Tsunekazu Kita

Effects of bevacizumab and pegylated liposomal doxorubicin for the patients with recurrent or refractory ovarian cancers.

OBJECTIVESnCurrently, pegylated liposomal doxorubicin (PLD) is regarded as one of the standard treatment options in recurrent ovarian cancers (ROC). Bevacizumab has shown significant antitumor activity for ROC in single-agent or in combination with cytotoxic agents. We have conducted a preliminary study to investigate effects of combination of bevacizumab and PLD for heavily pretreated patients with ROC.nnnMETHODSnThirty patients with ROC were treated with combination therapy with weekly bevacizumab and PLD, 2 mg/kg of continuous weekly bevacizumab and 10 mg/m(2) of PLD (3 weeks on, 1 week off). The treatment was continued until development of disease progression, or unmanageable adverse effects. Response evaluation was based upon Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and Gynecologic Cancer Intergroup (GCIG) CA125 response criteria. Adverse effects were analyzed according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.nnnRESULTSnOverall response rate was 33%, and clinical benefit rate (CR+PD+SD) was 73%. Median progression-free survival was 6 months (range: 2-20 months), and a 6-months progression-free survival was 47%. Any hematological toxicities more than grade 3 were not observed. Two cases developed non-hematologic toxicities more than grade 2; a case with grade 3 hand-foot syndrome, another with grade 3 gastrointestinal perforation (GIP). The case with GIP was conservatively treated and recovered after 2 months, and there was no case with treatment-related death.nnnCONCLUSIONnThe present investigation suggested that combination therapy with bevacizumab and PLD was active and well tolerated for patients with ROC. We recommend the regimen be evaluated in further clinical studies.

Weekly administration of temsirolimus for heavily pretreated patients with clear cell carcinoma of the ovary: a report of six cases

Clear cell carcinoma (CCC) of the ovary is well-known to be chemotherapy resistant compared with other histologic subtypes. An inhibitor against the mammalian target of rapamycin, temsirolimus (TEM) has been reported to be effective in renal CCC. Therefore, we investigated the effects of TEM in patients with CCC of the ovary. Six patients with CCC of the ovary who had been heavily pretreated by more than 4 regimens were given TEM: the cycle consisted of weekly TEM (10xa0mg/m2) for 3xa0weeks followed by 1xa0week off. The treatment was continued until development of either progressive disease, or unmanageable adverse effects. Response evaluation was based upon the Response Evaluation Criteria in Solid Tumors version 1.0. Adverse effects were analyzed according to Common Terminology Criteria for Adverse Events version 3.0. The median cycle of weekly TEM was 3 (range 2–14). Among five cases in which responses could be evaluated, partial response was observed in one case (20%) and stabilized disease was seen in another case (20%). There were no toxicities greater than grade 3, and no case developed severe toxicity requiring discontinuation of weekly TEM. The patient who showed a partial response obtained a progression-free period of 14xa0months. In conclusion, weekly TEM shows a potential therapeutic benefit for patients with CCC of the ovary. Further studies including a translational approach are needed to select candidates for whom TEM therapy would be beneficial.

Phase II study of neoadjuvant chemotherapy with irinotecan hydrochloride and nedaplatin followed by radical hysterectomy for bulky stage Ib2 to IIb, cervical squamous cell carcinoma: Japanese Gynecologic Oncology Group study (JGOG 1065).

The efficacy and adverse events of neoadjuvant chemotherapy with irinotecan hydrochloride and nedaplatin were evaluated in patients with bulky stage Ib2 to IIb cervical squamous cell carcinoma. Eligibility included patients who received irinotecan (60 mg/m2) on days 1 and 8 and nedaplatin (80 mg/m2) on day 1 of a 21-day cycle. After 1-3 courses of chemotherapy, radical hysterectomy was performed. Sixty-eight patients were enrolled. Sixty-six were included in the full analysis set. Their median age was 47 years (range 22-71), the FIGO stage was Ib2 in 18 patients, IIa in 10, and IIb in 38. Radical hysterectomy was performed after NAC in 63 patients (95.5%). The number of administered courses of NAC was 1 in 13 patients, 2 in 43, and 3 in 10. The response rate, the primary endpoint of this study, was 75.8% (CR in 2 patients, PR in 48, SD in 12, PD in 0, and NE in 4). The mean number of treatment courses required for a response was 1.42 (1 course in 30 patients, 2 courses in 19, and 3 courses in 1). The incidences of grade 3 or 4 hematological toxicities were: neutropenia 72.2%, leukopenia 16.7%, anemia 13.6%, thrombocytopenia 7.6%, febrile neutropenia 1.5%, and elevations of alanine aminotransferase and aspartate aminotransferase 1.5%. Grade 3 or 4 non-hematologic toxicities were as follows: diarrhea 6.1%, nausea 3%, anorexia 1.5%, vomiting 1.5%, fever 1.5%, allergic reactions 1.5%, ileus 1.5% and vesicovaginal fistula 1.5%. Neoadjuvant chemotherapy with irinotecan and nedaplatin was an effective and well-tolerated treatment for patients with bulky stage Ib2 to IIb squamous cell carcinoma of the uterine cervix.

Surgical principles for managing stage IB2, IIA2, and IIB uterine cervical cancer (Bulky Tumors) in Japan: a survey of the Japanese Gynecologic Oncology Group.

Objective The aim of this study was to determine the current operative management of International Federation of Gynecology and Obstetrics (FIGO) stage IB2, IIA2, and IIB uterine cervical cancer (bulky tumors) in Japan by surveying the member institutions of the Japanese Gynecologic Oncology Group. Methods We conducted a survey to assess current operative management, including indications and treatment, at all 199 active member institutions of the Japanese Gynecologic Oncology Group. Results A total of 166 institutions (83.4%) responded to the survey. For patients with stage IIB squamous cell carcinoma, 35.5% (59/166) of the institutions performed surgery. For stage IIB nonsquamous cell carcinoma, surgery was performed at 88 (53.7%) of 164 institutions. Neoadjuvant chemotherapy was provided by 75 (45.5%) of 165 institutions (actively in 44 and reluctantly in 31). At 101 (61.2%) of 165 institutions, para-aortic node dissection was performed as part of radical surgery in patients with any indications. At 96 (57.9%) of 166 institutions, high-risk patients underwent chemoradiotherapy after surgery. On the other hand, adjuvant chemotherapy was given to high-risk and intermediate-risk patients at 19.9% and 33.1% institutions, respectively. More than half of the 166 institutions considered the number of metastatic nodes (91/166, 54.8%) and tumor histology (116/166, 69.9%) when selecting adjuvant therapy. Conclusions This survey provided information regarding the current surgical management of uterine cervical cancer (stages IB2, IIA2, and IIA) in Japan.

Potential impact of combined high‐ and low‐risk human papillomavirus infection on the progression of cervical intraepithelial neoplasia 2

Few studies have examined the effect of combined low‐risk human papillomavirus (LR‐HPV) and high‐risk human papillomavirus (HR‐HPV) infection on the progression of cervical intraepithelial neoplasia (CIN)2 to CIN3. This multi‐institutional prospective cohort study investigated the risk of progression of CIN2 with various combinations of HR‐HPV and LR‐HPV infection.

Complete remission of recurrent ovarian clear cell carcinoma by chemotherapy with bevacizumab, trabectedin and oxaliplatin

Clear cell carcinoma of the ovary has shown an exceedingly chemo‐resistant phenotype, especially in cases that are recurrent or refractory to previous therapy. Also, progression‐free survival was less than 6 months, even in the patients that achieved response when they were treated with conventional anti‐cancer cytotoxic agents. We present a case with recurrent and refractory ovarian clear cell carcinoma that achieved complete remission using a combination of bevacizumab, trabectedin and oxaliplatin. The progression‐free interval of the patient is over 30 months, and she is still receiving the combination therapy without toxicities of more than grade 2.

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.

Prospective evaluation of the Amplicor HPV test for predicting progression of cervical intraepithelial neoplasia 2

The aim of this study was to evaluate the clinical performance of the Amplicor HPV test, which detects 13 high‐risk human papillomaviruses (HR‐HPV), and to determine the association between consistent HR‐HPV infection and progression of cervical intraepithelial neoplasia (CIN) 2 to CIN3.

Abstract LB-226: The effect of cabozantinib to temozolomide and bevacizumab in patients with heavily pretreated relapsed uterine leiomyosarcoma

Background: Although uterine leiomyosarcoma (ULMS) has been treated with adriamycin, dacarbazine, ifosfamide, gemcitabine, docetaxel, et al, the effect is not satisfactory. We have reported the effect of temozolomide (T) combined with bevacizumab (B) in heavily pretreated relapsed ULMS. In this study, we evaluated the effects of addition of cabozantinib (C) to T and B. Methods: From 2009 to 2015, total 18 patients (pts) with heavily pretreated relapsed ULMS were enrolled. They were treated with T (80mg/body/day) and B (2mg/kg; days 1, 8 and 15, q4 weeks). Since 2013, we expected better efficacy, nine pts out of 18 pts were treated by adding C (140mg/body/week) which is a c-MET inhibitor (TB, n = 9, CTB, n = 9). Treatment was continued until disease progression and/or unmanageable toxicities. The response and adverse events were evaluated using the response evaluation criteria in solid tumors (RECIST), and common terminology criteria for adverse events (CTCAE) version 3.0. Results: As shown in Table, three (18%) of 17 pts had complete response (CR), two (12%) had partial response (PR) and eight (47%) had stable disease (SD) for at least three months. The response rate (RR; CR+PR) and clinical benefit rate (CBR; CR+PR+SD>3mo) were 29% and 76%, respectively. The median progression-free survival was 9.6 (3 - 58) months. When compared CTB with TB, CBR was better in CTB (87.5% vs 67%), but the median administration cycles and progression free interval were not improved. Two peritoneal perforation were observed in CTB. Conclusions: Not only TB but also CTB showed remarkable effect in heavily pretreated relapsed ULMS. These results warrant further prospective and randomized studies.n Citation Format: Sayaka Ikeda, Kazuya Kudoh, Naoki Sasaki, Masashi Takano, Tomoko Goto, Ryoko Kikuchi, Tsunekazu Kita, Masaru Sakamoto, Nobuyuki Susumu, Daisuke Aoki, Hiroko Kouta, Yoshihiro Kikuchi. The effect of cabozantinib to temozolomide and bevacizumab in patients with heavily pretreated relapsed uterine leiomyosarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-226.