Shizuo Machida

Inhibition of peritoneal dissemination of ovarian cancer by tyrosine kinase receptor inhibitor SU6668 (TSU‐68)

SU6668 (TSU‐68) is a small‐molecule synthetic inhibitor of the angiogenic related receptor tyrosine kinases Flk‐1/KDR, PDGFRβ, and FGFR1. Using a mouse model of peritoneally disseminated ovarian cancer, we investigated whether SU6668 inhibits peritoneal dissemination and prolongs survival time. BALB/c nude mice were intraperitoneally (i.p.) inoculated with SHIN‐3 (VEGF‐hypersecretory) or KOC‐2S (PDGF‐hypersecretory) ovarian serous adenocarcinoma cells with marked peritoneal dissemination ability. From the day after i.p. inoculation of tumor cells, SU6668 was orally administered 6 times weekly at a daily dose of 100 mg/kg or 400 mg/kg. The SU6668‐administered group and the vehicle‐administered control group were compared for the number of tumor vascular endothelial cells, weight of peritoneally disseminated tumors, amount of ascitic fluid and survival time. As a result, these 3 parameters were significantly smaller in the SHIN‐3‐inoculated, SU6668‐administered mice than in the control group (p = 0.03, p = 0.002, and p = 0.02, respectively). The mean survival time was significantly longer, at 58.1 ± 11.2 days, in the SU6668‐administered mice than that (34.5 ± 8.8 days) in the control group (p = 0.002). Similarly, in the KOC‐2S‐inoculated mice, the oral administration of SU6668 significantly reduced these 3 parameters (p = 0.04, p = 0.04, and p = 0.03, respectively), and significantly prolonged survival (16.6 ± 1.7 days vs. 11.0 ± 0.7 days, p = 0.008). Thus, the oral administration of SU6668 inhibited angiogenesis and peritoneal dissemination and prolonged survival in mice with peritoneally disseminated ovarian cancer. These effects were observed with both the VEGF‐ and PDGF‐hypersecretory cell lines. Our results suggest that molecular targeting with oral SU6668 will become a new therapeutic strategy targeting peritoneally disseminated ovarian cancer.

In vivo delivery of siRNA targeting vasohibin-2 decreases tumor angiogenesis and suppresses tumor growth in ovarian cancer

Vasohibin‐2 (VASH2) is a homolog of vasohibin‐1 and exhibits pro‐angiogenic activity. We recently reported that VASH2 is expressed in certain ovarian cancers and promotes tumor growth through angiogenesis. To further demonstrate the effectiveness of molecular targeting of VASH2 for anticancer treatment, we applied in vivo delivery of siRNA targeting VASH2 (siVASH2) using atelocollagen to a xenograft model of ovarian cancer. We inoculated mice s.c. with DISS and SKOV‐3, two representative human ovarian serous adenocarcinoma cell lines. When tumors were measurable, we initiated treatment with control or siVASH2 mixed with atelocollagen, which enveloped the whole tumor. Treatment with siVASH2 significantly inhibited s.c. tumor growth by abrogating tumor angiogenesis. We confirmed that expression of VASH2 mRNA in the tumor was downregulated by siVASH2 treatment. In addition, the siVASH2‐treated tumor contained more blood vessels covered with pericytes, indicating that knockdown of VASH2 contributes to the normalization of tumor blood vessels. Based on these results, VASH2 may be a promising molecular target for ovarian cancer treatment.

Decidualization of Ovarian Endometriosis during Pregnancy Mimicking Malignancy : Report of Three Cases with a Literature Review

Background: Intracystic papillary excrescence is a characteristic morphological feature of ovarian malignancy. A few recent reports have demonstrated that ovarian endometriotic cysts, undergoing decidualization during pregnancy, occasionally show excrescence, necessitating surgery during pregnancy; however, this phenomenon is not well recognized among clinicians. Cases: Three pregnant women with decidualized ovarian endometriosis showed excrescence. Both ultrasound and magnetic resonance imaging (MRI) preoperatively suggested the presence of underlying ovarian endometriotic cysts in 2 women, but not in the other. Intracystic papillary excrescence prompted us to perform laparotomy at 14, 14, and 19 weeks of pregnancy, respectively, with 1 woman aborting in the 21st week, and with 2 delivering healthy term infants. Histological examination confirmed the diagnosis of decidualized ovarian endometriotic cysts in all 3 patients. Conclusions: We provide the first report of pregnant women in whom excrescence occurred from ovarian endometriotic cysts without preoperative evidence. Decidualized ovarian endometriosis, even without preoperative morphological features of endometriosis, should be added to the differential diagnosis of ovarian malignancy during pregnancy.

Indoleamine-2,3-dioxygenase, an immunosuppressive enzyme that inhibits natural killer cell function, as a useful target for ovarian cancer therapy

This study examined the role of the immunosuppressive enzyme indoleamine-2,3-dioxygenase (IDO) in ovarian cancer progression, and the possible application of this enzyme as a target for ovarian cancer therapy. We transfected a short hairpin RNA vector targeting IDO into the human ovarian cancer cell line SKOV-3, that constitutively expresses IDO and established an IDO downregulated cell line (SKOV-3/shIDO) to determine whether inhibition of IDO mediates the progression of ovarian cancer. IDO downregulation suppressed tumor growth and peritoneal dissemination in vivo, without influencing cancer cell growth. Moreover, IDO downregulation enhanced the sensitivity of cancer cells to natural killer (NK) cells in vitro, and promoted NK cell accumulation in the tumor stroma in vivo. These findings indicate that downregulation of IDO controls ovarian cancer progression by activating NK cells, suggesting IDO targeting as a potential therapy for ovarian cancer.

Downregulation of indoleamine-2,3-dioxygenase in cervical cancer cells suppresses tumor growth by promoting natural killer cell accumulation

This study examined the role of the immunosuppressive enzyme indoleamine-2,3-dioxygenase (IDO) in cervical cancer progression and the possible use of this enzyme for cervical cancer therapy. We analyzed IDO protein expression in 9 cervical cancer cell lines (SKG-I, -II, -IIIa, -IIIb, SiHa, CaSki, BOKU, HCS-2 and ME-180) stimulated with interferon-γ. IDO expression was observed in all cell lines except for SKG-IIIb. We transfected the human cervical cancer cell line CaSki that constitutively expresses IDO with a short hairpin RNA vector targeting IDO, and established an IDO-downregulated cell line to determine whether inhibition of IDO mediates cervical cancer progression. IDO downregulation suppressed tumor growth in vivo, without influencing cancer cell growth in vitro. Moreover, IDO downregulation enhanced the sensitivity of cervical cancer cells to natural killer (NK) cells in vitro and promoted NK cell accumulation in the tumor stroma in vivo. These findings indicate that downregulation of IDO controls cervical cancer progression by activating NK cells, suggesting IDO as a potential therapy for cervical cancer.

Phase I Study of Combination Chemotherapy Using Irinotecan Hydrochloride and Nedaplatin for Advanced or Recurrent Cervical Cancer

Objective: We performed a phase I clinical study to evaluate combination chemotherapy with irinotecan hydrochloride (CPT-11) and nedaplatin (CPT-11/nedaplatin) for cervical cancer. Methods: This study included patients with primary or recurrent cervical cancer. The regimen for CPT-11/nedaplatin therapy consisted of CPT-11 administered 3 times over 2 weeks (days 1, 8 and 15) and nedaplatin infused intravenously as a single dose (day 1). This course was repeated at 4-week intervals. The step 1 doses of the two agents were 50 mg/m2, respectively. Dose escalation was performed in tandem. Plasma CPT-11, SN-38, total platinum, and filterable platinum levels were measured. Results: In step 3 (CPT-11, 60 mg/m2; nedaplatin, 60 mg/m2), dose-limiting toxicity was observed in 2 of 3 patients. The step 3 doses were regarded as the maximum tolerated doses. The incidences of grade 3/4 adverse events in the first courses (n = 12) [and all courses (n = 45)] were: leukopenia 33% (22%), neutropenia 42% (31%), anemia 17% (20%), nausea 8% (7%), and diarrhea 8% (7%). Following CPT-11 administration, the mean areas under the curve (AUC; ng·h/ml) of SN-38 were 0.11 at 50 mg/m2 and 0.17 at 60 mg/m2. Following nedaplatin administration, the mean AUCs (µg·h/ml) of filterable platinum were 6.0 at 50 mg/m2, and 6.0 at 60 mg/m2. The response rate was 50% (2 complete responses and 2 partial responses). Conclusion: The recommended doses of CPT-11 and nedaplatin for a phase II clinical study were established as 50 and 60 mg/m2, respectively.

Radiation Therapy for Chemotherapy-Resistant Recurrent Epithelial Ovarian Cancer

Objectives: While radiation therapy is administered as a palliative treatment for recurrent ovarian cancer, it remains unclear whether it improves the prognosis. Methods: The effects and adverse events of radiation therapy for patients with recurrent epithelial ovarian cancer were investigated using medical records. Results: Herein, 46 subjects comprising 33 patients whose recurrent lesions were contained within the irradiation field (therapeutic radiation group; TRG) and 13 patients with some recurrent lesions outside the irradiation field (palliative radiation group; PRG) were included. The TRG achieved a response rate (RR) of 66%, a disease control rate (DCR) of 100%, a progression-free survival (PFS) of 10 months, and an overall survival (OS) of 20 months. The PFS after radiation therapy was significantly longer than that following chemotherapy received just before radiation therapy. The PFS of patients with recurrent intrapelvic lesions was longer than that of patients with some extrapelvic recurrence. There was no significant association between PFS after radiation therapy and the duration from the previous chemotherapy or histological type. The RR, DCR, PFS, and OS of the PRG were 30 and 90% and 2 and 6 months, respectively. Serious adverse events were rare. Conclusions: Radiation therapy is a potential option for chemotherapy-resistant, localized recurrent ovarian cancer.

Frequency and characteristics of endometrial carcinoma and atypical hyperplasia detected on routine infertility investigations in young women: a report of six cases

Infertility patients are known to be at increased risk of endometrial carcinoma (EC) and atypical hyperplasia (AH). However, the incidence and clinical features of EC and AH in these patients remain to be clarified. In this study, we examined the rate at which a routine infertility workup revealed EC/AH and investigated the clinicopathological features of EC/AH detected in this way. Among patients diagnosed with EC or AH at the Jichi Medical University Hospital between the 10-year period from 1997 to 2006, six patients were referred from Tochigi Central Clinic, a specialized infertility facility. We report the clinicopathological features of these patients and calculate the incidence of EC/AH in patients who underwent infertility investigations at Tochigi Central Clinic. All six patients were younger than 40 and had early stage disease (final diagnosis: EC stage IA: 3, EC stage IB: 1, AH: 2). A total of 19 826 patients underwent routine infertility investigations at Tochigi Central Clinic during the same period. The incidence of EC/AH detected from these investigations was 0.03% (6/19 826) and that of EC was 0.02% (4/19 826): 5-10 times higher than the overall incidence in Japanese women of the same age. Routine infertility investigations may provide an opportunity to examine the corpus uteri of young women in whom examination is otherwise limited, contributing to the early detection of EC/AH.

Influences of uterine adenomyosis on muscle invasion and prognosis of endometrioid adenocarcinoma.

Objective Endometrial cancer often coexists with uterine adenomyosis. However, little is known about the clinical characteristics of these cases. Thus, cases of endometrial cancer occurring with and without uterine adenomyosis were compared, and the influences of uterine adenomyosis on the clinical progress of endometrial cancer were examined. Materials and Methods Of endometrial cancer patients who underwent hysterectomies in our facility from 2002 to 2011, we included only endometrioid adenocarcinoma patients in our study. The patients were divided into 2 groups, adenomyosis group and nonadenomyosis group, according to the presence/absence of uterine adenomyosis. Patient characteristics, stage, histopathological grade, muscle invasion, recurrence, and mortality were retrospectively compared and examined. Results There were 362 cases of endometrioid adenocarcinoma of the uterine body, of which 121 (33.4%) and 241 cases (66.6%) were in the adenomyosis and nonadenomyosis group, respectively. There were no significant differences with respect to the disease stages or ratios of the histopathological grade between the 2 groups. In the adenomyosis group/nonadenomyosis group, 5-year progression-free survival for International Federation of Gynecology and Obstetrics (FIGO) stages I and II was 89.9%/93.7% and that for stages III and IV was 70.6%/62.0%; the 5-year overall survival was 100%/95.9% for FIGO stages I and II, and 88.0%/73.5% for stages III and IV. There were no significant between-group differences for either progression-free survival or overall survival. When limiting the results to only FIGO stage I endometrioid adenocarcinoma, despite no grade variance between the 2 groups, a significant difference was observed in the ratios of outer-half muscle invasion between the adenomyosis and nonadenomyosis groups (19.5% [17/87] vs 10.1% [16/158], P < 0.05); however, the prognosis was similar in the 2 groups. Conclusions Uterine adenomyosis is associated with deep myometrial invasion in stage I endometrioid adenocarcinoma; however, it did not affect the recurrence or mortality rates.

Abnormal fragile histidine triad expression in advanced cervical cancer and evaluation of its utility as a prognostic factor.

Objective: The relationship between the abnormal expression of fragile histidine triad (FHIT) and the prognosis in advanced cervical cancer was investigated, focusing on the relation with radiosensitivity. Methods: A retrospective study was performed in 54 patients with stage IIIb cervical squamous cell carcinoma who received radiation therapy as the initial treatment. Formalin-fixed paraffin-embedded tissues were immunohistochemically stained using anti-FHIT antibody. The survival curve for patients with abnormal FHIT expression (low expression) was prepared and the prognosis was compared with that for the normal expression group. The decrease rate of the serum squamous cell carcinoma antigen (SCC) levels (SCC index = SCC level after radiotherapy/SCC level before radiotherapy) was calculated. Results: Abnormal FHIT expression was observed in 25 patients (46%). There were no significant differences in clinical backgrounds between the abnormal and normal FHIT expression groups. The 5-year survival rate was 72% in the abnormal expression group, showing no significant difference from that in the normal expression group (64%). The SCC indices were 0.21 ± 0.14 and 0.29 ± 0.19 in the abnormal and normal expression groups, respectively, showing no significant difference between the two groups. Conclusions: Abnormal FHIT expression was not correlated with radiosensitivity in patients with stage IIIb cervical cancer, showing that abnormal FHIT expression cannot be used as a prognostic factor.