Akira Kurosaki

Serum folate receptor alpha as a biomarker for ovarian cancer: Implications for diagnosis, prognosis and predicting its local tumor expression

Folate receptor alpha (FRA) is a GPI‐anchored glycoprotein and encoded by the FOLR1 gene. High expression of FRA is observed in specific malignant tumors of epithelial origin, including ovarian cancer, but exhibits very limited normal tissue expression, making it as an attractive target for the ovarian cancer therapy. FRA is known to shed from the cell surface into the circulation which allows for its measurement in the serum of patients. Recently, methods to detect the soluble form of FRA have been developed and serum FRA (sFRA) is considered a highly promising biomarker for ovarian cancer. We prospectively investigated the levels of sFRA in patients clinically suspected of having malignant ovarian tumors. A total of 231 patients were enrolled in this study and analyzed for sFRA as well as tumor expression of FRA by immunohistochemistry. High sFRA was predominantly observed in epithelial ovarian cancer patients, but not in patients with benign or borderline gynecological disease or metastatic ovarian tumors from advanced colorectal cancers. Levels of sFRA were highly correlated to clinical stage, tumor grade and histological type and demonstrated superior accuracy for the detection of ovarian cancer than did serum CA125. High sFRA was significantly associated with shorter progression‐free survival in both early and advanced ovarian cancer patients. Finally, tumor FRA expression status was strongly correlated with sFRA levels. Taken together, these data suggest that sFRA might be a useful noninvasive serum biomarkers for future clinical trials assessing FRA‐targeted therapy.

Intravenous/intraperitoneal paclitaxel and intraperitoneal carboplatin in patients with epithelial ovarian, fallopian tube, or peritoneal carcinoma: a feasibility study.

Objective This study aimed to evaluate intravenous (IV)/intraperitoneal (IP) paclitaxel and IP carboplatin (TCipTip therapy) feasibility in epithelial ovarian (EOC), fallopian tube (FTC), or peritoneal carcinoma (PC) patients. Methods From December 2007 to August 2010, 20 women with histologically confirmed stage IC to IV EOC, FTC, or PC received 6 TCipTip cycles after the primary cytoreductive surgery. Intravenous paclitaxel was administered at 135 mg/m2 followed by IP carboplatin based on the area under the curve = 6 on day 1; IP paclitaxel at 60 mg/m2 was administered on day 8. The toxicity grade was determined by CTCAE version 3.0. The institutional review board requested we reduce the IP paclitaxel dose in the first cycle to ensure safety. Results Twenty women, including 18 with EOC, 1 with stage IIC FTC, and 1 with stage IV primary PC, received TCipTip therapy. There were 12 serous, 5 endometrioid, 1 mucinous, 1 clear cell adenocarcinoma, and 1 mixed carcinoma (clear cell and endometrioid) cases. Eleven women achieved optimal status at primary surgery. Grade 3/4 hematologic toxicity incidence was 73% (neutrocytopenia), 9% (thrombocytopenia), and 24% (anemia). Grade 3/4 nonhematologic toxicities were observed in 5 patients (4 with grade 3 allergy and 1 with grade 3 ileus). Twelve patients (60%) completed more than 6 chemotherapy cycles. Reasons for interruption included paclitaxel allergy, grade 2 abdominal pain, carboplatin allergy during the seventh cycle, disease progression, pleural embolism, ileus, and address change. Conclusions Toxicities for TCipTip therapy were acceptable; this therapy is feasible for EOC, FTC, or PC patients. Further TCipTip therapy evaluation is warranted.

Feasibility Study of Combination Chemotherapy with Paclitaxel, Doxorubicin and Cisplatin without Prophylactic Granulocyte Colony-stimulating Factor Injection for Intermediate-to-high Risk or Recurrent Endometrial Cancer

OBJECTIVE We evaluated the feasibility of combination chemotherapy with paclitaxel, doxorubicin and cisplatin without prophylactic granulocyte colony-stimulating factor injection for intermediate-to-high-risk or recurrent endometrial cancer. METHODS Women with histologically confirmed FIGO Stages I-II with >1/2 myometrial invasion, Stage III/IV or recurrent endometrial cancer were enrolled. Patients received intravenous doxorubicin (45 mg/m(2)), followed by cisplatin (50 mg/m(2)) on Day 1 and intravenous paclitaxel (160 mg/m(2)) on Day 2. Granisetron (75 µg) was administered depending on neutrophil counts on Days 3 and 8. Treatment was repeated every 21 days for six cycles or until disease progression or unacceptable toxicity. The primary endpoint was the completion rate of the scheduled chemotherapy; secondary endpoints were Grade 3/4 toxicity and response rate in patients with measurable lesions. RESULTS From September 2010 to December 2012, 35 women, including 7 with FIGO Stage I, 4 with Stage II, 13 with Stage III, 10 with Stage IV and 1 with recurrent endometrial cancer, were enrolled. There were 26 endometrial carcinomas (Grade 1, 16; Grade 2, 6; Grade 3, 4), 4 carcinosarcomas, 2 serous adenocarcinomas, 1 neuroendocrine carcinoma, 1 poorly differentiated carcinoma and 1 mixed carcinoma. Twenty-five patients (71%) completed six chemotherapy cycles. Grade 3/4 hematological toxicities included neutrocytopenia (97%), thrombocytopenia (6%) and anemia (34%). Three patients (9%) experienced neutropenic fever. Grade 3/4 non-hematological toxicities were observed in 13 patients. In 15 patients with evaluable lesions, the response rate was 80%. CONCLUSIONS Combination chemotherapy with paclitaxel, doxorubicin and cisplatin without prophylactic granulocyte colony-stimulating factor injection is feasible.

Clinical trials of neoadjuvant chemotherapy for ovarian cancer: what do we gain after an EORTC trial and after two additional ongoing trials are completed?

The aim of neoadjuvant chemotherapy is to reduce the tumor volume or spread of the disease before the main treatment, and it could possibly make the main procedures easier or less invasive. Although the standard therapeutic strategy for advanced ovarian cancer is a maximum primary debulking surgery followed by chemotherapy, a European Organisation for Research and Treatment of Cancer (EORTC) prospective randomized trial demonstrated that neoadjuvant chemotherapy followed by interval debulking surgery was not inferior to the standard procedure. This study raised a number of controversies, particularly regarding the quality of debulking surgery. To solve the questions, we need to wait for the results of two additional ongoing randomized trials. However, the results of those two trials must be carefully assessed, because the quality of debulking surgery would significantly affect survival, and may make the interpretation of the trial results more confusing and difficult.

The Risk of Ovarian Malignancy Algorithm (ROMA) as a Predictive Marker of Peritoneal Dissemination in Epithelial Ovarian Cancer Patients

Background: This study aimed to determine the efficacy of the risk of ovarian malignancy algorithm (ROMA), calculated using the carbohydrate antigen 125 (CA125) and human epididymis protein 4 (HE4) levels and the menopausal status, as a predictor of peritoneal dissemination in ovarian cancer. Methods: The CA125 and HE4 levels and the ROMA were compared between ovarian cancer patients (n = 122) with or without peritoneal dissemination. The sensitivity, specificity, positive predictive value, and negative predictive value were calculated, and the results were compared with those of computed tomography (CT). Results: The CA125, HE4, and ROMA values differed significantly depending on the presence of peritoneal dissemination (p < 0.0001). The cut-off values were 181 U/ml for CA125, 161 pmol/ml for HE4, 44% for the ROMA (premenopausal), and 86% for the ROMA (postmenopausal). Among these markers, the ROMA (premenopausal) was the strongest predictor of peritoneal dissemination, with a specificity of 85.0% and a positive predictive value of 81.3%. In addition, the detection rates of small disseminations with less than 2 cm in diameter for the ROMA (93%) and HE4 (60%) were superior to that of CT (53%). Conclusions: The ROMA was a significant predictor of peritoneal dissemination and may be superior to CT for the detection of patients with small disseminations.

The Efficacy of Low-Dose Paclitaxel Added to Combination Chemotherapy of Carboplatin and Gemcitabine or Pegylated Liposomal Doxorubicin.

Objective Paclitaxel is known to produce the “platelet-sparing effect” that prevents the carboplatin-induced decrease in platelet count. We conducted a pilot study to assess whether the addition of low-dose paclitaxel to carboplatin-based combination chemotherapy prevents thrombocytopenia. Methods Patients with platinum-sensitive recurrent ovarian cancer received intravenous (IV) paclitaxel at 60 mg/m2 followed by IV carboplatin at an area under the curve of 6 and IV pegylated liposomal doxorubicin at 30 mg/m2 on day 1 in a 28-day cycle (DC-LOP) or IV gemcitabine at 1000 mg/m2 on days 1 and 8 in a 21-day cycle (GC-LOP). Results During May 2011 to December 2011, 7 patients received 29 cycles of DC-LOP; during January 2012 to May 2013, 15 patients received 88 cycles of GC-LOP. Grade 3/4 thrombocytopenia occurred in 2 (33%) of 6 and 9 (56%) of 16 patients in the DC-LOP and GC-LOP groups, respectively. No grade 3/4 nonhematological toxicity was observed. Only one patient who received GC-LOP had grade 2 sensory and motor peripheral neuropathy. Paclitaxel-related toxicities, including muscle pain, arthralgia, and peripheral neuropathy, were consistently rare and mild. The response rates of DC-LOP and GC-LOP were 33% (0, complete response; 2, partial response; 3, stable disease; 1, progression disease) and 50% (2, complete response; 6, partial response; 7, stable disease; 1, progression disease), respectively. Conclusions Although low-dose paclitaxel addition did not alleviate thrombocytopenia in the setting of this pilot study, the results do not deny the existence of the “platelet-sparing effect” by low-dose paclitaxel. Further investigation of the carboplatin-based combination chemotherapy including a drug with mild hematological toxicity is warranted.

Synchronous mucinous metaplasia and neoplasia of the female genital tract with external urethral meatus neoplasm: A case report

Highlights • We present a case of multiple mucinous metaplasia and neoplasia of cervix, endometrium, fallopian tube, ovary, and mesenterium with external urethral meatus neoplasm.• Immunohistochemistry showed almost same pattern in each neoplasms.• PCR-direct sequencing showed no existence of both KRAS and GNAS mutations.• This report suggests a possibility of synchronous mucinous metaplasia and neoplasia “beyond” female genital tract.

Pre-operative evaluation of circulating KL-6 levels as a biomarker for epithelial ovarian carcinoma and its correlation with tumor MUC1 expression

Krebs von den Lungen-6 (KL-6), a mucinous sialylated sugar chain on human mucin-1 glycoprotein (MUC1), is a diagnostic marker for interstitial lung diseases. Furthermore, elevated serum KL-6 levels have been observed in certain malignant tumor types of epithelial origin. The expression of MUC1 has been observed in patients with epithelial ovarian cancer (EOC) and is considered a potential therapeutic target. In the present study, KL-6 serum levels were investigated in patients clinically suspected of having malignant ovarian tumors. A total of 219 patients were enrolled in the study, which analyzed their serum KL-6 levels in addition to tumor expression of MUC1 using immunohistochemistry. High serum KL-6 levels were predominantly observed in patients with EOC, and did not occur in patients with benign or borderline tumors. The level of serum KL-6 was highly correlated with tumor stage, grade and histological type, and demonstrated superior sensitivity for the detection of ovarian cancer compared with that of serum cancer antigen 125. High serum KL-6 was significantly associated with shorter progression-free survival. In addition, tumor MUC1 expression status was significantly correlated with serum KL-6 levels. These data suggest that serum KL-6 may be a useful, non-invasive biomarker surrogate for tumor MUC1 expression in future clinical trials of MUC1-targeted therapy.