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.

A case of nasal septal perforation caused by bevacizumab for advanced cervical cancer.

Nasal septal perforation caused by bevacizumab is rarely reported in other cancers such as ovarian cancer and breast cancer, but it has not been reported in cervical cancer. A 48-year-old woman with a medical history of chronic allergic rhinitis was diagnosed stage 4B (T2bN1M0) cervical cancer and paclitaxel and carboplatin along with bevacizumab (triweekly) were administered. After eight courses of chemotherapy, nasal septal perforation was noted. The possibility of nasal septal perforation by bevacizumab was considered by excluding other causes. We report the first case of nasal septal perforation caused by bevacizumab for advanced cervical cancer.

Lymphatic vessel involvement is predictive for lymph node metastasis and an important prognostic factor in endometrial cancer.

BACKGROUND: Lymphovascular space involvement is reported to be an important risk factor in endometrial cancer. This study was conducted to evaluate the separate prognostic effects of lymphatic invasion and venous invasion on the outcomes of patients with endometrial cancer. METHODS: From 2006 to 2013, 189 histologically confirmed endometrial cancer patients were examined. To study the venous invasion (v) of the endometrial cancer, Victoria blue-H&E staining-which positively stains the elastic fibers of vessels-was performed. Immunohistochemical staining with D2-40 was used to study the lymphatic invasion (ly) of the endometrial cancer. RESULTS: The median age of the patients was 57 (range 25-84) years. ly(+) and/or v(+) patients were significantly more likely to present an advanced cancer stage, G3 tumor, and deep myometrial invasion than ly(-)/v(-) patients. The incidence of lymph node metastasis was high in ly(+) patients, and that of ovarian metastasis was high in v(+) patients. Lymphatic vessel invasion was significantly correlated with regional lymph node metastasis. We found a significantly higher incidence of distant metastasis in ly(+) patients. Most recurrences in ly(+)/v(-) patients occurred in lymph nodes, while those in ly(+)/v(+) patients occurred mainly at distant organs. Finally, the prognosis was significantly poorer for ly(+) patients, in whom lymphatic invasion was an independent prognostic factor along with distant metastasis. CONCLUSIONS: Our study suggests that by separately evaluating lymphatic invasion and blood vessel invasion in endometrial cancer cases, useful information for predicting lymph node metastasis and recurrence sites as well as prognostic information can be obtained.

Therapy-free interval has prognostic value in patients with recurrent cervical cancer treated with chemotherapy following definitive concurrent chemoradiotherapy.

PURPOSE: Patients with cervical cancer recurrence after concurrent chemoradiotherapy (CCRT) who are not candidates for surgical resection or salvage radiotherapy have a dismal prognosis. The predictive factors for the effects of chemotherapy and prognostic factors in these patients were analyzed. METHODS: We collected data for patients with recurrent cervical cancer who were primarily treated with CCRT between 2000 and 2013. Among them, 57 patients treated with only systemic chemotherapy were analyzed for the overall survival (OS), the overall response rate (ORR), and prognostic factors. RESULTS: The median age was 47 years. Inside the irradiated field recurrence occurred in 24, outside in 20 and both in 13 patients. Time to recurrence after the CCRT (i.e., therapy-free interval; TFI) were <6 months in 11, 6-12 months in 15, ≥12 months in 23 patients, and persistent disease in 8 patients. The median OS was 18 months and ORR was 15.7%. Those with a longer TFI showed a tendency for better ORR (p = 0.051) and those receiving a taxane-containing regimen showed significantly higher ORR (p = 0.0232). Multivariate analysis revealed a significant correlation between the median OS and TFI (HR = 4.688, 95% CI = 2.178-11.10, p < 0.0001) and chemotherapy response (HR = 20.08, 95% CI = 3.936-368.4, p < 0.0001). Furthermore, even in patients with stable disease, the median OS increased corresponding to the length of the TFI (p < 0.0001). CONCLUSIONS: TFI has predictive value for response to chemotherapy and prognosis of patients with recurrent cervical cancer after definitive CCRT.

Prognostic Factors of Cervical Adenocarcinoma With Positive Pelvic Lymph Node Metastases Without Preoperative Lymph Node Enlargement Treated With Radical Hysterectomy.

BACKGROUND/AIM: Pelvic lymph node (LN) metastases are found histopathologically after radical hysterectomy (RH) in some cases of cervical adenocarcinoma with no enlarged LNs on preoperatively. The aim was to clarify whether LN metastasis is a prognostic factor in these patients, and whether any postoperative therapy is advisable. PATIENTS AND METHODS: Sixty-one patients with stage I-II cervical adenocarcinoma [International Federation of Obstetrics and Gynecology (FIGO) 2008] with no enlarged pelvic LNs on preoperative imaging evaluation who underwent RH at our institution were retrospectively examined for clinicopathological, treatment, and prognosis-related factors. RESULTS: The median age was 47 years. FIGO stages were IB1 in 44 patients, IB2 in 10, IIA in 4, and IIB in 3. Seventeen patients (27.9%) had positive pelvic LNs. The multivariate analysis for both overall (OS) and disease-free (DFS) survival showed only pelvic LN metastasis was an independent prognostic factor. In a multivariate analysis of LN-positive cases, multiple LN metastases was an independent prognostic factor for poorer DFS. OS rates were 100%, 83.3%, and 30.0%, and DFS rates were 85.5%, 83.3%, and 12.5% for patients with no LN metastasis, single metastasis, and multiple metastases, respectively, showing a significant difference. Eight recurrences were observed in 10 patients with multiple node-positive disease, and six (75%) had an intrapelvic recurrence. CONCLUSION: Among patients who underwent RH for cervical adenocarcinoma with no preoperative enlarged LN and positive pelvic LNs confirmed postoperatively, multiple positive pelvic LNs are an independent poor prognostic factor. Because pelvic recurrence is common, concurrent chemoradiotherapy, possibly using paclitaxel and cisplatin, should be considered as adjuvant therapy.

Caspase cleaves Drosophila BubR1 to modulate spindle assembly checkpoint function and lifespan of the organism.

Caspases cleave over 1500 substrates in the human proteome in both lethal and non-lethal scenarios. However, reports of the physiological consequences of substrate cleavage are limited. Additionally, the manner in which caspase cleaves only a subset of substrates in the non-lethal scenario remains to be elucidated. BubR1, a spindle assembly checkpoint component, is a caspase substrate in humans, the physiological function of which remains unclear. Here, we found that caspases, especially Drice, cleave Drosophila BubR1 between the N-terminal KEN box motif and C-terminal kinase domain. By using proximity labelling, we found that Drice, but not Dcp-1, is in proximity to BubR1, suggesting that protein proximity facilitates substrate preference. The cleaved fragments displayed altered subcellular localization and protein-protein interactions. Flies that harboured cleavage-resistant BubR1 showed longer duration of BubR1 localization to the kinetochore upon colchicine treatment. Furthermore, these flies showed extended lifespan. Thus, we propose that the caspase-mediated cleavage of BubR1 limits spindle assembly checkpoint and organismal lifespan. Our results highlight the importance of the individual analysis of substrates in vivo to determine the biological significance of caspase-dependent non-lethal cellular processes.

Effects of Pegylated Liposomal Doxorubicin and CA125 Level Variability Analysis in Platinum-refractory/resistant Recurrent Ovarian Cancer.

BACKGROUND/AIM: Ovarian cancer is a disease with significant impact, because more than half of cases exhibit recurrence despite platinum therapy. The choice of drug for cases of recurrence remains controversial, but the current option is pegylated liposomal doxorubicin (PLD). PATIENTS AND METHODS: We retrospectively reviewed the use of PLD in patients with ovarian cancer refractory or resistant to platinum-based therapy at our Department. We also examined efficacy, predictive indices of efficacy, and adverse events as well. RESULTS: In this study of PLD monotherapy for 60 platinum-refractory/resistant recurrent ovarian cancers, there was a median progression-free survival (PFS) of 4 months, median overall survival (OS) of 11 months, and the disease control rate (DCR) was 71.7%. The treatment effect can be predicted by the reduction of CA125 level after 2 courses. Patients with an increase and decrease in CA125 after 2 cycles of PLD, respectively, had a median OS of 14.5 (2-60) and 8 (2-51) months and a median PFS of 6 (2-38) months and 3 (0-47) months. CONCLUSION: PLD is clinically effective and useful because it provides a high DCR and is tolerable to adverse events. These findings can help support the use of PLD and guide physicians in their choice of treatment when encountering such cases.

Comprehensive Genomic Profiling for Therapeutic Decision and Identification of Gene Mutation in Uterine Endometrial Dedifferentiated Carcinoma.

Endometrial dedifferentiated carcinoma is a new concept among endometrial malignancies, is rare, and has a poor prognosis as it is discovered in advanced stages and has no established treatment. It has higher rates of gene mutations, such as mismatch repair, than general endometrial cancer and has been associated with Lynch syndrome. However, due to its heterogeneity, case-by-case searches are needed. Comprehensive genomic profiling by Foundation One® CDx can comprehensively identify over 300 gene mutations via a next-generation sequencer and can evaluate biomarkers, such as the microsatellite status and tumor mutation burden. Therefore, it may be beneficial in identifying therapeutic targets and drugs for diseases whose treatment has not been established. In this case, 13 therapies, including immune checkpoint inhibitor therapy for microsatellite instability-High and 40 clinical trials for several gene mutations might be beneficial. We report a case of endometrial dedifferentiated carcinoma for which Foundation One® CDx gene profiling was used to propose treatment.

Low-set umbilicus in a pregnant woman with bladder pseudoexstrophy: A case report.

Bladder pseudoexstrophy is a rare form of bladder exstrophy. Bladder exstrophy occurs in 1 in every 30,000 to 50,000 live births. Because bladder pseudoexstrophy is asymptomatic, it may be undiagnosed even in adulthood. A 31-year-old woman with uterus bicornis unicollis and a low-set umbilicus underwent emergency cesarean delivery during the 37th week of pregnancy for chorioamnionitis. Perioperatively, asymptomatic anatomical abnormalities were identified, which included separated rectus abdominis muscles and diastasis of the symphysis pubis. The urinary tract was normal. The patient was diagnosed with bladder pseudoexstrophy. A low-set umbilicus may be a potential marker for the diagnosis of bladder pseudoextrophy.

Changes in HPV16/18 Prevalence among Unvaccinated Women with Cervical Intraepithelial Neoplasia in Japan: Assessment of Herd Effects following the HPV Vaccination Program.

Since the human papillomavirus (HPV) vaccination program for Japanese girls aged 12-16 years began in 2010, vaccination uptake has been low in women born before 1993 but high (approximately 70%) in those born during 1994-1999. We previously compared the prevalence of vaccine types HPV16 and HPV18 in cervical intraepithelial neoplasia grade 1-3 (CIN1-3) or adenocarcinoma in situ (AIS) between vaccinated and unvaccinated cohorts and found direct protection effects among vaccinated women in Japan. In this study, we focused on changes in HPV16/18 prevalence among "unvaccinated" cohorts with CIN/AIS. We analyzed HPV16/18 prevalence among 5051 unvaccinated women aged <40 years, newly diagnosed with CIN/AIS during 2012-2021 for time trends. Declining trends in HPV16/18 prevalence over 9 years were observed in CIN1 (36.0-10.0%, Ptrend = 0.03) and CIN2-3/AIS (62.5-36.4%, Ptrend = 0.07) among women aged <25 years. HPV16/18 prevalence in CIN1 and CIN2-3/AIS diagnosed at age 20-24 years was lower in 1994-1999 birth cohorts compared with 1988-1993 birth cohorts (4.5% vs. 25.7% for CIN1 and 40.0% vs. 58.1% for CIN2-3/AIS, both p = 0.04). Significant reduction in HPV16/18 prevalence among young unvaccinated women with CIN1 and CIN2-3/AIS suggests herd effects of HPV vaccination in Japan.

Hyperbaric Oxygen Therapy for Suburethral Vaginal Mucosal Necrosis after Interstitial Irradiation for Recurrent Cervical Cancer.

Patients with gynecological malignancies can develop radiation injuries, such as cystitis, proctitis, and soft tissue necrosis which have approved indications for hyperbaric oxygen therapy (HBOT). A 76-year-old Japanese woman with vaginal recurrence of cervical cancer was treated with the high-dose rate interstitial brachytherapy. Twenty-one months after the irradiation, she developed radiation necrosis on the external urethral opening. Two cycles of HBOT were performed. HBOT consisted of delivering 100% oxygen for 60 minutes at 2.4 atmospheres absolute. Pressure exposure was performed once daily, 5 days a week for 6 weeks. Eventually, the necrotic mucosa was completely replaced by the normal mucosa. No adverse effects were observed. We successfully treated a case of late adverse events of radiation therapy with HBOT. It was noninvasive and appears to be a useful treatment option which should be considered standard treatment practice.

A high-risk gestational trophoblastic neoplasia derived from a complete hydatidiform mole with coexisting fetus identified by short tandem repeats analysis: A case report.

A complete hydatidiform mole coexisting with a fetus (CHMCF) is a rare form of twin pregnancy. High-risk gestational trophoblastic neoplasia (GTN) can occur after a CHMCF pregnancy, although the frequency is low. In cases of GTN, the clinical diagnosis and that based on the International Federation of Gynecology and Obstetrics (FIGO) scoring system can differ. This case report concerns a patient with a choriocarcinoma that was initially diagnosed and treated as a low-risk stage III GTN following a live birth from a CHMCF pregnancy. We used short tandem repeat (STR) analysis to identify the causative pregnancy as the patient's earlier complete hydatidiform mole. Clinicians should anticipate a high-risk GTN when treating persistent trophoblastic disease (PTD) in patients with a non-typical course.

Long-term Outcomes of Cervical Adenocarcinoma Treated With Concurrent Chemoradiotherapy Using Paclitaxel and Cisplatin.

BACKGROUND/AIM: We retrospectively analyzed the locally advanced adenocarcinoma (AC)/adenosquamous carcinoma (ASC) of the uterine cervix treated with concurrent chemoradiotherapy using cisplatin plus paclitaxel (TP-CCRT). PATIENTS AND METHODS: Thirty patients with stage IB-IVA AC/ASC were treated with whole pelvis external beam radiotherapy. A high-dose-rate intracavitary brachytherapy was delivered once per week at a fractional dose of 6 Gy. For TP-CCRT, the patients received cisplatin and paclitaxel. RESULTS: A complete response was achieved in 17 patients (77.3%) in the TP-CCRT group and 4 patients (50.0%) in the P-CCRT group. The 5-year OS rate in the TP-CCRT and P-CCRT groups was 74.2% and 25.0% (p=0.0094), the central DFS rate was 58.0% and 12.5% (p=0.0267), and the distant DFS rate was 63.6% and 12.5% (p=0.0042), respectively. CONCLUSION: TP-CCRT achieves a considerably better disease control for AC of the cervix, leading to a better OS.

Hysterectomy for Recurrent/Residual Cervical Cancer Following Definitive Radiotherapy.

BACKGROUND/AIM: Radical hysterectomy has been used for local recurrent or persistent (LR) cervical cancer after radiotherapy (RT), but the rate of serious complications is high and tolerance is low. This study determined the efficacy, safety, and prognostic factors of adjuvant simple hysterectomy in LR cervical cancer post-RT. PATIENTS AND METHODS: A total of 21 patients who underwent hysterectomy for LR cervical cancer post-RT in our Department between May 2007 and September 2018 were included in the study. Primary, definitive RT was performed. Histological response by definitive RT in the extirpated uterus was classified on the basis of histological response criteria: effect (Ef) 0-3. RESULTS: The 5-year overall survival (OS) and disease-free survival (DFS) rates were 51.9% and 50.1%, respectively. Ef 1 was significantly associated with poorer prognosis compared to Ef 2 or Ef 3. CONCLUSION: Adjuvant hysterectomy could be a treatment of choice for LR cervical cancer post-RT.

A Phase II Study of Neoadjuvant Chemotherapy Followed by Extended Field Concurrent Chemoradiotherapy for Para-aortic Lymph Node Positive Cervical Cancer.

BACKGROUND/AIM: We conducted a phase II study of neoadjuvant chemotherapy followed by extended field concurrent chemoradiotherapy in patients with cervical cancer with para-aortic node metastasis. PATIENTS AND METHODS: Thirty-seven women with stage IB1-IVA cervical cancer were enrolled. RESULTS: The median age was 52 years. Thirty-four patients other than 3 progressive disease, proceeded to extended field concurrent chemoradiotherapy. The 3-year overall survival and progression-free survival rates were 70.1% and 48.5%, respectively. The 3-year overall survival according to stages was significantly worse in stage IIIB. Twelve of the 17 patients with stage IIIB died of the disease. CONCLUSION: Neoadjuvant chemotherapy followed by extended field concurrent chemoradiotherapy may improve the prognosis of patients with stages IB and II cervical cancer with positive para-aortic node. However, new strategies should be investigated to improve a poor prognosis in stage IIIB disease with positive para-aortic node.

Tube-ovarian abscess caused by Rothia aeria.

Rothia aeria is a gram-positive amorphous bacillus and was discovered in the Russian space station 'Mir' in 1997. It shows phylogenetic similarity to Actinomyces israelii, and as determined using 16 s ribosomal RNA gene analysis R. aeria is classified as a bacteria of the genus Actinomyces It was found to colonise in the human oral cavity, and there are some infectious reports but none specifies gynaecological infection. A 57-year-old woman, who had been continuously using intrauterine contraceptive device, presented with fever and lower abdominal pain. She was suspected tube-ovarian abscess caused by A. israelii, but the uterine cavity culture revealed R. aeria infection. Considering surgical treatment, conservative treatment by intravenous benzylpenicillin and subsequently oral ampicillin for 6 months improved the abscess, and she has no recurrence for over 1 year.

Methotrexate-induced hemothorax in a woman with low-risk metastatic gestational trophoblastic disease.

•Patients with invasive mole have a risk of bleeding to fragility and vascularity of the tumor.•Some patients may experience life-threatening bleeding.•Chemotherapy of patients with invasive/metastatic mole may induce bleeding.•In our patient with pulmonary metastatic mole, massive hemorrhage occurred 2 h after the first dose of MTX.•Our patient was successfully treated with partial resection of the bleeding tumor and additional 2 cycles of MTX.

High-risk gestational choriocarcinoma with an unusual presentation and the treatment course of refractory or quiescent/minimally invasive disease.

•A patient with high-risk choriocarcinoma who had refractory or quiescent/minimally invasive disease.•She was treated with seven lines of chemotherapy and salvage surgeries.•The patient had persistently low hCG levels without evidence of disease for 4 years.•Then radiological evidence of pulmonary metastasis was finally achieved, and the patient was salvaged by surgery.•It is crucial to identify the site of active disease to facilitate surgical resection and cure.

Secondary uterine carcinosarcoma after concurrent chemoradiotherapy for cervical cancer: Case reports.

•Secondary uterine sarcomas occur in < 1% of patients treated with CCRT.•Secondary uterine sarcomas can occur > 5 years from CCRT.•The median survival period from the secondary tumor occurrence was only 4 months.•All our patients had heterologous carcinosarcoma of the uterine corpus.

Fetal Thoracoamniotic Shunting in a Case of Congenital Pulmonary Airway Malformations with Hydrops Fetalis.

Aim We report a case of congenital pulmonary airway malformation (CPAM) with hydrops in which the fetus underwent thoracoamniotic shunting. Case Report A 40-year-old (G1P1) woman was diagnosed with a macrocystic CPAM. Thoracoamniotic shunting was performed at 19 weeks of gestation but not well drained and was successfully performed again at 23 weeks. However, the CPAM volume ratio, abdominal circumference, and amniotic fluid index started increasing from 28 weeks and hydrops worsened. The insufficient shunting and the fetal cardiac failure had to be considered. At 32 weeks, a male infant with general edema and massive ascites was born weighing 3,362 g (+4.79 SD) with Apgar scores of 2 and 4. The infant was intubated and high-frequency oscillation and nitric oxide therapies were instituted. The resection of CPAM was performed on day 2. Nasal continuous positive airway pressure was instituted on day 16. The infant was discharged and prescribed with home oxygen therapy (HOT) on day 65. The infant was able to leave the HOT at 30 months and is currently 34 months of age in good condition. Conclusion Fetal thoracoamniotic shunting may be life-saving in CPAM complicated by hydrops and that this treatment might be sufficient to cure the child.