Paclitaxel-carboplatin plus bevacizumab therapy for advanced neuroendocrine carcinoma of the uterine cervix: A retrospective case series.

AIM: There is no conclusive data on the prognosis of patients who receive paclitaxel-carboplatin (TC) plus bevacizumab therapy for advanced neuroendocrine carcinoma (NEC) of the uterine cervix, a rare histological subtype of cervical cancer. Thus, the aim of this study was to determine the efficacy of TC chemotherapy plus bevacizumab and bevacizumab single maintenance therapy for advanced NEC of the cervix. METHODS: This was a retrospective review of patients who received TC plus bevacizumab therapy for metastatic, recurrent, or persistent NEC of the cervix at seven institutions between 2015 and 2020. Relevant data were extracted from the patients' medical records and analyzed. RESULTS: Seven patients, including six with small-cell NEC and one with large-cell NEC, were included for analysis. Three patients received bevacizumab single maintenance therapy following TC plus bevacizumab therapy, whereas four patients did not receive bevacizumab single maintenance therapy. The median overall survival and progression-free survival of the patients who received bevacizumab single maintenance therapy were longer than those of the patients who did not receive the therapy (34 months vs. 10.5 months and 19 months vs. 5 months, respectively). However, the patients who received bevacizumab single maintenance therapy had received cisplatin-based chemotherapy previously. CONCLUSIONS: On the premise that cisplatin-based chemotherapy is administered as the first-line treatment for advanced NEC of the cervix, bevacizumab single maintenance therapy following TC plus bevacizumab may be considered the second- or third-line treatment. However, the risk of adverse events, such as intestinal perforation, should be discussed with patients.

Positive Ascites Cytology, Postoperative Chemotherapy and Prognosis of Stage I Ovarian Clear Cell Carcinoma.

BACKGROUND/AIM: Ovarian clear cell carcinoma (CCC) is associated with a poor prognosis and is resistant to chemotherapy. The aim of this study was to investigate the prognosis of CCC in Mie prefecture and to identify poor prognostic factors. PATIENTS AND METHODS: In this multi-center retrospective study, we analyzed the data of patients with CCC between February 2012 and December 2020. Patients were staged according to the International Federation of Gynecology and Obstetrics (FIGO) 2014 system. Statistical analyses were performed using the Kaplan-Meier method and compared between the two groups using the log-rank test. RESULTS: A total of 112 patients were included and the median follow-up time was 48 months. There was no difference in the prognosis between stages IA, IC1, and IC2. For patients at stages IA, IC1, and IC2, there was no difference in progression-free survival (PFS) and overall survival between the adjuvant chemotherapy and no chemotherapy groups. Median postrecurrent survival was 18 and 20 months in the stages I-II and III-IV groups, respectively. Multivariate analysis revealed that positive ascites cytology (p=0.006) was associated with PFS for patients at stages I-II and that the stage (p=0.039) was associated with PFS for patients at stages III-IV. CONCLUSION: Positive ascites cytology was a poor prognostic factor for patients at an early stage of CCC. Postoperative chemotherapy could be omitted for patients in stages IA and IC1. Relapsed patients did not respond to the standard treatment and had a poor prognosis regardless of the primary stage.

Real-world efficacy and safety of bevacizumab single-maintenance therapy following platinum-paclitaxel chemotherapy plus bevacizumab in patients with advanced cervical cancer.

OBJECTIVE: Bevacizumab maintenance therapy following platinum-based combination chemotherapy for metastatic, recurrent, or persistent cervical cancer is not recommended as standard therapy. This pilot study aimed to evaluate the efficacy and safety of bevacizumab maintenance therapy and the contribution of the platinum-free interval to the efficacy of subsequent chemotherapy for advanced cervical cancer. METHODS: We retrospectively identified 115 patients with metastatic, recurrent, or persistent cervical cancer treated with platinum-paclitaxel chemotherapy plus bevacizumab at 7 institutions between 2015 and 2020. The primary endpoints were overall survival (OS) and progression-free survival (PFS) in patients who received bevacizumab maintenance therapy and those who did not. We also analyzed the adverse events associated with bevacizumab and survival time from the start of subsequent chemotherapy in both groups. RESULTS: Following platinum-paclitaxel plus bevacizumab chemotherapy, 34 patients received bevacizumab maintenance therapy and 81 patients did not. Of the 115 patients, 56 received chemotherapy for subsequent relapse. Although bevacizumab maintenance therapy prolonged PFS (median of 16.0 months vs. 9.0 months, p=0.041), significant differences were not observed in OS (p=0.374). Furthermore, bevacizumab maintenance therapy did not prolong OS and PFS after the start of subsequent chemotherapy (p=0.663 and p=0.136, respectively). Bevacizumab maintenance therapy significantly increased hypertension (p=0.035) and proteinuria (p=0.005) but did not cause complications leading to death. CONCLUSION: Bevacizumab single-maintenance therapy for advanced cervical cancer can be considered in selected cases, such as those with acceptable bevacizumab-related side effects. The outcomes of our study will likely contribute to decision-making regarding practical treatment strategies.

Awareness of Infectious Disease Screening During Early Pregnancy and Knowledge About its Vertical Transmission in Japan: A Report from the Pregnant Women Health Initiative.

OBJECTIVES: We aimed to clarify the accuracy of pregnant women's knowledge and understanding regarding infectious disease screening in early pregnancy and clarify the roles that should be played by health care providers in promoting the health of pregnant women and their children. METHODS: A cross-sectional questionnaire survey was conducted in 25 hospitals across Japan from May 2018 to September 2019. We compared the agreement rates regarding screening results for hepatitis B virus (HBV), hepatitis C virus (HCV), syphilis, human T-cell leukemia virus-1 (HTLV-1), and cervical cytology in the medical records and understanding of their results by pregnant women. We then investigated whether participants had knowledge regarding the risk of mother-to child transmission in these diseases and factors associated with their knowledge. RESULTS: We enrolled 2,838 respondents in this study. The rates of agreement for HBV and cervical cancer screening related to human papillomavirus infection were "substantial," those for syphilis was "moderate," and those for HCV and HTLV-1 were "fair," according to the Kappa coefficient. The rate of knowledge regarding mother-to-child transmission of syphilis was highest (37.0%); this rate for the other items was approximately 30%. Increased knowledge was associated with higher educational level and higher annual income. CONCLUSIONS FOR PRACTICE: Pregnant women in Japan had generally good levels of understanding regarding their results in early-pregnancy infectious disease screening. However, they had insufficient knowledge regarding mother-to-child transmission of these diseases. Health care providers should raise awareness in infectious disease prevention among pregnant women and the general public, providing appropriate measures and implementing effective perinatal checkups and follow-ups for infectious diseases.

Does Vaginal Cuff Creation and Avoidance of a Uterine Manipulator Improve the Prognosis of Total Laparoscopic Radical Hysterectomy for Early Cervical Cancer? A Retrospective Multicenter Study.

Our goal was to compare the treatment outcomes of open-abdominal radical hysterectomy (O-RH) and total laparoscopic hysterectomy (TLRH) with vaginal cuff creation and without using a uterine manipulator in stage IB1-B2 (tumor size < 4 cm) cervical cancer cases. In this retrospective multicenter analysis, 94 cervical cancer stage IB1-B2 patients who underwent O-RH or TLRH in six hospitals in Japan between September 2016 and July 2020 were included; 36 patients underwent TLRH. Propensity score matching was performed because the tumor diameter was large, and positive cases of lymph node metastases were included in the O-RH group due to selection bias. The primary endpoint was progression-free survival (PFS) and recurrence sites of TLRH and O-RH. PFS and OS (overall survival) were not significant in both the TLRH (n = 27) and O-RH (n = 27) groups; none required conversion to laparotomy. The maximum tumor size was <2 and ≥2 cm in 12 (44.4%) and 15 (55.6%) patients, respectively, in both groups. Reportedly, the TLRH group had lesser bleeding than the O-RH group (p < 0.001). Median follow-up was 33.5 (2−65) and 41.5 (6−75) months in the TLRH and O-RH groups, respectively. PFS and OS were not significantly different between the two groups (TLRH: 92.6%, O-RH: 92.6%; log-rank p = 0.985 and 97.2%, 100%; p = 0.317, respectively). The prognosis of early cervical cancer was not significantly different between TLRH and O-RH. Tumor spillage was prevented by creating a vaginal cuff and avoiding the use of a uterine manipulator. Therefore, TLRH might be considered efficient.

Clinicopathological features and programmed death-ligand 1 immunohistochemical expression in a multicenter cohort of uterine and ovarian melanomas: a retrospective study in Japan (KCOG-G1701s).

The objective of this study was to propose prognostic factors and optimal treatment strategies by analyzing the clinicopathological features and programmed death-ligand 1 (PD-L1) expression. We analyzed 31 patients diagnosed with uterine or ovarian melanoma between 1997 and 2017 in the Kansai Clinical Oncology Group/Intergroup. Twenty-four and seven patients with cervical and ovarian melanomas were included, respectively. Immune checkpoint inhibitors were used in seven patients, and the objective response rate was 40%. Notably, two patients with objective responses had a high PD-L1 expression. Ten and four patients with cervical and ovarian melanomas, respectively, had high PD-L1 immunohistochemical expressions. Multivariate analysis revealed that tumor stage was an independent prognostic factor for progression-free survival in patients with cervical melanomas. In patients with ovarian melanomas, the 1-year cumulative progression-free and overall survival rates were 0 and 29%, respectively. Kaplan-Meier analyses revealed that age <60 years was associated with poorer progression-free and overall survivals in patients with ovarian melanomas. In patients with cervical melanomas, the 1-, 3-, and 5-year cumulative overall survival rates were 53, 32, and 16%, respectively. Histological atypia was associated with a poorer progression-free survival, but there was no difference in survival between patients who underwent radical hysterectomy and those who did not. The present study is a large cohort study of uterine and ovarian melanomas, which are aggressive tumors with a significantly poor prognosis, even after standard surgery and adjuvant therapy. The use of immune checkpoint inhibitors is a promising and effective treatment option.

Paclitaxel-carboplatin and bevacizumab combination with maintenance bevacizumab therapy for metastatic, recurrent, and persistent uterine cervical cancer: An open-label multicenter phase II trial (JGOG1079).

OBJECTIVE: This multicenter, open-label, phase II study aimed to evaluate the efficacy and safety of paclitaxel-carboplatin, bevacizumab, and bevacizumab-based maintenance therapy for metastatic, recurrent, and persistent uterine cervical cancer. METHODS: Patients with measurable diseases that were not adapted to regional therapies, such as surgery or radiotherapy, and were systematic chemotherapy-naïve were eligible. The participants received paclitaxel (175 mg/m2), carboplatin (AUC 5), and bevacizumab (15 mg/m2) every three weeks until disease progression or unacceptable adverse events occurred. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall response rate (ORR), overall survival (OS), safety, and time to treatment failure. RESULTS: Sixty-nine patients were analyzed using our protocol. The median paclitaxel- carboplatin therapy duration was six cycles; 40% of patients received bevacizumab maintenance therapy. The median PFS was 11.3 months. The median OS was not reached; the median time to treatment failure was 5.9 months. The ORR was 79.7% [95% confidence interval (CI) 63.8-88.4]; 16 patients (23.2%) showed complete response (CR) and 39 patients (56.5%) showed partial response (PR). The median PFS was 14.3 months (95% CI 7.3-17 months) for the 25 patients who received maintenance therapy and 7.4 months (95% CI 6.1-11 months) for nonrecipients (p = 0.0449). Gastrointestinal perforation/fistulas occurred in four patients (5.6%), all of whom had a history of radiation therapy. CONCLUSIONS: Paclitaxel-carboplatin and bevacizumab therapy is an acceptable and tolerable treatment for advanced or recurrent cervical cancer.

Practical use of C1 esterase inhibitor concentrate for clinical amniotic fluid embolism.

Amniotic fluid embolism (AFE) causes consumption coagulopathy, which requires a massive transfusion to save the mother's life. The preparation of such a massive transfusion is too time-consuming in extremely emergent clinical settings and occasionally leads to devastating side effects such as transfusion-associated acute lung injury. C1 esterase inhibitor (C1INH) is a protein with the ability to inhibit complement, coagulation and kinin pathways. The C1INH concentration in AFE patients is low, and it has been speculated that the administration of C1INH concentrate could have a striking and beneficial effect on AFE patients in critical condition by ameliorating their perturbed coagulation system. We report the case of a 32-year-old Japanese AFE patient in whom deteriorated vital signs and coagulopathy recovered within minutes after an injection of C1INH concentrate. C1INH concentrate can quickly revive the deteriorated vital signs and the atonic uterus that stem from AFE and may reduce the total amount of transfusion.

Comparing Papanicolaou test results obtained during pregnancy and post-partum.

AIM: Cervical cancer onset initially occurs during youth. Papanicolaou tests performed in early pregnancy can detect cervical cancer; however, Papanicolaou tests during pregnancy have been noted to be inaccurate, reflecting changes associated with pregnancy. Therefore, we assessed the effect of pregnancy on Papanicolaou test results. METHODS: Of 1351 pregnant women who delivered at Ise Red Cross Hospital between January 2010 and December 2014, 1213 underwent Papanicolaou tests at early pregnancy and post-partum. We compared the Papanicolaou test results. RESULTS: The results of the Papanicolaou test were different in 32 patients. Of the 1191 patients negative for intraepithelial lesions or malignancy in early pregnancy, 16 had other cytological abnormalities post-partum. We performed therapeutic conization post-partum in four patients. The Papanicolaou test results in early pregnancy of the four patients were negative for intraepithelial lesions or malignancy in one patient, atypical squamous cells of undetermined significance in one and high-grade squamous intraepithelial lesion in two. CONCLUSION: The results of the Papanicolaou test during pregnancy may not be accurate because of the influence of hormones associated with pregnancy. Taking advantage of the one-month post-partum screening visit can lead to early detection and treatment of cervical cancer in young people.

Spontaneous uterine rupture in the 35th week of gestation after laparoscopic adenomyomectomy.

Uterine rupture rarely occurs during pregnancy, but it is a critical situation if so. It is already known that a history of uterine surgeries, such as cesarean section or myomectomy, is a risk factor for uterine rupture. Currently, the laparoscopic adenomyomectomy is a widely performed procedure, but associated risks have not been defined. We observed a case of spontaneous uterine rupture in a patient during the 35th week of gestation, after a laparoscopic adenomyomectomy. A 42-year-old, gravida 2, para 0 woman became pregnant after a laparoscopic adenomyomectomy and her pregnancy was conventional. At a scheduled date in the 35th week of gestation, after combined spinal epidural anesthesia and frequent uterine contractions, a weak pain suddenly ensued. After 13 minutes of uterine contractions, vaginal bleeding was evident. A cesarean section was performed, and the uterine rupture was found in the scar. After a laparoscopic adenomyomectomy, a pregnant uterus can easily rupture by rather weak and short uterine contractions, and is characterized by vaginal bleeding. When uterine bleeding is observed in pregnant women that have a history of adenomyomectomy, one should consider uterine rupture.

Does positive peritoneal cytology not affect the prognosis for stage I uterine endometrial cancer?: the remaining controversy and review of the literature.

OBJECTIVE: The objective of this study was to elucidate factors that affect prognosis in patients with stage I endometrial cancer. METHODS: The study group comprised 265 patients with stage I endometrial cancer treated surgically at either of our facilities between January 1998 and December 2010 (238 patients with negative peritoneal cytology and 27 patients with positive peritoneal cytology). Progression-free survivals were evaluated between the 2 groups, and multivariate analysis was conducted with correlation factors including positive peritoneal cytology, vessel permeation, lymph node dissection, histologic diagnosis, age at diagnosis, adjuvant chemotherapy, and the depth of myometrial invasion. RESULTS: Disease-free survival was significantly poorer for patients with positive peritoneal cytology than those with negative peritoneal cytology on stage I disease (P = 0.000). The stratified log-rank test with vessel permeation shows the similar results. By univariate Cox model, positive peritoneal cytology, vessel permeation, and systemic lymph node dissection at surgery are significant factors on stage I endometrial cancer. CONCLUSIONS: Although this is a small-scale preliminary study with adjustment of other factors, positive peritoneal cytology can contribute to the risk of progression-free survival in patients with stage I endometrial cancer.

Association of CXC chemokine receptor type 4 expression and clinicopathologic features in human vulvar cancer.

OBJECTIVE: Although CXC chemokine receptor type 4 (CXCR4) is known to be expressed in various solid tumors and plays an integral role in cancer invasion and metastasis, expression of CXCR4 in human vulvar cancer has not yet been investigated. We examined distribution and expression of this chemokine receptor in specimens of invasive and noninvasive human vulvar neoplasms to elucidate its clinical significance. METHODS: Study patients were 38 consecutive patients (31 with primary vulvar cancers and 7 with intraepithelial neoplasms) treated at one of our hospitals. Sections of all specimens were evaluated for CXCR4 expression by means of immunohistochemistry. Relations between CXCR4 expression and clinicopathologic features including prognosis were investigated. RESULTS: None of the 7 vulvar intraepithelial lesions expressed CXCR4. Of the 31 invasive vulvar tumor samples examined, 19 (61%) stained positively for CXCR4; 15 (68%) of 22 squamous cell carcinomas and 2 (29%) of 7 Paget tumors were CXCR4 positive. The difference in expression between invasive cancers and intraepithelial neoplasms was significant (P = 0.003). FIGO (International Federation of Gynecology and Obstetrics) stage III-IV cancers, in comparison to FIGO stage I-II cancers, were more likely to be positive for CXCR4 (82% vs 50%, P = 0.08). In terms of disease-free survival, prognosis of cancers that expressed CXCR4 was poorer than that of CXCR4-negative cancers (P = 0.013), but in terms of disease-specific survival, prognosis did not differ significantly between CXCR4-positive and -negative cancers (P = 0.111). CONCLUSIONS: More than half of invasive squamous cell vulvar cancers can be expected to express CXCR4, and CXCR4 expression correlates with poor disease prognosis.

New terminology for intrauterine endometrial samples: a group study by the Japanese Society of Clinical Cytology.

OBJECTIVE: To evaluate the sensitivity and specificity of endometrial cytology obtained by intrauterine sample using a descriptive reporting format for endometrial cytological diagnosis. STUDY DESIGN: 10,152 consecutive endometrial scrapings obtained in 13 different Japanese hospitals were analyzed. Cytological results were classified as 'negative for malignancy', 'atypical endometrial cells' (ATEC), 'endometrial hyperplasia', 'atypical endometrial hyperplasia' or 'malignant tumor'. ATEC was subclassified as 'ATEC, of undetermined significance' (ATEC-US) and 'ATEC, cannot exclude atypical endometrial hyperplasia or more' (ATEC-A). Cytological results were compared with the histological diagnosis as a gold standard. When the cytological result was 'negative for malignancy' and there was no subsequent histological examination, the case was considered a true negative when the endometrium was assessed as normal on transvaginal ultrasonography and there was no abnormal uterine bleeding. RESULTS: 1,083 cases in which histology was not performed, 557 cases of 'unsatisfactory specimen' and 76 cases of ATEC-US were excluded. In the remaining 8,436 cases, the sensitivity and specificity, positive predictive value and negative predictive value for detecting atypical endometrial hyperplasia or malignant tumors were 79.0 and 99.7, 92.9 and 98.9%, respectively. CONCLUSION: The current diagnostic standards for endometrial cytology in Japan were established. Specificity is satisfactory for excluding cancer or precancerous diseases.