Glutamine and amino acid metabolism as a prognostic signature and therapeutic target in endometrial cancer.

INTRODUCTION: Endometrial cancer (EC) is the most common female reproductive system cancer in developed countries with growing incidence and associated mortality, which may be due to the growing prevalence of obesity. Metabolism reprogramming including glucose, amino acid, and lipid remodeling is a hallmark of tumors. Glutamine metabolism has been reported to participate in tumor proliferation and development. This study aimed to develop a glutamine metabolism-related prognostic model for EC and explore potential targets for cancer treatment. METHOD: Transcriptomic data and survival outcome of EC were retrieved from The Cancer Genome Atlas (TCGA). Differentially expressed genes related to glutamine metabolism were recognized and utilized to build a prognostic model by univariate and multivariate Cox regressions. The model was confirmed in the training, testing, and the entire cohort. A nomogram combing prognostic model and clinicopathologic features was established and tested. Moreover, we explored the effect of a key metabolic enzyme, PHGDH, on the biological behavior of EC cell lines and xenograft model. RESULTS: Five glutamine metabolism-related genes, including PHGDH, OTC, ASRGL1, ASNS, and NR1H4, were involved in prognostic model construction. Kaplan-Meier curve suggested that patients recognized as high risk underwent inferior outcomes. The receiver operating characteristic (ROC) curve showed the model was sufficient to predict survival. Enrichment analysis recognized DNA replication and repair dysfunction in high-risk patients whereas immune relevance analysis revealed low immune scores in the high-risk group. Finally, a nomogram integrating the prognostic model and clinical factors was created and verified. Further, knockdown of PHGDH showed cell growth inhibition, increasing apoptosis, and reduced migration. Promisingly, NCT-503, a PHGDH inhibitor, significantly repressed tumor growth in vivo (p = 0.0002). CONCLUSION: Our work established and validated a glutamine metabolism-related prognostic model that favorably evaluates the prognosis of EC patients. DNA replication and repair may be the crucial point that linked glutamine metabolism, amino acid metabolism, and EC progression. High-risk patients stratified by the model may not be sufficient for immune therapy. PHGDH might be a crucial target that links serine metabolism, glutamine metabolism as well as EC progression.

Targeting Cancer Metabolism Plasticity with JX06 Nanoparticles via Inhibiting PDK1 Combined with Metformin for Endometrial Cancer Patients with Diabetes.

Diabetes is closely related to the occurrence of endometrial cancer (EC) and its poor prognosis. However, there is no effective clinical treatment for EC patients with diabetes (patientEC+/dia+ ). To explore new therapeutic targets, Ishikawa is cultured with high glucose (IshikawaHG ) mimicking hyperglycemia in patientEC+/dia+ . Subsequently, it is discovered that IshikawaHG exhibits glucose metabolic reprogramming characterized by increased glycolysis and decreased oxidative phosphorylation. Further, pyruvate dehydrogenase kinase 1 (PDK1) is identified to promote glycolysis of IshikawaHG by proteomics. Most importantly, JX06, a novel PDK1 inhibitor combined metformin (Met) significantly inhibits IshikawaHG proliferation though IshikawaHG is resistant to Met. Furthermore, a reduction-sensitive biodegradable polymer is adopted to encapsulate JX06 to form nanoparticles (JX06-NPs) for drug delivery. It is found that in vitro JX06-NPs have better inhibitory effect on the growth of IshikawaHG as well as patient-derived EC cells (PDC) than JX06. Additionally, it is found that JX06-NPs can accumulate to the tumor of EC-bearing mouse with diabetes (miceEC+/dia+ ) after intravenous injection, and JX06-NPs combined Met can significantly inhibit tumor growth of miceEC+/dia+ . Taken together, the study demonstrates that the combination of JX06-NPs and Met can target the cancer metabolism plasticity, which significantly inhibits the growth of EC, thereby provides a new adjuvant therapy for patientsEC+/dia+ .

Sentinel Lymph Node Mapping in Endometrial Cancer: A Comprehensive Review.

Endometrial cancer (EC) is known as a common gynecological malignancy. The incidence rate is on the increase annually. Lymph node status plays a crucial role in evaluating the prognosis and selecting adjuvant therapy. Currently, the patients with high-risk (not comply with any of the following: (1) well-differentiated or moderately differentiated, pathological grade G1 or G2; (2) myometrial invasion< 1/2; (3) tumor diameter < 2 cm are commonly recommended for a systematic lymphadenectomy (LAD). However, conventional LAD shows high complication incidence and uncertain survival benefits. Sentinel lymph node (SLN) refers to the first lymph node that is passed by the lymphatic metastasis of the primary malignant tumor through the regional lymphatic drainage pathway and can indicate the involvement of lymph nodes across the drainage area. Mounting evidence has demonstrated a high detection rate (DR), sensitivity, and negative predictive value (NPV) in patients with early-stage lower risk EC using sentinel lymph node mapping (SLNM) with pathologic ultra-staging. Meanwhile, SLNM did not compromise the patient's progression-free survival (PFS) and overall survival (OS) with low operative complications. However, the application of SLNM in early-stage high-risk EC patients remains controversial. As revealed by the recent studies, SLNM may also be feasible, effective, and safe in high-risk patients. This review aims at making a systematic description of the progress made in the application of SLNM in the treatment of EC and the relevant controversies, including the application of SLNM in high-risk patients.

Effects of Metabolic Syndrome and Its Components on the Prognosis of Endometrial Cancer.

Objective: To explore the effects of metabolic syndrome (MetS) on the prognosis of endometrial cancer (EC) and to identify key components of MetS associated with EC. Methods: A total of 506 patients surgically diagnosed with EC were analyzed in this study. These patients were diagnosed with EC in the Department of Obstetrics and Gynecology at the People's Hospital of Peking University between 2010 and 2016. The follow-up time was cut off at December 2019. MetS was characterized based on standards provided by the Chinese Diabetes Society in 2004. Results: Among the 506 EC patients analyzed, 153 patients were diagnosed with MetS. MetS patients were more likely to be older and postmenopausal. MetS was positively related to tumor grade, stage, LNM, LVSI, and MI. The univariate analysis showed that MetS was closely related to the OS (HR = 2.14; P = 0.032) and RFS (HR = 1.80; P = 0.045) of EC patients. K-M analysis also indicated that EC patients with MetS had shorter OS and RFS than EC patients without MetS. More specifically, patients that had ≥3 components showed a worse outcome compared with patients only having 0 or 1-2 components (P <0.05). In the multivariate-adjust model, after adjusting for age, histotype, tumor grade, and stage, HDL-C was found to be associated with increased risk of death related to EC (HR = 2.2, P = 0.034). However, MetS did not significantly correlate with this. ROC analysis revealed that the area under the ROC curve of combined factors (HDL-C + grade + stage) was better than traditional stage or grade at 1-, 3-, and 5-year survival rates. From this, a nomogram based on HDL-C, grade, and stage was constructed to predict survival of EC patients. Calibration curve analysis and decision curve analysis (DCA) showed the nomogram we constructed could better predict the survival of EC patients. Conclusion: MetS is closely related to poor prognosis in EC patients. The prevalence of individual MetS components increase with worse outcomes in EC patients. A nomogram based on HDL-C, grade, and stage has good ability to predict survival of EC patients.

Primary ovarian carcinoid: Two cases report and review of literature.

INTRODUCTION: Carcinoid tumor is one of the most frequent neuroendocrine tumors, and the majority of which are usually observed in the lungs and gastrointestinal tract. The prevalence of ovarian carcinoids is merely 0.1% in ovarian neoplasms and 1% in carcinoid tumors. We described 2 rare cases in our hospital of primary ovarian carcinoid (POC), causing carcinoid syndrome (CS) of the diarrhea, constipation, and carcinoid heart disease. Besides, we also reviewed related literatures about its origin, variant, clinical manifestation, diagnosis methods, pathological features, treatment strategies and prognosis from 2009 to 2019. PATIENT CONCERNS: Case 1 was a 61-year-old postmenopausal woman and presented with diarrhea, abdominal pain, enlargement, bloating and dizziness. Case 2 was a 49-year-old patient who complained of constipation, abdominal pain, bloating, and headache. DIAGNOSIS: Both patients were diagnosed as primary ovarian carcinoid, insular type. INTERVENTIONS: Total abdominal hysterectomy (TAH), bilateral salpingo-oophorectomy (BSO), omentectomy, pelvic lymphadenectomy, and appendectomy without chemotherapy were performed in case 1. Cervix resection, right salpingo-oophorectomy, appendectomy, and pelvic lesion resection with chemotherapy was conducted in case 2. OUTCOMES: Both patients achieved satisfactory treatment effects. The follow-up period was 18 and 17 months in case 1 and case 2, respectively. Case 1 encountered carcinoid heart disease and received percutaneous transluminal coronary angioplasty (PTCA) postoperatively. Case 2 suffered multiple metastases postoperatively. However, after effective treatment, both patients were in good condition during follow-up duration. CONCLUSION: POC is an extraordinarily rare disease, and commonly with a satisfactory outcome. TAH+BSO with or without postoperative chemotherapy has been considered as an acceptable treatment strategy for POC patients.

Pregnancy with giant ovarian dysgerminoma: A case report and literature review.

RATIONALE: Dysgerminoma is an extraordinarily rare neoplasm arising from the malignant germ cells of the ovary. Early antenatal diagnosis and proper management of the neoplasm to improve maternal-neonatal results are the considerable challenges facing the gyne-oncologist. We summarize the clinical features and discuss treatment strategies of the ovary dysgerminoma (OD). Besides, we also review the literature on OD in PubMed, Web of Science Core Collection, Library of Congress, and LISTA from 1939 to 2019 to evaluate its clinical characteristics, feto-maternal compromise, management, and fertility outcome. PATIENT CONCERNS: A 25-year-old pregnant woman reported lower abdominal pain and vomiting. DIAGNOSIS: The patient was diagnosed as right OD. INTERVENTIONS: She received a cesarean section due to severe abdominal pain, delivered a healthy girl at 38 C 4 weeks of gestation, and accepted fertility-preserving surgery. However, the patient refused chemotherapy postoperatively. OUTCOMES: The patient was followed up 42 days, 3 months, and 6 months after surgery, and no tumor recurrence was observed. LESSONS: OD has non-specificity characteristics, including age, symptoms, image date, and tumor marks. However, these abnormal indicators may provide some evidence for accurate antenatal diagnosis. The management strategies should be considered comprehensively on an individual basis, and fertility-preserving surgery should be carried out in the second trimester if further pregnancy is desired. Adjuvant chemotherapy needs to be applied to the treatment of OD patients with The International Federation of Gynecology and Obstetrics (FIGO) stages II, III, and IV and timely chemotherapy is suggested if there are several weeks before the expected date of delivery. The overall prognosis of OD patients is excellent.