- Epigenetic Crosstalk between the Tumor Microenvironment and Ovarian Cancer Cells: A Therapeutic Road Less Traveled. [Review]
- CCancers (Basel) 2018 Aug 30; 10(9)
- Metastatic dissemination of epithelial ovarian cancer (EOC) predominantly occurs through direct cell shedding from the primary tumor into the intra-abdominal cavity that is filled with malignant asci...
Metastatic dissemination of epithelial ovarian cancer (EOC) predominantly occurs through direct cell shedding from the primary tumor into the intra-abdominal cavity that is filled with malignant ascitic effusions. Facilitated by the fluid flow, cells distribute throughout the cavity, broadly seed and invade through peritoneal lining, and resume secondary tumor growth in abdominal and pelvic organs. At all steps of this unique metastatic process, cancer cells exist within a multidimensional tumor microenvironment consisting of intraperitoneally residing cancer-reprogramed fibroblasts, adipose, immune, mesenchymal stem, mesothelial, and vascular cells that exert miscellaneous bioactive molecules into malignant ascites and contribute to EOC progression and metastasis via distinct molecular mechanisms and epigenetic dysregulation. This review outlines basic epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA regulators, and summarizes current knowledge on reciprocal interactions between each participant of the EOC cellular milieu and tumor cells in the context of aberrant epigenetic crosstalk. Promising research directions and potential therapeutic strategies that may encompass epigenetic tailoring as a component of complex EOC treatment are discussed.
- Ubiquitin-Proteasome Axis, Especially Ubiquitin-Specific Protease-17 ( USP17) Gene Family, is a Potential Target for Epithelial-Mesenchymal Transition in High-Grade Serous Ovarian Cancer. [Journal Article]
- RSReprod Sci 2018 Sep 09; :1933719118799189
- CONCLUSIONS: Gene expression difference between primary tumor and the peritoneal implant is not as much as the difference between primary tumor and free cells in the ascites. These results show that malignant cells in the ascites return into its genetic origin after they invade on the peritoneum. Significantly increased expression of DUB-enzyme genes, SNAR gene family, and ribosomal pathway genes in epithelial-mesenchymal transition suggests that this regulation is ubiquitin-proteasome dependent. Especially, this is the first study that offers USP17 as a potential target for epithelial-mesenchymal transition.
- PD-1+ TIM-3+ T cells in malignant ascites predict prognosis of gastrointestinal cancer. [Journal Article]
- CSCancer Sci 2018; 109(9):2986-2992
- The liquid biopsy of ascites fluid could be an excellent source of tumor and microenvironment for the study of prognostic biomarkers because of its accessibility. Tumor-infiltrating lymphocytes (TILs...
The liquid biopsy of ascites fluid could be an excellent source of tumor and microenvironment for the study of prognostic biomarkers because of its accessibility. Tumor-infiltrating lymphocytes (TILs) can predict prognosis in multiple malignancies, including the response to immune checkpoint inhibitors, a breakthrough cancer therapy. However, TILs' profiles from malignant ascites have not been extensively studied. Using flow cytometric analysis, we quantified the proportion of exhausted T cells and memory/naive/effector T-cell subsets, among the CD4+ and CD8+ T-cell populations of paired TILs and peripheral blood T cell samples (n = 22). The correlation between CD4+ and CD8+ subset profiles suggested that the combined analysis of CD4+ and CD8+ cells in malignant ascites was clinically significant. We found that cells positive for the exhaustion markers programmed cell death-1 (PD-1), and T-cell immunoglobulin and mucin domain 3 (TIM-3), and cells coexpressing PD-1 and TIM-3 abundantly exist among malignant ascites TILs. Furthermore, patients with high frequency of PD-1+ TIM-3+ cells among the CD4+ and CD8+ T-cell population showed worse clinical outcome in multivariate analysis (n = 27). We propose that exhausted ascites TILs represent a clinically significant prognostic biomarker in advanced gastrointestinal cancer and represent an important target for immune checkpoint inhibitors.
- Combined antitumor effects of P-5m octapeptide and 5-fluorouracil on a murine model of H22 hepatoma ascites. [Journal Article]
- ETExp Ther Med 2018; 16(3):1586-1592
- The present study has demonstrated that P-5m octapeptide (P-5m) has therapeutic potential in metastatic human hepatocarcinoma, possibly through the modulation of matrix metalloproteinase-2 expression...
The present study has demonstrated that P-5m octapeptide (P-5m) has therapeutic potential in metastatic human hepatocarcinoma, possibly through the modulation of matrix metalloproteinase-2 expression. The purpose of the present study was to evaluate the antitumor effect of P-5m combined with 5-fluorouracil (5-Fu) on the treatment of hepatoma 22 (H22) hepatocarcinoma malignant ascites in a mouse model. The inhibitory effect on the growth of mouse ascites tumors was monitored by measuring body weight gain, survival time, ascites volume, numbers of tumor cells, DNA synthesis and peritoneal capillary permeability analysis. The present data revealed a significant reduction in ascites volume and cell count in mice that were treated with P-5m plus 5-Fu. Furthermore, the median survival time in mice in the combination group was prolonged compared with the disease control group. Moreover, a significant reduction in the total H22 ascites cell count in mice from the combination group was observed when compared with the disease control group. P-5m plus 5-Fu was able to induce the cell cycle arrest and inhibit the peritoneal capillary permeability of the mice. To conclude, the present study indicated that P-5m may have therapeutic potential in ascites caused by hepatocellular carcinoma.
- Underlying etiology determines the outcome in atraumatic chylous ascites. [Journal Article]
- IRIntractable Rare Dis Res 2018; 7(3):177-181
- Chylous ascites is an uncommon entity and infectious etiology is the most common cause in developing countries. However, recently, whether there is any change in trend of etiologies in developing cou...
Chylous ascites is an uncommon entity and infectious etiology is the most common cause in developing countries. However, recently, whether there is any change in trend of etiologies in developing countries is not known. In this study, a retrospective analysis of the data of cases of atraumatic chylous ascites was conducted. Twelve patients of atraumatic chylous ascites with a mean age of 35 years were studied and 6 of them were males. The mean duration of symptoms was 9.6 months and the clinical presentation was abdominal distension (12 cases), pain abdomen (10 cases), loss of appetite and weight (9 cases), peripheral lymphadenopathy (4 cases) and fever (3 cases). Etiologies were tuberculosis (3 cases), malignancy (2 cases), radiotherapy related (2 cases), pancreatitis related (2 cases), lymphatic malformation (2 cases) and multifactorial (1 case). Eight improved with conservative measures, 2 were lost to follow up and 2 died. Our outcomes found infectious etiology still as the most common cause of atraumatic chylous ascites. Benign treatable causes could be managed successfully with conservative measures while malignant etiology had a poor prognosis. Underlying etiology determines the outcome in atraumatic chylous ascites.
- Anaplastic carcinoma in ovarian seromucinous cystic tumor of borderline malignancy. [Journal Article]
- JOJ Ovarian Res 2018 Sep 03; 11(1):77
- CONCLUSIONS: Imaging studies with pathognomonic findings contributed to ovarian cancer diagnosis in this case. To the best of our knowledge, this is the first study in English literature to report detailed classification of mucinous borderline malignancy, seromucinous cystic, and anaplastic carcinoma in an ovarian seromucinous cystic tumor of borderline malignancy.
- Methylglyoxal at metronomic doses sensitizes breast cancer cells to doxorubicin and cisplatin causing synergistic induction of programmed cell death and inhibition of stemness. [Journal Article]
- BPBiochem Pharmacol 2018 Aug 29; 156:322-339
- Potent anticancer activity coupled with absence of toxicity at therapeutic dose established the glycolytic metabolite, methylglyoxal, as a promising candidate against malignant neoplasia. In this pre...
Potent anticancer activity coupled with absence of toxicity at therapeutic dose established the glycolytic metabolite, methylglyoxal, as a promising candidate against malignant neoplasia. In this preclinical study we illustrate the applicability of methylglyoxal in formulating an optimally designed combination regimen with chemotherapeutic drugs against breast cancer. Results demonstrated a synergistic augmentation in doxorubicin and cisplatin mediated cytotoxicity in human breast cancer cell lines MDA MB 231 & MCF 7 with methylglyoxal co-treatment at metronomic concentrations. The cell death due to combination treatment was significantly prevented by N-Acetylcysteine and the synergistic effects were attenuated in presence of inhibitors for apoptosis and necroptosis, in MDA MB 231 and MCF 7 cells, respectively. Additionally, acridine orange staining and immunoblotting with LC3B antibody indicated the suppression of doxorubicin induced autophagy flux with methylglyoxal co-treatment. This report documents for the first time the preferential targeting of breast cancer stem cells by methylglyoxal. Combination treatment with doxorubicin or cisplatin hindered mammosphere forming efficiency and inclusively eliminated both cancer stem as well as non-stem cancer cells. The synergistic effect was validated in Ehrlich mammary carcinoma cell induced murine ascites model and the combination advantage in vivo was achieved without any additional deleterious effect to liver and kidney. Our present study evidences the implications of methylglyoxal inclusion in adjuvant multimodal chemotherapeutics against breast cancer and offers noteworthy insights into the possible outcome.
- Detection of EGFR T790M in a Large Amount of Malignant Ascites Cellblock. [Journal Article]
- GTGan To Kagaku Ryoho 2018; 45(8):1185-1187
- Osimertinib is a highly active agent for patients with progression of lung cancer despite epidermal growth factor receptor (EGFR)tyrosine kinase inhibitor treatment. This resistance is usually due to...
Osimertinib is a highly active agent for patients with progression of lung cancer despite epidermal growth factor receptor (EGFR)tyrosine kinase inhibitor treatment. This resistance is usually due to EGFR exon 20 T790M mutation, which can be detected by repeat biopsy. We report a case in which EGFR exon 20 T790M mutation was detected by repeat ascitic fluid examination. A 71-year-old woman with lung adenocarcinoma harboring EGFR exon 19 deletion was started on erlotinib(25 mg/day)as second-line therapy. Two years later, there was increase in pleural effusion, with concomitant malignant ascites; however, pathologic examination of the pleural and ascitic fluids did not detect EGFR T790Mmutation. Afatinib(2 0mg/day) was started, but there was no decrease in the severity of ascites. Two months later, her condition was extremely deteriorated. Finally, a much larger amount of ascitic fluid obtained by paracentesis was processed for cellblock, which demonstrated EGFR exon 20 T790M mutation. Thereafter, the ascites and the primary lesion dramatically decreased after treatment with osimerti- nib(80mg/day).
- Ancillary studies in pleural, pericardial, and peritoneal effusion cytology. [Review]
- CCCancer Cytopathol 2018; 126 Suppl 8:590-598
- Pleural, pericardial, and peritoneal effusion specimens present diagnostic challenges and clinical opportunities for cytology. For the patient, these specimens may be the first diagnosis of malignanc...
Pleural, pericardial, and peritoneal effusion specimens present diagnostic challenges and clinical opportunities for cytology. For the patient, these specimens may be the first diagnosis of malignancy or the first sign of disease recurrence. This review aims to provide useful approaches with which to resolve key difficulties in cytologic diagnosis through the use of ancillary studies, focusing on immunohistochemistry. These approaches are suggested in concert with clinical, radiographic, and morphologic findings. The differentiation of reactive mesothelial cells from malignant mesothelioma and adenocarcinoma is a recurring theme, and Wilms tumor 1 (WT1)/AE1/AE3, claudin 4, and BRCA1-associated protein 1 (BAP1) immunostains are useful new tools in the armamentarium. A targeted workup is suggested for patients with no known primary site or with multiple prior malignancies. Molecular and other biomarker testing can be performed on even modestly cellular fluid specimens and may allow patients to benefit from targeted therapy without the need for additional tissue biopsies. Cancer Cytopathol 2018;000:000-000. © 2018 American Cancer Society.
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- Presurgical diagnostic difficulties in an asymptomatic patient with primary transitional cell carcinoma of the oviduct: case report. [Journal Article]
- PMPrz Menopauzalny 2018; 17(2):91-93
- Primary transitional cell carcinoma of the fallopian tube is a very rare condition. We present a case of a 70-year-old asymptomatic Caucasian patient with an irregular solid right adnexal mass of 67 ...
Primary transitional cell carcinoma of the fallopian tube is a very rare condition. We present a case of a 70-year-old asymptomatic Caucasian patient with an irregular solid right adnexal mass of 67 × 35 × 59 mm which was discovered during routine ultrasound pelvic examination. There was no acoustic shadow and the patient did not feel pain during examination. No evidence of metastases or ascites was found by ultrasound. There was moderate vascularization of the mass. The mass was considered malignant according to the subjective assessment of the examiner. Serum level of CA125 was elevated to 519 U/ml. The results of logistic regression model LR2 according to the International Ovarian Tumor Analysis (IOTA) group was 64.4%, suggesting the malignant nature of the mass. The IOTA-ADNEX model showed 97% probability of malignancy, probably (85.5%) stage II-IV ovarian cancer. The risk of malignancy being borderline, stage I and metastatic was 0.6%, 3.9% and 7%, respectively. Omitting CA125 in the IOTA-ADNEX model slightly decreased the probability of malignancy to 81.3%, still most likely (54.2%) stage II-IV ovarian cancer. The results of risk of malignancy indices RMI I-IV were 1557, 2076, 1557 and 2076, respectively, reflecting the malignant nature of the mass. The final diagnosis was transitional cell carcinoma of the fallopian tube, stage IIIc according to FIGO.