BackgroundPositron emission tomography (PET)/MRI biomarkers have been shown to have prognostic significance in patients with cervical cancer. Their associations with progression‐free survival (PFS) and overall survival (OS) merit further investigation.PurposeTo evaluate the association between PET/MRI biomarkers and tumor stage, PFS, and OS in patients with cervical cancer.Study TypeProspective cohort study.PopulationIn all, 54 patients with newly diagnosed cervical cancer and measurable tumors (>1 cm) were included in the image analysis.Field Strength/Sequence3.0T integrated PET/MRI including diffusion‐weighted echo‐planar imaging (b = 50 and 1000 s/mm2) and [18F]fluorodeoxyglucose PET.AssessmentTwo radiologists measured the minimum and mean apparent diffusion coefficient (ADCmin and ADCmean), maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of the primary tumors.Statistical TestsA Mann–Whitney U‐test was used to evaluate the association between the imaging biomarkers and tumor stage. A Cox proportional hazards model was used to assess the relationships between the imaging biomarkers and survival.ResultsIn advanced tumors (T ≥ 1b2, M1, stage ≥ IB3), ADCmin was significantly lower and MTV, TLG, MTV/ADCmin, and TLG/ADCmin were significantly higher (P values between <0.001 and 0.036). In N1 tumors, ADCmin was significantly lower and MTV and MTV/ADCmin were significantly higher (P values between 0.005 and 0.016). In survival analysis, SUVmax was an independent predictor of PFS (hazard ratio [HR] = 4.57, P < 0.05), and ADCmin was an independent predictor of OS (HR = 0.02, P < 0.05). In subgroup analysis of patients with different stages, MTV/ADCmin was a predictor of PFS in stage I disease (P = 0.003), ADCmin (P = 0.038), and MTV (P = 0.020) in stage II, SUVmax (P = 0.006), and TLG (P = 0.006) in stage IV; and ADCmin was a predictor of OS in stage III disease (P = 0.008).Data ConclusionPET/MRI biomarkers of cervical cancer are associated with tumor stage and survival. SUVmax and ADCmin are independent predictors of PFS and OS, respectively.Level of Evidence1Technical Efficacy3

Supplementary Figure 2 from IL-6 Trans-Signaling in Formation and Progression of Malignant Ascites in Ovarian Cancer

Supplementary Figure 1 from IL-6 Trans-Signaling in Formation and Progression of Malignant Ascites in Ovarian Cancer

Basket trials evaluate a single drug targeting a single genetic variant in multiple cancer cohorts. Empirical findings suggest that treatment efficacy across baskets may be heterogeneous. Most modern basket trial designs use Bayesian methods. These methods require the prior specification of at least one parameter that permits information sharing across baskets. In this study, we provide recommendations for selecting a prior for scale parameters for adaptive basket trials by using Bayesian hierarchical modeling. Heterogeneity among baskets attracts much attention in basket trial research, and substantial heterogeneity challenges the basic assumption of exchangeability of Bayesian hierarchical approach. Thus, we also allowed each stratum-specific parameter to be exchangeable or nonexchangeable with similar strata by using data observed in an interim analysis. Through a simulation study, we evaluated the overall performance of our design based on statistical power and type I error rates. Our research contributes to the understanding of the properties of Bayesian basket trial designs.

Coral reefs in the Central Indo-Pacific region comprise some of the most diverse and yet threatened marine habitats. While reef monitoring has grown throughout the region in recent years, studies of coral reef benthic cover remain limited in spatial and temporal scales. Here, we analysed 24,365 reef surveys performed over 37 years at 1972 sites throughout East Asia by the Global Coral Reef Monitoring Network using Bayesian approaches. Our results show that overall coral cover at surveyed reefs has not declined as suggested in previous studies and compared to reef regions like the Caribbean. Concurrently, macroalgal cover has not increased, with no indications of phase shifts from coral to macroalgal dominance on reefs. Yet, models incorporating socio-economic and environmental variables reveal negative associations of coral cover with coastal urbanisation and sea surface temperature. The diversity of reef assemblages may have mitigated cover declines thus far, but climate change could threaten reef resilience. We recommend prioritisation of regionally coordinated, locally collaborative long-term studies for better contextualisation of monitoring data and analyses, which are essential for achieving reef conservation goals.

Supplementary Figure 3 from IL-6 Trans-Signaling in Formation and Progression of Malignant Ascites in Ovarian Cancer

Introduction In recent years, promising survival benefits from maintenance therapy with poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) has changed the management of epithelial ovarian cancer (EOC) in newly diagnosed and recurrent disease. Identification of BRCA and/or homologous recombination (HR) gene mutation is critical for selecting patients for PARPi treatment and as a prognostic and predictive biomarker in high-grade serous carcinoma (HGSOC), yet its role in other histology remains controversial. Our study aims to retrospectively analyze the correlation of BRCA/HR gene mutation with the clinical outcomes of EOC patients. Methods 318 women diagnosed with EOC who had received debulking surgery and platinum-based adjuvant chemotherapy at NTUH were retrospectively reviewed. The tumor tissue was sent for genetic analysis for somatic mutation of genes in HR gene panel, including BRCA 1/2. Clinical data were obtained from medical records. Results 25.4% of patients with HGSOC (n = 177) had BRCA/HR mutation and showed better sensitivity to platinum-based chemotherapy (83.9% vs. 69.5%, P=0.029) and longer progression-free survival (PFS) (P=0.004 and <0.001, respectively). However, only 7.8% of patients with non-serous histology had BRCA/HR mutation and showed no correlation with platinum sensitivity, PFS, or overall survival. Through the multivariate analysis, we confirmed the protective effect of BRCA/HR mutation with disease recurrence and death in patients with HGSOC yet no effect was found on non-serous histologic type. Conclusion/Implications BRCA/HR mutation is a prognostic biomarker in HGSOC yet not in non-serous patients. Further study is needed to follow up on the clinical response to PARPi in these patients and find out other proper prognostic biomarkers.

Supplementary Tables 1-2, Figure Legends 1-3 from IL-6 Trans-Signaling in Formation and Progression of Malignant Ascites in Ovarian Cancer

Epithelial ovarian cancer (EOC) is usually diagnosed at an advanced stage and has poor prognosis. Theranostic agents are the current trend in drug development, but are lacking in EOC. YKL40 is predominantly expressed and involved in tumorigenesis in EOC. In this study, we developed a companion theranostic agent targeting YKL40. We measured YKL40 expression levels in ascites using ELISA and correlated them with the clinical outcomes of patients with EOC. We developed radionuclide labeled In-111/Lu-177-DTPA-YKL40 neutralizing antibodies and investigated their radiochemical purity, SPECT/CT imaging, bio-distribution, and therapeutic responses in ovarian cancer xenograft mice. We demonstrated that YKL40 expression levels in ascites were significantly higher in EOC patients with serous histological type, high tumor grade, advanced stage, tumor recurrence, chemoresistance, and tumor-related death. The radiochemical purity of In-111/Lu-177-DTPA-YKL40 neutralizing antibodies reached more than 90% after 24 h of labeling. SPECT/CT imaging showed significant accumulation of In-111-DTPA-YKL40 and Lu-177-DTPA-YKL40 antibodies at the tumor site of ovarian cancer xenograft mice 24 h after administration. Lu-177-DTPA-YKL40 antibodies significantly inhibited tumor growth in ovarian cancer xenograft mice. Our study indicated that In-111/Lu-177-DTPA-YKL40 neutralizing antibodies could be potential companion theranostic agents for patients with EOC.

Most ovarian cancer patients experience disease recurrence and chemotherapeutic resistance, and the underlying mechanisms are unclear. Identifying relevant pathways could reveal new therapeutic targets. Here we examined expression of transmembrane protein 102 (TMEM102), a biomarker of prognosis and chemoresistance, in epithelial ovarian cancer (EOC), and assessed its role in inhibiting tumor cell apoptosis. We performed qRT-PCR to investigate the association of TMEM102 expression with clinical outcomes in 226 EOC patients. We also conducted in vitro studies to explore possible mechanisms through which TMEM102 may influence chemoresistance, including the effects of downregulating TMEM102 expression with small interfering RNA. Serous and high-grade carcinomas expressed significantly higher TMEM102 than normal ovarian tissues. TMEM102 was also overexpressed in patients with advanced-stage disease and chemoresistance. Reduction of TMEM102 expression by small interfering RNA induced ovarian cancer cell apoptosis after cytotoxic treatment. TMEM102 overexpression enhanced chemoresistance via upregulation of heat shock proteins 27, 60, and 70; and survivin, resulting in decreased cytochrome c in the mitochondria and decreased caspase 9 expression. Our results indicate that TMEM102 overexpression may promote chemoresistance via inhibition of a mitochondria-associated apoptotic pathway.

AbstractBackgroundWomen with endometrial cancer (EC) have favorable prognoses, leaving them vulnerable to the development of second primary cancers (SPCs). We investigated the SPC risk and survival outcomes among EC patients treated with surgery alone in order to exclude the impact of adjuvant treatment on the results.MethodsData from the Taiwan Cancer Registry from 1995 to 2013 were analyzed. Standardized incidence ratios (SIRs) of SPCs among EC survivors were calculated.ResultsAmong 7725 women enrolled, 478 developed an SPC. The overall SIR for SPCs in EC survivors was 2.84 (95% confidence interval [CI] 2.59–3.10) compared with the general female population. Women diagnosed with EC at age <50 years had a higher SIR for an SPC than those diagnosed at age ≥50 years (SIR = 4.38 vs. 1.28). The most frequent site of an SPC was the small intestine (SIR = 8.39, 95% CI 2.72–19.58), followed by the kidney (SIR = 4.84, 95% CI 1.78–10.54), and oral cavity (SIR = 4.52, 95% CI 2.17–8.31). Women, regardless of age at EC diagnosis, had significantly higher SIRs for subsequent breast, colorectal, lung, and thyroid cancer, and lymphoma. Women with an SPC had shorter overall survival than those without (5‐year: 88.9 vs. 94.2%, 10‐year: 71.3 vs. 89.8%, 15‐year: 62.3 vs. 86.1%, and 20‐year: 47.6 vs. 81.1%, all ps<0.001).ConclusionsEven women treated for EC with surgery alone, especially young EC survivors, had an increased risk of SPCs. Genetic counseling/testing is recommended for young EC patients, and all are recommended to receive regular surveillance and screening for breast, colorectal, and lung cancers.

DNA damage response (DDR) is important for maintaining genomic integrity of the cell. Aberrant DDR pathways lead to accumulation of DNA damage, genomic instability and malignant transformations. Gene mutations have been proven to be associated with epithelial ovarian cancer, and the majority of the literature has focused on BRCA. In this study, we investigated the somatic mutation of DNA damage response genes in epithelial ovarian cancer patients using a multiple-gene panel with next-generation sequencing. In all, 69 serous, 39 endometrioid and 64 clear cell carcinoma patients were enrolled. Serous carcinoma patients (69.6%) had higher percentages of DDR gene mutations compared with patients with endometrioid (33.3%) and clear cell carcinoma (26.6%) (p < 0.001, chi-squared test). The percentages of DDR gene mutations in patients with recurrence (53.9 vs. 32.9% p = 0.006, chi-squared test) or cancer-related death (59.2 vs. 34.4% p = 0.001, chi-squared test) were higher than those without recurrence or living patients. In endometrioid carcinoma, patients with ≥2 DDR gene mutations had shorter PFS (p = 0.0035, log-rank test) and OS (p = 0.015, log-rank test) than those with one mutation or none. In clear cell carcinoma, patients with ≥2 DDR gene mutations had significantly shorter PFS (p = 0.0056, log-rank test) and OS (p = 0.0046, log-rank test) than those with 1 DDR mutation or none. In the EOC patients, somatic DDR gene mutations were associated with advanced-stage tumor recurrence and tumor-related death. Type I EOC patients with DDR mutations had an unfavorable prognosis, especially for clear cell carcinoma.

The optimal adjuvant treatment for stage IB endometrial cancer remains undefined. We investigated the benefit of modern adjuvant radiotherapy for women with stage IB endometrial cancer. We retrospectively reviewed patients with surgically staged, pure stage IB endometrioid adenocarcinoma (2010 to 2018). Adjuvant modern radiotherapy consists of external-beam radiotherapy (EBRT) by intensity, volumetric-modulated arc radiotherapy, or image-guided vaginal brachytherapy (VBT). The study included 180 stage IB patients. Patients with grade 3 diseases had frequent aggressive histology patterns (lymphovascular space invasion (LVSI); low uterine segment involvement) and experienced significantly shorter recurrence-free survival (RFS) and overall survival (OS) than patients with grade 1/2 diseases. Adjuvant modern radiotherapy decreased the incidence of acute/chronic grade ≥2 gastrointestinal toxicity. In IB grade 1/2 patients, EBRT significantly lengthened survival (RFS/OS); patients with age >60 years, myometrial invasion beyond the outer third, or LVSI benefited the most from EBRT. EBRT also significantly improved survival (RFS/OS) in IB grade 3 patients, where patients with bulky tumors or LVSI benefited the most from EBRT. Therefore, EBRT may be beneficial for all stage IB patients.

A biosimilar is a biological product that is highly similar to an existing approved reference drug and has no clinically meaningful difference from it. Biosimilars are composed of or derived from living cells or organisms. Therefore, they are often sensitive to slight variations in the manufacturing process. Consequently, in demonstrating biosimilarity, it might be inappropriate to focus solely on the mean difference, or ratio of means, while ignoring the variabilities associated with the test and reference products. It is important to account for the entire population of clinical outcomes. Thus, we propose using the concept of tolerance intervals and related hypothesis testing for assessing biosimilarity. Our approach has the advantage of considering entire populations associated with both groups. A real example is used to illustrate our proposed method, and our approach is more stringent than those that employ confidence intervals. This is specifically the case when the mean difference of two drugs is not sufficiently large, but the biosimilar has a higher variability than that in the reference drug.

Abstract Tolerance intervals (TIs) are widely used in numerous industries, ranging from engineering to pharmaceuticals. In these applications, it is commonly assumed that data are normally distributed. However, the normality assumption may not apply in many situations, such as in the case of multiple production lines. As a result, the mixture normal distribution may be a more applicable model than the normal distribution to fit real data. Although the conventional distribution-free TI can be adopted for the mixture normal distribution, it leads to an unsatisfactory coverage probability when the sample size is not sufficiently large. In this study, we propose two Tls for the mixture normal distribution. The first is based the expectation-maximization (EM) algorithm combined with the bootstrap method and the second is based on the asymptotic property of sample quantiles. The simulation results show that the proposed TIs have coverage probability closer to the nominal level than the distribution-free interval. A real engineering data example is used to illustrate the methods.

Background Inadequate hospital cleaning may contribute to cross-transmission of pathogens. It is important to implement effective cleaning for the safe hospital environment. We conducted a three-phase study using human factors engineering (HFE) approach to enhance environmental cleanliness. Methods This study was conducted using a prospective interventional trial, and 28 (33.3%) of 84 wards in a medical center were sampled. The three-phases included pre-intervention analysis (Phase 1), implementing interventions by HFE principles (Phase 2), and programmatic analysis (Phase 3). The evaluations of terminal cleaning and disinfection were performed using the fluorescent marker, the adenosine triphosphate bioluminescence assay, and the aerobic colony count method simultaneously in all phases. Effective terminal cleaning and disinfection was qualified with the aggregate outcome of the same 10 high-touch surfaces per room. A score for each high-touch surface was recorded, with 0 denoting a fail and 10 denoting a pass by the benchmark of the evaluation method, and the total terminal cleaning and disinfection score (TCD score) was a score out of 100. Results In each phase, 840 high-touch surfaces were collected from 84 rooms after terminal cleaning and disinfection. After the interventions, the TCD score by the three evaluation methods all showed significant improved. The carriage incidence of multidrug-resistant organism (MDRO) decreased significantly from 4.1 per 1000 patient-days to 3.6 per 1000 patient-days ( P = .03). Conclusion The HFE approach can improve the thoroughness and the effectiveness of terminal cleaning and disinfection, and resulted in a reduction of patient carriage of MDRO at hospitals. Larger studies are necessary to establish whether such efforts of cleanliness can reduce the incidence of healthcare-associated infection.

In this retrospective study, we investigated adverse events and outcomes in patients treated with bevacizumab for ovarian, fallopian tube, or primary peritoneal cancers at a single hospital. We determined the cumulative incidences of various bevacizumab-related adverse events and the correlation between dose and adverse event incidences. We analyzed data from 154 patients that received 251 rounds of bevacizumab as first-line, first salvage, >2 salvage treatments. Adverse events of any grade were observed in 121 (78.6%) patients; at least one grade 3 or 4 adverse event occurred in 32 (20.8%) patients. The two most common events were proteinuria (38.3%) and hypertension (33.8%). The first-line treatment group displayed significantly higher frequencies of hypertension (52.7% vs. 18.9% vs. 15.5%, p < 0.001), wound complications (9.1% vs. 0% vs. 1.2%, p = 0.010), arthralgia (29.1% vs. 11.3% vs. 8.3%, p = 0.003), and reduced range of joint motion (14.5% vs. 5.7% vs. 3.6%, p = 0.046), compared to those in the first and >2 lines salvage groups, respectively (Kruskal-Wallis test). The cumulative incidences of all grades and grades 3/4 of hypertension cumulative incidence plateaued at around 30% for all grades and 10% for grades 3 and 4, at bevacizumab doses above 8080 and 3510 mg, respectively. The proteinuria cumulative incidence plateaued at around 35% for all grades and 3% for grades 3 and 4, at bevacizumab doses above 11,190 and 4530 mg, respectively. We concluded that, in this realistic clinical population, different kinds and higher cumulative incidences of adverse events were observed compared to those reported in previous clinical trials. Moreover, bevacizumab doses showed cumulative toxicity and plateau effects on hypertension and proteinuria.

Background The standard treatment for epithelial ovarian carcinoma (EOC) is surgery followed by platinum/paclitaxel-based chemotherapy, but the overall survival rate is poor. The purpose of this study was to investigate the therapeutic potential of chemotherapy combined with inhibition of B and T lymphocyte attenuator (BTLA) for clinical use to treat EOC. Methods Initially, we evaluated the potential application of chemotherapy combined with anti-BTLA antibody in an animal model. We then analyzed the distribution and regulation of BTLA expression on immunocytes in vitro. Finally, we examined the correlation between BTLA expression levels in cancerous tissues and prognosis in 254 EOC cases. Results The combination of chemotherapy and anti-BTLA antibody for inhibiting BTLA significantly reduced peritoneal tumor volume and extended survival in tumor-bearing mice. In addition, BTLA could be identified mostly on B lymphocytes, especially on CD19hi B cells, rather than on T lymphocytes and natural killer cells. Under regulation of interleukins 6 and 10, more BTLA+CD19hi B lymphocytes could be induced through AKT and STAT3 signaling pathways. Detectable BTLA expression in ovarian cancerous tissues was associated with worse disease-free and overall survivals of EOC patients. Conclusions BTLA detected in cancerous tissues can predict poor outcome of EOC patients. Inhibition of BTLA combined with chemotherapy can elevate immune activation and generate potent anti-tumor effects. Thus, the combination of chemotherapy and anti-BTLA antibody may hold potential clinical application for the treatment of EOC patients. Trial registration The Trial Registration Number was NCT00854399.