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Ovarian mucinous tumors with sarcomatous mural nodules are rare. Sarcomatous nodules have a bad prognosis. Its diagnosis and treatment are controversial.It is still controversial whether malignant mural nodules represent a dedifferentiated form of mucinous tumors or collisional tumors. This is a case report of a 32-year-old female diagnosed with ovarian mucinous tumor recurred as a mucinous carcinoma combined with sarcomatoid and undifferentiated sarcoma mural nodules after surgery and chemotherapy. The primary lesion did not have a sarcomatous component after comprehensive sampling and repeated review, while the recurrent lesion had a predominantly sarcomatous component. The patient received a second operation and postoperative chemotherapy plus Anlotinib with no progression at 16 months of follow-up. Primary mucinous carcinoma and sarcomatous mural nodules revealed the same K-RAS mutation(c.35G>T, pG12V), TP53 mutation (c.817C>T, p.R273C), MLL2 mutation(c.13450C>T, p.R4484) and NF1 mutation(c.7876A>G, p.S2626G). We present a comprehensive analysis on morphologic characteristics, molecular detection results, clinical management, and prognosis of ovarian mucinous tumors with mural nodules of sarcomatoid and undifferentiated sarcoma. Mutation sharing between primary mucinous carcinoma and recurrent sarcomatous nodules supports monoclonal origin of primary and recurrent tumors, suggesting a tendency for sarcomatous differentiation during the progression of epithelial tumors. Malignant mural nodules represent dedifferentiation in mucinous ovarian tumors rather than collision of two different tumor types. Therefore, it is imperative to conduct comprehensive sampling, rigorous clinical examination, and postoperative follow-up in order to thoroughly evaluate all mural nodules of ovarian mucinous tumors due to their potential for malignancy and sarcomatous differentiation. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Mucinous ovarian carcinoma (MOC) is a rare histotype of ovarian cancer, with low response rates to standard chemotherapy, and very poor survival for patients diagnosed at advanced stage. There is a limited understanding of the MOC immune landscape, and consequently whether immune checkpoint inhibitors could be considered for a subset of patients. METHODS: We performed multicolor immunohistochemistry (IHC) and immunofluorescence (IF) on tissue microarrays in a cohort of 126 MOC patients. Cell densities were calculated in the epithelial and stromal components for tumor-associated macrophages (CD68+/PD-L1+, CD68+/PD-L1-), T cells (CD3+/CD8-, CD3+/CD8+), putative T-regulatory cells (Tregs, FOXP3+), B cells (CD20+/CD79A+), plasma cells (CD20-/CD79a+), and PD-L1+ and PD-1+ cells, and compared these values with clinical factors. Univariate and multivariable Cox Proportional Hazards assessed overall survival. Unsupervised k-means clustering identified patient subsets with common patterns of immune cell infiltration. RESULTS: Mean densities of PD1+ cells, PD-L1- macrophages, CD4+ and CD8+ T cells, and FOXP3+ Tregs were higher in the stroma compared to the epithelium. Tumors from advanced (Stage III/IV) MOC had greater epithelial infiltration of PD-L1- macrophages, and fewer PD-L1+ macrophages compared with Stage I/II cancers (p = 0.004 and p = 0.014 respectively). Patients with high epithelial density of FOXP3+ cells, CD8+/FOXP3+ cells, or PD-L1- macrophages, had poorer survival, and high epithelial CD79a + plasma cells conferred better survival, all upon univariate analysis only. Clustering showed that most MOC (86%) had an immune depleted (cold) phenotype, with only a small proportion (11/76,14%) considered immune inflamed (hot) based on T cell and PD-L1 infiltrates. CONCLUSION: In summary, MOCs are mostly immunogenically cold, suggesting they may have limited response to current immunotherapies.

Objective: To evaluate the clinicopathological characteristics of primary mucinous ovarian carcinoma (MOC) and define oncologic outcomes. Material and Methods: This retrospective study reviewed patients diagnosed with primary MOC at a single institution and underwent primary treatment between 1990 and 2019. The clinicopathological factors affecting oncological outcomes and treatment response were evaluated. The Kaplan-Meier method was used to evaluate survival outcomes. Survival curves were compared using the log-rank test. Results: The cohort's (n=92) median (range) age was 48 (15-82) years. Seventy-five (81.5%) patients were in the International Federation of Gynecology and Obstetrics stage I-II. Forty patients received platinum-based adjuvant chemotherapy. The 5-year progression-free survival was 98% in stage I-II and 17% for stage III-IV (p<0.001). In multivariate analysis, the only independent risk factor for disease failure was stage (hazard ratio: 6.838, 95% confidence interval: 1,358-34,415; p=0.020). Conclusion: Advanced stage was an independent poor prognostic factor for recurrence in patient with MOC. [ABSTRACT FROM AUTHOR]

Mucinous ovarian carcinoma (MOC) is a rare histological type of epithelial ovarian cancer. It has poor response to conventional platinum-based chemotherapy regimens and PARPi-based maintenance treatment, resulting in short survival and poor prognosis in advanced-disease patients. MOC is characterized by mucus that is mainly composed of mucin in the cystic cavity. Our review discusses in detail the role of mucins in MOC. Mucins are correlated with MOC development. Furthermore, they are valuable in the differential diagnosis of primary and secondary ovarian mucinous tumors. Some types of mucins have been studied in the context of chemoresistance and targeted therapy for ovarian cancer. This review may provide a new direction for the diagnosis and treatment of advanced MOC.

Introduction: Ovarian cancer (OC) is the leading cause of gynecological cancer-related death. Of the main OC histologic subtypes, invasive mucinous carcinomas (MC) account for only 3% of OC cases and are frequently associated with favorable prognosis. Nevertheless, MCs differ greatly from the other OC histotypes in clinical, pathological, and biological behavior. However, the origin and molecular pathogenesis of MC are not yet fully understood. Therefore, identification of novel diagnostic markers could potentially facilitate early diagnosis of OC, particularly the MC histotype, thereby leading to the development of histotype-specific treatment regimens and improved survival rates. Methods: In the present study, Trefoil factor gene family members (TFF1, TFF2 and TFF3) were identified as MC histotype-specific biomarkers using RNA sequencing (RNA-seq) data for 95 stage I-II OCs. The diagnostic value of TFF1, TFF2 and TFF3 was then evaluated by immunohistochemistry on 206 stage I-II OCs stratified by histotype (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], clear cell carcinoma [CCC], and MC). Results: We showed significantly elevated intracytoplasmic protein expression levels for TFF1, TFF2 and TFF3 in MC samples, thereby revealing an association between expression of Trefoil factor gene family members and the MC histotype. Taken together, these findings suggest that the TFF proteins may play a pivotal role in tumor initiation and progression for the MC histotype. Conclusion: Taken together, these findings suggest that the TFF proteins may play a pivotal role in tumor initiation and progression for the MC histotype. Moreover, these novel histotype-specific diagnostic biomarkers may not only improve patient stratification of early-stage ovarian carcinomas but may also be candidates for the development of molecular targeted therapies. [ABSTRACT FROM AUTHOR]

IntroductionOvarian cancer (OC) is the leading cause of gynecological cancer-related death. Of the main OC histologic subtypes, invasive mucinous carcinomas (MC) account for only 3% of OC cases and are frequently associated with favorable prognosis. Nevertheless, MCs differ greatly from the other OC histotypes in clinical, pathological, and biological behavior. However, the origin and molecular pathogenesis of MC are not yet fully understood. Therefore, identification of novel diagnostic markers could potentially facilitate early diagnosis of OC, particularly the MC histotype, thereby leading to the development of histotype-specific treatment regimens and improved survival rates.MethodsIn the present study, Trefoil factor gene family members (TFF1, TFF2 and TFF3) were identified as MC histotype-specific biomarkers using RNA sequencing (RNA-seq) data for 95 stage I-II OCs. The diagnostic value of TFF1, TFF2 and TFF3 was then evaluated by immunohistochemistry on 206 stage I-II OCs stratified by histotype (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], clear cell carcinoma [CCC], and MC).ResultsWe showed significantly elevated intracytoplasmic protein expression levels for TFF1, TFF2 and TFF3 in MC samples, thereby revealing an association between expression of Trefoil factor gene family members and the MC histotype. Taken together, these findings suggest that the TFF proteins may play a pivotal role in tumor initiation and progression for the MC histotype.ConclusionTaken together, these findings suggest that the TFF proteins may play a pivotal role in tumor initiation and progression for the MC histotype. Moreover, these novel histotype-specific diagnostic biomarkers may not only improve patient stratification of early-stage ovarian carcinomas but may also be candidates for the development of molecular targeted therapies.

Advanced or recurrent mucinous carcinoma of the ovary minimally responds to current cytotoxic treatments and has a poor prognosis. Despite multimodal treatment with chemotherapy and surgery, most patients ultimately progress and require palliative systemic therapy. Anti-HER2 therapy has been demonstrated to be an effective strategy for the treatment of HER2-positive breast cancer. However, the role of anti-HER2 therapy in ovarian cancer remains largely unknown. Here, we report the case of a young woman with FIGO Stage IIIc recurrent mucinous ovarian carcinoma (MOC) who developed trastuzumab resistance and disease progression following cross-treatment with trastuzumab combined with pertuzumab. HER2 amplification was discovered using next-generation sequencing (NGS). The patient then received bevacizumab, and pyrotinib (an irreversible HER2 antagonist) plus capecitabine treatment, and achieved a long-term clinical benefit for 22 months. Pyrotinib combined with bevacizumab is a potential treatment for MOC patients who are heavily pretreated and harbor a HER2 amplification. Our case may provide valuable treatment information for patients with advanced or recurrent MOC. [ABSTRACT FROM AUTHOR]

Objective: The aim of the present study was to evaluate evolution and prognosis of mucinous ovarian carcinomas (mOC), with respect to the two invasive patterns: expansile and infiltrative invasion. Methods: This was a descriptive, retrospective, multicenter study conducted in 13 French centres from 1 January 2001 to 31 December 2019. All patients operated on for epithelial ovarian neoplasia of the mucinous type (infiltrative/expansile) were included, whether the surgery was performed immediately or after neoadjuvant chemotherapy. Results: A total of 94 women with mucinous carcinomas were included in the present study. Mucinous tumours were divided into 35 expansile (37%) and 59 infiltrative (63%) mOC. There was a statistically significant difference in early and late stages at initial diagnosis between expansile and infiltrative mOC. None of the expansile mOC showed metastatic lymph nodes, whereas almost a quarter of the infiltrative mOC were metastatic to the pelvic/para-aortic region. There was a clear difference in RFS, in favour of expansile mOC, with 90% survival at 5 years, compared with 60% for infiltrative mOC. Conclusions: Although infiltrative and expansile mOC belong to the same histological family, they present many distinctions in clinical presentation, histological invasion, and disease course. [ABSTRACT FROM AUTHOR]

Objective: Considering the clinical evidence of BRAF inhibitors that can treat melanoma patients successfully, we aimed to investigate the status of BRAF mutations of primary mucinous ovarian carcinomas (MOC) in Taiwanese women, and apply the emerging paradigm classification of BRAF mutation groups. Materials and methods: 20 archived primary MOC samples were analyzed. The BRAF mutations of activation segment (exon 15), CR3 (conserved regions 3), kinase domain of the BRAF gene were analyzed using the highly sensitive BRAF mutant enriched kit (FemtoPath®) with Sanger sequencing method. Additionally, we extended our prior reported data of HER2 aberrations and KRAS mutation into this study in order to compare with the status of BRAF mutation. Results: Of them (n = 20), 16 (80%) harbored BRAF missense mutations. Their mutation profile and case number (n) were categorized as (1) class I: V600E (n=1), V600M (n = 1); (2) class II: A598V (n = 1), T599I (n = 10); (3) class III: none (n = 0); and (4) unclassified variants: S602F (n = 2), T599I/S602F (n = 1). The BRAF S602F is novel. The prevalence of BRAF mutation is significantly higher than either HER2 mutation (80% vs. 35%; p = 0.022) or HER2 amplification (80% vs. 35%; p = 0.022). However, the mutation rates of BRAF and KRAS were not significantly different (80% vs. 60%; p = 0.289). Conclusion: Activating BRAF mutation, HER2 amplification, HER2 mutation and KRAS mutation were not mutually exclusive. However, they may even have a synergistic effect in tumorigenesis. BRAF mutation is not uncommon in primary MOC of Taiwanese. The BRAF mutant (T599I) stands the majority. We suggested that there was a lower potential response to the existing V600 BRAF inhibitors, but may be responsive to dual BRAF plus MEK inhibitors or single MEK inhibitor. Further studies are warranted to investigate the clinical benefits of newly targeted therapy in recurrent or advanced stage primary MOC patients carrying different classes of BRAF mutation.

Ovarian mucinous tumors with sarcomatous mural nodules are rare. Sarcomatous nodules have a bad prognosis. Its diagnosis and treatment are controversial.It is still controversial whether malignant mural nodules represent a dedifferentiated form of mucinous tumors or collisional tumors. This is a case report of a 32-year-old female diagnosed with ovarian mucinous tumor recurred as a mucinous carcinoma combined with sarcomatoid and undifferentiated sarcoma mural nodules after surgery and chemotherapy. The primary lesion did not have a sarcomatous component after comprehensive sampling and repeated review, while the recurrent lesion had a predominantly sarcomatous component. The patient received a second operation and postoperative chemotherapy plus Anlotinib with no progression at 16 months of follow-up. Primary mucinous carcinoma and sarcomatous mural nodules revealed the same K-RAS mutation(c.35G>T, pG12V), TP53 mutation (c.817C>T, p.R273C), MLL2 mutation(c.13450C>T, p.R4484) and NF1 mutation(c.7876A>G, p.S2626G). We present a comprehensive analysis on morphologic characteristics, molecular detection results, clinical management, and prognosis of ovarian mucinous tumors with mural nodules of sarcomatoid and undifferentiated sarcoma. Mutation sharing between primary mucinous carcinoma and recurrent sarcomatous nodules supports monoclonal origin of primary and recurrent tumors, suggesting a tendency for sarcomatous differentiation during the progression of epithelial tumors. Malignant mural nodules represent dedifferentiation in mucinous ovarian tumors rather than collision of two different tumor types. Therefore, it is imperative to conduct comprehensive sampling, rigorous clinical examination, and postoperative follow-up in order to thoroughly evaluate all mural nodules of ovarian mucinous tumors due to their potential for malignancy and sarcomatous differentiation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Zhu, Jiang, Guo, Hou, Liu, Yang and Yang.)

Objective: The aim of the present study was to evaluate evolution and prognosis of mucinous ovarian carcinomas (mOC), with respect to the two invasive patterns: expansile and infiltrative invasion. Methods: This was a descriptive, retrospective, multicenter study conducted in 13 French centres from 1 January 2001 to 31 December 2019. All patients operated on for epithelial ovarian neoplasia of the mucinous type (infiltrative/expansile) were included, whether the surgery was performed immediately or after neoadjuvant chemotherapy. Results: A total of 94 women with mucinous carcinomas were included in the present study. Mucinous tumours were divided into 35 expansile (37%) and 59 infiltrative (63%) mOC. There was a statistically significant difference in early and late stages at initial diagnosis between expansile and infiltrative mOC. None of the expansile mOC showed metastatic lymph nodes, whereas almost a quarter of the infiltrative mOC were metastatic to the pelvic/para-aortic region. There was a clear difference in RFS, in favour of expansile mOC, with 90% survival at 5 years, compared with 60% for infiltrative mOC. Conclusions: Although infiltrative and expansile mOC belong to the same histological family, they present many distinctions in clinical presentation, histological invasion, and disease course.

Early-stage (I and II) ovarian carcinoma patients generally have good prognosis. Yet, some patients die earlier than expected. Thus, it is important to stratify early-stage patients into risk groups to identify those in need of more aggressive treatment regimens. The prognostic value of 29 histotype-specific biomarkers identified using RNA sequencing was evaluated for early-stage clear-cell (CCC), endometrioid (EC) and mucinous (MC) ovarian carcinomas (n = 112) using immunohistochemistry on tissue microarrays. Biomarkers with prognostic significance were further evaluated in an external ovarian carcinoma data set using the web-based Kaplan-Meier plotter tool. Here, we provide evidence of aberrant protein expression patterns and prognostic significance of 17 novel histotype-specific prognostic biomarkers [10 for CCC (ARPC2, CCT5, GNB1, KCTD10, NUP155, RPL13A, RPL37, SETD3, SMYD2, TRIO), three for EC (CECR1, KIF26B, PIK3CA), and four for MC (CHEK1, FOXM1, KIF23, PARPBP)], suggesting biological heterogeneity within the histotypes. Combined predictive models comprising the protein expression status of the validated CCC, EC and MC biomarkers together with established clinical markers (age, stage, CA125, ploidy) improved the predictive power in comparison with models containing established clinical markers alone, further strengthening the importance of the biomarkers in ovarian carcinoma. Further, even improved predictive powers were demonstrated when combining these models with our previously identified prognostic biomarkers PITHD1 (CCC) and GPR158 (MC). Moreover, the proteins demonstrated improved risk prediction of CCC-, EC-, and MC-associated ovarian carcinoma survival. The novel histotype-specific prognostic biomarkers may not only improve prognostication and patient stratification of early-stage ovarian carcinomas, but may also guide future clinical therapy decisions.

ObjectiveThe main aim of this study was to evaluate cancer antigen 125 (CA125)/carcinoembryonic antigen (CEA) ratio (CCR), as a reliable marker to differentiate ovarian mucinous carcinoma from other epithelial ovarian carcinomas (EOCs), namely serous, clear cell, and endometrioid carcinomas.MethodsFemale patients suffering from different kinds of EOCs whom were subjected to elective surgery at the Gangnam Severance Hospital between January 2008 and December 2016, were included in this study. The serum levels of CA125 and CEA were assayed using commercially available kits per the manufacturer's instructions.ResultsThe CCR in mucinous carcinoma (mean 32.1) was significantly lower than that of clear cell (mean 235.0) and endometrioid carcinoma (mean 427.0) in stage I (all P

Early-stage (I and II) ovarian carcinoma patients generally have good prognosis. Yet, some patients die earlier than expected. Thus, it is important to stratify early-stage patients into risk groups to identify those in need of more aggressive treatment regimens. The prognostic value of 29 histotype-specific biomarkers identified using RNA sequencing was evaluated for early-stage clear-cell (CCC), endometrioid (EC) and mucinous (MC) ovarian carcinomas (n = 112) using immunohistochemistry on tissue microarrays. Biomarkers with prognostic significance were further evaluated in an external ovarian carcinoma data set using the web-based Kaplan-Meier plotter tool. Here, we provide evidence of aberrant protein expression patterns and prognostic significance of 17 novel histotype-specific prognostic biomarkers [10 for CCC (ARPC2, CCT5, GNB1, KCTD10, NUP155, RPL13A, RPL37, SETD3, SMYD2, TRIO), three for EC (CECR1, KIF26B, PIK3CA), and four for MC (CHEK1, FOXM1, KIF23, PARPBP)], suggesting biological heterogeneity within the histotypes. Combined predictive models comprising the protein expression status of the validated CCC, EC and MC biomarkers together with established clinical markers (age, stage, CA125, ploidy) improved the predictive power in comparison with models containing established clinical markers alone, further strengthening the importance of the biomarkers in ovarian carcinoma. Further, even improved predictive powers were demonstrated when combining these models with our previously identified prognostic biomarkers PITHD1 (CCC) and GPR158 (MC). Moreover, the proteins demonstrated improved risk prediction of CCC-, EC-, and MC-associated ovarian carcinoma survival. The novel histotype-specific prognostic biomarkers may not only improve prognostication and patient stratification of early-stage ovarian carcinomas, but may also guide future clinical therapy decisions. [ABSTRACT FROM AUTHOR]

Objective: Mucinous ovarian carcinoma (MOC) is an uncommon subtype of epithelial ovarian cancers, and the pathogenesis is still poorly understood because of its rarity. We conducted a gene set-based analysis to investigate the pathogenesis of MOC by integrating microarray gene expression datasets based on the regularity of functions defined by gene ontology or canonical pathway databases. Materials and methods: Forty-five pairs of MOC and normal ovarian tissue sample gene expression profiles were downloaded from the National Center for Biotechnology Information Gene Expression Omnibus database. The gene expression profiles were converted to the gene set regularity indexes by measuring the change of gene expression ordering in a gene set. Then the pathogenesis of MOC was investigated with the differences of function regularity with the gene set regularity indexes between the MOC and normal control samples. Results: The informativeness of the gene set regularity indexes was sufficient for machine learning to accurately recognize and classify the functional regulation patterns with an accuracy of 99.44%. The statistical analysis revealed that the GTPase regulators and receptor tyrosine kinase erbB-2 (ERBB2) were the most important aberrations; the exploratory factor analysis revealed phosphoinositide 3-kinase-activating kinase, G-protein coupled receptor pathway, oxidoreductase activity, immune response, peptidase activity, regulation of translation, and transport and channel activity were also involved in the pathogenesis of MOC. Conclusion: Investigating the pathogenesis of MOC with the functionome provided a comprehensive view of the deregulated functions of this disease. In addition to GTPase regulators and ERBB2, a plenty of deregulated functions such as phosphoinositide 3-kinase, G-protein coupled receptor pathway, and immune response also participated in the interaction network of MOC pathogenesis.

Mucinous epithelial ovarian cancer (mEOC) is a rare subset of epithelial ovarian cancer. When diagnosed at a late stage, its prognosis is very poor, as it is quite chemo-resistant. To find new therapeutic options for mEOC, we performed high-throughput screening using a siRNA library directed against human protein kinases in a mEOC cell line, and polo-like kinase1 (PLK1) was identified as the kinase whose downregulation interfered with cell proliferation. Both PLK1 siRNA and two specific PLK1 inhibitors (onvansertib and volasertib) were able to inhibit cell growth, induce apoptosis and block cells in the G2/M phase of the cell cycle. We evaluated, in vitro, the combinations of PLK1 inhibitors and different chemotherapeutic drugs currently used in the treatment of mEOC, and we observed a synergistic effect of PLK1 inhibitors and antimitotic drugs. When translated into an in vivo xenograft model, the combination of onvansertib and paclitaxel resulted in stronger tumor regressions and in a longer mice survival than the single treatments. These effects were associated with a higher induction of mitotic block and induction of apoptosis, similarly to what was observed in vitro. These data suggest that the combination onvansertib/paclitaxel could represent a new active therapeutic option in mEOC.

Mucinous ovarian cancer (MOC) is a rare subtype of epithelial ovarian carcinoma (EOC). Whereas all EOC subtypes are addressed in the same way, MOC is a distinct entity. Appreciating the pathological features and genomic profile of MOC may result in the improvement in management and, hence, the prognosis. Distinguishing primary MOC from metastatic mucinous carcinoma can be challenging but is essential. Early-stage MOC carries an excellent prognosis, with advanced disease having a poor outcome. Surgical management plays an essential role in the early stage and in metastatic disease. Chemotherapy is usually administered for stage II MOC and beyond. The standard gynecology protocol is frequently used, but gastrointestinal regimens have also been administered. As MOC is associated with multiple molecular alterations, targeted therapy could be the answer to treat this disease.

Mucinous ovarian carcinoma (MOC) is a rare histological type of epithelial ovarian cancer. It has poor response to conventional platinum-based chemotherapy regimens and PARPi-based maintenance treatment, resulting in short survival and poor prognosis in advanced-disease patients. MOC is characterized by mucus that is mainly composed of mucin in the cystic cavity. Our review discusses in detail the role of mucins in MOC. Mucins are correlated with MOC development. Furthermore, they are valuable in the differential diagnosis of primary and secondary ovarian mucinous tumors. Some types of mucins have been studied in the context of chemoresistance and targeted therapy for ovarian cancer. This review may provide a new direction for the diagnosis and treatment of advanced MOC., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Introduction: Ovarian cancer (OC) is the leading cause of gynecological cancer-related death. Of the main OC histologic subtypes, invasive mucinous carcinomas (MC) account for only 3% of OC cases and are frequently associated with favorable prognosis. Nevertheless, MCs differ greatly from the other OC histotypes in clinical, pathological, and biological behavior. However, the origin and molecular pathogenesis of MC are not yet fully understood. Therefore, identification of novel diagnostic markers could potentially facilitate early diagnosis of OC, particularly the MC histotype, thereby leading to the development of histotype-specific treatment regimens and improved survival rates., Methods: In the present study, Trefoil factor gene family members (TFF1, TFF2 and TFF3) were identified as MC histotype-specific biomarkers using RNA sequencing (RNA-seq) data for 95 stage I-II OCs. The diagnostic value of TFF1, TFF2 and TFF3 was then evaluated by immunohistochemistry on 206 stage I-II OCs stratified by histotype (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], clear cell carcinoma [CCC], and MC)., Results: We showed significantly elevated intracytoplasmic protein expression levels for TFF1, TFF2 and TFF3 in MC samples, thereby revealing an association between expression of Trefoil factor gene family members and the MC histotype. Taken together, these findings suggest that the TFF proteins may play a pivotal role in tumor initiation and progression for the MC histotype., Conclusion: Taken together, these findings suggest that the TFF proteins may play a pivotal role in tumor initiation and progression for the MC histotype. Moreover, these novel histotype-specific diagnostic biomarkers may not only improve patient stratification of early-stage ovarian carcinomas but may also be candidates for the development of molecular targeted therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Werner Rönnerman, Pettersson, Nemes, Dahm-Kähler, Kovács, Karlsson, Parris and Helou.)

Though ovarian malignancies are common, mucinous ovarian carcinomas of high grade are rare. They usually occur in a young female under 40 years of age. Here, we present a case of mucinous ovarian carcinoma (stage III), with omental involvement and incidental hydronephrosis in a 67-year-old female patient. A 67-year-old female patient presented to us with a history of lower abdominal pain for 2 months and per-vaginal discharge for the last 6 days. On deep palpation of the abdomen, a nodular mass occupying the suprapubic region was found. Bimanual palpation revealed a mass on the right and left adnexa. After visualization of septate cystic mass bilaterally on CECT, she was planned for staging laparotomy with bilateral salpingo-oophorectomy (BSO) with infra-colic omentectomy with peritoneal cytology. Incidentally, a horseshoe-shaped kidney with right mild hydronephrosis was found. After surgery and histopathologic examination, mucinous ovarian carcinoma (stage III), with omental involvement was confirmed. Mucinous ovarian carcinomas are rare malignancies, with different natural history, molecular profile, and prognosis as compared to other epithelial tumors of the ovary. These carcinomas can be either primary or secondary (those metastasized to the ovary from elsewhere), and this differentiation is essential. The therapeutic approach to the patients depends upon the stage at which these carcinomas are diagnosed. Mucinous ovarian carcinomas are rare and have unique features among the epithelial ovarian carcinomas. Appreciation of these features will surely make a positive impact in improving the management and thus the prognosis of these carcinomas. • Mucinous ovarian carcinomas are rare ovarian malignancies • They have distinct features when compared to other epithelial ovarian cancers • Appreciating the pathologic features will make diagnosis easier and hence a better prognosis [ABSTRACT FROM AUTHOR]

Objective: Considering the clinical evidence of BRAF inhibitors that can treat melanoma patients successfully, we aimed to investigate the status of BRAF mutations of primary mucinous ovarian carcinomas (MOC) in Taiwanese women, and apply the emerging paradigm classification of BRAF mutation groups., Materials and Methods: 20 archived primary MOC samples were analyzed. The BRAF mutations of activation segment (exon 15), CR3 (conserved regions 3), kinase domain of the BRAF gene were analyzed using the highly sensitive BRAF mutant enriched kit (FemtoPath®) with Sanger sequencing method. Additionally, we extended our prior reported data of HER2 aberrations and KRAS mutation into this study in order to compare with the status of BRAF mutation., Results: Of them (n = 20), 16 (80%) harbored BRAF missense mutations. Their mutation profile and case number (n) were categorized as (1) class I: V600E (n=1), V600M (n = 1); (2) class II: A598V (n = 1), T599I (n = 10); (3) class III: none (n = 0); and (4) unclassified variants: S602F (n = 2), T599I/S602F (n = 1). The BRAF S602F is novel. The prevalence of BRAF mutation is significantly higher than either HER2 mutation (80% vs. 35%; p = 0.022) or HER2 amplification (80% vs. 35%; p = 0.022). However, the mutation rates of BRAF and KRAS were not significantly different (80% vs. 60%; p = 0.289)., Conclusion: Activating BRAF mutation, HER2 amplification, HER2 mutation and KRAS mutation were not mutually exclusive. However, they may even have a synergistic effect in tumorigenesis. BRAF mutation is not uncommon in primary MOC of Taiwanese. The BRAF mutant (T599I) stands the majority. We suggested that there was a lower potential response to the existing V600 BRAF inhibitors, but may be responsive to dual BRAF plus MEK inhibitors or single MEK inhibitor. Further studies are warranted to investigate the clinical benefits of newly targeted therapy in recurrent or advanced stage primary MOC patients carrying different classes of BRAF mutation., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2021. Published by Elsevier B.V.)

Mucinous epithelial ovarian cancer (mEOC) is a rare subset of epithelial ovarian cancer. When diagnosed at a late stage, its prognosis is very poor, as it is quite chemo-resistant. To find new therapeutic options for mEOC, we performed high-throughput screening using a siRNA library directed against human protein kinases in a mEOC cell line, and polo-like kinase1 (PLK1) was identified as the kinase whose downregulation interfered with cell proliferation. Both PLK1 siRNA and two specific PLK1 inhibitors (onvansertib and volasertib) were able to inhibit cell growth, induce apoptosis and block cells in the G2/M phase of the cell cycle. We evaluated, in vitro, the combinations of PLK1 inhibitors and different chemotherapeutic drugs currently used in the treatment of mEOC, and we observed a synergistic effect of PLK1 inhibitors and antimitotic drugs. When translated into an in vivo xenograft model, the combination of onvansertib and paclitaxel resulted in stronger tumor regressions and in a longer mice survival than the single treatments. These effects were associated with a higher induction of mitotic block and induction of apoptosis, similarly to what was observed in vitro. These data suggest that the combination onvansertib/paclitaxel could represent a new active therapeutic option in mEOC. [ABSTRACT FROM AUTHOR]

Mucinous ovarian cancer (MOC) is a rare subtype of epithelial ovarian carcinoma (EOC). Whereas all EOC subtypes are addressed in the same way, MOC is a distinct entity. Appreciating the pathological features and genomic profile of MOC may result in the improvement in management and, hence, the prognosis. Distinguishing primary MOC from metastatic mucinous carcinoma can be challenging but is essential. Early-stage MOC carries an excellent prognosis, with advanced disease having a poor outcome. Surgical management plays an essential role in the early stage and in metastatic disease. Chemotherapy is usually administered for stage II MOC and beyond. The standard gynecology protocol is frequently used, but gastrointestinal regimens have also been administered. As MOC is associated with multiple molecular alterations, targeted therapy could be the answer to treat this disease. [ABSTRACT FROM AUTHOR]

Jayson GC et al. remarked in Lancet that nearly 100% of mucinous ovarian cancer cases have Kras mutation as well as a high frequency of Her2 amplification. Using the Abbott PathVysion Her2 DNA Probe Kit and Kras mutantenriched PCR Kits (FemtoPath®), 21 samples of primary ovarian mucinous cystadenocarcinomas from Taiwanese patients were examined to determine the status of Her2 amplification and Kras mutations. Our results showed the Her2 amplification rates were 33.33%, while the Kras mutation rates were 61.90%. We present here our results in order to enlighten the readership that the ~100% Kras mutant frequency and the high Her2 amplification rate reported by Jayson et al. may be too exaggerated to be applicable into all populations. Additionally, we report another 2 novel Kras mutations (A11V, V14I). [ABSTRACT FROM AUTHOR]

Objective: The main aim of this study was to evaluate cancer antigen 125 (CA125)/carcinoembryonic antigen (CEA) ratio (CCR), as a reliable marker to differentiate ovarian mucinous carcinoma from other epithelial ovarian carcinomas (EOCs), namely serous, clear cell, and endometrioid carcinomas., Methods: Female patients suffering from different kinds of EOCs whom were subjected to elective surgery at the Gangnam Severance Hospital between January 2008 and December 2016, were included in this study. The serum levels of CA125 and CEA were assayed using commercially available kits per the manufacturer's instructions., Results: The CCR in mucinous carcinoma (mean 32.1) was significantly lower than that of clear cell (mean 235.0) and endometrioid carcinoma (mean 427.0) in stage I (all P <0.05). In stage II-IV, CCR in mucinous carcinoma (mean 37.6) was significantly lower than that of serous carcinoma (mean 148.0) ( P <0.01). The sensitivity and specificity of CCR in detecting mucinous carcinoma from other types of EOC was 75.0% and 77.5%, respectively in stage I and 100.0% and 84.4%, respectively in stage II-IV (both cut-off value <90.7)., Conclusion: The present results suggest that pretreatment CCR might provide higher specificity and clinically relevant information as a criterion for the differentiation between ovarian mucinous carcinoma and other types of EOC., Competing Interests: Conflict of interest: No potential conflict of interest relevant to this article was reported.

Objective: Mucinous ovarian carcinoma (MOC) is an uncommon subtype of epithelial ovarian cancers, and the pathogenesis is still poorly understood because of its rarity. We conducted a gene set-based analysis to investigate the pathogenesis of MOC by integrating microarray gene expression datasets based on the regularity of functions defined by gene ontology or canonical pathway databases., Materials and Methods: Forty-five pairs of MOC and normal ovarian tissue sample gene expression profiles were downloaded from the National Center for Biotechnology Information Gene Expression Omnibus database. The gene expression profiles were converted to the gene set regularity indexes by measuring the change of gene expression ordering in a gene set. Then the pathogenesis of MOC was investigated with the differences of function regularity with the gene set regularity indexes between the MOC and normal control samples., Results: The informativeness of the gene set regularity indexes was sufficient for machine learning to accurately recognize and classify the functional regulation patterns with an accuracy of 99.44%. The statistical analysis revealed that the GTPase regulators and receptor tyrosine kinase erbB-2 (ERBB2) were the most important aberrations; the exploratory factor analysis revealed phosphoinositide 3-kinase-activating kinase, G-protein coupled receptor pathway, oxidoreductase activity, immune response, peptidase activity, regulation of translation, and transport and channel activity were also involved in the pathogenesis of MOC., Conclusion: Investigating the pathogenesis of MOC with the functionome provided a comprehensive view of the deregulated functions of this disease. In addition to GTPase regulators and ERBB2, a plenty of deregulated functions such as phosphoinositide 3-kinase, G-protein coupled receptor pathway, and immune response also participated in the interaction network of MOC pathogenesis., (Copyright © 2017. Published by Elsevier B.V.)