Surgical anatomy of the common iliac veins during para-aortic and pelvic lymphadenectomy for gynecologic cancer

Kazuyoshi Kato,Shinichi Tate,Kyoko Nishikimi,Makio Shozu 대한부인종양학회 2014 Journal of Gynecologic Oncology Vol.25 No.1

Objective: Compression of the left common iliac vein between the right common iliac artery and the vertebrae is known to be associated with the occurrence of left iliofemoral deep vein thrombosis (DVT). In this study, we described the variability in vascular anatomy of the common iliac veins and evaluated the relationship between the degree of iliac vein compression and the presence of DVT using the data from surgeries for gynecologic cancer. Methods: The anatomical variations and the degrees of iliac vein compression were determined in 119 patients who underwent systematic para-aortic and pelvic lymphadenectomy during surgery for primary gynecologic cancer. Their medical records were reviewed with respect to patient-, disease-, and surgery-related data. Results: The degrees of common iliac vein compression were classified into three grades: grade A (n=28, 23.5%), with a calculated percentage of 0%-25% compression; grade B (n=47, 39.5%), with a calculated percentage of 26%-50% compression; and grade C (n=44, 37%), with a calculated percentage of more than 50% compression. Seven patients (5.9%) had common iliac veins with anomalous anatomies; three were divided into small caliber vessels, two with a flattened structure, and two had double inferior vena cavae. The presence of DVT was associated with the elevated D-dimer levels but not with the degree of iliac vein compression in this series. Conclusion: Although severe compression of the common iliac veins was frequently observed, the degree of compression might not be associated with DVT in surgical patients with gynecologic cancer. Anomalous anatomies of common iliac veins should be considered during systematic para-aortic and pelvic lymphadenectomy in the gynecologic cancer patients.

Predictors of postoperative pancreatic fistula after splenectomy with or without distal pancreatectomy performed as a component of cytoreductive surgery for advanced ovarian cancer

Kyoko Nishikimi,Shinichi Tate,Ayumu Matsuoka,Satoyo Otsuka,Makio Shozu 대한부인종양학회 2022 Journal of Gynecologic Oncology Vol.33 No.3

Objective: Splenectomy with or without distal pancreatectomy is occasionally performed during cytoreductive surgery for advanced ovarian cancer. We investigated pre-, intra-, postoperative risk factors and predictors of clinically relevant postoperative pancreatic fistula (CR-POPF) in patients who underwent cytoreductive surgery for advanced ovarian cancer. Methods: We investigated 165 consecutive patients with ovarian, fallopian tube, and peritoneal carcinoma categorized as stage III/IV disease, who underwent splenectomy with or without distal pancreatectomy as a component of cytoreductive surgery performed as initial treatment at Chiba University Hospital. Patient characteristics, clinical factors, and surgical outcomes were compared between those with and without CR-POPF. Results: CR-POPF occurred in 20 patients (12%). There were no significant intergroup differences in the characteristics between patients with CR-POPF and patients without CR-POPF except for operative time, intraoperative blood loss, amylase (AMY) levels in drain fluid on postoperative day (POD)1 and POD3, and pancreatic stump thickness. Multivariate analysis showed that the POD3 drain fluid AMY level was the only significant risk factor and predictor of CR-POPF in patients who underwent cytoreductive surgery for advanced ovarian cancer. The receiver operating characteristic curve of the POD3 drain fluid AMY level, which predicted development of CR-POPF showed an area under the curve of 0.77, and the optimal cut-off value of AMY was 808 U/L. A pancreatic fistula did not occur in patients with POD3 drain fluid AMY levels <130 U/L. Conclusion: The POD3 drain fluid AMY level can be early diagnostic predictor CR-POPF after splenectomy with or without distal pancreatectomy for advanced ovarian cancer.

Integrative analysis reveals early epigenetic alterations in high-grade serous ovarian carcinomas

Machino Hidenori,Dozen Ai,Konaka Mariko,Komatsu Masaaki,Nakamura Kohei,Ikawa Noriko,Shozu Kanto,Asada Ken,Kaneko Syuzo,Yoshida Hiroshi,Kato Tomoyasu,Nakayama Kentaro,Saloura Vassiliki,Kyo Satoru,Hamam 생화학분자생물학회 2023 Experimental and molecular medicine Vol.55 No.-

High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecological malignancy. To date, the profiles of gene mutations and copy number alterations in HGSOC have been well characterized. However, the patterns of epigenetic alterations and transcription factor dysregulation in HGSOC have not yet been fully elucidated. In this study, we performed integrative omics analyses of a series of stepwise HGSOC model cells originating from human fallopian tube secretory epithelial cells (HFTSECs) to investigate early epigenetic alterations in HGSOC tumorigenesis. Assay for transposase-accessible chromatin using sequencing (ATAC-seq), chromatin immunoprecipitation sequencing (ChIP-seq), and RNA sequencing (RNA-seq) methods were used to analyze HGSOC samples. Additionally, protein expression changes in target genes were confirmed using normal HFTSECs, serous tubal intraepithelial carcinomas (STICs), and HGSOC tissues. Transcription factor motif analysis revealed that the DNA-binding activity of the AP-1 complex and GATA family proteins was dysregulated during early tumorigenesis. The protein expression levels of JUN and FOSL2 were increased, and those of GATA6 and DAB2 were decreased in STIC lesions, which were associated with epithelial-mesenchymal transition (EMT) and proteasome downregulation. The genomic region around the FRA16D site, containing a cadherin cluster region, was epigenetically suppressed by oncogenic signaling. Proteasome inhibition caused the upregulation of chemokine genes, which may facilitate immune evasion during HGSOC tumorigenesis. Importantly, MEK inhibitor treatment reversed these oncogenic alterations, indicating its clinical effectiveness in a subgroup of patients with HGSOC. This result suggests that MEK inhibitor therapy may be an effective treatment option for chemotherapy-resistant HGSOC.

Well-trained gynecologic oncologists can perform bowel resection and upper abdominal surgery safely

Kyoko Nishikimi,Shinichi Tate,Kazuyoshi Kato,Ayumu Matsuoka,Makio Shozu 대한부인종양학회 2020 Journal of Gynecologic Oncology Vol.31 No.1

Objective: This study was performed to examine the safety of bowel resection and upper abdominal surgery in patients with advanced ovarian cancer performed by gynecologic oncologists after training in a monodisciplinary surgical team. Methods: We implemented a monodisciplinary surgical team consisting of specialized gynecologic oncologist for advanced ovarian cancer. In the initial learning period in 65 patients with International Federation of Gynecology and Obstetrics (FIGO) III/IV, a gynecologic oncologist who had a certification as a general surgeon trained 2 other gynecologic oncologists in bowel resection and upper abdominal surgery for 4 years. After the initial learning period, the trained gynecologic oncologists performed surgeries without the certificated general surgeon in 195 patients with FIGO III/IV. The surgical outcomes and perioperative complications during the 2 periods were evaluated. Results: The rates of achieving no gross disease after cytoreductive surgery were 80.0% in the initial learning period and 83.6% in the post-learning period (p=0.560). The incidence of anastomotic leakage after rectosigmoid resection, symptomatic pleural effusion or pneumothorax after right diaphragm resection, and pancreatic fistula after splenectomy with distal pancreatectomy in the 2 periods were 2 of 34 (6.0%), 1 of 33 (3.0%), and 3 of 15 (20.0%) patients in the initial learning period, and 12 of 147 (8.2%), 1 of 118 (0.8%), and 11 of 84 (13.1%) patients in the post-learning period, respectively. There were no significant differences between the 2 groups (p=0.270, p=0.440, p=0.520, respectively). Conclusion: Bowel resection and upper abdominal surgery can be performed safely by gynecologic oncologists.

Treatment results of the second-line chemotherapy regimen for patients with low-risk gestational trophoblastic neoplasia treated with 5-day methotrexate and 5-day etoposide

Toshiyuki Kanno,Hideo Matsui,Yoshika Akizawa,Hirokazu Usui,Makio Shozu 대한부인종양학회 2018 Journal of Gynecologic Oncology Vol.29 No.6

Objective: Highly effective chemotherapy for patients with low-risk gestational trophoblastic neoplasia (GTN) is associated with almost a 100% cure rate. However, 20%–30% of patients treated with chemotherapy need to change their regimens due to severe adverse events (SAEs) or drug resistance. We examined the treatment outcomes of second-line chemotherapy for patients with low-risk GTN. Methods: Between 1980 and 2015, 281 patients with low-risk GTN were treated. Of these 281 patients, 178 patients were primarily treated with 5-day intramuscular methotrexate (MTX; n=114) or 5-day drip infusion etoposide (ETP; n=64). We examined the remission rates, the drug change rates, and the outcomes of second-line chemotherapy. Results: The primary remission rates and drug resistant rates of 5-day ETP were significantly higher (p<0.001) and significantly lower (p=0.002) than those of 5-day MTX, respectively. Forty-seven patients (26.4%) required a change in their chemotherapy regimen due to the SAEs (n=16) and drug resistance (n=31), respectively. Of these 47 patients failed the first-line regimen, 39 patients (39/47, 82.9%) were re-treated with single-agent chemotherapy, and 35 patients (35/39, 89.7%) achieved remission. Four patients failed second-line, single-agent chemotherapy and eight patients (17.0%) who failed first-line regimens were treated with combined or multi-agent chemotherapy and achieved remission. Conclusions: Patients with low-risk GTN were usually treated with single-agent chemotherapy, while 20%–30% patients had to change their chemotherapy regimen due to SAEs or drug resistance. The second-line regimens of single-agent chemotherapy were effective; however, there were several patients who needed multiple agents and combined chemotherapy to achieve remission.

Tailored-dose chemotherapy with gemcitabine and irinotecan in patients with platinum-refractory/resistant ovarian or primary peritoneal cancer: a phase II trial

Shinichi Tate,Kyoko Nishikimi,Ayumu Matsuoka,Satoyo Otsuka,Kazuyoshi Kato,Yutaka Takahashi,Makio Shozu 대한부인종양학회 2021 Journal of Gynecologic Oncology Vol.32 No.1

Objective: We investigated the efficacy and toxicity of tailored-dose chemotherapy withgemcitabine and irinotecan for platinum-refractory/resistant ovarian or primary peritoneal cancer. Methods: We enrolled patients with ovarian or primary peritoneal cancer who received ≥2previous chemotherapeutic regimens but developed progressive disease during platinum based chemotherapy or within 6 months post-treatment. All patients received gemcitabine(500 mg/m2) and irinotecan (50 mg/m2) on days 1 and 8 every 21 days at the starting dose. Thedose was increased or decreased by 4 levels in subsequent cycles based on hematological ornon-hematological toxicities observed. The primary endpoint was progression-free survival(PFS), and secondary endpoints were disease control rate (DCR), overall survival (OS), andadverse events. Results: We investigated 25 patients who received 267 cycles (median 8 cycles/patient)between October 2008 and May 2011. Tailored-dose gemcitabine was administered up to the5th cycle as follows: 1,000 mg/m2in 1 (4%), 750 mg/m2in 16 (64%), 500 mg/m2in 6 (24%),and 250 mg/m2in 2 patients (8%). The median PFS and OS were 6.2 months (95% confidenceinterval [CI]=2.7–10.7) and 16.8 months (95% CI=9.4–30.7), respectively. The DCR was 76%,and PFS was >6 months in 12 of 25 patients (48%). Grade 3 hematological toxicities includedleukopenia (9.4%), neutropenia (11.2%), anemia (9.8%), and thrombocytopenia (1.1%). Grade 3/4 non-hematological toxicities did not occur except for fatigue in one patient. Conclusions: Tailored-dose chemotherapy with gemcitabine and irinotecan was effective andwell tolerated in patients with platinum-refractory/resistant ovarian or primary peritoneal cancer. Trial Registration: UMIN Clinical Trials Registry Identifier: UMIN000004449

Microscopic diseases remain in initial disseminated sites after neoadjuvant chemotherapy for stage III/IV ovarian, tubal, and primary peritoneal cancer

Shinichi Tate,Kyoko Nishikimi,Kazuyoshi Kato,Ayumu Matsuoka,Michiyo Kambe,Takako Kiyokawa,Makio Shozu 대한부인종양학회 2020 Journal of Gynecologic Oncology Vol.31 No.3

Objective: This study aimed to evaluate the presence of pathological residual tumor (pRT) in each initial disseminated site after neoadjuvant chemotherapy (NACT) to assess the appropriate surgical margins during interval debulking surgery (IDS) for a favorable prognosis. Methods: This prospective descriptive study included patients with stage IIIC–IV epithelial ovarian, fallopian tubal, and peritoneal cancer. One hundred eleven patients underwent diagnostic exploratory laparotomy, and their initial intra-abdominal dissemination statuses were recorded. Any tumor >1 cm in diameter found during the exploratory laparotomy was resected during IDS even if it was macroscopically invisible after NACT. The pRT rate after NACT and negative predictive value (NPV; probability that sites with macroscopically invisible tumors have no pRT) during IDS were assessed in each disseminated site. Results: A median of 5 NACT cycles were performed. Sites with a high incidence of pRT and low NPV included the rectosigmoid colon (71.4%, 38.6%), transverse mesentery (70.3%, 50.0%), greater omentum (68.3%, 51.7%), right diaphragm (61.9%, 48.1%), paracolic gutters (61.1%, 50.0%), and vesicouterine pouch (56.6%, 50.0%). Organs/tissues with a high incidence of pRT featured a low NPV. The median progression-free survival and overall survival in this cohort were 27.7 and 71.9 months, respectively. Conclusion: Even if a disseminated site >1 cm in diameter before NACT is invisible during IDS, microscopic disease remains present within it. The appropriate surgical margins for IDS with a favorable prognosis could be secured by resecting a lesion of >1 cm before NACT even if it is invisible during IDS.

Long-term outcomes of progestin plus metformin as a fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer patients

Akira Mitsuhashi,Yuji Habu,Tatsuya Kobayashi,Yoshimasa Kawarai,Hiroshi Ishikawa,Hirokazu Usui,Makio Shozu 대한부인종양학회 2019 Journal of Gynecologic Oncology Vol.30 No.6

Objective: The present study investigated long-term outcomes of medroxyprogesteroneacetate (MPA) plus metformin therapy in terms of control of atypical endometrial hyperplasia(AEH) and endometrial cancer (EC), and post-treatment conception. Methods: We retrospectively analyzed 63 patients (42 with EC; 21 with AEH) who underwentfertility-sparing management using MPA plus metformin. MPA (400 mg/day) and metformin(750–2,250 mg/day) were administered to achieve complete response (CR). Metformin wasadministered until conception, even after MPA discontinuation. Results: Of the total patients, 48 (76%) had a body mass index (BMI) ≥25 kg/m2 and 43 (68%)showed insulin resistance. Sixty-one patients (97%) achieved CR within 18 months. CR ratesat 6, 8–9, and 12 months were 60%, 84%, and 90%, respectively. During a median followupperiod of 57 months (range, 13–115 months), relapse occurred in 8 of 61 patients (13.1%)who had achieved CR. Relapse-free survival (RFS) in all patients at 5 years was 84.8%. Uponunivariate analysis, patients with BMI ≥25 kg/m2 had significantly better prognoses than didthose with BMI <25 kg/m2 (odds ratio=0.19; 95% confidence interval=0.05–0.66; p=0.009). Overall pregnancy and live birth rates per patient were 61% (19/31) and 45% (14/31), respectively. Conclusions: MPA plus metformin is efficacious in terms of RFS and post treatmentconception. Moreover, metformin may be more efficacious for patients with BMI ≥25 kg/m2.