BACKGROUND Retroperitoneal high-grade serous carcinoma(HGSC)of unknown origin is a sporadic tumor that can originate from ovarian cancer.Herein,we report the case of a woman with retroperitoneal HGSC of unknown origin...BACKGROUND Retroperitoneal high-grade serous carcinoma(HGSC)of unknown origin is a sporadic tumor that can originate from ovarian cancer.Herein,we report the case of a woman with retroperitoneal HGSC of unknown origin and describe how she was diagnosed and treated.CASE SUMMARY A 71-year-old female presented with the tumor marker CA125 elevated to 1041.9 U/mL upon a regular health examination.Computed tomography revealed retroperitoneal lymph node enlargement.Subsequently,positron emission tomography scanning revealed lesions with increased F-18 fluorodeoxyglucose uptake at the nodes.As a result,she underwent laparoscopic lymph node resection,and pathology revealed metastatic adenocarcinoma with CK7(+),PAX8(+),WT1(+),PR(-),and p53 mutational loss of expression,indicating that the origin may be from the adnexa.The patient was admitted to our ward and underwent laparoscopic staging;however,the pathological results were negative.Under the suspicion of retroperitoneal HGSC of unknown origin,chemotherapy and targeted therapy were initiated.Tumor marker levels decreased after treatment.CONCLUSION We present a case of HGSC of unknown origin managed using retroperitoneal lymphadenectomy,staging surgery,chemotherapy,and targeted therapy.展开更多
BACKGROUND Few studies have reported an association between an increased risk of acquiring cancers and survival in patients with 4q deletion syndrome.This study presents a rare association between chromosome 4q abnorm...BACKGROUND Few studies have reported an association between an increased risk of acquiring cancers and survival in patients with 4q deletion syndrome.This study presents a rare association between chromosome 4q abnormalities and fallopian tube highgrade serous carcinoma(HGSC)in a young woman.CASE SUMMARY A 35-year-old woman presented with acute dull abdominal pain and a known chromosomal abnormality involving 4q13.3 duplication and 4q23q24 deletion.Upon arrival at the emergency room,her abdomen appeared ovoid and distended with palpable shifting dullness.Ascites were identified through abdominal ultrasound,and computed tomography revealed an omentum cake and an enlarged bilateral adnexa.Blood tests showed elevated CA-125 levels.Paracentesis was conducted,and immunohistochemistry indicated that the cancer cells favored an ovarian origin,making us suspect ovarian cancer.The patient underwent debulking surgery,which led to a diagnosis of stage IIIC HGSC of the fallopian tube.Subsequently,the patient received adjuvant chemotherapy with carboplatin and paclitaxel,resulting in stable current condition.CONCLUSION This study demonstrates a rare correlation between a chromosome 4q abnormality and HGSC.UBE2D3 may affect crucial cancer-related pathways,including P53,BRCA,cyclin D,and tyrosine kinase receptors,thereby possibly contributing to cancer development.In addition,ADH1 and DDIT4 may be potential influencers of both carcinogenic and therapeutic responses.展开更多
Background:The cellular tumor protein p53(TP53)is a tumor suppressor gene that is frequently mutated in human cancers.Among various cancer types,the very aggressive high-grade serous ovarian carcinoma(HGSOC)exhibits t...Background:The cellular tumor protein p53(TP53)is a tumor suppressor gene that is frequently mutated in human cancers.Among various cancer types,the very aggressive high-grade serous ovarian carcinoma(HGSOC)exhibits the high-est prevalence of TP53 mutations,present in>96%of cases.Despite intensive efforts to reactivate p53,no clinical drug has been approved to rescue p53 func-tion.In this study,our primary objective was to administer in vitro-transcribed(IVT)wild-type(WT)p53-mRNA to HGSOC cell lines,primary cells,and ortho-topic mouse models,with the aim of exploring its impact on inhibiting tumor growth and dissemination,both in vitro and in vivo.Methods:To restore the activity of p53,WT p53 was exogenously expressed in HGSOC cell lines using a mammalian vector system.Moreover,IVT WT p53 mRNA was delivered into different HGSOC model systems(primary cells and patient-derived organoids)using liposomes and studied for proliferation,cell cycle progression,apoptosis,colony formation,and chromosomal instabil-ity.Transcriptomic alterations induced by p53 mRNA were analyzed using RNA sequencing in OVCAR-8 and primary HGSOC cells,followed by ingenuity path-way analysis.In vivo effects on tumor growth and metastasis were studied using orthotopic xenografts and metastatic intraperitoneal mouse models.Results:Reactivation of the TP53 tumor suppressor gene was explored in differ-ent HGSOC model systems using newly designed IVT mRNA-based methods.The introduction of WT p53 mRNA triggered dose-dependent apoptosis,cell cycle arrest,and potent long-lasting inhibition of HGSOC cell proliferation.Transcriptome analysis of OVCAR-8 cells upon mRNA-based p53 reactivation revealed significant alterations in gene expression related to p53 signaling,such as apoptosis,cell cycle regulation,and DNA damage.Restoring p53 function concurrently reduces chromosomal instability within the HGSOC cells,under-scoring its crucial contribution in safeguarding genomic integrity by moderating the baseline occurrence of double-strand breaks arising from replication stress.Furthermore,in various mouse models,treatment with p53 mRNA reduced tumor growth and inhibited tumor cell dissemination in the peritoneal cavity in a dose-dependent manner.Conclusions:The IVT mRNA-based reactivation of p53 holds promise as a potential therapeutic strategy for HGSOC,providing valuable insights into the molecular mechanisms underlying p53 function and its relevance in ovarian cancer treatment.展开更多
Background:High-grade serous ovarian cancer(HGSOC)is the biggest cause of gynecological cancer-related mortality because of its extremely metastatic nature.This study aimed to explore and evaluate the characteristics ...Background:High-grade serous ovarian cancer(HGSOC)is the biggest cause of gynecological cancer-related mortality because of its extremely metastatic nature.This study aimed to explore and evaluate the characteristics of candidate factors associated with the metastasis and progression of HGSOC.Methods:Transcriptomic data of HGSOC patients’samples collected from primary tumors and matched omental metastatic tumors were obtained from three independent studies in the National Center for Biotechnology Information(NCBI)Gene Expression Omnibus(GEO)database.Differentially expressed genes(DEGs)were selected to evaluate the effects on the prognosis and progression of ovarian cancer using data from The Cancer Genome Atlas(TCGA)database.Hub genes’immune landscapes were estimated by the Tumor Immune Estimation Resource(TIMER)database.Finally,using 25 HGSOC patients'cancer tissues and 10 normal fallopian tube tissues,immunohistochemistry(IHC)was performed to quantify the expression levels of hub genes associated with International Federation of Gynecology and Obstetrics(FIGO)stages.Results:Fourteen DEGs,ADIPOQ,ALPK2,BARX1,CD37,CNR2,COL5A3,FABP4,FAP,GPR68,ITGBL1,MOXD1,PODNL1,SFRP2,and TRAF3IP3,were upregulated in metastatic tumors in every database while CADPS,GATA4,STAR,and TSPAN8 were downregulated.ALPK2,FAP,SFRP2,GATA4,STAR,and TSPAN8 were selected as hub genes significantly associated with survival and recurrence.All hub genes were correlated with tumor microenvironment infiltration,especially cancer-associated fibroblasts and natural killer(NK)cells.Furthermore,the expression of FAP and SFRP2 was positively correlated with the International Federation of Gynecology and Obstetrics(FIGO)stage,and their increased protein expression levels in metastatic samples compared with primary tumor samples and normal tissues were confirmed by IHC(P=0.0002 and P=0.0001,respectively).Conclusions:This study describes screening for DEGs in HGSOC primary tumors and matched metastasis tumors using integrated bioinformatics analyses.We identified six hub genes that were correlated with the progression of HGSOC,particularly FAP and SFRP2,which might provide effective targets to predict prognosis and provide novel insights into individual therapeutic strategies for HGSOC.展开更多
The diagnosis of pancreatic cancer associates an appalling significance.Detection of preinvasive stage of pancreatic cancer will ameliorate the survival of this deadly disease.Premalignant lesions such as Intraductal ...The diagnosis of pancreatic cancer associates an appalling significance.Detection of preinvasive stage of pancreatic cancer will ameliorate the survival of this deadly disease.Premalignant lesions such as Intraductal Papillary Mucinous Neoplasms or Mucinous Cystic Neoplasms of the pancreas are detectable on imaging exams and this permits their management prior their invasive development.Pancreatic intraepithelial neoplasms(PanIN)are the most frequent precursors of pancreatic adenocarcinoma(PDAC),and its particular type PanIN high-grade represents the malignant non-invasive form of PDAC.Unfortunately,PanINs are not detectable on radiologic exams.Nevertheless,they can associate indirect imaging signs which would rise the diagnostic suspicion.When this suspicion is established,the patient will be enrolled in a follow-up strategy that includes performing of blood test and serial imaging test such as computed tomography or magnetic resonance imaging,which will cost in the best-case scenario a burden of healthcare systems,and potential mortality in the worst-case scenario when the patient underwent resection surgery,worthless when there is no moderate or high grade dysplasia in the final histopathology.This issue will be avoid having at its disposal a diagnostic technique capable of detecting high-grade PanIN lesions,such is the cytology of pancreatic juice obtained by nasopancreatic intubation.Herein,we review the possibility of detection of early malignant lesions before they become invasive PADC.展开更多
Junctional adhesion molecule-A(JAM-A),also known as the F11 receptor(F11R),is one of the tight junction components.JAM-A is a transmembrane glycoprotein that regulates many cellular processes,i.e.,angiogenesis,leukocy...Junctional adhesion molecule-A(JAM-A),also known as the F11 receptor(F11R),is one of the tight junction components.JAM-A is a transmembrane glycoprotein that regulates many cellular processes,i.e.,angiogenesis,leukocyte transendothelial migration,intercellular permeability,epithelial-to-mesenchymal transition,and platelet activation.Of note,it is involved in the pathogenesis of various cancer types,including gynecological cancers.Only a few studies are available about this cancer type.Observed aberrant JAM-A expression in gynecological cancers correlates with poor patient prognosis.To the best of our knowledge,conflicting JAM-A roles in various cancer types suggest that its involvement is complex and tumor-type specific.The underlying molecular mechanisms and pathways responsible for JAM-A functions were not fully elucidated and need to be identified.Finding appropriate novel molecular cancer biomarkers may reduce observed very high mortality rates and could contribute to personalized treatment development.The main aim of the present viewpoint article is to report the current knowledge about JAM-A participation in gynecological malignancies.展开更多
Background: Ovarian serous adenocarcinoma can be divided into low- and high-grade tumors, which exhibit substantial differences in pathogenesis, clinicopathology, and prognosis. This study aimed to investigate the d...Background: Ovarian serous adenocarcinoma can be divided into low- and high-grade tumors, which exhibit substantial differences in pathogenesis, clinicopathology, and prognosis. This study aimed to investigate the difl'erences in the PH domain leucine-rich repeat protein phosphatase (PHLPP), tbrkhead llomeobox type O3a (FoxO3a), and RAD51 protein expressions, and their associations with prognosis in patients with low- and high-grade ovarian serous adenocarcinomas. Methods: The PH LPP, FoxO3a, and RA D51 protein expressions were examined in 94 high- and 26 low-grade ovarian serous adenocarcinomas by immunohistochemistry. The differences in expression and their relationships with pathological features and prognosis were analyzed. Results: In high-grade serous adenocarcinomas, the positive rates of PHLPP and goxO3a were 24.5% and 26.6%, while in low-grade tumors, they were 23.1% and 26.9%, respectively (P 〈 0.05 vs. the control specimens; low- vs. high-grade: P 〉 0.(15). The positive rates of RAD51 were 70.2% and 65.4% in high- and low-grade serous adenocarcinomas, respectively (P 〈 0.(15 vs. the control specimens; low- vs. high-grade: P 〉 0.05). Meanwhile, in high-grade tumors, Stage Ⅲ/Ⅳ tumors and lymph node and omental metastases were significantly associated with lower PHLPP and FoxO3a and higher RAD51 expression. The 5-year survival rates of patients with PHLPP- and FoxO3a-positive high-grade tumors (43.5% and 36.0%) were significantly higher than in patients with PHLPP-negative tumors (5.6% and 7.2%, respectively; P 〈 0.05). Similarly, the 5-year survival rate of RAD5 l-positive patients (3.0%) was significantly lower than in negative patients (42.9%: P〈 0.05). In low-grade tumors, the PHLPP, FoxO3a, and RAD51 expressions were not significantly correlated with lymph node metastasis, omental metastasis, Federation of Gynecology and Obstetrics stage, or prognosis. Conclusions: Abnormal PHLPP, FoxO3a, and RAD51 protein expressions may be involved in the development of high- and low-grade ovarian serous adenocarcinomas, suggesting conlmon molecular pathways. Decreased PH LPP and FoxO3a and increased RAD51 protein expression may be important molecular markers for poor prognosis, and RAD51 may be an independent prognosis factor, of high-grade, but not low-grade, ovarian serous adenocarcinomas.展开更多
文摘BACKGROUND Retroperitoneal high-grade serous carcinoma(HGSC)of unknown origin is a sporadic tumor that can originate from ovarian cancer.Herein,we report the case of a woman with retroperitoneal HGSC of unknown origin and describe how she was diagnosed and treated.CASE SUMMARY A 71-year-old female presented with the tumor marker CA125 elevated to 1041.9 U/mL upon a regular health examination.Computed tomography revealed retroperitoneal lymph node enlargement.Subsequently,positron emission tomography scanning revealed lesions with increased F-18 fluorodeoxyglucose uptake at the nodes.As a result,she underwent laparoscopic lymph node resection,and pathology revealed metastatic adenocarcinoma with CK7(+),PAX8(+),WT1(+),PR(-),and p53 mutational loss of expression,indicating that the origin may be from the adnexa.The patient was admitted to our ward and underwent laparoscopic staging;however,the pathological results were negative.Under the suspicion of retroperitoneal HGSC of unknown origin,chemotherapy and targeted therapy were initiated.Tumor marker levels decreased after treatment.CONCLUSION We present a case of HGSC of unknown origin managed using retroperitoneal lymphadenectomy,staging surgery,chemotherapy,and targeted therapy.
文摘BACKGROUND Few studies have reported an association between an increased risk of acquiring cancers and survival in patients with 4q deletion syndrome.This study presents a rare association between chromosome 4q abnormalities and fallopian tube highgrade serous carcinoma(HGSC)in a young woman.CASE SUMMARY A 35-year-old woman presented with acute dull abdominal pain and a known chromosomal abnormality involving 4q13.3 duplication and 4q23q24 deletion.Upon arrival at the emergency room,her abdomen appeared ovoid and distended with palpable shifting dullness.Ascites were identified through abdominal ultrasound,and computed tomography revealed an omentum cake and an enlarged bilateral adnexa.Blood tests showed elevated CA-125 levels.Paracentesis was conducted,and immunohistochemistry indicated that the cancer cells favored an ovarian origin,making us suspect ovarian cancer.The patient underwent debulking surgery,which led to a diagnosis of stage IIIC HGSC of the fallopian tube.Subsequently,the patient received adjuvant chemotherapy with carboplatin and paclitaxel,resulting in stable current condition.CONCLUSION This study demonstrates a rare correlation between a chromosome 4q abnormality and HGSC.UBE2D3 may affect crucial cancer-related pathways,including P53,BRCA,cyclin D,and tyrosine kinase receptors,thereby possibly contributing to cancer development.In addition,ADH1 and DDIT4 may be potential influencers of both carcinogenic and therapeutic responses.
基金This work was supported by grants from the Deutsche Krebshilfe(70114007)Wilhelm Sander Stiftung(Nr.2021.023.1),German Cancer Consortium(DKTK),Heidelberg.
文摘Background:The cellular tumor protein p53(TP53)is a tumor suppressor gene that is frequently mutated in human cancers.Among various cancer types,the very aggressive high-grade serous ovarian carcinoma(HGSOC)exhibits the high-est prevalence of TP53 mutations,present in>96%of cases.Despite intensive efforts to reactivate p53,no clinical drug has been approved to rescue p53 func-tion.In this study,our primary objective was to administer in vitro-transcribed(IVT)wild-type(WT)p53-mRNA to HGSOC cell lines,primary cells,and ortho-topic mouse models,with the aim of exploring its impact on inhibiting tumor growth and dissemination,both in vitro and in vivo.Methods:To restore the activity of p53,WT p53 was exogenously expressed in HGSOC cell lines using a mammalian vector system.Moreover,IVT WT p53 mRNA was delivered into different HGSOC model systems(primary cells and patient-derived organoids)using liposomes and studied for proliferation,cell cycle progression,apoptosis,colony formation,and chromosomal instabil-ity.Transcriptomic alterations induced by p53 mRNA were analyzed using RNA sequencing in OVCAR-8 and primary HGSOC cells,followed by ingenuity path-way analysis.In vivo effects on tumor growth and metastasis were studied using orthotopic xenografts and metastatic intraperitoneal mouse models.Results:Reactivation of the TP53 tumor suppressor gene was explored in differ-ent HGSOC model systems using newly designed IVT mRNA-based methods.The introduction of WT p53 mRNA triggered dose-dependent apoptosis,cell cycle arrest,and potent long-lasting inhibition of HGSOC cell proliferation.Transcriptome analysis of OVCAR-8 cells upon mRNA-based p53 reactivation revealed significant alterations in gene expression related to p53 signaling,such as apoptosis,cell cycle regulation,and DNA damage.Restoring p53 function concurrently reduces chromosomal instability within the HGSOC cells,under-scoring its crucial contribution in safeguarding genomic integrity by moderating the baseline occurrence of double-strand breaks arising from replication stress.Furthermore,in various mouse models,treatment with p53 mRNA reduced tumor growth and inhibited tumor cell dissemination in the peritoneal cavity in a dose-dependent manner.Conclusions:The IVT mRNA-based reactivation of p53 holds promise as a potential therapeutic strategy for HGSOC,providing valuable insights into the molecular mechanisms underlying p53 function and its relevance in ovarian cancer treatment.
基金supported by the grant from Beijing Natural Science Foundation(No.7222202)
文摘Background:High-grade serous ovarian cancer(HGSOC)is the biggest cause of gynecological cancer-related mortality because of its extremely metastatic nature.This study aimed to explore and evaluate the characteristics of candidate factors associated with the metastasis and progression of HGSOC.Methods:Transcriptomic data of HGSOC patients’samples collected from primary tumors and matched omental metastatic tumors were obtained from three independent studies in the National Center for Biotechnology Information(NCBI)Gene Expression Omnibus(GEO)database.Differentially expressed genes(DEGs)were selected to evaluate the effects on the prognosis and progression of ovarian cancer using data from The Cancer Genome Atlas(TCGA)database.Hub genes’immune landscapes were estimated by the Tumor Immune Estimation Resource(TIMER)database.Finally,using 25 HGSOC patients'cancer tissues and 10 normal fallopian tube tissues,immunohistochemistry(IHC)was performed to quantify the expression levels of hub genes associated with International Federation of Gynecology and Obstetrics(FIGO)stages.Results:Fourteen DEGs,ADIPOQ,ALPK2,BARX1,CD37,CNR2,COL5A3,FABP4,FAP,GPR68,ITGBL1,MOXD1,PODNL1,SFRP2,and TRAF3IP3,were upregulated in metastatic tumors in every database while CADPS,GATA4,STAR,and TSPAN8 were downregulated.ALPK2,FAP,SFRP2,GATA4,STAR,and TSPAN8 were selected as hub genes significantly associated with survival and recurrence.All hub genes were correlated with tumor microenvironment infiltration,especially cancer-associated fibroblasts and natural killer(NK)cells.Furthermore,the expression of FAP and SFRP2 was positively correlated with the International Federation of Gynecology and Obstetrics(FIGO)stage,and their increased protein expression levels in metastatic samples compared with primary tumor samples and normal tissues were confirmed by IHC(P=0.0002 and P=0.0001,respectively).Conclusions:This study describes screening for DEGs in HGSOC primary tumors and matched metastasis tumors using integrated bioinformatics analyses.We identified six hub genes that were correlated with the progression of HGSOC,particularly FAP and SFRP2,which might provide effective targets to predict prognosis and provide novel insights into individual therapeutic strategies for HGSOC.
文摘The diagnosis of pancreatic cancer associates an appalling significance.Detection of preinvasive stage of pancreatic cancer will ameliorate the survival of this deadly disease.Premalignant lesions such as Intraductal Papillary Mucinous Neoplasms or Mucinous Cystic Neoplasms of the pancreas are detectable on imaging exams and this permits their management prior their invasive development.Pancreatic intraepithelial neoplasms(PanIN)are the most frequent precursors of pancreatic adenocarcinoma(PDAC),and its particular type PanIN high-grade represents the malignant non-invasive form of PDAC.Unfortunately,PanINs are not detectable on radiologic exams.Nevertheless,they can associate indirect imaging signs which would rise the diagnostic suspicion.When this suspicion is established,the patient will be enrolled in a follow-up strategy that includes performing of blood test and serial imaging test such as computed tomography or magnetic resonance imaging,which will cost in the best-case scenario a burden of healthcare systems,and potential mortality in the worst-case scenario when the patient underwent resection surgery,worthless when there is no moderate or high grade dysplasia in the final histopathology.This issue will be avoid having at its disposal a diagnostic technique capable of detecting high-grade PanIN lesions,such is the cytology of pancreatic juice obtained by nasopancreatic intubation.Herein,we review the possibility of detection of early malignant lesions before they become invasive PADC.
文摘Junctional adhesion molecule-A(JAM-A),also known as the F11 receptor(F11R),is one of the tight junction components.JAM-A is a transmembrane glycoprotein that regulates many cellular processes,i.e.,angiogenesis,leukocyte transendothelial migration,intercellular permeability,epithelial-to-mesenchymal transition,and platelet activation.Of note,it is involved in the pathogenesis of various cancer types,including gynecological cancers.Only a few studies are available about this cancer type.Observed aberrant JAM-A expression in gynecological cancers correlates with poor patient prognosis.To the best of our knowledge,conflicting JAM-A roles in various cancer types suggest that its involvement is complex and tumor-type specific.The underlying molecular mechanisms and pathways responsible for JAM-A functions were not fully elucidated and need to be identified.Finding appropriate novel molecular cancer biomarkers may reduce observed very high mortality rates and could contribute to personalized treatment development.The main aim of the present viewpoint article is to report the current knowledge about JAM-A participation in gynecological malignancies.
文摘Background: Ovarian serous adenocarcinoma can be divided into low- and high-grade tumors, which exhibit substantial differences in pathogenesis, clinicopathology, and prognosis. This study aimed to investigate the difl'erences in the PH domain leucine-rich repeat protein phosphatase (PHLPP), tbrkhead llomeobox type O3a (FoxO3a), and RAD51 protein expressions, and their associations with prognosis in patients with low- and high-grade ovarian serous adenocarcinomas. Methods: The PH LPP, FoxO3a, and RA D51 protein expressions were examined in 94 high- and 26 low-grade ovarian serous adenocarcinomas by immunohistochemistry. The differences in expression and their relationships with pathological features and prognosis were analyzed. Results: In high-grade serous adenocarcinomas, the positive rates of PHLPP and goxO3a were 24.5% and 26.6%, while in low-grade tumors, they were 23.1% and 26.9%, respectively (P 〈 0.05 vs. the control specimens; low- vs. high-grade: P 〉 0.(15). The positive rates of RAD51 were 70.2% and 65.4% in high- and low-grade serous adenocarcinomas, respectively (P 〈 0.(15 vs. the control specimens; low- vs. high-grade: P 〉 0.05). Meanwhile, in high-grade tumors, Stage Ⅲ/Ⅳ tumors and lymph node and omental metastases were significantly associated with lower PHLPP and FoxO3a and higher RAD51 expression. The 5-year survival rates of patients with PHLPP- and FoxO3a-positive high-grade tumors (43.5% and 36.0%) were significantly higher than in patients with PHLPP-negative tumors (5.6% and 7.2%, respectively; P 〈 0.05). Similarly, the 5-year survival rate of RAD5 l-positive patients (3.0%) was significantly lower than in negative patients (42.9%: P〈 0.05). In low-grade tumors, the PHLPP, FoxO3a, and RAD51 expressions were not significantly correlated with lymph node metastasis, omental metastasis, Federation of Gynecology and Obstetrics stage, or prognosis. Conclusions: Abnormal PHLPP, FoxO3a, and RAD51 protein expressions may be involved in the development of high- and low-grade ovarian serous adenocarcinomas, suggesting conlmon molecular pathways. Decreased PH LPP and FoxO3a and increased RAD51 protein expression may be important molecular markers for poor prognosis, and RAD51 may be an independent prognosis factor, of high-grade, but not low-grade, ovarian serous adenocarcinomas.