Abstract Hepatocellular carcinoma (HCC) is a common malignancy worldwide and is a leading cause of death. To contribute to the development and improvement of molecular markers for diagnostics and prognostics and of therapeutic targets for the disease, we have largely expanded the currently available human liver tissue maps and studied the differential expression of proteins in normal and cancer tissues. Reference two‐dimensional electrophoresis (2‐DE) maps of human liver tumor tissue include labeled 2‐DE images for total homogenate and soluble fraction separated on pH 3–10 gels, and also images for soluble fraction separated on pH 4–7 and pH 6–9 gels for a more detailed map. Proteins were separated in the first dimension by isoelectric focusing on immobilized pH gradient (IPG) strips, and by 7.5–17.5% gradient sodium dodecyl sulfate‐polyacrylamide gel electrophoresis (SDS‐PAGE) gels in the second dimension. Protein identification was done by peptide mass fingerprinting with delayed extraction‐matrix assisted laser desorption/ionization‐time of flight‐mass spectrometry (DE‐MALDI‐TOF‐MS). In total, 212 protein spots (117 spots in pH 4–7 map and 95 spots in pH 6–9) corresponding to 127 different polypeptide chains were identified. In the next step, we analyzed the differential protein expression of liver tumor samples, to find out candidates for liver cancer‐associated proteins. Matched pairs of tissues from 11 liver cancer patients were analyzed for their 2‐DE profiles. Protein expression was comparatively analyzed by use of image analysis software. Proteins whose expression levels were different by more than three‐fold in at least 30% (four) of the patients were further analyzed. Numbers of protein spots overexpressed or underexpressed in tumor tissues as compared with nontumorous regions were 9 and 28, respectively. Among these 37 spots, 1 overexpressed and 15 underexpressed spots, corresponding to 11 proteins, were identified. The physiological significance of the differential expressions is discussed.
The aim of this study was to compare the survival outcomes of adenosquamous carcinoma (ASC) and adenocarcinoma (AC) of the cervix.
Methods
We searched PubMed and Embase for observational studies that compared the outcomes of 2 histologic subtypes. Hazards ratios (HRs) with 95% confidence intervals (CIs) were calculated with a fixed effects model.
Results
A total of 17 studies were included in the analyses. Patients with ASC were associated significantly with poorer overall survival (death HR, 1.27; 95% CI, 1.12–1.43; I2 = 0%) and recurrence-free survival (recurrence HR, 1.43; 95% CI, 1.05–1.95; I2 = 19.4%) than those with AC. For clinical stages I and II in particular, ASC predicted significantly poorer outcomes compared with AC (death HR, 1.41; 95% CI, 1.17–1.70; I2 = 0%).
Conclusions
This meta-analysis suggests that ASC may have poorer outcomes compared with AC of the cervix.
A pilot study of biomarker-driven targeted therapy in patients with platinum-resistant recurrent ovarian cancer has been started in Korea. Archival tumor samples were tested for HRD and PD-L1 status. Treatment arms will be allocated according to the test results. For HRD+ patients, we tested the synergistic effects of olaparib and other agents; treatment arms will randomly be allocated. (Arm 1: olaparib and cediranib; Arm 2: olaparib and durvalumab). For HRD- patients, we tested the role of biomarker-driven immunotherapy according to PD-L1 expression (Arm 3: durvalumab and chemotherapy in patients with high PD-L1 expression; Arm 4: durvalumab, tremelimumab, and chemotherapy in patients with low PD-L1 expression). Sixty-eight patients will be included from three Korean institutions within 1 year. The primary endpoint is the response rate according to RECIST 1.1 (6 months after treatment initiation). This trial has been registered with clinicaltrials.gov, and the registration number is NCT03699449.
<div>Abstract<p>BRCA1/2 mutations account for only a small fraction of homologous recombination (HR) deficiency (HRD) cases. Recently developed genomic HRD (gHRD) tests suffer confounding factors that cause low precision in predicting samples that will respond to PARP inhibitors and DNA damaging agents. Here we present molecular and clinical evidence of transcriptional HRD (tHRD) that is based on aberrant transcript usage (aTU) of minor isoforms. Specifically, increased TU of nonfunctional isoforms of DNA repair genes was prevalent in breast and ovarian cancer with gHRD. Functional assays validated the association of aTU with impaired HR activity. Machine learning–based tHRD detection by the transcript usage (TU) pattern of key genes was superior to directly screening for gHRD or BRCA1/2 mutations in accurately predicting responses of cell lines and patients with cancer to PARP inhibitors and genotoxic drugs. This approach demonstrated the capability of tHRD status to reflect functional HR status, including in a cohort of olaparib-treated ovarian cancer with acquired platinum resistance. Diagnostic tests based on tHRD are expected to broaden the clinical utility of PARP inhibitors.</p>Significance:<p>A novel but widespread transcriptional mechanism by which homologous recombination deficiency arises independently of BRCA1/2 mutations can be utilized as a companion diagnostic for PARP inhibitors.</p></div>
Objective: Recently, a symptom index for identification of ovarian cancer, based on specific symptoms along with their frequency and duration, was proposed.The current study aimed at validation of this index in Korean population.Methods: A case-control study of 116 women with epithelial ovarian cancer and 209 control women was conducted using questionnaires on eight symptoms.These included pelvic/abdominal pain, urinary urgency/frequency, increased abdominal size/bloating, difficulty eating/feeling full.The symptom index was considered positive if any of the 8 symptoms present for ＜1 year that occurred＞12 times per month.The symptoms were compared between ovarian cancer group and control group using chi-square test.Logistic regression analysis was used to determine whether the index predicted cancer.Sensitivity and specificity of the symptom index were also determined. Results:The symptom index was positive in 65.5% of women with ovarian cancer, in 31.1% of women with benign cysts, and in 6.7% of women on routine screening (ps＜0.001).Significantly higher proportion of ovarian cancer patients were positive for each symptom as compared with control group (ps＜0.001).Results from the logistic regression indicated that the symptom index independently predicted cancer (p＜0.001;OR, 10.51; 95% CI, 6.14 to 17.98).Overall, the sensitivity and specificity of the symptom index were 65.5% and 84.7%, respectively.Analyses of sensitivity by stage showed that the index was positive in 44.8% of patients with stage I/II disease and in 72.9% of patients with stage III/IV disease. Conclusion:The current study supported previous studies suggesting that specific symptoms were useful in identifying women with ovarian cancer.
Massive multi-input multi-output (MIMO) is shown to significantly increase spectral efficiency by exploiting a large number of antennas to support high-order multiuser MIMO. In 3GPP Release-13, a full-dimension MIMO (FD-MIMO) technology was introduced to address practical aspects for massive MIMO in cellular systems; extensive simulations show 2–4 times capacity gain compared with current LTE systems. FD-MIMO has been identified as one of the key 5G technologies and is being continuously improved in 3GPP new radio standards. However, several practical challenges such as interference mitigation among MIMO streams for a large number of users with limited channel feedback, hardware limitations, such as calibration errors that limit the precoding capabilities need to be addressed carefully. A proof of concept (PoC) base-station and user equipment (UE) prototype has been designed to validate the potential of FD-MIMO technology and demonstrate commercial implementation feasibility. In this paper, we present theory and architecture behind an FD-MIMO prototype and share the field test results with LTE-based UEs in a multi-user MIMO setup. We also analyze the impact of transmitter and receiver calibration errors on the performance of the FD-MIMO system.
High-grade serous ovarian cancer (HGSOC) represents most epithelial ovarian cancers. Whilst initially responding to platinum-based therapy, ~75% of patients develop resistance, conferring poor prognosis. Homologous recombination repair proficiency is associated with platinum resistance and limited response to PARP inhibitors. PI3K pathway inhibition downregulates BRCA expression, abrogating homologous recombination repair proficiency, and may lead to (re)sensitization to PARP inhibitors. As alpelisib (PI3Kα inhibitor) + olaparib (PARP inhibitor) demonstrated preliminary evidence of synergism in platinum-resistant/refractory, BRCA-wild-type, recurrent HGSOC in a phase 1b study, the EPIK-O study is further evaluating this combination.
Methods
EPIK-O/ENGOT-OV61 (NCT04729387) is a phase 3, randomized (1:1), open-label, active-controlled trial evaluating the efficacy and safety of alpelisib + olaparib versus single-agent chemotherapy in patients (N≈358) with no germline BRCA mutation and platinum-resistant/refractory HGSOC. Adult patients with platinum-resistant/refractory, histologically confirmed HGSOC, high-grade endometrioid ovarian, fallopian tube, or primary peritoneal cancer, with no germline BRCA1/2 mutation, are included; patients must have received 1–3 prior systemic therapies. In Arm 1, patients receive alpelisib 200 mg orally OD + olaparib 200 mg orally BID; in Arm 2, patients receive paclitaxel 80 mg/m2 IV weekly or pegylated liposomal doxorubicin 40–50 mg/m2 IV Q28D (investigator's choice). The primary endpoint is progression-free survival per RECIST 1.1 assessment by a blinded independent review committee. Key secondary endpoint is overall survival. Other secondary endpoints include overall response rate, clinical benefit rate, safety, and quality of life. Enrollment is planned in 26 countries; completion of data collection for the primary endpoint is anticipated in 2023.
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