Comprehensive proteomic analysis reveals distinct features and a diagnostic biomarker panel for early pregnancy loss in histological subtypes.

Early pregnancy loss (EPL) is a common event in human reproduction and is classified into histological subtypes such as hydropic abortion (HA) and hydatidiform moles (HMs), including complete hydatidiform moles (CHMs) and partial hydatidiform moles (PHMs). However, accurate diagnosis and improved patient management remain challenging due to high rates of misdiagnosis and diverse prognostic risks. Therefore, diagnostic biomarkers for EPL are urgently needed. Our study aimed to identify biomarkers for EPL through comprehensive proteomic analysis. Ten CHMs, six PHMs, ten HAs and ten normal control (NC) products of conception (POC) were used to obtain a proteomic portrait. Parallel reaction monitoring (PRM)-targeted proteomic and regression analyses were used to verify and select the diagnostic signatures. Finally, 14 proteins were selected and a panel of diagnostic classifiers (DLK1, SPTB/COL21A1, and SAR1A) was built to represent the CHM, PHM, and NC groups (auROC=0.900, 0.804/0.885, and 0.991, respectively). This high diagnostic power was further validated in another independent cohort (n = 148) by immunohistochemistry (IHC) (n = 120) and western blot (WB) analyses (n = 28). The protein SPTB was selected for further biological behaviour experiments in vitro. Our data suggest that SPTB maintains trophoblast cell proliferation, angiogenesis, cell motility and the cytoskeleton network. This study provides a comprehensive proteomic portrait and identifies potential diagnostic biomarkers. These findings enhance our understanding of EPL pathogenesis and offer novel targets for diagnosis and therapeutic interventions.

Stage IIB-IVA cervix carcinoma in elderly patients treated with radiation therapy: a longitudinal cohort study by propensity score matching analysis.

OBJECTIVE: We aimed to evaluate the treatment modality and prognostic impact of the age at diagnosis on stage IIB-IVA cervix carcinoma (CC) patients who received radiotherapy (RT).The evaluation was performed using the Surveillance, Epidemiology, and End Results (SEER) database. PATIENTS AND METHODS: From the SEER database, we included the patients with a histopathological diagnosis of CC between 2004 and 2016. Subsequently, we compared the treatment outcomes between patients aged ≥ 65 years (OG) and < 65 years (YG) by propensity score matching (PSM) analysis and Cox proportional hazard regression models. RESULTS: The data of 5,705 CC patients were obtained from the SEER database. We observed that the OG patients were significantly less likely to receive chemotherapy, brachytherapy, or combination treatment compared to the YG (P < 0.001). Further, the advanced age at diagnosis was an independent prognostic factor associated with decreasing overall survival (OS) before and after PSM. Even in the subgroup analysis of patients who received trimodal therapy, an advanced age had a significant negative impact on OS compared to their younger counterparts. CONCLUSION: Advanced age is associated with less aggressive treatment regimens and is independently associated with impaired OS for stage IIB-IVA CC patients who received RT. Hence, future studies should incorporate geriatric assessment into clinical decision-making to select appropriate and effective treatment strategies for elderly CC patients.

Microtubule-severing protein Fidgetin-like 1 promotes spindle organization during meiosis of mouse oocytes.

Microtubule-severing proteins (MTSPs) play important roles in mitosis and interphase. However, to the best of our knowledge, no previous studies have evaluated the role of MTSPs in female meiosis in mammals. It was found that FIGNL1, a member of MTSPs, was predominantly expressed in mouse oocytes and distributed at the spindle poles during meiosis in the present study. FIGNL1 was co-localized and interacted with γ-tubulin, an important component of the microtubule tissue centre (MTOC). Fignl1 knockdown by specific small interfering RNA caused spindle defects characterized by an abnormal length:width ratio and decreased microtubule density, which consequently led to aberrant chromosome arrangement, oocyte maturation and fertilization obstacles. In conclusion, the present results suggested that FIGNL1 may be an essential factor in oocyte maturation by influencing the meiosis process via the formation of spindles.

Spastin interacts with CRMP5 to promote spindle organization in mouse oocytes by severing microtubules.

Microtubule-severing protein (MTSP) is critical for the survival of both mitotic and postmitotic cells. However, the study of MTSP during meiosis of mammalian oocytes has not been reported. We found that spastin, a member of the MTSP family, was highly expressed in oocytes and aggregated in spindle microtubules. After knocking down spastin by specific siRNA, the spindle microtubule density of meiotic oocytes decreased significantly. When the oocytes were cultured in vitro, the oocytes lacking spastin showed an obvious maturation disorder. Considering the microtubule-severing activity of spastin, we speculate that spastin on spindles may increase the number of microtubule broken ends by severing the microtubules, therefore playing a nucleating role, promoting spindle assembly and ensuring normal meiosis. In addition, we found the colocalization and interaction of collapsin response mediator protein 5 (CRMP5) and spastin in oocytes. CRMP5 can provide structural support and promote microtubule aggregation, creating transportation routes, and can interact with spastin in the microtubule activity of nerve cells (30). Knocking down CRMP5 may lead to spindle abnormalities and developmental disorders in oocytes. Overexpression of spastin may reverse the abnormal phenotype caused by the deletion of CRMP5. In summary, our data support a model in which the interaction between spastin and CRMP5 promotes the assembly of spindle microtubules in oocytes by controlling microtubule dynamics, therefore ensuring normal meiosis.

Surgical and Pathological Outcomes of Laparoscopic Versus Abdominal Radical Hysterectomy With Pelvic Lymphadenectomy and/or Para-aortic Lymph Node Sampling for Bulky Early-Stage Cervical Cancer.

BACKGROUND AND OBJECTIVES: The aim of this study was to compare the feasibility, morbidity, and recurrence rate of total laparoscopic radical hysterectomy (LRH) with those of abdominal radical hysterectomy (ARH) for bulky early-stage cervical cancer. METHODS: We performed a retrospective cohort study of 112 patients with stage IB1 or IIA2 cervical cancer in which the tumor diameter was 3 cm or greater. All patients underwent LRH (n = 30) or ARH (n = 82) with pelvic lymphadenectomy and/or para-aortic lymph node sampling between May 2011 and November 2014. Perioperative outcomes were compared between the 2 surgical groups. RESULTS: The laparoscopic approach consisted of 4 trocar insertions. Age, tumor diameter, and pelvic lymph nodes significantly differed between the 2 cohorts. Body mass index, International Federation of Gynecology and Obstetrics stage, histologic type and grade, deep stromal invasion, lymphovascular space invasion, positive margins, and adjuvant therapy were not significantly different between the 2 cohorts. Laparoscopic radical hysterectomy exhibited favorable results compared with ARH in terms of operating time, blood loss, intestinal exhaust time, and length of hospital stay. In addition, recurrence was observed in 5 LRH patients (16.7%) and 9 ARH patients (11.7%). CONCLUSIONS: The surgical outcomes of LRH with pelvic lymphadenectomy and/or para-aortic lymph node sampling exhibited a similar therapeutic efficacy to those of the ARH approach.

[Association between metabolic syndrome and prognosis of endometrioid carcinoma].

OBJECTIVE: To study the association between metabolic syndrome(MS)and prognosis of endometrioid carcinoma. METHODS: A total of 256 patients with endometrioid carcinoma at, Zhejiang Cancer Hospital between January, 2001 and December, 2008 were chosen. The deadline for follow up was December 2008. The general conditions(including age and body mass index), whether coupled with MS and it's risk factors(including waist circumference, fasting plasma glucose, triglycerides, high- density lipoprotein, systolic and diastolic blood pressure) were analyzed. The outcome of 256 patients whether coupled with MS were analyzed using Kaplan-Meier curve. Relative risks were estimated using Cox proportional hazards regression model. RESULTS: A total of 256 cases were followed-up successfully.Sixty-four (33.0%) cases coupled with MS among the 194 patients survived, while thirty-two (51.6%) coupled with MS from 62 cases died, there was significant difference between them(χ² = 6.953, P = 0.008). The total five-year survival rate was 75.8%, the survival time was (78.0 ± 3.4) months. The rate and the survival time of patients coupled with MS [66.7%, (67.0 ± 2.4) months] were significantly lower than those coupled with no MS [81.3%, (85.0 ± 4.0) months; P < 0.05]. The Cox proportional hazards regression results showed that coupled with MS, body mass index ≥ 25 kg/m², waist circumference > 80 cm, abnormol systolic and diastolic blood pressure, abnormal fasting plasma glucose and more than two components of definitions of MS were related to bad prognosis of endometrioid carcinoma (P < 0.05). CONCLUSION: Metabolic syndrome may be lead to a bad prognosis of endometrioid carcinoma.

Cynaroside regulates the AMPK/SIRT3/Nrf2 pathway to inhibit doxorubicin-induced cardiomyocyte pyroptosis. / 木犀草苷通过调节AMPK/SIRT3/Nrf2é€šè·¯æŠ‘åˆ¶é˜¿éœ‰ç´ è¯±å¯¼çš„å¿ƒè‚Œç»†èƒžç„¦äº¡.

Doxorubicin (DOX) is a commonly administered chemotherapy drug for treating hematological malignancies and solid tumors; however, its clinical application is limited by significant cardiotoxicity. Cynaroside (Cyn) is a flavonoid glycoside distributed in honeysuckle, with confirmed potential biological functions in regulating inflammation, pyroptosis, and oxidative stress. Herein, the effects of Cyn were evaluated in a DOX-induced cardiotoxicity (DIC) mouse model, which was established by intraperitoneal injections of DOX (5 mg/kg) once a week for three weeks. The mice in the treatment group received dexrazoxane, MCC950, and Cyn every two days. Blood biochemistry, histopathology, immunohistochemistry, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and western blotting were conducted to investigate the cardioprotective effects and potential mechanisms of Cyn treatment. The results demonstrated the significant benefits of Cyn treatment in mitigating DIC; it could effectively alleviate oxidative stress to a certain extent, maintain the equilibrium of cell apoptosis, and enhance the cardiac function of mice. These effects were realized via regulating the transcription levels of pyroptosis-related genes, such as nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), caspase-1, and gasdermin D (GSDMD). Mechanistically, for DOX-induced myocardial injury, Cyn could significantly modulate the expression of pivotal genes, including adenosine monophosphate-activated protein kinase (AMPK), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), sirtuin 3 (SIRT3), and nuclear factor erythroid 2-related factor 2 (Nrf2). We attribute it to the mediation of AMPK/SIRT3/Nrf2 pathway, which plays a central role in preventing DOX-induced cardiomyocyte injury. In conclusion, the present study confirms the therapeutic potential of Cyn in DIC by regulating the AMPK/SIRT3/Nrf2 pathway.

Developing an erythrocyte‒MHC-I conjugate for cancer treatment.

Mature erythrocytes are known to lack major histocompatibility complex (MHC) proteins. However, the presence of MHC molecules on erythrocytes has been occasionally reported, though without a defined function. In this study, we designed erythrocyte conjugated solely with a fusion protein consisting of an antigenic peptide linked to MHC class I (MHC-I) protein, termed MHC-I‒Ery. The modified erythrocyte, decorated with the peptide derived from human papillomavirus (HPV) 16 oncoprotein E6/E7, effectively activated antigen-specific CD8+ T cells in peripheral blood mononuclear cells (PBMCs) from HPV16+ cervical cancer patients. Additionally, MHC-I‒Ery monotherapy was shown to inhibit antigen-positive tumor growth in mice. This treatment immediately activated CD8+ T cells and reduced suppressive myeloid cells in the spleen, leading to systemic anti-tumor activity. Safety and tolerability evaluations of MHC-I‒Ery in non-human primates further supported its clinical potential. Our results first demonstrated that erythrocytes equipped solely with antigen peptide‒MHC-I complexes can robustly stimulate the immune system, suggesting a novel and promising approach for advancing cancer immunotherapy.

Reappraisal and refined diagnosis of ultrasonography and histological findings for hydatidiform moles: a multicentre retrospective study of 821 patients.

AIMS: Specific identification of a hydatidiform mole (HM) and subclassification of a complete hydatidiform mole (CHM) or partial hydatidiform mole (PHM) are critical. This study aimed to reappraise the diagnostic performance of ultrasonography and histology with a refined diagnosis. METHODS: This was a retrospective, multicentre cohort study of 821 patients with histologically suspected HM specimens. Refined diagnostic algorithms with p57 immunohistochemistry and short tandem repeat (STR) genotyping were performed and used as the true standard for assessing the diagnostic performance of the original ultrasonography and morphology methods. The diagnostic performance was calculated using accuracy, agreement rate, sensitivity and the positive predictive value (PPV) compared with refined diagnostic results. RESULTS: Of the 821 histologically suspected HM cases included, 788 (95.98%) were successfully reclassified into 448 CHMs, 213 PHMs and 127 non-molar (NM) abortuses. Ultrasonography showed an overall accuracy of 44.38%, with a sensitivity of 44.33% for CHM and 37.5% for PHM. The overall classification accuracy of the original morphological diagnosis was 65.97%. After exclusion of the initially untyped HMs, the overall agreement rate was 59.11% (κ=0.364, p<0.0001) between the original and refined diagnoses, with a sensitivity of 40.09% and PPV of 96.05% for diagnosing CHMs and a sensitivity of 84.98% and a PPV of 45.59% for diagnosing PHMs. The interinstitutional variability of morphology in diagnosing HMs was significant among the 15 centres (range, 8.33%-100.00%, p<0.0001). CONCLUSION: The current diagnosis of HM based solely on ultrasound or morphology remains problematic, and ancillary techniques, particularly p57 immunohistochemistry and DNA genotyping, should be integrated into routine practice as much as possible.

Triage performance of PAX1m/JAM3m in opportunistic cervical cancer screening of non‒16/18 human papillomavirus-positive women: a multicenter prospective study in China.

OBJECTIVES: In this study, we aimed to validate the performance of the PAX1 and JAM3 methylation (PAX1m/JAM3m) test as a triage tool for detecting cervical intraepithelial neoplasia grade 3 or worse (CIN3 +) in non-16/18 high-risk human papillomavirus-positive patients (non-16/18 hrHPV +). METHODS: The triage performance of liquid-based cytology (LBC) and the PAX1m/JAM3m test for detecting CIN3 + were compared. RESULTS: In total, 1851 participants had cervical histological outcomes and were included in the analysis. The sensitivity/specificity of the LBC test results with atypical squamous cells of undetermined significance or worse (LBC ≥ ASCUS) and the PAX1m/JAM3m test were 90.1%/26.7% and 84.8%/88.5%, respectively. PAX1m/JAM3m( +) had the highest diagnostic AUC (0.866, 95% confidence interval (CI) 0.837-0.896) in the whole cohort. All cancers (n = 20) were detected by PAX1m/JAM3m(+). Compared with LBC ≥ ASCUS, PAX1m/JAM3m(+) reduced the number of patients who needed referral for colposcopy by 57.21% (74.66% vs. 17.45%). The odds ratios for detecting CIN3 + by LBC ≥ ASCUS and PAX1m/JAM3m(+) were 3.3 (95% CI 2.0-5.9) and 42.6 (27.1-69.6), respectively (p < 0.001). The combination of LBC ≥ ASCUS or PAX1m/JAM3m(+) slightly increased the diagnostic sensitivity (98.0%, 95% CI: 95.8-100%) and referral rate (77.09%) but reduced the diagnostic specificity (24.8%, 22.7-26.8%). CONCLUSIONS: In non-16/18 hrHPV(+) women, PAX1m/JAM3m was superior to cytology for detecting CIN3 + . Compared with LBC ≥ ASCUS, PAX1m/JAM3m(+) reduced the number of significant referrals to colposcopy without compromising diagnostic sensitivity.

Clinical analysis of acute postoperative pain after total laparoscopic hysterectomy for adenomyosis and uterine fibroids - a prospective observational study.

OBJECTIVE: To investigate the outcome of total laparoscopic hysterectomy (TLH) and postoperative pain characteristics and compare the pain severity after TLH for adenomyosis or uterine fibroids. METHODS: This prospective observational study collected 101 patients received TLH for adenomyosis (AD group) including 41 patients were injected goserelin (3.6 mg) 28 days before TLH, while other adenomyosis patients received TLH without preoperative treatment, and 113 patients received TLH for uterine fibroids (UF group). Pain scores were evaluated at different time sites from operation day to postoperative 72 h using the numeric rating scale. Clinical data were collected from clinical record. RESULTS: Operative time and anaesthetic time were longer in the AD group than those in the UF group (66.88 ± 8.65 vs. 64.46 ± 7.21, p = 0.04; 83.95 ± 10.05 vs. 79.77 ± 6.88, p < 0.01), severe endometriosis was quite more common in AD group (23.76% vs. 2.65%, p < 0.01). Postoperative usage of Flurbiprofen in AD group were more than that of UF group (15.48 ± 38.00 vs. 4.79 ± 18.16, p = 0.02). Total pains and abdominal visceral pains of AD group were more severe compared with UF group in motion and rest pattern at several time sites, while incision pain and shoulder pain were similar. The total postoperative pains after goserelin preoperative treatment in AD group were less than that without goserelin preoperative treatment (p < 0.05). The levels of serum NPY, PGE2 and NGF after laparoscopic hysterectomy of adenomyosis reduced with GnRH agonist pretreatment. CONCLUSIONS: Acute postoperative pain for adenomyosis and uterine fibroids showed considerably different severity, postoperative total pain and abdominal visceral pains of TLH for adenomyosis were more severe compared with uterine fibroids. While patients received goserelin before laparoscopic hysterectomy of adenomyosis suffered from less severity of postoperative total pain than that without goserelin preoperative treatment.

Acute postoperative pain for adenomyosis and uterine fibroids showed considerably different severity, postoperative total pain and abdominal visceral pains of TLH for adenomyosis were more severe compared with uterine fibroids.Patients received goserelin before laparoscopic hysterectomy of adenomyosis suffered from less severity of postoperative total pain than that without goserelin preoperative treatment.

Parkin regulates IGF2BP3 through ubiquitination in the tumourigenesis of cervical cancer.

BACKGROUND: Insulin-like growth Factor 2 mRNA-binding protein 3 (IGF2BP3) is a highly conserved RNA-binding protein and plays a critical role in regulating posttranscriptional modifications. METHODS: Immunoprecipitation was used to examine the interaction of Parkin and IGF2BP3. Mass spectrometry was performed to identify the ubiquitination sites of IGF2BP3. RNA-immunoprecipitation was conducted to examine the target genes of IGF2BP3. Xenograft mouse model was constructed to determine the tumorigenesis of IGF2BP3. RESULTS: IGF2BP3 expression is negatively correlated with Parkin expression in human cervical cancer cells and tissues. Parkin directly interacts with IGF2BP3, and overexpression of Parkin causes the proteasomal degradation of IGF2BP3, while knockdown of PARK2 increases the protein levels of IGF2BP3. Mechanistically, in vivo and in vitro ubiquitination assays demonstrated that Parkin is able to ubiquitinate IGF2BP3. Moreover, the ubiquitination site of IGF2BP3 was identified at K213 in the first KH domain of IGF2BP3. IGF2BP3 mutation results in the loss of its oncogenic function as an m6A reader, resulting in the inactivation of the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signalling pathways. In addition, IGF2BP3 mutation results in the attenuation of Parkin-mediated mitophagy, indicating its inverse role in regulating Parkin. Consequently, the tumourigenesis of cervical cancer is also inhibited by IGF2BP3 mutation. CONCLUSION: IGF2BP3 is ubiquitinated and regulated by the E3 ubiquitin ligase Parkin in human cervical cancer and ubiquitination modification plays an important role in modulating IGF2BP3 function. Thus, understanding the role of IGF2BP3 in tumourigenesis could provide new insights into cervical cancer therapy.

A 5-year survival status prognosis of nonmetastatic cervical cancer patients through machine learning algorithms.

BACKGROUND: Prediction models with high accuracy rates for nonmetastatic cervical cancer (CC) patients are limited. This study aimed to construct and compare predictive models on the basis of machine learning (ML) algorithms for predicting the 5-year survival status of CC patients through using the Surveillance, Epidemiology, and End Results public database of the National Cancer Institute. METHODS: The data registered from 2004 to 2016 were extracted and randomly divided into training and validation cohorts (8:2). The least absolute shrinkage and selection operator (LASSO) regression was employed to identify significant factors. Then, four predictive models were constructed, including logistic regression (LR), random forest (RF), support vector machine (SVM), and extreme gradient boosting (XGBoost). The predictive models were evaluated and compared using Receiver-operating characteristics with areas under the curves (AUCs) and decision curve analysis (DCA), respectively. RESULTS: A total of 13,802 patients were involved and classified into training (N = 11,041) and validation (N = 2761) cohorts. By using the LASSO regression method, seven factors were identified. In the training cohort, the XGBoost model showed the best performance (AUC = 0.8400) compared to the other three models (all p < 0.05 by Delong's test). In the validation cohort, the XGBoost model also demonstrated a superior prediction ability (AUC = 0.8365) than LR and SVM models (both p < 0.05 by Delong's test), although the difference was not statistically significant between the XGBoost and the RF models (p = 0.4251 by Delong's test). Based on the DCA results, the XGBoost model was also superior, and feature importance analysis indicated that the tumor stage was the most important variable among the seven factors. CONCLUSIONS: The XGBoost model proved to be an effective algorithm with better prediction abilities. This model is proposed to support better decision-making for nonmetastatic CC patients in the future.

Development and validation of a radiomics-based nomogram for the prediction of postoperative malnutrition in stage IB1-IIA2 cervical carcinoma.

Objective: In individuals with stage IB1-IIA2 cervical cancer (CC) who received postoperative radiotherapy ± chemotherapy (PORT/CRT), the interaction between sarcopenia and malnutrition remains elusive, let alone employing a nomogram model based on radiomic features of psoas extracted at the level of the third lumbar vertebra (L3). This study was set to develop a radiomics-based nomogram model to predict malnutrition as per the Patient-Generated Subjective Global Assessment (PG-SGA) for individuals with CC. Methods: In total, 120 individuals with CC underwent computed tomography (CT) scans before PORT/CRT. The radiomic features of psoas at L3 were obtained from non-enhanced CT images. Identification of the optimal features and construction of the rad-score formula were conducted utilizing the least absolute shrinkage and selection operator (LASSO) logistic regression to predict malnutrition in the training dataset (radiomic model). Identification of the major clinical factors in the clinical model was performed by means of binary logistic regression analysis. The radiomics-based nomogram was further developed by integrating radiomic signatures and clinical risk factors (combined model). The receiver operating characteristic (ROC) curves and decision curves analysis (DCA) were employed for the evaluation and comparison of the three models in terms of their predictive performance. Results: Twelve radiomic features in total were chosen, and the rad-score was determined with the help of the non-zero coefficient from LASSO regression. Multivariate analysis revealed that besides rad-score, age and Eastern Cooperative Oncology Group performance status could independently predict malnutrition. As per the data of this analysis, a nomogram prediction model was constructed. The area under the ROC curves (AUC) values of the radiomic and clinical models were 0.778 and 0.847 for the training and 0.776 and 0.776 for the validation sets, respectively. An increase in the AUC was observed up to 0.972 and 0.805 in the training and validation sets, respectively, in the combined model. DCA also confirmed the clinical benefit of the combined model. Conclusion: This radiomics-based nomogram model depicted potential for use as a marker for predicting malnutrition in stage IB1-IIA2 CC patients who underwent PORT/CRT and required further investigation with a large sample size.

Mesonephric-Like Adenocarcinoma of Uterine Corpus: A Clinicopathological and Targeted Genomic Profiling Study in a Single Institution.

Background: Mesonephric-like adenocarcinoma (MLA) is a recently characterized, rare, and aggressive neoplasm that mostly arises in the uterine corpus and ovary. MLA shows characteristic pathological features similar to mesonephric adenocarcinoma of the cervix. The origin of MLA is still controversial and recognition of it remains challenging for pathologists. The aim of this study was to enrich the clinicopathological features of MLA in the uterine corpus and explore its molecular alterations by targeted next-generation sequencing (NGS). Methods: Four cases of MLA were identified among a total of 398 endometrial carcinomas diagnosed in our institution between January 2014 and December 2021. Immunohistochemistry and targeted NGS spanning 437 cancer-relevant genes were performed. Results: The most common symptom was abnormal vaginal bleeding, and the average age was 68 years. Histologically, the tumors showed a mixture of varied growth patterns including papillary, glandular, tubular, cribriform, solid, and slit-like architectures, which were lined by columnar to cuboidal cells with overlapping vesicular nuclei and sometimes nuclear grooves. Intraluminal eosinophilic colloid-like secretions were focally evident in three of the four cases. Immunohistochemically, the MLAs were positive for GATA3 (4/4), TTF-1 (3/3), luminal CD10 (3/3), calretinin (2/3), and patchy P16 (3/3) and were negative for ER (0/4) and PR (0/4). The expression of P53 was "wild type" (4/4). By targeted NGS, 3/4 (75%), 2/4 (50%), and 1/4 (25%) cases harbored PIK3CA, KRAS, and PTEN mutations, respectively. None of the tumors had mutations in DNA mismatch repair genes, ARID1A/B, POLE, CTNNB1, SMARCA4, or TP53. At the time of diagnosis, three were presented with FIGO IB stage and one with IIIC stage. Two patients received postoperative chemotherapy and radiotherapy and they were alive without evidence of disease at 8 and 56 months follow-up, respectively. One patient developed pulmonary metastasis 13 months after surgery and chemotherapy, and one was dead of the disease 24 months after the operation without adjuvant therapy. Conclusions: MLA is a rare and aggressive malignancy, representing approximately 1% of all endometrial carcinomas. It exhibits mixed architectures associated with distinctive immunophenotype and recurrent KRAS and PIK3CA mutations, supporting classified as of Müllerian origin with mesonephric differentiation.

Surgery in platinum-resistant recurrent epithelial ovarian carcinoma.

BACKGROUND: Ovarian cancer is one of the three most common malignant tumors of the female reproductive tract and ranks first in terms of mortality among gynecological tumors. Epithelial ovarian carcinoma (EOC) is the most common ovarian malignancy, accounting for 90% of all primary ovarian tumors. The clinical value of cytoreductive surgery in patients with platinum-resistant recurrent EOC remains largely unclear. AIM: To evaluate the feasibility of secondary cytoreductive surgery for treating platinum-resistant recurrent EOC. METHODS: This was a retrospective study of the clinical data of patients with platinum-resistant EOC admitted to the Cancer Hospital of the University of Chinese Academy of Sciences between September 2012 and June 2018. Patient baseline data were obtained from clinical records. Routine follow-up of disease progression was performed as follows. CA125 assessment and physical examination were performed every 3 wk during treatment, including gynecological examination. Imaging assessment was carried out every 12 wk by B-mode ultrasound, computed tomography, or magnetic resonance imaging. The primary outcome was progression-free survival (PFS). Secondary outcomes included overall survival (OS), chemotherapy-free interval (CFI), and complications. Follow-up ended on April 15, 2019. RESULTS: A total of 38 patients were included. R0 resection was achieved in 25 (65.8%) patients and R1/2 in 13 (34.2%). Twenty-five (65.8%) patients required organ resection. Nine (23.7%) patients had operative complications, 36 (94.7%) received chemotherapy, and five (13.2%) had targeted therapy. Median PFS and OS were 10 (95%CI: 8.27-11.73) months and 28 (95%CI: 12.75-43.25) months, respectively; median CFI was 9 (95%CI: 8.06-9.94) months. R0 resection and postoperative chemotherapy significantly prolonged PFS and OS (all P < 0.05), and R0 resection also significantly prolonged CFI (P < 0.05). Grade ≥ 3 complications were observed, including rectovaginal fistula (n = 1), intestinal and urinary fistulas (n = 1), and renal failure-associated death (n = 1). Except for the patient who died after surgery, all other patients with complications were successfully managed. Two patients developed intestinal obstruction and showed improvement after conservative treatment. CONCLUSION: Secondary cytoreductive surgery is feasible for treating platinum-resistant recurrent EOC. These findings provide important references for the selection of clinical therapeutic regimens.

Expression of WW domain-containing oxidoreductase and its clinical implication in endometrial adenocarcinoma patients with metabolic syndrome.

AIM: Metabolic syndrome (MS) is tightly associated with the oncogenesis and prognosis of endometrioid adenocarcinoma, but the underlying mechanism is unclear. Here, we studied the relation between the expression status of WW domain-containing oxidoreductase (WWOX) and the clinicopathological features of endometrioid adenocarcinoma patients with MS. METHODS: Fifty-seven samples of endometrial adenocarcinoma were chosen for detection of expression level of WWOX. Overall survival (OS) time of these patients was analyzed by univariate and multivariate analysis. Survival analysis of patients with different WWOX expression levels from the Cancer Genome Atlas (TCGA) database was also performed. RESULTS: The WWOX expression is significantly higher in MS group than that in non-MS group (36.4% vs 65.7%, P = .03). WWOX was closely related to MS (P = .03) and muscle invasion of tumor cells (P = .04), but age, tumor grade, status of lymphatic metastasis, and FIGO (International Federation of Gynecology and Obstetrics) stage were not significantly different between the two WWOX expression status. Univariate analysis revealed that lymphatic metastasis (P = .023) and lower stage (P = .006) are significantly associated with OS. Multivariate analysis demonstrated that stage was an independent prognostic factor for OS (hazard ratio = 0.197; 95% CI, 0.043-0.896). Downregulation of WWOX was statistically associated with OS in patients from TCGA database (P = .04). CONCLUSION: WWOX may play an important role in the progression of endometrial cancer with MS.

[Feasibility of unilateral or bilateral nerve-sparing radical hysterectomy in patients with cervical cancer and evaluation of the post-surgery recovery of the bladder and rectal function].

OBJECTIVE: To investigate the feasibility of unilateral or bilateral nerve-sparing radical hysterectomy and evaluate the recovery of bladder and bowel function postoperatively. METHODS: From August 2008 to October 2009, sixty-one patients with cervical cancer stage Ib1 to IIa underwent radical hysterectomy (33 cases) and nerve-sparing radical hysterectomy (28 cases). Unilateral nerve-sparing radical hysterectomy was performed in 10 patients, and bilateral nerve-sparing radical hysterectomy (BNS) was performed in 18 patients. The data of operation time, blood loss, postoperative hospital stay days, residual urine volume, and postoperative complications were collected. The postoperative recovery of bladder and bowel function was evaluated. RESULTS: There were no significant differences between nerve-sparing radical hysterectomy (NSRH) and radical hysterectomy (RH) groups in operation time [NSRH: (224.5 ± 40.0) min, RH: (176.4 ± 30.0 min)], blood loss [NSRH: (464.3 ± 144.0) ml, RH: (374.2 ± 138.7) ml], postoperative hospital stay days [NSRH: (8.4 ± 2.0) d, RH: (9.2 ± 1.8) d, and residual urine volume [NSRH: (64.8 ± 16.9) ml, RH: (70.6 ± 16.0) ml]. There were also no significant differences between UNSRH and BNSRH groups in operation time [UNSRH: (208.5 ± 28.5) min, BNSRH: (233.3 ± 43.1) min], blood loss [UNSRH: (440.0 ± 104.9) ml, BNSRH: (477.8 ± 162.90) ml], postoperative hospital stay days [UNSRH: 9.1 ± 1.8) d, BNSRH: (8.7 ± 2.1 d], and the residual urine volume [UNSRH: (68.3 ± 12.5) ml, BNSRH: (62.8 ± 20.0) ml]. There was a significant difference in the time of the Foley catheter removal between NSRH [(12.4 ± 5.2) d] and RH [(22.4 ± 9.7) d] groups. There was a significant difference in the time of the Foley catheter removal between UNSRH [(18.2 ± 3.6) d] and BNSRH [(9.1 ± 2.0) d] groups. During the postoperative 3 weeks follow-up, the patients in the NSRH group had a higher rate of satisfaction at urination and defecation (100%, 75%) than the RH group (54.5%, 24.2%). CONCLUSION: UNSRH and BNSRH are safe and feasible techniques for early stage cervical cancer, and may significantly improve the recovery of bladder and rectal function.

Association of pretreatment SUVmax of cervix and SCC-antigen with FIGO2018 stage in Stage IIB-IVB squamous cervical cancer and relationship to prognosis.

OBJECTIVE: To evaluate the association of pretreatment maximum standardized 18 F-fluorodeoxyglucose uptake value (SUVmax ) of cervix and serum squamous cell carcinoma antigen (SCC-ag) with FIGO2018 stage and prognosis among women with Stage IIB-IVB squamous cervical cancer. METHODS: Retrospective study of 116 women with FIGO2018 Stage IIB-IVB cervical cancer treated in Hangzhou, China, 2013-2015. The relationship between pretreatment SUVmax or SCC-ag and prognostic factors was evaluated by univariate and multivariate analyses. RESULTS: Women were stratified by mean SUVmax and mean SCC-ag. There was a significant difference between low (<12.9) and high (≥12.9) SUVmax groups in menopause (P = 0.004), FIGO2018 stage (P = 0.015), and survival rate (P < 0.001). The low group had better overall and progress-free survival by Kaplan-Meier evaluation (both P = 0.022). High SCC-ag (≥14.6 ng/mL) was associated with FIGO2018 stage (P = 0.038) and distant metastasis (P = 0.011). There was a significant correlation between SUVmax and serum SCC-ag (P = 0.026). In multivariate Cox regression analyses, FIGO2018 stage (P = 0.019) and SUVmax of cervix (P = 0.015) were independent predictors of poor outcome in squamous cervical cancer. CONCLUSION: Both SUVmax of cervix and SCC-ag were associated with FIGO2018 stage in squamous cervical cancer. Pretreatment high SUVmax of cervix and advanced FIGO2018 stage might indicate a poor prognosis.

Transcriptome aberration in mice uterus associated with steroid hormone response and inflammation induced by dioxybenzone and its metabolites.

Benzophenone-type UV filters have been implicated in multiple adverse reproductive outcomes, yet the underlying processes and molecular targets on the female reproductive tract remain largely unknown. Herein, we investigated the effect of dioxybenzone, one of the widely used congeners, and its demethylated (M1) and hydroxylated (M2) metabolites on transcriptome profiles of ICR mice uterus and identified potential cellular targets in human endometrial stromal cells (HESCs) separated from normal endometrium tissues. Dioxybenzone, M1 and M2 (20 mg/kg bw/d) significantly induced transcriptome aberration with the induction of 683, 802, and 878 differentially expressed genes mainly involved in cancer, reproductive system disease and inflammatory disease. Compared to dioxybenzone, M1 and M2 exhibited a transcriptome profile more similar to estradiol in mice uterus, and subsequently promoted thicker endometrial columnar epithelial layer through upregulation of estrogen receptor target genes-Sprr2s. Dioxybenzone, M1 and M2 (0.1 or 1 µM) also exhibited estrogenic disrupting effect via increasing the mRNA expressions and production of the growth factors responsible for epithelial proliferation, including Fgfs and Igf-1 in HESCs. Additionally, the mRNA expressions of several inflammatory cytokines especially IL-1ß in mice uterus and HESCs was significantly upregulated by dioxybenzone and its metabolites. Overall, we revealed that dioxybenzone and its metabolites triggered transcriptome perturbation dually associated with abnormal steroid hormone response and inflammation, both as key determinants to reproductive health risks.