Integrated genomic and transcriptomic analysis reveals the activation of PI3K signaling pathway in HPV-independent cervical cancers.

BACKGROUND: HPV-independent cervical cancers (HPV-ind CCs) are uncommon with worse prognosis and poorly understood. This study investigated the molecular characteristics of HPV-ind CCs, aiming to explore new strategies for HPV-ind CCs. METHODS: HPV status of 1010 cervical cancer patients were detected by RT-PCR, PCR and RNA-sequencing (RNA-seq). Whole exome sequencing (WES) and RNA-seq were performed in identified HPV-ind CCs. The efficacy of PI3Kα inhibitor BYL719 in HPV-ind CCs was evaluated in cell lines, patient-derived organoids (PDOs) and patient-derived xenografts (PDXs). RESULTS: Twenty-five CCs were identified as HPV-ind, which were more common seen in older, adenocarcinoma patients and exhibited poorer prognosis as well as higher tumor mutation burden compared to HPV-associated CCs. HPV-ind CCs were featured with highly activated PI3K/AKT signaling pathway, particularly, PIK3CA being the most predominant genomic alteration (36%). BYL719 demonstrated superior tumor suppression in vitro and in vivo. Furthermore, HPV-ind CCs were classified into two subtypes according to distinct prognosis by gene expression profiles, the metabolism subtype and immune subtype. CONCLUSIONS: This study reveals the prevalence, clinicopathology, and molecular features of HPV-ind CCs and emphasizes the importance of PIK3CA mutations and PI3K pathway activation in tumorigenesis, which suggests the potential significance of PI3Kα inhibitors in HPV-ind CC patients.

Prediction of recurrence-related factors for patients with early-stage cervical cancer following radical hysterectomy and adjuvant radiotherapy.

OBJECTIVE: To analyze recurrent factors in patients with clinical early-stage cervical cancer (ESCC) following hysterectomy and adjuvant radiotherapy. METHODS: We collected data from patients with ESCC, staged according to the 2009 Federation International of Gynecology and Obstetrics (FIGO) staging criteria, who underwent hysterectomy followed by adjuvant radiotherapy between 2012 and 2019. These patients were subsequently restaged using the 2018 FIGO criteria. Univariable and multivariable analyses, along with nomogram analyses, were conducted to explore factors associated with recurrence-free survival (RFS). RESULTS: A total of 310 patients met the inclusion criteria, with a median follow-up time of 46 months. Among them, 126 patients with ESCC were restaged to stage III C1 or III C2 after surgery due to lymph node metastasis (LNM) based on the 2018 FIGO staging criteria. Of these, 60 (19.3%) experienced relapse. The 1-, 3-, and 5-year RFS rates were 93.9%, 82.7%, and 79.3%, respectively. Multivariate analysis revealed that the number of positive lymph nodes (LNs), tumor diameter (TD) > 4 cm, and parametrial invasion (PI) were associated with recurrence. The nomogram indicated their predictive value for 3-year and 5-year RFS. Notably, the 5-year recurrence rate (RR) increased by 30.2% in patients with LNM, particularly those with ≥ 3 positive LNs (45.5%). Patients with stage III C2 exhibited a significantly higher RR than those with IIIC1 (56.5% vs. 24.3%, p < 0.001). The 5-year RFS for patients with TD > 4 cm was 65.8%, significantly lower than for those with TD ≤ 4 cm (88.2%). Subgroup analysis revealed higher 5-year RRs in patients with stage III C2 than that in patients with III-C1 (56.5% vs. 24.3%, p < 0.001), demonstrating a significant difference in the RFS survival curve. CONCLUSION: RR in patients with clinical ESCC after hysterectomy followed by adjuvant radiotherapy is correlated with the number of positive LNs, TD > 4 cm, and PI. Emphasis should be placed on the common high-risk factor of LNM association with recurrence after radical hysterectomy in ESCC.

Targeting PI3Kα increases the efficacy of anti-PD-1 antibody in cervical cancer.

Targeting programmed death 1(PD-1) has been approved for relapsed cervical cancer with unsatisfactory clinical efficacy. This study aims to analyse the impact of PI3K pathway activation on tumour immune microenvironment and evaluates the immune sensitization effect by PI3K inhibition in cervical cancer. The effect of PIK3CA mutation on PD-L1 expression and CD8+ T cells differentiation was determined in cervical cancer tissues. Luciferase and ChIP-qPCR/PCR assays were used to determine the transcriptional regulation of PD-L1 by PIK3CA-E545K. The effects of PI3K inhibitor treatment on immune environment in vitro and in vivo were evaluated by RNA sequencing (RNA-seq) and flow cytometry. The efficacy of PI3K inhibitor and anti-PD-1 therapy was assessed in cell-derived xenografts (CDX) and patients-derived xenografts (PDX). PD-L1 overexpression is more frequently observed in elder women with squamous cervical carcinoma. It predicts longer progress-free survival and overall survival. PIK3CA mutation results in increased mRNA and protein levels of PD-L1, the repression of CD8+ T cell differentiation in cervical cancer. Here, we report a case that continuous pembrolizumab monotherapy treatment induced complete remission of a recurrent cervical cancer patient with systemic metastasis and PIK3CA-E545K mutation, implying that PIK3CA mutation is potentially a biomarker for pembrolizumab treatment in cervical cancer. Specifically, this mutation promotes the expression of PD-L1 by upregulating the transcription factor IRF1. PI3Kα-specific inhibitor markedly activates immune microenvironment by regulating the PD-1/L1-related pathways and promoting CD8+ T cell differentiation and proliferation in Caski-CDXs with PIK3CA-E545K mutation. PI3Kα inhibitor significantly enhances the anti-tumour efficacy of PD-1 blockade in CDXs and PDXs. PIK3CA mutations may predict the response of cervical cancer to PD-1 blockade. The efficacy of PI3Kα inhibitors combined with PD-1 antibodies is promising in cervical cancer and warrants additional clinical and mechanistic investigations.

A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal radical hysterectomy for cervical cancer (stage IA1 with LVSI, IA2): study protocol of the LAUNCH 1 trial.

BACKGROUND: A retrospective study and a randomized controlled trial published in a high quality journal in late 2018 have shown that laparoscopic radical hysterectomy (RH) was associated with worse survival than abdominal RH among patients with early stage cervical cancer. Radical hysterectomy in cervical cancer has been a classic landmark surgery in gynecology, therefore this conclusion is pivotal. The current trial is designed to reconfirm whether there is a difference between laparoscopic RH and abdominal RH in cervical cancer (stage IA1 with LVSI, IA2) patient survival under stringent operation standards and consistent tumor-free technique. This paper reports the rationale, design, and implementation of the trial. METHODS: This is an investigator-initiated, prospective, randomized, open, blinded endpoint (PROBE) controlled trial. A total of 690 patients with stage IA1 (with intravascular), and IA2 cervical cancer will be enrolled over a period of three years. Patients are randomized (1:1) to either the laparoscopic RH or the abdominal RH group. Patients will then be followed-up for at least five years. The primary endpoint will be 5-year progression-free survival. Secondary endpoints will include 5-year overall survival rates, recurrence rates, operation time, intraoperative blood loss, surgery-related complications, and quality of life. DISCUSSION: The results of the trial will provide valuable evidence for guiding clinical decision of choosing appropriate treatment strategies for stage IA1 (LVSI) and stage IA2 cervical cancer patients. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT04934982 , Registered on 22 June 2021).

Who really benefits from intraperitoneal chemotherapy for advanced ovarian cancer? A treatment-free survival analysis of the AICE trial.

OBJECTIVE: To investigate whether peritoneal disease extent can predict the survival benefit of intraperitoneal/intravenous (IP/IV) chemotherapy in ovarian cancer. DESIGN: A treatment-free survival (TFS) analysis. SETTING: Five-centre trial. POPULATION: An extended follow-up of the Additional Intraperitoneal Cisplatin and Etoposide in ovarian cancer (AICE) trial (NCT01669226), with data cut-off on 27 August 2020. Patients were categorised into subgroups with high tumour burden (HTB) and low tumour burden (LTB). METHODS: Overall survival (OS) was divided into time on protocol treatment exposure (T), time free of subsequent treatment or death (TFS) and time after the first subsequent therapy (REL). TFS analyses and quality-adjusted OS were calculated by multiplying the mean time in each health state by its assigned utility: quality-adjusted OS = ut  × T + TFS + urel  × REL. MAIN OUTCOME MEASURES: The area under each Kaplan-Meier curve was estimated using the 96-month restricted mean time, with threshold utility analyses used to illustrate quality-adjusted OS comparisons. RESULTS: In the HTB subgroup, the restricted mean TFS was 33.9 months and 18.7 months in the IP/IV and IV groups, respectively (p = 0.005), with a significant quality-adjusted OS gain (13.2-16.0 months). In the LTB subgroup, IP/IV therapy yielded no survival benefit in either TFS (p = 0.268) or quality-adjusted OS (range: 1.4-6.3 months). CONCLUSIONS: Both TFS and quality-adjusted OS was longer across all utility weight values with IP/IV than with standard IV therapy in the HTB subgroup, whereas patients in the LTB subgroup did not benefit from the therapy. The tumour burden of ovarian cancer should be assessed before deciding on IP/IV versus IV treatment.

Inhibition of the PIN1-NRF2/GPX4 axis imparts sensitivity to cisplatin in cervical cancer cells.

The incidence of cervical cancer (CC) ranks the fourth in female malignant tumors globally. Chemoresistance is one of the main causes of treatment failure in advanced recurrent CC. Prolyl isomerase 1 (PIN1) is overexpressed in a variety of tumors, and is closely associated with the malignant potential of tumor cells, such as transformation, proliferation, invasion and metastasis. In the present study, we demonstrate that cell death induced by suppression of PIN1 could be inhibited by ferrostatin-1 (Fer-1) and ferroptosis biomarkers including lactate dehydrogenase (LDH) release, lipid peroxidation and malondialdehyde (MDA) are upregulated by downregulating PIN1. We then discover that abrogation of PIN1 greatly decreases the level of glutathione peroxidase 4 (GPX4) and the level of PIN1 is positively correlated with the level of GPX4. Furthermore, the knockdown of PIN1 promotes ferroptosis induced by RSL3. The mechanism involves PIN1 silencing which downregulates GPX4 by decreasing the level of nuclear factor E2-related factor 2 (NRF2). Furthermore, overexpression of NRF2 inhibits RSL3-mediated ferroptosis of CC cells when PIN1 is silenced. In addition, our results indicate that cisplatin (DDP) induces ferroptosis, which is restrained by overexpression of PIN1. The PIN1 inhibitor, KPT-6566, promotes the cytotoxic effect of DDP. The present study reveals that PIN1 affects ferroptosis and sensitivity to DDP in CC cells via the NRF2/GPX4 axis, thereby identifying PIN1 as a potential therapeutic target for CC.

The surgical outcomes and perioperative complications of bowel resection as part of debulking surgery of advanced ovarian cancer patients.

BACKGROUND: To review the utilization of bowel resection in ovarian cancer surgery in our institution. METHODS: All ovarian cancer patients who received bowel resection between 2006/01 and 2018/12 were identified. Postoperative morbidities were assessed according to the Clavien-Dindo classification (CDC). RESULTS: There were 182 patients in the anastomosis group and 100 patients in the ostomy group, yielding a total of 282 patients. The median age was 57 years, and most patients had high-grade serous histology (88.7%). Forty-nine (17.3%) patients received neoadjuvant chemotherapy. During the operation, 78.7% of patients had ascites, and the median volume was 800 mL. Extensive bowel resection (at least two-segment) and upper abdominal operation were performed in 29 (10.2%) and 69 (24.4%) patients, respectively. The rectosigmoid colon was the most commonly resected (83.8%) followed by right hemicolectomy (5.9%) and small bowel resection (2.8%). No macroscopic residual disease was observed in 42.9% of the patients, whereas 87.9% had residual disease ≤ 1 cm. Among the entire cohort, 23.0% (65/282) experienced different complications. Severe complications (CDC 3-5) accounted for 9.2% of complications and were mostly categorized as pleural effusion requiring drainage (3.5%) followed by wound dehiscence requiring delayed repair in the operating room (1.8%). Nine patients experienced anastomotic leakage (AL): one in the ostomy group with extensive bowel resection and eight in the anastomosis group. The overall AL rate was 4.2% (9/212) per anastomosis. CONCLUSIONS: The execution of bowel resection as part of debulking surgery in patients with newly diagnosed ovarian cancer resulted in a severe morbidity rate of 9.2%.

The next generation sequencing of cancer-related genes in small cell neuroendocrine carcinoma of the cervix.

OBJECTIVE: Small cell neuroendocrine carcinoma of the cervix (SCNEC) is a lethal malignancy and little treatment progress has been made for decades. We sought to map its genetic profiles, and identify whether SCNEC harbor mutations and potential targets for therapeutic interventions. METHODS: Primary tumor tissue and blood samples were obtained from 51 patients with SCNEC. The next-generation sequencing was carried out to detect mutations of 520 cancer-related genes, including the entire exon regions of 312 genes and the hotspot mutation regions of 208 genes. Quantitative multiplex PCR was performed for the detection of seven high-risk HPV types. RESULTS: Of the 51 detected patients, 92.16% were positive for HPV 18. Ninety-eight percent of cases harbored genetic alterations. Two cases were observed with hypermutated phenotype and determined as MSI-H/dMMR. Genetic mutations were clustering in RTK/RAS(42.86%), PI3K-AKT(38.78%), p53 pathway(22.45%) and MYC family(20.41%). Mutations in genes involved in the p53 pathway indicate a poorer prognosis (3-year OS, 33.5% vs 59.9%, p = 0.031). A total of seven patients harboring mutations in homogeneous recombination repair (HRR) genes were reported. In addition, IRS2 and SOX2 were amplified in 14.9% and 6.12% of SCNEC patients, respectively. CONCLUSIONS: SCNEC is specifically associated with HPV 18 infection. Its genetic alterations are characterized by a combined feature of high-risk HPV driven events and mutations observed in common neuroendocrine carcinoma. We identified several targetable mutated genes, including KRAS, PIK3CA, IRS2, SOX2, and HRR genes, indicating the potential efficacy of target therapies in these patients. MSI-H/dMMR individuals may benefit from checkpoint blockade therapies.

Highly immunosuppressive HLADRhi regulatory T cells are associated with unfavorable outcomes in cervical squamous cell carcinoma.

Regulatory T cells (Tregs) are crucial for the maintenance of peripheral tolerance, but they also limit beneficial responses through cancer-induced immunoediting. The roles of Treg subsets in cervical squamous cell carcinoma (CSCC) are currently unknown. Here, we aimed to perform an extensive study with an increased resolution of the Treg compartment in the peripheral blood and tumor tissues of CSCC patients. We first identified that an HLADRhi Treg population in the peripheral blood was significantly increased in CSCC patients compared to precancer patients and healthy donors. We found that HLADRhi Tregs express high levels of a panel of inhibition and activation markers and the TCR-responsive transcription factors BATF and IRF4. However, this Treg subset showed reduced calcium influx after TCR crosslinking. In addition, HLADRhi Tregs are highly proliferative and vulnerable to apoptosis. Further studies demonstrated that the HLADRhi Tregs display high levels of suppressive activity. Quantitative multiplexed immunohistochemistry revealed that an increase in the number of tumor-infiltrating HLADRhi Tregs is associated with unfavorable classical risk parameters of advanced disease stage and stromal invasion. Context-based quantification revealed that a high frequency of stromal HLADRhi Tregs in patients is significantly associated with worse progression-free survival. In the current study, we characterized a population of highly activated and immunosuppressive HLADRhi Tregs in CSCC patients. An increased HLADRhi Treg frequency may be a potential biomarker to stratify CSCC patients and evaluate therapeutic efficacies in personalized immuno-oncology studies.

Clinical significance of peripheral blood and tumor tissue lymphocyte subsets in cervical cancer patients.

BACKGROUND: Alterations in peripheral blood lymphocytes in cervical cancer have been reported, although conflicting views exist. The present study investigated the distributions of lymphocyte subsets in tumor tissue and peripheral blood samples from cervical cancer patients and precancerous lesion patients, and evaluated the correlations of lymphocyte subsets with clinicopathological and prognostic variables. METHODS: A total of 44 patients with stage IB1-IIA2 cervical cancer and 13 precancerous lesion patients were included. Lymphocytes were collected from the tumor tissue and the peripheral blood, and isolated by Lymphoprep density gradient centrifugation. The percentages of lymphocyte subsets were quantified by flow cytometry analysis, and the differences between lymphocyte subsets in the tumor tissue and peripheral blood were compared by SPSS. In addition, the relationships between lymphocyte subsets and clinicopathological and prognostic variables were analyzed. RESULTS: Our results revealed that the amount of total T lymphocytes, CD8+ T cells, granulocytes, pDCs, CD16+ monocytes and CD56high NK cells were significantly higher in the tumor tissue than in the peripheral blood in the cervical cancer patients, while those of CD4+ T cells, CD4+/CD8+ cell ratio, rdT cells, BDCA1+ mDCs, total monocytes, CD14+ monocytes, NK cells and CD56low NK cells exhibited the opposite trend (p < 0.05). The levels of total pDCs and BDCA1+ mDCs in the peripheral blood were significantly lower in the cervical cancer patients than in the precancerous lesion patients, while the proportion of CD16+ monocytes was elevated (p < 0.05). In addition, some lymphocyte subsets, especially CD4+ cells and CD8+ cells, and the CD4+/CD8+ cell ratio were closely associated with clinicopathological and prognostic parameters. CONCLUSIONS: These results suggested that distinct alterations in infiltrating lymphocyte subsets occurred in the tumor and were associated with clinicopathological and prognostic parameters. Systemic impairment of the immune system may occur in the antitumor response of cervical cancer patients.

The kinetic profile and clinical implication of SCC-Ag in squamous cervical cancer patients undergoing radical hysterectomy using the Simoa assay: a prospective observational study.

BACKGROUND: To study the kinetic profile and clinicopathological implications of squamous cell carcinoma antigen (SCC-Ag) in cervical cancer patients who underwent surgery by a self-developed SCC-Ag single molecule assay (Simoa) prototype immunoassay. METHODS: Participants were prospectively enrolled between 04/2016 and 06/2017. Consecutive serum samples were collected at five points: day 0 (the day before surgery), postoperative day 4, weeks 2-4, months 2-4 and months 5-7. In total, 92 patients and 352 samples were included. The kinetic change in SCC-Ag levels and their associations with clinicopathological characteristics were studied. RESULTS: Simoa SCC-Ag was validated by comparison with the Architect assay. SCC-Ag levels measured by the Simoa assay were highly correlated with the Architect assay's levels (Pearson's correlation coefficient = 0.979, Passing-Bablok regression slope 0.894 (0.847 to 0.949), intercept - 0.009 (- 0.047 to 0.027)). The median values for each time-point detected by the Simoa assay were 2.49, 0.66, 0.61, 0.72, and 0.71 ng/mL, respectively. The SCC-Ag levels decreased dramatically after surgery and then stabilized and fluctuated to some extent within 6 months. Patients with certain risk factors had significantly higher SCC-Ag values than their negative counterparts before surgery and at earlier time points after surgery, while no difference existed at the end of observation. Furthermore, although patients with positive lymph nodes had sustained higher SCC-Ag levels compared to those with negative lymph nodes, similar kinetic patterns of SCC-Ag levels were observed after surgery. Patients who received postoperative treatment had significantly higher SCC-Ag values than those with surgery only at diagnosis, while no difference existed after treatment. CONCLUSIONS: The Simoa SCC-Ag prototype was established for clinical settings. The SCC-Ag levels were higher in patients with risk factors, whereas the kinetic trend of SCC-Ag might be mainly affected by postoperative adjuvant therapy. These data indicate that the SCC-Ag level might be a good predictor for the status of cervical cancer, including disease aggressiveness and treatment response.

18F-FDG PET/CT-based metabolic metrics in recurrent tumors of ovarian clear cell carcinoma and their prognostic implications.

BACKGROUND: Glucose metabolism has been suggested as a therapeutic target in ovarian clear cell carcinoma (CCC). We attempted to clarify 18F-FDG PET/CT-based metabolic metrics in the recurrent ovarian CCC patients and their prognostic values. METHODS: Quantitative metabolic parameters included maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Two different methods were employed for defining the threshold SUV to delineate MTV: 1) SUV of 2.5 (designated as MTV); 2) a fixed ratio including 40% (MTV40), 50% (MTV50) and 60% (MTV60) of SUVmax. The Kaplan-Meier model and Cox regression were used in survival analysis. RESULTS: Among the 35 patients, platinum-resistant recurrence accounted for 34.3% and the median progression-free survival was 13 months (range, 2-135). Fifteen (42.9%) patients presented with single tumor recurrence, while 51 recurrent lesions were identified, with the most common sites in pelvis (29.4%), followed by lymph node metastases (19.6%) and peritoneal carcinomatosis (15.7%). Except four patients with FDG-inavid tumor, the median SUVmax of the 31 patients with high glucose metabolic activity was 7.10 (range, 3.00-20.60). After a median follow-up of 36.5 months (range, 7-155), 22 patients (64.7%) were dead from disease. The median post-relapse survival (PRS) was 17 months (range, 4-126). Platinum-resistant recurrence, peritoneal carcinomatosis and high TLG60 proved to be negative predicators of overall survival after multivariate analysis. CONCLUSIONS: TLG60, platinum-resistant recurrence and peritoneal carcinomatosis were independent negative predicators of overall survival. Whether patients with higher TLG60 required more aggressive treatment warranted further study.

Total pelvic peritonectomy for ovarian cancer with extensive peritoneal carcinomatosis in pelvic cavity.

BACKGROUND: Ovarian cancer is characteristic of superficial implantation and peritoneal carcinomatosis. Hudson introduced a novel technique 50 years ago, which removed the entire Douglas pouch as a false capsule of the tumor (Hudson, 1968 [1]). Angeles et al. standardized the procedure in 10 steps in a previous publication (Angeles et al., 2019 [2]). We made small modifications of the Hudson procedure in this video. Ovarian cancer is characteristic of superficial implantation and peritoneal carcinomatosis. Hudson introduced a novel technique 50 years ago, which removed the entire Douglas pouch as a false capsule of the tumor (Hudson, 1968 [1]). Angeles et al. standardized the procedure in 10 steps in a previous publication (Angeles et al., 2019 [2]). We made small modifications of the Hudson procedure in this video. METHODS: The key points of the procedure were summarized as follows. Firstly, dissecting off the pelvic parietal peritoneum very superficially. Secondly, the round ligament, infundibulo-pelvic ligament, medial umbilical ligament, and umbilical artery are divided and ligated in the extraperitoneal space. Thirdly, the bladder is mobilized caudally and the vesico-vaginal space is exposed after completely dissecting off the vesical peritoneum. Fourthly, the ureter is isolated and mobilized laterally. Then, uterine vessels and parametria are divided and ligated, which is followed by colpotomy to access the recto-vaginal septum. By retracting the total specimen cranially, the Douglas pouch is dissected retrogradely according to Hudson procedure. Lastly, the peritoneum of the mesorectum and mesosigmoid is shaved at the pelvic brim. Therefore, using this method, almost all the pelvic visceral peritoneum was dissected (). In addition, we didn't intentionally expose the anatomical spaces (pre-vesical, para-vesical, para-rectal, and pre-sacral) completely, which was effective and time-saving. RESULTS: Complete removal of the disseminated tumors in both parietal and visceral peritoneum was achieved by the method introduced in our video. CONCLUSION: Our method, modified from Hudson procedure, is effective for complete cytoreduction in selected ovarian cancer patients with extensive peritoneal carcinomatosis sparing rectosigmoid resection.

ERBB2 mutation: A promising target in non-squamous cervical cancer.

OBJECTIVE: ERBB2 mutations have been found in a subset of invasive cervical cancer (ICC). Nevertheless, the prevalence, mutation spectrum, clinicopathological relevance, human papillomavirus (HPV)-genotype association and prognostic significance of ERBB2-mutated ICCs have not been well established. METHODS: In this study, ICC samples (N=1015) were assessed for mutations in ERBB2, KRAS, and PIK3CA by cDNA-based Sanger sequencing. RESULTS: Somatic ERBB2 mutations were detected in 3.15% patients. The ERBB2 mutation rate was significantly higher in adenocarcinoma (4.52%, 7/155), adenosquamous carcinoma (7.59%, 6/79) and neuroendocrine carcinoma (10.34%, 3/29) than that in squamous carcinoma (2.14%, 16/749) (P=0.004, Fisher exact test). In addition, 18.75% of the patients carrying ERBB2 mutations concomitantly harbored PIK3CA or KRAS mutations. Patients with ERBB2-mutated ICCs tended to have a worse prognosis than those with wild-type or PIK3CA-mutated ICCs but a better prognosis than those with KRAS-mutated ICCs. CONCLUSIONS: This study provided a promising rationale for the clinical investigation of tyrosine kinase inhibitors for the treatment of cervical cancer with ERBB2 mutations. Patients with non-squamous cell carcinomas have priority as candidates for ERBB2-targeted therapy. Concurrent PIK3CA/RAS mutations should be considered in the design of clinical trials.

Diaphragmatic Surgery and Related Complications In Primary Cytoreduction for Advanced Ovarian, Tubal, and Peritoneal Carcinoma.

BACKGROUND: To evaluate the procedures and complications of diaphragm peritonectomy (DP) and diaphragm full-thickness resection (DFTR) during primary cytoreduction for advanced stage epithelial ovarian cancer. METHODS: All the patients with epithelial ovarian carcinoma who underwent diaphragm procedures at our institution between January 2009 and August 2015 were identified. Clinicopathological data were retrospectively collected from the patients' medical records. Postoperative morbidities were assessed according to the Memorial Sloan-Kettering Cancer Center (MSKCC) grading system. RESULTS: A total of 150 patients were included in the study. The majority of the patients had ovarian cancer (96%), stage IIIC disease (76%) and serous histology (89.3%). DP and DFTR were performed in 124 (82.7%) and 26 (17.3%) patients, respectively. A total of 142 upper abdominal procedures in addition to the diaphragmatic surgery were performed in 77 (51.3%) patients. No macroscopic residual disease was observed in 35.3% of the patients, while 84% of the total patient cohort had residual disease ≤1 cm. The overall incidence of at least one major morbidity (MSKCC grades 3-5) was 18.0%, whereas pleural effusions (33.3%), pneumonia (15.3%) and pneumothorax (7.3%) were the most commonly reported morbidities. The rate of postoperative pleural drainage was 14.6% in total, while half the patients in the DFTR group received drainage intraoperatively (11.5%) and postoperatively (38.5%). The incidence of postoperative pleural effusion was associated with stage IV disease (hazard ratio [HR], 17.2; 95% confidence interval [CI]: 4.5-66.7; P < 0.001), DFTR (HR, 4.9; 95% CI: 1.2-19.9; P = 0.028) and a long surgery time (HR, 15.4; 95% CI: 4.3-55.5; P < 0.001). CONCLUSIONS: Execution of DP and DFTR as part of an extensive upper abdominal procedure resulted in an acceptable morbidity rate. Pleural effusion, pneumonia and pneumothorax were the most common pulmonary morbidities. The pleural drainage rate was not high enough to justify prophylactic chest tube placement for all the patients. However, patients who underwent DFTR merited special consideration for intraoperative prophylactic drainage.

Cycles of cisplatin and etoposide affect treatment outcomes in patients with FIGO stage I-II small cell neuroendocrine carcinoma of the cervix.

OBJECTIVE: This study sought to explore the outcomes and prognostic factors of patients with small cell neuroendocrine carcinoma of the cervix (SCNEC) and to determine the effects of adjuvant treatment on survival in patients with FIGO stage I-II SCNEC after radical surgery. METHODS: A single-institution retrospective analysis was performed in 92 patients who underwent radical surgery for SCNEC. All clinicopathological variables and treatment strategies were reviewed. Kaplan-Meier and Cox regression methods were used for survival analyses. RESULTS: During a median follow-up period of 38months (23.6-52.4), 43 (46.7%) patients experienced disease recurrence, and distant metastases were documented in 35 (81.4%) patients. The 3-year recurrence-free survival (RFS) for the entire group was 50.1%. The median RFS was 39months. The multivariate analysis confirmed that lymph node metastasis, positive parametrial extension and cycles of etoposide plus platinum (EP) were independent prognostic factors for disease recurrence. Adjuvant chemotherapy for at least 5cycles of EP (EP 5+, n=39) was associated with improved 5-year RFS compared with other treatments (n=46) (67.6% vs. 20.9%, p<0.001). Additional radiotherapy or concurrent chemoradiation failed to validate further improved RFS in patients with EP 5+, and this finding was consistent in the subset of patients with high-risk factors (positive lymph nodes or positive parametrium). CONCLUSIONS: Half of stage I-II SCNEC patients experienced disease failure within 3years, and distant metastasis was an outstanding issue. EP regimen for at least 5cycles improved long-term RFS after radical surgery. Additional radiation might be unnecessary, even in patients with high-risk factors.

Validation of the new FIGO staging system (2009) for vulvar cancer in the Chinese population.

OBJECTIVE: A new FIGO staging system for vulvar cancer was issued in 2009. The aim of this study was to identify its value in estimating the outcome of patients with vulvar squamous cell carcinoma (VSCC) in the Chinese population. METHODS: A total of 184 patients who underwent radical surgery for VSCC were recruited. Their medical records and pathology slides were reviewed. Disease reclassification was conducted according to the FIGO staging system (2009). The primary outcomes were cause-specific survival (CSS), relapse-free survival (RFS) and overall survival (OS). RESULTS: A total of 76 patients (41.3%) were downstaged and no patients were upstaged in the new FIGO staging system (2009). The stage distribution was as follows: stage I (99), stage II (13), stage III (65) and stage IV (7). According to CSS, the patients were classified into 4 groups: stage IA (group 1), stage IB/II/IIIA (group 2), stage IIIB (group 3), and stage IIIC/IV (group 4) (5-year CSS: 100%, 85%, 34.6% and 0%, respectively). The 5-year CSS was similar among the patients with stage IB, II and IIIA carcinomas (84.4%, 84.6% and 84.8%, respectively, p=0.986), whereas, significant decline of the CSS was found with increased substages of stages IIIA, IIIB and IIIC (84.8%, 34.6%, and 0 respectively, p<0.001). CONCLUSIONS: The 2009 FIGO staging system for VSCC displayed good performance for the subdivisions of stage III VSCC, but it failed to stratify survival well between stages IB, II and IIIA.

Supragastric lesser sac: an insidious site for surgical exploration during the debulking surgery in advanced ovarian cancer.

OBJECTIVE: Metastases in the supragastric lesser sac (SGLS) are not only occult but are also barriers to complete resection of ovarian cancer. We describe a cohort of patients with SGLS disease undergoing debulking surgery. METHODS: We identified all patients who underwent evaluation and eventual resection of SGLS disease as part of cytoreductive surgery for stage IIIC-IVB high-grade epithelial ovarian cancer at our institution from January 2018 to August 2022. RESULTS: Thirty-three of 286 patients (11.5%) underwent resection of SGLS disease. Metastases in the SGLS were identified by preoperative imaging in 4 of 33 patients (12.1%). The median peritoneal cancer index score was 22 (range, 9-33). Through surgical exploration, metastases were frequently seen in the right diaphragm (100%), hepatorenal recess (97%), lesser omentum (81.8%), left diaphragm (78.8%), supracolic omentum (75.8%), anterior transverse mesocolon (72.7%), splenic hilum (63.6%), ligamentum teres hepatis (60.6%), and gallbladder fossa (51.5%). The lesser omentum was normal in 6 of 33 (18.2%) patients, despite metastases within the SGLS. A total of 54.5% of patients underwent complex surgery (surgical complexity scores; median, 8; range, 3-14). Complete resections were achieved in 19 (57.6%) patients. No complications were related to the resection of SGLS disease. The median length of progression-free survival was 24.8 months (95% confidence interval=16.6-32.9). CONCLUSION: Metastases to the SGLS are not uncommon in advanced ovarian cancer, particularly those with widely disseminated disease. Disease in this recess is rarely identified by preoperative imaging and deserves systematic surgical exploration to attain complete cytoreduction.