Uterine Endometrial Carcinoma Research Articles

Evaluation of Uterine Carcinosarcoma and Uterine Endometrial Carcinoma Using Magnetic Resonance Imaging Findings and Texture Features.

Aim This study aimed to evaluate the diagnostic feasibility of magnetic resonance imaging (MRI) findings and texture features (TFs) for differentiating uterine endometrial carcinoma from uterine carcinosarcoma. Methods This retrospective study included 102 patients who were histopathologically diagnosed after surgery with uterine endometrial carcinoma (n=68) or uterine carcinosarcoma (n=34) between January 2008 and December 2021. We assessed conventional MRI findings and measurements (cMRFMs) and TFs on T2-weighted images (T2WI) and apparent diffusion coefficient (ADC) map, as well as their combinations, in differentiating between uterine endometrial carcinoma and uterine carcinosarcoma. The least absolute shrinkage and selection operator (LASSO) was used to select three features with the highest absolute value of the LASSO regression coefficient for each model and construct a discriminative model. Binary logistic regression analysis was used to analyze the disease models and conduct receiver operating characteristic analyses on the cMRFMs, T2WI-TFs, ADC-TFs, and their combined model to compare the two diseases. Results A total of four models were constructed from each of the three selected features. The area under the curve (AUC) of the discriminative model using these features was 0.772, 0.878, 0.748, and 0.915 for the cMRFMs, T2WI-TFs, ADC-TFs, and a combined model of cMRFMs and TFs, respectively. The combined model showed a higher AUC than the other models, with a high diagnostic performance (AUC=0.915). Conclusion A combined model using cMRFMs and TFs might be helpful for the differential diagnosis of uterine endometrial carcinoma and uterine carcinosarcoma.

Abstract IA012: The role of the serine/threonine phosphatase PP2A in endometrial cancer development and progression: lessons learned from mutations and small molecules

Abstract Uterine cancer is the most common gynecologic malignancy in the United States with approximately 60,000 new diagnoses each year. While many cases of uterine endometrial carcinoma (EMCA) have favorable outcomes with recurrence-free long-term survival, outcomes for the high-grade, treatment-refractory histological subtypes, including uterine serous carcinoma (USC) and uterine carcinosarcoma (UCS), remain an important clinical problem. Uterine serous carcinomas and uterine carcinosarcomas tumors are the most aggressive subtypes of uterine cancer, displaying a high propensity to invade the peritoneal cavity and to metastasize to distant sites. Accordingly, 50-70% of high-grade tumors exhibit extrauterine spread at time of initial surgery and have limited treatment options. The inherent aggressiveness of these tumors suggests that they are intrinsically equipped to disseminate and propagate tumors at secondary sites. The molecular drivers of this phenotype, however, have yet to be completely characterized. A lack of established and validated molecular drivers of the high-grade subtypes, especially those that are responsible for the high rate of metastasis, has limited the use of targeted treatment strategies. However, we and other groups have shown that PPP2R1A, the scaffolding subunit of the tumor suppressor protein phosphatase 2A, is mutated in up to 40% of USC patients, and these recurrent mutations are found at both the primary and metastatic sites. These mutations are heterozygous, and two specific mutations: P179R and S256F, occur exclusively within these high-grade subtypes of uterine cancer (i.e., are not found in any other cancer type). PP2A, is a family of serine/threonine phosphatases, where the active heterotrimeric form of the enzyme is comprised of a catalytic (C) subunit, a scaffolding (A) subunit, and a substrate directing regulatory (B) subunit. In aggregate, PP2A is considered a tumor suppressor protein, but certain heterotrimers have tumor promoting roles. Here we present data related to the molecular and biological basis through which these recurrent pathogenic mutations drive endometrial cancer development and progression using disease relevant cellular and in vivo model systems. Additionally, building from previously published work from our group, we have developed a novel series of small molecule molecular glues (PMGs) that specifically correct the mutant heterotrimer driving tumor regressions in both cellular and patient derived xenograft models of high-grade endometrial cancer. Collectively, this data suggests that recurrent pathogenic mutations in the PPP2R1A gene drive endometrial cancer pathogenesis and these mutations can be therapeutically targeted using a series of pharmaceutically tractable small molecules. Citation Format: Goutham Narla. The role of the serine/threonine phosphatase PP2A in endometrial cancer development and progression: lessons learned from mutations and small molecules [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr IA012.

Mutational Landscape of ER Receptor Negative Endometrial Cancer Patients Categorized as No Specific Molecular Profile (NSMP)

The endometrial cancer (EC) molecular classification introduced by The Cancer Genome Atlas (TCGA) has initiated molecular-based classification with clear prognostic value. Four major tumor subtypes exist: 1) TP53 mutation (p53abn); 2) POLE mutation (POLEmut); 3) mismatch repair protein deficient (MMRd); and 4) no specific molecular profile (NSMP). Of these subtypes, p53abn patients exhibited the worst prognosis. Recently, a prognostic refinement of NSMP EC using estrogen receptor (ER) status, from PORTEC-III trial data, showed that (ER-) NSMP patients had a strikingly poor prognosis, similar to p53abn patients. Currently, drivers of NSMP (ER-) disease are unknown and require genomic characterization. In this study, we perform an integrated molecular analysis to characterize this aggressive and poorly understood cohort. RNAseq and mutational data was downloaded from the TCGA, PanCancer Atlas, Uterine Endometrial Carcinoma dataset via the genomic data commons (GDC). All patients in this cohort demonstrated endometrioid histology. P53abn, and POLE mutated patients were filtered using mutational data. MMRd and NSMP ESR1 gene low expressors (ER Low) were filtered using Z-score cutoffs of RNAseq expression data. Survival analysis was performed using the Survival R-package. Gene expression testing was performed using the EdgeR R-package. Pathway Enrichment analysis was conducted using EnrichR software. Forty-two patients out of 529 samples met our GDC NSMP (ER low) filtering criteria (7%), similar to the 5% of PORTEC-III patients classified as NSMP (ER -). Strikingly 83% percent of GDC NSMP (ER low) patients harbored a mutation in the PI3K-AKT-mTOR signaling pathway, with 48% of GDC NSMP (ER low) patients carrying a mutation in the p110 alpha (PIK3CA) gene. Interestingly, of the patients with PIK3CA mutant tumors, 2/20 patients died in 5 years (10%), compared to 9/22 patients whose tumors were PIK3CA WT (41%) (p = 0.02). Among GDC NSMP (ER low) patients with PIK3CA WT tumors gene expression signatures were enriched for MYC target genes (p = 1.1e-51), DNA replication (p = 4.3e-30), cell cycle (p = 9.32e-20), and cell cycle checkpoints (p = 6.4e-20) pathways. Additionally, strongly in PIK3CA WT tumors are mitochondrial membrane proteins (p = 1.63e-37) and ribosomal proteins (2.9e-24). In this analysis, we show that GDC NSMP (ER low) tumors nearly all harbor a mutation in the PI3K-AKT-mTOR signaling pathway. Further we demonstrate that the most common gene mutation in the cohort, PIK3CA, is counterintuitively a marker of improved survival. Additionally, we show that within that this subpopulation, PIK3CA WT patients exhibit robustly upregulated gene expression programs dedicated to energy production, cell cycling, and division.

Dynamic contrast-enhanced MR imaging of uterine endometrial carcinoma with/without squamous differentiation.

Endometrial carcinoma with strong enhancement on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is suggestive of high-grade type II endometrial carcinoma. However, low-grade type I endometrial carcinoma may also sometimes show strong enhancement. We hypothesized that squamous differentiation would contribute to the strong enhancement at the early phase on DCE-MRI-like uterine cervical squamous cell carcinoma and compared the DCE-MRI findings of endometrial carcinoma with and without squamous differentiation. DCE-MRI of endometrial carcinoma including 41 low-grade type I endometrial carcinomas without squamous differentiation (LG), 39 low-grade type I endometrial carcinomas with squamous differentiation (LGSD), and 20 high-grade type II endometrial carcinomas (HG) was retrospectively evaluated. Significant difference in the time-intensity curves was found between LG and HG and LG and LGSD, whereas no significant difference was seen between HG and LGSD. Curve type 3 (initial signal rise which is steeper than that of the myometrium) was more frequent in HG (60%) and LGSD (77%) than in LG (34%). It should be recognized as a pitfall that high-grade type II endometrial carcinoma and low-grade type I endometrial carcinoma with squamous differentiation may show similar early strong enhancement on DCE-MRI.

Loss of LOXL2 Promotes Uterine Hypertrophy and Tumor Progression by Enhancing H3K36ac-Dependent Gene Expression.

LOXL2 loss reprograms the epigenetic landscape to promote uterine cancer initiation and progression and repress the efficacy of anti-PD-1 immunotherapy, indicating that LOXL2 is a tumor suppressor.

Clinicopathological spectrum of ovarian neoplasms in pre and post menopausal Indian women

Ovarian cancers are the third most common cancers in women trailing behind cervical and breast cancer. Various molecular insults are seen in hereditary cancer syndromes that results in different morphological types of ovarian cancer.Accurate histological typing suggests screening of the first degree relatives and also targeted therapy for the same. Age specific incidence rate showed that ovarian cancer increases from 35 years of age and peaks between 55 to 64 years of age. Present study was conducted to know the clinical and histopathological spectrum of ovarian neoplasms. To correlate the histopathological subtype with the pre and post menopausal age group. This is a retrospective observational study of 196 cases found over 2.5 years during January 2018 to June 2020. Surface epithelial tumors(SET) are commonest in our study (benign 50%, borderline 6% and malignant 17%) followed by germ cell tumors (12%), sex cord stromal tumors (9%), secondary tumors (5%) and mixed epithelial and mesenchymal tumor (0.5%). Benign SET and germ cell tumors are significantly associated with premenopausal age whereas malignant SET has significant association with post menopausal age. However sex cord stromal tumors did not show any significant association with both the groups. Bilateral involvement was commonest with secondary tumors followed by malignant SET. Mean age of presentation was 41 years with maximum cases presenting in 4 and 5 decade. Various histomorphological parameters were evaluated in detail along with immunohistochemistry(IHC). Inhibin negativity helped to differentiate sertoliform variant of endometrial carcinoma from sertoli cell tumor. WT1 positivity in serous carcinoma ruled out poorly differentiated endometrioid carcinoma in two cases. Thirteen cases show extraovarian spread. Synchronous neoplasms of female genital tract (fibroma with uterine endometrial carcinoma and Brenner with basaloid carcinoma cervix ) were found. Collision tumors (sex cord stromal tumors with germ cell tumors) were also found in present study. Using WHO classification, ovarian tumors can be precisely subcategorized into different morphological subtypes. However overlapping features may need IHC to pinpoint the correct diagnosis. Age specific occurrence of different morphological subtypes may suggest other ancillary investigations and different treatment modalities

MicroRNA 182, 183, 200a, and 200b exhibit strong correlations but no involvement in PTEN protein regulation in uterine endometrial carcinoma

ObjectiveIn this study, we focused on five microRNAs (miRNAs) that have been reported to regulate phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene expression, namely miR-182, miR-183, miR-200a, miR-200b, and miR-205, and examined their relationships with PTEN protein expression in endometrial cancer tissues. MethodsBy utilizing paraffin-embedded blocks of normal endometrium (NE) and endometrial carcinoma (EC) tissue (40 cases each), we measured the expression of miRNAs by real-time PCR. Conversely, we examined PTEN protein expression by immunohistochemistry and computer-assisted image analysis. ResultsThe expression of all five miRNAs was significantly higher in the EC group than in the NE group (all P ≤ 0.0001). There was no inverse correlation between PTEN positivity in glandular and/or stromal areas and the expression of the five miRNAs in both groups. Conversely, miR-182, miR-183, miR-200a, and miR-200b displayed similar expression patterns in the EC group, whereas miR-205 displayed moderate correlations with the other four miRNAs. ConclusionUsing endometrial cancer tissues, we found for the first time that miR-182, miR-183, miR-200a, and miR-200b were strongly correlated with each other, whereas miR-205 was not strongly correlated with the other four miRNAs. In addition, the five miRNAs examined in this study only had weak effects on PTEN protein expression based on the lack of clear inverse correlations.

Prognostic role of computed tomography-based, artificial intelligence-driven waist skeletal muscle volume in uterine endometrial carcinoma

ObjectivesTo investigate the impact of computed tomography (CT)-based, artificial intelligence-driven waist skeletal muscle volume on survival outcomes in patients with endometrial cancer.MethodsWe retrospectively identified endometrial cancer patients who received primary surgical treatment between 2014 and 2018 and whose pre-treatment CT scans were available (n = 385). Using an artificial intelligence-based tool, the skeletal muscle area (cm2) at the third lumbar vertebra (L3) and the skeletal muscle volume (cm3) at the waist level were measured. These values were converted to the L3 skeletal muscle index (SMI) and volumetric SMI by normalisation with body height. The relationships between L3, volumetric SMIs, and survival outcomes were evaluated.ResultsSetting 39.0 cm2/m2 of L3 SMI as cut-off value for sarcopenia, sarcopenia (< 39.0 cm2/m2, n = 177) and non-sarcopenia (≥ 39.0 cm2/m2, n = 208) groups showed similar progression-free survival (PFS; p = 0.335) and overall survival (OS; p = 0.241). Using the median value, the low-volumetric SMI group (< 206.0 cm3/m3, n = 192) showed significantly worse PFS (3-year survival rate, 77.3% vs. 88.8%; p = 0.004) and OS (3-year survival rate, 92.8% vs. 99.4%; p = 0.003) than the high-volumetric SMI group (≥ 206.0 cm3/m3, n = 193). In multivariate analyses adjusted for baseline body mass index and other factors, low-volumetric SMI was identified as an independent poor prognostic factor for PFS (adjusted HR, 1.762; 95% CI, 1.051–2.953; p = 0.032) and OS (adjusted HR, 5.964; 95% CI, 1.296–27.448; p = 0.022).ConclusionsWaist skeletal muscle volume might be a novel prognostic biomarker in patients with endometrial cancer. Assessing body composition before treatment can provide important prognostic information for such patients.

Amide proton transfer imaging in differentiation of type II and type I endometrial carcinoma: a pilot study

PurposeThis study aimed at evaluating the efficacy of amide proton transfer (APT) imaging in differentiation of type II and type I uterine endometrial carcinoma.Materials and methodsThirty-three patients diagnosed with uterine endometrial carcinoma, including 24 with type I and 9 with type II carcinomas, underwent APT imaging. Two readers evaluated the magnetization transfer ratio at 3.5 ppm [MTRasym (3.5 ppm)] in each type of carcinoma. The average MTRasym (APTmean) and the maximum MTRasym (APTmax) were analyzed. The receiver operating characteristic (ROC) curve analysis was performed.ResultsThe APTmax was significantly higher in type II carcinomas than in type I carcinomas (reader1, p = 0.004; reader 2, p = 0.014; respectively). However, APTmean showed no significant difference between type I and II carcinomas. Based on the results reported by reader 1, the area under the curve (AUC) pertaining to the APTmax for distinguishing type I from type II carcinomas was 0.826, with a cut-off, sensitivity, and specificity of 9.90%, 66.7%, and 91.3%, respectively. Moreover, based on the results reported by reader 2, the AUC was 0.750, with a cut-off, sensitivity, and specificity of 9.80%, 62.5%, and 87.5%, respectively.ConclusionAPT imaging has the potential to determine the type of endometrial cancer.

Abstract 2432: Somatic mutations in the STAT3 activation pathway are associated with improved survival in gynecologic malignancies and provide a molecular rationale for therapeutic targeting

Abstract Background: Signal transducer and activator of transcription 3 (STAT3) activation promotes tumor cell survival, immune evasion, metastasis, and drug resistance in PARP inhibitors and platinum-based chemotherapy. Objective: Based on our in-vitro findings of the tumoricidal potential of STAT3 inhibition in BRCAwild-type and PARP inhibitor-resistant tumor cells, we sought to evaluate whether ovarian and uterine cancer patients with somatic mutations in the STAT3 activation pathway had improved overall survival (OS) compared to those with intact STAT3 activation pathway-related genes. Method: We induced Olaparib resistance in BRCAwild-type ovarian cancer cell lines (OVCAR8 and A2780) and treated both parental and PARP inhibitor-resistant cell lines with various STAT3 inhibitors. We then attempted to establish clinical correlations of our in-vitro studies and queried the Cancer Genome Atlas (TCGA) Pan-Cancer Atlas for uterine and ovarian cancers. OS in patients with somatic mutations in the STAT3 gene and/or associated STAT3 activation genes (IL6ST, GNAS, JAK1, JAK2) was compared to OS in patients with intact STAT3 pathway-related genes. Kaplan-Meier survival curves were compared using the log-rank test. Results: In-vitro, STAT3 inhibition demonstrated potent, tumoricidal propensity in all cell lines (EC50: 0.34uM-0.46uM) including A2780parental, A2780parpi-resistant, OVCAR8parental, and OVCAR8parpi-resistant. Clinically, 1,154 total patients were identified in TCGA, including 571 high-grade serous ovarian carcinoma, 397 uterine endometrioid adenocarcinomas, 109 uterine serous carcinoma/uterine papillary serous carcinomas, 56 uterine carcinosarcomas/uterine malignant mixed Mullerian tumors, and 21 uterine mixed endometrial carcinomas. When pooling all uterine and ovarian cancer patients, median survival (MS) was 52 months (0-185) in patients with intact STAT3 (n=1,007) compared to not reached (NR, 0-225) in the STAT3 mutated group (n=147) with a Hazard Ratio (HR) of 0.25 and Confidence Interval (CI) 0.20-0.32 (p&amp;lt;0.001). In ovarian cancer patients, MS was 45 months (0-180) in patients with intact STAT3 (n=551) compared to 95 months (0-145) in the STAT3 mutated group (n=20) with a HR of 0.48 and CI 0.29-0.80 (p=0.038). In uterine cancer patients, MS was 112 months (0-185) in patients with intact STAT3 (n=456) compared to NR (0-225) in the STAT3 mutated group (n=127) with a HR of 0.40 and CI 0.25-0.64 (p=0.003). Conclusion: Pharmacologic and genetic (siRNA) inhibition of the STAT3 activation pathway killed PARP inhibitor-resistant ovarian cancer cells in-vitro. Clinically, somatic mutations in the STAT3 activation pathway were associated with improved OS in both ovarian and uterine cancer. These findings provide a rationale for the therapeutic targeting of this pathway in gynecologic malignancies. Citation Format: Adrian Kohut, Antons Martincuks, Thanh Dellinger, Hua Yu, Lorna Rodriguez-Rodriguez. Somatic mutations in the STAT3 activation pathway are associated with improved survival in gynecologic malignancies and provide a molecular rationale for therapeutic targeting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2432.

A case of synchronous serous ovarian cancer and uterine serous endometrial intraepithelial carcinoma

BackgroundSerous endometrial intraepithelial carcinoma (SEIC) is now considered to represent an early stage of uterine serous carcinoma (USC). It is an intraepithelial lesion but has been reported to cause extrauterine metastases. We report a case of SEIC with serous ovarian carcinoma and lymph node metastasis.Case presentationA 57-year-old post-menopausal woman (gravida 3, para 2, SA1) was referred to our hospital with lower abdominal pain. An ultrasound and MRI showed that the ovary had swollen to 8 cm in size and had a solid lesion. The uterus was normal. The patient underwent exploratory laparoscopy on the suspicion of torsion of the ovarian tumor. Intraoperative findings showed a right ovarian tumor, but no ovarian tumor torsion was observed. A small amount of bloody ascites was found in the Douglas fossa, and bleeding was observed from the tumor itself. A right salpingo-oophorectomy was then performed. Histopathological results revealed a high-grade serous carcinoma. Forty days after the first surgery, we performed a staging laparotomy: a total abdominal hysterectomy, left salpingo-oophorectomy, systematic pelvic and paraaortic lymphadenectomy, and a partial omentectomy. A complete cytoreduction was achieved. In the pathological examination, the invasion of the serous carcinoma was observed in the left ovarian ligament, and lymph node metastasis was found in the paraaortic lymph nodes. Atypical columnar cells formed irregular papillary lesions which had proliferated in the endometrium, and this was diagnosed as SEIC. The final diagnosis was serous ovarian cancer, FIGO stage IIIA1(ii), pT2bN1M0, with SEIC.ConclusionWe report a case of SEIC with synchronous serous carcinoma of the adnexa uteri. Both were serous carcinomas and, thus, it was difficult to identify the primary lesion. The distinction between metastatic cancer and two independent primary tumors is important for an accurate diagnosis and tumor staging. Histological diagnostic criteria remain controversial, and further development of a method for differentiating between both diseases is required.

Novel strategy to treat lung metastases: Hybrid therapy involving surgery and radiofrequency ablation.

BackgroundThis study was performed to evaluate the clinical outcomes of hybrid treatment involving surgical resection and percutaneous radiofrequency ablation for patients with multiple lung metastases.MethodsSeventeen patients (6 men, 11 women; median age, 52 years; range, 16–78 years) underwent hybrid treatment involving surgery and radiofrequency ablation to treat multiple lung metastases (median number, 4; range, 2–26) between May 2014 and February 2020. The primary lesions were colorectal carcinoma (n = 9), uterine endometrial carcinoma (n = 3), osteosarcoma (n = 2), renal cell carcinoma (n = 1), glottic carcinoma (n = 1), and fibrolamellar hepatocellular carcinoma (n = 1). Twenty‐four sessions each of surgery and radiofrequency ablation were performed. Safety, disease‐free survival, and overall survival were evaluated. Safety was assessed according to the Clavien‐Dindo Classification.ResultsA grade IVa adverse event of empyema developed in one patient (4%, 1/24) after surgery. A grade IIIa adverse event of pneumothorax and a grade II adverse event of lung abscess occurred in four (17%, 4/24) and one session (4%, 1/24) after radiofrequency ablation, respectively. During the median follow up of 34 months (range, 8–67 months), 10 patients (59%, 10/17) developed new metastases. The 5‐year disease‐free survival rate was 32%. Four or fewer lung metastases (p = 0.008) and metastases from colorectal carcinoma (p = 0.02) were factors significantly associated with longer disease‐free survival. One patient (6%, 1/17) died of tumor progression 29 months after initial treatment. The 5‐year overall survival rate was 88%.ConclusionsThe strategy of hybrid treatment involving surgery and radiofrequency ablation may offer good outcomes for patients with multiple lung metastases.

Brain Metastases from Uterine Cervical and Endometrial Cancer.

Simple SummaryThis review investigated the prevalence, clinical characteristics, clinical presentation, diagnosis, treatment, and prognosis of patients with brain metastases from uterine cervical carcinoma (CC) and uterine endometrial carcinoma (EC). The findings of this review indicate the factors that can facilitate better treatment selection and, consequently, better outcomes in patients with CC and EC.Reports on brain metastases (BMs) from uterine cervical carcinoma (CC) and uterine endometrial carcinoma (EC) have recently increased due to the development of massive databases and improvements in diagnostic procedures. This review separately investigates the prevalence, clinical characteristics, clinical presentation, diagnosis, treatment, and prognosis of BMs from CC and uterine endometrial carcinoma EC. For patients with CC, early-stage disease and poorly differentiated carcinoma lead to BMs, and elderly age, poor performance status, and multiple BMs are listed as poor prognostic factors. Advanced-stage disease and high-grade carcinoma are high-risk factors for BMs from EC, and multiple metastases and extracranial metastases, or unimodal therapies, are possibly factors indicating poor prognosis. There is no “most effective” therapy that has gained consensus for the treatment of BMs. Treatment decisions are based on clinical status, number of the metastases, tumor size, and metastases at distant organs. Surgical resection followed by adjuvant radiotherapy appears to be the best treatment approach to date. Stereotactic ablative radiation therapy has been increasingly associated with good outcomes in preserving cognitive functions. Despite treatment, patients died within 1 year after the BM diagnosis. BMs from uterine cancer remain quite rare, and the current evidence is limited; thus, further studies are needed.

SUN-LB132 Frequency and Impact of Mutations in Tumor Suppressor Gene CDC73 in General Population and Malignant Tumors

Background: CDC73 gene is a putative tumor suppressor gene, and somatic and germline mutations of this gene have been linked with parathyroid tumors. There are also some reports suggesting that germline CDC73 mutations may increase risk of jaw, kidney and uterine tumors. However, the incidence and significance of CDC73 somatic mutations is largely unknown in tumors other than parathyroid tumors. Methods/Design: 1) Assess CDC73 germline mutation frequency and genotypes in general population using ExAC (Exome Aggregation Consortium) and gnomAD (Genome Aggregation Database); 2) Assess CDC73 somatic mutation frequency in various type of tumors using the Cancer Genome Atlas (TCGA) and non-TCGA datasets; 3) Examine significance of CDC73 mutation in uterine endometrial carcinoma (UCEC). Overall survival, CDC73 mutation signature, gene expression profile (GEP) and tumor immune microenvironment were compared between the UCEC samples with and without CDC73 mutations. Results: In ExAC and gnomAD databases, most of CDC73 germline mutations were mapped to the intron regions of the CDC73 gene and nonsynonymous CDC73 mutations are very rare, with allele frequency ranging from 8.24e-06 to 9.92e-05 and 3.97e-06 to 7.43e-05, respectively. Missense mutations accounted for more than 95% of the nonsynonymous mutations in the CDC73 gene in both databases. 2) In 155 cancer genomics studies including both TCGA and non-TCGA datasets with no overlapping samples, CDC73 was mutated in 0.7% cases and missense mutations comprised 78% of the CDC73 mutations. CDC73 somatic mutations were undetected or rarely detected in endocrine tumors except for parathyroid tumors. 3) UCEC is the tumor type that has the second highest CDC73 somatic mutation rate (8%) after parathyroid tumors. The UCEC with CDC73 mutations had a significantly better overall survival with a logrank p-value of 0.033 compared to the tumors with CDC73 WT. GEP analysis revealed that the CDC73-mutated UCEC tumors had significant upregulation of immunological markers and enriched immunologic signature compared to the CDC73-WT tumors. In silico analysis of tumor immune microenvironment showed higher fractions of cytotoxic CD8 cells, T follicular helper cells and M1 macrophage in the CDC73-mutated UCEC tumors. The majority of the CDC73-mutated tumors were POLE ultra-mutated and microsatellite instability (MSI) subtypes, which likely account for a better survival and an increased immune-cell infiltrate of these tumors. Conclusion: CDC73 mutations is rare in general population and tumors except for parathyroid carcinoma and UCEC. CDC73 mutation is a marker for better prognosis in UCEC and is associated with increased immune cell infiltrate in tumor microenvironment, likely due to majority of the CDC73-mutated tumors were POLE ultra-mutated and microsatellite instability (MSI) subtypes.

Gamma Knife Surgery for Brain Metastases from Uterine Malignant Tumor

Uterine malignant tumors (uterine cervical carcinoma [UCC], uterine endometrial carcinoma, and uterine sarcoma) are common in women. Brain metastases from uterine malignant tumors are rare, but its incidence has been increasing. The present study aimed to investigate the characteristics of brain metastases from uterine malignant tumors, evaluate predictive factors, and assess the efficacy of Gamma Knife surgery (GKS) for metastases from uterine malignant tumors. We retrospectively reviewed the records of patients with brain metastases from uterine malignant tumors treated at Tokyo Gamma Unit Center from 2005 to2017. We identified 37 patients: 16 had UCC, 12 had uterine endometrial carcinoma, and 9 had uterine sarcoma. Their median age at diagnosis of brain metastases was 54.0 years. The median interval from diagnosis of uterine malignant tumor to brain metastases was 21.0 months, the median number of brain metastases was 3.0, and the median Karnofsky Performance Status at first GKS was 80%. The median survival after first GKS was 6.0 months. All patients had other metastases. Six-month and 1-year survival after first GKS were 48.9% and 32.6%, respectively, and the tumor control rate at 6 months after GKS was 90.8%. Brain metastases from UCC were significantly correlated with good tumor control (P= 0.024). Multivariate analysis determined that Karnofsky Performance Status was significantly associated with patient survival (P= 0.001). The results of our study suggest that GKS is an acceptable choice for controlling brain metastases from uterine malignant tumors. In particular, GKS provides excellent local control for metastases from UCC.

ALDH-Dependent Glycolytic Activation Mediates Stemness and Paclitaxel Resistance in Patient-Derived Spheroid Models of Uterine Endometrial Cancer.

SummaryUterine endometrial cancer is associated with poor survival outcomes in patients with advanced-stage disease. Here, we developed a three-dimensional cell cultivation method of endometrioid cancer stem-like cells with high aldehyde dehydrogenase (ALDH) activity from clinical specimens. ALDH inhibition synergized with paclitaxel to block cancer proliferation. In the clinical setting, high ALDH1A1 expression was associated with poor survival. A high level of ALDH correlated with an increase of glucose uptake, activation of the glycolytic pathway, and elevation of glucose transporter 1 (GLUT1). Blockade of GLUT1 inhibited characteristics of cancer stem cells. Similarly to ALDH inhibition, GLUT1 inhibition synergized with paclitaxel to block endometrial cancer proliferation. Our data indicated that ALDH-dependent GLUT1 activation and the resulting glycolytic activation are of clinical importance for both prognostic evaluation and therapeutic decision-making in endometrial cancer patients. In addition, the synergistic effects of taxane compounds and ALDH or GLUT1 inhibitors may serve as a new clinical treatment option for endometrial cancer.

Idiopathic Postmenopausal Uterine Inversion: A Case Report

Inversion of the uterus is a rare gynecological condition. The majority of reported cases were encountered in the immediate postpartum period. A non-puerperal inversion occurs when the uterus acts to expel a submucous lesion attached to the fundus, such as uterine fibroid, endometrial carcinoma, sarcoma or polyp. We report a case of spontaneous postmenopausal uterine inversion without underlying pathology. The diagnosis of non-puerperal uterine inversion is often difficult and requires a high index of suspicion J Med Cases. 2019;10(4):110-112 doi: https://doi.org/10.14740/jmc3290

A New Function of Granulocyte Colony-stimulating Factor (G-CSF): Suppression of Cell Proliferation in Uterine Endometrial Carcinoma

Granulocyte colony-stimulating factor (G-CSF) is cytokine which belongs to the family of colony-stimulating factors and recombinant human G-CSF has been widely used in clinical practice for treating patients with neutropenia for over 20 years. Recently, it has also seen use in assisted reproductive technology (ART) treatment based on the hypothesis that G-CSF might help the uterine endometrium proliferate and prepare for implantation. However, the risk of this treatment has not been fully assessed yet and there is a potential complication with its usage. It has been reported that G-CSF stimulates cell proliferation in hematopoietic cells and various other cell types, including cancer cells, suggesting that repeated local G-CSF administration into the uterine cavity might raises the risk of contracting uterine endometrial carcinoma. Based on this hypothesis, we assessed the effect of G-CSF on human uterine carcinoma cell proliferation, using cell lines. Our study showed that G-CSF administration produced dose-dependent suppression of proliferation of human uterine endometrial carcinoma cells through a G-CSF receptor-independent mechanism via a part of mitogen-activated protein kinase (MAPK) signaling pathway. While further studies will be needed to confirm G-CSFs efficacy in improving the outcomes of ART treatment, our data at least suggests that repeated G-CSF administration does not increase the risk of uterine endometrial carcinoma and may even lower it.

TP53 mutations as potential prognostic markers for specific cancers: analysis of data from The Cancer Genome Atlas and the International Agency for Research on Cancer TP53 Database.

Mutations in the tumor suppressor gene TP53 are associated with a variety of cancers. Therefore, it is important to know the occurrence and prognostic effects of TP53 mutations in certain cancers. Over 29,000 cases from the April 2016 release of the International Agency for Research on Cancer (IARC) TP53 Database were analyzed to determine the distribution of germline and somatic mutations in the TP53 gene. Subsequently, 7,893 cancer cases were compiled in cBioPortal for Cancer Genomics from the 33 most recent The Cancer Genome Atlas (TCGA) studies to determine the prevalence of TP53 mutations in cancers and their effects on survival and disease-free survival times. The data were analyzed, and it was found that the majority of TP53 mutations were missense and the major mutational hotspots were located at codons 248, 273, 175, and 245 in exons 4-8 for somatic mutations with the addition of codon 337 and other mutations in exons 9-10 for germline mutations. Out of 33 TGCA studies, the effects of TP53 mutations were statistically significant in nine cancers (lung adenocarcinoma, hepatocellular carcinoma, head and neck squamous cell carcinoma, acute myeloid leukemia, clear cell renal cell carcinoma (RCC), papillary RCC, chromophobe RCC, uterine endometrial carcinoma, and thymoma) for survival time and in five cancers (pancreatic adenocarcinoma, hepatocellular carcinoma, chromophobe RCC, acute myeloid leukemia, and thymoma) for disease-free survival time. It was also found that the most common p53 mutation in hepatocellular carcinomas (R249S) was a much better indicator for poor prognosis than TP53 mutations as a whole. In addition, in cases of ovarian serous cystadenocarcinoma, the co-occurrence of TP53 and BRCA mutations resulted in longer survival and disease-free survival times than the presence of neither TP53 nor BRCA mutations. TP53 mutations are potential prognostic markers that can be used to further improve the accuracy of predicting survival and disease-free survival times of cancer patients.

Clonal analysis revealed functional heterogeneity in cancer stem-like cell phenotypes in uterine endometrioid adenocarcinoma

Uterine endometrial carcinoma is one of the common cancers in females. Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are a small subpopulation of cancer cells that are tumorigenic and are resistant to treatments, thus they are focused as treatment targets. However, the heterogeneity of CSCs/CICs is still elusive, and we therefore analyzed CSCs/CICs at the clonal level. We previously established sphere-cultured CSCs/CICs from primary human uterine endometrial carcinoma, and we isolated several clones from CSCs/CICs in this study. Interestingly, we established two types of clones based on the growth pattern. The clones were termed sphere clones (S clones) and leukemia-like clones (LL clones). Functional analysis revealed that S clones are resistant to chemotherapy, whereas LL clones are sensitive to chemotherapy. On the other hand, S clones are less tumorigenic, while LL clones are highly tumorigenic. Transcriptome analysis using serial analysis of gene expression sequencing (SAGE-Seq) revealed distinctive gene expression profiles in S clone cells and LL clone cells. The results indicate that CSCs/CICs are composed of functionally heterogenic subpopulations including highly tumorigenic clones and treatment-resistant clones and that the characteristics of CSCs/CICs might be determined by the characteristics of different clones that compose CSCs/CICs.