Folate Receptor Alpha Expression and the Tumor Immune Microenvironment in Patients with Cervical Cancer.

Folate receptor α (FRα) is a cell-surface protein and an attractive target for cancer treatment. We investigated the association between FRα expression and the tumor immune microenvironment in patients with cervical cancer. We examined whole tumor sections of 123 patients with cervical cancer: 67 and 56 sections of squamous cell carcinoma (SCC) and non-SCC, respectively. FRα expression was assessed using immunohistochemical staining with the anti-FRα monoclonal antibody clone 26B3. Programmed death-ligand 1 (PD-L1) expression was assessed using a combined positive score (CPS). The intratumoral CD3 and CD8 cell densities were calculated as the average number of positive cells in five independent areas. FRα-positivity was identified in 72.4% of the patients, and it differed by histology (SCC vs. non-SCC; 55.2% vs. 92.9%, P<0.001). PD-L1 status was positive (CPS ≥1) in 75.6% and was more commonly expressed in patients with SCC (SCC vs. non-SCC; 83.5% vs. 66.1%, P=0.02). FRα expression had a weak correlation with PD-L1 expression (r=-0.22, P<0.001) and CD8-positive cells (r=-0.19, P=0.03). FRα-positivity was more frequently observed in the PD-L1 CPS <10 group than in the PD-L1 CPS ≥10 group (81% vs. 64%, P=0.03). FRα-high was significantly associated with poor prognosis, especially in the PD-L1 CPS ≥10 groups (hazard ratio: 4.10, 95% confidence interval: 1.39-12.06, P=0.01). In conclusion, FRα expression was higher in patients with cervical cancer and PD-L1 CPS <10 than in those with CPS ≥10. Targeting FRα expression may be a potential therapeutic strategy for cervical cancer patients with low or negative PD-L1 expression.

Integrative prognostic analysis of tumor-infiltrating lymphocytes, CD8, CD20, programmed cell death-ligand 1, and tertiary lymphoid structures in patients with early-stage triple-negative breast cancer who did not receive adjuvant chemotherapy.

PURPOSE: Stromal tumor-infiltrating lymphocytes (TILs) are independent prognostic factors in systemically untreated early-stage triple-negative breast cancer (TNBC). Other immune biomarkers including CD8, CD20, programmed cell death-ligand 1 (PD-L1), and tertiary lymphoid structures (TLS) are also reported to be associated with prognosis. However, whether combining other immune biomarkers with TILs would allow for further prognostic stratification is unknown. METHODS: We retrospectively analyzed 125 patients with early-stage TNBC not receiving perioperative chemotherapy. Stromal TILs and TLS were evaluated on hematoxylin-eosin slides. PD-L1 expression was evaluated using the SP142 assay. CD8 and CD20 were assessed by immunohistochemistry and counted by digital pathology. RESULTS: Immune biomarker levels were positively correlated (p < 0.001). Adding CD8 and PD-L1 to multivariable analysis including clinicopathological factors (stage and histological grade) and TILs significantly improved the prognostic model (likelihood ratio χ2 = 9.24, p = 0.01). In Cox regression analysis, high CD8 was significantly associated with better prognosis [hazard ratio (HR) 0.69, 95% confidence interval (CI) 0.48-0.98, p = 0.04], and PD-L1 positivity was significantly associated with worse prognosis (HR 4.33, 95%CI 1.57-11.99, p = 0.005). Patients with high CD8/PD-L1 (-) tumors had the most favorable prognosis [5 year invasive disease-free survival (iDFS), 100%], while patients with low CD8/PD-L1( +) tumors had the worst prognosis (5 year iDFS, 33.3%). CONCLUSION: CD8 and PD-L1 levels add prognostic information beyond TILs for early-stage TNBC not receiving perioperative chemotherapy. CD8-positive T cells and PD-L1 may be useful for prognostic stratification and in designing future clinical trials of TNBC.

Changes in HER3 expression profiles between primary and recurrent gynecological cancers.

BACKGROUND: Human epidermal growth factor receptor-3 (HER3) is a member of the epidermal growth factor receptor family of receptor tyrosine kinases, and its overexpression is associated with inferior prognosis in several cancers. However, it is unclear whether HER3 expression status changes in tumor tissue at recurrence. Therefore, this study aimed to evaluate the changes in HER3 expression between primary and recurrent status in gynecological cancers. METHODS: This retrospective study used matched-pair tissues of gynecological cancer patients at initial diagnosis and at recurrence. Immunohistochemical (IHC) scores of 3 + or 2 + were termed "HER3-high", while IHC scores of 1 + or 0 were designated as "HER3-low/zero". RESULTS: A total of 86 patients (40 with ovarian cancers, 32 with endometrial cancers, and 14 with cervical cancers) were included in this study. In ovarian cancer, 67.5% and 80.0% of the patients received a HER3-high at initial and recurrent diagnosis, respectively. The H-score was significantly increased at recurrence (p = 0.004). The proportion of HER3-high endometrial cancer patients increased from 46.9% at initial diagnosis to 68.8% at recurrence, and the H-score tended to increase at recurrence (p = 0.08). The fraction of HER3-high-rated cervical cancer patients remained unchanged at 85.7% both at initial and recurrent diagnosis. The discordance rate of HER3 expression detection in initial and recurrent diagnosis samples was 27.5%, 53.1%, and 14.3% for ovarian, endometrial, and cervical cancers, respectively. Ovarian and endometrial cancers with a HER3-high recurrent score tended to show shorter median survival time than those with a HER3-low/zero recurrent rating. CONCLUSION: Our findings suggest that, in main types of gynecological cancers, the proportion of patients having a HER3-high score increased from initial to recurrent diagnosis.

Folate receptor alpha is widely expressed and a potential therapeutic target in uterine and ovarian carcinosarcoma.

OBJECTIVE: Folate receptor alpha (FRα), which is expressed in various cancers, is a potential therapeutic target. However, its expression and clinical significance in uterine (UCS) and ovarian carcinosarcoma (OCS) remain to be elucidated. METHODS: This retrospective study included patients with gynecologic carcinosarcoma who underwent primary surgery between 1997 and 2019 at our institution. Immunohistochemical staining of surgical FFPE specimens was performed for FRα and HER2. FRα was evaluated using the H-score and the 4-tired scoring system (0 to 3+). Subsequently, FRα expression (≥5% of tumor cells with ≥1+ intensity) and FRα-high (score 2+ and 3+) were evaluated. HER2 was scored according to the modified ASCO/CAP criteria. The association between FRα-high and clinicopathological features, HER2 expression, and survival was assessed in UCS. RESULTS: A total of 120 patients with UCS and nine patients with OCS were included. In UCS, FRα expression was observed in all patients, whereas FRα-high status was present in 20% of patients. Among HER2-negative UCS, 34% exhibited FRα-high. No significant association was observed between clinicopathological characteristics and FRα status. During the follow-up period (median 34.5 mo), FRα-high was not strongly associated with progression, free survival, and overall survival. All the OCS tumor specimens showed FRα-high expression. CONCLUSIONS: FRα expression was observed in all the UCS and OCS specimens, including HER2-negative UCS patients. This widespread FRα expression suggests that FRα-targeted therapies may hold promise for the treatment for gynecologic carcinosarcoma. However, in uterine carcinosarcoma, no significant relationship was observed between FRα expression and clinicopathological features or prognosis.

Discordances in expression of human epidermal growth factor receptor 2 between primary and metastatic uterine carcinosarcoma: A proposal for HER2-targeted therapy specimen selection.

Uterine carcinosarcoma (UCS) frequently expresses human epidermal growth factor receptor 2 (HER2) and metastasizes. However, little is known about changes in the HER2 expression status in metastatic lesions and its impact on clinical outcomes. In 41 patients with synchronous or metachronous metastases and matched primary UCSs, we assessed the HER-2 expression using immunohistochemistry and scored it per the 2016 American Society of Clinical Oncology/College of American Pathologists guidelines, modified for UCS. We compared HER2 scores between paired primary and metastatic lesions and reviewed the association between clinicopathological characteristics and impact on overall survival. HER2 scores of 3+, 2+, 1+, and 0 were observed in 12.2 %, 34.2 %, 26.8 %, and 26.8 % of primary tumors, respectively, and 9.8 %, 19.5 %, 43.9 %, and 26.8 % of metastatic tumors, respectively. HER2 intratumoral heterogeneity occurred in 46.3 % and 19.5 % of the primary and metastatic lesions, respectively. The agreement rate of the HER2 score was 34.2 % in the four-tiered scale, while it was 70.7 % in the two-tiered scale (score 0 vs. score ≥ 1+) with fair agreement (к = 0.26). Patients with HER2 discordance showed significantly shorter overall survival (hazard ratios = 2.38, 95 % confidence interval 1.01-5.5, p = 0.049). HER2 discordance was not associated with specific clinicopathological characteristics. Discordance in HER2 status between primary and metastatic tumors in UCS was frequently observed regardless of clinicopathological characteristics and was a poor prognostic factor. Even if one tumor (primary or metastatic) is HER2 negative, HER2 testing of other tumors may be beneficial in terms of patient treatment options.

Human papillomavirus vaccine effectiveness by age at first vaccination among Japanese women.

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.

Diagnostic value of tumor markers in identifying favorable or unfavorable subsets in patients with cancer of unknown primary: a retrospective study.

BACKGROUND: Routine measurement of tumor markers is not recommended in daily clinical practice for patients with cancer of unknown primary (CUP). We evaluated the diagnostic value of tumor markers in identifying favorable or unfavorable subsets in patients with CUP. METHODS: We retrospectively reviewed the medical records of patients who were diagnosed with CUP between October 2010 and July 2015 at the National Cancer Center Hospital. The tumor markers of the patients were examined, including squamous cell carcinoma antigen, cytokeratin fraction, carcinoembryonic antigen, sialyl Lewis X, neuron-specific enolase, pro-gastrin-releasing peptide, α-fetoprotein, protein induced by vitamin K absence or antagonist II, prostate-specific antigen, soluble interleukin-2 receptor, carbohydrate antigen 19-9, cancer antigen 125, cancer antigen 15-3, NCC-ST-439 (ST439), elastase-1, human chorionic gonadotropin, and sialyl-Tn (STN). RESULTS: Among 199 patients with suspected CUP, 90 were diagnosed with confirmed CUP (12 in the favorable subset and 78 in the unfavorable subset). No tumor markers showed 100% sensitivity for unfavorable subsets. ST439 (p = 0.03) and STN (p = 0.049) showed 100% specificity for unfavorable subsets. CONCLUSIONS: For patients with suspected CUP who show elevated ST439 or STN levels, the treatment strategy should be based on the premise that the patient is likely to be placed in the unfavorable subset.

Regional differences in human papillomavirus type 52 prevalence among Japanese women with cervical intraepithelial neoplasia†.

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.

Phase II study of a new multidisciplinary therapy using once every 3 week carboplatin plus dose-dense weekly paclitaxel before and after radical hysterectomy for locally advanced cervical cancer.

BACKGROUND: We proposed a novel treatment strategy, consisting of triweekly cisplatin plus dose-dense weekly paclitaxel before and after radical hysterectomy without adjuvant radiation therapy to treat locally advanced cervical cancer. However, cisplatin-related severe non-hematologic toxicities were frequent during this strategy. This study aimed to assess the applicability of replacing cisplatin with carboplatin in our proposed strategy. METHODS: Women with International Federation of Gynecology and Obstetrics (FIGO) 2008 stage IB2, IIA2, or IIB cervical cancer received three cycles of carboplatin (based on an area under the curve of six), each 21 days apart, starting on day 1, and 80 mg/m2 of paclitaxel on days 1, 8, and 15 of each 21-day cycle before undergoing radical hysterectomy. Patients with one or more high-risk factors, including lymph vascular invasion, parametrial invasion, lymph-node metastasis, or positive margins, received three additional cycles of chemotherapy after hysterectomy. Concurrent chemoradiation therapy was only applied to those patients who failed to respond to neoadjuvant chemotherapy. RESULTS: Between September 2014 and July 2016, 50 women (13 women with FIGO stage IB2, 5 with stage IIA2, and 32 with stage IIB) were enrolled in this study. The overall response rate to chemotherapy was 92%, including 22% with pathological complete response. Forty-nine women (98%) completed the planned radical hysterectomy, and 11 (22%) women with one or more high-risk factors received three additional cycles of chemotherapy. Only four women (8%) received concurrent chemoradiation therapy after surgery. The 2- and 3-year progression-free survival rates were 88.0% and 83.8%, respectively, and the 2- and 3-year overall survival rates were 98.0% and 95.4%, respectively. Only two patients reported grade 3 or higher non-hematologic toxicities including grade 3 nausea in one patient and grade 3 liver dysfunction in one patient. CONCLUSIONS: Replacement the platinum agent resulted in equivalent efficacy, with reduced toxicity, in women with locally advanced cervical cancer. This strategy could considerably diminish the application of radiation therapy without reduced survival. A study to identify those patients who will benefit from this new multidisciplinary strategy is warranted.

Survival impact of adjuvant concurrent chemoradiotherapy after radical hysterectomy in FIGO stage IIIC1 cervical adenocarcinoma.

BACKGROUND: We evaluated the survival effect of adjuvant concurrent chemoradiotherapy after radical hysterectomy in patients with clinical pelvic node-positive cervical adenocarcinoma. METHODS: Patients with pelvic node-positive cervical adenocarcinoma diagnosed between 2000 and 2016 at our institution were identified. Survival was compared between patients who underwent radical hysterectomy alone and those who received concurrent chemoradiotherapy as an adjuvant treatment. Survival analysis using log-rank test and Cox proportional hazards model was performed. RESULTS: We identified 80 patients who underwent radical hysterectomy for clinical pelvic node-positive cervical adenocarcinoma; of these, four with pathological pelvic node-negative adenocarcinoma were excluded. Of the 76 patients, 27 underwent radical hysterectomy alone and 49 received radical hysterectomy followed by concurrent chemoradiotherapy. With a median follow-up of 53 months, the 5-year overall survival rate was 51.0% in patients who underwent radical hysterectomy alone versus 53.0% in patients who received additional concurrent chemoradiotherapy (log-rank p = 0.455). CONCLUSION: The addition of concurrent chemoradiotherapy after radical hysterectomy did not significantly improve survival among patients with pelvic node-positive cervical adenocarcinoma. More appropriate treatment strategies are needed to improve the survival outcomes of these patients.

Treatment strategy for locally advanced squamous cell cervical cancer with clinically positive pelvic lymph nodes metastasis.

AIM: To determine the optimal treatment for locally advanced squamous cell cervical cancer with clinical positive pelvic lymph nodes metastasis (cN1). METHODS: We enrolled patients with squamous cell cervical cancer with 2008 FIGO stages IB, IIA, or IIB diagnosed with cN1, who were treated at Hyogo Cancer Center between April 2010 and December 2016. Patients with para-aortic lymph nodes metastasis were excluded. RESULTS: Of the 69 eligible patients, 24 underwent concurrent chemoradiotherapy (CCRT), 11 underwent radical hysterectomy with pelvic lymphadenectomy (RH) with or without adjuvant RT, and 34 underwent neoadjuvant chemotherapy (NAC) followed by RH as initial treatment. The regimens of NAC included dose-dense TC (paclitaxel 80 mg/m2 , days 1, 8, 15; and carboplatin at an area under the curve = 6 on day 1, every 3 weeks) and dose-dense TP (paclitaxel 80 mg/m2 on days 1, 8, 15; and cisplatin 75 mg/m2 on day 1, every 3 weeks). The median observation period was 57 (12-107) months. The 5-year disease-free survival rates of the CCRT, RH, and NAC groups were 78.7%, 63.6%, and 88.2%, respectively (p = 0.14). The 5-year overall survival rates of the CCRT, RH, and NAC groups were 78.6%, 70.1%, and 94.1%, respectively (p = 0.11). CONCLUSIONS: We recommend avoiding RH as primary treatment for cN1 with locally advanced squamous cell cervical cancer. Although CCRT should be considered for cN1, further studies are required to determine if NAC followed by RH will serve as an effective option.

Quality of life assessment of cell-free and concentrated ascites reinfusion therapy during initial treatment for advanced ovarian cancer: A prospective cohort study.

AIM: Cell-free and concentrated ascites reinfusion therapy (CART) is applied to relieve symptoms in patients with malignant ascites. We performed a prospective cohort study to evaluate the efficacy and safety of CART performed on patients with advanced ovarian and peritoneal cancers with massive ascites during the initial treatment. METHODS: From April 2018 to July 2020, CART was performed during the initial treatment of 31 patients with advanced ovarian and peritoneal cancers with cancerous ascites. Patient characteristics and clinical information before and after CART were collected. We performed quality of life assessment using the Japanese version of the M.D. Anderson Symptom Inventory (MDASI-J) 24 h before and after CART. RESULTS: CART was performed 38 times in 24 patients before or during neoadjuvant chemotherapy and 11 times in 11 patients prior to surgery. Four patients underwent CART before primary surgery and before and/or during chemotherapy. Grade 1-2 fever was observed in 18 of 31 cases (58%), and all were controllable by nonsteroidal anti-inflammatory drugs. CART did not adversely affect the main treatment, chemotherapy, or surgery. CART significantly improved the MDASI-J symptom and interference scores within 24 h after the procedure. The symptom and interference scores decreased from 2.4 to 1.8 and from 4.8 to 3.0, respectively. CONCLUSIONS: CART can be safely performed and is useful for symptom relief and improvement of general condition prior to initial surgery and during initial chemotherapy in ovarian and peritoneal cancers. Performing CART at the time of initial treatment may facilitate initiation of the main treatment.

Human papillomavirus genotype contribution to cervical cancer and precancer: Implications for screening and vaccination in Japan.

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.

Suppressive effect upon carboplatin hypersensitivity reaction via pegylated liposomal doxorubicin combination therapy.

BACKGROUND: Occurrence of hypersensitivity reaction (HSR) in patients having received multiple doses of carboplatin has been reported. Several studies demonstrated reduction of carboplatin-associated HSR with in combination with pegylated liposomal doxorubicin (PLD). The objective of this study was to determine the suppressive effect on carboplatin-induced HSR via combined treatment with PLD within clinical practice. METHODS: We reviewed the medical records of women with primary or recurrent ovarian, fallopian tube, or peritoneal cancer treated with carboplatin containing regimen at our hospital between January 2009 and March 2019. We compared the incidence of carboplatin-induced HSR among patients who received more than one cycle of PLD plus carboplatin (PLD-C) therapy (i.e., PLD-C group) versus patients who never received PLD-C therapy (non-PLD-C group). RESULTS: A total of 414 women were included in this study (48: PLD-C group, 366: non-PLD-C group). Carboplatin-induced HSR occurred in 34 total patients (8.2%) [1/48 (2.1%) in the PLD-C group and 33/366 (9.0%) in the non-PLD-C group], with a median cycle number of carboplatin administration at onset of HSR being 9. Incidences of carboplatin-induced HSR within the PLD-C versus non-PLD-C group at the 8th, 12th, and 16th cycles of carboplatin administration were 2.2% vs 11.2%, 2.2% vs 28.6%, and 2.2% vs 39.1%, respectively [hazard ratio: 19.2 (95% confidence interval: 9.82-39.4), p < 0.0001]. CONCLUSION: Based on the data analyzed here, a suppressive effect on carboplatin-induced HSR via combination therapy with PLD was confirmed within clinical practice.

Dose-dense paclitaxel and carboplatin vs. conventional paclitaxel and carboplatin as neoadjuvant chemotherapy for advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: a retrospective study.

BACKGROUND: The purpose of this study was to determine the optimal regimen of neoadjuvant chemotherapy (NAC) for advanced epithelial ovarian, fallopian tube, and peritoneal cancers. METHODS: A clinical information survey involving 171 patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer was conducted. These patients underwent NAC followed by interval debulking surgery at the Hyogo Cancer Center (Hyogo, Japan) between January 2006 and December 2015. RESULTS: The median observation period was 41 (range 4-138) months. Dose-dense paclitaxel and carboplatin (TC) was administered in 101 patients (59%); tri-weekly TC was administered 70 patients (41%). Median progression-free survival was 21 [95% confidence interval (CI) 18-23] months and 15 (95% CI 13-17) months in the dose-dense TC and conventional-TC group [hazard ratio (HR) = 0.69, 95% CI 0.46-0.96; p = 0.02], respectively. The median overall survival was 59 (95% CI 46-72) and 40 (95% CI 32-57) months in the dose-dense TC group and conventional-TC group (HR = 0.72, 95% CI 0.48-1.06; p = 0.09). Multivariate analysis for progression-free survival demonstrated that dose-dense TC represented an independent prognostic factor (HR = 0.70, 95% CI 0.50-0.99; p = 0.04). CONCLUSIONS: Dose-dense TC is a promising regimen of NAC for advanced epithelial ovarian cancer.

Human Papillomavirus (HPV) Genotyping Assay Suitable for Monitoring the Impact of the 9-Valent HPV Vaccine.

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.

Reduction in HPV16/18 prevalence among young women with high-grade cervical lesions following the Japanese HPV vaccination program.

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.

Phase II trial of paclitaxel, carboplatin, and bevacizumab for advanced or recurrent cervical cancer.

OBJECTIVE: We evaluated the efficacy and safety of the combination of paclitaxel, carboplatin, and bevacizumab in patients with advanced or recurrent cervical cancer. METHODS: Subjects included patients with advanced or recurrent cervical cancer not amenable to curative treatment with surgery or radiation therapy. Treatment consisted of paclitaxel 175 mg/m2, carboplatin area under the curve 6 mg/mL/min, and bevacizumab 15 mg/kg every 21 days until disease progression, complete remission, or limiting toxicity. The primary endpoint was the objective response. RESULTS: In total, 34 patients received a median of 6 treatment cycles (range 2-25). The median follow-up period was 18.5 months (range 2-29). The objective response was 88% (95% confidence interval: 72.5%-96.7%). Seventeen patients (50%) experienced complete response, whereas 13 patients experienced (38%) partial response with a median duration of 6 months. Grades 3 and 4 hematologic toxicities manifested as neutropenia in 14 (41.2%), leukopenia in 14 (41.2%), anemia in 11 (32.4%), and thrombocytopenia in 9 (26.5%) patients. One patient who underwent prior pelvic irradiation developed grade 2 rectovaginal fistula. CONCLUSION: The combination of paclitaxel, carboplatin, and bevacizumab is effective and safe in patients with advanced or recurrent cervical cancer.

Correlation between pre-operative and final histological diagnosis on endometrial cancer.

OBJECTIVE: We conducted a retrospective study to evaluate the correlation between pre-operative and post-operative histological diagnoses on endometrial cancer, and to describe the treatments and outcomes when post-operative diagnoses are downgraded from pre-operative histology. METHODS: Patients who underwent surgery for endometrial cancer in our facility between 2010 and 2013 were enrolled in the study. The definition of downgrade discordance is in accordance with the following criteria: 1) the pre-operative and post-operative histological diagnoses were both endometrioid and the final pathology was a lower grade than the pre-operative pathology and 2) the pre-operative diagnosis was not endometrioid, whereas the post-operative diagnosis was endometrioid grade 2 or less. RESULTS: A total of 250 patients were enrolled, and the concordance rates were 56% for endometrioid adenocarcinoma grade 1 (EMG1), 67% for EMG2, 67% for EMG3, 82% for carcinosarcoma, 71% for serous carcinoma, and 67% for clear cell carcinoma. Eighteen cases (6.6%) were identified as downgrade discordancy. Of the 18 patients, the triage for adjuvant therapy remained the same for 15 cases (83%), all of whom had no evidence of disease at their last visit. Three cases had discordances with respect to triage for adjuvant therapy; the therapies were triaged based on post-operative diagnosis. Of these patients one had a recurrence. CONCLUSIONS: Good correlation was observed between pre-operative and final histological diagnoses of endometrioid carcinoma (56%-67%) and type 2 carcinoma (67%-82%). Approximately 7% (18/250) of patients had downgrade discordancy; however, triage for adjuvant therapy did not change for approximately 80% (15/18) of the patients with downgrade discordancy. Further studies are needed to evaluate the effectiveness of triages that are based on post-operative diagnoses.

Pelvic fractures after definitive and postoperative radiotherapy for cervical cancer: A retrospective analysis of risk factors.

OBJECTIVES: This study clarified the incidence of and identified the risk factors for post-radiation pelvic insufficiency fractures (PIFs) in women who received postoperative definitive or adjuvant radiotherapy (RT) for cervical cancer. PATIENTS AND METHODS: The medical records and data of imaging studies, including computed tomography scan and magnetic resonance imaging, of women with cervical cancer who received external-beam RT for the entire pelvic area between January 2003 and December 2012 at our institution were reviewed. RESULTS: A total of 533 patients with histologically diagnosed cervical cancer who received RT (298: definitive RT, 235: adjuvant RT) were included in this study. Eighty-four patients (15.8%) developed PIF in the irradiated field. Median age at onset of PIF was 72.5years (range: 54-95years), and 82 of them (98%) were postmenopausal women. Sixty-nine patients (80%) developed PIF within 3years from the completion of RT. The median time for the development of PIF was 14months (range: 1-81months). The most commonly involved fracture site was the sacral bone. Postmenopausal state, coexistence of rheumatoid arthritis, and high-dose-rate intracavitary brachytherapy (HDR-ICBT) use were significant predisposing factors for the development of PIF, according to multivariate analysis. CONCLUSIONS: The incidence rate of PIF among patients who received RT for locally advanced cervical cancer was 15.8%. The principal predisposing factors for post-radiation PIF were postmenopausal state, rheumatoid arthritis, and HDR-ICBT use. Active interventions, including bone density screening followed by medication, should be considered during the early stage of RT for women with high-risk factors of PIF.