriptum hinder its distinction. In this regard, our cases of high-grade squamous intraepithelial lesion, located adjacent to vulvar lymphangioma circumscriptum, support the notion that active surgical excision is necessary for the treatment of vulvar lymphangioma circumscriptum. PMID:27329721

  1. Patient and caregiver perceptions of communication of prognosis in high grade glioma.

    PubMed

    Lobb, E A; Halkett, G K B; Nowak, A K

    2011-08-01

    This study sought the views of patients and their caregivers on their experience of being diagnosed with high grade glioma. Purposive sampling was used to recruit 19 patients and 21 caregivers from the medical oncology unit of a tertiary hospital. A semi-structured face-to-face interview was conducted. Interviews were audio-taped and transcribed verbatim. Data was analysed based on Grounded Theory and using the constant comparison method. This paper focuses on patient and carer perceptions of the initial communication about the diagnosis of high grade glioma and its prognosis. Themes identified included: (a) shock at hearing the diagnosis; (b) trying to understand and process prognostic information when still in shock; (c) the perception of hope being taken away; (d) individualizing prognostic information; and (e) clinicians' lack of communication skills. This study shows that the first communication of prognosis to patients with high grade glioma and their caregivers requires careful negotiation. It illustrates the inability of individuals to process detailed prognostic information when in a state of initial shock and distress. The importance of balancing honesty with hope in the communication of a poor prognosis is highlighted. We recommend that clinicians seek patient preferences for the amount and type of information they require and that prognostic information be individualized. Detailed discussions of prognosis should only take place with senior medical staff, or advanced trainees who have demonstrated acceptable communication skills.

  2. Integrative bioinformatic analyses of an oncogenomic profile reveal the biology of endometrial cancer and guide drug discovery.

    PubMed

    Wong, Henry Sung-Ching; Juan, Yung-Shun; Wu, Mei-Shin; Zhang, Yan-Feng; Hsu, Yu-Wen; Chen, Huang-Hui; Liu, Wei-Min; Chang, Wei-Chiao

    2016-02-02

    A major challenge in personalized cancer medicine is to establish a systematic approach to translate huge oncogenomic datasets to clinical situations and facilitate drug discovery for cancers such as endometrial carcinoma. We performed a genome-wide somatic mutation-expression association study in a total of 219 endometrial cancer patients from TCGA database, by evaluating the correlation between ~5,800 somatic mutations to ~13,500 gene expression levels (in total, ~78, 500, 000 pairs). A bioinformatics pipeline was devised to identify expression-associated single nucleotide variations (eSNVs) which are crucial for endometrial cancer progression and patient prognoses. We further prioritized 394 biologically risky mutational candidates which mapped to 275 gene loci and demonstrated that these genes collaborated with expression features were significantly enriched in targets of drugs approved for solid tumors, suggesting the plausibility of drug repurposing. Taken together, we integrated a fundamental endometrial cancer genomic profile into clinical circumstances, further shedding light for clinical implementation of genomic-based therapies and guidance for drug discovery.

  3. 5α-reductase Inhibitors and Risk of High-grade or Lethal Prostate Cancer

    PubMed Central

    Preston, Mark A.; Wilson, Kathryn; Markt, Sarah C.; Ge, Rongbin; Morash, Christopher; Stampfer, Meir J.; Loda, Massimo F.; Giovannucci, Edward; Mucci, Lorelei A.; Olumi, Aria F.

    2014-01-01

    Importance 5α-reductase inhibitors (5ARIs) are widely used for benign prostatic hyperplasia despite controversy regarding potential risk of high-grade prostate cancer with use. Furthermore, the effect of 5ARIs on progression and prostate cancer death remains unclear. Objective To determine the association between 5ARI use and development of high-grade or lethal prostate cancer. Design, Setting, and Participants Prospective observational study of 38,058 men followed for prostate cancer diagnosis and outcomes between 1996–2010 in the Health Professionals Follow-up Study. Exposure Use of 5ARIs between 1996–2010. Main Outcome Measures Cox proportional hazards models were used to estimate risk of prostate cancer diagnosis or development of lethal disease with 5ARI use, adjusting for possible confounders including prostate specific antigen testing. Results During 448,803 person-years of follow-up, we ascertained 3681 incident prostate cancer cases. Of these, 289 were lethal (metastatic or fatal), 456 were high-grade (Gleason 8–10), 1238 were Gleason grade 7, and 1600 were low-grade (Gleason 2–6). A total of 2878 (7.6%) men reported use of 5ARIs between 1996 and 2010. After adjusting for confounders, men who reported ever using 5ARIs over the study period had a reduced risk of overall prostate cancer (HR 0.77; 95% CI, 0.65–0.91). 5ARI users had a reduced risk of Gleason 7 (HR 0.67; 95% CI, 0.49–0.91) and low-grade (Gleason 2–6) prostate cancer (HR 0.74; 95% CI, 0.57–0.95). 5ARI use was not associated with risk of high-grade (Gleason 8–10, HR 0.97; 95% CI, 0.64–1.46) or lethal disease (HR 0.99; 95% CI, 0.58–1.69). Increased duration of use was associated with significantly lower risk of overall prostate cancer (HR for 1 year of additional use 0.95; 95% CI, 0.92–0.99), localized (HR 0.95; 95% CI, 0.90–1.00), and low-grade disease (HR 0.92; 95% CI, 0.85–0.99). There was no association for lethal, high-grade, or grade 7 disease. Conclusions and

  4. 21 CFR 884.1060 - Endometrial aspirator.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... and pipette, or catheter. This device is used to study endometrial cytology (cells). (b) Classification. Class II. The special controls for this device are: (1) FDA's: (i) “Use of International Standard...) Sterility Review Guidance of 2/12/90 (K90-1),” (2) Labeling: (i) Indication: Only to evaluate...

  5. 21 CFR 884.1185 - Endometrial washer.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... with negative pressure. This device is used to study endometrial cytology (cells). (b) Classification. Class II. The special controls for this device are: (1) FDA's: (i) “Use of International Organization... Testing,’ ” and (ii) “510(k) Sterility Review Guidance of 2/12/90 (K90-1),” (2) Labeling: (i)...

  6. Molecular Biology and Prevention of Endometrial Cancer

    DTIC Science & Technology

    2009-07-01

    of the oral contraceptive pill (OCP). Project 1: Objectives completed and data previously submitted with 2004 report. Data published this past year...molecular aberrations associated with endometrial carcinogenesis and the biologic mechanisms underlying the protective effect of oral contraceptive (OC...not been altered appreciably. Despite the known protective effect of oral contraceptives , little has been learned regarding the underlying mechanism

  7. Composite encapsulated papillary carcinoma and solid papillary carcinoma.

    PubMed

    Cui, Xiaoyan; Wei, Shi

    2015-03-01

    Encapsulated papillary carcinoma (EPC) and solid papillary carcinoma (SPC) are distinctive variants of intraductal papillary carcinomas, each accounting for <1% of breast carcinomas. Here we report a composite carcinoma consisting of EPC and SPC. A 73-year-old woman was found to have a high density mass in the left breast on mammogram. A biopsy showed intermediate to high grade ductal carcinoma in situ (DCIS). Gross examination of the lumpectomy specimen revealed a solid, multinodular mass. Microscopic examination demonstrated two morphologically distinct intraductal carcinomas intermingled with each other. One had delicate papillae in multi-cystic spaces surrounded by thick fibrous capsule, consistent with EPC. The other had solid tumor nests with delicate fibrovascular cores. The cells were monotonous with round nuclei and salt and pepper-like chromatin, characteristic of SPC. The lack of myoepithelial cells within the papillae and at the periphery of the lesion was confirmed by immunostaining for p63 and CK5/6. Neuroendocrine differentiation of SPC was demonstrated by neuron specific enolase staining. To our knowledge, this is the first reported case of composite EPC and SPC. It raises an interesting question as to a possible common pathway of carcinogenesis of these two rare variants.

  8. Elucidation of Molecular Alterations in Precursor Lesions of Ovarian Serous Carcinoma

    DTIC Science & Technology

    2013-07-01

    Precursor Lesions of Ovarian Serous Carcinoma PRINCIPAL INVESTIGATOR: Robert Kurman, M.D...5a. CONTRACT NUMBER Elucidation of Molecular Alterations in Precursor Lesions of Ovarian Serous Carcinoma 5b. GRANT NUMBER W81XWH-09-1-0249...Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT 15. SUBJECT TERMS prevention, p53 mutations, high grade serous

  9. Endometrial polyp surveillance in premenopausal breast cancer patients using tamoxifen

    PubMed Central

    Jeon, Se Jeong; Lee, Jae Il; Kim, Hee Seung; Kim, Jae Weon; Park, Noh Hyun; Song, Yong Sang

    2017-01-01

    Objective To describe the endometrial pathologic lesions in premenopausal breast cancer patients with a history of tamoxifen (TMX) use. Methods We retrospectively reviewed the medical records of 120 premenopausal breast cancer patients with a history of TMX use that had undergone a gynecological examination. Results Among 120 patients, 44.2% (n=53) were asymptomatic with an endometrial thickness ≥5 mm, as assessed by transvaginal ultrasonography. Of the patients that reported abnormal uterine bleeding, 5% (n=6) had an endometrial thickness <5 mm and 20% (n=24) had an endometrial thickness ≥5 mm by transvaginal ultrasonography. The final group of patients were asymptomatic, but showed an abnormal endometrial lesion, such as an endometrial polyp, by transvaginal ultrasonography (30.8%, n=37). Of the 56 benign lesions that were histologically reviewed, 50 (41.7%) were endometrial polyps, 3 (2.5%) were submucosal myomas, 2 (1.7%) were endometrial hyperplasias, and 1 (0.8%) was chronic endometritis. There were 64 (53.3%) other non-pathologic conditions, including secreting, proliferative, and atrophic endometrium, or in some cases, there was insufficient material for diagnosis. In our data, only one case was reported as a complex hyperplasia without atypia arising from an endometrial polyp, and one patient was diagnosed with endometrioid adenocarcinoma. Conclusion For premenopausal breast cancer patients with a history of TMX use, the majority of the patients were asymptomatic, and endometrial polyps were the most common endometrial pathology observed. Therefore, we believe that endometrial assessment before starting TMX treatment, and regular endometrial screening throughout TMX treatment, are reasonable suggestions for premenopausal breast cancer patients. PMID:28217668

  10. Endometrial study in patients with postmenopausal metrorrhagia

    PubMed Central

    de Merlo, Gaspar González; Mirasol, Esteban González; García, María Teresa Gómez; Parra, Carmen Ángel; Goy, Enrique Iglesias

    2016-01-01

    Introduction The aim of the study was to devise a strategy to diagnose malign endometrial pathologies (adenocarcinoma or atypical hyperplasia) that minimizes the number of invasive tests done (hysteroscopy, aspirati