Satoshi Nakagawa

The value of vaginal cytology for postoperative surveillance of endometrial cancer

The value of conducting vaginal cytology surveillance after endometrial cancer (EC) surgery has not been fully established, yet in Japan it is still performed routinely in many institutions. We have retrospectively examined its diagnostic and prognostic values. We studied 759 EC cases that underwent hysterectomy at our hospital in Osaka, Japan from January 2010 to December 2019. Information on the clinicopathological factors at the time of initial and postoperative treatments, and the sites and diagnostic timing of recurrences were extracted from medical records and analyzed. Recurrences from primary EC were observed in 11.2% of the patients (85/759). In 23.5% of the cases (20/85), the recurrence included a vaginal component. The two most common single-sites of recurrence were vagina (14.1%, 12/85) and lung (12.9%, 11/85). The diagnosis of vaginal recurrence was made from symptoms and gynecological examination in 14 of the 20 cases. Only one was diagnosed solely by vaginal cytology; in that case, macroscopic lesions appeared two months after obtaining the abnormal cytology. We found that, in postoperative follow-up surveillance for EC, most cases of vaginal recurrence were first diagnosed by a careful pelvic examination. For current routine postoperative practice, monitoring critical symptoms and conducting careful gynecological examinations has been shown to be more important than cytological examinations.

Phase III double-blind randomized placebo controlled trial of atezolizumab in combination with carboplatin and paclitaxel in women with advanced/recurrent endometrial carcinoma: the Asian cohort of the AtTEnd/ENGOT-EN7 trial

This post-hoc analysis of the AtTEnd trial explored differences in the prognostic characteristics and in the efficacy of atezolizumab between Asians and non-Asians. The role of Asian race was evaluated on progression-free survival (PFS) using Cox-models and on time to appearance of new lesions using Fine and Gray models. From October 2018 to February 2022, 549 patients were randomized, of whom, 20.4% were Asian. Asians showed a better prognostic profile in terms of age, body mass index, Eastern Cooperative Oncology Group performance status, disease status and previous treatments. The prognostic impact of Asian race on PFS was confirmed in the placebo arm (adjusted hazard ratio [HR]=0.41; 95% confidence interval [CI]=0.24-0.70). In proficient mismatch repair (pMMR) tumors, the HRs for PFS comparing atezolizumab versus placebo were 0.82 (95% CI=0.63-1.05) in non-Asians, and 1.42 (95% CI=0.80-2.50) in Asians. In the pMMR population randomized to atezolizumab, the subdistribution HRs comparing Asians to non-Asians were 0.68 (95% CI=0.43-1.09) for progression with new lesions and 1.21 (95% CI=0.73-2.03) for progression without new lesions. Asians showed a higher occurrence of severe adverse events in atezolizumab compared to placebo arm (Asians: 82.1% vs. 64.3%, p=0.036; non-Asian: 63.3% vs. 63.6%, p=0.949). Race seems to affect the safety of the addition of atezolizumab and, in pMMR tumors, also its efficacy. In the atezolizumab arm, Asian patients seem to have a lower cumulative incidence of new lesions when primary tumor regrowth was considered a competing risk, and a higher cumulative incidence of primary tumor regrowth when new lesions appearance was the competing risk. ClinicalTrials.gov Identifier: NCT03603184.

VRK1 Is a Novel Therapeutic Target for Small Cell Neuroendocrine Carcinoma of the Cervix

ABSTRACT Small cell neuroendocrine carcinoma of the cervix (SCNEC) is classified as a high‐grade neuroendocrine carcinoma with a worse prognosis than other major histological types of cervical cancer. Identifying novel therapeutic targets based on its molecular characteristics is highly desirable but challenging due to the rarity of SCNEC and the resulting lack of research resources. In this study, we identified vaccinia‐related kinase 1 (VRK1) as a potential therapeutic target for SCNEC. VRK1 was prioritized based on our previously reported proteomic analysis of patient‐derived organoids. Immunohistochemistry of patient samples consistently revealed high VRK1 expression in SCNEC, as opposed to its variable expression in other cervical carcinomas. Although VRK1 knockdown in SCNEC had only a limited effect on cell proliferation in two‐dimensional cultures, it significantly suppressed cell proliferation in three‐dimensional cultures and inhibited xenograft tumor growth in vivo. Gene set enrichment analysis of RNA‐sequencing data from mouse xenograft models demonstrated that VRK1 is associated with mitochondrial‐related pathways. Furthermore, under oxidative stress conditions, VRK1 knockdown resulted in a reduction of mitochondrial membrane potential, an indicator of mitochondrial integrity, and decreased expression of cytochrome c oxidase subunit IV (COX IV), a nuclear‐encoded subunit of cytochrome c oxidase, the terminal enzyme complex of the mitochondrial respiratory chain. These findings suggest that VRK1 knockdown indirectly impaired mitochondrial function. Collectively, these anti‐tumor effects highlight VRK1 as a promising therapeutic target for SCNEC.

Corrected human papillomavirus vaccination rates for each birth fiscal year in Japan

AbstractIn Japan, the serious adverse events after human papillomavirus (HPV) vaccination were widely reported in the media. The Ministry of Health, Labour and Welfare of Japan (MHLW) announced the suspension of the governmental recommendation of HPV vaccine in 2013, and the inoculation rate has since sharply declined. The estimated inoculation rate for each birth fiscal year (FY) announced by the MHLW and the actual numbers for each birth FY surveyed by local governments were very different. In particular, the cumulative vaccination rate of girls born in FY2000 was regarded to be as high as 42.9% by the Council of the MHLW. However, this estimation included a confusion. When the suspension of the governmental recommendation was announced in FY2013, the girls born in FY2000 turned 13 years old, the targeted starting age of the HPV vaccination. The vaccination rate of this generation is considered to be quite low. The numbers were recalculated in this study. This study revealed that the real vaccination rate is only 14.3%. Female individuals born in or after FY2000 have been confirmed to be exposed to the same cervical cancer risk as before the HPV vaccine was introduced in Japan.

Effect of Immersive Virtual Reality on Chemotherapy-Related Side Effects in Patients Receiving Paclitaxel-Carboplatin With or Without Bevacizumab: 2-Arm Randomized Controlled Trial

Abstract Background Symptomatic drug treatment is generally used to treat various side effects associated with paclitaxel-carboplatin (TC) or TC plus bevacizumab (TC+Bev). However, this can lead to increased adverse effects from additional drugs. Immersive virtual reality (iVR) reduces pain and anxiety. Objective This study aimed to investigate the efficacy of iVR in managing side effects associated with TC or TC+Bev therapy. Methods This 2-arm randomized controlled trial included patients with gynecologic cancer scheduled to undergo their first course of TC/TC+Bev. Patients in the intervention group received iVR for approximately 10 minutes/day for 7 consecutive days, starting on the first day of treatment. The primary endpoint was the severity of physical and psychiatric symptoms measured using the Japanese version of the revised Edmonton Symptom Rating System (ESAS-r-J). The secondary endpoint included the proportion of patients who used additional antiemetic medications, the complete response (CR) rate to nausea, and the severity of anxiety, measured using the state-trait anxiety inventory-JYZ (STAI) Y-1. Patients in the nonintervention group received supportive and symptomatic treatments. Results The analysis included 28 and 30 patients in the intervention and nonintervention groups, respectively. The change in ESAS-r-J scores between days 1 and 7 and nausea were significantly worse in the intervention group on day 4 only (P<.001); however, the nonintervention group showed significantly worse scores on days 3, 4, and 5. Depression was not significantly worse in the intervention group on any day other than on day 1; however, the nonintervention group showed significantly worse scores on day 4. The proportion of patients who used additional antiemetic medications from days 2 to 7 was significantly lower in the intervention group than in the nonintervention group (P=.02). Regarding the change in STAI Y-1 on day 1 of TC or TC+Bev therapy, the mean score was significantly lower after the iVR experience than before the experience in the intervention group (from 43.8 to 34.8; P<.001), whereas, in the nonintervention group, no significant difference was observed before and after anticancer drug administration (from 44.9 to 43.9; P=.54). Conclusions iVR may reduce the deterioration of nausea and depression more effectively in patients with gynecologic cancer undergoing TC or TC+Bev therapy than in those undergoing nonintervention, especially in delaying the onset of nausea and accelerating recovery.

Prognostic significance of para-aortic node metastasis in endometrial cancer: Japanese Gynecologic Oncology Group Study JGOG2043 post hoc analysis

This study aimed to assess the prognostic significance of para-aortic lymphadenectomy (PALX) and para-aortic lymph node metastasis in endometrial cancer (EC) patients at risk of post-operative recurrence. Japanese Gynecologic Oncology Group (JGOG) 2043 was a randomized controlled trial assessing the efficacy of adjuvant chemotherapy in EC patients at risk for post-operative recurrence. A retrospective analysis included patients who underwent pelvic lymphadenectomy (PLX) alone or both PLX and PALX in JGOG2043. Data on positive lymph nodes and other clinicopathological risk factors were collected. PLX and PALX were performed on 402 patients, while PLX alone was conducted on 250 patients. Evaluating the effect of PALX on survival was challenging through a comparison of the outcomes of the 2 cohorts since PALX was predominantly administered to higher-risk patients. Patients with 2 or more metastases in para-aortic nodes exhibited significantly poorer overall survival than those with no or 1 metastasis, respectively (p<0.001, p=0.031). Multivariate analysis revealed that 2 or more metastases in para-aortic nodes is independent risk factors for disease-free survival (hazard ratio [HR]=1.72; 95% confidence interval [CI]=1.10-2.72; p=0.019) and are marginally significant for overall survival (HR=1.58; 95% CI=0.92-2.72; p=0.096) compared to no or a single metastasis. The clinical relevance of PALX was challenging to evaluate in the JGOG2043 cohort; however, the presence of 2 or more para-aortic node metastases was identified as an independent unfavorable prognostic factor in EC patients at risk of recurrence.

Prognostic impact of the number of resected pelvic nodes in endometrial cancer: Japanese Gynecologic Oncology Group Study JGOG2043 post hoc analysis

This study aimed to determine whether the number of resected pelvic lymph nodes (PLNs) affects the prognosis of endometrial cancer (EC) patients at post-operative risk of recurrence. JGOG2043 was a randomized controlled trial to assess the efficacy of three chemotherapeutic regimens as adjuvant therapy in EC patients with post-operative recurrent risk. A retrospective analysis was conducted on 250 patients who underwent pelvic lymphadenectomy alone in JGOG2043. The number of resected and positive nodes and other clinicopathologic risk factors for survival were retrieved. There were 83 patients in the group with less than 20 PLNs removed (group A), while 167 patients had 20 or more PLNs removed (group B). There was no significant difference in patients' backgrounds between the two groups, and the rate of lymph node metastasis was not significantly different. There was a trend toward fewer pelvic recurrences in group B compared with group A (3.5% vs. 9.6%; p=0.050). Although Kaplan-Meier analysis showed no statistically significant difference in survival rates between the two groups (5-year overall survival [OS]=90.3% vs. 84.3%; p=0.199), multivariate analysis revealed that resection of 20 or more nodes is one of the independent prognostic factors (hazard ratio=0.49; 95% confidence interval=0.24-0.99; p=0.048), as well as surgical stage, high-risk histology, and advanced age for OS. Resection of 20 or more PLNs was associated with improved pelvic control and better survival outcomes in EC patients at risk of recurrence who underwent pelvic lymphadenectomy alone and were treated with adjuvant chemotherapy.