Sadako Nishimura

Outcomes of fertility-sparing surgery for stage I epithelial ovarian cancer: a proposal for patient selection.

PURPOSE The objective of this study was to assess clinical outcomes and fertility in patients treated conservatively for unilateral stage I invasive epithelial ovarian cancer (EOC). PATIENTS AND METHODS A multi-institutional retrospective investigation was undertaken to identify patients with unilateral stage I EOC treated with fertility-sparing surgery. Favorable histology was defined as grade 1 or grade 2 adenocarcinoma, excluding clear cell histology. RESULTS A total of 211 patients (stage IA, n = 126; stage IC, n = 85) were identified from 30 institutions. Median duration of follow-up was 78 months. Five-year overall survival and recurrence-free survival were 100% [corrected] and 97.8% for stage IA and favorable histology (n = 108), 100% and 100% for stage IA and clear cell histology (n = 15), 100% and 33.3% for stage IA and grade 3 (n = 3), 96.9% and 92.1% for stage IC and favorable histology (n = 67), 93.3% and 66.0% for stage IC and clear cell histology (n = 15), and 66.7% and 66.7% for stage IC and grade 3 (n = 3). Forty-five (53.6%) of 84 patients who were nulliparous at fertility-sparing surgery and married at the time of investigation gave birth to 56 healthy children. CONCLUSION Our data confirm that fertility-sparing surgery is a safe treatment for stage IA patients with favorable histology and suggest that stage IA patients with clear cell histology and stage IC patients with favorable histology can be candidates for fertility-sparing surgery followed by adjuvant chemotherapy.

Paclitaxel Plus Carboplatin Versus Paclitaxel Plus Cisplatin in Metastatic or Recurrent Cervical Cancer: The Open-Label Randomized Phase III Trial JCOG0505

PURPOSE In metastatic or recurrent cervical cancer, cisplatin-based chemotherapy is standard. The JCOG0505 randomized phase III trial evaluated the clinical benefits of carboplatin-based regimen. PATIENTS AND METHODS Eligible patients had metastatic or recurrent cervical cancer and had ≤ one platinum-containing treatment and no prior taxane. Patients were randomly assigned either to conventional paclitaxel plus cisplatin (TP; paclitaxel 135 mg/m(2) over 24 hours on day 1 and cisplatin 50 mg/m(2) on day 2, repeated every 3 weeks) or paclitaxel plus carboplatin (TC; paclitaxel 175 mg/m(2) over 3 hours and carboplatin area under curve 5 mg/mL/min on day 1, repeated every 3 weeks). Primary end point was overall survival (OS). Planned sample size was 250 patients to confirm the noninferiority of TC versus TP with the threshold hazard ratio (HR) of 1.29. RESULTS Between February 2006 and November 2009, 253 patients were enrolled. The HR of OS was 0.994 (90% CI, 0.79 to 1.25; noninferiority P = .032 by stratified Cox regression). Median OS was 18.3 months with TP versus 17.5 months with TC. Among patients who had not received prior cisplatin, OS was shorter with TC (13.0 v 23.2 months; HR, 1.571; 95% CI, 1.06 to 2.32). One treatment-related death occurred with TC. Proportion of nonhospitalization periods was significantly longer with TC (P < .001). CONCLUSION TC was noninferior to TP and should be a standard treatment option for metastatic or recurrent cervical cancer. However, cisplatin is still the key drug for patients who have not received platinum agents.

Photodynamic Therapy for Cervical Intraepithelial Neoplasia

Objectives: Photodynamic therapy (PDT) is a minimally invasive treatment for cervical intraepithelial neoplasia (CIN). We report the effectiveness of PDT in 105 cases of CIN. Methods: All patients received photofrin (PHE) 2 mg/kg intravenously and, 48–60 h later, phototherapy was performed using the Excimer dye laser or a YAG-OPO laser with an irradiation dose of 100 J/cm2 using 630 nm wavelength. Results: Mild photosensitivity occurred in 48% (50/105) of patients. The complete response (CR) rate was 90% (94/105) at 3 months following treatment. In the remaining 11 patients, 5 patients had CIN1, 2 patients had CIN2, and 4 patients had mild cytologic findings. However, in 9 of these 11 patients, CR was achieved 6 months after PDT. In 69 patients, human papilloma virus (HPV) typing was performed before and after PDT therapy. Pre-treatment, 64 of 69 patients (93%), were HPV-positive including 30 cases of high-risk HPV (43%). Testing performed 3, 6 and 12 months following PDT revealed no HPV-DNA in 75% (52/69), 74% (48/65) and 72% (41/57) of patients. At present, the median follow-up period is 636 days (90–2,232 days). In 3 patients, recurrence requiring surgical treatment was identified at 646, 717 and 895 days after PDT. Conclusions: PDT is an effective and minimally invasive treatment for CIN, which also appears to eradicate HPV infection.

The urinary incontinence score in the diagnosis of female urinary incontinence.

Objective: Our purpose was to determine whether the urinary incontinence (UI) score is significantly useful in evaluating the clinical status of UI. Method: The questionnaire was administered to 198 UI patients (27–73 years of age) diagnosed by conventional procedures. It consisted of 15 questions, and the answers were assigned points divided into a stress score (s‐s) and urge score (u‐s) according to severity. Results: The patients were classified into a stress incontinence group (SI; 125 cases), urge incontinence group (URI; 29 cases), mixed incontinence group (MI; 41 cases), and overflow incontinence group (3 cases). Classification by questionnaire yielded 110 SI cases, 31 URI cases, and 46 MI cases, accuracy of 83.2%, 86.2%, and 61.0%, respectively. A significant correlation was observed with s‐s of SI (r=0.669, P<0.001) and u‐s of URI (r=0.583, P<0.005). Conclusion: The UI score will be a simple, clinically effective diagnostic procedure for UI for use by general gynecologists.

Successful preoperative diagnosis of massive ovarian edema aided by comparative imaging study using magnetic resonance and ultrasound.

Massive ovarian edema (MOE) is a rare disease. Therefore, preoperative diagnostic method of massive ovarian edema (MOE) has not been established. We have succeeded in making a preoperative diagnosis of MOE aided by ultrasonogram and magnetic resonance imaging (MRI) and the patients ovaries were preserved. Characteristics and proposed diagnostic imaging criteria for MOE are discussed.

Overexpression of cofilin 1 can predict progression-free survival in patients with epithelial ovarian cancer receiving standard therapy.

The aim of this study was to examine the relation between cofilin 1 expression and progression-free survival in advanced epithelial ovarian cancer. We performed quantitative reverse transcriptase polymerase chain reaction and immunohistochemical analysis in 78 patients with advanced epithelial ovarian cancer (excluding those with mucinous and clear-cell types). All patients received the standard therapy, including staging laparotomy and adjuvant chemotherapy consisting of carboplatin and paclitaxel. Of 78 samples, RNA from 62 samples was available for reverse transcriptase polymerase chain reaction analysis. We defined cofilin 1 high expression as relative gene expression equal to or higher than the median and low expression as gene expression lower than median. The progression-free survival was longer in cofilin 1 low-expression cases than in high-expression cases (P = .039). Multivariate analysis demonstrated that stage and cofilin 1 expression were significant predictors of progression-free survival. Of the 78 samples, 54 were appropriate for immunohistochemical study. In 35 of those 54 cases, cofilin 1 protein expression was detected. The progression-free survival was longer in cofilin 1 protein-negative cases than in protein-positive cases (P = .042). Expression of cofilin 1 may predict the progression-free survival of patients with advanced epithelial ovarian cancer receiving standard therapy.

Lipolytic activity of anemia-inducing substance from tumor-bearing rabbits.

Anemia-inducing substance (AIS) is a protein of approximately 50,000 molecular weight secreted by malignant tumor tissue that depresses erythrocyte and immuno-competent cell functions; in this study, its biological effects on adipocytes were examined. Changes in body weight, total body fat, and food intake were investigated in rabbits after VX2 carcinoma transplantation, and the results showed reductions of 11%, 24%, and 30%, respectively, at 40 days after transplantation compared with baseline values (before transplantation). The values were even more markedly reduced 70 days after transplantation. When cyclic plasma perfusion (2 times/wk) was started at 40 days after transplantation, the values at 70 days after transplantation (30 days after beginning plasma perfusion) recovered to 91%, 84%, and 87%, respectively, of the baseline values. AIS fractions were isolated from rabbit plasma by using a phenyl-Sepharose column before transplantation, 40 and 70 days after transplantation, and 30 days after start of plasma perfusion, and AIS activity and lipolytic activity were measured. The results showed enhancement of AIS activity and lipolytic activity as the tumors grew. Lipolytic activity also returned to baseline value as AIS was removed by adsorption by plasma perfusion, and there was a high correlation between lipolytic activity and AIS kinetics. These results strongly suggest that AIS might be one of the substances involved in the enhanced lipolytic activity in advanced tumor-bearing subjects.

Expression profiles of carcinosarcoma of the uterine corpus—are these similar to carcinoma or sarcoma?

Uterine carcinosarcoma (CS) is usually classified as uterine endometrial carcinoma (EC). However, CS is more aggressive even compared with high grade EC. CS is also reported to undergo epithelial to mesenchymal transition (EMT). In this study, we compared the gene expression profiles of CS, EC, and uterine sarcoma (US) and evaluated the role of EMT and chromosomal aberrations in CS tumor formation. Frozen tissues of 46 patients (14 CS, 24 EC, and 8 US) were included. The similarity was examined by Gene Set Enrichment Analysis (GSEA), Fishers exact test, and clustering using “intrinsic gene set”. We examined the expression of 39 EMT‐related genes and evaluated TGF‐beta signaling by phospho‐SMAD2/3 (p‐SMAD2/3) staining. Chromosomal regions differing between CS and EC were identified by chromosomal GSEA and comparative genomic hybridization (CGH) microarrays. Three statistical methods confirmed that CS resembled US rather than EC. Acquired markers of EMT were upregulated and attenuated markers of EMT were downregulated in CS. Immunohistochemistry showed that carcinomatous region of CS have higher expression of p‐SMAD2/3 than EC (P = 0.008). Chromosomal GSEA showed that genes located at 19q13 had higher expression in CS. Furthermore, CGH microarray indicated that the TGFB1 locus at 19q13.1 was amplified in 4 of 7 samples. Based on the expression profile, CS resembles US rather than EC. TGF‐beta signaling is activated in CS and chromosomal gains at 19q13, which includes the TGFB1 locus, suggest that this may contribute to high expression of TGF‐beta and thereby EMT phenotype of CS.

EGRI and FOSB gene expressions in cancer stroma are independent prognostic indicators for epithelial ovarian cancer receiving standard therapy

Stromal components interact with cancer cells to promote growth and metastasis. The purpose of this study was to identify genes expressed in stroma, which could provide prognostic information in epithelial ovarian cancer (EOC). Seventy‐four patients were included. We performed gene expression profiling and confirmed array data using RT‐PCR and immunohistochemistry. By microarray analysis, 52 candidate genes associated with progression free survival (PFS) were identified (P < 0.005). Expression of the early growth response 1 (EGR1) and FBJ murine osteosarcoma viral oncogene homolog B (FOSB) genes was further analyzed. Array data were confirmed by RT‐PCR and multivariate analysis demonstrated that both EGR1 and FOSB expression in cancer stroma, and EGR1 expression in cancer are independent prognostic factors in EOC. Immunohistochemically, EGR1 protein is localized in cancer cells and α‐smooth muscle actin positive stromal fibroblasts. The EGR1 and FOSB expression in stromal cells and EGR1 expression in cancer cells are prognostic indicators in EOC.

Phase II study of irinotecan plus doxorubicin for early recurrent or platinum-refractory ovarian cancer: interim analysis

The aim of this study was to evaluate the efficacy and toxicity of irinotecan and doxorubicin in the treatment of patients with early recurrent or platinum-refractory ovarian cancer. Nineteen woman from five different institutions were treated. Two patients had platinum-refractory cancer, 11 had platinum-resistant disease, and 6 had platinum-sensitive tumors. An intravenous infusion of Irinotecan (50mg/m2) was given on days 1, 8, and 15, while doxorubicin (40mg/m2) was administered as an intravenous bolus on day 3. This treatment schedule was repeated every 4 weeks. Among the 13 patients defined as having platinum-refractory/platinum-resistant disease, 4 patients achieved a clinical response (30.8%, 95% CI: 9.1–61.4), while only one of 6 patients defined as having platinum-sensitive disease achieved a clinical response (16.7%, 95% CI: 0.4–64.1). Leukopenia and neutropenia were the major dose- limiting toxicities. Grade 3 or 4 leukopenia and neutropenia were noted in 24 (48%) and 33 (66%) of the courses, while febrile neutropenia occurred in 2 courses. Five patients (26%) had grade 2 or worse diarrhea during 7 courses. Our data demonstrated that this regimen might be comparable to standard approved agents in patients with early recurrent or platinum refractory ovarian cancer.