Adverse Events Associated With Long-term Treatment of Epithelial Ovarian Cancer With Bevacizumab and Chemotherapy.

BACKGROUND/AIM: Adverse events associated with long-term bevacizumab administration for ovarian cancer have been poorly documented in Japan. This study aimed to evaluate the adverse events of bevacizumab combined with chemotherapy for treating primary and recurrent epithelial ovarian cancer in Japan. PATIENTS AND METHODS: In this single-center retrospective study, we analyzed data of patients with advanced and recurrent epithelial ovarian cancer treated with bevacizumab and chemotherapy between January 2013 and November 2019. Statistical analyses were performed using the Fisher's exact test and Kaplan-Meier method. RESULTS: A total of 46 patients were included and the follow-up time was 30 months. The median duration of bevacizumab treatment was 14 months, and the median total dose of bevacizumab was 247.5 mg/kg. The most common adverse events were hypertension (n=30; 65.2%) and proteinuria (n=24; 49%) in all grades. The onset of hypertension and proteinuria occurred at a median of 2 months and 14 months after treatment initiation in all grades, respectively. Gastrointestinal perforation occurred significantly more frequently in patients with a history of radiation therapy. CONCLUSION: This study included cases of primary advanced and recurrent epithelial ovarian cancer, and had a longer observation period and reported more adverse events of bevacizumab with chemotherapy than previous reports. The administration of bevacizumab therapy in patients with a history of radiation should be carefully considered due to increased chances of gastrointestinal perforation.

Comparison of perinatal outcomes between controlled-release dinoprostone vaginal delivery system (PROPESS) and metreurynter for cervical ripening in labor induction: A retrospective single-center study in Japan.

AIM: This study aimed to compare the efficacy and safety of a controlled-release dinoprostone vaginal delivery system (PROPESS) and a metreurynter for labor induction. METHODS: This retrospective case-controlled study included 117 pregnant women (51 and 66 in the PROPESS and metreurynter groups, respectively) who required labor induction after >37 weeks' gestation at Mie University Hospital between January 2018 and September 2020. The primary outcome was the success rate of vaginal delivery. The secondary outcomes were changes in the Bishop score from the first insertion of PROPESS or the metreurynter to removal, uterine hyperstimulation and non-reassuring fetal status during the first insertion, proportion of pregnant women who needed pre-delivery oxytocin after removal, time to vaginal delivery after the first insertion, proportion of pregnant women who delivered vaginally within 12 or 24 h after the first insertion, and neonatal outcomes. RESULTS: The proportion of pregnant women, especially primiparas, who delivered vaginally was significantly higher in the PROPESS group (26/34 [76.5%]) than in the metreurynter group (25/52 [48.1%]; p = 0.01). Moreover, among multiparas in the PROPESS group who delivered vaginally, nine (56.3%) out of 16 women delivered vaginally within 3 h of labor onset. CONCLUSIONS: PROPESS for cervical ripening may reduce the risk of undergoing cesarean section in pregnant women requiring labor induction, especially primiparas. It is important to consider the possibility of precipitate labor when using the PROPESS in multiparas.

Short-term outcomes of robot-assisted versus conventional laparoscopic surgery for early-stage endometrial cancer: A retrospective, single-center study.

AIM: We compared the short-term outcomes between conventional laparoscopic surgery (CLS) and robot-assisted surgery (RAS) to assess the technical feasibility of the latter for early-stage endometrial cancer. METHODS: We retrospectively compared the perioperative outcomes between two groups of 223 patients (CLS group, n = 102; RAS group, n = 121) with early-stage endometrial cancer. Surgical procedures included hysterectomy, bilateral salpingo-oophorectomy and retroperitoneal lymphadenectomy. We analyzed the data from intrapelvic surgery alone because para-aortic lymphadenectomy was performed via conventional endoscopic extraperitoneal approach without robot for both groups. RESULTS: No differences were identified in patients' age and body mass index. The mean operative time was 133 ± 28 versus 178 ± 41 min (P < 0.01), mean blood loss was 196 ± 153 versus 237 ± 146 mL (P = 0.047), mean length of postoperative hospital stay was 9 ± 4 versus 8 ± 3 days (P = 0.01) and mean rate of perioperative complications of Clavien-Dindo grade III or higher was 2.0 versus 3.4% (P = 0.53) for the CLS versus RAS groups, respectively. There was no significant difference in the number of resected lymph nodes. CONCLUSION: The operative time was significantly longer and blood loss was significantly greater in the RAS group than in the CLS group, without a significant difference in the number of resected lymph nodes. These differences are within an acceptable clinical range, showing that RAS is feasible and safe for early-stage endometrial cancer, providing short-term outcomes comparable to those of conventional surgery. Future studies are warranted to compare the long-term oncological outcomes by extending the observation period and including para-aortic lymphadenectomy data.

Long-term oncological outcomes of minimally invasive radical hysterectomy for early-stage cervical cancer: A retrospective, single-institutional study in the wake of the LACC trial.

AIM: The objective of this study was to investigate the long-term oncological outcomes of minimally invasive radical hysterectomy (MIRH) for the treatment of early-stage cervical cancer retrospectively in the wake of the laparoscopic approach to cervical cancer (LACC) trial. METHODS: A total of 109 patients with stage IA1 with lymphovascular space involvement, IA2, and IB1 cervical cancers were included in this study. The surgical and oncological outcomes were retrospectively evaluated. All patients underwent type C MIRH with a no-touch isolation technique for cervical tumor. RESULTS: The median number of resected pelvic lymph nodes was 36 (range, 14-94), and 10 patients (9.2%) had positive nodes. One patient (0.9%) had positive surgical margins. Forty-six patients (42%) underwent adjuvant therapy. The median follow-up time was 73 months (range, 30-146 months). Five patients (4.6%) developed recurrent disease, and 3 patients (2.8%) died of cervical cancer. The 5-year disease-free survival and overall survival rates were 96.3% and 97.2%, respectively. A comparison between patients with tumor diameter ≤ 2 cm (n = 59) and those with tumor diameter > 2 cm (n = 50) did not identify any significant differences, with 5-year disease-free survival 96.6% versus 94.0% and 5-year overall survival 98.3% versus 96.0%, respectively. CONCLUSION: In this retrospective study, MIRH with a no-touch isolation technique for stage IA to IB1 cervical cancer was a safe approach in terms of oncological outcomes. However, every surgeon who treats early-stage cervical cancer should inform each patient of the results of the LACC trial because it has an exceedingly high impact.

9-(2-C-Cyano-2-deoxy-beta-D-arabino-pentofuranosyl)guanine, a potential antitumor agent against B-lymphoma infected with Kaposi's sarcoma-associated herpesvirus.

Several 9-(2-C-cyano-2-deoxy-l-beta-D-arabino-pentofuranosyl)purine derivatives were tested against Kaposi's sarcoma-associated herpesvirus (KSHV)-infected primary effusion lymphoma (PEL) cells. The guanine derivative (2, CNDAG) as well as the 2-amino-6-substituted-purine derivatives 3, 4 and 5 inhibited KSHV-positive cell growth but showed no cytotoxicity against KSHV-negative cells at >15 muM concentrations. Therefore, it was found that compounds 2, 3, 4 and 5 showed selective cytotoxicity against PEL cells infected with KSHV.

9-(2-C-Cyano-2-deoxy-beta-D-arabino-pentofuranosyl)guanine, a potential antitumor agent against B-lymphoma infected with Kaposi's sarcoma-associated herpesvirus.

Several 9-(2-C-cyano-2-deoxy-l-beta-d-arabino-pentofuranosyl)purine derivatives were tested against Kaposi's sarcoma-associated herpesvirus (KSHV)-infected primary effusion lymphoma (PEL) cells. The guanine derivative (3, CNDAG), as well as the 2-amino-6-substituted-purine derivatives 4, 5, and 6, exhibited cell growth inhibitory activity against KSHV-infected cells, but showed no cytotoxicity against KSHV-negative cells at >15 microM concentrations. Therefore, it was found that compounds 3, 4, 5, and 6 showed selective cytotoxicity against PEL cells infected with KSHV.

Epidemiology of Epstein-Barr virus, cytomegalovirus, and Kaposi's sarcoma-associated herpesvirus infections in peripheral blood leukocytes revealed by a multiplex PCR assay.

A multiplex polymerase chain reaction (PCR) has been developed for the simultaneous detection of Epstein-Barr virus (EBV), cytomegalovirus (CMV), and Kaposi's sarcoma-associated herpesvirus (KSHV) in a clinical sample. Primers of multiplex PCR were designed to amplify specific regions of the EBV EBNA1, CMV IE2, and KSHV LANA genes. This multiplex PCR assay was found to have detection sensitivities of 1-10 copies of purified viral DNA cloned into the plasmid. To assess diagnostic and pre-clinical applications with this method, we utilized KSHV-positive primary effusion lymphoma (PEL) cells, EBV-positive Burkitt's lymphoma cells, CMV-infected fibroblast cells, and clinically prepared peripheral blood leukocytes (PBLs) that had been infected with viruses. We found that this multiplex PCR assay has high sensitivity and specificity for simultaneous detection of EBV, CMV, and KSHV genomes in a single amplification from a clinical material. Using this multiplex PCR assay, we investigated the prevalence of EBV, CMV, and KSHV in PBL samples from normal Japanese randomly selected. KSHV, EBV, and CMV genomes were detected in samples from 2 (0.2%), 377 (39.5%), and 27 (2.8%) of the 953 blood donors, respectively. Interestingly, both EBV and CMV genomes were detected in samples from all KSHV-positive donors.

Apoptotic effect of ganciclovir on primary effusion lymphoma cells infected with Kaposi's sarcoma-associated herpesvirus.

We evaluated the cytotoxic and apoptotic effects of two purine nucleoside analogues, acyclovir (ACV) and ganciclovir (GCV), on lymphoma cells stably harboring Kaposi's sarcoma-associated herpesvirus (KSHV). Colorimetric caspase assay, flow cytometry, and immunoblotting with antibodies against apoptosis-related molecules revealed that GCV has cytotoxic activity toward KSHV-infected primary effusion lymphoma cells, while ACV has weak or little activity. In addition to the GCV-induced cytotoxicity, apoptosis via caspase-7/8, cleavage of poly(ADP-ribose) polymerase, and accumulation of p53 and p21 were induced by GCV treatment. In contrast, neither ACV nor GCV have cytotoxicity- or apoptosis-inducing activities toward uninfected cells.

Multiplex PCR-based DNA array for simultaneous detection of three human herpesviruses, EVB, CMV and KSHV.

Human lymphotropic herpesviruses, Epstein-Barr virus (EBV), cytomegalovirus (CMV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are responsible for a wide variety of human diseases. Due to an increase in diseased states associated with immunosuppression, more instances of co-morbid infections with these herpesviruses have resulted in viral reactivations that have caused numerous fatalities. Therefore, the development of rapid and accurate method to detect these viruses in immunocompromised patients is vital for immediate treatment with antiviral prophylactic drugs. In this study, we developed a new multiplex PCR method coupled to DNA array hybridization, which can simultaneously detect all three human herpesviruses in one single cell sample. Multiplex PCR primers were designed to amplify specific regions of the EBV (EBER1), CMV (IE) and KSHV (LANA) viral genomes. Pre-clinical application of this method revealed that this approach is capable of detecting as few as 1 copy of the viral genomes for KSHV and CMV and 100 copies of the genome for EBV. Furthermore, this highly sensitive test showed no cross-reactivity among the three viruses and is capable of detecting both KSHV and EBV viral genomes simultaneously in the lymphoblastoid cells that have been double infected with both viruses. Thus, this array-based approach serves as a rapid and reliable diagnostic tool for clinical applications.

Helicobacter pylori CagA induces Ras-independent morphogenetic response through SHP-2 recruitment and activation.

The CagA protein of Helicobacter pylori, which is injected from the bacteria into bacteria-attached gastric epithelial cells, is associated with gastric carcinoma. CagA is tyrosine-phosphorylated by Src family kinases, binds the SH2 domain-containing SHP-2 phosphatase in a tyrosine phosphorylation-dependent manner, and deregulates its enzymatic activity. We established AGS human gastric epithelial cells that inducibly express wild-type or a phosphorylation-resistant CagA, in which tyrosine residues constituting the EPIYA motifs were substituted with alanines. Upon induction, wild-type CagA, but not the mutant CagA, elicited strong elongation of cell shape, termed the "hummingbird" phenotype. Time-lapse video microscopic analysis revealed that the CagA-expressing cells exhibited a marked increase in cell motility with successive rounds of elongation-contraction processes. Inhibition of CagA phosphorylation by an Src kinase inhibitor, PP2, or knockdown of SHP-2 expression by small interference RNA (siRNA) abolished the CagA-mediated hummingbird phenotype. The morphogenetic activity of CagA also required Erk MAPK but was independent of Ras or Grb2. In AGS cells, CagA prolonged duration of Erk activation in response to serum stimulation. Conversely, inhibition of SHP-2 expression by siRNA abolished the sustained Erk activation. Thus, SHP-2 acts as a positive regulator of Erk activity in AGS cells. These results indicate that SHP-2 is involved in the Ras-independent modification of Erk signals that is necessary for the morphogenetic activity of CagA. Our work therefore suggests a key role of SHP-2 in the pathological activity of H. pylori virulence factor CagA.