Tadahiro Shoji

Clinical outcome and risk factors for recurrence in borderline ovarian tumours

We investigated the long-term prognosis of borderline ovarian tumours and determined risk factors for recurrence. One hundred and twenty-one borderline ovarian tumours treated between 1994 and 2003 at the participating institutions in the Tohoku Gynecologic Cancer Unit were retrospectively investigated for clinical stage, histopathological subtype, surgical technique, postoperative chemotherapy, the presence or absence of recurrence, and prognosis. The median follow-up period was 57 months (1–126 months). One hundred and nine cases (90.6%) were at clinical stage I. The histopathological subtypes consisted of 91 cases of mucinous tumour (75.2%), 27 cases of serous tumour (22.3%), and three cases of endometrioid tumour. Conservative surgery was used in 53 cases (43.8%), radical surgery in 68 cases (56.2%), a staging laparotomy in 43 cases (35.5%), and postoperative adjuvant therapy in 30 cases (24.8%). Recurrence was found in eight cases, but no tumour-related deaths were reported. Although no significant difference in disease-free survival rate was seen between different clinical stages, the difference in disease-free survival rate between serous and nonserous (mucinous and endometrioid) types was significant (P<0.05). The 10-year disease-free survival rate was 89.1% for the radical surgery group and 57.4% for the conservative surgery group – this difference was significant (P<0.05). In the conservative surgery group, cystectomy and serous tumour were independent risk factors for recurrence. Although recurrence was observed, the long-term prognosis of borderline ovarian tumour was favourable, without tumour-related deaths. Considering the favourable prognosis, conservative surgery can be chosen as far as the patient has a nonserous tumour and receive adnexectomy. However, in cases of serous type and/or receiving cystectomy special care should be given as relative risk rates of recurrence elevate by 2–4-folds.

Phase II clinical study of the combination chemotherapy regimen of irinotecan plus oral etoposide for the treatment of recurrent ovarian cancer (Tohoku Gynecologic Cancer Unit 101 Group Study).

Objective: To evaluate the efficacy and safety of the combination chemotherapy regimen of irinotecan plus oral etoposide for the treatment of patients with recurrent ovarian cancer after previous treatment with platinum and taxane agents. Patients and Methods: A total of 42 patients with recurrent ovarian cancer who had an evaluable lesion and provided informed consent for participation in the present study were analyzed. Irinotecan was administered intravenously at a dose of 60 mg/m2 on days 1 and 15. Etoposide was administered orally at a daily dose of 50 mg/body weight from days 1 to 21. A 28-day period comprised one cycle. The tumor response, adverse events, progression-free survival, and overall survival were examined. Tumor response was evaluated based on the Response Evaluation Criteria in Solid Tumors and the serum CA125 levels (Gynecologic Cancer Intergroup criteria). Adverse events were assessed according to the NCI-CTCAE (version 3.0). Results: Partial response was observed in 21 patients, stable disease in 14 patients, and progressive disease in 7 patients. The response rate was 50.0%, and the clinical benefit (partial response + stable disease) rate was 83.3%. Hematological toxicities of at least grade 3 severity included leukopenia in 21 patients (50.0%), neutropenia in 22 patients (52.4%), thrombocytopenia in 1 patient (2.4%), anemia in 9 patients (21.4%), and febrile neutropenia in 3 patients (7.1%). Nonhematological toxicities of at least grade 3 severity included queasy feeling in 5 patients (11.9%), vomiting in 3 patients (7.1%), and diarrhea in 2 patients (4.8%). Acute myeloid leukemia occurred in one patient (2.4%). Conclusions: It is suggested that combination chemotherapy with irinotecan plus oral etoposide offers significant clinical benefit to patients with recurrent ovarian cancer previously treated with platinum and taxane agents.

Pazopanib Maintenance Therapy in East Asian Women With Advanced Epithelial Ovarian Cancer: Results From AGO-OVAR16 and an East Asian Study.

Objective The recent phase 3 trial AGO-OVAR16 demonstrated that pazopanib maintenance improved median progression-free survival in patients with ovarian cancer whose disease did not progress during first-line treatment. However, this improvement was not seen in the subset of East Asian patients. The current analysis evaluated the efficacy and safety of pazopanib maintenance in East Asian patients from AGO-OVAR16 and a separate East Asian study. Materials and Methods East Asian patients from AGO-OVAR16 (n = 209) and the East Asian study (N = 145) were randomized 1:1 to receive pazopanib 800 mg/d or placebo for up to 24 months. The primary end point for each study was progression-free survival by RECIST (Response Evaluation Criteria in Solid Tumors) based on investigator assessment. Clinical and genetics data were analyzed separately by study or pooled according to separate predetermined statistical plans. Results Pazopanib maintenance had a detrimental effect on median progression-free survival versus placebo in East Asian patients from the combined studies (n = 354; 17.9 vs 21.5 months; hazard ratio, 1.114; 95% confidence interval, 0.818–1.518; P = 0.4928). Pazopanib maintenance showed a disadvantage in overall survival in East Asian patients from AGO-OVAR16 versus placebo (hazard ratio, 1.706; 95% confidence interval, 1.010–2.883; P = 0.0465); overall survival analysis was not performed in the East Asian study because of insufficient event numbers. Pazopanib-treated patients had a significantly higher incidence of grade 3 or higher hypertension (27%) and neutropenia (13%) versus placebo. Conclusions The treatment effect of maintenance pazopanib in East Asian patients seemed to differ from that in non-Asian patients. In study-specific and pooled analyses, none of the potential factors analyzed could satisfactorily explain the different efficacy results of pazopanib in East Asian patients.

Tako-Tsubo Cardiomyopathy Caused Immediately following Cesarean Section Delivery of Triplets: A Case Report

The name ‘tako-tsubo’ cardiomyopathy was initially used to describe a unique ‘short-neck round-flask’-shaped form of left ventricular apical ballooning, resembling a Japanese tako-tsubo, a jar (tsubo) used for capturing octopus (tako). Tako-tsubo cardiomyopathy exhibits acute onset, transient left ventricular apical wall motion abnormalities with chest symptoms and minimal myocardial enzymatic release, mimicking acute myocardial infarction in patients without angiographic stenosis on coronary angiography. There have been few case reports on tako-tsubo cardiomyopathy, and this disorder is especially rare in pregnant women. A 30-year-old woman who was pregnant with triplets, and had been treated with ritodrine hydrochloride for 12 weeks for threatened premature delivery, underwent cesarean section with spinal anesthesia at 30 weeks’ gestation. Three hours later, she complained of acute chest pain, dyspnea and episodes of unconsciousness. She was transferred to the intensive care unit and intubated for ventilatory support. We diagnosed heart failure due to tako-tsubo cardiomyopathy based on heart ultrasonography, blood tests, chest X-ray, electrocardiogram and myocardial scintigraphy. She was extubated from the ventilator after 3 days of catecholamine, furosemide and carperitide administration. She was discharged from the hospital on day 53 without symptoms.

Comparative Cytogenetic Studies of Benign, Borderline, and Malignant Epithelial Ovarian Tumors

Comparative cytogenetic studies were performed in 40 cases of untreated epithelial ovarian tumors. Of these 40 tumors, 13 were classified as benign, 3 as borderline, and 24 as malignant, according to the WHO classification for ovarian tumors. Of 13 benign ovarian tumors, 4 (30.8%) showed chromosomal abnormalities. Of 4 ovarian tumors, 3 (75%) had single chromosomal abnormalities, and the remaining tumor (25%) retained multiple chromosomal abnormalities.

Case of peptide‐YY‐producing strumal carcinoid of the ovary: A case report and review

Ovarian carcinoid is a rare tumor accounting for approximately 0.1% of all ovarian malignancies. We describe a case of peptide‐YY‐producing strumal carcinoid of the ovary associated with severe constipation. A 48‐year‐old woman was found to have a pelvic mass on ultrasonography when she visited her primary doctor for a health check‐up. She was thus referred to our department. Magnetic resonance imaging revealed a solid right ovarian tumor 60 × 50 mm in size. The patient underwent a right adnexectomy and was histopathologically diagnosed as having strumal carcinoid of the ovary. On immunohistochemical examination, the tumor cells were positive for peptide YY. The patients constipation resolved rapidly after surgery. Based on her clinical course, her constipation was considered to have been caused by the strumal carcinoid of the ovary. The clinical course of this case supports the previously recognized correlation between peptide‐YY‐producing ovarian carcinoid and constipation.

Triple simultaneous primary invasive gynecological malignancies: a case report.

Double gynecologic cancer (primary cancers in two organs) is relatively rare. However, triple gynecologic cancer (primary cancers in three organs) is extremely rare. We experienced a case of triple cancer, with primary cervical, endometrial and ovarian cancers, each showing different histopathological features. A 50‐year‐old woman with a preoperative diagnosis of cervical cancer stage Ib1 with a pathological diagnosis of mucinous adenocarcinoma underwent radical hysterectomy. The pathological diagnoses of the extracted masses were endometrioid adenocarcinoma in the uterine corpus and serous adenocarcinoma in the left ovary. Consequently, triple cancer was diagnosed. After the operation, six cycles of a paclitaxel/carboplatin regimen were administered, and no relapse of the cancers has been observed to date. To our knowledge, this is only the second case report in the international literature of concurrent gynecologic triple cancers of epithelial origin; that is, invasive cervical, endometrial and ovarian cancers, each with different histopathological features.

Chemoradiotherapy with irinotecan (CPT-11) for adenoid cystic carcinoma of Bartholin's gland: A case report and review of the literature

► Adenoid cystic carcinoma of Bartholins gland is extremely rare, and only 80 cases have been reported in the international literature. ► We have presented a case in which a favorable outcome was achieved by chemoradiotherapy with CPT-11. ► This is the first report, to our knowledge, on chemoradiotherapy with CPT-11 for adenoid cystic carcinoma of Bartholins gland.

Does severe anemia caused by dose-dense paclitaxel-carboplatin combination therapy have an effect on the survival of patients with epithelial ovarian cancer? Retrospective analysis of the Japanese gynecologic oncology group 3016 trial

Introduction To evaluate the incidence of anemia in patients with epithelial ovarian cancer receiving paclitaxel-carboplatin combination therapy (TC) using data from the Japanese Gynecologic Oncology Group (JGOG) 3016 trial, and to examine the effect of severe anemia on survival during dose-dense TC. Methods Retrospective analysis was conducted in patients enrolled in the JGOG 3016 trial who underwent at least one cycle of the protocol therapy (n = 622). Hemoglobin values at enrollment and during each cycle of TC were collected. One-to-one matching was performed between patients with and patients without grade 3/4 anemia during TC (anemia and nonanemia groups) to adjust the baseline characteristics of the patients. The cumulative survival curve and median progression-free survival were estimated using the Kaplan-Meier method. Results Grades 2 to 4 anemia was observed in 19.8% of patients before first-line TC. The incidence of grade 3/4 anemia rapidly increased to 56.1% after the fourth cycle of dose-dense TC. After matching, the median progression-free survival in the anemia (hemoglobin <8.0 g/dL) and nonanemia (hemoglobin >8.0 g/dL) groups was 777 and 1100 days, respectively (P = 0.3493) for patients receiving dose-dense TC. The median progression-free survival in patients receiving conventional TC was similar between the 2 groups. Conclusions The difference in progression-free survival between patients with epithelial ovarian cancer with and those without severe anemia during TC was not statistically significant, but for patients receiving dose-dense TC, severe anemia seems to have prognostic relevance. Prospective trials are needed to investigate whether the optimal management of chemotherapy-induced anemia, including appropriate use of erythropoiesis-stimulating agents, would further improve the survival of patients with ovarian cancer receiving dose-dense TC.

Fibroblast growth factor receptor 2 is associated with poor overall survival in clear cell carcinoma of the ovary and may be a novel therapeutic approach.

Objective We previously found that gene and protein expression of fibroblast growth factor receptor (FGFR) 2 were increased in ovarian clear cell carcinoma (CCC); here, we examined FGFR2 expression in CCC tumor tissues and its correlation with clinical parameters. We also analyzed the effect of an FGFR inhibitor on the growth of CCC cells to investigate whether FGFR2 could be a therapeutic target for this disease. Methods We analyze the protein expression of FGFR2 by immunohistochemical staining in CCC from 112 patients and evaluated the association of these molecular parameters with clinical outcome. We treated the 11 CCC cell lines with an FGFR inhibitor, and then assessed cell viability, the expression of protein in FGFR2 signaling pathway, and cell cycle distribution. Results The expressions of FGFR2 were found in 96% of CCC. The 5-year survival rate for patients with a moderate or strong expression of FGFR2 was significantly lower than that for those with an absent or poor expression of FGFR2 (54% vs 79%). Multivariable analysis revealed that FGFR2 expression and disease stage were independent prognostic factors. The FGFR inhibitor effectively suppressed the growth of CCC cells with induction of G1 cell cycle arrest and down-regulated the expression of phosphorylated Akt and phosphorylated ERK. Conclusions FGFR2 is an important biomarker predictive of patient outcome and is a potential target for CCC. Further study is warranted for FGFR inhibitor to treat CCC.