The anti-tumor effects of AZD4547 on ovarian cancer cells: differential responses based on c-Met and FGF19/FGFR4 expression.

BACKGROUND: The FGF/FGFR signaling pathway plays a critical role in human cancers. We analyzed the anti-tumor effect of AZD4547, an inhibitor targeting the FGF/FGFR pathway, in epithelial ovarian cancer (EOC) and strategies on overcoming AZD4547 resistance. METHODS: The effect of AZD4547 on cell viability/migration was evaluated and in vivo experiments in intraperitoneal xenografts using EOC cells and a patient-derived xenograft (PDX) model were performed. The effect of the combination of AZD4547 with SU11274, a c-Met-specific inhibitor, FGF19-specific siRNA, or an FGFR4 inhibitor was evaluated by MTT assay. RESULTS: AZD4547 significantly decreased cell survival and migration in drug-sensitive EOC cells but not drug-resistant cells. AZD4547 significantly decreased tumor weight in xenograft models of drug-sensitive A2780 and SKOV3ip1 cells and in a PDX with drug sensitivity but not in models with drug-resistant A2780-CP20 and SKOV3-TR cells. Furthermore, c-Met expression was high in SKOV3-TR and HeyA8-MDR cells, and co-administration of SU11274 and AZD4547 synergistically induced cell death. In addition, expressions of FGF19 and FGFR4 were high in A2780-CP20 cells. Combining AZD4547 with FGF19 siRNA or with a selective FGFR4 inhibitor led to significantly reduced cell proliferation in A2780-CP20 cells. CONCLUSIONS: This study showed that AZD4547 has significant anti-cancer effects in drug-sensitive cells and PDX models but not in drug-resistant EOC cells. In drug-resistant cells, the expression level of c-Met or FGF19/FGFR4 may be a predictive biomarker for AZD4547 treatment response, and a combination strategy of drugs targeting c-Met or FGF19/FGFR4 together with AZD4547 may be an effective therapeutic strategy for EOC.

Active Surface Area-Dependent Water Harvesting of Desert Beetle-Inspired Hybrid Wetting Surfaces.

The increasing frequency of water scarcity is an acute worldwide problem. Nature-inspired water harvesting from fog is an important method to obtain freshwater in arid areas. Existing literature reports varied and diversified results in water harvesting capacity by employing a biphilic surface with control over hydrophilic and hydrophobic patterns. In this study, we first demonstrate a facile and scalable method to fabricate a biphilic surface using a simple electroless etching and desilanization technique. Considering the nucleation, growth, and transport of condensate, biphilic surfaces with controlled active surface area of hydrophilic spots were given special attention. We studied the water collection performance of pattern shape with its associated active surface area and further evaluated the critical surface area beyond which the water collection efficiency decreases. A high water collection capacity of 2050 mg cm-2 h-1 was achieved, and the hydrophilic active area-engineered surface retained its efficiency even after 50 test cycles. We further demonstrate high collection efficiency with a square pattern compared to a triangular path-like-patterned surface. The observations and surface engineering strategies reported in this study can provide insights into efficient and sustainable water harvesting devices.

Anti-cancer effects of benzimidazole derivative BNZ-111 on paclitaxel-resistant ovarian cancer.

OBJECTIVE: Ovarian cancer, a leading cause of cancer-related deaths in women, remains a formidable challenge, especially in the context of platinum-resistant disease. This study investigated the potential of the benzimidazole derivative BNZ-111 as a novel treatment strategy for platinum-resistant ovarian cancer. METHODS: The human EOC cell lines A2780, HeyA8, SKOV3ip1, A2780-CP20, HeyA8-MDR, and SKOV3-TR were treated with BNZ-111, and cell proliferation, apoptosis, and cell cycle were assessed. RESULTS: It demonstrated strong cytotoxicity in both chemo-sensitive and chemo-resistant epithelial ovarian cancer cell lines, inducing apoptosis and G2/M cell cycle arrest. In vivo experiments using orthotopic and patient-derived xenograft models showed significant tumor growth inhibition without apparent toxicity to vital organs. Unlike paclitaxel, BNZ-111 proved effective in paclitaxel-resistant cells, potentially by bypassing interaction with MDR1 and modulating ß-3 tubulin expression to suppress microtubule dynamics. CONCLUSION: BNZ-111, with favorable drug-like properties, holds promise as a therapeutic option for platinum-resistant ovarian cancer, addressing a critical clinical need in gynecologic oncology.

Risk Factors Affecting Clinical Outcomes of Low-risk Early-stage Human Papillomavirus-Associated Endocervical Adenocarcinoma Treated by Surgery Alone: Application of Silva Pattern.

This study aimed to report the clinical outcomes and risk factors for survival of patients with low-risk early-stage human papillomavirus-associated (HPVA) endocervical adenocarcinoma (EAC) treated with surgery alone. This retrospective study obtained the clinicopathological data of patients with early-stage HPVA EAC who underwent surgery between 2012 and 2018. The Silva pattern of invasion was determined by reviewing pathology slides. Locoregional recurrence-free survival (RFS), RFS, and overall survival were calculated, and the risk factors for survival were analyzed. One hundred seventeen patients with a median follow-up of 5.2 years (0.5-9.7 yr) were included. The most common histologic type was usual (94/117, 80.3%). The Silva pattern was A in 79 patients (67.5%), B in 30 (25.6%), and C in 8 (6.8%). The 5-year locoregional RFS, RFS, and overall survival rates were 92.4%, 87.8%, and 97.2%, respectively. The presence of intermediate-risk factors and Silva pattern C were significantly associated with worse survival. Based on these findings, patients were categorized into 2 groups: Group 1 (Silva pattern A or Silva pattern B without intermediate-risk factors) and Group 2 (Silva pattern B with intermediate-risk factors or Silva pattern C ). Group 2 showed significantly worse outcomes than Group 1, including the 5-year locoregional RFS (98.6% vs 68.0%), RFS (96.4% vs 54.6%), and overall survival (100.0% vs 86.5%). In conclusion, surgery alone for early-stage HPVA EAC resulted in favorable outcomes. Consideration of the Silva pattern, in addition to well-known risk factors, could help in precise risk group stratification of low-risk, early-stage HPVA EAC.

Prognostic Impact of Visceral Adipose Tissue Imaging Parameters in Patients with Cholangiocarcinoma after Surgical Resection.

Visceral adiposity is known to be related to poor prognosis in patients with cholangiocarcinoma; however, the prognostic significance of the qualitative features of adipose tissue in cholangiocarcinoma has yet to be well defined. This study investigated the prognostic impact of adipose tissue imaging parameters reflecting the quantity and qualitative characteristics of subcutaneous (SAT) and visceral (VAT) adipose tissue on recurrence-free survival (RFS) and overall survival (OS) in 94 patients undergoing resection of cholangiocarcinoma. The area, mean computed tomography (CT) attenuation, and mean 2-deoxy-2-[18F]fluoro-D-glucose (FDG) uptake of SAT and VAT on positron emission tomography (PET)/CT for staging work-up were measured, and the relationship of these adipose tissue imaging parameters with clinicopathological factors and survival was assessed. TNM stage, histologic grade, lymphovascular invasion, and the size of cholangiocarcinoma showed positive correlations with adipose tissue imaging parameters. Multivariate survival analysis demonstrated that the visceral-to-subcutaneous adipose tissue area ratio (VSR) (p = 0.024; hazard ratio, 1.718) and mean FDG uptake of VAT (p = 0.033; hazard ratio, 9.781) were significant predictors for RFS, but all of the adipose tissue imaging parameters failed to show statistical significance for predicting OS. In addition to visceral adiposity, FDG uptake of VAT might be a promising prognostic parameter for predicting RFS in patients with cholangiocarcinoma.

Metastatic Infection Following Ear Piercing Detected by FDG PET/CT.

ABSTRACT: Ear piercing is currently a common practice. Although rare, ear piercing can cause systemic infections. We present a case of an 18-year-old woman who underwent FDG PET/CT for prolonged fever and bacteremia. FDG PET/CT showed multifocal FDG uptake at the site of piercing in the left ear, and in the spleen and left atrium and deep thigh vessel. The patient was diagnosed with an ear piercing infection with multiple metastatic infections.

Assessing the Adequacy of Traditional Vertebral Landmarks as Upper Border of Whole Pelvic Radiotherapy Field for Stage IB2-IIB Cervical Cancer.

This study investigates the impact of insufficient common iliac lymph node (CIN) irradiation on treatment outcomes in patients with stage IB2-IIB cervical cancer receiving concurrent chemoradiotherapy (CCRT). We retrospectively analyzed 68 patients with Federation of Gynecology and Obstetrics stage IB2-IIB, treated with weekly cisplatin-based CCRT from 2008 to 2018. Patients received external-beam whole pelvic radiotherapy (WPRT) and concurrent cisplatin chemotherapy, followed by high-dose-rate brachytherapy. The WPRT upper border was at L4-5 in 61 patients and L3-4 in 7 patients. Thirty-seven patients had the CIN area fully included (full-CIN group), while 31 had partial inclusion (partial-CIN group). Recurrence rates and survival outcomes were analyzed over a median follow-up of 111 months. Patient characteristics and the irradiated dose were comparable. Treatment failure occurred in three patients (8.1%) in the full-CIN group and in six patients (19.4%) in the partial-CIN group, with CIN and para-aortic lymph node recurrence in two and one patients, respectively. The 5-year cumulative recurrence rate was 0% for the full-CIN group and 11.4% for the partial-CIN group (p = 0.04). Cause-specific survival was 100% vs. 87.1% (p = 0.025), and the overall survival was 94.3% vs. 87.1% (p = 0.44). Fully including the CIN area in WPRT is crucial for stage IB2-IIB cervical cancer. Vascular anatomical margins should be considered over vertebral landmarks.

Combined radiomics-clinical model to predict platinum-sensitivity in advanced high-grade serous ovarian carcinoma using multimodal MRI.

Introduction: We aimed to predict platinum sensitivity using routine baseline multimodal magnetic resonance imaging (MRI) and established clinical data in a radiomics framework. Methods: We evaluated 96 patients with ovarian cancer who underwent multimodal MRI and routine laboratory tests between January 2016 and December 2020. The patients underwent diffusion-weighted, contrast-enhanced T1-weighted, and T2-weighted MRI. Subsequently, 293 radiomic features were extracted by manually identifying tumor regions of interest. The features were subjected to the least absolute shrinkage and selection operators, leaving only a few selected features. We built the first prediction model with a tree-based classifier using selected radiomics features. A second prediction model was built by combining the selected radiomic features with four established clinical factors: age, disease stage, initial tumor marker level, and treatment course. Both models were built and tested using a five-fold cross-validation. Results: Our radiomics model predicted platinum sensitivity with an AUC of 0.65 using a few radiomics features related to heterogeneity. The second combined model had an AUC of 0.77, confirming the incremental benefits of the radiomics model in addition to models using established clinical factors. Conclusion: Our combined radiomics-clinical data model was effective in predicting platinum sensitivity in patients with advanced ovarian cancer.

Relationship of FDG PET/CT imaging features with tumor immune microenvironment and prognosis in colorectal cancer: a retrospective study.

BACKGROUND: Imaging features of colorectal cancers on 2-deoxy-2-[18F]fluoro-d-glucose (FDG) positron emission tomography/computed tomography (PET/CT) have been considered to be affected by tumor characteristics and tumor immune microenvironment. However, the relationship between PET/CT imaging features and immune reactions in tumor tissue has not yet been fully evaluated. This study investigated the association of FDG PET/CT imaging features in the tumor, bone marrow, and spleen with immunohistochemical results of cancer tissue and recurrence-free survival (RFS) in patients with colorectal cancer. METHODS: A total of 119 patients with colorectal cancer who underwent FDG PET/CT for staging work-up and received curative surgical resection were retrospectively enrolled. From PET/CT images, 10 first-order imaging features of primary tumors, including intensity of FDG uptake, volumetric metabolic parameters, and metabolic heterogeneity parameters, as well as FDG uptake in the bone marrow and spleen were measured. The degrees of CD4+, CD8+, and CD163 + cell infiltration and interleukin-6 (IL-6) and matrix metalloproteinase-11 (MMP-11) expression were graded through immunohistochemical analysis of surgical specimens. The relationship between FDG PET/CT imaging features and immunohistochemical results was assessed, and prognostic significance of PET/CT imaging features in predicting RFS was evaluated. RESULTS: Correlation analysis with immunohistochemistry findings showed that the degrees of CD4 + and CD163 + cell infiltration and IL-6 and MMP-11 expression were correlated with cancer imaging features on PET/CT. Patients with enhanced inflammatory response in cancer tissue demonstrated increased FDG uptake, volumetric metabolic parameters, and metabolic heterogeneity. FDG uptake in the bone marrow and spleen was positively correlated with the degree of CD163 + cell infiltration and IL-6 expression, respectively. In multivariate survival analysis, the coefficient of variation of FDG uptake in the tumor (p = 0.019; hazard ratio, 0.484 for 0.10 increase) and spleen-to-liver uptake ratio (p = 0.020; hazard ratio, 24.901 for 1.0 increase) were significant independent predictors of RFS. CONCLUSIONS: The metabolic heterogeneity of tumors and FDG uptake in the spleen were correlated with tumor immune microenvironment and showed prognostic significance in predicting RFS in patients with colorectal cancer.

Comparison of RNA-Seq and microarray in the prediction of protein expression and survival prediction.

Gene expression profiling using RNA-sequencing (RNA-seq) and microarray technologies is widely used in cancer research to identify biomarkers for clinical endpoint prediction. We compared the performance of these two methods in predicting protein expression and clinical endpoints using The Cancer Genome Atlas (TCGA) datasets of lung cancer, colorectal cancer, renal cancer, breast cancer, endometrial cancer, and ovarian cancer. We calculated the correlation coefficients between gene expression measured by RNA-seq or microarray and protein expression measured by reverse phase protein array (RPPA). In addition, after selecting the top 103 survival-related genes, we compared the random forest survival prediction model performance across test platforms and cancer types. Both RNA-seq and microarray data were retrieved from TCGA dataset. Most genes showed similar correlation coefficients between RNA-seq and microarray, but 16 genes exhibited significant differences between the two methods. The BAX gene was recurrently found in colorectal cancer, renal cancer, and ovarian cancer, and the PIK3CA gene belonged to renal cancer and breast cancer. Furthermore, the survival prediction model using microarray was better than the RNA-seq model in colorectal cancer, renal cancer, and lung cancer, but the RNA-seq model was better in ovarian and endometrial cancer. Our results showed good correlation between mRNA levels and protein measured by RPPA. While RNA-seq and microarray performance were similar, some genes showed differences, and further clinical significance should be evaluated. Additionally, our survival prediction model results were controversial.

Evaluation of Anticancer Efficacy of D-α-Tocopheryl Polyethylene-Glycol Succinate and Soluplus® Mixed Micelles Loaded with Olaparib and Rapamycin Against Ovarian Cancer.

Purpose: Ovarian cancer has the highest mortality rate and lowest survival rate among female reproductive system malignancies. There are treatment options of surgery and chemotherapy, but both are limited. In this study, we developed and evaluated micelles composed of D-α-tocopheryl polyethylene-glycol (PEG) 1000 succinate (TPGS) and Soluplus® (SOL) loaded with olaparib (OLA), a poly(ADP-ribose)polymerase (PARP) inhibitor, and rapamycin (RAPA), a mammalian target of rapamycin (mTOR) inhibitor in ovarian cancer. Methods: We prepared micelles containing different molar ratios of OLA and RAPA embedded in different weight ratios of TPGS and SOL (OLA/RAPA-TPGS/SOL) were prepared and physicochemical characterized. Furthermore, we performed in vitro cytotoxicity experiments of OLA, RAPA, and OLA/RAPA-TPGS/SOL. In vivo toxicity and antitumor efficacy assays were also performed to assess the efficacy of the mixed micellar system. Results: OLA/RAPA-TPGS/SOL containing a 4:1 TPGS:SOL weight ratio and a 2:3 OLA:RAPA molar ratio showed synergistic effects and were optimized. The drug encapsulation efficiency of this formulation was >65%, and the physicochemical properties were sustained for 180 days. Moreover, the formulation had a high cell uptake rate and significantly inhibited cell migration (**p < 0.01). In the in vivo toxicity test, no toxicity was observed, with the exception of the high dose group. Furthermore, OLA/RAPA-TPGS/SOL markedly inhibited tumor spheroid and tumor growth in vivo. Conclusion: Compared to the control, OLA/RAPA-TPGS/SOL showed significant tumor inhibition. These findings lay a foundation for the use of TPGS/SOL mixed micelles loaded with OLA and RAPA in the treatment of ovarian cancer.

Prognostic Significance of the Bone Marrow-to-Aorta Uptake Ratio on 2-Deoxy-2-[18F]fluoro-d-glucose Positron Emission Tomography/Computed Tomography in Patients with Cholangiocarcinoma.

2-Deoxy-2-[18F]fluoro-d-glucose (FDG) uptake of the reticuloendothelial system on positron emission tomography/computed tomography (PET/CT) is known to be related to systemic inflammatory response to cancer cells in patients with diverse malignancies. This retrospective study aimed to investigate whether FDG uptake by the reticuloendothelial system had a prognostic value in predicting progression-free survival (PFS) and overall survival (OS) in 138 cholangiocarcinoma patients. Quantifying FDG uptake of the aorta, bone marrow (BM), liver, and spleen from staging FDG PET/CT images, we found significant correlations between the BM-to-aorta uptake ratio (BAR), spleen-to-aorta uptake ratio, and BM-to-liver uptake ratio with tumor stage and serum inflammatory markers. In the multivariate survival analysis, BAR was an independent predictor of PFS (p = 0.016; hazard ratio, 2.308) and OS (p = 0.030; hazard ratio, 2.645). Patients with stages III-IV of the disease and a high BAR exhibited low 1-year PFS (35.8%) and OS (60.2%) rates, while those with stages I-II of the disease and low BAR showed robust rates of 90.0% and 96.7%, respectively. BAR measured on staging FDG PET/CT might be a potential imaging biomarker offering insights into the systemic inflammatory response and predicting prognosis in cholangiocarcinoma. This study highlights BAR as a promising, independent predictor with potential for personalized prognostication and treatment strategies.

Efficacy and safety of BVAC-C in HPV type 16- or 18-positive cervical carcinoma who failed 1st platinum-based chemotherapy: a phase I/IIa study.

Background: BVAC-C, a B cell- and monocyte-based immunotherapeutic vaccine transfected with recombinant HPV E6/E7, was well tolerated in HPV-positive recurrent cervical carcinoma patients in a phase I study. This phase IIa study investigates the antitumor activity of BVAC-C in patients with HPV 16- or 18-positive cervical cancer who had experienced recurrence after a platinum-based combination chemotherapy. Patients and methods: Patients were allocated to 3 arms; Arm 1, BVAC-C injection at 0, 4, 8 weeks; Arm 2, BVAC-C injection at 0, 4, 8, 12 weeks; Arm 3, BVAC-C injection at 0, 4, 8, 12 weeks with topotecan at 2, 6, 10, 14 weeks. Primary endpoints were safety and objective response rate (ORR) as assessed by an independent radiologist according to Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included the disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: Of the 30 patients available for analysis, the ORR was 19.2% (Arm 1: 20.0% (3/15), Arm 2: 33.3% (2/6), Arm3: 0%) and the DCR was 53.8% (Arm 1: 57.1%, Arm 2: 28.6%, Arm3: 14.3%). The median DOR was 7.5 months (95% CI 7.1-not reported), the median PFS was 5.8 months (95% CI 4.2-10.3), and the median OS was 17.7 months (95% CI 12.0-not reported). All evaluated patients showed not only inflammatory cytokine responses (IFN-γ or TNF-α) but also potent E6/E7-specific T cell responses upon vaccinations. Immune responses of patients after vaccination were correlated with their clinical responses. Conclusion: BVAC-C represents a promising treatment option and a manageable safety profile in the second-line setting for this patient population. Further studies are needed to identify potential biomarkers of response. Clinical trial registration: ClinicalTrials.gov, identifier NCT02866006.

Current treatment strategies for ovarian cancer in the East Asian Gynecologic Oncology Trial Group (EAGOT).

Ovarian cancer, notable for its severe prognosis among gynecologic cancers, has seen substantial progress in treatment approaches recently. Enhanced protocols in chemotherapy and the introduction of poly (ADP-ribose) polymerase (PARP) inhibitors for maintenance therapy have markedly improved outcomes for patients with specific genetic profiles, such as those positive for BRCA mutations or exhibiting homologous recombination deficiency (HRD). Additionally, the method of intraperitoneal chemotherapy administration has emerged as a valuable alternative to traditional transvenous routes, showing promise for wider clinical adoption. The field of surgery has also evolved, with increasing exploration into the benefits and feasibility of laparoscopic methods over more invasive traditional surgeries, aiming for complete tumor removal but with reduced patient impact. The hereditary nature of ovarian cancer underscores the importance of genetic testing, which has become integral in tailoring treatment strategies, particularly in determining suitability for PARP inhibitors. The formation of the East Asian Gynecologic Oncology Trial Group (EAGOT) aims to optimize treatment across Japan, Korea, China, and Taiwan. The ovarian cancer committee of EAGOT shared the current policies, focusing on 5 topics: 1) strategies for maintenance therapy after initial surgery and chemotherapy, 2) drug regimens for platinum-sensitive and platinum-resistant recurrence, 3) intraperitoneal chemotherapy, 4) laparoscopic surgery as an alternative to laparotomy, and 5) current status of genetic testing (BRCA, HRD, and panel tests) for ovarian cancer and its prospects. EAGOT's multi-national trials aim to harmonize these evolving treatment strategies, ensuring that the latest and most effective protocols are accessible across the region, thereby significantly impacting patient outcomes in East Asia.

Initial experience with the enhanced recovery after surgery (ERAS) protocols in gynecologic surgery at an urban academic tertiary medical center.

Background: The enhanced recovery after surgery (ERAS) protocols have been consistently associated with improved patient experience and surgical outcomes. Despite the release of ERAS Society guidelines specific to gynecologic oncology, the adoption of ERAS in gynecology on global level has been disappointingly low and some centers have shown minimal improvement in clinical outcomes after adopting ERAS. The aim of this study is to describe the development and early experience of ERAS protocols in gynecologic surgery at an urban academic tertiary medical center. Methods: This was an observational prospective cohort study. The target patient population included those with low comorbidities who were scheduled to undergo various types of gynecologic surgeries for both benign and malignant diseases between October 2020 and February 2021. Two attending surgeons implemented the protocols for their patients (ERAS cohort) while three attending surgeons maintained the conventional perioperative care for their patients (non-ERAS cohort). Baseline characteristics, surgical outcomes and patients' answers to a 12-question survey were compared. A case-matched comparative analysis was also performed between the ERAS cohort and the historical non-ERAS cohort (those who received the same types of surgical procedures from the two ERAS attending surgeons prior to the implementation of the protocols). Results: A total of 244 patients were evaluated (122 in the ERAS cohort vs. 122 in the non-ERAS cohort). The number of vials of opioid analgesia used during the first two postoperative days was significantly lower whereas the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen was more frequent in the ERAS cohort group. The patients in the ERAS group reported less postoperative pain, feelings of hunger and thirst, and greater amount of exercise postoperatively. These benefits of the ERAS cohort were more pronounced in the patients who underwent laparotomic surgeries than those who underwent laparoscopic surgeries. The case-matched comparative analysis also showed similar results. The length of hospital stay did not differ between those who underwent the ERAS protocols and those who did not. Conclusions: The results of the study demonstrated the safety, clinical feasibility and benefits of the ERAS protocols for patients undergoing gynecologic surgeries for both benign and malignant indications.