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Abstract. Peripheral primitive neuroectodermal tumor (PNET) of the cervix uteri is extremely rare. Two cases of PNET of the cervix are presented herein. Two female patients, aged 48 and 43 years, presented with irregular uterine bleeding over the course of 1 year, and increased urinary frequency for 1 month, respectively. On gynecological examination, a mass in the cervix was palpated and a biopsy performed. The findings of the initial biopsy revealed small-cell carcinoma in both patients. Following neoadjuvant chemotherapy and radiotherapy, radical hysterectomy was performed in both patients. One patient received 5 courses of consolidation chemotherapy and postoperative radiotherapy, whereas the other patient received 1 course of consolidation chemotherapy. At the time of the article submission, both patients remained disease-free at 27 and 12 months, respectively, after their initial diagnosis. Only a limited number of cases of PNET of the cervix uteri have been reported in the literature to date. Multimodal therapies, including total excision, adjuvant chemotherapy and/or radiotherapy, have been adopted to treat patients with PNET of the cervix. IntroductionThe term primitive neuroectodermal tumor (PNET) was first introduced by Hart and Earle to describe tumors composed of small round cells with different degrees of neural, glial and ependymal differentiation (1). PNETs have been classified according to the World Health Organization as central-and peripheral-type. Central PNETs usually involve the brain and spinal cord, whereas peripheral PNET involve the sympathetic nervous system, skeleton and soft tissues (2).PNETs of the cervix are extremely rare. To the best of our knowledge, only 14 cases have been described between 1987 and 2015 in the English literature (3-14) and there are currently no universally accepted standard treatment guidelines. Data on long-term follow-up are not available and the clinical outcome of PNET patients remains elusive (4-6). The aim of this study was to present two cases of primary PNET of the cervix and describe the diagnostic and treatment procedures. Case reportsCase 1. A 48-year-old woman, gravida 3, para 2, presented with irregular uterine bleeding over the course of 1 year. On gynecological examination, a cervical mass rich in blood vessels was identified, measuring 6.0 cm in its greatest dimension (Fig. 1). The left parametrium was also involved, and the tumor was staged as IIb. A cervical biopsy was performed and the initial diagnosis was small-cell carcinoma.Histologically, the tumor comprised small blue-stained tumor cells with scant cytoplasm, arranged in dense sheets, without rosette or gland formation. Areas of necrosis were present. The neoplastic cells, some of which exhibited prominent nucleoli, infiltrated several capillaries. The cells uniformly expressed CD99 and vimentin, whereas synaptophysin (Syn), CD56, S-100 and epithelial membrane antigen were focally positive. Neuron-specific enolase (NSE), chromogranin A (CgA), cytokeratin (CK), CK5, CK8/18, P16, leukoc...

Cancer stem cells (CSCs) are a class of cancer cells characterized by self-renewal, differentiation and tumorigenic potential. We previously established a model of cScs by culturing mouse induced pluripotent stem cells (miPSCs) for four weeks in the presence of a conditioned medium (CM) of cancer cell lines, which functioned as the tumor microenvironment. Based on this methodology of developing CSCs from miPSCs, we assessed the risk of 110 non-mutagenic chemical compounds, most of which are known as inhibitors of cytoplasmic signaling pathways, as potential carcinogens. We treated miPSCs with each compound for one week in the presence of a CM of Lewis lung carcinoma (LLC) cells. However, one-week period was too short for the CM to convert miPSCs into CSCs. Consequently, PDO325901 (MEK inhibitor), CHIR99021 (GSK-3β inhibitor) and Dasatinib (Abl, Src and c-Kit inhibitor) were found to confer miPSCs with the CSC phenotype in one week. The tumor cells that survived exhibited stemness markers, spheroid formation and tumorigenesis in Balb/c nude mice. Hence, we concluded that the three signal inhibitors accelerated the conversion of mipScs into cScs. Similarly to our previous study, we found that the PI3K-Akt signaling pathway was upregulated in the CSCs. Herein, we focused on the expression of relative genes after the treatment with these three inhibitors. Our results demonstrated an increased expression of pik3ca, pik3cb, pik3r5 and pik3r1 genes indicating class IA PI3K as the responsible signaling pathway. Hence, AKT phosphorylation was found to be up-regulated in the obtained CSCs. Inhibition of Erk1/2, tyrosine kinase, and/or GSK-3β was implied to be involved in the enhancement of the PI3K-AKT signaling pathway in the undifferentiated cells, resulting in the sustained stemness, and subsequent conversion of miPSCs into CSCs in the tumor microenvironment. Alexander A. Maximow, a Russian cell biologist, was the first who proposed the concept of stem cells in 1909 1. In 1961, the two basic features defining stem cells, namely abilities of self-renewal and differentiation into mature cells, were uncovered by Till and McCulloch 2. CSCs were first identified in the granulocytes of acute myeloid leukemia in 1994 3. Since 1997 when Bonnet and Dick identified the CSCs by the ability of self-renewal from

Cancer stem cells (CSCs) are capable of continuous proliferation, self-renewal and are proposed to play significant roles in oncogenesis, tumor growth, metastasis and cancer recurrence. We have established a model of CSCs that was originally developed from mouse induced pluripotent stem cells (miPSCs) by proposing miPSCs to the conditioned medium (CM) of cancer derived cells, which is a mimic of carcinoma microenvironment. Further research found that not only PI3K-Akt but also EGFR signaling pathway was activated during converting miPSCs into CSCs. In this study, we tried to observe both of PI3Kγ inhibitor Eganelisib and EGFR inhibitor Gefitinib antitumor effects on the models of CSCs derived from miPSCs (miPS-CSC) in vitro and in vivo. As the results, targeting these two pathways exhibited significant inhibition of cell proliferation, self-renewal, migration and invasion abilities in vitro. Both Eganelisib and Gefitinib showed antitumor effects in vivo while Eganelisib displayed more significant therapeutic efficacy and less side effects than Gefitinib on all miPS-CSC models. Thus, these data suggest that the inhibitiors of PI3K and EGFR, especially PI3Kγ, might be a promising therapeutic strategy against CSCs defeating cancer in the near future.