Makio Shozu

Bevacizumab in frontline chemotherapy improved the survival outcome for advanced ovarian clear cell carcinoma: a multicenter retrospective analysis

Advanced ovarian clear cell carcinoma (OCCC) is associated with poor outcomes owing to chemoresistance. Bevacizumab (Bev) is increasingly being used to treat advanced ovarian cancer; however, its efficacy in OCCC remains unclear. This study evaluated the treatment outcomes of frontline bevacizumab chemotherapy in patients with OCCC. This retrospective multi-institutional study included patients diagnosed with advanced OCCC at eight institutions in Japan between 2008 and 2018. Patients were categorized into pre and post-market groups based on the Bev approval dates. Progression-free survival (PFS) and overall survival (OS) were analyzed using univariate and multivariate methods. Additionally, patients were classified into Bev-treated (Bev+) and non-Bev-treated (Bev-) groups, and their prognoses were compared. A total of 96 patients were in the pre-market group and 82 in the post-market group. The post-market group had a significantly higher proportion of patients with poor performance status and patients who underwent interval debulking surgery (p<0.01 and p<0.01, respectively). Univariate analysis demonstrated a better PFS in the post-market group (p=0.041). In multivariate analysis, better PFS (hazard ratio [HR]=0.52; p=0.002) and OS (HR=0.47; p=0.002) were observed in the post-market group than in the pre-market group. Bev+ patients had significantly better PFS and OS than Bev- patients in univariate (p<0.001 and p<0.001, respectively) and multivariate analyses (PFS: HR=0.36; p<0.001 and OS: HR=0.21; p=0.001, respectively). Incorporating Bev into frontline chemotherapy may improve outcomes in patients with advanced OCCC.

Intra- and postoperative complications associated with diaphragmatic surgery for advanced ovarian cancer

Diaphragmatic resection is frequently required to achieve optimal cytoreduction with no residual disease in patients with advanced ovarian cancer. Pleural effusion and pneumothorax are known short-term postoperative complications of diaphragmatic resection; however, few studies have reported intraoperative and long-term postoperative complications of this procedure. We investigated the intraoperative, as well as short- and long-term postoperative complications of diaphragmatic resection. Of the patients with stage III/IV ovarian cancer, who were initially treated at our hospital between 2008 and 2020, 267 patients who underwent diaphragmatic resection were included in this study. We recorded details regarding the type of diaphragmatic resection, type of closure, and intraoperative, as well as short- and long-term postoperative complications. Of the 264 patients who underwent right-sided diaphragmatic resection, 235 underwent full-thickness resection and 29 underwent peritoneal stripping. Of the 118 patients who underwent left-sided diaphragmatic resection, 23 underwent full-thickness resection and 95 underwent peritoneal stripping. Intraoperative complications occurred in 5 patients (massive bleeding from the right hepatic vein [n=1], massive bleeding during excision of the liver adherent to the diaphragm [n=1], and lung injury [n=3]). Short-term complications included pleural effusion that necessitated drainage in 2 and pneumothorax after drain removal in 1 patient. Long-term complications included right diaphragmatic hernia in 1, left diaphragmatic hernia in 2, and pancreaticopleural fistula in 1 patient. Diaphragmatic resection was associated with a low incidence of intra- and postoperative complications, which highlights the safety of this approach for management of advanced ovarian cancer.

Therapy‐related myeloid neoplasms after treatment for ovarian cancer: A retrospective single‐center case series

Abstract Objective Therapy‐related myeloid neoplasms (t‐MNs) are often fatal and arise as late complications of previous anticancer drug treatment. No single‐center case series has examined t‐MNs in epithelial ovarian cancer (EOC). Methods All patients with EOC treated at Chiba University Hospital between 2000 and 2021 were included. We retrospectively analyzed the characteristics, clinical course, and outcomes of patients who developed t‐MNs. Results Among 895 cases with EOC, 814 cases were treated with anticancer drugs. The median follow‐up period was 45 months (interquartile range, 27–81) months. Ten patients (1.2%) developed t‐MNs (FIGO IIIA in one case, IIIC in three, IVA in one, and IVB in five). Nine patients were diagnosed with myelodysplastic syndrome and one with acute leukemia. One patient with myelodysplastic syndrome developed acute leukemia. The median time from the first chemotherapy administration to t‐MN onset was 42 months (range, 21–94 months), with t‐MN diagnoses resulting from pancytopenia in four cases, thrombocytopenia in three, and blast or abnormal cell morphology in four. The median number of previous treatment regimens was four (range, 1–7). Paclitaxel + carboplatin therapy was administered to all patients, gemcitabine and irinotecan combination therapy to nine, bevacizumab to eight, and olaparib to four. Six patients received chemotherapy for t‐MN. All patients died (eight cancer‐related deaths and two t‐MN‐related deaths). None of the patients was able to restart cancer treatment. The median survival time from t‐MN onset was 4 months. Conclusions Patients with EOC who developed t‐MN were unable to restart cancer treatment and had a significantly worse prognosis.

Evaluation of the usefulness of sentinel lymph node mapping using indocyanine green in patients with cervical and endometrial cancers: A single‐center prospective exploratory study

AbstractAimSentinel lymph node (SLN) mapping using indocyanine green (ICG) is an alternative for reducing comprehensive lymph node dissection and its associated morbidity. This trial aimed to assess the efficacy and safety of ICG for SLN detection in patients with cervical and endometrial cancers at a single academic teaching hospital.MethodsThis single‐arm, open‐label trial conducted at Chiba University Hospital included patients with endometrial or cervical cancer, aged 20–70 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1. ICG was injected into the uterine cervix after anesthesia induction. For patients with endometrial cancer, ICG was additionally injected into the uterine myometrium after laparotomy. Imaging‐assisted surgery was then performed to locate and remove the SLNs. Systematic pelvic lymph node dissection was performed as the standard procedure, with additional para‐aortic lymph node dissection in selected cases.ResultsThe overall and bilateral SLN detection rates were 80.4% (37/46) and 50.0% (23/46), respectively. SLN identification was successful in 37 patients. Of these, 34 had pathologically negative SLNs, and all of them showed no lymph node metastasis in the backup dissection (negative predictive value: 100%). The remaining three cases had pathologically positive SLNs. No adverse events were observed in a total of 49 enrolled patients.ConclusionsICG injection was found to be safe. SLN mapping using ICG has demonstrated significant potential in reducing surgical interventions and associated complications in the treatment of early‐stage gynecological cancers.

High prevalence of pulmonary embolism prior to cancer therapies in patients with ovarian and endometrial cancers detected by contrast‐enhanced CT using D‐dimer as an index

AbstractObjectiveWe aimed to evaluate the prevalence of pulmonary embolism (PE) before cancer therapies in patients with ovarian and endometrial cancers with enhanced computed tomography (CT) using D‐dimer (DD), and determine the optimal cut‐off level of DD.MethodsSince 2009, we have performed preoperative venous thromboembolism (VTE) screening of patients with ovarian and endometrial cancer. For patients with DD levels of more than 1.0 μg/ml, enhanced CT images were obtained from the pulmonary apex to the foot to detect PE and deep venous thrombosis (DVT) simultaneously.ResultsAmong patients with ovarian cancer, 84 of 413 (20.3%) had VTEs (DVT alone, n = 31 [7.5%]; PE with or without DVT, n = 53 [12.8%]; PE alone, n = 12 [2.9%]). Among patients with endometrial cancer, 50 of 455 (11.0%) had VTEs (DVT alone, n = 19 [4.2%]; PE with or without DVT, n = 31 [6.8%], PE alone, n = 14 [3.1%]). The optimal cut‐off level of DD was estimated to be ≥1.5 and ≥1.2 μg/ml in ovarian and endometrial cancers, respectively.ConclusionOur study revealed a high prevalence of PE before cancer therapies in patients with ovarian and endometrial cancers by enhanced CT using DD.

Resolution of pelvic postoperative spindle cell nodule with sarcomatous onset after 9 years of follow‐up

AbstractIntroductionPostoperative spindle cell nodules are benign and reactive lesions that occur at the previous surgical site. It often develops like a sarcoma and is resected via highly invasive procedures. To date, there have been no published reports on the natural progression of postoperative spindle cell nodules without surgical intervention.CaseA 45‐year‐old woman underwent a total abdominal hysterectomy for leiomyoma. A 5‐cm pelvic mass exposed in the vaginal stump developed 7 weeks later, causing genital bleeding. Positron emission tomography–computed tomography revealed a pelvic mass and an enlarged pelvic lymph node with high uptake. We suspected an invasive sarcoma in the pelvis. However, through a transvaginal needle biopsy, the mass was diagnosed as a postoperative spindle cell nodule posthysterectomy. The nodule slowly reduced in size and completely disappeared 9 years posthysterectomy.ConclusionsCorrect diagnosis of this nodule with sarcomatous onset based on biopsy was important to avoid unnecessary surgeries. The lesion completely disappeared spontaneously after long‐term follow‐up.

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

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. 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. 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. 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.

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

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. 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. 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). Bowel resection and upper abdominal surgery can be performed safely by gynecologic oncologists.

Survival and reproductive outcomes after fertility‐sparing surgery performed for borderline epithelial ovarian tumor in Japanese adolescents and young adults: Results of a retrospective nationwide study

AbstractObjectiveEpithelial borderline ovarian tumor (BOT) frequently occurs in young women. Because progression‐free survival, overall survival, and reproductive function are important outcomes, BOT is often treated by fertility‐sparing surgery (FSS). We conducted a Japan‐wide study to understand post‐FSS prognosis in relation to clinical characteristics and types of FSS performed.MethodsWe analyzed clinical and outcome data pertaining to 531 adolescent and young adult (AYA) patients (aged 15–39 years) who underwent FSS for BOT between 2009 and 2013.ResultsMedian (range) age was 30 (15–39) years, and median observation time was 70 (2–120) months. The disease was of FIGO stage I in 492 (93%) patients. Histopathologically, tumors were of the mucinous (n = 372, 70%), serous (n = 120, 23%), seromucinous (n = 23, 4%), and other (n = 16, 3%) types. Five‐year overall survival was 99.5% among patients with stage I and 100% among those with stage II–IV. Five‐year progression‐free survival was 96.7% and 69.3%, respectively. Multivariate analysis in cases of stage I showed a positive peritoneal cytology to be a significant risk factor for recurrence (HR, 5.199; p = 0.0188). The post‐FSS pregnancy rate was relatively low for patients aged ≥30 years (OR, 0.868; 95% CI, 1.16–3.00; p = 0.0090).ConclusionPost‐FFS outcomes in terms of overall and progression‐free survival are favorable, especially for AYA patients with stage I BOT. However, the relapse rate is high for patients with FIGO stage II–IV and for those with stage I but a positive peritoneal cytology. A long‐term prospective observation is needed before reproductive outcomes can be fully established.

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

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. 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. 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. The POD3 drain fluid AMY level can be early diagnostic predictor CR-POPF after splenectomy with or without distal pancreatectomy for advanced ovarian cancer.

Fertility-sparing trachelectomy for early-stage cervical cancer: A proposal of an ideal candidate

To propose an ideal patient candidate with early-stage cervical cancer for undergoing fertility-sparing trachelectomy. This nationwide, multicenter, retrospective study was conducted by the Japan Society of Obstetrics and Gynecology involving women aged <45 years with clinical stage I-II cervical cancer who had planned fertility-sparing trachelectomy and pelvic lymphadenectomy between 2009 and 2013 (n = 393). Ideal candidates were defined to have a tumor size of ≤2 cm, no lymph node metastasis, no deep stromal invasion, and no high-risk histology (n = 284, 69.6%). Less-ideal candidates were defined to have any one of these four characteristics (n = 109, 30.4%). Propensity score inverse probability of treatment weighting was used to assess survival outcomes. Less-ideal candidates were more likely to undergo hysterectomy conversion (22.9% versus 3.2%), receive postoperative radiotherapy (11.9% versus 0.4%), or chemotherapy (32.1% versus 3.2%) compared with ideal candidates (all, P < 0.05). The weighted model revealed that among those who underwent trachelectomy (ideal candidates, n = 275 and less-ideal candidates, n = 84), less-ideal candidates had significantly decreased disease-free survival (5-year rates: 85.5% versus 95.5%; HR 3.93, 95% CI 1.99-7.74; P < 0.001) and cause-specific survival (92.5% versus 98.6%; HR 5.47, 95% CI 1.68-17.8, P = 0.001) compared with ideal candidates. Similarly, less-ideal candidates were significantly associated with decreased disease-free survival compared with ideal candidates among those who were young age, had small tumors or squamous histology, and underwent surgery alone (all, P < 0.05). Less-ideal candidates had approximately four-fold higher recurrence risk and cancer mortality compared with ideal candidates. Ideal candidates for fertility-sparing trachelectomy for early-stage cervical cancer proposed in our study may be useful as the future framework for developing guidelines for fertility-sparing trachelectomy in Japan.

Acceptability of self-sampling human papillomavirus test for cervical cancer screening in Japan: A questionnaire survey in the ACCESS trial

PurposeIn terms of medical policy for cervical cancer prevention, Japan lags far behind other industrialized countries. We initiated a randomized controlled trial to evaluate the self-sampling human papillomavirus (HPV) test as a tool to raise screening uptake and detection of pre-cancer. This study was conducted to explore the acceptability and preference of self-sampling using a subset of the data from this trial.MethodsA pre-invitation letter was sent to eligible women, aged 30−59 years who had not undergone cervical cancer screening for three or more years. After excluding those who declined to participate in this trial, the remaining women were assigned to the self-sampling and control groups. A second invitation letter was sent to the former group, and those wanting to undergo the self-sampling test ordered the kit. A self-sampling HPV kit, consent form, and a self-administered questionnaire were sent to participants who ordered the test.ResultsOf the 7,340 participants in the self-sampling group, 1,196 (16.3%) administered the test, and 1,192 (99.7%) answered the questionnaire. Acceptability of the test was favorable; 75.3−81.3% of participants agreed with positive impressions (easy, convenient, and clarity of instruction), and 65.1−77.8% disagreed with negative impressions (painful, uncomfortable, and embarrassing). However, only 21.2% were confident in their sampling procedure. Willingness to undergo screening with a self-collected sample was significantly higher than that with a doctor-collected sample (89.3% vs. 49.1%; p&lt;0.001). Willingness to undergo screening with a doctor-collected sample was inversely associated with age and duration without screening (both p&lt;0.001), but that with a self-collected sample was not associated.ConclusionsAmong women who used the self-sampling HPV test, high acceptability was confirmed, while concerns about self-sampling procedures remained. Screening with a self-collected sample was preferred over a doctor-collected sample and the former might alleviate disparities in screening rates.