Predicting Lymph Node Metastasis From Primary Cervical Squamous Cell Carcinoma Based on Deep Learning in Histopathologic Images.

We developed a deep learning framework to accurately predict the lymph node status of patients with cervical cancer based on hematoxylin and eosin-stained pathological sections of the primary tumor. In total, 1524 hematoxylin and eosin-stained whole slide images (WSIs) of primary cervical tumors from 564 patients were used in this retrospective, proof-of-concept study. Primary tumor sections (1161 WSIs) were obtained from 405 patients who underwent radical cervical cancer surgery at the Fudan University Shanghai Cancer Center (FUSCC) between 2008 and 2014; 165 and 240 patients were negative and positive for lymph node metastasis, respectively (including 166 with positive pelvic lymph nodes alone and 74 with positive pelvic and para-aortic lymph nodes). We constructed and trained a multi-instance deep convolutional neural network based on a multiscale attention mechanism, in which an internal independent test set (100 patients, 228 WSIs) from the FUSCC cohort and an external independent test set (159 patients, 363 WSIs) from the Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma cohort of the Cancer Genome Atlas program database were used to evaluate the predictive performance of the network. In predicting the occurrence of lymph node metastasis, our network achieved areas under the receiver operating characteristic curve of 0.87 in the cross-validation set, 0.84 in the internal independent test set of the FUSCC cohort, and 0.75 in the external test set of the Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma cohort of the Cancer Genome Atlas program. For patients with positive pelvic lymph node metastases, we retrained the network to predict whether they also had para-aortic lymph node metastases. Our network achieved areas under the receiver operating characteristic curve of 0.91 in the cross-validation set and 0.88 in the test set of the FUSCC cohort. Deep learning analysis based on pathological images of primary foci is very likely to provide new ideas for preoperatively assessing cervical cancer lymph node status; its true value must be validated with cervical biopsy specimens and large multicenter datasets.

Head-to-head comparison of [18F]-FDG and [68 Ga]-DOTA-FAPI-04 PET/CT for radiological evaluation of platinum-sensitive recurrent ovarian cancer.

PURPOSE: Precise radiological evaluation is pivotal for the management of platinum-sensitive recurrent ovarian cancer. We aimed to compare the value of [68 Ga]-FAPI and [18F]-FDG PET/CT for the detection of relapsed lesions. METHODS: Twenty-nine suspected platinum-sensitive recurrent ovarian cancers were enrolled from January 2022 to July 2022. [18F]-FDG and [68 Ga]-FAPI PET/CT were obtained within 1 week for radiological evaluation. Treatment strategies, visual scores, and Eisenkop scores were recorded. A paired T test was used to compare differences between two scans. Sensitivity, specificity, PPV, NPV, and accuracy were also evaluated. RESULTS: Up to 22 (75.86%) patients displayed inconsistency between two scans. Among them, 4 patients with negative [18F]-FDG imaging had measurable lesions in [68 Ga]-FAPI scans. The treatment strategies were changed in 5 patients (17.24%) due to discrepancies. Finally, 15 (35.7%) patients underwent surgeries, and 14 patients achieved complete resection, except for 1 patient who had milliarc residual disease. TBR, but not SUVmax, of [68 Ga]-FAPI was significantly higher than that of [18F]-FDG in recurrent lesions. Compared with [18F]-FDG, [68 Ga]-FAPI PET presented higher sensitivity and accuracy for lesion detection (96.30% vs. 49.07% and 97.40% vs. 63.87%, respectively). Additionally, [68 Ga]-FAPI PET showed a much higher visual score than [18F]-FDG PET (41 vs. 4), especially for peritoneal metastasis (35 vs. 1). [68 Ga]-FAPI PET also presented a larger tumor burden than [18F]-FDG according to the Eisenkop score (27 vs. 16, p = 0.025). CONCLUSIONS: [68 Ga]-FAPI was superior to [18F]-FDG PET/CT for the detection of recurrent lesions, which is pivotal for the individualized management of platinum-sensitive recurrent ovarian cancer.

Developing a nomogram for preoperative prediction of cervical cancer lymph node metastasis by multiplex immunofluorescence.

BACKGROUND: Most traditional procedures can destroy tissue natural structure, and the information on spatial distribution and temporal distribution of immune milieu in situ would be lost. We aimed to explore the potential mechanism of pelvic lymph node (pLN) metastasis of cervical cancer (CC) by multiplex immunofluorescence (mIF) and construct a nomogram for preoperative prediction of pLN metastasis in patients with CC. METHODS: Patients (180 IB1-IIA2 CC patients of 2009 FIGO (International Federation of Gynecology and Obstetrics)) were divided into two groups based on pLN status. Tissue microarray (TMA) was prepared and tumor-infiltrating immune markers were assessed by mIF. Multivariable logistic regression analysis and nomogram were used to develop the predicting model. RESULTS: Multivariable logistic regression analysis constructs a predictive model and the area under the curve (AUC) can reach 0.843. By internal validation with the remaining 40% of cases, a new ROC curve has emerged and the AUC reached 0.888. CONCLUSIONS: This study presents an immune nomogram, which can be conveniently used to facilitate the preoperative individualized prediction of LN metastasis in patients with CC.

Diffusion-weighted magnetic resonance imaging for the pre-operative evaluation of epithelial ovarian cancer patients.

OBJECTIVE: To investigate the value diffusion-weighted magnetic resonance imaging (DWI/MR) in the selection of ovarian cancer patients suitable for primary debulking surgery. METHODS: Patients with suspected ovarian cancer who underwent pre-operative DWI/MR were enrolled between April 2020 and March 2022. All participants received preoperative clinic-radiological assessment according to the Suidan criteria for R0 resection with a predictive score. Data for patients with primary debulking surgery were prospectively recorded. The diagnostic value was calculated with ROC curves, and the cut-off value for the predictive score was also explored. RESULTS: 80 patients with primary debulking surgery were included in the final analysis. The majority (97.5%) of patients were at advanced stage (III-IV), and 90.0% of patients had high-grade serous ovarian histology. 46 (57.5%) patients had no residual disease (R0), and 27 (33.8%) patients had optimal debulking surgery with zzmacroscopic disease less than or equal to 1 cm (R1). Patients with BRCA1 mutation had lower R0 resection rate, higher R1 resection rate compared with wild-type patients (42.9% vs 63.0%, 50.0% vs 29.6%, respectively). The median (range) predictive score was 4 (0-13), and the AUC for R0 resection was 0.742 (0.632-0.853). The R0 rates for patients with predictive score 0-2, 3-5, and ≥ 6 were 77.8%, 62.5% and 23.8%, respectively. CONCLUSION: DWI/MR was a sufficient technique for pre-operative evaluation of ovarian cancer. Patients with predictive score 0-5 were suitable for primary debulking surgery at our institution.

SPOP promotes cervical cancer progression by inducing the movement of PD-1 away from PD-L1 in spatial localization.

BACKGROUND: Metastasis is a major obstacle in the treatment of cervical cancer (CC), and SPOP-mediated regulatory effects are involved in metastasis. However, the mechanisms have not been fully elucidated. METHODS: Proteomic sequencing and SPOP immunohistochemistry (IHC) were performed for the pelvic lymph node (pLN)-positive and non-pLN groups of CC patients. The corresponding patients were stratified by SPOP expression level for overall survival (OS) and relapse-free survival (RFS) analysis. In vitro and in vivo tests were conducted to verify the causal relationship between SPOP expression and CC metastasis. Multiplex immunofluorescence (m-IF) and the HALO system were used to analyse the mechanism, which was further verified by in vitro experiments. RESULTS: SPOP is upregulated in CC with pLN metastasis and negatively associated with patient outcome. In vitro and in vivo, SPOP promotes CC proliferation and metastasis. According to m-IF and HALO analysis, SPOP may promote CC metastasis by promoting the separation of PD-1 from PD-L1. Finally, it was further verified that SPOP can achieve immune tolerance by promoting the movement of PD-1 away from PD-L1 in spatial location and function. CONCLUSION: This study shows that SPOP can inhibit the immune microenvironment by promoting the movement of PD-1 away from PD-L1, thereby promoting pLN metastasis of CC and resulting in worse OS and RFS.

Extraperitoneal laparoscopy for para-aortic lymphadenectomy in endometrial carcinoma staging: an approach with higher efficiency.

BACKGROUND: Removing more inframesenteric nodes is not only significantly increases the likelihood of finding metastasis for endometrial cancer, but also can add survival advantage. As most patients diagnosed with endometrial cancer are overweight or obesity, a high efficiency approach is important. Aim of this study was to compare the surgical outcomes of extraperitoneal laparoscopic, transperitoneal laparoscopic, and laparotomic para-aortic lymphadenectomy in endometrial carcinoma staging. METHODS: We retrospectively reviewed data of all patients diagnosed with primary endometrial carcinoma who were treated at the Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center from 1 January 2017 to 31 December 2019. The numbers of para-aortic lymph nodes, surgical time, complications, blood loss and hospital stay were compared. The patients' medical records and pathological reports were carefully reviewed. Statistical significance was defined as p < 0.05. RESULTS: We retrospectively compared patients who underwent extraperitoneal laparoscopy (Group E, n = 20), transperitoneal laparoscopy (group T, n = 21), and laparotomy (group L, n = 135). The median number of para-aortic lymph nodes was significantly higher in group E than in groups T and L (9.5, 5, and 6, respectively; p = 0.004 and 0.0004, respectively). All patients in group E underwent successfully dissection to the renal vessel level. The median operation time was significantly shorter in group L than in groups T and E (94, 174, and 233 min, respectively; p < 0.0001). The median estimated blood loss volume was higher in group L than in groups T and E (200, 100, and 142.5 ml, respectively; all comparisons p < 0.001), and the length of hospital stay was significantly longer in group L than in Groups T and E (6, 5, and 6 days, respectively; all comparisons p < 0.001). CONCLUSION: The extraperitoneal laparoscopic approach for staging endometrial carcinoma harvested higher numbers of para-aortic lymph nodes which could be considered for endometrial carcinoma staging, especially for para-aortic lymph node harvest.

Reproductive and obstetric outcomes after abdominal radical trachelectomy (ART) for patients with early-stage cervical cancers in Fudan, China.

OBJECTIVE: To report the reproductive and obstetric outcomes of patients undergoing abdominal radical trachelectomy (ART) for the treatment of early-stage cervical cancers in Fudan, China. METHODS: We retrospectively reviewed a prospectively collected database of 360 patients with stage IA1-IB1 cervical cancers who underwent ART between 2004 and 2018. RESULTS: Overall, 211 women (58.6%) did not plan to get pregnant immediately after ART, and 89.6% of them were due to childbearing before surgery or unmarried. Among 149 women who attempted to conceive, 26 (17.4%) of them achieved 30 pregnancies. Eighty-six patients (57.7%) had infertility problems, 44 attempted to conceive with assisted reproductive technologies, and 12 (27.3%) succeeded. Post-operative cervical stenosis (26, 27.4%) and fallopian tube obstruction (22, 23.2%) were the most common reasons for infertility after surgery. Among the patients who conceived, there were 3 first-trimester miscarriages, 6 second-trimester miscarriages, and 2 elective terminations. A total of 19 pregnancies reached the third trimester, and 84.2% of them ended after 36 weeks. Twelve of 20 cases in patients with cerclage placed had full-term birth, while 3 of 5 patients without cerclage placed suffered from second-trimester miscarriage or preterm birth. CONCLUSIONS: Immediately after ART, many patients were reluctant to conceive, while others suffered from cervical stenosis or fallopian tube obstruction, which had led to low pregnancy rate. Pregnant patients might experience miscarriage or preterm labor which could be prevented by cervical cerclage. Assisted reproductive technology should be encouraged to improve obstetric outcomes.

Metastatic patterns do not provide additional prognostic information for patients with FIGO stage IV high-grade serous ovarian cancer.

BACKGROUND: The aim of our study was to investigate whether metastatic patterns were associated with the prognosis of patients with FIGO stage IV high-grade serous ovarian cancer (HGSC). METHODS: We retrospectively investigated 83 consecutive patients with FIGO stage IV HGSC who underwent primary surgery between April 2005 and June 2013 at our institution. Metastatic patterns were defined as pleural effusion (stage IVA), parenchymal metastases (stage IVB), and extra-abdominal lymph node metastases (stage IVB). Correlations of clinical characteristics and prognosis with metastatic patterns were analyzed. RESULTS: Forty-two (50.6%) patients were stage IVA with pleural effusion. Among the remaining stage IVB patients, 19 (22.9%) patients had parenchymal metastases and 22 (26.5%) had extra-abdominal lymph node metastases. FIGO IVA and IVB subclassification did not have a prognostic impact on progression-free survival (PFS) (P = .361). In addition, no differences in PFS were observed among patients presenting the three metastatic patterns (P = .506). The 5-year overall survival (OS) rates of patients with stage IVA and IVB diseases were 35.2% and 34.3%, respectively, (P = .856). In addition, metastatic patterns did not provide additional prognostic information for OS (P = .292). CONCLUSION: Neither the subclassification into FIGO IVA and IVB stages nor metastatic patterns of FIGO stage IV provided additional prognostic information.

Long non-coding RNA SNHG6 promotes cell proliferation and migration through sponging miR-4465 in ovarian clear cell carcinoma.

Dysregulation of small nucleolar RNA host gene 6 (SNHG6) exerts critical oncogenic effects and facilitates tumourigenesis in human cancers. However, little information about the expression pattern of SNHG6 in ovarian clear cell carcinoma (OCCC) is available, and the contributions of this long non-coding RNA to the tumourigenesis and progression of OCCC are unclear. In the present study, we showed via quantitative real-time PCR that SNHG6 expression was abnormally up-regulated in OCCC tissues relative to that in unpaired normal ovarian tissues. High SNHG6 expression was correlated with vascular invasion, distant metastasis and poor survival. Further functional experiments demonstrated that knockdown of SNHG6 in OCCC cells inhibited cell proliferation, migration and invasion in vitro as well as tumour growth in vivo. Moreover, SNHG6 functioned as a competing endogenous RNA (ceRNA), effectively acting as a sponge for miR-4465 and thereby modulating the expression of enhancer of zeste homolog 2 (EZH2). Taken together, our data suggest that SNHG6 is a novel molecule involved in OCCC progression and that targeting the ceRNA network involving SNHG6 may be a treatment strategy in OCCC.

The preoperative prognostic nutritional index is a predictive and prognostic factor of high-grade serous ovarian cancer.

BACKGROUND: The aim of our study was to investigate whether an inflammation-based prognostic score, the prognostic nutritional index (PNI), was associated with clinical characteristics and prognosis in patients with high-grade serous ovarian cancer (HGSC). METHODS: We retrospectively investigated 875 patients who underwent primary staging or debulking surgery for HGSC between April 2005 and June 2013 at our institution. None of these patients received neoadjuvant chemotherapy. Preoperative PNI was calculated as serum albumin (g/L) + 0.005 × lymphocyte count (per mm3). The optimal PNI cutoff value for overall survival (OS) was identified using the online tool "Cutoff Finder". Clinical characteristics and PNI were compared with chi-square or Fisher's exact tests, as appropriate. The impact of PNI on OS was analyzed using the Kaplan-Meier method and Cox proportional hazards model. RESULTS: The median (range) PNI was 46.2 (29.2-67.7). The 45.45 cutoff value discriminated patients into the high-PNI and low-PNI groups. A low preoperative PNI was associated with an advanced FIGO stage, increased CA125 level, more extensive ascites, residual disease and platinum resistance. For univariate analyses, a high PNI was associated with increased OS (p < 0.001). In multivariate analyses, the PNI remained an independent predictor of OS as a continuous variable (p = 0.021) but not as dichotomized groups (p = 0.346). CONCLUSION: Our study demonstrated that the PNI could be a predictive and prognostic parameter for HGSC.

Prognostic Value of Serum CA19-9 and Perioperative CA-125 Levels in Ovarian Clear Cell Carcinoma.

BACKGROUND: There are no effective biomarkers for surveillance in ovarian clear cell carcinoma (OCCC), and the value of carbohydrate antigen 125 (CA-125) is limited. We sought to determine the value of both carbohydrate antigen 19-9 (CA19-9) and CA-125 levels postoperatively on the prognosis for OCCC. METHODS: A total of 130 patients with OCCC who were consecutively treated by cytoreduction at Fudan University Shanghai Cancer Center were reviewed retrospectively. Univariate log-rank analyses and Cox regression multivariate analyses were performed to identify predictors of recurrence-free (RFS) and overall survival (OS) rates. RESULTS: The survival in patients with postoperative normalization of CA-125 was significantly better than those with decreased but still elevated CA-125 (5-year RFS rates, 57.9% vs 45.2%, P = 0.046; 5-year OS rates, 81.4% vs 54.4%, P = 0.016), or those with increased CA-125 (5-year RFS rates, 57.9% vs 29.2%, P = 0.001; 5-year OS rates, 81.4% vs 33.6%, P < 0.001). An elevated level of postoperative CA-125 level was an independent risk factor for recurrence and survival [RFS: hazard ratio (HR), 2.2; P = 0.033; OS: HR, 4.3; P = 0.019]. Elevated postoperative CA19-9 was an independent risk factor for both RFS and OS in patients with normal postoperative CA-125 levels (RFS: HR, 5.0; P = 0.005; OS: HR, 1.1; P = 0.035). CONCLUSIONS: Combining postoperative CA19-9 and CA-125 appeared to be of great clinical value for prognosis in patients with OCCC after initial debulking.

Angiotensin II-mediated suppression of synaptic proteins in mouse hippocampal neuronal HT22 cell was inhibited by propofol: role of calcium signaling pathway.

PURPOSE: Angiotensin II (Ang II) has been shown to be involved in neurological disorders. Propofol demonstrated neuroprotective effects in neurons. METHODS: Mouse hippocampal HT22 cells were pre-treated with propofol, followed by Ang II treatment. The expression of synaptic proteins (synapsin I and PSD95) was examined. The effects of propofol on Ang II-induced NADPH oxidase expression and superoxide anion generation were examined. The effects of propofol on intracellular calcium concentration, the activation of calcium/calmodulin-dependent protein kinase II (CaMKII), and protein kinase C (PKC) were measured. RESULTS: Ang II reduced the expression of synapsin I and PSD95, which was attenuated by propofol. Ang II-induced effects were blocked by Ang II type 1 receptor (AT1 receptor) blocker. Ang II induced the expression of NADPH oxidase and caused superoxide anion accumulation, which were attenuated by propofol. In addition, propofol induced intracellular calcium concentration, and activated CaMKII as well as PKCß. Importantly, the Ang II-mediated effects were diminished by α-tocopherol, and the propofol-mediated effects were alleviated by calcium chelator, CaMKII inhibitor, and PKCß inhibitor. CONCLUSION: Ang II, via AT1 receptor, induced oxidative stress and reduced the expression of synapsin I and PSD95 in HT22 cells. Propofol may increase synapsin I and PSD95 expression by inhibiting oxidative stress and stimulating calcium signaling pathway.

The Survival Rate and Surgical Morbidity of Abdominal Radical Trachelectomy Versus Abdominal Radical Hysterectomy for Stage IB1 Cervical Cancer.

PURPOSE: To compare the survival rates and morbidities of abdominal radical trachelectomy (ART) to abdominal radical hysterectomy (ARH) for stage IB1 cervical cancer and to evaluate the safety of ART for tumors measuring 2-4 cm. METHODS: We performed a retrospective study to compare the outcomes of patients with stage IB1 cervical cancer who underwent ART to patients treated with ARH who met the inclusion criteria of a fertility-sparing surgery. All of the patients were treated by the same surgeon at our institution in the same period. RESULTS: Of the 107 and 141 patients who underwent ART and ARH, respectively, 61 and 82 patients had a tumor ≥2 cm (P = NS). With a median follow-up of 30 and 49 months, 2 patients treated with ART and 3 patients treated with ARH recurred: the 5-year RFS rate was 96.5 and 94.8%, respectively, for tumors ≥2 cm (P = NS). Only 3 patients died in the ARH group: the 5-year OS rate was 100% for the ART and 94.8% for the ARH group for tumors ≥2 cm (P = NS). Incidence rates of intraoperative complications were similar in the two groups (1.9% for ART and 0.7% for ARH, P = NS). However, incidence rates of postoperative complications were higher in the ART group (36.4% for ART and 19.1% for ARH, P < 0.05). CONCLUSIONS: ART appears to have equal survival rates to ARH and can be performed safely in stage IB1 cervical cancers ≥2 cm. However, ART is associated with more postoperative morbidities compared with ARH.

Surgical and pathological outcomes of abdominal radical trachelectomy versus hysterectomy for early-stage cervical cancer.

OBJECTIVES: The aim of this study was to compare the surgical and pathological outcomes for patients with early-stage cervical cancer after abdominal radical trachelectomy (ART) and abdominal radical hysterectomy (ARH). METHODS: A prospective database of ART and ARH procedures performed in a standardized manner by the same surgical group was analyzed. The 3-segment technique was used for the accurate analysis of parametrial lymph nodes (PMLNs), and parametrial measurements were recorded by the same pathologist. Standard statistical tests were used. RESULT: Between August 2012 and August 2013, ART was attempted in 39 patients (28.6%), and ARH was attempted in 90 patients (71.4%). The parametrium resection length was similar with ART and ARH (44.60 vs 45.48 mm, P = 0.432), as were additional surgical and pathological outcomes, including histology, lymph node positive rate, and operation time. The PMLNs were found in 28 patients (77.78%) in the ART group and in 86 (95.56%) in the ARH group (P > 0.05). Solitary PMLN metastases were observed in 3 patients (10.71%) in the ART group and in 6 (6.98%) in the ARH group. Five (55.6%) of these 9 patients had tumors of 2 cm or greater. The ARH patients (36, 40.00%) were more likely to receive postoperative chemotherapy or radiation compared with ART patients (13, 33.33%; P = 0.017). At a median follow-up of 12 and 12.5 months (P = 0.063), respectively, there were no recurrences or deaths in the ART or ARH groups. CONCLUSIONS: Using standardized techniques, ART provides similar surgical and pathological outcomes as ARH. For the patients with tumors of 2 cm or greater, PMLNs should be examined carefully. Further prospective data are urgently needed.

Clinical characteristics and genomic profiling of outpatients with endometrial cancer at a Chinese tertiary cancer center.

OBJECTIVE: Endometrial cancer is stepping into the era of precision therapy. Genomic test is recommended for newly diagnostic patients. However, outpatients displayed more complex characteristics. Here, we elucidated the clinical characteristics and genomic profiling of outpatients with endometrial cancer at our institution. METHODS: Between 2018 and 2023, 68 endometrial cancer received genomic tests at outpatient department of Fudan University Shanghai Cancer Center. Data, including age, pathological histology, FIGO stage and treatment strategy were collected. Germline mutations, molecular subtypes and other somatic mutations were also summarized. RESULTS: Overall, 72.1% (49/68) of patients receive genomic tests at primary diagnosis, while 27.9% (19/68) of patients received tests at recurrence. Nine patients had deleterious germline mutations, including BRCA1(2), MLH1(1), MSH2(2, including one with co-mutation of RAD50), MSH6(2), FANCA(1), MUTYH(1). Molecular subtypes were recognized among 62 patients, as POLE super-mutation(4, 6.5%), MSI-H(7, 11.3%), CN-Low(36, 58.1%) and CN-High(15, 24.2%). Ten patients received anti-PD1 monotherapy or in combination with chemotherapy or anti-angiogenic therapy, with the duration of disease control of 1 to 35 months. The ORR rate was 30%, and six patients had stable disease. The median (range) follow-up time was 18(2-160) months. 23(33.8%) relapses were recorded, and CN-High subtype displayed worst PFS compared with other subtypes (P < 0.01). 6 deaths were reported including 2(5.6%) of CN-Low and 4(26.7%) of CN-High. CONCLUSION: Outpatients department gathered a considerable proportion of recurrent patients with complex genomic features. Patients with worse prognosis could be well studied, and anti-PD1 therapy was a promising salvage therapy in the real world.

Germline Mutational Landscape and Novel Targetable RAD51D Variant in Chinese Patients With Ovarian Cancer.

PURPOSE: Genetic variants of ovarian cancer (OV) show ethnic differences, but data from the Chinese population are still insufficient. Here, we elucidate the inheritance landscape in Chinese patients with OV and examine the functional implications of a Chinese-enriched RAD51D variant. METHODS: Between 2015 and 2018, 373 consecutive patients with OV were prospectively enrolled. Variants of BRCA1/2, other homologous recombination repair (HRR) genes, and DNA mismatch repair (MMR) genes were analyzed using next-generation sequencing. An enriched RAD51D variant was identified, and its functional effects were examined using Cell Counting Kit-8, colony formation, transwell migration, and drug sensitivity assays. RESULTS: Overall, 31.1% (116/373) of patients had at least one pathogenic or likely pathogenic germline variant. BRCA1 and BRCA2 accounted for 16.09% and 5.36%, respectively, with one patient having both variants. In addition, 32 (8.58%) patients carried other HRR gene variants, whereas three (0.8%) patients had MMR gene variants. The RAD51D variant ranked third (8/373, 2.1%), and its rate was much higher than that in other populations. Remarkably, all eight patients harbored the RAD51D K91fs variant (c.270_271dup, p.Lys91Ilefs*13) and demonstrated satisfactory platinum response and favorable prognosis. This variant confers enhanced sensitivity to poly (ADP-ribose) polymerase inhibitors in OV cells. However, the effects on platinum sensitivity were inconsistent across different cell lines. Against the background of the TP53 variant, RAD51D K91fs variant showed increased sensitivity to cisplatin. CONCLUSION: Our study revealed the inheritance landscape of OV and identified an enriched RAD51D variant in Chinese patients with OV. This can serve as an important reference for OV management and a potential therapeutic target.

Targeting RAC1 reactivates pyroptosis to reverse paclitaxel resistance in ovarian cancer by suppressing P21-activated kinase 4.

Pyroptosis may play an important role in the resistance of ovarian cancer (OC) to chemotherapy. However, the mechanism by which pyroptosis modulation can attenuate chemotherapy resistance has not been comprehensively studied in OC. Here, we demonstrated that RAS-associated C3 botulinum toxin substrate 1 (RAC1) is highly expressed in OC and is negatively correlated with patient outcomes. Through cell function tests and in vivo tumor formation tests, we found that RAC1 can promote tumor growth by mediating paclitaxel (PTX) resistance. RAC1 can mediate OC progression by inhibiting pyroptosis, as evidenced by high-throughput automated confocal imaging, the release of lactate dehydrogenase (LDH), the expression of the inflammatory cytokines IL-1ß/IL-18 and the nucleotide oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. Mechanically, RNA-seq, gene set enrichment analysis (GSEA), coimmunoprecipitation (Co-IP), mass spectrometry (MS), and ubiquitination tests further confirmed that RAC1 inhibits caspase-1/gasdermin D (GSDMD)-mediated canonical pyroptosis through the P21-activated kinase 4 (PAK4)/mitogen-activated protein kinase (MAPK) pathway, thereby promoting PTX resistance in OC cells. Finally, the whole molecular pathway was verified by the results of in vivo drug combination tests, clinical specimen detection and the prognosis. In summary, our results suggest that the combination of RAC1 inhibitors with PTX can reverse PTX resistance by inducing pyroptosis through the PAK4/MAPK pathway.

PARP1-stabilised FOXQ1 promotes ovarian cancer progression by activating the LAMB3/WNT/ß-catenin signalling pathway.

Metastasis is an important factor that causes ovarian cancer (OC) to become the most lethal malignancy of the female reproductive system, but its molecular mechanism is not fully understood. In this study, through bioinformatics analysis, as well as analysis of tissue samples and clinicopathological characteristics and prognosis of patients in our centre, it was found that Forkhead box Q1 (FOXQ1) was correlated with metastasis and prognosis of OC. Through cell function experiments and animal experiments, the results show that FOXQ1 can promote the progression of ovarian cancer in vivo and in vitro. Through RNA-seq, chromatin immunoprecipitation sequencing (ChIP-seq), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment analysis (GSEA), Western blotting (WB), quantitative real-time polymerase chain reaction (qRT‒PCR), immunohistochemistry (IHC), luciferase assay, and ChIP-PCR, it was demonstrated that FOXQ1 can mediate the WNT/ß-catenin pathway by targeting the LAMB promoter region. Through coimmunoprecipitation (Co-IP), mass spectrometry (MS), ubiquitination experiments, and immunofluorescence (IF), the results showed that PARP1 could stabilise FOXQ1 expression via the E3 ubiquitin ligase Hsc70-interacting protein (CHIP). Finally, the whole mechanism pathway was verified by animal drug combination experiments and clinical specimen prognosis analysis. In summary, our results suggest that PARP1 can promote ovarian cancer progression through the LAMB3/WNT/ß-catenin pathway by stabilising FOXQ1 expression.

Abdominal radical trachelectomy: Is it safe for IB1 cervical cancer with tumors ≥ 2 cm?

OBJECTIVES: As abdominal radical trachelectomy (ART) has become a favored fertility-sparing procedure, the relative contraindication of a tumor ≥ 2 cm in size has been questioned. The aim of the study was to report the surgical and oncological safety of ART for selected patients with cervical cancer ≥ 2 cm in size. METHODS: We conducted a retrospective review of a prospectively maintained database of patients undergoing ART at our institution from 04/2004 to 01/2013. The largest tumor dimension was determined by physical exam, MRI or final pathology. Clinical and pathological data were tabulated. All patients were followed postoperatively. RESULTS: Of the 133 patients who underwent planned ART, 62 (46.6%) had tumors ≥ 2 cm in size (2-4 cm). Forty-six patients were documented by exam or MRI, while 16 were documented by pathology reports. The mean age was 30.4 years, and 42 patients (67.7%) were nulliparous. Fifty (80.7%) had squamous carcinoma, 7 (11.3%) had adenocarcinoma and 5 (8%) had adenosquamous carcinoma. Due to frozen-section results, 6 patients (9.7%) underwent an immediate hysterectomy. Due to high-risk features on final pathology, 27 patients (43.5%) were treated with adjuvant chemotherapy (n=20) or chemoradiation (n=7). In total, 55 (88.7%) of 62 patients with a tumor ≥ 2 cm in size preserved their fertility potential. Among these patients, 35 underwent ART without further adjuvant treatment. At a median follow-up of 30.2 months, there were no recurrences. CONCLUSIONS: Expanding the ART inclusion criteria to cervical cancers ≥ 2 cm in size allows a fertility-sparing procedure in young women who would have otherwise been denied the option with no apparent compromise in oncological outcome. However, this may result in higher rates of conversion to hysterectomy or the need for adjuvant chemotherapy/or chemoradiation.

A prospective study of fertility-sparing treatment with megestrol acetate following hysteroscopic curettage for well-differentiated endometrioid carcinoma and atypical hyperplasia in young women.

PURPOSE: To investigate the feasibility and efficacy of curettage with hysteroscopy followed by megestrol acetate (MA) for well-differentiated endometrioid carcinoma (EC) confined to the endometrium and for atypical hyperplasia (AH) in young women. PATIENTS AND METHODS: Fourteen patients with EC and 12 patients with AH were prospectively enrolled in this study. All of the patients received at least 12 weeks of oral MA (160 mg/day) following thorough curettage with hysteroscopy. The response was assessed histologically every 12 weeks. The primary endpoint was the complete response rate. Adverse events, pregnancy rates and recurrence rates were secondary end points. RESULTS: Twenty-one (80.8 %) patients responded to treatment. The median time to response was 12 weeks. After a median follow-up of 32 months, 6 patients had recurrences. Significantly, more patients with infertility or PCOS experienced recurrence (P = 0.040, P = 0.015). Eight patients attempted to conceive after complete response; two spontaneous conceptions and one normal delivery were achieved. No disease-related or treatment-related deaths were observed. CONCLUSIONS: Fertility-sparing treatment with MA following entirely hysteroscopic curettage is effective, demonstrating the least toxicity for rigorously selected young women with well-differentiated EC confined to the endometrium or with AH; however, close follow-up is required for the potential consequences of improper patient selection and a substantial rate of recurrence.