Published papers

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.

In Japan, the National Immunization Program against human papillomavirus (HPV) targets girls aged 12-16 years, and catch-up vaccination is recommended for young women up to age 26 years. Because HPV infection rates increase soon after sexual debut, we evaluated HPV vaccine effectiveness by age at first vaccination. Along with vaccination history, HPV genotyping results from 5795 women younger than 40 years diagnosed with cervical intraepithelial neoplasia grade 2-3 (CIN2-3), adenocarcinoma in situ (AIS), or invasive cervical cancer were analyzed. The attribution of vaccine-targeted types HPV16 or HPV18 to CIN2-3/AIS was 47.0% for unvaccinated women (n = 4297), but 0.0%, 13.0%, 35.7%, and 39.6% for women vaccinated at ages 12-15 years (n = 36), 16-18 years (n = 23), 19–22 years (n = 14), and older than 22 years (n = 91), respectively, indicating the greater effectiveness of HPV vaccination among those initiating vaccination at age 18 years or younger (P <.001). This finding was supported by age at first sexual intercourse; among women with CIN2-3/AIS, only 9.2% were sexually active by age 14 years, but the percentage quickly increased to 47.2% by age 16 and 77.1% by age 18. Additionally, the HPV16/18 prevalence in CIN2-3/AIS was 0.0%, 12.5%, and 40.0% for women vaccinated before (n = 16), within 3 years (n = 8), and more than 3 years after (n = 15) first intercourse, respectively (P =.004). In conclusion, our data appear to support routine HPV vaccination for girls aged 12-14 years and catch-up vaccination for adolescents aged 18 years and younger in Japan.

Several human papillomaviruses (HPV) are associated with the development of cervical carcinoma. HPV DNA synthesis is increased during the differentiation of infected host keratinocytes as they migrate from the basal layer of the epithelium to the spinous layer, but the molecular mechanism is unclear. Nucleosome positioning affects various cellular processes such as DNA replication and repair by permitting the access of transcription factors to promoters to initiate transcription. In this study, nucleosome positioning on virus chromatin was investigated in normal immortalized keratinocytes (NIKS) stably transfected with HPV16 or HPV18 genomes to determine if there is an association with the viral life cycle. Micrococcal nuclease-treated DNA analyzed by Southern blotting using probes against HPV16 and HPV18 and quantified by nucleosome scanning analysis using real-time PCR revealed mononucleosomal-sized fragments of 140–200 base pairs that varied in their location within the viral genome according to whether the cells were undergoing proliferation or differentiation. Notably, changes in the regions around nucleotide 110 in proliferating and differentiating host cells were common to HPV16 and HPV18. Our findings suggest that changes in nucleosome positions on viral DNA during host cell differentiation is an important regulatory event in the viral life cycle.

Purpose: To date, no studies have assessed climacteric symptoms after hystero-adnexectomy for endometrial, cervical, or ovarian cancer. Thus, this study aimed to compare climacteric symptoms among patients who underwent surgery for these three cancer types. Methods: In this cross-sectional study, we interviewed patients who were registered at a menopausal outpatient clinic between January 1999 and July 2016 after undergoing total hysterectomy, intrapelvic only or intrapelvic plus para-aortic lymph node dissection, and bilateral adnexectomy performed via laparotomy as a cancer treatment. Climacteric symptoms were assessed using a patient-reported questionnaire covering core domains with five symptoms only at the initial consultation. Each symptom was graded from 0 (no symptoms) to 3 (severe symptoms). We evaluated the frequency of symptom severity according to the time elapsed since surgery and the cancer type. Results: The numbers of patients with endometrial, ovarian, and cervical cancer were 328, 90, and 107, respectively. Overall, climacteric symptoms were more severe in patients with cervical cancer than in those with endometrial or ovarian cancer; symptom severity decreased with increasing time since surgery. However, symptom severity did not decrease significantly over time in patients with cervical cancer even after > 5 years had elapsed since surgery. Conclusion: The climacteric symptoms were less severe in patients with endometrial or ovarian cancer with longer time elapsed since surgery but not in those with cervical cancer. Patients with cervical cancer may require more prompt interventions, including symptomatic treatment and longer follow-up period, than those with endometrial or ovarian cancer.

Objective: Human papillomavirus subtypes are predictive indicators of cervical intraepithelial neoplasia (CIN) progression. While colposcopy is also an essential part of cervical cancer prevention, its accuracy and reproducibility are limited because of subjective evaluation. This study aimed to develop an artificial intelligence (AI) algorithm that can accurately detect the optimal lesion associated with prognosis using colposcopic images of CIN2 patients by utilizing objective AI diagnosis. Methods: We identified colposcopic findings associated with the prognosis of patients with CIN2. We developed a convolutional neural network that can automatically detect the rate of high-grade lesions in the uterovaginal area in 12 segments. We finally evaluated the detection accuracy of our AI algorithm compared with the scores by multiple gynecologic oncologists. Results: High-grade lesion occupancy in the uterovaginal area detected by senior colposcopists was significantly correlated with the prognosis of patients with CIN2. The detection rate for high-grade lesions in 12 segments of the uterovaginal area by the AI system was 62.1% for recall, and the overall correct response rate was 89.7%. Moreover, the percentage of high-grade lesions detected by the AI system was significantly correlated with the rate detected by multiple gynecologic senior oncologists (r=0.61). Conclusion: Our novel AI algorithm can accurately determine high-grade lesions associated with prognosis on colposcopic images, and these results provide an insight into the additional utility of colposcopy for the management of patients with CIN2.

Objective: To identify candidate predictors for the prognosis of cervical intraepithelial neoplasia 2 (CIN2) lesions and evaluate the prognostic value of the local immune response. Methods: One hundred fifteen CIN2 patients were enrolled. The percentage of p16-, minichromosome maintenance complex component 2-or apolipoprotein B mRNA editing enzyme catalytic subunit 3G (APOBEC3G)-positive cells was determined immunohistochemically. Tumor-infiltrating lymphocytes (TILs) in intertumoral lesions were scored using an automated system. CIN3 disease progression and regression rates were estimated by the Kaplan–Meier method. A case-control study was conducted to screen CIN2 prognostic factors in 10 regression and 10 progression patients. Selected factors were examined in a cohort study to determine their prognostic value for CIN2. Results: Among all participants, the cumulative progression and regression rates at 60 months were 0.477 and 0.510, respectively. In the case-control study, p16-and APOBEC3G-positive cells were higher in the progression group (p=0.043, p=0.023). Additionally, CD4+ cell infiltration was enhanced in the regression group (p=0.023). The cohort study revealed a significantly increased progression rate in patients with elevated p16-positive cells (p<0.001), and increased CD4+ TIL infiltration was associated with better regression (p=0.011). Kaplan– Meier analysis according to human papillomavirus (HPV) positivity revealed a greater CIN3 development risk in HPV16-positive patients than in HPV16-negative cases. Finally, multivariate analysis identified HPV16 infection and CD4+ TIL infiltration as independent prognostic factors in CIN2 regression. Conclusion: CD4+ TIL infiltration in intertumoral lesions was related with CIN2 regression. Our findings suggest CD4+ TIL infiltration may be useful for the triage of CIN2 patients.

Hydronephrosis in extramammary Paget’s disease (EMPD) with distant metastasis (metastatic EMPD) has been observed in medical practice; however, its prognosis remains unclear. Retrospective analyses were performed to assess the management and outcomes of hydronephrosis in metastatic EMPD. During a follow-up of 44 patients with metastatic EMPD, 13 (30%) developed hydronephrosis. Ten (77%) of the 13 patients with hydronephrosis had impaired renal function (estimated glomerular filtration rate: <60 ml/min/1.73 m2), and ureteral stents were placed in every patient with impaired renal function. The stent was placed successfully in all 10 patients, and their renal function recovered within a median period of 7 days. Importantly, each of these patients continued chemotherapy, and none of them experienced stent failure. The median overall survival time (OS) in patients with metastatic EMPD and hydronephrosis (n = 13) was 7.8 months. Treatment for hydronephrosis was not a significant factor for OS, and median OS in patients who underwent ureteral stent replacement (n = 10) was 14.7 months. Collectively, our results indicate that hydronephrosis is relatively common, and ureteral stent placement should be considered in cases of metastatic EMPD with hydronephrosis to maintain renal function and continue chemotherapy toward a better prognosis.

Pembrolizumab plus chemotherapy with or without bevacizumab demonstrated prolonged progression-free survival (PFS) and overall survival (OS) versus chemotherapy in patients with persistent, recurrent, or metastatic cervical cancer in the phase 3, randomized, double-blind, placebo-controlled KEYNOTE-826 study. We report outcomes in patients enrolled in Japan. Patients received pembrolizumab 200 mg or placebo Q3W for up to 35 cycles plus chemotherapy (paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 or carboplatin AUC 5) with or without bevacizumab 15 mg/kg. Dual primary endpoints were PFS per RECIST v1.1 by investigator assessment and OS in the global population; these were evaluated in patients with tumors with PD-L1 combined positive score (CPS) ≥1, all-comers, and PD-L1 CPS ≥10. Fifty-seven patients from Japan were randomized (pembrolizumab plus chemotherapy, n = 35; placebo plus chemotherapy, n = 22). Pembrolizumab plus chemotherapy improved PFS versus placebo plus chemotherapy in patients with PD-L1 CPS ≥1 (n = 51; hazard ratio [HR; 95% CI], 0.36 [0.16–0.77]), all-comers (n = 57; 0.45 [0.22–0.90]), and patients with PD-L1 CPS ≥10 (n = 25; 0.36 [0.12–1.07]). HRs (95% CI) for OS were 0.38 (0.14–1.01), 0.41 (0.17–1.00), and 0.37 (0.10–1.30), respectively. Incidence of grade 3–5 AEs was 94% in the pembrolizumab group and 100% in the placebo group. Consistent with findings in the global KEYNOTE-826 study, pembrolizumab plus chemotherapy with or without bevacizumab may prolong survival versus placebo plus chemotherapy with or without bevacizumab and had a manageable safety profile in Japanese patients with persistent, recurrent, or metastatic cervical cancer.

Although geographical differences in the distribution of human papillomavirus genotypes have been observed worldwide, no studies have reported on national differences in the prevalence of human papillomavirus types in Japan. Here, we report a cross-sectional study to explore regional differences in the prevalence of human papillomavirus types among Japanese women with cervical intraepithelial neoplasia or invasive cervical cancer. Using human papillomavirus genotyping data from the nationwide prospective study on human papillomavirus vaccine effectiveness, we compared the frequency of detection of 15 high-risk and two low-risk human papillomavirus types in each disease category between the women who visited hospitals located in eastern Japan and those who visited hospitals located in western Japan. The risk of cervical intraepithelial neoplasia progression was assessed by calculating a prevalence ratio of each human papillomavirus type for cervical intraepithelial neoplasia grade 2/3 versus grade 1. Among the human papillomavirus types studied, human papillomavirus 52 was detected significantly more frequently in western hospitals than in eastern hospitals in cervical intraepithelial neoplasia grade 1 patients, but was less frequent in cervical intraepithelial neoplasia grade 2/3. The prevalence of particular human papillomavirus types was not significantly different between patients in hospitals in eastern Japan and those in hospitals in western Japan for invasive cervical cancer. In both eastern and western hospitals, a higher risk of cervical intraepithelial neoplasia progression was observed in patients infected with human papillomavirus 16, 31 or 58. In contrast, there was a significantly higher prevalence of human papillomavirus 52 infection in women with cervical intraepithelial neoplasia grade 2/3 than in those with cervical intraepithelial neoplasia grade 1 in eastern hospitals (prevalence ratio, 1.93; 95% confidence interval, 1.48-2.58), but not in western hospitals (prevalence ratio, 1.03; 95% confidence interval, 0.83-1.30). Regional differences of human papillomavirus 52 prevalence in cervical intraepithelial neoplasia lesions may exist and emphasize the importance of continuous monitoring of human papillomavirus type prevalence throughout the country in order to accurately assess the efficacy of human papillomavirus vaccines.

Background: Adjuvant therapy is usually considered for surgically treated patients with uterine cervical cancer harboring intermediate risk (IR) factors such as large tumor diameter, stromal invasion to the outer half, and lymphovascular space invasion (LVSI). However, the indications and types of adjuvant therapy for the IR group remain controversial. This study aimed to analyze the differences in patient outcomes in the IR group to provide novel insights for tailoring adjuvant therapy. Methods: Data from 6192 patients with cervical cancer who underwent radical hysterectomy at 116 institutions belonging to the Japanese Gynecologic Oncology Group were reviewed. Results: In total, 1688 patients were classified into the IR group, of whom 37.3% did not receive adjuvant therapy. Conversely, approximately equal proportions of the remaining patients received adjuvant radiotherapy, concurrent chemoradiotherapy, and chemotherapy. Patients with all three risk factors showed worse overall survival than those with one or two risk factors. In addition to LVSI, non-squamous cell carcinoma histology, and vaginal invasion were identified as independent risk factors for both recurrence and mortality in multivariate analyses. Tumor diameter greater than 40 mm and surgical center volume were identified as independent risk factors for recurrence. Stromal invasion to the outer half and ovarian metastasis were identified as independent risk factors for mortality. Conclusions: This study revealed the significant differences in prognosis in the IR group. The indications for adjuvant therapy should be further studied, focusing on conventional risk factors and other pathological findings.

New treatments, particularly second-line options, are needed to improve outcomes for patients with recurrent/metastatic cervical cancer (r/mCC). Tisotumab vedotin (TV) is an antibody–drug conjugate directed to tissue factor, a transmembrane protein commonly expressed in cancer cells, to deliver cytotoxic monomethyl auristatin E. This single-arm, open-label phase 1/2 trial evaluated the consistency of safety and efficacy outcomes of TV in Japanese patients with r/mCC to bridge the current findings with those reported in previous trials in non-Japanese patients in the United States and Europe. In part 1 (dose escalation; N = 6), patients with advanced solid tumors received TV 1.5 or 2.0 mg/kg once every 3 weeks to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Part 2 (dose expansion; N = 17) evaluated the RP2D in r/mCC patients with 1–2 prior lines of therapy. In part 1, no dose-limiting toxicities were observed, the MTD was not reached, and TV 2.0 mg/kg was established as the RP2D. In part 2, the most common treatment-emergent adverse events were anemia (58.8%), nausea (58.8%), alopecia (47.1%), epistaxis (47.1%), and diarrhea (35.3%); adverse events of special interest were bleeding (76.5%), ocular events (35.3%), and peripheral neuropathy (17.6%), and were mostly grade 1/2. In part 2, confirmed objective response rate was 29.4%, median duration of response was 7.1 months, and median time to response was 1.2 months. In Japanese patients with r/mCC, TV demonstrated a manageable and tolerable safety, pharmacokinetics, and efficacy profile consistent with that observed in non-Japanese patients.

Persistent infection with oncogenic human papillomaviruses (HPVs) causes cervical cancer, accompanied by the accumulation of somatic mutations into the host genome. There are concomitant genetic changes in the HPV genome during viral infection; however, their relevance to cervical carcinogenesis is poorly understood. Here, we explored within-host genetic diversity of HPV by performing deep-sequencing analyses of viral whole-genome sequences in clinical specimens. The whole genomes of HPV types 16, 52, and 58 were amplified by type-specific PCR from total cellular DNA of cervical exfoliated cells collected from patients with cervical intraepithelial neoplasia (CIN) and invasive cervical cancer (ICC) and were deep sequenced. After constructing a reference viral genome sequence for each specimen, nucleotide positions showing changes with >0.5% frequencies compared to the reference sequence were determined for individual samples. In total, 1,052 positions of nucleotide variations were detected in HPV genomes from 151 samples (CIN1, n = 56; CIN2/3, n = 68; ICC, n = 27), with various numbers per sample. Overall, C-to-T and C-to-A substitutions were the dominant changes observed across all histological grades. While C-to-T transitions were predominantly detected in CIN1, their prevalence was decreased in CIN2/3 and fell below that of C-to-A transversions in ICC. Analysis of the trinucleotide context encompassing substituted bases revealed that TpCpN, a preferred target sequence for cellular APOBEC cytosine deaminases, was a primary site for C-to-T substitutions in the HPV genome. These results strongly imply that the APOBEC proteins are drivers of HPV genome mutation, particularly in CIN1 lesions.IMPORTANCE HPVs exhibit surprisingly high levels of genetic diversity, including a large repertoire of minor genomic variants in each viral genotype. Here, by conducting deep-sequencing analyses, we show for the first time a comprehensive snapshot of the within-host genetic diversity of high-risk HPVs during cervical carcinogenesis. Quasispecies harboring minor nucleotide variations in viral whole-genome sequences were extensively observed across different grades of CIN and cervical cancer. Among the within-host variations, C-to-T transitions, a characteristic change mediated by cellular APOBEC cytosine deaminases, were predominantly detected throughout the whole viral genome, most strikingly in low-grade CIN lesions. The results strongly suggest that within-host variations of the HPV genome are primarily generated through the interaction with host cell DNA-editing enzymes and that such within-host variability is an evolutionary source of the genetic diversity of HPVs.

To improve current cancer immunotherapies, strategies to modulate various immunosuppressive cells including myeloid derived suppressor cells (MDSC) which were shown to be negative factors in immune-checkpoint blockade therapy, need to be developed. In the present study, we evaluated the role of the local renin-angiotensin system (RAS) in the tumor immune-microenvironment using murine models bearing tumor cell lines in which RAS was not involved in their proliferation and angiogenetic ability. Giving angiotensin II receptor blockers (ARB) to C57BL/6 mice bearing murine colon cancer cell line MC38 resulted in significant enhancement of tumor antigen gp70 specific T cells. ARB administration did not change the numbers of CD11b(+) myeloid cells in tumors, but significantly reduced their T-cell inhibitory ability along with decreased production of various immunosuppressive factors including interleukin (IL)-6, IL-10, vascular endothelial growth factor (VEGF), and arginase by CD11b(+) cells in tumors. ARB also decreased expression of immunosuppressive factors such as chemokine ligand 12 and nitric oxide synthase 2 in cancer-associated fibroblasts (CAF). Last, combination of ARB and anti-programmed death-ligand 1 (PD-L1) antibodies resulted in significant augmentation of anti-tumor effects in a CD8(+) T cell-dependent way. These results showed that RAS is involved in the generation of an immunosuppressive tumor microenvironment caused by myeloid cells and fibroblasts, other than the previously shown proliferative and angiogenetic properties of cancer cells and macrophages, and that ARB can transform the immunosuppressive properties of MDSC and CAF and could be used in combination with PD-1/PD-L1 immune-checkpoint blockade therapy.

© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. The Japanese government began a human papillomavirus (HPV) vaccination program for girls aged 12-16 years in 2010 but withdrew its recommendation in 2013 because of potential adverse effects, leading to drastically reduced vaccination uptake. To evaluate population-level effects of HPV vaccination, women younger than 40 years of age newly diagnosed with cervical intraepithelial neoplasia grade 1-3 (CIN1-3), adenocarcinoma in situ (AIS), or invasive cervical cancer (ICC) have been registered at 21 participating institutes each year since 2012. A total of 7709 women were registered during 2012-2017, of which 5045 were HPV genotyped. Declining trends in prevalence of vaccine types HPV16 and HPV18 during a 6-year period were observed in CIN1 (50.0% to 0.0%, Ptrend <.0001) and CIN2-3/AIS (83.3% to 45.0%, Ptrend =.07) only among women younger than 25 years of age. Overall, HPV vaccination reduced the proportion of HPV16/18-attributable CIN2-3/AIS from 47.7% to 33.0% (P =.003): from 43.5% to 12.5% as routine vaccination (P =.08) and from 47.8% to 36.7% as catch-up vaccination (P =.04). The HPV16/18 prevalence in CIN2-3/AIS cases was significantly reduced among female individuals who received their first vaccination at age 20 years or younger (P =.02). We could not evaluate vaccination effects on ICC owing to low incidence of ICC among women aged less than 25 years. We found HPV vaccination to be effective in protecting against HPV16/18-positive CIN/AIS in Japan; however, our data did not support catch-up vaccination for women older than 20 years. Older adolescents who skipped routine vaccination due to the government’s suspension of its vaccine recommendation could benefit from receiving catch-up vaccination before age 20 years.

© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. Precision medicine based on cancer genomics is being applied in clinical practice. However, patients do not always derive benefits from genomic testing. Here, we performed targeted amplicon exome sequencing-based panel tests, including 160 cancer-related genes (PleSSision-160), on 88 malignant ovarian tumors (high-grade serous carcinoma, 27; endometrioid carcinoma, 15; clear cell carcinoma, 30; mucinous carcinoma, 6; undifferentiated carcinoma, 4; and others, 6 (immature teratoma, 1; carcinosarcoma, 3; squamous cell carcinoma, 1; and mixed, 1)), to assess treatment strategies and useful biomarkers for malignant ovarian tumors. Overall, actionable gene variants were found in 90.9%, and druggable gene variants were found in 40.9% of the cases. Actionable BRCA1 and BRCA2 variants were found in 4.5% of each of the cases. ERBB2 amplification was found in 33.3% of mucinous carcinoma cases. Druggable hypermutation/ultramutation (tumor mutation burden ≥ 10 SNVs/Mbp) was found in 7.4% of high-grade serous carcinoma, 46.7% of endometrioid carcinoma, 10% of clear cell carcinoma, 0% of mucinous carcinoma, 25% of undifferentiated carcinoma, and 33.3% of the other cancer cases. Copy number alterations were significantly higher in high-grade serous carcinoma (P <.005) than in other histologic subtypes; some clear cell carcinoma showed high copy number alterations that were correlated with advanced stage (P <.05) and worse survival (P <.01). A high count of copy number alteration was associated with worse survival in all malignant ovarian tumors (P <.05). Our study shows that targeted agents can be detected in approximately 40% of malignant ovarian tumors via multigene panel testing, and copy number alteration count can be a useful marker to help assess risks in malignant ovarian tumor patients.

© Kato et al. Current xenogeneic mouse models cannot evaluate on-target off-tumor adverse effect, hindering the development of chimeric antigen receptor (CAR) T cell therapies for solid tumors, due to limited human/mouse cross-reactivity of antibodies used in CAR and sever graft-versus-host disease induced by administered human T cells. We have evaluated safety and antitumor efficacy of CAR-T cells targeting glypican-1 (GPC1) overexpressed in various solid tumors. GPC1-specific human and murine CAR-T cells generated from our original anti-human/mouse GPC1 antibody showed strong antitumor effects in xenogeneic and syngeneic mouse models, respectively. Importantly, the murine CAR-T cells enhanced endogenous T cell responses against a non-GPC1 tumor antigen through the mechanism of antigen-spreading and showed synergistic antitumor effects with anti-PD-1 antibody without any adverse effects in syngeneic models. Our study shows the potential of GPC1 as a CAR-T cell target for solid tumors and the importance of syngeneic and xenogeneic models for evaluating their safety and efficacy.

In Japan, a bivalent human papillomavirus (HPV) vaccine against carcinogenic HPV16/18 was licensed in 2009, and a quadrivalent vaccines against HPV16/18 and non-carcinogenic HPV6/11 was licensed in 2011. Recently, the next-generation 9-valent vaccine targeting HPV6/11/16/18/31/33/45/52/58 has been approved. Accurate HPV genotyping is essential for HPV vaccine research and surveillance. The Roche Linear Array (LA) has long been a standard assay for HPV genotyping, but its recent product discontinuation notice has urged us to introduce an alternative assay with comparable performance. In the present study, an in-house HPV genotyping assay that employs PCR with PGMY09/11 primers and reverse blotting hybridization (PGMY-CHUV) was compared with LA to assess genotype-specific agreement. A total of 100 cervical precancer specimens were subjected to both PGMY-CHUV and LA. For detection of genotypes included in the 9-valent vaccine, PGMY-CHUV completely agreed with LA for detection of HPV6, HPV11, HPV16, HPV18, HPV33 and HPV45, and showed near-complete agreement for HPV31 and HPV58 (98% and 99%, respectively). Moreover, PGMY-CHUV detected a significantly higher prevalence of HPV52 than LA (22% vs. 14%, P = 0.008 by McNemar’s exact test), with 92.0% overall agreement, 63.6% positive agreement and a kappa value of 0.73. Most (87.5%) of HPV52 discordant cases involved mixed infections with HPV35 or HPV58. In conclusion, while the two assays present equivalent data for assessing the effectiveness of the bivalent and quadrivalent vaccines, PGMY-CHUV is more suitable for evaluating the impact of the current 9-valent vaccine because of its superior detection of HPV52 in co-infection cases.

© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. To obtain baseline data for cervical cancer prevention in Japan, we analyzed human papillomavirus (HPV) data from 5045 Japanese women aged less than 40 years and diagnosed with cervical abnormalities at 21 hospitals during 2012-2017. These included cervical intraepithelial neoplasia grade 1 (CIN1, n = 573), CIN2-3 (n = 3219), adenocarcinoma in situ (AIS, n = 123), and invasive cervical cancer (ICC, n = 1130). The Roche Linear Array was used for HPV genotyping. The HPV type-specific relative contributions (RCs) were estimated by adding multiple infections to single types in accordance with proportional weighting attributions. Based on the comparison of type-specific RCs between CIN1 and CIN2-3/AIS/ICC (CIN2+), RC ratios were calculated to estimate type-specific risks for progression to CIN2+. Human papillomavirus DNA was detected in 85.5% of CIN1, 95.7% of CIN2-3/AIS, and 91.2% of ICC. Multiple infections decreased with disease severity: 42.9% in CIN1, 40.4% in CIN2-3/AIS, and 23.7% in ICC (P <.0001). The relative risk for progression to CIN2+ was highest for HPV16 (RC ratio 3.78, 95% confidence interval [CI] 3.01-4.98), followed by HPV31 (2.51, 1.54-5.24), HPV18 (2.43, 1.59-4.32), HPV35 (1.56, 0.43-8.36), HPV33 (1.01, 0.49-3.31), HPV52 (0.99, 0.76-1.33), and HPV58 (0.97, 0.75-1.32). The relative risk of disease progression was 1.87 (95% CI, 1.71-2.05) for HPV16/18/31/33/35/45/52/58, but only 0.17 (95% CI, 0.14-0.22) for HPV39/51/56/59/66/68. Human papillomavirus 16/18/31/33/45/52/58/6/11 included in a 9-valent vaccine contributed to 89.7% (95% CI, 88.7-90.7) of CIN2-3/AIS and 93.8% (95% CI, 92.4-95.3) of ICC. In conclusion, our data support the Japanese guidelines that recommend discriminating HPV16/18/31/33/35/45/52/58 genotypes for CIN management. The 9-valent vaccine is estimated to provide over 90% protection against ICC in young Japanese women.

Recent cancer immunotherapy development with immune checkpoint inhibitors has shown durable clinical responses in a wide variety of tumor types. These drugs targeting programmed cell death 1, its ligand programmed death ligand 1 and cytotoxic T cell lymphocyte-associated antigen 4 have revolutionized the field of cancer treatment. It is of significant interest in optimizing the immunotherapy for cancer patients beyond the conventional treatments such as surgery, chemotherapy and radiation. Many clinical trials evaluating the safety and efficacy of various combined regimens with immune checkpoint inhibitors have been reported and are in progress. Among gynecologic malignancy, endometrial cancers have distinct subtypes with microsatellite instability-high status and polymerase ɛ mutation. These types have been shown to immunogenic tumors and appropriated candidate for immune checkpoint inhibitors. Also, recurrent cervical cancer showed a promising objective response with single anti-PD1 Ab treatment. Despite their definite outcome and considerable potential of immunotherapy, not all patients received a survival benefit and further understanding of human tumor immunology is essential to improve this type of therapy. In this review, we have summarized the updated results of clinical trials of cancer immunotherapy for gynecologic malignancies and discussed the future perspectives.