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2.
Gynecol Oncol ; 156(1): 6-12, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31711656

RESUMEN

OBJECTIVES: Peritoneal implants of ovarian borderline serous tumors are diagnostically challenging. Distinguishing invasive from non-invasive cases is crucial for patient management. This study aims to develop a molecular signature to distinguish invasive implants with malignant potential from those with benign. METHODS: Archival formalin-fixed paraffin embedded tissues were retrieved from 3 institutions, with consensus histologic review. Lesions were classified as a non-invasive implant (n = 10), invasive implant (n = 9) or high grade (HG) peritoneal metastasis from HG serous ovarian carcinoma (n = 4). The nCounter® GX Human Cancer Gene Reference Assay was used to profile expression of 230 cancer genes and 6 control genes. The DEGs in HG peritoneal metastases compared to non-invasive implants were identified using T-tests performed in the NanoString Diff package, then used to cluster cases using the Eisen cluster 3.0 package. Lasso in glmnet package was used to select the subset of genes that most strongly correlate with a malignant potential. RESULTS: 37 genes were downregulated and 16 genes were upregulated in HG peritoneal metastases. Using this 53-gene signature, one of nine of the invasive implants clustered with the HG peritoneal metastasis. Expression of ABCB1, CDC2, CDKN1A, FAT1, MMP9, MSH2, NQO1 and TOP2A were sufficient to indicate malignant potential of implants. The HG peritoneal metastasis and one invasive implant exhibited a high malignant likelihood (>92%) whereas the non-invasive implants and eight invasive implants displayed a low malignant likelihood (≤0.1%). CONCLUSIONS: Invasive implants are heterogenous and often morphologically indistinguishable lesions with transcriptomes that may be classified as malignant or not. Additional research is needed to determine the importance of these genes as drivers and/or surrogates of malignant potential, and their utility for triaging invasive implants.


Asunto(s)
Cistadenocarcinoma Seroso/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Neoplasias Peritoneales/genética , Neoplasias Peritoneales/secundario , Adulto , Cistadenocarcinoma Seroso/genética , Femenino , Expresión Génica , Heterogeneidad Genética , Humanos , Persona de Mediana Edad , Invasividad Neoplásica , Neoplasias Peritoneales/patología , Estándares de Referencia , Adulto Joven
3.
Int J Cancer ; 146(6): 1553-1567, 2020 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-31503345

RESUMEN

Detachment of cancer cells from the primary tumor and formation of spheroids in ascites is required for implantation metastasis in epithelial ovarian cancer (EOC), but the underlying mechanism of this process has not been thoroughly elucidated. To mimic this process, ovarian cancer cells were grown in 3D and 2D culture. Hey and OVCA433 spheroids exhibited decreased cell proliferation and enhanced adhesion and invasion. SMYD3 expression was elevated in ovarian carcinoma spheroids in association with increased H3K4 methylation. Depletion of SMYD3 by transient siRNA, stable shRNA knockdown and the SMYD3 inhibitor BCI-121 all decreased spheroid invasion and adhesion. Gene expression arrays revealed downregulation of integrin family members. Inhibition assays confirmed that invasion and adhesion of spheroids are mediated by ITGB6 and ITGAM. SMYD3-deficient cells regained the ability to invade and adhere after forced overexpression of SMYD3, ITGB6 and ITGAM. However, this biological ability was not restored by forced overexpression of SMYD3 in ITGB6- and/or ITGAM-deficient cancer cells. SMYD3 and H3K4me3 binding at the ITGB6 and ITGAM promoters was increased in spheroids compared to that in monolayer cells, and the binding was decreased when SMYD3 expression was inhibited, consistent with the expression changes in integrins. SMYD3 expression and integrin-mediated adhesion were also activated in an intraperitoneal xenograft model and in EOC patient spheroids. In vivo, SMYD3 knockdown inhibited tumor metastasis and reduced ascites volume in both the intraperitoneal xenograft model and a PDX model. Overall, our results suggest that the SMYD3-H3K4me3-integrin pathway plays a crucial role in ovarian cancer metastasis to the peritoneal surface.


Asunto(s)
Ascitis/patología , Carcinoma Epitelial de Ovario/secundario , N-Metiltransferasa de Histona-Lisina/metabolismo , Integrinas/genética , Neoplasias Ováricas/patología , Neoplasias Peritoneales/secundario , Adulto , Anciano , Ascitis/etiología , Carcinoma Epitelial de Ovario/genética , Adhesión Celular/genética , Técnicas de Cultivo de Célula , Línea Celular Tumoral , Metilación de ADN , Regulación hacia Abajo , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , N-Metiltransferasa de Histona-Lisina/genética , Histonas/metabolismo , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/genética , Neoplasias Peritoneales/genética , Regiones Promotoras Genéticas/genética , Esferoides Celulares , Ensayos Antitumor por Modelo de Xenoinjerto
4.
J Surg Res ; 246: 325-334, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-30737098

RESUMEN

BACKGROUND: Mutant KRAS tumors are purported to metastasize differently than wild-type KRAS tumors. The biological heterogeneity of tumors from different parts of the colon are also reported to affect metastasis. This study aims to characterize the metastatic profile by evaluating these factors in unison. METHODS: Retrospective analysis of 899 patients with metastatic colorectal cancers treated from January 2010 to December 2014 was conducted. KRAS mutation status and primary tumors location were correlated with single-site metastasis (liver, lung, and peritoneum) and dual-site metastases (liver-peritoneum, liver-lung, and lung-peritoneum). Patients without KRAS analyses were excluded. RESULTS: Right-sided tumors had highest frequency of peritoneal metastasis as compared to left-sided or rectal tumors (34.7% versus 15.8% versus 8.8%, P = 0.00) regardless of KRAS status (32.6% versus 38.5%, P = 0.62). Left-sided tumors with wild-type KRAS had greater proportion of liver metastasis (78.6% versus 53.5%, P = 0.00), whereas those with mutant KRAS had greater proportion of lung metastasis (23.3% versus 8.7%, P = 0.02). Rectal tumors with wild-type KRAS tend to spread to the liver (81.4% versus 48.0%, P = 0.00) and not to the peritoneum (2.3% versus 20.0%, P = 0.01). In dual-site metastases, left-sided tumors with wild-type KRAS had more liver-peritoneal metastases (75.0% versus 29.4%, P = 0.00), whereas mutant KRAS had greater lung-liver metastases (64.7% versus 20.8%, P = 0.01). Rectal tumors had the predilection for lung-liver metastases as compared to right-sided and left-sided tumors (92.3% versus 40.0% versus 39.0%, P = 0.00) regardless of KRAS status (100% versus 75%, P = 0.12). CONCLUSIONS: Our results may streamline surveillance programs based on primary tumor location and KRAS mutational status.


Asunto(s)
Neoplasias Colorrectales/patología , Neoplasias Hepáticas/epidemiología , Neoplasias Pulmonares/epidemiología , Neoplasias Peritoneales/epidemiología , Proteínas Proto-Oncogénicas p21(ras)/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Neoplasias Colorrectales/genética , Femenino , Humanos , Incidencia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundario , Masculino , Persona de Mediana Edad , Mutación , Neoplasias Peritoneales/genética , Neoplasias Peritoneales/secundario , Estudios Retrospectivos , Adulto Joven
5.
Gut ; 69(1): 18-31, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31171626

RESUMEN

OBJECTIVE: Peritoneal carcinomatosis (PC) occurs frequently in patients with gastric adenocarcinoma (GAC) and confers a poor prognosis. Multiplex profiling of primary GACs has been insightful but the underpinnings of PC's development/progression remain largely unknown. We characterised exome/transcriptome/immune landscapes of PC cells from patients with GAC aiming to identify novel therapeutic targets. DESIGN: We performed whole-exome sequencing (WES) and whole transcriptome sequencing (RNA-seq) on 44 PC specimens (43 patients with PC) including an integrative analysis of WES, RNA-seq, immune profile, clinical and pathological phenotypes to dissect the molecular pathogenesis, identifying actionable targets and/or biomarkers and comparison with TCGA primary GACs. RESULTS: We identified distinct alterations in PC versus primary GACs, such as more frequent CDH1 and TAF1 mutations, 6q loss and chr19 gain. Alterations associated with aggressive PC phenotypes emerged with increased mutations in TP53, CDH1, TAF1 and KMT2C, higher level of 'clock-like' mutational signature, increase in whole-genome doublings, chromosomal instability (particularly, copy number losses), reprogrammed microenvironment, enriched cell cycle pathways, MYC activation and impaired immune response. Integrated analysis identified two main molecular subtypes: 'mesenchymal-like' and 'epithelial-like' with discriminating response to chemotherapy (31% vs 71%). Patients with the less responsive 'mesenchymal-like' subtype had high expression of immune checkpoint T-Cell Immunoglobulin And Mucin Domain-Containing Protein 3 (TIM-3), its ligand galectin-9, V-domain Ig suppressor of T cell activation (VISTA) and transforming growth factor-ß as potential therapeutic immune targets. CONCLUSIONS: We have uncovered the unique mutational landscape, copy number alteration and gene expression profile of PC cells and defined PC molecular subtypes, which correlated with PC therapy resistance/response. Novel targets and immune checkpoint proteins have been identified with a potential to be translated into clinics.


Asunto(s)
Adenocarcinoma/secundario , Neoplasias Peritoneales/secundario , Neoplasias Gástricas/genética , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Inestabilidad Cromosómica , Variaciones en el Número de Copia de ADN/genética , ADN de Neoplasias/genética , Femenino , Perfilación de la Expresión Génica/métodos , Humanos , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida/métodos , Mutación , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Peritoneales/genética , Neoplasias Peritoneales/inmunología , Ploidias , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/inmunología , Secuenciación del Exoma Completo/métodos
7.
In Vivo ; 33(5): 1485-1492, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31471396

RESUMEN

BACKGROUND/AIM: We aimed to demonstrate the use of next-generation sequencing (NGS) to confirm the presence of tumor protein 53 (TP53) mutations in tubo-ovarian and peritoneal high-grade serous carcinoma (HGSC) with a wild-type p53 immunostaining pattern and investigate whether the TP53 mutational status is altered by chemotherapy. MATERIALS AND METHODS: A commercial NGS panel comprising 171 genes was used to analyze the genetic profiles of 15 HGSC samples. Paired specimens obtained before and after chemotherapy were available for four patients. RESULTS: All examined samples exhibited TP53 mutations. For all the patients who underwent neoadjuvant or postoperative adjuvant chemotherapy, TP53 mutations identified in samples obtained after chemotherapy were the same as those detected in pre-chemotherapeutic samples. CONCLUSION: HGSCs exhibit TP53 mutations even though a subset of HGSCs displayed a wild-type p53 immunostaining pattern. Chemotherapy does not affect the TP53 mutational status in HGSC.


Asunto(s)
Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patología , Neoplasias de las Trompas Uterinas/genética , Neoplasias de las Trompas Uterinas/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Neoplasias Peritoneales/genética , Neoplasias Peritoneales/patología , Proteína p53 Supresora de Tumor/genética , Anciano , Biomarcadores de Tumor , Neoplasias de las Trompas Uterinas/metabolismo , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Mutación , Clasificación del Tumor , Estadificación de Neoplasias , Proteína p53 Supresora de Tumor/metabolismo
8.
Cancer Sci ; 110(10): 3204-3214, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31385416

RESUMEN

Peritoneal dissemination is the most frequent metastatic route of ovarian cancer. However, due to the high heterogeneity in ovarian cancer, most conventional studies lack parental tumor controls relevant to metastases and, thus, it is difficult to trace the molecular changes of cancer cells along with the selection by the abdominal microenvironment. Here, we established an in vivo mouse peritoneal dissemination scheme that allowed us to select more aggressive sublines from parental ovarian cancer cells, including A2780 and SKOV-3. Microarray and gene profiling analyses indicated that autophagy-related genes were enriched in selected malignant sublines. Detection of LC3-II, p62 and autophagic puncta demonstrated that these malignant variants were more sensitive to autophagic induction when exposed to diverse stress conditions, such as high cell density, starvation and drug treatment. As compared with parental A2780, the selected variant acquired the ability to grow better under high-density stress; however, this effect was reversed by addition of autophagic inhibitors or knockdown of ATG5. When analyzing the clinical profiles of autophagy-related genes identified to be enriched in malignant A2780 variant, 73% of them had prognostic significance for the survival of ovarian cancer patients. Taken together, our findings indicate that an increase in autophagic potency among ovarian cancer cells is crucial for selection of metastatic colonies in the abdominal microenvironment. In addition, the derived autophagic gene profile can not only predict prognosis well but can also be potentially applied to precision medicine for identifying those ovarian cancer patients suitable for taking anti-autophagy cancer drugs.


Asunto(s)
Proteínas Relacionadas con la Autofagia/genética , Perfilación de la Expresión Génica/métodos , Proteínas Asociadas a Microtúbulos/genética , Neoplasias Ováricas/patología , Neoplasias Peritoneales/secundario , Proteínas de Unión al ARN/genética , Animales , Autofagia , Línea Celular Tumoral , Supervivencia Celular , Femenino , Humanos , Ratones , Trasplante de Neoplasias , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Neoplasias Peritoneales/genética , Neoplasias Peritoneales/patología , Medicina de Precisión , Pronóstico , Microambiente Tumoral
9.
Anticancer Res ; 39(8): 4065-4071, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31366489

RESUMEN

BACKGROUND: Surgical orthotopic implantation of human colon cancer tissue to the ceca of mice has been used to mimic behavior of cancer in human patients for the development of precision cancer medicine. However, with the current method of serosal surface implantation (SSI) of pieces of human colon cancer tissue, cancer cells are exposed to the peritoneum, which can artificially increase the rate of peritoneal carcinomatosis (PC) during the disease course. The objective of the present study was to introduce a tumor-sealing method (TSM) and compare it with SSI for the ability to produce clinically-relevant metastases without artificial PC. MATERIALS AND METHODS: HCT116 colon cancer cells transfected with green fluorescence protein (GFP) were cultured and then injected into the subcutaneous layer of athymic nude mice. Subcutaneous tumors were allowed to grow sufficiently to supply adequate tumor for orthotopic implantation. For SSI, a 1 mm3-sized tumor fragment was sutured to partially torn serosa of the cecum. For TSM, the blind end of the cecum was folded over the tumor fragment and sealed with sutures. At 20 days after implantation, all mice were opened to visualize PC by intravital fluorescence imaging. At necropsy, distant metastasis was investigated using frozen section of whole blocks of organs. RESULTS: At 20 days after implantation, PC rates in the SSI group and the TSM group were 80% (12/15) and 20% (3/15), respectively (p<0.001). The liver metastasis rate was 41.7% (5/12) in the SSI group and 50% (5/10) in the TSM group (p=0.696). The lung metastasis rate was 0% (0/12) in the SSI group and 10% (1/10) in the TSM group (p=0.201). The mean survival of mice without PC on the 20th day was significantly longer than that of mice with PC on the 20th day (69.1±14.7 vs. 44.5±12.4 days, p=0.001). CONCLUSION: These results suggest that TSM might be a more patient-like and useful method as a model of metastatic colon cancer than SSI.


Asunto(s)
Carcinogénesis/genética , Neoplasias del Colon/patología , Neoplasias Hepáticas/patología , Neoplasias Pulmonares/patología , Animales , Neoplasias del Colon/genética , Neoplasias del Colon/cirugía , Modelos Animales de Enfermedad , Proteínas Fluorescentes Verdes/química , Células HCT116 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundario , Ratones , Metástasis de la Neoplasia , Trasplante de Neoplasias/métodos , Imagen Óptica , Neoplasias Peritoneales/genética , Neoplasias Peritoneales/patología , Ensayos Antitumor por Modelo de Xenoinjerto
11.
JAMA ; 322(7): 666-685, 2019 08 20.
Artículo en Inglés | MEDLINE | ID: mdl-31429902

RESUMEN

Importance: Pathogenic mutations in breast cancer susceptibility genes BRCA1 and BRCA2 increase risks for breast, ovarian, fallopian tube, and peritoneal cancer in women; interventions reduce risk in mutation carriers. Objective: To update the 2013 US Preventive Services Task Force review on benefits and harms of risk assessment, genetic counseling, and genetic testing for BRCA1/2-related cancer in women. Data Sources: Cochrane libraries; MEDLINE, PsycINFO, EMBASE (January 1, 2013, to March 6, 2019, for updates; January 1, 1994, to March 6, 2019, for new key questions and populations); reference lists. Study Selection: Discriminatory accuracy studies, randomized clinical trials (RCTs), and observational studies of women without recently diagnosed BRCA1/2-related cancer. Data Extraction and Synthesis: Data on study methods, setting, population characteristics, eligibility criteria, interventions, numbers enrolled and lost to follow-up, outcome ascertainment, and results were abstracted. Two reviewers independently assessed study quality. Main Outcomes and Measures: Cancer incidence and mortality; discriminatory accuracy of risk assessment tools for BRCA1/2 mutations; benefits and harms of risk assessment, genetic counseling, genetic testing, and risk-reducing interventions. Results: For this review, 103 studies (110 articles; N = 92 712) were included. No studies evaluated the effectiveness of risk assessment, genetic counseling, and genetic testing in reducing incidence and mortality of BRCA1/2-related cancer. Fourteen studies (n = 43 813) of 8 risk assessment tools to guide referrals to genetic counseling demonstrated moderate to high accuracy (area under the receiver operating characteristic curve, 0.68-0.96). Twenty-eight studies (n = 8060) indicated that genetic counseling was associated with reduced breast cancer worry, anxiety, and depression; increased understanding of risk; and decreased intention for testing. Twenty studies (n = 4322) showed that breast cancer worry and anxiety were higher after testing for women with positive results and lower for others; understanding of risk was higher after testing. In 8 RCTs (n = 54 651), tamoxifen (relative risk [RR], 0.69 [95% CI, 0.59-0.84]; 4 trials), raloxifene (RR, 0.44 [95% CI, 0.24-0.80]; 2 trials), and aromatase inhibitors (RR, 0.45 [95% CI, 0.26-0.70]; 2 trials) were associated with lower risks of invasive breast cancer compared with placebo; results were not specific to mutation carriers. Mastectomy was associated with 90% to 100% reduction in breast cancer incidence (6 studies; n = 2546) and 81% to 100% reduction in breast cancer mortality (1 study; n = 639); oophorectomy was associated with 69% to 100% reduction in ovarian cancer (2 studies; n = 2108); complications were common with mastectomy. Conclusions and Relevance: Among women without recently diagnosed BRCA1/2-related cancer, the benefits and harms of risk assessment, genetic counseling, and genetic testing to reduce cancer incidence and mortality have not been directly evaluated by current research.


Asunto(s)
Neoplasias de la Mama/genética , Genes BRCA1 , Genes BRCA2 , Asesoramiento Genético , Pruebas Genéticas , Mutación , Neoplasias Ováricas/genética , Neoplasias de la Mama/prevención & control , Neoplasias de las Trompas Uterinas/genética , Neoplasias de las Trompas Uterinas/prevención & control , Femenino , Predisposición Genética a la Enfermedad , Humanos , Neoplasias Ováricas/prevención & control , Neoplasias Peritoneales/genética , Neoplasias Peritoneales/prevención & control , Medición de Riesgo
12.
JAMA ; 322(7): 652-665, 2019 08 20.
Artículo en Inglés | MEDLINE | ID: mdl-31429903

RESUMEN

Importance: Potentially harmful mutations of the breast cancer susceptibility 1 and 2 genes (BRCA1/2) are associated with increased risk for breast, ovarian, fallopian tube, and peritoneal cancer. For women in the United States, breast cancer is the most common cancer after nonmelanoma skin cancer and the second leading cause of cancer death. In the general population, BRCA1/2 mutations occur in an estimated 1 in 300 to 500 women and account for 5% to 10% of breast cancer cases and 15% of ovarian cancer cases. Objective: To update the 2013 US Preventive Services Task Force (USPSTF) recommendation on risk assessment, genetic counseling, and genetic testing for BRCA-related cancer. Evidence Review: The USPSTF reviewed the evidence on risk assessment, genetic counseling, and genetic testing for potentially harmful BRCA1/2 mutations in asymptomatic women who have never been diagnosed with BRCA-related cancer, as well as those with a previous diagnosis of breast, ovarian, tubal, or peritoneal cancer who have completed treatment and are considered cancer free. In addition, the USPSTF reviewed interventions to reduce the risk for breast, ovarian, tubal, or peritoneal cancer in women with potentially harmful BRCA1/2 mutations, including intensive cancer screening, medications, and risk-reducing surgery. Findings: For women whose family or personal history is associated with an increased risk for harmful mutations in the BRCA1/2 genes, or who have an ancestry associated with BRCA1/2 gene mutations, there is adequate evidence that the benefits of risk assessment, genetic counseling, genetic testing, and interventions are moderate. For women whose personal or family history or ancestry is not associated with an increased risk for harmful mutations in the BRCA1/2 genes, there is adequate evidence that the benefits of risk assessment, genetic counseling, genetic testing, and interventions are small to none. Regardless of family or personal history, the USPSTF found adequate evidence that the overall harms of risk assessment, genetic counseling, genetic testing, and interventions are small to moderate. Conclusions and Recommendation: The USPSTF recommends that primary care clinicians assess women with a personal or family history of breast, ovarian, tubal, or peritoneal cancer or who have an ancestry associated with BRCA1/2 gene mutations with an appropriate brief familial risk assessment tool. Women with a positive result on the risk assessment tool should receive genetic counseling and, if indicated after counseling, genetic testing. (B recommendation) The USPSTF recommends against routine risk assessment, genetic counseling, or genetic testing for women whose personal or family history or ancestry is not associated with potentially harmful BRCA1/2 gene mutations. (D recommendation).


Asunto(s)
Neoplasias de la Mama/genética , Genes BRCA1 , Genes BRCA2 , Asesoramiento Genético , Pruebas Genéticas , Mutación , Neoplasias Ováricas/genética , Neoplasias de la Mama/prevención & control , Neoplasias de las Trompas Uterinas/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Neoplasias Ováricas/prevención & control , Neoplasias Peritoneales/genética , Medición de Riesgo
13.
Int J Oncol ; 55(3): 755-765, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31322193

RESUMEN

Refractory peritoneal carcinomatosis is a common terminal feature of epithelial ovarian cancer (EOC). Previous reports have suggested that immunotherapy is a promising therapeutic strategy for EOC. Interleukin (IL)­33 is a member of the IL­1 superfamily of cytokines. The role of IL­33 in tissue inflammation and promoting type 2 immune responses has been established, and recently, there is accumulating evidence to suggest the involvement of IL­33 in carcinogenesis. In this study, we focused on the association between the tumor expression of IL­33 and ovarian peritoneal carcinomatosis. We used an immunosufficient murine model of peritoneal carcinomatosis and human EOC samples. The overexpression of IL­33 in the ID8 mouse EOC cell line tumors significantly prolonged the survival of immunocompetent mice in the peritoneal carcinomatosis setting, but not in the subcutaneous model. In addition, the silencing of IL­33 in ID8­T6 cells (subclone with high dissemination potential) significantly shortened the survival of the tumor­bearing mice. This was likely due to the intratumoral accumulation of CD8+ and CD4+ T cells, and a decrease in CD11b+Gr1+ cells. Furthermore, IL­33 induced the intraperitoneal microenvironment favoring tumor elimination through the inhibition of differentiation into CD11b+Gr1+ cells. On the whole, the findings of this study suggest IL­33 to be a cytokine that reflects antitumor peritoneal conditions. Further investigation of the antitumorigenic role of IL­33 may aid in the development of more effective therapeutic approaches for the treatment of EOC with peritoneal carcinomatosis.


Asunto(s)
Carcinoma Epitelial de Ovario/inmunología , Interleucina-33/metabolismo , Neoplasias Ováricas/inmunología , Neoplasias Peritoneales/inmunología , Animales , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Carcinoma Epitelial de Ovario/genética , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Interleucina-33/genética , Ratones , Trasplante de Neoplasias , Neoplasias Ováricas/genética , Neoplasias Peritoneales/genética , Pronóstico
14.
Anticancer Res ; 39(6): 2883-2889, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-31177126

RESUMEN

BACKGROUND/AIM: High-grade serous carcinoma (HGSC) is the most common histological subtype of ovarian carcinoma. Somatic mutation of tumor protein 53 (TP53) is a hallmark of tubo-ovarian HGSC and is observed in almost all such cases. Highly sensitive targeted genomic sequencing can be used to identify novel mutations that may become potential druggable targets and aid in therapeutic decisions. The aim of this study was to describe the clinicopathological and molecular characteristics of HGSCs with novel somatic TP53 mutations identified by next-generation sequencing (NGS). MATERIALS AND METHODS: A commercial NGS panel comprising 170 genes, including TP53, was used to analyze the genetic profiles of 132 ovarian carcinoma cases. The clinicopathological characteristics and p53 immunostaining results of two HGSCs exhibiting novel TP53 mutations were investigated. RESULTS: Eighty-eight (66.7%) out of 132 ovarian carcinoma cases were diagnosed as HGSC. Novel TP53 in-frame deletion mutations c.719_727delGTTCCTGCA (p53 p.Ser240_Cys242del) and c.634_642delTTTCGACAT (p53 p.F212_H214del) were detected in a single case of HGSC each. Both patients were postmenopausal women. Imaging and laboratory studies revealed peritoneal carcinomatosis and elevated levels of serum tumor markers. The patients underwent primary debulking surgery and were diagnosed as having stage IIIC HGSC. In both cases, p53 immunostaining revealed uniform nuclear immunoreactivity in 90% or more of tumor cells at a very strong intensity. CONCLUSION: Targeted genomic sequencing revealed novel in-frame deletion mutations of TP53 leading to p53 overexpression in tubo-ovarian HGSC. This discovery of previously unreported somatic TP53 mutations provides insight into the translation of NGS technology into personalized medicine and identifies new potential targets for therapeutic applications.


Asunto(s)
Cistadenocarcinoma Seroso/cirugía , Neoplasias de las Trompas Uterinas/cirugía , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Neoplasias Ováricas/cirugía , Neoplasias Peritoneales/cirugía , Eliminación de Secuencia , Proteína p53 Supresora de Tumor/genética , Regulación hacia Arriba , Núcleo Celular/metabolismo , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patología , Procedimientos Quirúrgicos de Citorreducción , Neoplasias de las Trompas Uterinas/genética , Neoplasias de las Trompas Uterinas/metabolismo , Neoplasias de las Trompas Uterinas/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Persona de Mediana Edad , Mutación , Clasificación del Tumor , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Neoplasias Peritoneales/genética , Neoplasias Peritoneales/metabolismo , Neoplasias Peritoneales/patología , Posmenopausia , Medicina de Precisión , Análisis de Secuencia de ADN , Proteína p53 Supresora de Tumor/metabolismo
15.
Ann Surg Oncol ; 26(8): 2595-2604, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31111351

RESUMEN

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are currently the most accepted treatment for peritoneal metastases from colorectal cancer. Restrictive selection criteria are essential to obtain the best survival benefits for this complex procedure. The most widespread score for patient selection, the peritoneal surface disease severity score (PSDSS), does not include current biological factors that are known to influence on prognosis. We investigated the impact of including RAS mutational status in the selection criteria for these patients. METHODS: We studied the risk factors for survival by multivariate analysis using a prospective database of consecutive patients with carcinomatosis from colorectal origin treated by CRS and HIPEC in our unit from 2009 to 2017. The risk factors obtained were validated in a multicentre, international cohort, including a total of 520 patients from 15 different reference units. RESULTS: A total of 77 patients were selected for local análisis. Only RAS mutational status (HR: 2.024; p = 0.045) and PSDSS stage (HR: 2.90; p = 0.009) were shown to be independent factors for overall survival. Early PSDSS stages I and II associated to RAS mutations impaired their overall survival with no significant differences with PSDSS stage III overall survival (p > 0.05). These results were supported by the international multicentre validation. CONCLUSIONS: By including RAS mutational status, we propose an updated RAS-PSDSS score that outperforms PSDSS alone providing a quick and feasible preoperative assessment of the expected overall survival for patients with carcinomatosis from colorectal origin undergone to CRS + HIPEC.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia del Cáncer por Perfusión Regional/mortalidad , Neoplasias Colorrectales/mortalidad , Procedimientos Quirúrgicos de Citorreducción/mortalidad , Hipertermia Inducida/mortalidad , Mutación , Neoplasias Peritoneales/mortalidad , Proteínas ras/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapia , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Peritoneales/genética , Neoplasias Peritoneales/secundario , Neoplasias Peritoneales/terapia , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia
16.
G Chir ; 40(2): 145-148, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31131816

RESUMEN

Benign multi-cystic peritoneal mesothelioma (BMCM) is a very rare disease (about 150 cases observed). The aetiology is currently little-known, and the data collected, without having achieved conclusive re sults, identify two possible causes: neoplastic and reactive inflammatory. This case report refers to a recidivism of BCMC in a patient whose brother, few months before, underwent a left nephrectomy and right renal Radio Frequency Termo Ablation (RFTA) for bilateral papillary renal cell carcinoma. For the recurring trend, the onset in a male young patient without chronic inflammatory diseases evidence, the presence of a first degree relative with a rare carcinoma we supposed a neoplastic aetiology. The available literature suggests that both tumours (BCMC and renal cell carcinoma) are susceptible to oestrogens. This biomolecular mechanism could represent a valid antipathogenic hypothesis.


Asunto(s)
Carcinoma de Células Renales/genética , Neoplasias Renales/genética , Mesotelioma Quístico/genética , Recurrencia Local de Neoplasia/genética , Neoplasias Peritoneales/genética , Humanos , Masculino , Persona de Mediana Edad
17.
J Ovarian Res ; 12(1): 50, 2019 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-31128592

RESUMEN

INTRODUCTION: The management of Serous Tubal Intraepithelial Carcinoma (STIC) found at the time of Risk-Reducing Salpingo-Oophorectomy (RRSO) remains unclear. We set out to analyse the incidence of peritoneal carcinomas developed after prophylactic surgery and to formulate further guidance for these patients. METHODS: This is a retrospective study of 300 consecutive RRSO performed at the Royal Marsden Hospital between January 2008 and January 2017. RESULTS: The median age at RRSO was 47.8 years (range 34 to 60 years) and median BMI was 26.2 kg/m2 (range 16 to 51 kg/m2). A total of 273 patients (91%) were tested for BRCA mutations. Of these, 124 (45.4%) had a BRCA 1 mutation, 118 (43.2%) had a BRCA 2 mutation, 2 (0.7%) had both a BRCA 1 and a BRCA 2 mutation and 29 (10.6%) had no BRCA mutation detected. Isolated STIC lesions were identified in 7 cases (2.3%) and p53 signatures in 75 cases (25%). There were five (1.6%) incidental tubal carcinomas and one (0.3%) ovarian carcinoma at the time of surgery. Two (28.6%) of the 7 patients with STIC identified following RRSO had high grade serous peritoneal carcinoma diagnosed at 53 and 75 months. One (0.3%) patient from the other 287 patients from our series with no STIC diagnosis or incidental carcinomas at RRSO developed high grade serous carcinoma of peritoneal origin after 92 months. CONCLUSION: This study demonstrates that when a STIC lesion is identified following RRSO there is a significantly higher risk of a subsequent peritoneal cancer. Although there is no published consensus in literature, we recommend that consideration should be given for long term follow-up if a STIC lesion is identified at RRSO.


Asunto(s)
Cistadenocarcinoma Seroso/epidemiología , Cistadenocarcinoma Seroso/secundario , Neoplasias de las Trompas Uterinas/patología , Neoplasias de las Trompas Uterinas/cirugía , Neoplasias Peritoneales/epidemiología , Neoplasias Peritoneales/secundario , Adulto , Proteína BRCA1/genética , Proteína BRCA2/genética , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/prevención & control , Neoplasias de las Trompas Uterinas/genética , Femenino , Humanos , Incidencia , Persona de Mediana Edad , Mutación , Ovariectomía , Neoplasias Peritoneales/genética , Neoplasias Peritoneales/prevención & control , Procedimientos Quirúrgicos Profilácticos , Estudios Retrospectivos , Salpingectomía
18.
J Surg Res ; 240: 130-135, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-30928770

RESUMEN

BACKGROUND: Metastatic colorectal cancer (mCRC) with peritoneal carcinomatosis is an increasingly prevalent disease that carries significant mortality if left untreated. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) in this patient population is associated with improved outcomes but high morbidity. We sought to study the prognostic significance of the known genomic driver, RAS, in patients with mCRC undergoing CRS/HIPEC to allow for improved assessment of risk-benefit ratio in this patient population. METHODS: Patients undergoing CRS/HIPEC for mCRC between 2010 and 2017 at our institution were identified. Patient demographics, RAS mutation status, perioperative morbidity, overall survival (OS), and relapse-free survival (RFS) were evaluated. RESULTS: Forty-seven patients met inclusion criteria. RAS mutant versus RAS wild-type groups were well matched with no difference in the clinicopathologic factors between groups. RAS mutation was associated with decreased RFS but no difference in OS. CONCLUSIONS: RAS mutation is an independent marker of early recurrence in patients undergoing CRS/HIPEC for mCRC and may identify patients who do not derive benefit from this high-risk procedure.


Asunto(s)
Neoplasias Colorrectales/terapia , GTP Fosfohidrolasas/genética , Proteínas de la Membrana/genética , Recurrencia Local de Neoplasia/diagnóstico , Neoplasias Peritoneales/terapia , Proteínas Proto-Oncogénicas p21(ras)/genética , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Quimioterapia del Cáncer por Perfusión Regional , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Procedimientos Quirúrgicos de Citorreducción , Supervivencia sin Enfermedad , Femenino , Humanos , Hipertermia Inducida , Masculino , Persona de Mediana Edad , Mutación , Recurrencia Local de Neoplasia/prevención & control , Selección de Paciente , Neoplasias Peritoneales/genética , Neoplasias Peritoneales/mortalidad , Neoplasias Peritoneales/secundario , Pronóstico , Proteínas Proto-Oncogénicas B-raf , Estudios Retrospectivos , Medición de Riesgo/métodos
19.
Int J Pharm ; 564: 256-262, 2019 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-31015002

RESUMEN

RNA interference (RNAi) is one of the most promising strategies for cancer therapeutics. The successful translation of RNAi therapeutics to a clinic setting requires a delivery system that is efficient and simple to upscale. In this study, we devised a simple industrial method to manufacture lipoplex, which includes short hairpin RNA against the expression of thymidylate synthase (TS shRNA) - a key molecule for DNA biosynthesis. An aqueous solution of TS shRNA was gently mixed with either a precursor of cationic liposome (Presome DF-1) or a cationic lipid mixture in an o/w emulsion. This solution was subsequently lyophilized under optimal conditions to obtain either FD-lipoplex-1 or FD-lipoplex-2, respectively. With this method, a lipoplex in activated form was obtained via a simple "one-step" hydration with saline. Both forms of FD-lipoplex showed physicochemical properties comparable to those of conventional lipoplex. FD-lipoplexes stably retained TS shRNA within their formulations in the presence of tumor ascites fluid. Intraperitoneal treatment with either FD-lipoplex-1 or FD-lipoplex-2 provided a therapeutic level of efficacy comparable to that of conventional lipoplex in the treatment of a peritoneal disseminated gastric cancer mouse model. Collectively, established freeze-drying-based methods for RNAi-therapeutic preparation could realistically be used in a clinical setting for the treatment of patients with peritoneal disseminated cancer.


Asunto(s)
Neoplasias Peritoneales/terapia , ARN Interferente Pequeño/administración & dosificación , Neoplasias Gástricas/terapia , Timidilato Sintasa/genética , Animales , Línea Celular Tumoral , Liofilización , Humanos , Liposomas , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Peritoneales/genética , Interferencia de ARN , ARN Interferente Pequeño/química , Tratamiento con ARN de Interferencia , Neoplasias Gástricas/genética
20.
Cancer Res ; 79(9): 2271-2284, 2019 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-30862717

RESUMEN

Peritoneal metastases are the leading cause of morbidity and mortality in high-grade serous ovarian cancer (HGSOC). Accumulating evidence suggests that mesothelial cells are an important component of the metastatic microenvironment in HGSOC. However, the mechanisms by which mesothelial cells promote metastasis are unclear. Here, we report that the HGSOC tumor-mesothelial niche was hypoxic, and hypoxic signaling enhanced collagen I deposition by mesothelial cells. Specifically, hypoxic signaling increased expression of lysyl oxidase (LOX) in mesothelial and ovarian cancer cells to promote collagen crosslinking and tumor cell invasion. The mesothelial niche was enriched with fibrillar collagen in human and murine omental metastases. Pharmacologic inhibition of LOX reduced tumor burden and collagen remodeling in murine omental metastases. These findings highlight an important role for hypoxia and mesothelial cells in the modification of the extracellular matrix and tumor invasion in HGSOC. SIGNIFICANCE: This study identifies HIF/LOX signaling as a potential therapeutic target to inhibit collagen remodeling and tumor progression in HGSOC.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/9/2271/F1.large.jpg.


Asunto(s)
Colágeno/metabolismo , Cistadenocarcinoma Seroso/secundario , Epitelio/fisiopatología , Matriz Extracelular/metabolismo , Hipoxia/fisiopatología , Neoplasias Ováricas/patología , Neoplasias Peritoneales/secundario , Adulto , Anciano , Anciano de 80 o más Años , Animales , Apoptosis , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Proliferación Celular , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Ratones , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Neoplasias Peritoneales/genética , Neoplasias Peritoneales/metabolismo , Pronóstico , Proteína-Lisina 6-Oxidasa/genética , Proteína-Lisina 6-Oxidasa/metabolismo , Transducción de Señal , Células Tumorales Cultivadas , Microambiente Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto
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