Pharmacological inhibition of the LIF/LIFR autocrine loop reveals vulnerability of ovarian cancer cells to ferroptosis.

Of all gynecologic cancers, epithelial-ovarian cancer (OCa) stands out with the highest mortality rates. Despite all efforts, 90% of individuals who receive standard surgical and cytotoxic therapy experience disease recurrence. The precise mechanism by which leukemia inhibitory factor (LIF) and its receptor (LIFR) contribute to the progression of OCa remains unknown. Analysis of cancer databases revealed that elevated expression of LIF or LIFR was associated with poor progression-free survival of OCa patients and a predictor of poor response to chemotherapy. Using multiple primary and established OCa cell lines or tissues that represent five subtypes of epithelial-OCa, we demonstrated that LIF/LIFR autocrine signaling is active in OCa. Moreover, treatment with LIFR inhibitor, EC359 significantly reduced OCa cell viability and cell survival with an IC50 ranging from 5-50 nM. Furthermore, EC359 diminished the stemness of OCa cells. Mechanistic studies using RNA-seq and rescue experiments unveiled that EC359 primarily induced ferroptosis by suppressing the glutathione antioxidant defense system. Using multiple in vitro, ex vivo and in vivo models including cell-based xenografts, patient-derived explants, organoids, and xenograft tumors, we demonstrated that EC359 dramatically reduced the growth and progression of OCa. Additionally, EC359 therapy considerably improved tumor immunogenicity by robust CD45+ leukocyte tumor infiltration and polarizing tumor-associated macrophages (TAMs) toward M1 phenotype while showing no impact on normal T-, B-, and other immune cells. Collectively, our findings indicate that the LIF/LIFR autocrine loop plays an essential role in OCa progression and that EC359 could be a promising therapeutic agent for OCa.

Novel LIPA-Targeted Therapy for Treating Ovarian Cancer.

Ovarian cancer (OCa) is the most lethal form of gynecologic cancer, and the tumor heterogeneities at the molecular, cellular, and tissue levels fuel tumor resistance to standard therapies and pose a substantial clinical challenge. Here, we tested the hypothesis that the heightened basal endoplasmic reticulum stress (ERS) observed in OCa represents an exploitable vulnerability and may overcome tumor heterogeneity. Our recent studies identified LIPA as a novel target to induce ERS in cancer cells using the small molecule ERX-41. However, the role of LIPA and theutility of ERX-41 to treat OCa remain unknown. Expression analysis using the TNMplot web tool, TCGA data sets, and immunohistochemistry analysis using a tumor tissue array showed that LIPA is highly expressed in OCa tissues, compared to normal tissues. ERX-41 treatment significantly reduced the cell viability and colony formation ability and promoted the apoptosis of OCa cells. Mechanistic studies revealed a robust and consistent induction of ERS markers, including CHOP, elF2α, PERK, and ATF4, upon ERX-41 treatment. In xenograft and PDX studies, ERX-41 treatment resulted in a significant reduction in tumor growth. Collectively, our results suggest that ERX-41 is a novel therapeutic agent that targets the LIPA with a unique mechanism of ERS induction, which could be exploited to treat heterogeneity in OCa.

The LIFR Inhibitor EC359 Effectively Targets Type II Endometrial Cancer by Blocking LIF/LIFR Oncogenic Signaling.

Endometrial cancer (ECa) is the most common female gynecologic cancer. When comparing the two histological subtypes of endometrial cancer, Type II tumors are biologically more aggressive and have a worse prognosis than Type I tumors. Current treatments for Type II tumors are ineffective, and new targeted therapies are urgently needed. LIFR and its ligand, LIF, have been shown to play a critical role in the progression of multiple solid cancers and therapy resistance. The role of LIF/LIFR in the progression of Type II ECa, on the other hand, is unknown. We investigated the role of LIF/LIFR signaling in Type II ECa and tested the efficacy of EC359, a novel small-molecule LIFR inhibitor, against Type II ECa. The analysis of tumor databases has uncovered a correlation between diminished survival rates and increased expression of leukemia inhibitory factor (LIF), suggesting a potential connection between altered LIF expression and unfavorable overall survival in Type II ECa. The results obtained from cell viability and colony formation assays demonstrated a significant decrease in the growth of Type II ECa LIFR knockdown cells in comparison to vector control cells. Furthermore, in both primary and established Type II ECa cells, pharmacological inhibition of the LIF/LIFR axis with EC359 markedly decreased cell viability, long-term cell survival, and invasion, and promoted apoptosis. Additionally, EC359 treatment reduced the activation of pathways driven by LIF/LIFR, such as AKT, mTOR, and STAT3. Tumor progression was markedly inhibited by EC359 treatment in two different patient-derived xenograft models in vivo and patient-derived organoids ex vivo. Collectively, these results suggest LIFR inhibitor EC359 as a possible new small-molecule therapeutics for the management of Type II ECa.

PELP1 inhibition by SMIP34 reduces endometrial cancer progression via attenuation of ribosomal biogenesis.

Endometrial carcinoma (ECa) is the fourth most common cancer among women. The oncogene PELP1 is frequently overexpressed in a variety of cancers, including ECa. We recently generated SMIP34, a small-molecule inhibitor of PELP1 that suppresses PELP1 oncogenic signaling. In this study, we assessed the effectiveness of SMIP34 in treating ECa. Treatment of established and primary patient-derived ECa cells with SMIP34 resulted in a significant reduction of cell viability, colony formation ability, and induction of apoptosis. RNA-seq analyses showed that SMIP34-regulated genes were negatively correlated with ribosome biogenesis and eukaryotic translation pathways. Mechanistic studies showed that the Rix complex, which is essential for ribosomal biogenesis, is disrupted upon SMIP34 binding to PELP1. Biochemical assays confirmed that SMIP34 reduced ribosomal biogenesis and new protein synthesis. Further, SMIP34 enhanced the efficacy of mTOR inhibitors in reducing viability of ECa cells. SMIP34 is also effective in reducing cell viability in ECa organoids in vitro and explants ex vivo. Importantly, SMIP34 treatment resulted in a significant reduction of the growth of ECa xenografts. Collectively, these findings underscore the potential of SMIP34 in treating ECa.

Pharmacological inhibition of KDM1A/LSD1 enhances estrogen receptor beta-mediated tumor suppression in ovarian cancer.

Ovarian cancer (OCa) is the most lethal gynecologic cancer. Emerging data indicates that estrogen receptor beta (ERß) functions as a tumor suppressor in OCa. Lysine-specific histone demethylase 1A (KDM1A) is an epigenetic modifier that acts as a coregulator for steroid hormone receptors. However, it remain unknown if KDM1A interacts with ERß and regulates its expression/functions in OCa. Analysis of TCGA data sets indicated KDM1A and ERß expression showed an inverse relationship in OCa. Knockout (KO), knockdown (KD), or inhibition of KDM1A increased ERß isoform 1 expression in established and patient-derived OCa cells. Further, KDM1A interacts with and functions as a corepressor of ERß, and its inhibition enhances ERß target gene expression via alterations of histone methylation marks at their promoters. Importantly, KDM1A-KO or -KD enhanced the efficacy of ERß agonist LY500307, and the combination of KDM1A inhibitor (KDM1Ai) NCD38 with ERß agonist synergistically reduced the cell viability, colony formation, and invasion of OCa cells. RNA-seq and DIA mass spectrometry analyses showed that KDM1A-KO resulted in enhanced ERß signaling and that genes altered by KDM1A-KO and ERß agonist were related to apoptosis, cell cycle, and EMT. Moreover, combination treatment significantly reduced the tumor growth in OCa orthotopic, syngeneic, and patient-derived xenograft models and proliferation in patient-derived explant models. Our results demonstrate that KDM1A regulates ERß expression/functions, and its inhibition improves ERß mediated tumor suppression. Overall, our findings suggest that KDM1Ai and ERß agonist combination therapy is a promising strategy for OCa.

Inhibition of LIFR Blocks Adiposity-Driven Endometrioid Endometrial Cancer Growth.

Endometrial cancer (EC) is the fourth most common cancer in women, and half of the endometrioid EC (EEC) cases are attributable to obesity. However, the underlying mechanism(s) of obesity-driven EEC remain(s) unclear. In this study, we examined whether LIF signaling plays a role in the obesity-driven progression of EEC. RNA-seq analysis of EEC cells stimulated by adipose conditioned medium (ADP-CM) showed upregulation of LIF/LIFR-mediated signaling pathways including JAK/STAT and interleukin pathways. Immunohistochemistry analysis of normal and EEC tissues collected from obese patients revealed that LIF expression is upregulated in EEC tissues compared to the normal endometrium. Treatment of both primary and established EEC cells with ADP-CM increased the expression of LIF and its receptor LIFR and enhanced proliferation of EEC cells. Treatment of EEC cells with the LIFR inhibitor EC359 abolished ADP-CM induced colony formation andcell viability and decreased growth of EEC organoids. Mechanistic studies using Western blotting, RT-qPCR and reporter assays confirmed that ADP-CM activated LIF/LIFR downstream signaling, which can be effectively attenuated by the addition of EC359. In xenograft assays, co-implantation of adipocytes significantly enhanced EEC xenograft tumor growth. Further, treatment with EC359 significantly attenuated adipocyte-induced EEC progression in vivo. Collectively, our data support the premise that LIF/LIFR signaling plays an important role in obesity-driven EEC progression and the LIFR inhibitor EC359 has the potential to suppress adipocyte-driven tumor progression.

Therapeutic Targeting of Ovarian Cancer Stem Cells Using Estrogen Receptor Beta Agonist.

Ovarian cancer (OCa) is the deadliest gynecologic cancer. Emerging studies suggest ovarian cancer stem cells (OCSCs) contribute to chemotherapy resistance and tumor relapse. Recent studies demonstrated estrogen receptor beta (ERß) exerts tumor suppressor functions in OCa. However, the status of ERß expression in OCSCs and the therapeutic utility of the ERß agonist LY500307 for targeting OCSCs remain unknown. OCSCs were enriched from ES2, OV90, SKOV3, OVSAHO, and A2780 cells using ALDEFLUOR kit. RT-qPCR results showed ERß, particularly ERß isoform 1, is highly expressed in OCSCs and that ERß agonist LY500307 significantly reduced the viability of OCSCs. Treatment of OCSCs with LY500307 significantly reduced sphere formation, self-renewal, and invasion, while also promoting apoptosis and G2/M cell cycle arrest. Mechanistic studies using RNA-seq analysis demonstrated that LY500307 treatment resulted in modulation of pathways related to cell cycle and apoptosis. Western blot and RT-qPCR assays demonstrated the upregulation of apoptosis and cell cycle arrest genes such as FDXR, p21/CDKN1A, cleaved PARP, and caspase 3, and the downregulation of stemness markers SOX2, Oct4, and Nanog. Importantly, treatment of LY500307 significantly attenuated the tumor-initiating capacity of OCSCs in orthotopic OCa murine xenograft models. Our results demonstrate that ERß agonist LY500307 is highly efficacious in reducing the stemness and promoting apoptosis of OCSCs and shows significant promise as a novel therapeutic agent in treating OCa.

A rectovaginal septum mass in a BRCA1 positive patient years after risk reducing surgery: A case report.

•Rectovaginal septum mass in BRCA1 positive patient after risk reducing BSO years prior.•Papillary serous carcinoma presenting as a rectovaginal septum mass.•PAOLA-1 trial discussion for rectovaginal septum mass in BRCA1 positive patient.

PAI-1-Dependent Inactivation of SMAD4-Modulated Junction and Adhesion Complex in Obese Endometrial Cancer.

While plasminogen activator inhibitor-1 (PAI-1) is known to potentiate cellular migration via proteolytic regulation, this adipokine is implicated as an oncogenic ligand in the tumor microenvironment. To understand the underlying paracrine mechanism, here, we conduct transcriptomic analysis of 1,898 endometrial epithelial cells (EECs) exposed and unexposed to PAI-1-secreting adipose stromal cells. The PAI-1-dependent action deregulates crosstalk among tumor-promoting and tumor-repressing pathways, including transforming growth factor ß (TGF-ß). When PAI-1 is tethered to lipoprotein receptor-related protein 1 (LRP1), the internalized signaling causes downregulation of SMAD4 at the transcriptional and post-translational levels that attenuates TGF-ß-related transcription programs. Repression of genes encoding the junction and adhesion complex preferentially occurs in SMAD4-underexpressed EECs of persons with obesity. The findings highlight a role of PAI-1 signaling that renders ineffective intercellular communication for the development of adiposity-associated endometrial cancer.

Adipokines Deregulate Cellular Communication via Epigenetic Repression of Gap Junction Loci in Obese Endometrial Cancer.

Emerging evidence indicates that adipose stromal cells (ASC) are recruited to enhance cancer development. In this study, we examined the role these adipocyte progenitors play relating to intercellular communication in obesity-associated endometrial cancer. This is particularly relevant given that gap junctions have been implicated in tumor suppression. Examining the effects of ASCs on the transcriptome of endometrial epithelial cells (EEC) in an in vitro coculture system revealed transcriptional repression of GJA1 (encoding the gap junction protein Cx43) and other genes related to intercellular communication. This repression was recapitulated in an obesity mouse model of endometrial cancer. Furthermore, inhibition of plasminogen activator inhibitor 1 (PAI-1), which was the most abundant ASC adipokine, led to reversal of cellular distribution associated with the GJA1 repression profile, suggesting that PAI-1 may mediate actions of ASC on transcriptional regulation in EEC. In an endometrial cancer cohort (n = 141), DNA hypermethylation of GJA1 and related loci TJP2 and PRKCA was observed in primary endometrial endometrioid tumors and was associated with obesity. Pharmacologic reversal of DNA methylation enhanced gap-junction intercellular communication and cell-cell interactions in vitro. Restoring Cx43 expression in endometrial cancer cells reduced cellular migration; conversely, depletion of Cx43 increased cell migration in immortalized normal EEC. Our data suggest that persistent repression by ASC adipokines leads to promoter hypermethylation of GJA1 and related genes in the endometrium, triggering long-term silencing of these loci in endometrial tumors of obese patients. SIGNIFICANCE: Studies reveal that adipose-derived stem cells in endometrial cancer pathogenesis influence epigenetic repression of gap junction loci, which suggests targeting of gap junction activity as a preventive strategy for obesity-associated endometrial cancer.

Leiomyosarcoma of the uterine cervix associated with pregnancy: A case report and review of literature.

•Management of cervical leiomyosarcoma in pregnancy requires a multidisciplinary approach.•Ovarian preservation is preferred in young patients with early stage cervical leiomyosarcoma.•Routine lymphadenectomy in patients with early stage cervical leiomyosarcoma is not useful.

Clinical and Pathologic Features of Hispanic Endometrial Cancer Patients With Loss of Mismatch Repair Expression.

OBJECTIVES: Approximately 3% to 5% of endometrial cancers (EC) are associated with Lynch syndrome (LS). The clinical characteristics and prevalence of LS have not been well studied in the US Hispanic population. Hispanics are the largest and fastest growing ethnic minority group in the United States. We sought to characterize the demographics, tumor characteristics, and prevalence of loss of mismatch repair (MMR) protein expression in a large Hispanic population with EC. METHODS: From January 1, 2005, to August 1, 2012, 83 women of Hispanic ethnicity diagnosed with EC 50 years and younger were identified. Clinical and pathologic data were abstracted from the electronic medical record. Tumor studies included immunohistochemistry of MLH1, MSH2, MSH6, and PMS2 and methylation of the MLH1 promoter. RESULTS: Ninety-five percent of patients were overweight or obese. The mean body mass index was 40.1 kg/m, 75% had irregular menses, 36% had diabetes, 46% were nulliparous, and 95% had endometrioid histology. Thirteen patients (15.7%) had tumor MMR deficiency due to a presumed germline mutation (9 MSH6, 3 MSH2, and 1 MLH1). The pattern of MMR protein loss was consistent with the expected binding properties of the MMR heterodimer complexes. No significant difference was found in clinical or pathological variables between patients with and without MMR deficient tumors. CONCLUSIONS: The prevalence of molecular findings consistent with LS was at least as high as other populations of varied geography, race, and ethnicity. We found no reliable factors to include body mass index, family history, synchronous tumors, or pathologic tumor features to serve as triage markers for which ECs should be screened for MMR protein loss. Our findings support a recommendation for universal screening of ECs utilizing 2-antibody testing with MLH1 promoter methylation testing as indicated up to 60 years or older. Our recommendations should be generalizable to other Hispanic populations in the Southern United States.

Successful pregnancy following myomectomy for uterine smooth muscle tumor of uncertain malignant potential: A case report and review of the literature.

•STUMPs are rare smooth muscle tumors with an overall favorable prognosis.•Pregnancy is possible after diagnosis of STUMP treated with myomectomy•Management of patients desiring fertility with STUMPs requires a multidisciplinary approach.

Surgically managed stage I endometrial cancer in a low-volume center: outcomes and complications in a military residency program.

OBJECTIVE: The purpose of this study was to compare operative outcomes and complications for patients with endometrial cancer who underwent staging by laparoscopy vs laparotomy in a low-volume facility. STUDY DESIGN: Research was conducted with a retrospective cohort of surgical patients with clinical stage I endometrial cancer from 2004-2009. RESULTS: Eighty-six demographically similar patients (50 laparotomy and 36 laparoscopy) were identified. Laparoscopy had less estimated blood loss (339 vs 558 mL; P = .013) and lower rates of transfusion (5.6% vs 24%; P = .02). Laparoscopy was longer (281 vs 202 minutes; P < .0005) but required a shorter hospital stay (2.2 vs 5.5 days; P < .0005). Laparoscopy patients had fewer overall complications (16.7% vs 32%; P = .11). No differences in final surgical stage or lymph node yields between the groups were present. CONCLUSION: Although a longer procedure, laparoscopy had fewer complications and shorter hospital stays. Prolonged operative time, compared with published experience, is potentially the result of unique factors in our center.

Comparative assessment of hypercoagulability in women with and without gynecologic malignancies using the thromboelastograph coagulation analyzer.

The hypercoagulability status of women with and without gynecologic malignancies was compared using the thromboelastograph coagulation analyzer. Blood specimens from 25 women with newly diagnosed gynecologic malignancies and from 21 age-matched controls were analyzed. Hypercoagulability is defined by a short R value (min), a short K value (min), an elevated maximum amplitude (MA) value (mm), and a broad alpha-angle (degrees). A two-tailed, two-sample t-test was used for statistical analysis. When compared with specimens from age-matched controls, specimens from women with gynecologic malignancies demonstrated values consistent with hypercoagulability. The specific parameters are presented as a mean (+/- SD). Patients with gynecologic malignancies were found to have a short R value (7.1 +/- 2.1 vs. 11.8 +/- 1.8 min; P < 0.001), a short K value (3.1 +/- 0.9 vs. 4.6 +/- 0.9 min; P < 0.001), a prolonged MA value (64.7 +/- 5.4 vs. 58.8 +/- 6.1 mm; P = 0.001), and a greater alpha-angle (70.6 +/- 5.3 vs. 61.6 +/- 4.9 degrees ; P < 0.001). Detection of hypercoagulability as measured by thromboelastography is statistically more common among women with gynecologic malignancies compared with age-matched controls. Future studies may address the use of thromboelastography to identify patients at risk for gynecologic malignancies.

Delivery complicated by postpartum hemorrhage and lower extremity compartment syndrome.

BACKGROUND: Extremity compartment syndrome is a rare surgical complication in which increased intracompartmental pressure threatens the viability of the muscular and nervous tissue. We report a case of a delivery complicated by postpartum hemorrhage and a lower extremity compartment syndrome. CASE: A multigravida in her late 20s was admitted for induction of labor at 41 weeks of gestation. She underwent a cesarean delivery for a nonreassuring fetal heart rate tracing. The delivery was complicated by severe postpartum hemorrhage due to uterine atony, resulting in a cesarean hysterectomy. The patient developed a lower extremity compartment syndrome and underwent an emergent anterior tibial fasciotomy. CONCLUSION: Extremity compartment syndrome is rarely encountered in obstetric care; however, there may be an association with severe postpartum hemorrhage.

Characterization of human leukocyte antigen-G (HLA-G) expression in endometrial adenocarcinoma.

OBJECTIVES: The current study sought to determine if endometrial adenocarcinomas express human leukocyte antigen-G (HLA-G), an immune-regulatory protein, and if degree of expression correlates with the stage of carcinoma. METHODS: Forty-four primary endometrial adenocarcinomas were tested using immunohistochemical staining with the 4H84 anti-HLA-G monoclonal antibody. Metastatic implants were not included. A subset of 10 samples was tested using RNA in situ hybridization to confirm the presence of HLA-G transcript. Results of staining were analyzed with respect to grade, tumor histology, and stage of disease. Spearman rank correlation was used to assess tumor grade, histology, and disease stage as a function of HLA-G protein staining. Receiver-operator characteristic (ROC) curve analysis was used to determine the feasibility of HLA-G protein staining as a clinical marker for advanced stage disease. RESULTS: Immunohistochemical staining for HLA-G protein was seen in 55% (24/44) of primary site endometrial adenocarcinomas and localized to glandular but not stromal epithelium. RNA in situ hybridization confirmed the presence of transcript in the majority of samples tested and also localized to glandular epithelium. A significant correlation was seen with increasing HLA-G protein staining and increasing stage of endometrial cancer, P < 0.01. HLA-G was found to be a fair discriminator as a test for metastatic disease with an area under the ROC curve of 0.75 for metastatic versus non-metastatic disease. CONCLUSIONS: HLA-G protein is expressed in a significant number of endometrial adenocarcinomas, in which it is localized to the glandular epithelium. HLA-G may serve as a clinical marker for the preoperative prediction of metastatic endometrial cancer.

Coccidioidomycosis mimicking ovarian cancer.

BACKGROUND: Dissemination of coccidioidomycosis to the abdominal cavity is rare. No previous case of peritoneal coccidioidomycosis has presented as an adnexal mass. CASE: We report a case of peritoneal coccidioidomycosis mimicking ovarian carcinoma. The patient presented with a complex ovarian mass, ascites, omental caking, and an elevated CA 125. The ultimate diagnosis was not made until frozen section histopathology was performed at staging laparotomy. CONCLUSION: Peritoneal coccidioidomycosis can present with the clinical, radiographic, and serologic features of ovarian cancer. Although essential for diagnosis and staging, radiographic studies and tumor markers have limited specificity. Coccidioidomycosis now joins other benign conditions that comprise the differential diagnosis of patients who present with what seems to be advanced ovarian carcinoma. Infectious diseases consultation is recommended for the management of peritoneal coccidioidomycosis.

Adenosquamous histology predicts a poor outcome for patients with advanced-stage, but not early-stage, cervical carcinoma.

BACKGROUND: The objective of this study was to compare survival between patients with adenocarcinoma and patients with adenosquamous carcinoma of the cervix. METHODS: Patients who were diagnosed with invasive cervical carcinoma from 1988 to 1999 were identified from the Automated Central Tumor Registry for the United States Military Health Care System. Clinical data, including race, age at diagnosis, histology, tumor grade, disease stage, lymph node status, treatment modality, and survival, were collected. Survival analysis was performed with Kaplan-Meier survival curves and compared using the log-rank test. RESULTS: A total of 273 women were identified, 185 women with a histologic diagnosis of adenocarcinoma (AC) and 88 women with a diagnosis of adenosquamous carcinoma (ASC). Among the women with ASC, only 5% had Grade 1 tumors, and 66% had Grade 3 tumors. By comparison, among the women with AC, 37% had Grade 1 tumors, and 26% had Grade 3 tumors (P < 0.001). There was no difference in the incidence of positive lymph nodes or in the number of patients who underwent radical hysterectomy as primary treatment between patients with ASC and patients with AC. More patients with ASC received radiation therapy (51% vs. 28%) or chemotherapy (29% vs. 12%) as treatment (P < 0.001). Patients who had tumors with ASC histology had a significantly decreased 5-year survival rate compared with patients who had tumors with AC histology (65% vs. 83%; P < 0.002). When patients with early-stage cervical carcinoma (International Federation of Gynecology and Obstetrics [FIGO] Stage I) were examined separately, there was no statistically significant difference in the 5-year survival rate (AC, 89%; ASC, 86%; P = 0.644). However, when patients with advanced-stage disease (FIGO Stages II-IV) were analyzed, ASC was associated with a significant decrease in median and overall survival (P = 0.01). When the results were analyzed by grade, patients who had tumors with ASC histology had a shorter survival compared with patients who had AC histology of any grade; however, this was a significant difference only for patients with Grade 1 tumors: The 5-year survival rate for patients with Grade 1 AC was 93%, compared with 50% for patients with Grade 1 ASC (P < 0.01). CONCLUSIONS: ASC histology appears to be an independent predictor of poor outcome in women with cervical carcinoma compared with their counterparts who have pure AC. The significant decrease in survival was observed only in patients with advanced-stage cervical carcinoma. This decreased survival may be related mainly to the grade of ASC.