Yoshio Itani

Cancer stem-like cells of ovarian clear cell carcinoma are enriched in the ALDH-high population associated with an accelerated scavenging system in reactive oxygen species

OBJECTIVE In ovarian cancer cases, recurrence after chemotherapy is frequently observed, suggesting the involvement of ovarian cancer stem-like cells (CSCs). The chemoresistance of ovarian clear cell carcinomas is particularly strong in comparison to other epithelial ovarian cancer subtypes. We investigated the relationship between a CSC marker, aldehyde dehydrogenase 1 (ALDH1), and clinical prognosis using ovarian clear cell carcinoma tissue samples. Furthermore, we investigated the antioxidant mechanism by which CSCs maintain a lower reactive oxygen species (ROS) level, which provides protection from chemotherapeutic agents. METHODS Immunohistochemical staining was performed to examine the CSC markers (CD133, CD44, ALDH1) using ovarian clear cell carcinoma tissue samples (n=81). Clear cell carcinoma cell lines (KOC-7C, OVTOKO) are separated into the ALDH-high and ALDH-low populations by ALDEFLUOR assay and fluorescence-activated cell sorting (FACS). We compared the intracellular ROS level, mRNA level of the antioxidant enzymes and Nrf2 expression of the two populations. RESULTS High ALDH1 expression levels are related to advanced stage in clear cell carcinoma cases. ALDH1 expression significantly reduced progression free survival. Other markers are not related to clinical stage and prognosis. ALDH-high cells contained a lower ROS level than ALDH-low cells. Antioxidant enzymes were upregulated in ALDH-high cells. ALDH-high cells showed increased expression of Nrf2, a key transcriptional factor of the antioxidant system. CONCLUSIONS ALDH-positive CSCs might have increased Nrf2-induced antioxidant scavengers, which lower ROS level relevant to chemoresistance in ovarian clear cell carcinoma.

Growing teratoma syndrome after chemotherapy for a mixed germ cell tumor of the ovary

A retroperitoneal enlarging mass was detected and resected in a 24‐year‐old nulliparous woman after fertility‐preserving surgery and adjuvant chemotherapy for a malignant germ cell tumor (MGCT) of the right ovary. This enlarging mass contained only a mature teratoma component. Alpha‐fetoprotein, which was elevated to 21236.6 ng/mL before the initial surgery, persisted within normal after the completion of adjuvant platinum‐based chemotherapy. The patient was diagnosed with growing teratoma syndrome. Growing teratoma syndrome originating from ovarian germ cell tumor is very rare. Only 15 cases have been reported. Surgical resection and histological confirmation of growing mass after MGCT treatment is essential before conducting salvage chemotherapy.

Phase II trial of paclitaxel and nedaplatin in patients with advanced/recurrent uterine cervical cancer: A Kansai Clinical Oncology Group study

OBJECTIVE A multicenter phase II trial was conducted to evaluate the activity and toxicity of paclitaxel and nedaplatin (cis-diammineglycolatoplatonum) in patients with advanced/recurrent uterine cervical cancer. METHODS Patients were required to have measurable disease. Histologic confirmation of the primary diagnosis as uterine cervical cancer was mandatory. The treatment consisted of paclitaxel 175 mg/m(2) over 3 hours and nedaplatin 80 mg/m(2) intravenously over 1 hour on day 1 every 28 days until progressive disease or adverse effects prohibited further therapy. RESULTS Fifty patients were enrolled into the study protocol from October 2007 to February 2010. 45 patients(90%) were eligible for assessment of response (RECIST version 1.0) to treatment; 31 patients (62%) received prior radiotherapy and 23 patients (46%) received prior chemotherapy. The overall response rate was 44.4% (11 complete responses and 8 partial responses) with 22.2% of patients having stable disease. Grades 3 or 4 adverse events (NCI-CTCAE ver 3) included neutropenia (n=16, 32.7%), febrile neutropenia (n=1, 2.0%), anemia (n=9, 18.4%), but there was no significant thrombocytopenia. Non-hematologic toxicity was generally not serious and without a dominant pattern. The median progression-free survival was 7.5 months (95% C.I., 5.7, 9.4) and overall survival was 15.7 months (95% C.I., 9.4, 21.9). CONCLUSIONS Paclitaxel 175 mg/m(2) and nedaplatin 80 mg/m(2) intravenously on day 1 every 28 days in patients with advanced/recurrence uterine cervical cancer demonstrated easy administration, favorable antitumor activity, and the toxicity profile of this regimen would be decreased compared with cisplatin-containing combinations. Evaluation of this regimen in phase III trials is warranted.

Phase II study of interval debulking surgery followed by intraperitoneal chemotherapy for advanced ovarian cancer: A Kansai Clinical Oncology Group study (KCOG9812)☆

OBJECTIVE Intraperitoneal chemotherapy (IP) is known to be effective after optimal primary debulking surgery (PDS) for ovarian cancer (OC). Here, we conducted a phase II study to investigate its effectiveness after interval debulking surgery (IDS). METHODS Thirty-seven patients with FIGO stage IIIB-IV and suboptimal (≥1cm diameter) residual disease after PDS were enrolled. Carboplatin (AUC 4 IV, Day 1) and cisplatin (50mg/m(2) IV, Day 3) were given q21d for 3cycles. After IDS, paclitaxel (175mg/m(2) IV Day 1 or 60mg/m(2) IV Days 1, 8, and 15, since 2000) and cisplatin (75mg/m(2) IP Day 2) were given q21d for 4cycles. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS) and adverse events (CTCAE ver. 2.0). Clinical manifestations at first recurrence and subsequent treatment were also surveyed. RESULTS Of the 37 patients, high-grade, serous adenocarcinoma was found in 33. Stages IIIB, IIIC, and IV were found in 2, 24, and 11 patients, respectively. After IDS, 23 patients had no macroscopic residual tumor. No patients had permanent enterostomy, febrile neutropenia, or platelet transfusion. The treatment protocol was completed in 22 patients, and discontinued in 5 due to IP catheter-related complications. Median PFS and OS were 22 and 57months, respectively. Among the 28 patients with recurrence, 10 had no intraperitoneal disease at first recurrence. Among the 8 patients who underwent surgical cytoreduction, 6 had no residual tumor, while 2 had a <1-cm-diameter residual tumor. CONCLUSION IP after IDS for patients with initially suboptimally debulked OC was effective.

Malignant epithelial tumor of unknown origin of the broad ligament

Abstract Malignant epithelial tumor of the broad ligament is rare and to our knowledge only 17 cases have been reported. We report a 54-year-old Japanese woman in whom transvaginal sonography (TVS) and magnetic resonance imaging (MRI) showed a left adnexal tumor. Serum CA125 was elevated to 10000 U/ml.Preoperatively, we diagnosed this tumor was a left ovarian malignant tumor though, it was confirmed a the 47×57 mm tumor in the left broad ligament at laparotomy. Histologically most of the tumor showed serous papillary adenocarcinoma with changes similar to poorly differentiated carcinoma and as seen in transitional cell carcinoma on hematoxylin-eosin staining. After three courses of platinum based adjuvant chemotherapy, the patient is alive with no recurrence at 18 months postoperatively.

Cervical adenocarcinoma with stromal micropapillary pattern.

Adenocarcinoma with a stromal micropapillary pattern (SMP) has been described in various organs, but not in the uterus. We encountered a case of uterine cervical carcinoma with SMP. A54‐year‐old Japanese woman was referred to the hospital with abnormal vaginal bleeding. The cervical cytodiagnosis was adenocarcinoma with features resembling serous adenocarcinoma. Cervical cytology showed many small clusters of tumor cells, present in up to two or three layers, composed of atypical cells with markedly increased nucleus: cytoplasm ratios. A radical hysterectomy with bilateral adnexectomy and retroperitoneal lymph node dissection was performed. Microscopically, the tumor was composed predominantly of adenocarcinoma with SMP. The outer surface of the SMP cell clusters showed membranous expression of mucin‐1 (MUC‐1). Many lymph node metastases were detected. The tumor was diagnosed as a cervical adenocarcinoma with SMP and coexistent squamous cell carcinoma in situ. The pathology was classified as T1b1N1M1, stage IVB. The patient underwent postoperative adjuvant chemotherapy and is without local recurrence or distant metastasis 48 months after the operation. To the best of our knowledge, this is the first reported case of cervical adenocarcinoma with SMP. Diagn. Cytopathol. 2016;44:133–136.

Postoperative cytological findings from the use of the Integran microfibrillar collagen hemostatic matrix in conization

The Integran microfibrillar collagen hemostatic matrix is one form of microfibrillar collagen hemostat. This form has a sheet‐type structure and has explicitly been used in Japan. In gynecology, this sheet‐type matrix has helped effect uterine surface hemostasis, especially in myomectomy and cervical conization. However, cytotechnologists and pathologists have overlooked the foreign materials used for conization in postoperative cervical cytology. We report two cases describing the characteristic cervical cytology findings when Integran was used in conization. The first case was a 67‐year‐old woman who underwent conization because of cervical intraepithelial neoplasia (CIN) 3. Thirty‐six days after the surgery, many cylindrical fragments of glossy acellular materials appeared in the cervical cytology. Fortunately, the content did not impede the diagnosis of NILM. The patient then underwent hysterectomy two months after conization. Surgical specimen revealed a high degree of inflammation and granulation without malignancy. Following surgery, the cylindrical fragments disappeared from microscopic findings. The second case was a 45‐year‐old woman who underwent conization because of CIN3. Thirty‐four days after the surgery, many tubular pieces of glossy acellular materials appeared in cervical cytology, as seen in the first case. The cytological diagnosis was NILM. One hundred days after surgery, cervical cytology revealed many clue cells but no cylindrical fragments. These clusters of cylindrical fragments of glossy acellular materials in cervical cytology after conization might induce a delay in diagnosing the persistence and recurrence of cervical cancer. This article is the first report describing cervical cytology findings associated with Integran use.

Phase II trial of weekly paclitaxel and carboplatin (wTJ) for endometrial cancer (EC): Results of a Kansai Clinical Oncology Group trial (KCOG0015) in Japan

5085 Background: The chemotherapy (CT) for recurrent or post operative high risk patients (pts) of EC has not been established. Previously, we reported the usefulness of wTJ in EC for preliminary results (Ito et al; Proc ASCO 2002). Here we report the final results. METHODS Eligibility criteria included: histologically confirmed primary advanced or recurrent EC (group A), post-operative pts having high risk factors (above FIGO stage IC, G3 histology, capillary space invasion) (group B). Each cycle considered of three-weekly drug administrations: paclitaxel 80mg/m2 on days 1, 8 and 15 and carboplatin AUC 5 on day 1 as a 1-hr infusion of each drug, and more than 3 cycles of administration were planned. RESULTS Between 05/2000 and 03/2002, a total of 40 pts (median age was 58, range:30 -70) were enrolled and administered 163 cycles. Thirty-six pts (93%) completed more than 3 cycles (median 4, range:1-9). ECOG performance status (PS) was 0-1 in 39 pts, PS 2 in 1 pt. Thirty-eight pts (95%) had no prior CT. Group A contained 17 pts (6 recurrent pts, 8 neo-adjuvant CT pts for bulky stage IIb -IV, and 3 pts had post operative residual tumor). Group B contained 23 pts (primary stage I:10, II:5, III:6, IV:2pts). Toxicity, response and QOL were assessed by NCI-CTC ver2.0J in all pts, RECIST in 15pts had measurable disease in group A and EORTC-QLQC30J in 19 pts obtained their approval, respectively. Hematological toxicities(G3/G4) were neutropenia (31%/33%), thrombocytopenia (6%/0%). Febrile neutropenia was not observed. Reversible G3 hypersensitivity (5%) and G2 cardiotoxicity (3%: reversible PVC) were observed. The response rate was 80% (12/15) with 3CR, 9PR and 3SD. No pts remarkably failed own QOL in this trial. Now the median follow up period of group A is 28 months (range 15-40). The median time to progression and survival are 15+ (range 5-32+) and 25+ months (range 5-40+), respectively. And the median follow up period of group B is 26 months (range 18-39). No pts relapsed and all pts are alive. CONCLUSIONS This wTJ regimen was highly effective and feasible for EC pts. No significant financial relationships to disclose.

Phase I/II study of a docetaxel (DOC) and gemcitabine (GEM) combination for early recurrent (≤12 months)(ER) or refractory (R) epithelial ovarian cancer (EOC): Kansai Clinical Oncology Group, Japan

5046 Background:There is no standard chemotherapy regimen for EOC that does not respond to platinum-based chemotherapy (R-EOC), or responds but progresses within 12 months after completing chemotherapy (ER-EOC). PURPOSE To determine the efficacy of a DOC and GEM combination for R-EOC or ER-EOC, we conducted phase 1/2 study. METHODS Between October 2000 and November 2003, R-EOC or ER-EOC patients (pts) entered this multi-institutional study. Eligible criteria: histologically verified EOC, age 16 -75 years, ECOG-PS ≤2, adequate bone marrow, hepatic, and renal function, and written informed consent. GEM was administered on days 1 and 8, and DOC on day 8. This treatment was repeated every 3 weeks. The doses were escalated as follows: dose level 1 (DL1); DOC 70 mg/m2, GEM 800 mg/m2, DL2: DOC 70 mg/m2, GEM 1000 mg/m2. Toxicities were assessed according to NCI-CTC ver2.0J and responses were assessed according to both RECIST for measurable disease and Rustins criteria for CA125. RESULTS Thirty-four pts were enrolled and administered 95 cycles. The median cycle was 3 (1-7 cycles), median age was 56 years (21 to 74 years), and median interval from prior chemotherapy was 2 months (1 to 12 months). Seventeen pts received more than 3 chemotherapy regimens before the enrollment. Three pts experienced no dose-limiting toxicities (DLTs) in DL1. Two of the three pts in DL2 were experienced DLTs: febrile neutropenia grade 3 (1), and thrombocytopenia grade 4 (1). Then, 28 patients were subjected to the phase 2 study with DL1 as a recommended dose. Thirty-two patients were assessable for response. Response rate was 19.1% (6/32) with 1CR (3.1%), 5PR (16%), and 9SD(28%). One-year and 2-year survival were 51.2% and 23.4%, respectively. The median survival time was 13 months. Toxicities were mainly hematological (G3/G4): neutropenia (16%/50%), thrombocytopenia (19%/0%), anemia (13%/0%), and febrile neutropenia (3%/0%). There were no grade 3 or 4 non-hematological toxicities. CONCLUSIONS A DOC and GEM combination for R-EOC and ER-EOC with DL1 is active and well tolerable. [Table: see text].

A case of mesodermal mixed tumor(MMT) of the ovary. Cytological and immunohistochemical study.

卵巣原発の中胚葉性混合腫瘍mesodermal mixed tumor (以下MMT) はまれな疾患で, 国内の報告例は23例にすぎない. 今回, われわれは卵巣原発MMT homologous typeの症例を経験した.症例は54歳, 5妊4産, 閉経50歳の主婦で, 全身倦怠感, 腹部膨満感および呼吸困難を主訴として受診.超音波断層法とCTにて, 下腹部より横隔膜下におよぶhigh density partに一部cystic low density partを含む腫瘍と, 多量の胸・腹水を認めた.血清CA 125 440U/ml, LDH3, 212IU/lと上昇し, 開腹手術を行い卵巣悪性腫瘍IV期と診断し, cytoreductive surgeryを施行した.腹水細胞診では, レース状の細胞質と明瞭な核小体を有する腺癌細胞が主であり, 腫瘍の捺印細胞診では好塩基性に淡染する辺縁不明瞭な細胞質と, 紡錘形または類円形の核を有する非上皮性悪性細胞が存在した.病理組織学的には類内膜腺癌と肉腫成分が混在し, 免疫染色と特殊染色にてMMT homologous typeと診断した. carboplatinとetoposideの併用化学療法により軽快し, 一時的に外来通院可能となった.本症の細胞学的および病理組織学的検討を行い, さらに組織発生や化学療法についても考察した.