Phenotypic and metabolomic characteristics of mouse models of metabolic associated steatohepatitis.

BACKGROUND: Metabolic associated steatohepatitis (MASH) is metabolic disease that may progress to cirrhosis and hepatocellular carcinoma. Mouse models of diet-induced MASH, which is characterized by the high levels of fats, sugars, and cholesterol in diets, are commonly used in research. However, mouse models accurately reflecting the progression of MASH in humans remain to be established. Studies have explored the potential use of serological metabolites as biomarkers of MASH severity in relation to human MASH. METHODS: We performed a comparative analysis of three mouse models of diet-induced MASH in terms of phenotypic and metabolomic characteristics; MASH was induced using different diets: a high-fat diet; a Western diet; and a high-fat, high-cholesterol diet. Liver cirrhosis was diagnosed using standard clinical approaches (e.g., METAVIR score, hyaluronan level, and collagen deposition level). Mouse serum samples were subjected to nuclear magnetic resonance spectroscopy-based metabolomic profiling followed by bioinformatic analyses. Metabolomic analysis of a retrospective cohort of patients with hepatocellular carcinoma was performed; the corresponding cirrhosis scores were also evaluated. RESULTS: Using clinically relevant quantitative diagnostic methods, the severity of MASH was evaluated. Regarding metabolomics, the number of lipoprotein metabolites increased with both diet and MASH progression. Notably, the levels of very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) significantly increased with fibrosis progression. During the development of diet-induced MASH in mice, the strongest upregulation of expression was noted for VLDL receptor. Metabolomic analysis of a retrospective cohort of patients with cirrhosis indicated lipoproteins (e.g., VLDL and LDL) as predominant biomarkers of cirrhosis. CONCLUSIONS: Our findings provide insight into the pathophysiology and metabolomics of experimental MASH and its relevance to human MASH. The observed upregulation of lipoprotein expression reveals a feedforward mechanism for MASH development that may be targeted for the development of noninvasive diagnosis.

Ovarian clear cell carcinoma with uterine intramural recurrence: Case report of ovarian clear cell carcinoma with fertility sparing treatment.

OBJECTIVE: Ovarian clear cell carcinoma has a poor prognosis in comparison with other pathological types of epithelial ovarian carcinoma. It also has relative resistance to first-line platinum-based chemotherapy with a great risk of recurrence. CASE REPORT: We report a case of recurrent ovarian clear cell carcinoma status after left salpingo-oophorectomy (fertility-sparing debulking operation) and six courses of adjuvant chemotherapy (paclitaxel (175 mg/m2)/carboplatin (AUC 6)). However, two years after diagnosis, elevated CA-125 accompanied by an intrapelvic mass was noted. Uterine intramural recurrence was found during the second laparotomy. She was treated with right salpingo-oophorectomy and abdominal hysterectomy combined with systemic chemotherapy administration (paclitaxel (175 mg/m2)/carboplatin (AUC 6)) and maintenance therapy (bevacizumab (7.5 mg/kg)). There was no other recurrence until one and a half years postoperatively, and the patient was tumor free with regular follow-up. CONCLUSION: In young patients with stage I ovarian clear cell carcinoma, fertility-sparing surgery was considered. Most patients will suffer from tumor recurrence, and also intrauterine recurrence rarely happen.

Image-guided brachytherapy following external-beam radiation therapy for patients with inoperable endometrial cancer.

OBJECTIVE: To investigate the outcomes of definitive external-beam radiation therapy (EBRT) plus image-guided brachytherapy (IGBT) in patients with endometrial cancer (EC) unsuitable for surgery. METHODS: A total of 50 patients with inoperable EC were included. The patients received EBRT in a median dose of 45 Gy to the pelvis over 5 weeks. Thereafter, the patients received brachytherapy using tandem and ovoid applicators. High-risk clinical target volume (HR-CTV) and gross tumor volume in brachytherapy (GTVp) were defined by the assistance of patients' pre-IGBT magnetic resonance imaging. RESULTS: The medical records of the 50 patients were analyzed. The main causes of inoperability were anesthesia contraindications, namely medical comorbidities and obesity. The median cumulative D90s (the minimum dose delivered to 90% of the volume) in EQD2 (equivalent dose in 2-Gy fractions) to the HR-CTV and GTVp were 72.9 Gy10 (range, 64.9 to 80.3) and 166.2 Gy10 (range, 123.0 to 189.8), respectively. Over a median follow-up period of 27 months, 8 of the patients died of cancer. The 2-year overall and cancer-specific survival rates were 75% and 83%, respectively. The cumulative incidences of pelvic and distant failure were 4% (n = 2) and 16% (n = 8), respectively. Gastrointestinal complications of grade 2 or above were noted in 2 patients (4%), and a grade 2 genitourinary complication was noted in one. CONCLUSIONS: For patients with inoperable EC, EBRT followed by IGBT is an effective approach for achieving high local control without a high risk of complications.

Linoleate-pazopanib conjugation as active pharmacological ingredient to abolish hepatocellular carcinoma growth.

Small molecule compounds targeting multiple kinases involved in neoangiogenesis have shown survival benefits in patients with unresectable hepatocellular carcinoma (HCC). Nonetheless, despite the beneficial effects of multikinase inhibitors (MKIs), a lack of boosting adjuvant limits their objective response rate. Lipid conjugates have been used to improve delivery efficacy or pharmaceutical benefits for decades. However, the feasibility of utilizing lipid-drug conjugates (LDCs) in HCC regimens remains untested. In this study, oral feeding of linoleate-fluorescein isothiocyanate conjugates showed that the compound was well distributed in a spontaneous HCC mouse model. Therefore, a rationale design was developed for chemically synthesizing a linoleate-pazopanib conjugate (LAPC). The LAPC showed a significantly improved cytotoxicity compared to the parental drug pazopanib. Pazopanib's angiogenic suppressing signals were not observed in LAPC-treated HCC cells, potentially suggesting an altered mechanism of action (MOA). In an efficacy trial comparing placebo, oral pazopanib, and LAPC treatments in the hepatitis B virus transgene-related spontaneous HCC mouse model (HBVtg-HCC), the LAPC treatment demonstrated superior tumor ablating capacity in comparison to both placebo and pazopanib treatments, without any discernible systemic toxicity. The LAPC exposure is associated with an apoptosis marker (Terminal deoxynucleotidyl transferase dUTP nick end labeling [TUNEL]) and an enhanced ferroptosis (glutathione peroxidase 4 [GPX4]) potential in HBVtg-HCC tumors. Therefore, the LAPC showed excellent HCC ablative efficacy with altered MOA. The molecular mechanisms of the LAPC and LDCs for HCC therapeutics are of great academic interest. Further comprehensive preclinical trials (e.g., chemical-manufacture-control, toxicity, distribution, and pharmacokinetics/pharmacodynamics) are expected.

Predicting Long-Term Prognoses and Grading Platinum Sensitivity Using a Novel Progression-Free Interval Criterion in Ovarian Clear Cell Carcinoma: A Multi-Institutional Cohort Study.

This large-scale study aimed to determine the long-term influences of potential prognostic predictors and progression-free interval (PFI) criteria for grading platinum-sensitivity in ovarian clear cell carcinoma (OCCC). We retrospectively reviewed the medical records of OCCC patients presenting at nine tertiary centres (1995−2015), and evaluated patient characteristics, therapeutic factors, clinical outcomes, and hazard ratios for disease progression and death. We enrolled 536 patients (median follow-up, 36.6 months) and developed newly defined distributions of PFIs (seven and 14 months) for grading platinum sensitivity. In the multivariate model, preoperative CA125 levels and chemo-response independently predicted early-stage progression-free survival (PFS) risk. Post-progression cytoreduction correlated with reduced mortality risk. No unfavourable outcomes were observed with respect to coexisting endometriosis, fertility-sparing strategies, or platinum-based regimens. A PFI of <7 months, the strongest predictor of both post-progression mortality and second relapse risks, correlated with chemo-resistance, advanced tumour stage, and shortened post-progression survival. Chemotherapy regimens commonly used in front-line or relapse settings were limited in improving prognoses, especially in the advanced-stage cohort. Clinical trials of novel targeted agents and/or innovative biomarkers for chemoresistance should be comprehensively investigated and offered early to advanced-stage patients or those with OCCC progression occurring within seven months after receiving chemotherapy.

Androgen/Androgen Receptor Signaling in Ovarian Cancer: Molecular Regulation and Therapeutic Potentials.

Ovarian cancer (OVCA) arises from three cellular origins, namely surface epithelial cells, germ cells, and stromal cells. More than 85% of OVCAs are EOCs (epithelial ovarian carcinomas), which are the most lethal gynecological malignancies. Cancer stem/progenitor cells (CSPCs) are considered to be cancer promoters due to their capacity for unlimited self-renewal and drug resistance. Androgen receptor (AR) belongs to the nuclear receptor superfamily and can be activated through binding to its ligand androgens. Studies have reported an association between AR expression and EOC carcinogenesis, and AR is suggested to be involved in proliferation, migration/invasion, and stemness. In addition, alternative AR activating signals, including both ligand-dependent and ligand-independent, are involved in OVCA progression. Although some clinical trials have previously been conducted to evaluate the effects of anti-androgens in EOC, no significant results have been reported. In contrast, experimental studies evaluating the effects of anti-androgen or anti-AR reagents in AR-expressing EOC models have demonstrated positive results for suppressing disease progression. Since AR is involved in complex signaling pathways and may be expressed at various levels in OVCA, the aim of this article was to provide an overview of current studies and perspectives regarding the relevance of androgen/AR roles in OVCA.

Stereotactic body radiotherapy for pelvic boost in gynecological cancer patients with local recurrence or unsuitable for intracavitary brachytherapy.

OBJECTIVE: To evaluate efficacy of stereotactic body radiotherapy (SBRT) for pelvic boost irradiation in gynecological cancer patients with pelvic recurrence or with intact uterus unsuitable for brachytherapy. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 25 gynecological cancer patients who received SBRT boost for pelvic recurrence (salvage group, n = 14), or for local dose escalation instead of intracavitary brachytherapy due to unfavorable medical condition (definitive group, n = 11). The pelvis was irradiated with a median dose of 54 Gy in six weeks, and then SBRT was prescribed with a range of 10-25Gy in two to five fractions. The cumulative radiobiological equivalent dose in 2-Gy fractions (EQD2) to the tumors ranged from 62.5 to 89.5 Gy10 (median, 80.7). Overall survival (OS) and in-field relapse-free survival (IFRFS) were calculated using the Kaplan-Meier method. RESULTS: At the initial assessment, eighteen (72%) patients achieved complete or partial remission, and seven (28%) had stable or progressive disease. With a median follow duration of 12 months, the 1-year IFRFS for salvage and definitive group were 64.5% and 90.0%, whereas the 1-year OS for the two groups were 80.8% and 49.1%, respectively. One patient developed entero-vaginal fistula and one had sigmoid perforation. No patient experienced â‰§ grade 3 genitourinary complications. CONCLUSION: In gynecological cancer patients with recurrent pelvic tumors or intact uterus unsuitable for brachytherapy, local dose escalation with SBRT resulted in an initial response rate of 72% with acceptable early toxicities. A long-term follow-up is required to assess the impact on local control or survival.

Genomic Biomarkers of Survival in Patients with Adenocarcinoma of the Uterine Cervix Receiving Chemoradiotherapy.

This study investigated the prognostic effects of genomic biomarkers for predicting chemoradiotherapy (CRT)-based treatment outcomes in patients with adenocarcinoma (AC) of the uterine cervix. In all, 21 patients receiving definitive CRT were included. In accordance with the International Federation of Gynecology and Obstetrics (FIGO) staging system, 5, 8, and 8 patients were classified as having stage IB3, II, and III disease, respectively. Pretreatment biomarkers were analyzed using tissue microarrays from biopsy specimens. Genomic alterations were examined by next-generation sequencing (NGS). The outcome endpoints were disease-free survival (DFS), distant metastasis-free survival (DMFS), and local relapse-free survival (LRFS). A Cox regression model was used to examine the prognostic effects of the biomarkers and clinical parameters. The presence of myeloid cell leukemia-1 (MCL1) gene amplification and a lower immunohistochemical (IHC) marker of tumor necrotic factor alpha (TNF-α) H-score were two prognostic factors for inferior DFS. The four-year DFS was 28% and 68% for patients with or without MCL1 copy number gain, respectively (p = 0.028). In addition, MCL1 amplification predicted poor DMFS. A lower tumor mutation number (TMN) calculated from nonsynonymous mutations was associated with lower LRFS. For patients with adenocarcinoma of the uterine cervix receiving definitive CRT, prognostic information can be supplemented by MCL1 amplification, the TMN, and the TNF-α H score.

Targeting lipid droplet lysophosphatidylcholine for cisplatin chemotherapy.

This study aims to explore lipidic mechanism towards low-density lipoprotein receptor (LDLR)-mediated platinum chemotherapy resistance. By using the lipid profiling technology, LDLR knockdown was found to increase lysosomal lipids and decrease membranous lipid levels in EOC cells. LDLR knockdown also down-regulated ether-linked phosphatidylethanolamine (PE-O, lysosomes or peroxisomes) and up-regulated lysophosphatidylcholine [LPC, lipid droplet (LD)]. This implies that the manner of using Lands cycle (conversion of lysophospholipids) for LDs might affect cisplatin sensitivity. The bioinformatics analyses illustrated that LDLR-related lipid entry into LD, rather than an endogenous lipid resource (eg Kennedy pathway), controls the EOC prognosis of platinum chemotherapy patients. Moreover, LDLR knockdown increased the number of platinum-DNA adducts and reduced the LD platinum amount. By using a manufactured LPC-liposome-cisplatin (LLC) drug, the number of platinum-DNA adducts increased significantly in LLC-treated insensitive cells. Moreover, the cisplatin content in LDs increased upon LLC treatment. Furthermore, lipid profiles of 22 carcinoma cells with differential cisplatin sensitivity (9 sensitive vs 13 insensitive) were acquired. These profiles revealed low storage lipid levels in insensitive cells. This result recommends that LD lipidome might be a common pathway in multiple cancers for platinum sensitivity in EOC. Finally, LLC suppressed both cisplatin-insensitive human carcinoma cell training and testing sets. Thus, LDLR-platinum insensitivity can be due to a defective Lands cycle that hinders LPC production in LDs. Using lipidome assessment with the newly formulated LLC can be a promising cancer chemotherapy method.

Maintenance of pegylated liposomal doxorubicin/carboplatin in patients with advanced ovarian cancer: randomized study of an Asian Gynecologic Oncology Group.

OBJECTIVES: An Asian Gynecologic Oncology Group phase III randomized trial was conducted to determine whether maintenance chemotherapy could improve progression-free survival (PFS) in stages III/IV ovarian cancer. METHODS: Between 2007 and 2014, 45 newly-diagnosed ovarian cancer patients were enrolled after complete remission and randomized (1:1) to arm A (4-weekly carboplatin area under the curve 4 and pegylated liposomal doxorubicin [PLD] 30 mg/m², n=24) for 6 cycles or arm B (observation, n=21). The primary end-point was PFS. A post hoc translational study was conducted to deep sequence BRCA/homologous recombination deficiency (HRD) genes, because BRCA/HRD mutations (BRCA/HRDm) are known to be associated with better prognosis. RESULTS: Enrollment was slow, accrual was closed when 7+ years had passed. With a median follow-up of 88.9 months, the median PFS was significantly better in arm A (55.5 months) than arm B (9.2 months) (hazard ratio [HR]=0.40; 95% confidence interval [CI]=0.19-0.87; p=0.020), yet the median overall survival was not significantly different in arm A (not reached) than arm B (95.1 months) (p=0.148). Overall grade 3/4 adverse events were more frequent in arm A than arm B (60.9% vs 0.0%) (p<0.001). Quality of life was generally not significantly different. Distribution of BRCA1/2m or BRCA/HRDm was not significantly biased between the two arms. Wild-type BRCA/non-HRD subgroup seemed to fare better with maintenance therapy (HR=0.35; 95% CI=0.11-1.18; p=0.091). CONCLUSIONS: Despite limitations in small sample size, it suggests that maintenance carboplatin-PLD chemotherapy could improve PFS in advanced ovarian cancer.

LDLR-mediated lipidome-transcriptome reprogramming in cisplatin insensitivity.

Platinum-based therapy remains the cornerstone for cancer therapy; however, its efficacy varies. The role of lipoprotein receptor-mediated lipid entry for cancer development has been reported. Yet, the roles and mechanism of the low-density lipoprotein receptor (LDLR) in chemo-sensitivities are unknown. In the current report, we used epithelial ovarian cancer (EOC), composed of various cellularities, to study this issue. Using public cDNA microarray database and single cohort study, LDLR expressions were positively associated with epithelial ovarian carcinomas (EOCs) platinum-based chemotherapy patients' disease prognosis. In vitro and in vivo add-in/silencing LDLR was introduced to determine cisplatin sensitivity and cancer growth. Results revealed that knocked-down LDLR could sensitize while overexpressed LDLR could insensitize EOC cells to the cytotoxic effects of cisplatin. Moreover, the trans-omics approaches depicted an LDLR→LPC (Lyso-phosphatidylcholine)→FAM83B (phospholipase-related)→FGFRs (cisplatin sensitivity and phospholipase-related) regulatory axis. Finally, the manipulation of LDLR expression in EOC cells was found to determine the efficacy of cisplatin therapy in terms of tumor suppression. In conclusion, the LDLR→LPC→FAM83B→FGFRs axis is an example of tumor macroenvironmental regulation of therapy outcomes. Relatedly, LDLR expression could serve as a biomarker of chemotherapy sensitivity in EOCs. Significance: this study describes the role of LDLR in the development of insensitivity to platinum-based chemotherapy in epithelial ovarian cancer. The lipidome (e.g., LPC) and transcriptome (e.g., FAM38B) interactions revealed using trans-omics approaches an LDLR→LPC→FAM83B→FGFRs regulatory axis in cancer cells, in an animal model, and in patients.

Effectiveness of Image-guided Brachytherapy in Patients With Locally Advanced Cervical Squamous Cell Carcinoma Receiving Concurrent Chemoradiotherapy.

AIM: To compare the advantage of image-guided brachytherapy (IGBT) over conventional two-dimensional brachytherapy (2DBT) in patients with advanced cervical squamous cell carcinoma. PATIENTS AND METHODS: This study included 253 patients with stage IB2-IVA diseases treated with two schemes of brachytherapy. One hundred and thirty-six patients received 2DBT, whereas 117 patients received IGBT. Tumor stage, age, and tumor diameter were matched between the two groups. Local relapse-free survival, overall survival, and cumulative incidences of gastrointestinal and genitourinary complications were compared between the two groups. RESULTS: The overall and local relapse-free survival rates were similar between the two groups. The cumulative rate of grade 2 and higher gastrointestinal complication was 21.3% for the 2DBT group, and 8.5% for the IGBT group (p=0.007), whereas that of grade 2 and higher genitourinary injury was 11.8% for the 2DBT group, and 1.7% for the IGBT group (p=0.002). CONCLUSION: In patients with advanced cervical squamous cell carcinoma, IGBT achieves a higher therapeutic ratio compared to 2DBT technique by minimizing the late toxicities.

Immunohistochemical Biomarkers of Survival in Patients With Adenocarcinoma of the Uterine Cervix Receiving Chemoradiotherapy.

BACKGROUND/AIM: To determine the prognostic effects of immunohistochemical biomarkers for predicting chemoradiotherapy (CRT)-based treatment outcomes in patients with adenocarcinoma of the uterine cervix. MATERIALS AND METHODS: This study included 42 patients receiving definitive CRT. According to the International Federation of Gynecology and Obstetrics staging system, 13, 21, and 8 patients were classified as having stage IB2, II, and III disease, respectively. Baseline immunohistochemical biomarkers, including those for hypoxia, cell proliferation, cell adhesion, immunogenicity, and evasion of apoptosis, were analyzed using tissue microarrays from biopsy specimens. RESULTS: Myeloid cell leukemia-1 (MCL1) overexpression and the presence of pelvic lymph node metastasis were two prognostic factors for inferior cancer-specific survival. A higher H-score for c-MYC proto-oncogene, bHLH transcription factor (c-MYC) was associated with lower pelvic relapse-free survival. CONCLUSION: For patients with adenocarcinoma of the uterine cervix requiring definitive CRT, treatment outcomes can be stratified by the immunohistochemical biomarkers MCL1 and c-MYC for cancer death and local failure, respectively.

Prediction of local relapse and distant metastasis in patients with definitive chemoradiotherapy-treated cervical cancer by deep learning from [18F]-fluorodeoxyglucose positron emission tomography/computed tomography.

BACKGROUND: We designed a deep learning model for assessing 18F-FDG PET/CT for early prediction of local and distant failures for patients with locally advanced cervical cancer. METHODS: All 142 patients with cervical cancer underwent 18F-FDG PET/CT for pretreatment staging and received allocated treatment. To augment the amount of image data, each tumor was represented as 11 slice sets each of which contains 3 2D orthogonal slices to acquire a total of 1562 slice sets. In each round of k-fold cross-validation, a well-trained proposed model and a slice-based optimal threshold were derived from a training set and used to classify each slice set in the test set into the categories of with or without local or distant failure. The classification results of each tumor were aggregated to summarize a tumor-based prediction result. RESULTS: In total, 21 and 26 patients experienced local and distant failures, respectively. Regarding local recurrence, the tumor-based prediction result summarized from all test sets demonstrated that the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 71%, 93%, 63%, 95%, and 89%, respectively. The corresponding values for distant metastasis were 77%, 90%, 63%, 95%, and 87%, respectively. CONCLUSION: This is the first study to use deep learning model for assessing 18F-FDG PET/CT images which is capable of predicting treatment outcomes in cervical cancer patients. KEY POINTS: • This is the first study to use deep learning model for assessing 18 F-FDG PET/CT images which is capable of predicting treatment outcomes in cervical cancer patients. • All 142 patients with cervical cancer underwent 18 F-FDG PET/CT for pretreatment staging and received allocated treatment. To augment the amount of image data, each tumor was represented as 11 slice sets each of which contains 3 2D orthogonal slices to acquire a total of 1562 slice sets. • For local recurrence, all test sets demonstrated that the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 71%, 93%, 63%, 95%, and 89%, respectively. The corresponding values for distant metastasis were 77%, 90%, 63%, 95%, and 87%, respectively.

Increase Paclitaxel Sensitivity to Better Suppress Serous Epithelial Ovarian Cancer via Ablating Androgen Receptor/Aryl Hydrocarbon Receptor-ABCG2 Axis.

BACKGROUND: Epithelial ovarian cancer (EOC) is one of the most lethal gynecological malignancies and presents chemoresistance after chemotherapy treatment. Androgen receptor (AR) has been known to participate in proliferation. Yet the mechanisms of the resistance of this drug and its linkage to the AR remains unclear. METHODS: To elucidate AR-related paclitaxel sensitivity, co-IP, luciferase reporter assay and ChIP assay were performed to identify that AR direct-regulated ABCG2 expression under paclitaxel treatment. IHC staining by AR antibody presented higher AR expression in serous-type patients than other types. AR degradation enhancer (ASC-J9) was used to examine paclitaxel-associated and paclitaxel-resistant cytotoxicity in vitro and in vivo. RESULTS: We found AR/aryl hydrocarbon receptor (AhR)-mediates ABCG2 expression and leads to a change in paclitaxel cytotoxicity/sensitivity in EOC serous subtype cell lines. Molecular mechanism study showed that paclitaxel activated AR transactivity and bound to alternative ARE in the ABCG2 proximal promoter region. To identify AR as a potential therapeutic target, the ASC-J9 was used to re-sensitize paclitaxel-resistant EOC tumors upon paclitaxel treatment in vitro and in vivo. CONCLUSION: The results demonstrated that activation of AR transactivity beyond the androgen-associated biological effect. This novel AR mechanism explains that degradation of AR is the most effective therapeutic strategy for treating AR-positive EOC serous subtype.

Correlation of genomic alterations between tumor tissue and circulating tumor DNA by next-generation sequencing.

PURPOSE: Analysis of circulating tumor DNA (ctDNA) offers an unbiased and noninvasive way to assess the genetic profiles of tumors. This study aimed to analyze mutations in ctDNA and their correlation with tissue mutations in patients with a variety of cancers. METHODS: We included 21 cancer patients treated with surgical resection for whom we collected paired tissue and plasma samples. Next-generation sequencing (NGS) of all exons was performed in a targeted human comprehensive cancer panel consisting of 275 genes. RESULTS: Six patients had at least one mutation that was concordant between tissue and ctDNA sequencing. Among all mutations (n = 35) detected by tissue and blood sequencing, 20% (n = 7) were concordant at the gene level. Tissue and ctDNA sequencing identified driver mutations in 66.67% and 47.62% of the tested samples, respectively. Tissue and ctDNA NGS detected actionable alterations in 57.14% and 33.33% of patients, respectively. When somatic alterations identified by each test were combined, the total proportion of patients with actionable mutations increased to 71.43%. Moreover, variants of unknown significance that were judged likely pathogenic had a higher percentage in ctDNA exclusively. Across six representative genes (PIK3CA, CTNNB1, AKT1, KRAS, TP53, and MET), the sensitivity and specificity of detection using mutations in tissue sample as a reference were 25 and 96.74%, respectively. CONCLUSIONS: This study indicates that tissue NGS and ctDNA NGS are complementary rather than exclusive approaches; these data support the idea that ctDNA is a promising tool to interrogate cancer genetics.

Textural features of cervical cancers on FDG-PET/CT associate with survival and local relapse in patients treated with definitive chemoradiotherapy.

We retrospectively reviewed the records of 142 patients with stage IB-IIIB cervical cancer who underwent 18F-FDG-PET/CT before external beam radiotherapy plus intracavitary brachytherapy and concurrent chemotherapy. The patients were divided into training and validation cohorts to confirm the reliability of predictors for recurrence. Kaplan-Meier analysis was performed and a Cox regression model was used to examine the effects of variables on overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and pelvic relapse-free survival (PRFS). High gray-level run emphasis (HGRE) derived from gray-level run-length matrix most accurately and consistently predicted the presence of pelvic residual or recurrent tumors for both cohorts. In multivariate analysis, stages IIIA-IIIB (P = 0.001, hazard ratio [HR] = 4.07) and a low HGRE (P < 0.0001, HR = 4.34) were prognostic factors for low OS, whereas a low HGRE (P = 0.001, HR = 2.86) and nonsquamous cell histology (P = 0.003, HR = 2.76) were prognostic factors for inferior PFS. The nonsquamous cell histology (P < 0.0001, HR = 9.19) and a low HGRE (P = 0.001, HR = 4.69) were predictors for low PRFS. In cervical cancer patients receiving definitive chemoradiotherapy, pretreatment textural features on 18F-FDG-PET/CT can supplement the prognostic information.

Mitochondrial Acetyl-CoA Synthetase 3 is Biosignature of Gastric Cancer Progression.

Cholesterol affects cancer progression, and acetyl-CoA is the primary cholesterogenesis substrate. The previous work has defined cholesterol bioflux via lipoprotein/receptor route is the gastric cancer (GCa) prognosis biosignature. The prognosis importance of acetyl-CoA to cholesterogenesis (mevalonate pathway) in GCa is yet to be defined. Using Kaplan-Meier Plotter web-based gene survival analyzer and The Cancer Genome Atlas (TCGA)-database analyzed with DBdriver.v2 platform, we revealed acetyl-CoA production and the mevalonate pathway are associated with GCa prognosis. We found mitochondrial-derived acetyl-CoA contributing enzymes (acyl-coA synthetase super-family 3; ACSS3) is the GCa progression confounder. Interestingly, it is not HMGCR (the committee enzyme of mevalonate pathway), but lower mevalonate pathway enzymes (e.g., MVK, LSS, DHCR14A1, SC4MOL, HSD17B7, SC5D) promote GCa patients 5-years overall survival in a differential level. Advanced analyses found ACSS3 is prognosis biosignatures for multiple GCa disease conditions. This report uncovered a higher expression of ACSS3 in tumor comparing to normal parental lesions, which implicates a targeting value for GCa therapy. While knockdown ACSS3 could suppress growth and invasion of GCa cells, of which even more impactful under starvation condition. This is the first report, surprisingly, revealed ACSS3 as important cancer prognosis biomarker. Targeting ACSS3 could be a novel therapeutic strategy for cancer, in this case, GCa.

Short androgen receptor poly-glutamine-promoted endometrial cancer is associated with benzo[a]pyrene-mediated aryl hydrocarbon receptor activation.

The androgen receptor (AR) poly-glutamine polymorphism (AR-Q) was reported to play role in endometrial cancer (EMCA) development, yet controversial. Environmental factors interact with genetic variation have been reported in EMCA. Aerosol toxins, polycyclic aromatic hydrocarbon benzo[a]pyrene (BaP), are EMCA facilitators. This report examined the interplay between AR-Qs and BaP in EMCA. During analysing patient AR-Q polymorphism and Aryl hydrocarbon Receptor (AhR) expressions, we found overall survival (OS) benefit is ascending with AR-Q lengths (5-year OS of 61.3% in Q length <20 and 88% in Q length >23). And AhR is higher expressed in short AR-Q tumour compared to that in long AR-Q patient. In vitro study found androgen-response element (ARE) activity descends with AR-Qs length (Q13 > Q25 > Q35), whereas BaP suppresses ARE activities in EMCA cells. Furthermore, AR-Q13 (but not AR-Q25, or -35) enhances BaP-induced dioxin-responsive element (DRE) activity. Lastly, AR-Q13 exerts higher colony-forming capacity than other AR-Qs, and knock-down AhR abolished AR-Q13-mediated colony numbers. This study demonstrated a possible interaction of gene (AR-Q polymorphism) and environmental toxins (e.g. BaP) to affect cancer progression. A large-scale epidemiology and public health survey on the interaction of environmental toxin and AR poly-Q in EMCA is suggested.

Factors that affect outcomes of prolapse repair using single-incision vaginal mesh procedures.

AIMS: Single-incision vaginal mesh (SIVM) procedures for pelvic organ prolapse (POP) differed in mesh fabrication and implantation that may affect treatment outcomes. We aim to evaluate and compare the safety and effectiveness of two SIVM procedures, and explore factors that may have associations with surgical effectiveness. METHODS: Our data of using two SIVM procedures for a total (anterior and posterior) vaginal mesh repair were studied. Patients who had ≧stage 2 POP and underwent either Elevate (n = 85) using anchored, lightweight meshes or Prosima procedures (n = 95) using non-anchored, original meshes were assessed. A detailed comparison of 1 year outcomes was made. RESULTS: Of the 180 patients, 172 (95.6%) attended the 1-year follow-up. Demographic data were similar between groups except a higher average age (64.5 vs 60.4, P = 0.001) was noted in the Elevate (n = 84) group compared to the Prosima (n = 88) group. Surgical results were also similar except a significantly higher objective cure (POP stage ≦1) rate (89.3% vs 78.4%, P = 0.042) was noted in the Elevate group. The safety profile favored Elevate with a lower, but not statistically significant, rate (4.7% vs 12.5%, P = 0.106) of vaginal mesh exposure. After a statistical analysis, we found anatomic recurrence (POP stage ≧2) after the SIVM procedures had strong (P < 0.05) associations with "early surgical cases," "Prosima procedure," "advanced cystocele (Ba > +3 cm)," and "prior prolapse repair," respectively. CONCLUSIONS: Beyond a learning curve, Elevate performed better than Prosima in POP repair regarding surgical effectiveness. Meanwhile, several predisposing factors that may affect recurrence after SIVM procedures were found.