Efficacy and safety of olaparib maintenance monotherapy for Japanese patients with platinum-sensitive relapsed ovarian, fallopian tube, and primary peritoneal cancer.

BACKGROUND: Olaparib maintenance therapy for platinum-sensitive relapsed ovarian cancer has been approved in Japan since April 2018. Here, we report the experience administering this therapy in our hospital, with the aim of evaluating efficacy and safety in the Japanese population. METHODS: The study included 52 patients with platinum-sensitive relapsed ovarian, fallopian tube, and primary peritoneal cancer. All patients started olaparib at a dose of 300 mg twice daily. Information about treatment efficacy and adverse effects was collected retrospectively from medical records. RESULTS: Median age was 58 years old (range: 33-80), and 82.7% of the patients were diagnosed with high-grade serous carcinoma. Sixteen patients (30.8%) possessed the BRCA1/2 pathogenic variant (15 germline and 1 tissue), 3 (5.8%) possessed variants of unknown significance (2 germline and 1 tissue), 16 (30.8%) possessed wild type, and 17 (32.7%) were not analyzed. Median progression-free survival was 15.3 months (95% CI 9.0-21.6). Patients with BRCA1/2 pathogenic variants showed significantly longer PFS than patients with wild-type BRCA1/2 (p = 0.007). Disease progression caused 34 cases to discontinue olaparib. Eighteen (34.6%) individuals exhibited ≥ grade 3 anemia, although they recovered in response to appropriate management. One patient discontinued olaparib because of prolonged renal dysfunction. Another patient presented with grade 3 fatigue, but recovered after 2 weeks of interruption and continued olaparib treatment. CONCLUSION: Olaparib maintenance therapy for platinum-sensitive recurrent ovarian cancer in the Japanese population is sufficiently safe and no less effective than reports from previous studies.

ARID1A mutation/ARID1A loss is associated with a high immunogenic profile in clear cell ovarian cancer.

OBJECTIVES: ARID1A mutation is frequently found in clear cell ovarian cancer (CCC) and endometrioid ovarian cancer (EC). Anti-PD-1 monotherapy has been found to have limited efficacy in epithelial ovarian cancer; however, anti-PD-1 therapy showed significant clinical benefit in some CCC. We sought to define the relationship of ARID1A mutation/ARID1A expression to the immunogenic profile of different histologic subtypes of ovarian cancer. METHODS: We performed next-generation sequencing of 160 cancer-related genes. Also, we analyzed the immunohistochemical status of ARID1A, PD-L1, and CD8 with survival in different histologic subtypes of ovarian cancer in a total of 103 cases. RESULTS: ARID1A mutation was found in 0% of the high-grade serous ovarian cancer (HGSC) (n = 36), 41.5% of the CCC (n = 41), 45.0% of the EC (n = 20), and 33.3% of the mucinous ovarian cancer (MC) (n = 6) cases. ARID1A loss was found in 19.4% of the HGSC, 75.6% of the CCC, 60.0% of the EC and 0% of the MC cases. ARID1A mutation was found to be associated with high PD-L1 (p < 0.001) or CD8 levels (p < 0.001) in CCC but not in other histologic subtypes. Meanwhile, ARID1A loss was associated with high PD-L1 or CD8 levels in CCC (p < 0.001) and HGSC (p < 0.001) but not in EC and MC. In addition, ARID1A mutation was associated with high tumor mutation burden in CCC (p = 0.006). CONCLUSIONS: ARID1A mutation/ARID1A expression is associated with immune microenvironmental factors in CCC but not in EC. ARID1A status can be a biomarker for selecting candidates for immune checkpoint blockade in CCC.

A prospective cohort study on the safety and efficacy of bevacizumab combined with chemotherapy in Japanese patients with relapsed ovarian, fallopian tube or primary peritoneal cancer.

OBJECTIVE: this prospective cohort study aimed to assess the safety and efficacy of bevacizumab combined with chemotherapy in Japanese patients with relapsed ovarian, fallopian tube or primary peritoneal cancer. METHODS: in this study, 40 Japanese patients with relapsed ovarian, fallopian tube or primary peritoneal cancer selected to receive bevacizumab with chemotherapy were enrolled. Patients in poor general condition were excluded. Each patient was monitored prospectively for adverse events, administration status, disease status and survival. Treatment was continued until intolerable adverse events or disease progression. The primary endpoint was safety. RESULTS: bevacizumab plus platinum-based chemotherapy was performed for 30 patients (median cycle; 16.5), while bevacizumab plus non-platinum chemotherapy was performed for 10 patients (median cycle; 5.5). Among bevacizumab-related adverse events, hypertension occurred in 80% of patients, proteinuria in 83%, mucositis in 25%, bleeding in 20%, thromboembolic events in 5.0% and fistula in 2.5%. Gastrointestinal perforation or other life-threatening lethal adverse events were not observed. Response rate and median progression-free survival were 73% and 19.3 months for patients with bevacizumab plus platinum-based chemotherapy, and 30% and 3.9 months for patients with bevacizumab plus non-platinum chemotherapy, respectively. There was no correlation between response rate and occurrence of adverse events such as hypertension or proteinuria. CONCLUSION: bevacizumab combined with chemotherapy was tolerable and effective for Japanese patients with relapsed ovarian cancer, fallopian tube cancer or primary peritoneal cancer. Hypertension and proteinuria are frequently occurred and managed properly for continuing treatment.

Hysteroscopic Transcervical Resection for Atypical Polypoid Adenomyoma of the Uterus: A Valid, Fertility-Preserving Option.

STUDY OBJECTIVE: To evaluate hysteroscopic transcervical resection (TCR) for atypical polypoid adenomyoma of the uterus (APA). DESIGN: Retrospective study (Canadian Task Force classification II-2). SETTING: Single tertiary hospital. PATIENTS: Women who underwent TCR for APA at Kawasaki Municipal Hospital between 2003 and 2015. INTERVENTIONS: Clinical records were obtained. MEASUREMENTS AND MAIN RESULTS: Thirty-five patients with APA were evaluated. The median patient age was 35 years (range, 23-43 years), and the median tumor diameter was 22 mm (range, 9-51 mm). The median duration of observation after the first TCR was 34.0 months (range, 4.2-133.7 months). In 19 patients, the tumor recurred after the first TCR. A second TCR was performed in 13 patients, 11 of whom experienced recurrence. A third TCR was performed in 7 patients, all 7 of whom experienced recurrence. A fourth TCR was performed in 4 patients, 3 of whom experienced recurrence. The recurrence rate after the second TCR was higher than that after the first TCR (71.4%-84.6% vs 54.3%; p < .01, t test). The median disease-free interval was 12.4 months after the first TCR, 15.3 months after the second TCR, 10.5 months after the third TCR, and 10.9 months after the fourth TCR. Seven patients progressed to endometrial cancer; however, there was no mortality. Six of the 35 patients conceived, and 4 had a normal spontaneous delivery. CONCLUSION: Owing to disease-free intervals that follow treatment, TCR is a promising treatment modality as a fertility-preserving option for patients with APA under careful observation. Twenty percent of patients with APA develop cancer; however, the present study showed no mortality.

Impact of lymphadenectomy on the treatment of endometrial cancer using data from the JSOG cancer registry.

OBJECTIVE: Regional lymph node (LN) dissection is a standard surgical procedure for endometrial cancer, but there is currently no clear consensus on its therapeutic significance. We aimed to determine the impact of regional LN dissection on the outcome of endometrial cancer. METHODS: Study subjects comprised 36,813 patients who were registered in the gynecological tumor registry of the Japan Society of Obstetrics and Gynecology, had undergone initial surgery for endometrial cancer between 2004 and 2011, and whose clinicopathological factors and prognosis were appropriate for our investigation. The following clinicopathological factors were obtained from the registry: age, surgical stage classification, Union for International Cancer Control tumor, node, metastasis classification, histological type, histological differentiation, presence or absence of LN dissection, and postoperative treatment. We retrospectively analyzed the clinicopathological factors and therapeutic outcomes for patients with endometrial cancer. RESULTS: Analysis of all subjects showed that the group that underwent LN dissection had a significantly better overall survival than the group that did not undergo dissection. Analysis based on stage showed similar results across groups, except for stage Ia. Analysis based on stage and histological type showed similar results across groups, except for stage Ia endometrial carcinoma G1 or Ia G2. Multivariate analysis of prognostic factors indicated that LN dissection is an independent prognostic factor and that it has a greater impact on prognosis than adjuvant chemotherapy. CONCLUSION: Despite the limitations of a retrospective study with some biases, the results suggest that LN dissection in endometrial cancer has a prognostic effect.

Clinical implications of next-generation sequencing-based panel tests for malignant ovarian tumors.

Precision medicine based on cancer genomics is being applied in clinical practice. However, patients do not always derive benefits from genomic testing. Here, we performed targeted amplicon exome sequencing-based panel tests, including 160 cancer-related genes (PleSSision-160), on 88 malignant ovarian tumors (high-grade serous carcinoma, 27; endometrioid carcinoma, 15; clear cell carcinoma, 30; mucinous carcinoma, 6; undifferentiated carcinoma, 4; and others, 6 (immature teratoma, 1; carcinosarcoma, 3; squamous cell carcinoma, 1; and mixed, 1)), to assess treatment strategies and useful biomarkers for malignant ovarian tumors. Overall, actionable gene variants were found in 90.9%, and druggable gene variants were found in 40.9% of the cases. Actionable BRCA1 and BRCA2 variants were found in 4.5% of each of the cases. ERBB2 amplification was found in 33.3% of mucinous carcinoma cases. Druggable hypermutation/ultramutation (tumor mutation burden ≥ 10 SNVs/Mbp) was found in 7.4% of high-grade serous carcinoma, 46.7% of endometrioid carcinoma, 10% of clear cell carcinoma, 0% of mucinous carcinoma, 25% of undifferentiated carcinoma, and 33.3% of the other cancer cases. Copy number alterations were significantly higher in high-grade serous carcinoma (P < .005) than in other histologic subtypes; some clear cell carcinoma showed high copy number alterations that were correlated with advanced stage (P < .05) and worse survival (P < .01). A high count of copy number alteration was associated with worse survival in all malignant ovarian tumors (P < .05). Our study shows that targeted agents can be detected in approximately 40% of malignant ovarian tumors via multigene panel testing, and copy number alteration count can be a useful marker to help assess risks in malignant ovarian tumor patients.

[Development and evaluation of communication skills learning suitable for community pharmacy].

It is a prerequisite for community pharmacists to maintain appropriate communication with patients, but a pharmacist licensee usually must learn communication-skills after starting work as a pharmacist. However, an education system and its evaluation methods are expected to be established, since the extent of self-training and rapidity of skill acquisition may vary largely among pharmacists. Therefore in this study we developed a communication-skills education program suitable for community pharmacies, developed objective-structured clinical examination (OSCE) appraisal charts, and carried out that education and its evaluation for a period of 8 months. The appraisal charts created by us were based on items of the "patient-communication station" categorized as one of the six stations in the five areas of pharmacy OSCE. Our questionnaire for pharmacist trainees after receiving communication-skills education/evaluation resulted in responses including such comments as: the education helped to improve their communication-skills; was useful in actual patient consultations; and increased self-confidence in their work. The OSCE scores gradually increased as the trainees completed more courses in the education program. These results show that the education program, which employs an OSCE appraisal chart, leads to specific outcomes in communication skills learning.

Development of pseudoaneurysm in cesarean section scar pregnancy: a case report and literature review.

Cesarean scar pregnancy (CSP) is a rare type of ectopic pregnancy. It is becoming more common, but it can lead to uterine rupture and severe hemorrhage. Here, we report a case of a 37-year-old woman with CSP complicated with pseudoaneurysm. The pseudoaneurysm emerged following focal injection of methotrexate (MTX) and potassium chloride with systemic MTX treatment. Due to a risk of sudden bleeding, uterine artery embolization (UAE) was recommended, but the patient hoped to avoid this if possible. Because the serum human chorionic gonadotropin level and the gestational sac were still persistent, dilation and curettage were performed with interventional radiologists on standby. Severe hemorrhage occurred and continued during the procedure, which necessitated emergent UAE. We reviewed six CSP case reports with vascular abnormalities, and all of them necessitated UAE, surgical excision, or hysterectomy. In the case of CSP combined with pseudoaneurysm, treatment should be planned carefully considering the risk of massive hemorrhage.

Clear cell carcinoma of the lower uterine segment: A case report.

Uterine carcinoma of the lower uterine segment (LUS) is a rare tumor that accounts for 3-3.5% of cases of uterine malignant cancer. The tumor arises from the lower region of the uterine body through the upper region of the cervix. The present study reported a case of clear cell carcinoma that originated from the LUS. A 50-year-old woman visited a local hospital due to irregular vaginal bleeding. She was suspected to have a uterine tumor and was referred to Tachikawa Hospital (Tokyo, Japan). Transvaginal ultrasound and magnetic resonance imaging revealed a uterine tumor from the lower region of the uterine body through the upper region of the cervix. Endocervical curettage revealed clear cell carcinoma. Based on a diagnosis of clear cell carcinoma of the LUS, radical hysterectomy was performed with bilateral salpingo-oophorectomy, paraaortic lymph node dissection and omentectomy. Macroscopically, the tumor was limited to the lower region of the uterine body through the upper region of the cervix in the resected uterus. Histopathological findings indicated no tumors in the uterine corpus and uterine cervix, but clear cell carcinoma was observed in the LUS epithelium. At the 1-year follow-up, the patient remained free of local recurrence and metastasis. To the best of our knowledge, clear cell carcinoma of the LUS has not previously been reported. More cases are required to clarify the pathology.