Evaluation of the role of intraoperative frozen section and magnetic resonance imaging in endometrial cancer.

OBJECTIVE: To evaluate the accuracy of preoperative endometrial biopsy and magnetic resonance imaging (MRI) of endometrial cancer compared with that of intraoperative frozen section. METHODS: This retrospective study included 264 patients who underwent surgery with intraoperative frozen section for endometrial cancer at our institution between 2014 and 2018. Diagnosis was determined by histologic type, grade, and myometrial invasion. Concordance rate, sensitivity, and specificity of preoperative diagnosis and intraoperative frozen diagnosis were calculated, in comparison to the final pathologic diagnosis. RESULTS: Preoperative and intraoperative diagnoses showed no statistically significant difference in determining histologic type and grade (P = 0.152). Intraoperative diagnosis showed higher sensitivity for endometrioid carcinoma grade 3 and other types, and higher specificity for grade 1. For myometrial invasion, intraoperative diagnosis showed significantly higher concordance rate than preoperative MRI findings (P < 0.01). Intraoperative diagnosis showed higher sensitivity and specificity in patients with and without myometrial invasion, respectively. CONCLUSION: Higher agreement between intraoperative and final diagnoses, especially in myometrial invasion, suggests that intraoperative frozen section is a good indicator for appropriate surgical procedure decision making.

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.

Prospective feasibility study of neoadjuvant dose-dense paclitaxel plus carboplatin with bevacizumab therapy followed by interval debulking surgery for advanced ovarian, fallopian tube, and primary peritoneal cancer patients.

BACKGROUND: This study aimed to investigate the clinical benefit of dose-dense paclitaxel plus carboplatin (TC) with bevacizumab therapy for advanced ovarian, fallopian tube, and primary peritoneal cancer patients in the neoadjuvant setting. METHODS: Ovarian, fallopian tube or primary peritoneal cancer patients with stage III-IV disease received neoadjuvant chemotherapy (NAC) every 3 weeks consisting of paclitaxel (80 mg/m2) on days 1, 8, and 15; carboplatin (AUC 6.0 mg/mL × min.) on day 1; and bevacizumab (15 mg/kg) on day 1. Interval debulking surgery (IDS) was performed after 3 cycles of dose-dense TC-bevacizumab therapy. The primary endpoint was the rate of complete resection by IDS. Secondary endpoints were treatment completion rate, treatment exposure, response rate to NAC, adverse events, and perioperative complications. RESULTS: Twenty-four patients were included in this study. The median age was 55.5 years (37-80 years), and most patients had high-grade serous carcinoma accounted (n = 18). IDS was performed in all patients with complete resection achieved in 75% (95% confidence interval: 57.7-92.3%). The lower limit exceeded the preset threshold rate of 55%. The response rate to NAC was 79%, and serum CA125 levels were in the normal range after NAC in 57% of patients. Grade 4 hematological toxicities and grade 3/4 non-hematological toxicities occurred in 29% and 17% of patients during NAC, respectively. Grade 3/4 perioperative complications were seen in 29% of patients, but no gastrointestinal perforations or treatment-related deaths occurred. CONCLUSIONS: Neoadjuvant dose-dense TC-bevacizumab therapy was well tolerated, and a satisfactory rate of complete resection by IDS was achieved.

Germline multigene panel testing revealed a BRCA2 pathogenic variant in a patient with suspected Lynch syndrome.

There has been a rapid advance in germline multigene panel testing by next-generation sequencing, and it is being widely used in clinical settings. A 56-year-old woman suspected of having Lynch syndrome was identified as a BRCA2 pathogenic variant carrier by multigene panel testing. The patient was diagnosed with endometrial cancer at the age of 39 years, and total laparoscopic hysterectomy and bilateral salpingectomy were performed at the age of 49 years; however, bilateral oophorectomy was not performed at that time. As she had a family history of colorectal cancer and a history of endometrial cancer, Lynch syndrome was suspected. However, germline multigene panel testing revealed a pathogenic BRCA2 variant rather than pathogenic variants in mismatch repair genes. In this case, with conventional genetic risk assessment, we were unable to determine whether the patient had a high risk of hereditary breast and ovarian cancer; thus, germline multigene panel testing may provide valuable information to improve disease management strategies for patients in clinical settings. Particularly, germline multigene panel testing may be useful for detecting hereditary tumor syndromes if a patient does not present with a typical family history of cancer.

Familial pancreatic cancer with PALB2 and NBN pathogenic variants: a case report.

BACKGROUND: Family history is one of the risk factors for pancreatic cancer. It is suggested that patients with pancreatic cancer who have a familial history harbor germline pathogenic variants of BRCA1 and/or BRCA2 (BRCA1/2), PALB2, or ATM. Recently, some germline variants of familial pancreatic cancers (FPCs), including PALB2, have been detected. Several countries, including Japan, perform screening workups and genetic analysis for pancreatic cancers. We have been carrying out active surveillance for FPC through epidemiological surveys, imaging analyses, and genetic analysis. CASE PRESENTATION: Here, we present the case of a female patient harboring pathogenic variants of PALB2 and NBN, with a family history of multiple pancreatic cancer in her younger brother, her aunt, and her father. Moreover, her father harbored a PALB2 pathogenic variant and her daughter harbored the same NBN pathogenic variant. Given the PALB2 and NBN variants, we designed surveillance strategies for the pancreas, breast, and ovary. CONCLUSIONS: Further studies are required to develop strategies for managing FPCs to facilitate prompt diagnosis before their progression.

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.

Patient-derived ovarian cancer organoids capture the genomic profiles of primary tumours applicable for drug sensitivity and resistance testing.

The use of primary patient-derived organoids for drug sensitivity and resistance testing could play an important role in precision cancer medicine. We developed expandable ovarian cancer organoids in < 3 weeks; these organoids captured the characteristics of histological cancer subtypes and replicated the mutational landscape of the primary tumours. Seven pairs of organoids (3 high-grade serous, 1 clear cell, 3 endometrioid) and original tumours shared 59.5% (36.1-73.1%) of the variants identified. Copy number variations were also similar among organoids and primary tumours. The organoid that harboured the BRCA1 pathogenic variant (p.L63*) showed a higher sensitivity to PARP inhibitor, olaparib, as well as to platinum drugs compared to the other organoids, whereas an organoid derived from clear cell ovarian cancer was resistant to conventional drugs for ovarian cancer, namely platinum drugs, paclitaxel, and olaparib. The overall success rate of primary organoid culture, including those of various histological subtypes, was 80% (28/35). Our data show that patient-derived organoids are suitable physiological ex vivo cancer models that can be used to screen effective personalised ovarian cancer drugs.

Establishment and characterization of a new malignant peritoneal mesothelioma cell line, KOG-1, from the ascitic fluid of a patient with pemetrexed chemotherapy resistance.

Malignant peritoneal mesothelioma (MPeM) is a rare and aggressive form of malignant mesothelioma. Sufficient biological tools for studying the functional characteristics of this cancer have not been developed. Therefore, in this study, a novel human cancer cell line, KOG-1, was established from ascites fluids isolated from a 39-year-old Japanese woman with pemetrexed-resistant MPeM. Cells were dendritic or linear immediately after thawing, showed a jigsaw puzzle-like and spindle arrangement during growth, and formed monolayers without contact inhibition in two-dimensional (2D) culture. The population doubling time was 13.7 h. Karyotypic and molecular genetic analyses showed that chromosome numbers ranged from 62 to 142, with a peak of 73 with complicated copy number alterations. No germline BAP1 pathogenic variant was detected. Cells expressed various tumor markers of mesothelioma, such as calretinin, podoplanin, and Wilms tumor 1 (WT-1). Drug sensitivity and resistance testing with a set of 36 drugs using 2D and three-dimensional (3D) culture models demonstrated that KOG-1 cells showed high and low sensitivity to pemetrexed under 2D and 3D culture conditions, respectively, whereas control ovarian cancer cell lines showed low sensitivity to pemetrexed under both culture conditions. This newly established cell line will be a valuable biological resource to expand the feasibility of functional studies as well as drug testing for potential therapeutic purposes in MPeM.

Efficacy and safety of dose-dense paclitaxel plus carboplatin as neoadjuvant chemotherapy for advanced ovarian, fallopian tube or peritoneal cancer.

OBJECTIVE: Interval debulking surgery (IDS) after neoadjuvant chemotherapy (NAC) is currently one of the preferred treatment options for advanced ovarian, fallopian tube or peritoneal cancer. This study was conducted to evaluate the clinical efficacy and safety of dose-dense paclitaxel plus carboplatin therapy (ddTC therapy) as NAC for these cancers. PATIENTS AND METHODS: A retrospective study was conducted in 25 patients with Stage III/IV ovarian, fallopian tube or peritoneal cancer who received ddTC therapy as NAC. For ddTC therapy, paclitaxel (80 mg/m2) was administered intravenously on Days 1, 8 and 15 and carboplatin (AUC 6.0 mg/ml × min) was administered intravenously on Day 1 every 3 weeks. IDS was performed after three cycles of ddTC therapy, and ddTC therapy was also continued after surgery. RESULTS: With ddTC therapy as NAC, the response rate was 92% and disease progression did not occur in any patient. Grade 4 hematologic toxicity and ≥Grade 3 non-hematologic toxicity both occurred in 8% of the patients, but no patient discontinued NAC because of adverse events. When IDS was performed, the complete surgery rate was 64% and the optimal surgery rate was 96%. ≥Grade 3 perioperative complications occurred in 16% of the patients, but there were no perioperative deaths. Median overall survival was 35.7 months and median progression-free survival was 17.7 months. CONCLUSION: This study showed that ddTC therapy was considerably effective and tolerable as NAC. The complete surgery rate was high with IDS, and perioperative complications were acceptable.

Elevated preoperative neutrophil : lymphocyte ratio as a preoperative indicator of mature cystic teratoma with malignant transformation.

AIM: To examine the usefulness of the neutrophil : lymphocyte (N/L) ratio as a cost-effective and simple diagnostic marker of mature cystic teratoma (MCT) with malignant transformation (MT). METHODS: A retrospective chart review was performed between 1998 and 2013 of 12 MCT patients with MT and between 2009 and 2013 of 130 patients with benign MCT. Data were collected on age, tumor size, white blood cell count with differential counts, tumor marker levels, and presenting features. RESULTS: Older age, greater tumor size, higher CA19-9 or CA125, higher neutrophil count, and higher N/L ratio were associated with MT on univariate analysis. White blood cell count; lymphocyte count; and the tumor marker squamous cell carcinoma antigen were not associated with MT. Older age (≥median), larger tumor size (≥10 cm), and high N/L ratio (≥5.0) were predictors of MT (hazard ratio, 11.51, 5.87, and 11.11, respectively). Six of 12 patients were diagnosed with MT on preoperative magnetic resonance imaging and five of 12 had an N/L ratio ≥5.0. CONCLUSIONS: Neutrophil : lymphocyte ratio is a potential preoperative diagnostic marker of MT. The optimal cut-off should be determined in future large-scale studies.

UGT1A1 polymorphism as a prognostic indicator of stage I ovarian clear cell carcinoma patients treated with irinotecan.

We investigated whether UGT1A1 polymorphisms are associated with the prognosis of ovarian cancer patients treated with irinotecan. UGT1A1 genotypes were analyzed in 11 stage I ovarian clear cell carcinoma patients who received irinotecan as first-line therapy. Progression-free survival, overall survival and adverse events were also assessed for each genotype. Three patients harbored UGT1A1*1/*6 while another three harbored UGT1A1*1/*28. Two patients with a wild-type genotype experienced recurrence and one died, whereas no recurrence or death was observed in patients with heterozygous genotypes. Adverse events tended to be more severe in patients with UGT1A1*6 and *28, although progression-free survival and overall survival rates tended to be better than in wild-type; the differences were not significant. We conclude that UGT1A1 polymorphisms have the potential to be a prognostic marker of irinotecan treatment.