市川 亮子

Human papillomavirus (HPV) infection can persist in the cervical epithelium without provoking a strong host immune response, leading to the development of cervical cancer. Cytokines, which mediate innate and adaptive immune activities, are secreted in the cervical mucus; however, there is currently no appropriate method for assessing cytokine levels in mucus specimens. Here, we employed multiplexed bead-based immunoassays to examine cytokine levels in cervical mucus using both weighted-volume and total protein concentration methods to adjust for different specimen volumes in individual patients. Out of 18 cytokines initially examined in the primary cohort patient group (n = 28), 14 were detected in more than 10% of the samples. Of these 14 cytokines, expression levels of interferon (IFN)-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), RANTES, and eotaxin were significantly increased with the disease severity in the secondary cohort patient group (n = 235). We also examined associations between cytokine levels and clinical parameters, such as cytology and HPV genotype. Of the 14 cytokines, granulocyte colony-stimulating factor (G-CSF) was downregulated in HPV-positive specimens. Examination of co-expression patterns of cytokines in relation to HPV infection status revealed that several pairs of cytokines were simultaneously upregulated in HPV-positive cases, including INF-γ and interleukin (IL)-17A, GM-CSF and monocyte chemoattractant protein-1 (MCP-1), GM-CSF and RANTES, IL-17A and RANTES, and MCP-1 and eotaxin. Interestingly, upregulation of GM-CSF and RANTES might reflect a shift in immuno-regulatory cytokines in HPV-positive specimens, potentially associated with more severe cervical neoplasia.

microRNAs (miRNAs) play important roles in regulation of gene expression during cervical carcinogenesis. We investigated expression profiles of miRNAs in cervical cancer and its precursor lesions by utilizing cervical mucus. Cervical mucus was collected from 230 patients with a normal cervix, cervical intraepithelial neoplasia (CIN), squamous cell carcinoma (SCC), or adenocarcinoma (AD). The levels of miRNA in the mucus were quantified by miRNA array and real-time reverse-transcriptase polymerase chain reaction (RT-PCR). The performance for detecting diseases was statistically analysed. The expression of miRNAs was further validated in the surgical tissues of enrolled patients. Four miRNAs (miR-126-3p, -20b-5p, -451a, and -144-3p) were significantly up-regulated in SCC and AD compared with normal, and their expression levels correlated with disease severity and high-risk human papillomavirus infection. Receiver operating characteristic curve analyses revealed that the area under the curve values for miR-126-3p, -20b-5p, -451a, and -144-3p were 0.89, 0.90, 0.94, and 0.93, respectively, for SCC plus AD compared with normal, showing high accuracy of cancer detection. Real-time RT-PCR analyses confirmed the expression of these four miRNAs in frozen tissues from cervical cancer. miR-126-3p, -20b-5p, -451a, and -144-3p in cervical mucus are promising biomarkers for cervical cancer and high-grade CINs.

<p>  Ovarian cancer arising from an ovarian endometriotic cyst is frequently encountered; however, this condition has rarely been reported in young patients. We herein report a case of malignant transformation of an ovarian endometriotic cyst in a 26-year-old woman (gravida 0, para 0). During the initial examination at our hospital, ultrasound revealed an endometriotic cyst in the right ovary measuring 49×44×29 mm and an endometriotic cyst in the left ovary measuring 59×53×32 mm with no marked mural nodules on either side.<br> The patient was followed up every 3 months while receiving hormone therapy. At the 6-month follow-up, ultrasound revealed 10-mm mural nodules within the endometriotic cyst of the left ovary. At 10 months, ultrasound revealed that these the mural nodules had enlarged to 15 mm. Pelvic magnetic resonance imaging revealed that the tumor in the left ovary was 64×63 mm in size, which was slightly larger than in the previous scan. The patient underwent laparotomy because of the potential for malignant transformation. Pathological examination revealed clear cell adenocarcinoma. Although malignant transformation of this cancer is rare in women in their 20s, its possibility should be considered; this is true even when cyst enlargement can be controlled during hormone therapy. Magnetic resonance imaging is extremely useful in the diagnosis of malignant transformation.</p>

Alveolar soft part sarcoma (ASPS) that originates from the uterine cervix is extremely rare, with only thirteen cases reported. The participation of the ASPL-TFE3 chimeric gene, translocation (X; 17) (p11; q25), has been demonstrated in ASPS. Here, we report a case of cervical ASPS, along with a review of the literature. The patient, a 56-year-old woman, was referred for a 70 x 80 mm cervical tumor. She underwent a hysterectomy and bilateral salpingo-oophorectomy, and remained disease free for 66 months without adjuvant therapy. Pathological examination revealed features consistent with ASPS. In addition, the present case demonstrated strong positive nuclear staining for TFE3, and ASPL-TFE3 fusion gene type 1 was detected by RT-PCR. In a review of fourteen cases of this tumor (including the present case), the immunohistochemical expression patterns of myogenic or neuroendocrine markers were somewhat varied among cases. In all cases except for the present case, the patients were under 40 years of age, and the tumor sizes were under 5 cm. The prognosis of ASPS in the cervix was considerably better than that of ASPS in soft tissues. Complete resection with adequate margins is thought to be important, although the appropriate surgical method, including lymph node dissection, is uncertain. The role of chemotherapy or radiotherapy as adjuvant therapy has not been defined. Cervical ASPS is extremely rare, making case series the most viable option for understanding their natural history and for developing a treatment strategy, including an optimal surgical procedure and adjuvant therapy.

Objective: Several studies have suggested that excision repair cross-complementation group 1 (ERCC1), a protein involved in nucleotide excision repair, is associated with resistance to platinum agent-based chemotherapy or chemoradiotherapy with platinum agents in various types of cancer. Herein we evaluated ERCC1 protein expression in uterine cervical adenocarcinoma and the relationship between this expression, clinicopathological factors, and clinical outcome, particularly in patients receiving adjuvant cisplatin-based chemotherapy or chemoradiotherapy with cisplatin. Methods: Thirty-six patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB to stage IIB cervical adenocarcinoma who underwent radical hysterectomy were evaluated. Excision repair cross-complementation group 1 protein expression was examined by immunohistochemistry in tumor tissues. The relationship between ERCC1 expression levels and clinicopathological factors (age, FIGO stage, histological grade, tumor size, vascular invasion, cervical stromal invasion, and lymph node metastases) and prognosis was evaluated. Results: No significant differences between ERCC1 expression levels and clinicopathological factors were observed. The patients in the ERCC1 high-expression group (n = 7) experienced significantly worse disease-free survival than the patients in the ERCC1 low-expression group (n = 29; P = 0.005). Among the 25 patients who received cisplatin-based chemotherapy or chemoradiotherapy with cisplatin, those with high ERCC1 expression (n = 5) also experienced significantly worse disease-free survival than those with low ERCC1 expression (n = 20; P = 0.002). Moreover, univariate and multivariate analyses revealed that high ERCC1 expression was an independent prognostic factor in patients receiving cisplatin-based chemotherapy or chemoradiotherapy with cisplatin. Conclusions: This is the first analysis of the association between ERCC1 expression and clinical outcomes in patients with uterine cervical adenocarcinoma. High ERCC1 protein expression was revealed to be associated with worse disease-free survival in the patients who received adjuvant cisplatin-based chemotherapy or chemoradiotherapy with cisplatin and was shown to be an independent prognostic factor. Further evaluation with a larger number of patients is required to confirm these preliminary observations.

Purpose: The prognosis of advanced ovarian cancer primarily depends on maximal surgical debulking and chemosensitivity of the tumor. Neo-adjuvant chemotherapy (NAC), maintenance chemotherapy, and interval debulking surgery (IDS) are sometimes used to improve the prognosis of advanced ovarian cancer patients. In this study, we evaluated the outcomes of these therapeutic options in the treatment of FIGO stage III and IV ovarian cancers with intraperitoneal dissemination. Methods: Fifty patients with FIGO stage IIIc and TV ovarian cancer were evaluated. Progression-free survival (PFS) and overall survival (OS) were compared between different patient groups, including patients who underwent optimal surgery versus suboptimal surgery, patients who received NAC versus those who did not, patients who received 6 cycles of postoperative adjuvant chemotherapy versus those who received more than 7 cycles, and patients who underwent IDS versus those who did not. Results: 1) The 5- and 10-year OS rates were 52% and 21%, respectively. 2) Patients in the optimal surgery group experienced significantly longer PFS than patients in the suboptimal surgery group (p=0.04). 3) Although NAC increased the possible rate of optimal surgery from 31.2% to 66.7%, no significant differences in PFS or OS were observed between patients who did and did not receive NAC. 4) Patients who underwent more than 7 cycles of adjuvant chemotherapy after suboptimal surgery experienced significantly longer OS (p=0.001) and a tendency toward longer PFS (p=0.07) compared to patients who received 6 cycles of adjuvant chemotherapy. 5) Patients who achieved a complete response (CR) following adjuvant chemotherapy after suboptimal surgery experienced significantly longer PFS (p=0.001) and OS (p=0.001) compared to patients who did not obtain CR. Moreover, patients who underwent IDS and who did not obtain a CR after adjuvant chemotherapy tended to experience longer PFS than patients who did not undergo IDS (p=0.07). Conclusions: The results of this study are essentially compatible with those of recent randomized controlled trials (RCTs) evaluating NAC, maintenance chemotherapy, and IDS in advanced ovarian cancer. We hope to obtain additional RCT results that will allow improvement of the prognosis of advanced ovarian cancer patients.