Management of chylothorax after retrocrural lymphadectomy in a patient with ovarian cancer: a case report.

Introduction and importance: With the widespread use of positron emission tomography and computed tomography (PET/CT), a significantly greater proportion of patients with advanced ovarian cancer (OC) are now diagnosed with superior renal-vein lymph node metastases involving retrocrural and mediastinal nodes. To the authors' knowledge, retrocrural lymphadenectomy has not yet been reported in patients with OC. The authors performed retrocrural lymph node resection in a patient with ovarian cancer. Case presentation: A 64-year-old woman with ovarian cancer who had not undergone surgery upon initial diagnosis was admitted to the authors' hospital because tumour markers increased during bevacizumab maintenance therapy. PET/CT imaging revealed adnexal masses and multiple metastases in pelvic, para-aortic, retrocrural, and mediastinal lymph nodes. Reduction surgery was performed, and retrocrural lymph nodes were excised. However, the patient's postoperative course was complicated by a chylothorax. Because of the failure of conservative treatment, interventional embolization was performed, but failed to obstruct lymphatic vessels. The patient underwent reoperation. A fistula was located where Hem-o-lock clips penetrated the pleura, clearly indicating the injury site, which was then sutured and embedded in the surrounding diaphragmatic tissue and filled with gel sponge. The patient recovered from chylous leakage postoperatively. She later underwent chemotherapy and targeted maintenance therapy. Clinical discussion: The authors may have injured the communicating branch of the thoracic duct posterior to the diaphragm during the first operation and did not ligate it. The accumulated chylous fluid finally penetrated through the weak point on the pleura and led to chylothorax 3 days later. If conservative treatment or interventional embolization are unsuccessful, surgical treatment should be selected in time. Conclusion: The location of the retrocrural lymph node at the anastomosis of the chylous cistern and the thoracic duct may pose a significant risk of chylous leakage as a complication of lymphadenectomy. Full exposure of the surgical field and thorough ligation of the lymphatic vessels may lead to successful superior renal-vein lymphadenectomy.

Palmitoyltransferase ZDHHC3 Aggravates Nonalcoholic Steatohepatitis by Targeting S-Palmitoylated IRHOM2.

Underestimation of the complexity of pathogenesis in nonalcoholic steatohepatitis (NASH) significantly encumbers development of new drugs and targeted therapy strategies. Inactive rhomboid protein 2 (IRHOM2) has a multifunctional role in regulating inflammation, cell survival, and immunoreaction. Although cytokines and chemokines promote IRHOM2 trafficking or cooperate with partner factors by phosphorylation or ubiquitin ligases-mediated ubiquitination to perform physiological process, it remains unknown whether other regulators induce IRHOM2 activation via different mechanisms in NASH progression. Here the authors find that IRHOM2 is post-translationally S-palmitoylated at C476 in iRhom homology domain (IRHD), which facilitates its cytomembrane translocation and stabilization. Fatty-acids challenge can directly promote IRHOM2 trafficking by increasing its palmitoylation. Additionally, the authors identify Zinc finger DHHC-type palmitoyltransferase 3 (ZDHHC3) as a key acetyltransferase required for the IRHOM2 palmitoylation. Fatty-acids administration enhances IRHOM2 palmitoylation by increasing the direct association between ZDHHC3 and IRHOM2, which is catalyzed by the DHHC (C157) domain of ZDHHC3. Meanwhile, a metabolic stresses-triggered increase of ZDHHC3 maintains palmitoylated IRHOM2 accumulation by blocking its ubiquitination, consequently suppressing its ubiquitin-proteasome-related degradation mediated by tripartite motif containing 31 (TRIM31). High-levels of ZDHHC3 protein abundance positively correlate with the severity of NASH phenotype in patient samples. Hepatocyte-specific dysfunction of ZDHHC3 significantly inhibits palmitoylated IRHOM2 deposition, therefore suppressing the fatty-acids-mediated hepatosteatosis and inflammation in vitro, as well as NASH pathological phenotype induced by two different high-energy diets (HFHC & WTDF) in the in vivo rodent and rabbit model. Inversely, specific restoration of ZDHHC3 in hepatocytes markedly provides acceleration over the course of NASH development via increasing palmitoylation of IRHOM2 along with suppression of ubiquitin degradation. The current work uncovers that ZDHHC3-induced palmitoylation is a novel regulatory mechanism and signal that regulates IRHOM2 trafficking, which confers evidence associating the regulation of palmitoylation with NASH progression.

TIPE2 acts as a tumor suppressor and correlates with tumor microenvironment immunity in epithelial ovarian cancer.

BACKGROUND: Epithelial ovarian cancer (EOC) is one of the deadliest gynecologic cancers. The etiology of EOC has still not been elucidated thoroughly. Tumor necrosis factor-α-induced protein 8-like2 (TNFAIP8L2, TIPE2), an important regulator of inflammation and immune homeostasis, plays a critical role in the progression of various cancers. This study aims to investigate the role of TIPE2 in EOC. METHODS: Expression of TIPE2 protein and mRNA in EOC tissues and cell lines was examined using Western blot and quantitative real-time PCR (qRT-PCR). The functions of TIPE2 in EOC were investigated by cell proliferation assay, colony assay, transwell assay, and apoptosis analysis in vitro. To further investigate the regulatory mechanisms of TIPE2 in EOC, RNA-seq and western blot were performed. Finally, the CIBERSORT algorithm and databases including Tumor Immune Single-cell Hub (TISCH), Tumor Immune Estimation Resource (TIMER), Tumor-Immune System Interaction (TISIDB), and The Gene Expression Profiling Interactive Analysis (GEPIA) were used to elucidate its potential role in regulating tumor immune infiltration in the tumor microenvironment (TME). RESULTS: TIPE2 expression was shown to be considerably lower in both EOC samples and cell lines. Overexpression of TIPE2 suppressed EOC cell proliferation, colony formation, and motility in vitro. Mechanistically, TIPE2 suppressed EOC by blocking the PI3K/Akt signaling pathway, according to bioinformatics analysis and western blot in TIPE2 overexpression EOC cell lines, and the anti-oncogenic potentials of TIPE2 in EOC cells could be partially abrogated by the PI3K agonist, 740Y-P. Finally, TIPE2 expression was positively associated with various immune cells and possibly involved in the regulation of macrophage polarization in ovarian cancer. CONCLUSIONS: We detail the regulatory mechanism of TIPE2 in EOC carcinogenesis, as well as how it correlates with immune infiltration, emphasizing its potential as a therapeutic target in ovarian cancer.

Tislelizumab Combined with Carboplatin-Paclitaxel for Treatment of Metastatic or Recurrent Endometrial Cancer: a Retrospective Clinical Study.

BACKGROUND: Metastatic or recurrent endometrial cancers with low survival rate had no standard or limited therapy choice. The aim of our study was to determine the efficiency and safety of tislelizumab combined with carboplatin-paclitaxel as a front-line therapy for patients with metastatic or recurrent endometrial cancer. METHODS: This clinical retrospective cohort study examined 24 Chinese patients with metastasis or recurrence but had not yet received treatment. The therapeutic regimen consisted of 6 cycles of intravenous paclitaxel (175 mg/m2) and carboplatin (target AUC: 5 mg/mL/min) with tislelizumab (200 mg) once every 3 weeks, and then intravenous tislelizumab (200 mg) once every 3 weeks until disease progression or unacceptable toxicity. RESULTS: At the 18-month follow-up, 8 patients were still receiving treatment, 13 were dead, and 3 withdrew. The objective response rate (ORR) was 62.5%, the disease control rate was 75.00%. The ORR was 77.78% for patients positive for PD-L1 and 69.23% for patients positive for MSI-H. The median overall survival time was 11.50 months, and the median progression-free survival time was 6.00 months. Half of the patients experienced 3 - 4 grade adverse events. There were no allergic reactions or treatment-related deaths. CONCLUSIONS: Tislelizumab combined with carboplatin-paclitaxel was used as a front-line therapy, had a beneficial effect and was safe for patients with metastatic or recurrent endometrial cancer.

LPCAT1 functions as an oncogene in cervical cancer through mediating JAK2/STAT3 signaling.

Cervical cancer is a major gynecological tumor worldwide. Unfortunately, the molecular mechanisms involved in cervical cancer tumorigenesis still requires more clarification. Lysophosphatidylcholine acyltransferase 1 (LPCAT1), an enzyme involved in phosphatidylcholine metabolism, has been reported to regulate the proliferation, epithelial-mesenchymal transition (EMT) and recurrence of malignancies. Here in our study, we found that LPAT1 was over-expressed in clinical cervical cancer tissues, and its high expression was closely correlated with poor outcomes of patients. We further showed that LPCAT1 knockdown remarkably restrained the proliferation, migration and invasion of cervical cancer cells, while it significantly induced apoptosis. RNA-seq and bioinformatics assays initially showed that interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) pathway was a key mechanism for LPCAT1 to regulate cervical cancer progression. LPCAT1 silence strongly decreased IL-6, p-Janus kinase 2 (JAK2) and p-STAT3 expression levels in cervical cancer cells. Similarly, the expression levels of IL-6/STAT3 target genes were also highly down-regulated in cervical cancer cells with LPCAT1 deletion. Importantly, we found that human recombinant IL-6 addition considerably abolished the function of LPCAT1-knockdown to suppress the proliferation and EMT process in cervical cancer cells, accompanied with mitigated apoptotic cell death. Furthermore, our animal experiment results validated that stable LPCAT1 deletion efficiently reduced the tumor growth rates of xenograft mouse models and lung metastasis in vivo. Collectively, all our findings revealed that LPCAT1 may be a promising alternative prognostic biomarker and therapeutic target for cervical cancer through regulating JAK2/STAT3 signaling pathway.

Camrelizumab (SHR-1210) with carboplatin and albumin-binding paclitaxel in patients with metastatic or recurrent cervical cancer: An open-label, phase 2 trial.

Aims: This study evaluates the safety and preliminary antitumor efficacy of camrelizumab with albumin-binding paclitaxel and cisplatin as first-line therapy for patients with recurrent or metastatic cervical carcinoma. Methods and Material: In this phase 2, open-label, prospective study, 35 patients with recurrent or metastatic cervical carcinoma with no previous systemic chemotherapy were included. The patients were treated with a maximum of six cycles of camrelizumab on day 1, albumin-binding paclitaxel, and carboplatin on day 2, every 3 weeks, followed by camrelizumab once every 3 weeks. The primary outcomes were objective response rate (ORR) and disease control rate (DCR). Secondary outcomes were duration of response (DoR) and safety. Furthermore, 27 patients were included in the per-protocol set for efficacy analysis, whereas for the safety analysis, all patients were included. Results: The median follow-up was 4.53 months, and the complete response, partial response, and stable disease were also achieved in 4 (14.81%), 6 (22.22%), and 13 (48.15%) patients. The ORR and DCR were 40.00% (95% confidence interval: 21.13-61.33%) and 92.00% (73.97-99.01%), respectively. The median DoR was 6.70 months. In addition, the most common adverse events (AEs) were reactive cutaneous capillary endothelial proliferation (RCCEP) (23, 65.71%), gastrointestinal reaction (8, 22.86%), and fever (8, 22.86%). Grade 3 AEs included 5 (14.29%) myelosuppression, and grade 4 AEs included 1 (2.86%) RCCEP and 1 (2.86%) bladder inflammation. Conclusions: Combination therapy of camrelizumab and albumin-bound paclitaxel and carboplatin shows promising efficacy and manageable toxicities in patients with recurrent or metastatic cervical cancer.

Correlations between alterations of T-helper 17 cells and treatment efficacy after concurrent radiochemotherapy in locally advanced cervical cancer (stage IIB-IIIB): a 3-year prospective study.

BACKGROUND: Recently, T-helper 17 (Th17) cells have been proved to play an important role in promoting cervical cancer. But, till now, few study has been carried out to understand the involvement of these cells in efficacy of anti-tumor treatments. This study aimed to investigate the alterations in the percentage of circulating Th17 cells and related cytokines in locally advanced cervical cancer (LACC) patients before and after concurrent chemoradiotherapy (cCRT) and to analyze the correlations between the alterations in Th17 cells and treatment efficacy. METHODS: A prospective study with 49 LACC (International federation of gynecology and obstetrics [FIGO] stage IIB-IIIB) patients and 23 controls was conducted. Patients received the same cCRT schedule and were followed up for 3 years. Circulating Th17 cells (CD3+CD8- interleukin [IL]-17+ T cells) and related cytokines IL-17, transforming growth factor-ß (TGF-ß), IL-10, IL-23, IL-6, and IL-22 were detected before and after cCRT. Correlations between alterations of circulating Th17 cells and treatment efficacy were analyzed. Kaplan-Meier analysis was used for overall survival (OS) and progression-free survival (PFS). RESULTS: We found that 40 patients finished the entire cCRT schedule and met the endpoint of this study. The percentage of circulating Th17 cells in the LACC patients was higher than that in the controls, and it significantly decreased after cCRT (P < 0.05). After cCRT, patients were divided into two groups based on the average of the Th17 cells declined. The subgroup of patients with a prominent decrease in circulating Th17 cells after cCRT had a higher treatment efficacy and longer PFS and OS times. Compared with the control patients, LACC patients had higher IL-6, IL-10, IL-22, TGF-ß levels and a lower IL-23 level (P < 0.05). After cCRT, IL-6, IL-10, IL-17, IL-23 level significantly increased and TGF-ß level significantly decreased compared with the levels before cCRT (P < 0.05). CONCLUSION: Circulating Th17 cells in the LACC patients (FIGO stage IIB-IIIB) were higher than those in the controls, but they generally decreased after cCRT. A more pronounced decrease in circulating Th17 cells after cCRT was correlated with better therapeutic effect and longer PFS and OS times.

Cancer-associated fibroblasts induce epithelial-mesenchymal transition and cisplatin resistance in ovarian cancer via CXCL12/CXCR4 axis.

Aim: Cancer-associated fibroblasts (CAFs) are closely related to epithelial-mesenchymal transition (EMT) and chemoresistance in various cancers. Patients & methods: Experiments in vivo and retrospective studies were applied to explore the role of CAFs in epithelial ovarian cancer (EOC). Results: We found that CXCL12 expression was significantly increased in interstitial CAFs by immunofluorescence. CAF-derived CXCL12 induced EMT though CXCR4/Wnt/ß-catenin pathway in EOC cells. Inhibited EMT led to increased apoptosis and cisplatin sensitivity. Multivariate regression analysis shows that CXCL12 expression in the stromal cells and cytoreduction satisfaction are independent prognostic markers of platinum-containing chemotherapy sensitivity in 296 EOC patients. Conclusion: CAFs may activate the Wnt/ß-catenin pathway in EOC cells via CXCL12/CXCR4 axis, and then induce EMT and cisplatin resistance.

L1CAM promotes epithelial to mesenchymal transition and formation of cancer initiating cells in human endometrial cancer.

Identification of novel factors critical for epithelial to mesenchymal transition (EMT) and cancer initiating cell (CIC) formation may aid in the identification of novel therapeutics for the treatment of endometrial cancer. The present study demonstrated that L1 cell adhesion molecule (CAM) is critical for EMT and formation of CICs in endometrial cancer. Overexpression of L1CAM may promote EMT with increased formation of CICs in HEC-1A endometrial cancer cells. CICs and mesenchymal status resist chemotherapeutic drugs and may regenerate the various cell types in tumors, thereby resulting in relapse of the disease. The present study demonstrated that overexpressing L1CAM promoted paclitaxel resistance and regulated paclitaxel resistance-associated microRNA expression in HEC-1A cells. Furthermore, it was demonstrated that overexpressing L1CAM promoted anoikis resistance in HEC-1A cells. This link between L1CAM and EMT/CICs may provide a novel target for advancing anticancer therapy.

Antibody fragment-armed mesoporous silica nanoparticles for the targeted delivery of bevacizumab in ovarian cancer cells.

In order to enhance the therapeutic efficacy and intracellular concentration of bevacizumab (BVC), we have designed a novel tumor endothelial marker 1 (TEM1)/endosialin (Ab-/scFv)-conjugated mesoporous silica nanoparticles (MSN) to target ovarian cancer cell. The Ab-/scFv-conjugated MSN were prepared by the conjugation of amine functional group of antibody of the carboxyl group of MSN. The resultant MSN was nanosized, spherical shaped, and exhibited a controlled release phenomenon in pH 7.4 conditions. Furthermore, BMSN/Ab was found to increase the cellular uptake and intracellular distribution of BVC in OVCAR-5 cancer cells. The Ab- conjugated MSN exhibited a superior anticancer effect with profound apoptosis in cancer cells in a time- and concentration dependent manner. Consistently, BMSN/Ab effectively inhibited the colony formation in transwell plate. Finally, BMSN/Ab showed a notable increase in the proportion of cells in G2/M phase of cell cycle indicating promising anticancer efficacy profile. Overall, Ab-/scFv-conjugated MSN might provide an effective strategy for the therapeutic management of ovarian cancers.