[show abstract][hide abstract] ABSTRACT: The current study presents the case of a patient with a recurrent carcinoid tumor of the ovary, 13-years after the primary surgery. The primary surgery consisted of a total abdominal hysterectomy and bilateral salpingo-oophorectomy for a left ovarian tumor at 54 years old. Pathologically, the tumor was diagnosed as a carcinoid tumor of the ovary. Following the primary treatment, the patient was admitted to a cardiologist due to carcinoid-induced heart failure. At 67 years old, the patient was referred to Kyoto University Hospital with a solitary mass 8 cm in diameter and located in the paraaortic area, which was detected by routine ultrasonography and subsequent computed tomography (CT) scans. Urinary 5-hydroxyindole acetate (5-HIAA), a serotonin degradation metabolite, was present at elevated levels. With a diagnosis of a recurrent carcinoid tumor, the patient underwent a tumor resection. The pathological diagnosis was that of lymph node metastasis of the trabecular carcinoid. Post-operatively, the 5-HIAA levels returned to normal. Carcinoid tumors occasionally recur following surgery due to borderline malignant potential. Due to the slow growing nature of these tumors, in specific cases, recurrence occurs following a long interval. Therefore, a relatively long follow-up period is required.
[show abstract][hide abstract] ABSTRACT: The sensitivity of the current 10mm cut-off diameter that is used to diagnose lymph node (LN) metastasis is too low. This is the first study to develop a new criterion to diagnose LN metastasis in a region-by-region manner using multi-detector computed tomography (MDCT).
1) The short-axis diameter of the LNs in MDCT images from 1-mm slices obtained immediately prior to surgery was compared with the pathological diagnosis in 78 uterine cervical cancer patients undergoing primary surgery. For the region-by-region analysis, we divided para-aortic and pelvic spaces into 13 regions. 2) In 28 cases in which patients received neoadjuvant chemotherapy (NAC) followed by surgery, we compared MDCT images before and after NAC.
1) The optimal cut-off in the region-by-region analysis was 5mm, yielding 71% sensitivity and 79% specificity. 2) NAC significantly decreased LN size (p<0.0001). NAC decreased the number of swollen LN regions (>5mm) from 51% (81/158) to 26% (41/158).
The new criterion developed using MDCT could be effective for accurately assessing LN status. It also facilitates the assessment of NAC efficacy regarding the eradication of LN metastases.
[show abstract][hide abstract] ABSTRACT: Sorafenib is an oral multikinase inhibitor targeting Raf and other kinases. The anti-tumor effect of sorafenib is thought to be mediated through its inhibition of the RAS-Raf-Erk pathway, as well as its inhibition of VEGFR and PDGFR. Sorafenib has been effective at treating patients with renal cell carcinoma (RCC). Ovarian clear cell carcinoma (OCCC) is a chemoresistant subtype of ovarian cancer. OCCC is represented by cells with clear cytoplasm that resemble those observed in RCC. Using a microarray database, the gene expression profile of OCCC was similar to that of RCC. The effects of sorafenib against human OCCC are unknown. Therefore, we used sorafenib to treat two patients with recurrent chemoresistant OCCC, and observed good effect in both of them without severe side effects. We believe that sorafenib is an effective agent against OCCC. Given the chemoresistant nature of this tumor, this drug appears to be very valuable.
Cancer biology & therapy 10/2013; 15(1). · 3.29 Impact Factor
[show abstract][hide abstract] ABSTRACT: PURPOSE: Ovarian cancer often progresses by disseminating to the peritoneal cavity, but how the tumor cells evade host immunity during this process is poorly understood. Programmed cell death 1 ligand 1 (PD-L1) is known to suppress immune system and to be expressed on cancer cells. The purpose of this study is to elucidate the function of PD-L1 in peritoneal dissemination. EXPERIMENTAL DESIGN: Ovarian cancer cases were studied by microarray and immunohistochemistry. PD-L1 expression in mouse ovarian cancer cell line in various conditions was assessed by flow cytometry. PD-L1-overexpression cell line and PD-L1-depleted cell line were generated, and cytolysis by CTLs was analyzed, and alterations in CTLs were studied by means of timelapse and microarray. These cell lines were injected intraperitoneally to syngeneic immunocompetent mice. RESULTS: Microarray and immunohistochemistry in human ovarian cancer revealed significant correlation between PD-L1 expression and peritoneal positive cytology. PD-L1 expression on mouse ovarian cancer cells was induced upon encountering lymphocytes in the course of peritoneal spread in vivo and co-culture with lymphocytes in vitro. Tumor cell lysis by CTLs was attenuated when PD-L1 was overexpressed and promoted when it was silenced. PD-L1 overexpression inhibited gathering and degranulation of CTLs. Gene expression profile of CTLs caused by PD-L1-overexpressing ovarian cancer was associated with CTLs exhaustion. In mouse models, PD-L1 depletion resulted in inhibited tumor growth in the peritoneal cavity and prolonged survival. CONCLUSIONS: PD-L1 expression on tumor cell promotes peritoneal dissemination by repressing CTL function. PD-L1-targeted therapy is a promising strategy for preventing and treating peritoneal dissemination.
Clinical Cancer Research 01/2013; · 7.84 Impact Factor
[show abstract][hide abstract] ABSTRACT: Adenoid cystic carcinoma (ACC) is a relatively uncommon malignancy that most frequently arises in the salivary glands. In the genital tract, approximately 60 cases of ACC that originated from Bartholin glands have been reported to date. In this report, we describe a case of ACC that arose from Skene glands, a very rare origin for this disease. In this patient, the disease had an indolent clinical course, with few symptoms other than localized pain. During the surgical operation, the tumor was found to have invaded more extensively than had been estimated preoperatively, and it required pelvic exenteration with radical vulvectomy. Although the precise preoperative assessment and the preparation for an extended operation are difficult, they are necessary for the successful treatment of this rare disease.
International journal of gynecological pathology: official journal of the International Society of Gynecological Pathologists 09/2012; 31(6):596-600. · 2.07 Impact Factor
[show abstract][hide abstract] ABSTRACT: In an attempt to clarify the clinical characteristics of synchronous primary endometrial and ovarian cancer (SPC), we reviewed the clinicopathological features of 13 cases treated in the Department of Gynecology and Obstetrics at Kyoto University Hospital over the last 6 years and compared them with 186 cases of primary uterine corpus cancer (PCC) and 136 cases of primary ovarian cancer (POC). Comparisons were performed based on clinicopathological factors, including age, BMI, parity, complication of thrombosis and FIGO stage. For SPC patients, the mean age was 51.5 years; 6 (46%) were nulliparous, and 7 (53%) had complicated thrombosis. All had well-differentiated endometrial cancer and 12 (92%) had endometrioid cancer in the ovary. The mean age of the SPC patients was significantly lower than that of the PCC patients (51.5 vs. 58.9 years). Thrombosis occurred in the SPC patients at a significantly higher rate than in both the PCC and POC patients. When the incidence of endometriosis and the regularity of menstruation were compared between patients who developed SPC with those who develop PCC at a young age (under 45 years), the SPC patients exhibited a significantly higher rate of endometriosis (100 vs. 35%), whereas the PCC patients exhibited a higher rate of irregular menstruation (53 vs. 15%, p=0.05). As for thrombosis, the age and FIGO stage of thrombosis-positive patients were significantly higher than those of thrombosis-negative patients in PCC and POC, while in SPC patients there was no such difference. In conclusion, this study demonstrated the differences in clinical features between SPC and PCC, and also novel features of SPC, namely endometriosis and thrombosis, which are essential in the management of this disease.
[show abstract][hide abstract] ABSTRACT: Bone morphogenetic proteins (BMPs) are involved in patterning and cellular fate in various organs including the thymus. However, the redundancy of BMPs and their receptors have made it difficult to analyse their physiological roles. Here, we investigated the role of BMP signalling in peripheral CD4(+) T cells by analysing the effects of an inhibitor of BMP signalling, dorsomorphin. Dorsomorphin suppressed phosphorylation of SMAD1/5/8, suggesting that BMP signalling naturally occurs in T cells. At high doses, dorsomorphin suppressed proliferation of T cells in a dose-dependent manner, inducing G1 arrest. Also, dorsomorphin suppressed Th17 and induced Treg-cell differentiation, while preserving Th2 differentiation. Dorsomorphin efficiently suppressed IL-2 production even at low doses in mouse CD4(+) T cells, suggesting that the BMP-Smad signalling physiologically regulates IL-2 transcription in these cells. In addition, recombinant BMP2 induced a dose-dependent multiphasic pattern of IL-2 production, while Noggin suppressed IL-2 production at higher doses in Jurkat cells. Notably, BMP signalling controlled the phosphorylation of RUNX1, revealing the molecular nature of its effect. Collectively, we describe multiple effects of dorsomorphin and Noggin on T-cell activation and differentiation, demonstrating a physiological role for BMP signalling in these processes.
European Journal of Immunology 12/2011; 42(3):749-59. · 4.97 Impact Factor
[show abstract][hide abstract] ABSTRACT: The aim of this study was to evaluate the local immune status of human ovarian cancers by the comprehensive analysis of tumor-infiltrating immune cells and immunosuppressive factors, and to elucidate the local immunity in clinical course. The numbers of CD1α+, CD4+, CD8+, CD57+, forkhead box P3+ and programmed cell death-1+ cells were counted, and the intensity of immunosuppressive factors, such as programmed cell death-1 ligand (PD-L)1, PD-L2, cyclooxygenase (COX)-1, COX-2 and transforming growth factor β1, were evaluated in 70 ovarian cancer specimens stained by immunohistochemistry. Then hierarchical clustering of these parameters showed the four clusters into ovarian cancer cases. Cluster 1, which had significantly better prognosis than the others, was characterized by high infiltration of CD4+ and CD8+ cells. In conclusion the comprehensive analysis of local immune status led to subdivide ovarian cancers into groups with better or worse prognoses and may guide precise understanding of the local immunity.
[show abstract][hide abstract] ABSTRACT: Invasion into deep myometrium and/or lymphovascular space is a well-known risk factor for endometrial cancer metastasis, resulting in poor prognosis. It is therefore clinically important to identify novel molecules that suppress tumor invasion. Reduced expression of the metastasis suppressor, kisspeptin (KISS1), and its endogenous receptor, GPR54, has been reported in several cancers, but the significance of the KISS1/GPR54 axis in endometrial cancer metastasis has not been clarified. Metastin-10 is the minimal bioactive sequence of genetic products of KISS1. Clinicopathological analysis of 92 endometrial cancers revealed overall survival is improved in cancers with high expression of GPR54 (P < 0.05) and that GPR54 expression is associated with known prognostic factors including FIGO stage, grade, and deep myometrial invasion. Through RNAi and microarray analyses, metastin-10 was predicted to suppress metastasis of GPR54-expressing endometrial cancers in vivo. Methylation analysis revealed GPR54 is epigenetically regulated. Metastin-GPR54 axis function was restored following treatment with the DNA hypomethylating agent 5-aza-DC. These data suggest that metastin-10 may be effective at inhibiting the metastatic spread of endometrial cancers in combination with demethylating agents to induce GPR54 expression.
Molecular Cancer Therapeutics 01/2011; 10(4):580-90. · 5.60 Impact Factor
[show abstract][hide abstract] ABSTRACT: Ovarian cancer is the leading cause of death among gynecological malignancies. Chemotherapy alone is not sufficient to achieve long-term survival of the patient with advanced stage ovarian cancer. Although cancer immune therapy has long been expected as a new modality for ovarian cancer, very few trials have been clinically successful. One of the reasons for the failure in practical immune therapy is the immune-suppressive cancer microenvironment. We have reported that immune-suppressive molecules including PD-L1, Cox or ULBP-2 are expressed in human ovarian cancer, and they suppress local tumor immunity by disturbing CD8+T cell infiltration. Thus, we attempted to develop an immune therapy that can target multiple metastatic foci and increase CD8+T cell infiltration by altering local tumor environment. Endothelial progenitor cells (EPC) were transduced with the chemokine CCL19. When injected intravenously, this "immune-stimulatory EPC" was incorporated efficiently into local tumor vessels, and exerted an anti-tumor effect in a subcutaneous tumor model, a lung metastasis model and a peritoneal dissemination model. The anti-tumor effect was not observed when immunodeficient mice were used for the experiment, suggesting that the effect is mediated by immune cells. These results suggest that EPC are ideal carriers with which to deliver immune-stimulatory signals to multiple remote metastases. Alteration of local immune environment by this method may be used in the future for individualized cancer immune therapy.
[show abstract][hide abstract] ABSTRACT: FoxP3 is a key transcription factor for the development and function of natural CD4(+) regulatory T cells (Treg cells). Here we show that human FoxP3(+)CD4(+) T cells were composed of three phenotypically and functionally distinct subpopulations: CD45RA(+)FoxP3(lo) resting Treg cells (rTreg cells) and CD45RA(-)FoxP3(hi) activated Treg cells (aTreg cells), both of which were suppressive in vitro, and cytokine-secreting CD45RA(-)FoxP3(lo) nonsuppressive T cells. The proportion of the three subpopulations differed between cord blood, aged individuals, and patients with immunological diseases. Terminally differentiated aTreg cells rapidly died whereas rTreg cells proliferated and converted into aTreg cells in vitro and in vivo. This was shown by the transfer of rTreg cells into NOD-scid-common gamma-chain-deficient mice and by TCR sequence-based T cell clonotype tracing in peripheral blood in a normal individual. Taken together, the dissection of FoxP3(+) cells into subsets enables one to analyze Treg cell differentiation dynamics and interactions in normal and disease states, and to control immune responses through manipulating particular FoxP3(+) subpopulations.
[show abstract][hide abstract] ABSTRACT: In the clinical management of endometriotic cyst, three major clinical disruptions need to be addressed adequately: pain, infertility, and malignant transformation. Symptoms differ according to the patient’s age and her life stage, and they should be managed individually. This review discusses the role of medical treatment with currently available drug regimens as well as surgical interventions for endometriotic cyst in terms of each symptom. Endometriosis-associated ovarian cancer is an important issue in the management of endometriosis in relatively elderly women, although it is not yet widely recognized. The need for standard management of these patients is also discussed.