Efficacy, Immunogenicity, and Safety of a 9-Valent Human Papillomavirus Vaccine: Subgroup Analysis of Participants From Asian Countries.

Background: A 9-valent human papillomavirus-6/11/16/18/31/33/45/52/58 (9vHPV) vaccine extends coverage to 5 next most common oncogenic types (31/33/45/52/58) in cervical cancer versus quadrivalent HPV (qHPV) vaccine. We describe efficacy, immunogenicity, and safety in Asian participants (India, Hong Kong, South Korea, Japan, Taiwan, and Thailand) from 2 international studies: a randomized, double-blinded, qHPV vaccine-controlled efficacy study (young women aged 16-26 years; NCT00543543; Study 001); and an immunogenicity study (girls and boys aged 9-15 years; NCT00943722; Study 002). Methods: Participants (N = 2519) were vaccinated at day 1 and months 2 and 6. Gynecological samples (Study 001 only) and serum were collected for HPV DNA and antibody assessments, respectively. Injection-site and systemic adverse events (AEs) were monitored. Data were analyzed by country and vaccination group. Results: 9vHPV vaccine prevented HPV-31/33/45/52/58-related persistent infection with 90.4%-100% efficacy across included countries. At month 7, ≥97.9% of participants seroconverted for each HPV type. Injection-site AEs occurred in 77.7%-83.1% and 81.9%-87.5% of qHPV and 9vHPV vaccine recipients in Study 001, respectively, and 62.4%-85.7% of girls/boys in Study 002; most were mild to moderate. Conclusions: The 9vHPV vaccine is efficacious, immunogenic, and well tolerated in Asian participants. Data support 9vHPV vaccination programs in Asia. Clinical Trials Registration: NCT00543543; NCT00943722.

Clinical benefit of nomogram for predicting positive resection margins in breast conserving surgery.

PURPOSE: Previously, we reported a nomogram for the prediction of positive resection margin (RM) after breast conserving surgery (BCS). This study was conducted to evaluate the clinical usefulness of the nomogram. METHODS: Prospective patients who underwent operations using the nomogram between July 2012 and August 2013 (nomogram group; N = 260) were compared with past control patients who underwent operations between July 2010 and October 2011 and underwent frozen section biopsy (FSB) without use of the nomogram (N = 266). In the nomogram group, an intraoperative assessment of RM using FSB was only performed when the nomogram score was higher than predefined cut-off (>80). In addition, we conducted retrospective analysis of additional 181 patients who received BCS in another institute (Kyoto University Hospital). These patients did not undergo FSBs for RMs. RESULTS: Of 260 patients, 161 (61.9%) presented low nomogram scores and avoided FSB. The surgical decision to use the nomogram did not significantly increase reoperation rate due to positive RM compared with the control FSB group (4.6% vs. 3.8%, p = 0.47). The surgery time was significantly reduced by 18.1% (mean 14.7 min) in nomogram group (p < 0.001). Of 99 nomogram high-score patients, 14 presented with positive RM on FSB and 11 of them avoided reoperation. In the Kyoto cohort, the reoperation rate was significantly lower in low-score patients than in high-score patients (2.7% vs. 11.4%, p < 0.001). CONCLUSIONS: We showed that our nomogram is useful to reduce FSBs without increasing reoperation rate for surgeons who perform routine FSBs. For most surgeons, it can give useful information about the possibility of tumor-positive RMs.

Subjective apnoea symptoms are associated with daytime sleepiness in patients with moderate and severe obstructive sleep apnoea: a retrospective study.

OBJECTIVES: Most previous studies have failed to show a relation between daytime sleepiness and apnoea severity in patients with obstructive sleep apnoea (OSA). We determined the relation between daytime sleepiness and subjective and objective apnoea severity in newly diagnosed patients with moderate-to-severe OSA. DESIGN: Retrospective cross-sectional study. SETTING: Tertiary referral centre. PARTICIPANTS: A total of 559 adults with newly diagnosed moderate and severe OSA. MAIN OUTCOME MEASURES: Daytime sleepiness was evaluated using the Epworth Sleepiness Scale (ESS). Subjective and objective apnoea severities were assessed using the Sleep Breathing Scale (SBS) and polysomnography respectively. Sleep quality and depressive symptoms were evaluated using Medical Outcomes Study-Sleep Scale and Beck Depression Inventory (BDI) respectively. RESULTS: The mean ESS score was 9.8 (SD 5.0). ESS score was correlated with SBS score (P < 0.001), apnoea-hypopnoea index (AHI) (P = 0.027), minimal oxygen saturation (MinSaO2 ) (P = 0.021), body mass index (BMI) (P = 0.007) and BDI score (P < 0.001). Linear regression analysis showed that higher SBS (P = 0.005) and BDI scores (P < 0.001) were associated with higher ESS score after controlling for gender, BMI and AHI. Apnoea-hypopnoea index, MinSaO2 and BMI were not independently related to ESS score. CONCLUSIONS: Daytime sleepiness was related to subjective OSA symptoms but not objective apnoea severity measured by polysomnography in patients with moderate-to-severe OSA. These findings suggest the usefulness of the subjective apnoea severity as an indicator of OSA disease severity.

Cytomorphological characteristics of low-grade papillary urothelial carcinoma for differential diagnosis from benign papillary urothelial lesions: logistic regression analysis in SurePath(™) liquid-based voided urine cytology.

OBJECTIVE: The diagnosis of low-grade papillary urothelial carcinoma (LGPUC) in urine cytology specimens is challenging because of its subtle, minimally atypical findings. Furthermore, as SurePath(™) liquid-based cytology (LBC) is becoming a widely used method in urine cytology, the inevitable cytomorphological alterations resulting from this technique call for new morphological diagnostic criteria in LGPUC. METHODS: Logistic regression analysis was carried out on SurePath slides from surgically proven voided urine specimens. The study was designed to include a test set (n = 141) and a validation set (n = 61), and evaluated significant discriminative parameters between LGPUC and benign papillary urothelial neoplasm (BPUN). RESULTS: Of the seven cytological findings that were found to have statistical significance in univariate analysis, five were found to be independent variables: loss of polarity of papillaroid clusters, irregular contours, absence of columnar cells, hobnail features and hyperchromasia. These independent variables had an area under the curve (AUC) of 0.781. CONCLUSIONS: The distinctive cytological criteria identified above may prove to be helpful in cases in which other conventional criteria for LGPUC are insufficient for diagnosis.

Prognostic and predictive values of EGFR overexpression and EGFR copy number alteration in HER2-positive breast cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR) is overexpressed in a subset of human epidermal growth factor receptor 2 (HER2)-positive breast cancers, and coexpression of HER2 and EGFR has been reported to be associated with poor clinical outcome. Moreover, interaction between HER2 and EGFR has been suggested to be a possible basis for trastuzumab resistance. METHODS: We analysed the clinical significance of EGFR overexpression and EGFR gene copy number alterations in 242 HER2-positive primary breast cancers. In addition, we examined the correlations between EGFR overexpression, trastuzumab response and clinical outcome in 447 primary, and 112 metastatic HER2-positive breast cancer patients treated by trastuzumab. RESULTS: Of the 242 primary cases, the level of EGFR overexpression was 2+ in 12.7% and 3+ in 11.8%. High EGFR gene copy number was detected in 10.3%. Epidermal growth factor receptor overexpression was associated with hormone receptor negativity and high Ki-67 proliferation index. In survival analyses, EGFR overexpression, but not high EGFR copy number, was associated with poor disease-free survival in all patients, and in the subgroup not receiving adjuvant trastuzumab. In 447 HER2-positive primary breast cancer patients treated with adjuvant trastuzumab, EGFR overexpression was also an independent poor prognostic factor. However, EGFR overexpression was not associated with trastuzumab response, progression-free survival or overall survival in the metastatic setting. CONCLUSIONS: Epidermal growth factor receptor overexpression, but not high EGFR copy number, is a poor prognostic factor in HER2-positive primary breast cancer. Epidermal growth factor receptor overexpression is a predictive factor for trastuzumab response in HER2-positive primary breast cancer, but not in metastatic breast cancer.

Intermediate-risk grouping of cervical cancer patients treated with radical hysterectomy: a Korean Gynecologic Oncology Group study.

BACKGROUND: In this study, we sought to identify a criterion for the intermediate-risk grouping of patients with cervical cancer who exhibit any intermediate-risk factor after radical hysterectomy. METHODS: In total, 2158 patients with pathologically proven stage IB-IIA cervical cancer with any intermediate-risk factor after radical hysterectomy were randomly assigned to two groups, a development group and a validation group, at a ratio of 3 : 1 (1620 patients:538 patients). To predict recurrence, multivariate models were developed using the development group. The ability of the models to discriminate between groups was validated using the log-rank test and receiver operating characteristic (ROC) analysis. RESULTS: Four factors (histology, tumour size, deep stromal invasion (DSI), and lymphovascular space involvement (LVSI)) were significantly associated with disease recurrence and included in the models. Among the nine possible combinations of the four variables, models consisting of any two of the four intermediate-risk factors (tumour size ≥3 cm, DSI of the outer third of the cervix, LVSI, and adenocarcinoma or adenosquamous carcinoma histology) demonstrated the best performance for predicting recurrence. CONCLUSION: This study identified a 'four-factor model' in which the presence of any two factors may be useful for predicting recurrence in patients with cervical cancer treated with radical hysterectomy.

Efficacy of neoadjuvant chemotherapy in patients with FIGO stage IB1 to IIA cervical cancer: an international collaborative meta-analysis.

BACKGROUND: The efficacy of neoadjuvant chemotherapy before surgery (NCS) has not been well-established in FIGO stage IB1 to IIA cervical cancer when compared with primary surgical treatment (PST). Thus, we performed a meta-analysis to determine the efficacy of NCS in patients with FIGO stage IB1 to IIA cervical cancer when compared with PST. METHODS: We searched Pubmed, Embase and the Cochrane Library between January 1987 and September 2010. Since there was a relative lack of relevant randomized controlled trials (RCTs), we included 5 RCTs and 4 observational studies involving 1784 patients among 523 potentially relevant studies. RESULTS: NCS was related with lower rates of large tumor size (≥4 cm) (ORs, 0.22 and 0.10; 95% CI, 0.13-0.39 and 0.02-0.37) and lymph node metastasis (ORs, 0.61 and 0.38; 95% CI, 0.37-0.99 and 0.20-0.73) than PST in all studies and RCTs. Furthermore, NCS reduced the need of adjuvant radiotherapy (RT) in all studies (OR, 0.57; 95% CI, 0.33-0.98), and distant metastasis in all studies and RCTs (ORs, 0.61 and 0.61; 95% CI, 0.42-0.89 and 0.38-0.97). However, overall and loco-regional recurrences and progression-free survival were not different between the 2 treatments. On the other hand, NCS was associated with poorer overall survival in observational studies when compared with PST (HR, 1.68; 95% CI, 1.12-2.53). CONCLUSIONS: Although NCS reduced the need of adjuvant RT by decreasing tumor size and lymph node metastasis, and distant metastasis, it failed to improve survival when compared with PST in patients with FIGO stage IB1 to IIA cervical cancer.

Evaluation of sulfur and multi-walled carbon nanotube composite synthesized by dissolution and precipitation for Li/S batteries.

An elemental sulfur and multi-walled carbon nanotube (S-MWNT) composite was synthesized by dissolving sulfur in ammonium sulfides and then precipitating on MWNT. Morphology observation by scanning electron microscopy (SEM) confirmed that S-MWNT product was successfully prepared by incorporating sulfur into MWNT network. Without additional conducting material, the S-MWNT composite cathodes were prepared for electrochemical tests. The properties measured in discharge-charge cycling test showed that the composite had the initial discharge capacity of 1024 mAh g(-1), which is about 61% sulfur utilization. However, in the subsequent cycling, the capacities faded. To determine the reason of rapid capacity drop, S-MWNT composite cathodes were compared in the cycling tests with varying three kinds of electrolytes and the cathode was subjected to physical force by rolling. The changes in the cycle performances proved that the deterioration of S-MWNT composite cathodes was not related to the electrolytes but to physical bonding that may not maintain the conducting path between sulfur and MWNT.

Malignant mixed Müllerian tumors of the uterus: sonographic spectrum.

OBJECTIVE: To describe the sonographic findings for malignant mixed Müllerian tumors (MMMTs) of the uterus with particular emphasis on their features on saline contrast sonohysterography (SCSH) and color Doppler sonography, and to determine how they relate to pathological findings. METHODS: The SCSH and color Doppler findings in 29 histologically proven cases of uterine MMMT were reviewed retrospectively and their relationship to gross and histological findings were investigated. RESULTS: Of the 29 uterine tumors, 16 were located only in the corpus, nine only in the fundus and four in both the corpus and fundus. Mean tumor size was 5.4 cm. The most common appearance was a polypoid mass projecting into the endometrial cavity, found in 23 cases. Twenty-eight tumors had an irregular surface, which was papillary in 20 cases and lobulated in eight. Most appeared heterogeneously isoechoic (n = 16) or hypoechoic (n = 12), occasionally with a trabecular appearance, and they often had clefts or fissure-like cystic areas (n = 10), necrosis (n = 4) or hemorrhagic areas (n = 7). Myometrial invasion was present in 27 cases and dilatation of the endometrial cavity was seen in 11. Color Doppler sonography showed moderate to marked vascularity in 20 out of the 24 cases in which it was performed, with a mean resistance index of 0.41, and appeared as feeding (n = 15) or randomly dispersed (n = 9) vessels. CONCLUSIONS: Uterine MMMTs have distinct sonographic features that are related to pathological findings. Knowledge of the sonographic appearance of MMMTs may facilitate diagnosis.

An increase in cancer stem cell population after primary systemic therapy is a poor prognostic factor in breast cancer.

BACKGROUND: The cancer stem cell (CSC) hypothesis has important clinical implications for cancer therapeutics because of the proposed role of CSCs in chemoresistance. The aim of this study was to investigate changes in the CSC populations before and after primary systemic therapy (PST) and their prognostic role in human breast cancer. METHODS: Paired samples (before and after PST) of breast cancer tissue were obtained from clinical stage II or III patients (n=92) undergoing PST with the regimen of doxorubicin plus docetaxel (AD) (n=50) or doxorubicin plus cyclophosphamide (AC) (n=42) and subsequent breast resection. The proportions of putative CSCs with CD44+/CD24- or aldehyde dehydrogenase 1+ (ALDH1+) phenotypes were determined by immunohistochemistry. RESULTS: A higher proportion of CD44+/CD24- tumour cells and ALDH1 positivity in pre-chemotherapy tissue was correlated with higher histologic grade, oestrogen receptor (ER) negativity, high Ki-67 proliferation index and basal-like subtype of breast cancer. Aldehyde dehydrogenase 1 positivity in pre-chemotherapy biopsy was also associated with a higher rate of pathologic complete response following PST. In comparisons of putative CSC populations before and after PST, the proportions of CD44+/CD24- and ALDH1+ tumour cells were significantly increased after PST. The cases with increased CD44+/CD24- tumour cell populations after PST showed high Ki-67 proliferation index in post-chemotherapy specimens and those with increased ALDH1+ tumour cell population after PST were associated with ER negativity and p53 overexpression. Furthermore, cases showing such an increase had significantly shorter disease-free survival time than those with no change or a reduced number of CSCs, and the survival difference was most notable with regard to the changes of ALDH1+ tumour cell population in the patients who received AC regimen. CONCLUSION: The present study provides the clinical evidence that the putative CSCs in breast cancer are chemoresistant and are associated with tumour progression, emphasising the need for targeting of CSCs in the breast cancer therapeutics.

The effect of the respiratory cycle on liver stiffness values as measured by transient elastography.

The findings of several studies suggest that liver stiffness values can be affected by the degree of intrahepatic congestion respiration influence intrahepatic blood volume and may affect liver stiffness. We evaluated the influence of respiration on liver stiffness. Transient elastography (TE) was performed at the end of inspiration and at the end of expiration in patients with chronic liver disease. The median values obtained during the inspiration set and during the expiration set were defined as inspiratory and expiratory liver stiffness, respectively. A total of 123 patients with chronic liver disease were enrolled (mean age 49years; 64.2% men). Liver cirrhosis coexisted in 29 patients (23.6%). Expiratory liver stiffness was significantly higher than inspiratory liver stiffness (8.7 vs 7.9kPa, P=0.001), while the expiratory interquartile range/median ratio (IQR ratio) did not differ from the inspiratory IQR ratio. Expiratory liver stiffness was significantly higher than inspiratory liver stiffness in 49 (39.8%) patients (HE group), expiratory liver stiffness was significantly lower than inspiratory stiffness in 15 (12.2%) patients, and there was no difference in 59 (48.0%) patients. Liver cirrhosis was more frequent in those who had a lower liver stiffness reading in expiration, and only the absence of liver cirrhosis was significantly associated with a higher reading in expiration in multivariate analysis. In conclusion, liver stiffness was significantly elevated during expiration especially in patients without liver cirrhosis. The effect of respiration should be kept in mind during TE readings.