Deep epigastric lymph nodes implication in patients' recurrence pattern after cytoreductive surgery in ovarian peritoneal metastases.

INTRODUCTION: Although complete cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC) offers a good prognosis in patients with peritoneal metastasis of ovarian cancer (PMOC), recurrences are quite common. These recurrences can be intra-abdominal or systemic in nature. Our objective was to study and illustrate the global recurrence pattern in patients operated for PMOC, shedding light on a previously overlooked lymphatic basin at the level of the epigastric artery, the deep epigastric lymph nodes (DELN) basin. PATIENTS AND METHODS: This was a retrospective study including patients with PMOC who underwent surgery with curative-intent, from 2012 until 2018, at our cancer center, and who presented with any type of disease recurrence on follow-up. CT-scans, MRIs and PET-scans were reviewed in order to determine solid organs and lymph nodes (LN) recurrences. RESULTS: During the study period, 208 patients underwent CRS ± HIPEC, 115 (55.3%) presented with organ or lymphatic recurrence over a median follow-up of 81 months. Sixty percent of these patients had radiologically enlarged LN involvement. The pelvis/pelvic peritoneum was the most common intra-abdominal organ recurrence site (47%), while the retroperitoneal LN was the most common lymphatic recurrence site (73.9%). Previously overlooked DELN were found in 12 patients, with 17.4% implication in lymphatic basin recurrence patterns. CONCLUSION: Our study revealed the potential role of the DELN basin, previously overlooked in the systemic dissemination process of PMOC. This study sheds light on a previously unrecognized lymphatic pathway, as an intermediate checkpoint or relay, between the peritoneum, an intra-abdominal organ, and the extra-abdominal compartment.

A Photoacoustic Contrast Nanoagent with a Distinct Spectral Signature for Ovarian Cancer Management.

Photoacoustic imaging (PAI) has tremendous potential for improving ovarian cancer detection. However, the lack of effective exogenous contrast agents that can improve PAI diagnosis accuracy significantly limits this application. This study presents a novel contrast nanoagent with a specific spectral signature that can be easily distinguished from endogenous chromophores in cancer tissue, allowing for high-contrast tumor visualization. Constructed as a 40 nm biocompatible polymeric nanoparticle loaded with two naphthalocyanine dyes, this agent is capable of efficient ovarian tumor accumulation after intravenous injection. The developed nanoagent displays a spectral signature with two well-separated photoacoustic peaks of comparable PA intensities in the near-infrared (NIR) region at 770 and 860 nm, which remain unaffected in cancer tissue following systemic delivery. In vivo experiments in mice with subcutaneous and intraperitoneal ovarian cancer xenografts validate that this specific spectral signature allows for accurate spectral unmixing of the nanoagent signal from endogenous contrast in cancer tissue, allowing for sensitive noninvasive cancer diagnosis. In addition, this nanoagent can selectively eradicate ovarian cancer tissue with a single dose of photothermal therapy by elevating the intratumoral temperature to ≈49 °C upon exposure to NIR light within the 700-900 nm range.

Photoacoustic mediated multifunctional tumor antigen trapping nanoparticles inhibit the recurrence and metastasis of ovarian cancer by enhancing tumor immunogenicity.

The hypoimmunogenicity of tumors is one of the main bottlenecks of cancer immunotherapy. Enhancing tumor immunogenicity can improve the efficacy of tumor immunotherapy by increasing antigen exposure and presentation, and establishing an inflammatory microenvironment. Here, a multifunctional antigen trapping nanoparticle with indocyanine green (ICG), aluminum hydroxide (Al(OH)3) and oxaliplatin (OXA) (PPIAO) has been developed for tumor photoacoustic/ultrasound dual-modality imaging and therapy. The combination of photothermal/photodynamic therapy and chemotherapy induced tumor antigen exposure and release through immunogenic death of tumor cells. A timely capture and storage of antigens by aluminum hydroxide enabled dendritic cells to recognize and present those antigens spatiotemporally. In an ovarian tumor model, the photoacoustic-mediated PPIAO NPs combination therapy achieved a transition from "cold tumor" to "hot tumor" that promoted more CD8+ T lymphocytes activation in vivo and intratumoral infiltration, and successfully inhibited the growth of primary and metastatic tumors. An in situ tumor vaccine effect was produced from the treated tumor tissue, assisting mice against the recurrence of tumor cells. This study provided a simple and effective personalized tumor vaccine strategy for better treatment of metastatic and recurrent tumors. The developed multifunctional tumor antigen trapping nanoparticles may be a promising nanoplatform for integrating multimodal imaging monitoring, tumor treatment, and tumor vaccine immunotherapy.

CuS Nanoparticles-Loaded and Cisplatin Prodrug Conjugated Fe(III)-MOFs for MRI-Guided Combination of Chemotherapy and NIR-II Photothermal Therapy.

Ovarian cancer has become an urgent threat to global female healthcare. Cisplatin, as the traditional chemotherapeutic agent against ovarian cancer, retains several limitations, such as drug resistance and dose-limiting toxicity. In order to solve the above problems and promote the therapeutic effect of chemotherapy, combining chemotherapy and phototherapy has aroused wide interest. In this study, we constructed a versatile cisplatin prodrug-conjugated therapeutic platform based on ultrasmall CuS-modified Fe(III)-metal-organic frameworks (MIL-88) (named M-Pt/PEG-CuS) for tumor-specific enhanced synergistic chemo-/phototherapy. After intravenous injection, M-Pt/PEG-CuS presented obvious accumulation in tumor and Fe(III)-MOFs possessed magnetic resonance imaging (MRI) to guide synergy therapy. Both in vitro and in vivo experimental results showed that M-Pt/PEG-CuS could not only successfully inhibit tumor growth by combining chemotherapy and NIR-II PTT but also avoid the generation of liver damage by the direct treatment of cisplatin(II). Our work presented the development of the nanoplatform as a novel NIR-II photothermal agent, as well as gave a unique combined chemo-photothermal therapy strategy, which might provide new ways of ovarian cancer therapy for clinical translation.

CT Imaging Findings in Patients with Ovarian Cancer and Acute Abdominal Symptoms: Experience at a Tertiary Cancer Center.

PURPOSE: To evaluate computed tomography (CT) findings in patients with ovarian cancer presenting to a comprehensive cancer center's urgent care unit with acute abdominal symptoms. METHODS: This retrospective study included consecutive patients with ovarian cancer who underwent abdominal CT at a comprehensive cancer center's urgent care unit between January 1, 2018, and January 14, 2020, due to acute abdominal symptoms. Two abdominal radiologists reviewed the abdominal CT reports, categorizing imaging findings as follows: (a) no new or acute finding, (b) new or increased bowel or gastric obstruction, (c) new or increased ascites, (d) new or increased peritoneal carcinomatosis, (e) new or increased nonperitoneal metastases, (f) new inflammatory or infectious changes, (g) new or increased hydronephrosis, (h) new or increased biliary dilatation, (i) new vascular complications, or (j) new bowel perforation. RESULTS: A total of 200 patients (mean age, 59 years; range, 22-87) underwent a total of 259 abdominal CT scans, of which 217/259 (83.8%) scans were found to have new or increased findings. A total of 115/259 (44.4%) scans had only one finding while 102/259 (39.4%) scans had 2 or more findings. Altogether, 382 new or increased findings were detected: findings were most commonly related to bowel or gastric obstruction (92/382, 24.1%) with small bowel obstruction being the most common finding (80/382, 20.9%); ascites (78/382, 20.4%); peritoneal carcinomatosis (62/382, 16.2%); and nonperitoneal metastases (62/382, 16.2%). Inflammatory or infectious findings accounted for 30/382 (7.9%) findings. CONCLUSION: Most patients with ovarian cancer presenting with acute abdominal had relevant positive findings on abdominal CT, with small bowel obstruction being the most common finding.

Safe and efficient 2D molybdenum disulfide platform for cooperative imaging-guided photothermal-selective chemotherapy: A preclinical study.

Introduction: The striking imbalance between the ever-increasing amount of nanomedicines and low clinical translation of products has become the focus of intense debate. For clinical translation, the critical issue is to select the appropriate agents and combination regimen for targeted diseases, not to prepare increasingly complex nanoplatforms. Objectives: A safe and efficient platform, α-tocopheryl succinate (α-TOS) married 2D molybdenum disulfide, was devised by a facile method and applied for cooperative imaging-guided photothermal-selective chemotherapy of ovarian carcinoma. Methods: A novel platform of PEGylated α-TOS and folic acid (FA) conjugated 2D MoS2 nanoflakes was fabricated  for the cooperative multimode computed tomography (CT)/photoacoustic (PA)/thermal imaging-guided photothermal-selective chemotherapy of ovarian carcinoma. Results: The photothermal efficiency (65.3%) of the platform under safe near-infrared irradiation is much higher than that of other photothermal materials reported elsewhere. Moreover, the covalently linked α-TOS renders platform with selective chemotherapy for cancer cells. Remarkably, with these excellent properties, the platform can be used to completely eliminate the solid tumor by safe photothermal therapy, and then kill the residual cancer cells by selective chemotherapy to prevent tumor recurrence. More significantly, barely side effects occur in the whole treatment process. The excellent efficacy and safety benefits in vivo lead to the prominent survival rate of 100% over 91 days. Conclusion: The safe and efficient platform might be a candidate of clinical nanomedicines for multimode theranostics. This study demonstrates an innovative thought in precise nanomedicine regarding the design of next generation of cancer theranostic protocol for potential clinical practice.

Increasing referral of at-risk women for genetic counseling and BRCA testing using a screening tool in a community breast imaging center.

BACKGROUND: Genetic evaluation and testing for hereditary breast and ovarian cancer (HBOC) remain suboptimal. The authors evaluated the feasibility of using a screening tool at a breast imaging center to increase HBOC assessment referrals. METHODS: A brief questionnaire based on the National Comprehensive Cancer Network HBOC genetic counseling referral guidelines was developed and added to the standard intake forms of patients undergoing mammography at a community breast imaging center from 2012 through 2015. Patients who met the criteria in the guidelines were referred for genetic counseling. RESULTS: A total of 34,851 patients were screened during the study period, and 1246 (4%) patients were found to be eligible for referral; 245 of these patients made a genetic counseling appointment, and 142 patients received genetic counseling. Forty patients (28%) had a personal history of breast cancer but were not previously tested. Following counseling, 105 patients were tested for BRCA1/2. Eight patients (8%) tested positive for a pathogenic mutation and nine (9%) had a variant of unknown significance. Although they tested negative, many patients met the criteria to add breast magnetic resonance imaging to their screening due to greater than 20% lifetime breast cancer risk based on their family cancer history. This study led to improved clinical risk management in 67% of the patients who underwent genetic counseling. CONCLUSIONS: This study shows that large-scale screening of patients for HBOC syndromes at time of breast imaging is practical and highly feasible. The screening tool identified women with actionable BRCA1/2 mutations and mutation-negative but high-risk women, leading to significant changes in their risk management; these women would otherwise have been missed. LAY SUMMARY: Hereditary breast and ovarian cancer (HBOC) caused by pathogenic mutations in breast cancer genes (BRCA1/BRCA2) increase an individual's lifetime risk of getting HBOC. Identifying these high-risk individuals and using proven preventive clinical risk management strategies can significantly reduce their lifetime risk of HBOC. Using an innovative family cancer history questionnaire, 34,000 women were screened at a community breast imaging center, and genetic counseling and testing were provided to eligible women from the screening. Several women at high risk for HBOC were identified and this led to positive clinical risk management changes. These women would have been missed if not for intervention.

Nomogram of Combining CT-Based Body Composition Analyses and Prognostic Inflammation Score: Prediction of Survival in Advanced Epithelial Ovarian Cancer Patients.

PURPOSE: To investigate the value of body composition changes measured by quantitative computer tomography (QCT) in evaluating the prognosis of advanced epithelial ovarian cancer (AEOC) patients who underwent primary debulking surgery (PDS) and adjuvant platinum-based chemotherapy, and constructed a nomogram model for predicting survival in combination with prognostic inflammation score (PIS). METHOD: Fifty-seven patients with AEOC between 2012 and 2016 were retrospectively enrolled. Pre- and post-treatment CT images were used to analyze the body composition biomarkers. The subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), cross-sectional area of paraspinal skeletal muscle area (PMA), skeletal muscle density (SMD), body mineral density (BMD) were measured from two sets of CT images. RESULTS: In multivariate analyses, VFA gain, PMA loss, BMD loss, and PIS were independent risk factors of overall survival (OS) (HR = 3.7, 3.0, 2.8, 1.9, respectively, all p < 0.05). Receiver operating characteristic (ROC) curves showed that the prognostic model combining body composition changes (BCC) and PIS had the highest predictive performance (area under the curve = 0.890). The concordance index (C-index) of the prognostic nomogram was 0.779 (95% CI, 0.673-0.886). Decision curve analysis (DCA) demonstrated the prognostic nomogram had a great distinguishing performance. CONCLUSION: CT-based body composition analyses and PIS were associated with poor OS for AEOC patients who underwent PDS and adjuvant platinum-based chemotherapy. The prognostic nomogram with a combination of BCC and PIS was dependable in predicting survival for AEOC patients during treatment.

Antibody-functionalized theranostic protein nanoparticles for the synergistic deep red fluorescence imaging and multimodal therapy of ovarian cancer.

Among women, ovarian cancer is the fifth most frequent type of cancer, and despite benefiting from current standard treatment plans, 90% of patients relapse in the subsequent 18 months and, eventually, perish. As a result, via embracing nanotechnological advancements in the field of medical science, researchers working in the areas of cancer therapy and imaging are looking for the next breakthrough treatment strategy to ensure lower cancer recurrence rates and improved outcomes for patients. Herein, we design a novel phototheranostic agent with optical features in the biological window of the electromagnetic spectrum via encapsulating a newly synthesized phthalocyanine dye within biocompatible protein nanoparticles, allowing the targeted fluorescence imaging and synergistic dual therapy of ovarian cancer. The nanosized agent displays great biocompatibility and enhanced aqueous biostability and photothermal activity, as well as high reactive-oxygen-species generation efficiency. To achieve the active targeting of the desired malignant tissue and suppress the rapid clearance of the photosensitive agent from the peritoneal cavity, the nanoparticles are biofunctionalized with an anti-folate receptor antibody. A2780 ovarian cancer cells are employed to confirm the improved targeting capabilities and the in vitro cytotoxic efficiency of the theranostic nanoparticles after exposure to a 660 nm LED lamp; upon measurement via MTT and flow cytometry assays, a significant 95% decrease in the total number of viable cells is seen. Additionally, the therapeutic performance of our newly designed nanoparticles was evaluated in vivo, via real-time thermal monitoring and histopathological assays, upon the irradiation of tumour-bearing mice with a 660 nm LED lamp (0.05 W cm-2). Foremost, separately from steady-state fluorescence imaging, we found that, via utilizing FLIM investigations, the differences in fluorescence lifetimes of antibody biofunctionalized and non-functionalized nanoparticles can be correlated to different intracellular localization and internalization pathways of the fluorescent agent, which is relevant for the development of a cutting-edge method for the detection of cancer cells that overexpress folate receptors at their surfaces.

EANM guideline on the role of 2-[18F]FDG PET/CT in diagnosis, staging, prognostic value, therapy assessment and restaging of ovarian cancer, endorsed by the American College of Nuclear Medicine (ACNM), the Society of Nuclear Medicine and Molecular Imaging (SNMMI) and the International Atomic Energy Agency (IAEA).

In most patients with ovarian carcinoma, the diagnosis is reached when the disease is long past the initial stages, presenting already an advanced stage, and they usually have a very bad prognosis. Cytoreductive or debulking surgical procedures, platinum-based chemotherapy and targeted agents are key therapeutic elements. However, around 7 out of 10 patients present recurrent disease within 36 months from the initial diagnosis. The metastatic spread in ovarian cancer follows three pathways: contiguous dissemination across the peritoneum, dissemination through the lymphatic drainage and, although less importantly in this case, through the bloodstream. Radiological imaging, including ultrasound, CT and MRI, are the main imaging techniques in which management decisions are supported, CT being considered the best available technique for presurgical evaluation and staging purposes. Regarding 2-[18F]FDG PET/CT, the evidence available in the literature demonstrates efficacy in primary detection, disease staging and establishing the prognosis and especially for relapse detection. There is limited evidence when considering the evaluation of therapeutic response. This guideline summarizes the level of evidence and grade of recommendation for the clinical indications of 2-[18F]FDG PET/CT in each disease stage of ovarian carcinoma.

Folate-targeted Pluronic-chitosan nanocapsules loaded with IR780 for near-infrared fluorescence imaging and photothermal-photodynamic therapy of ovarian cancer.

Herein, we report the fabrication of a nanotherapeutic platform integrating near-infrared (NIR) imaging with combined therapeutic potential through photodynamic (PDT) and photothermal therapies (PTT) and recognition functionality against ovarian cancer. Owing to its NIR fluorescence, singlet oxygen generation and heating capacity, IR780 iodide is exploited to construct a multifunctional nanosystem for single-wavelength NIR laser imaging-assisted dual-modal phototherapy. We opted for loading IR780 into polymeric Pluronic-F127-chitosan nanoformulation in order to overcome its hydrophobicity and toxicity and to allow functionalization with folic acid. The obtained nanocapsules show temperature-dependent swelling and spectroscopic behavior with favorable size distribution for cellular uptake at physiological temperatures, improved fluorescence properties and good stability. The fabricated nanocapsules can efficiently generate singlet oxygen in solution and are able to produce considerable temperature increase (46 °C) upon NIR laser irradiation. Viability assays on NIH-OVCAR-3 cells confirm the successful biocompatibilization of IR780 by encapsulating in Pluronic and chitosan polymers. NIR fluorescence imaging assays reveal the ability of folic-acid functionalized nanocapsules to serve as intracellular contrast agents and demonstrate their active targeting capacity against folate receptor expressing ovarian cancer cells (NIH-OVCAR-3). Consequently, the targeted nanocapsules show improved NIR laser induced phototherapeutic performance against NIH-OVCAR-3 cells compared to free IR780. We anticipate that this class of nanocapsules holds great promise as theranostic agents for application in image-guided dual PDT-PTT and imaging assisted surgery of ovarian cancer.

Incorporating SULF1 polymorphisms in a pretreatment CT-based radiomic model for predicting platinum resistance in ovarian cancer treatment.

OBJECTIVE: Early detection of platinum resistance for ovarian cancer treatment remains challenging. This study aims to develop a machine learning model incorporating genomic data such as Single-Nucleotide Polymorphisms (SNPs) of Human Sulfatase 1 (SULF1) with a CT radiomic model based on pre-treatment CT images, to predict platinum resistance for ovarian cancer (OC) treatment. METHODS: A cohort of 102 patients with pathologically confirmed OC was retrospectively enrolled into this study from January 2006 to February 2018. All patients had platinum-based chemotherapy after maximal cyto-reductive surgery. This cohort was separated into two groups according to treatment response, i.e., the group with platinum-resistant disease (PR group) and the group with platinum-sensitive disease (PS group). We genotyped 12 SNPs of SULF1 for all OC patients using Mass Array Method. Radiomic features, SNP data and clinicopathological data of the 102 patients were used to build the differentiation models. The study participants were divided into two cohorts: the training cohort (n = 71) and the validation cohort (n = 31). Feature selection and predictive modeling were performed using least absolute shrinkage and selection operator (LASSO), Random Forest Classifier and Support Vector Machine methods. Model performance for predicting platinum resistance was assessed with respect to its calibration, discrimination, and clinical application. RESULTS: For prediction of platinum resistance, the approach combining the radiomics, clinicopathological data and SNP data demonstrated higher classification efficiency, with an AUC value of 0.993 (95 % CI: 0.83 to 0.98) in the training cohort and 0.967 (95 % CI: 0.83 to 0.98) in validation cohort, than the performance with only the SNPs of SULF1 model (AUC: training, 0.843 [95 %CI: 0.738-0.948]; validation, 0.815 [0.601-1.000]), or with only the radiomic model (AUC: training, 0.874 [95 %CI: 0.789-0.960]; validation, 0.832 [95 %CI: 0.687-0.976]). This integrated approach also showed good calibration and favorable clinical utility. CONCLUSIONS: A predictive model combining pretreatment CT radiomics with genomic data such as SNPs of SULF1 could potentially help to predict platinum resistance in ovarian cancer treatment.

Feasibility of Bone Marrow Mesenchymal Stem Cell-Mediated Synthetic Radiosensitive Promoter-Combined Sodium Iodide Symporter for Radiogenetic Ovarian Cancer Therapy.

Ovarian cancer is the most lethal gynecological cancer, most patients relapse within 12-24 months, and eventually die, especially platinum-resistant patients. Gene therapy has been one of the most potential methods for tumor treatment. Bone marrow mesenchymal stem cells (BMSCs) have been used for systemic delivery of therapeutic genes to solid tumors. Sodium iodide symporter (NIS) is an intrinsic membrane glycoprotein and can concentrate 131I, which is important for radionuclide therapy and nuclear medicine imaging in recent years. However, the rapid iodine efflux has become a bottleneck for NIS-mediated radionuclide gene therapy. Our previous studies found that the early growth response-1 (Egr1) promoter containing CC(A/T)6GG (CArG) elements had an 131I radiation-positive feedback effect on the NIS gene. Other research showed the synthesized Egr1 promoter containing four CArG elements, E4, was nearly three times as sensitive as the Egr1 promoter. In our study, BMSC-E4-NIS was engineered to express NIS under the control of E4 promoter using lentivirial vectors. After BMSC-E4-NIS implantation, no tumors were seen in BALB/c nude mice and BMSC-E4-NIS did not promote the growth of SKOV3 tumor. BMSCs migrated toward ovarian cancer samples in chemotaxis assays and to ovarian tumors in mice. Using micro-single-photon emission computed tomography/computed tomography (SPECT/CT) imaging, we found that E4 promoter produced a notable increase in 125I uptake after 131I irradiation, the radionuclide uptake is almost three and six times more than Egr1 and cytomegalovirus (CMV) promoters. These studies confirmed the feasibility of using BMSCs as carriers for lentivirus-mediated E4-NIS gene therapy for ovarian cancer. Further research on BMSC-E4-NIS gene therapy for ovarian cancer in vivo will also be carried on, and if successful, this might provide a new adjuvant therapeutical option for platinum-resistant ovarian cancer patients and provide a new method for dynamic evaluation of curative effect.

Feasibility of Imaging EpCAM Expression in Ovarian Cancer Using Radiolabeled DARPin Ec1.

Epithelial cell adhesion molecule (EpCAM) is overexpressed in 55%-75% of ovarian carcinomas (OC). EpCAM might be used as a target for a treatment of disseminated OC. Designed ankyrin repeats protein (DARPin) Ec1 is a small (18 kDa) protein, which binds to EpCAM with subnanomolar affinity. We tested a hypothesis that Ec1 labeled with a non-residualizing label might serve as a companion imaging diagnostic for stratification of patients for EpCAM-targeting therapy. Ec1 was labeled with 125I using N-succinimidyl-para-iodobenzoate. Binding affinity, specificity, and cellular processing of [125I]I-PIB-Ec1 were evaluated using SKOV-3 and OVCAR-3 ovarian carcinoma cell lines. Biodistribution and tumor-targeting properties of [125I]I-PIB-Ec1 were studied in Balb/c nu/nu mice bearing SKOV-3 and OVCAR-3 xenografts. EpCAM-negative Ramos lymphoma xenografts served as specificity control. Binding of [125I]I-PIB-Ec1 to ovarian carcinoma cell lines was highly specific and had affinity in picomolar range. Slow internalization of [125I]I-PIB-Ec1 by OC cells confirmed utility of non-residualizing label for in vivo imaging. [125I]I-PIB-Ec1 provided 6 h after injection tumor-to-blood ratios of 30 ± 11 and 48 ± 12 for OVCAR-3 and SKOV-3 xenografts, respectively, and high contrast to other organs. Tumor targeting was highly specific. Saturation of tumor uptake at a high dose of Ec1 in SKOV-3 model provided a rationale for dose selection in further studies using therapeutic conjugates of Ec1 for targeted therapy. In conclusion, [125I]I-PIB-Ec1 is a promising agent for visualizing EpCAM expression in OC.

Feasibility, patient compliance and acceptability of ovarian cancer surveillance using two serum biomarkers and Risk of Ovarian Cancer Algorithm compared to standard ultrasound and CA 125 among women with BRCA mutations.

OBJECTIVE: We assessed the feasibility, patient acceptability of and compliance of a new surveillance strategy for ovarian cancer surveillance in women with BRCA mutations, based on assessments of serum CA125 and HE4 every 4 months (Risk of Ovarian Cancer Algorithm (ROCA) arm), compared to Standard of Care (SOC) surveillance with CA125 blood tests and pelvic ultrasounds every 6 months. METHODS: Women were recruited 6/13/16-9/11/17 from an integrated health care system in California for this non-randomized prospective cohort study. Women were invited to participate in a novel serum biomarker surveillance strategy using ROCA or they could opt to be in the standard of care control arm with ultrasound and CA 125 every 6 months. Outcomes assessed included compliance, self-reported distress using the Impact of Event Scale (IES) and cancer anxiety using the Cancer Worry Scale. RESULTS: There were 159 women in the ROCA arm and 43 in the SOC arm. Overall, compliance was higher in the ROCA arm (83.2%) than in SOC (51.9%), p < 0.0001. Based on the IES, ROCA arm women reported less feelings about intrusion and avoidance at 12 months compared to baseline; the difference approached significance for intrusion (7.6% vs 4.1% severe, p = 0.057) and was statistically significant for avoidance (20.8% vs 9.9% severe, p = 0.034). CONCLUSIONS: This pilot demonstrated that compliance was high with blood tests performed every four months for ovarian cancer surveillance. Moreover, ROCA women had lower stress scores over time than SOC women. Given the lack of clinical utility and poor compliance shown with traditional ultrasound and CA125 tests, further investigation is warranted of longitudinal biomarker surveillance for early detection of ovarian cancer.

Molecular imaging-monitored radiofrequency hyperthermia-enhanced intratumoral herpes simplex virus-thymidine kinase gene therapy for rat orthotopic ovarian cancer.

Objective: To establish the technique of intratumoral combination therapy of radiofrequency hyperthermia (RFH) with herpes simplex virus-thymidine kinase/ganciclovir (HSV-TK/GCV) gene therapy for rat ovarian cancers.Material and methods: This study consisted of three parts: (1) in vitro experiments to establish the 'proof of principal' that combination of RFH and HSV-TK gene therapy has the synergistic effect on human ovarian cancer cells; (2) creation of bioluminescence imaging-detectable rat ovarian cancer model; and (3) in vivo experiments using this rat model to validate the technical feasibility of the combination therapy. Cells and nude rats were divided into four groups: (i) combination therapy (HSV-TK/GCV + RFH); (ii) RFH; (iii) HSV-TK/GCV; and (iv) phosphate-buffered saline (PBS). Data were analyzed using Dunnett t-test or Kruskal-Wallis test.Results: Cell proliferation assay demonstrated significantly greater reduction in viable cells with the combination therapy [0.52 (0.43, 0.61)] compared to other treatments [RFH 0.90 (0.84, 0.96), HSV-TK/GCV 0.71 (0.53, 0.88), PBS 1 (1, 1); p < .05]. For 24 rat models with bioluminescence imaging-detectable orthotopic ovarian cancer (n = 6 per group), optical imaging demonstrated significantly decreased relative bioluminescence signal with the combination therapy [0.81 (0.52, 1.08)] compared to other treatments [RFH 3.60 (2.34, 4.86), HSV-TK/GCV 2.21 (1.71, 2.71), PBS 3.74 (3.19, 4.29); p < .001]. Ultrasound imaging demonstrated the smallest relative tumor volume with the combination therapy [0.78 (0.45, 1.11) versus 3.50 (2.67, 4.33), 2.10 (0.83, 3.37), 3.70 (1.79, 5.61); p < .05].Conclusion: The feasibility of intratumoral RFH-enhanced HSV-TK/GCV gene therapy was established on a unique rat model with molecular imaging-detectable orthotopic ovarian cancer.

Primary Preclinical and Clinical Evaluation of 68Ga-DOTA-TMVP1 as a Novel VEGFR-3 PET Imaging Radiotracer in Gynecological Cancer.

PURPOSE: Tumor periphery and lymph nodes of tumor-induced lymphangiogenesis often abundantly express VEGFR-3. In our previous study, we identified a 5-amino acid peptide named TMVP1, which binds specifically to VEGFR-3. The objective of this study was to develop a novel 68Ga-labeled TMVP1 for VEGFR-3 PET imaging and to investigate its safety, biodistribution, and tumor-localizing efficacy in xenograft tumor models and a small cohort of patients with recurrent ovarian and cervical cancer. EXPERIMENTAL DESIGN: The DOTA-conjugated TMVP1 peptide was labeled with radionuclide 68Ga. SPR and saturation binding assays were used for the receptor-binding studies. Gynecologic xenograft tumors were employed for small-animal PET imaging and biodistribution of 68Ga-DOTA-TMVP1 in vivo. In the clinical study, 5 healthy volunteers and 8 patients with gynecologic cancer underwent whole-body PET/CT after being injected with 68Ga-DOTA-TMVP1. RESULTS: DOTA-TMVP1 was successfully labeled with 68Ga. LECs showed higher binding capacity with 68Ga-DOTA-TMVP1 than LEC(shVEGFR-3) and human umbilical vein endothelial cells. In mice with subcutaneous C33-A and SKOV-3 xenografts, the tracer was rapidly eliminated through the kidney to the bladder, and the small-animal PET/CT helped to clearly visualize the tumors. In patients with recurrent ovarian cancer and cervical cancer, tracer accumulation well above the background level was demonstrated in most identified sites of disease; especially with recurrent endodermal sinus tumors, the diagnostic value of 68Ga-DOTA-TMVP1 was comparable with that of 18F-FDG PET/CT. CONCLUSIONS: 68Ga-DOTA-TMVP1 is a potential PET tracer for imaging VEGFR-3 with favorable pharmacokinetics.

R2* Relaxation Affects Pharmacokinetic Analysis of Dynamic Contrast-Enhanced MRI in Cancer and Underestimates Treatment Response at 7 T.

Effective transverse relaxivity of gadolinium-based contrast agents is often neglected in dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Here, we assess time and tissue dependence of R2* enhancement and its impact on pharmacokinetic parameter quantification and treatment monitoring. Multiecho DCE-MRI was performed at 7 T on mice bearing subcutaneous TOV-21G human ovarian cancer xenografts (n = 8) and on the transgenic adenocarcinoma of the mouse prostate (TRAMP) model (n = 7). Subsequently, the TOV-21G tumor-bearing mice were treated with bevacizumab and rescanned 2 days later. Pharmacokinetic analysis (extended Tofts model) was performed using either the first echo signal only (standard single-echo DCE-MRI) or the estimated signal at TE = 0 derived from exponential fitting of R2* relaxation (R2*-corrected). Neglecting R2* enhancement causes underestimation of Gd-DOTA concentration (peak enhancement underestimated by 9.4%-16% in TOV-21G tumors and 13%-20% in TRAMP prostates). Median Ktrans and ve were underestimated in every mouse (TOV-21G Ktrans: 11%-19%, TOV-21G ve: 5.3%-8.9%; TRAMP Ktrans: 8.6%-19%, TRAMP ve: 12%-21%). Bevacizumab treatment reduced Ktrans in all TOV-21G tumors after 48 hours. Treatment effect was significantly greater in all tumors after R2* correction (median change of -0.050 min-1 in R2*-corrected Ktrans vs. -0.037 min-1 in uncorrected Ktrans). R2* enhancement in DCE-MRI is both time- and tissue-dependent and may not be negligible at 7 T in tissue with high Ktrans. This has consequences for the use of Ktrans and other DCE-MRI parameters as biomarkers, because treatment effect size can be underestimated when R2* enhancement is neglected.

An injectable hybrid hydrogel based on a genetically engineered polypeptide for second near-infrared fluorescence/photoacoustic imaging-monitored sustained chemo-photothermal therapy.

An injectable multifunctional hydrogel based on an engineered coiled-coil polypeptide, Ag2S quantum dots (QDs), and paclitaxel (PTX) has been developed for sustained chemo-photothermal therapy. Oil-soluble Ag2S QDs and PTX were first loaded into nanogels formed with engineered polypeptide PC10A by ultrasonic treatment to prepare PC10A/Ag2S QD/PTX nanogels. The multifunctional PC10A/Ag2S QD/PTX hydrogels were prepared by dissolving the PC10A/Ag2S QD/PTX nanogels into the PC10A hydrogel. The PC10A/Ag2S QD/PTX hydrogel can be injected directly into the site of tumors. In vitro and in vivo toxicity results showed that the PC10A/Ag2S QD/PTX hydrogel presented excellent biocompatibility. Compared with single near-infrared photothermal therapy and chemotherapy, the combined therapy could effectively suppress the growth of SKOV3 ovarian carcinoma tumor. In addition, real-time monitoring of the in vivo degradation of the PC10A/Ag2S QD/PTX hydrogel was achieved by near-infrared fluorescence imaging and photoacoustic imaging. These results demonstrated that this injectable multifunctional PC10A/Ag2S QD/PTX hydrogel has the potential as a theranostic platform for sustained cancer treatments.

CuS-MnS2 nano-flowers for magnetic resonance imaging guided photothermal/photodynamic therapy of ovarian cancer through necroptosis.

With a high incidence and high mortality rate, ovarian cancer presents a challenge for clinical practice. It is thus extremely urgent to investigate new diagnosis and therapy methods for the treatment of ovarian cancer. Ternary copper-based chalcogenide nanomaterials are attractive owing to their near infrared (NIR) response for cancer theranostic fields. However, improving the theranostic efficiency of these nanomaterials is challenging. Herein, CuS-MnS2 nano-flowers were easily synthesized and under NIR irradiation exhibited a relatively high photothermal conversion efficiency of 67.5% and a simultaneous reactive oxygen species (ROS) generation effect. Owing to these outstanding photothermal/photodynamic effects, excellent tumor ablation results could be achieved by the combined use of CuS-MnS2 nano-flowers and 808 nm NIR laser treatments. The main anticancer mechanism of CuS-MnS2 nano-flowers + NIR was likely necroptosis. In addition, the nano-flowers showed remarkable contrast enhancement according to magnetic resonance imaging (MRI). These CuS-MnS2 nano-flowers could thus serve as a promising multifunctional nanotheranostic agent for MRI and as a photothermal/photodynamic cancer therapy agent through necroptosis.