HPV ctDNA as a Biomarker for Monitoring Disease Progression in HPV16/18-Associated Cervical Cancer

PurposeTo investigate the added value of gadoxetic acid-enhanced MRI in monitoring liver function and disease progression in patients with primary sclerosing cholangitis (PSC).MethodsWe retrospectively identified 104 consecutive patients (75 males; mean age 41.98 ± 12.5 years) with confirmed diagnosis of PSC who underwent 227 gadoxetic acid-enhanced MRI examinations between January 2008 and May 2019. Relative enhancement (RE) of the liver was correlated with the results of liver function tests (LFTs), scoring models (Model for End-Stage Liver Disease (MELD) score, Mayo Risk Score (MRS), Amsterdam-Oxford model (AOM)), and qualitative MRI findings. In addition, results were analyzed separately for excretory MRI examinations (n = 164) and nonexcretory examinations (n = 63) depending on excretion of gadoxetic acid into the common bile duct in the hepatobiliary phase (HBP).ResultsThere was a significant correlation of RE with MRS (r = − 0.652), MELD score (r = − 0.474), AOM (r = − 0.468), and LFTs (P < 0.001). RE and albumin were significantly higher in the excretory group whereas scoring models, bilirubin, aspartate aminotransferase, alkaline phosphatase, and international normalized ratio were lower (P < 0.001). RE was lower in segments with absent HBP gadoxetic acid excretion into dilated bile ducts, reduced HBP parenchymal enhancement, atrophy, T2 hyperintensity, and bile duct abnormalities (P < 0.001).ConclusionRelative enhancement of the liver in gadoxetic acid-enhanced MRI can be used to evaluate global and regional liver function and monitor disease progression in patients with PSC. Hepatobiliary phase gadoxetic acid biliary excretion appears to be a reproducible qualitative parameter for evaluating disease severity that can be easily integrated into routine clinical practice.

The ability to monitor response to therapy and disease progression in metastatic breast cancer (MBC) patients is a major step in patient management. Imaging is the method of choice for the assessment of disease status and the monitoring of disease progression. However, this approach remains expensive, expose patients to radiation and thus is mainly performed every 2-3 months. During this time interval, the disease may progress significantly on ineffective treatment and the patient may present treatment related toxicities due to the inability to detect progression at earlier times. Circulating levels of tumor associated biomarkers such as CA15-3 and CEA are often determined to track disease status of MBC. However, even though they can provide information about disease progression, they do not always provide a reliable measure of response to therapy. The monitoring of disease status and progression through the measurement of drivers of disease should provide an alternative and complementary approach to existing strategies in order to better to monitor the disease status and enable proactive management of MBC patients. Progranulin also called Glycoprotein 88kDa (PGRN/GP88) is an autocrine growth factor overexpressed in breast cancer. Biological studies have established GP88 as a critical player in breast tumorigenesis. GP88 overexpression is associated with the malignant phenotype, estrogen independence, increased proliferation, survival, and drug resistance. High PGRN/GP88 tumor expression measured by immunohistochemistry in invasive ductal carcinoma is an independent prognostic marker associated with increased risk of recurrence and mortality. Clinical studies have demonstrated that GP88 circulating levels as measured by enzyme immunoassay are elevated in breast cancer patients, compared to healthy individuals. In MBC patients, circulating GP88 levels correlate with overall survival. These facts are supportive of the hypothesis that the measurement of circulating GP88 levels in MBC patients can serve as an additional biomarker to monitor MBC disease status and be predictive to outcome. A prospective study was established is to identify whether there is a statistically significant change in serum GP88 levels associated with time to progression of breast cancer as measured by RECIST 1.1 criteria in MBC patients. With the assumptions that patients will provide a baseline and four follow up visits and that 20% of the visits record a disease progression, time to progression. Taking the plausible and clinically relevant performance to be 75% sensitivity and 46% false positive, a sample of ninety patients would give 85% power. Under IRB approved protocols at the University of Maryland Greenebaum Comprehensive Cancer Center and at two Baltimore Medstar Health Facilities, a total of 103 female breast cancer patients with measurable or evaluable metastatic disease will be consented and enrolled. The patients have been re-staged within 4 weeks and will continue or begin new therapy. Currently, we have enrolled sixty-five subjects at the three facilities. In addition to standard laboratory assessment and radiographic imaging/staging every 2-3 months on study, blood samples will be collected from each patient. The samples are stored at -70C until evaluated for GP88 using a GP88 enzyme linked immunoassay. We will analyze the GP88 serum level in correlation with survival and with disease status determined as responder, stable or progressing based on the RECIST criteria. This study is supported by grant R44CA210817 from the National Cancer Institute to Ginette Serrero Principal Investigator. Citation Format: Ginette Serrero, Paula Rosenblatt, Nancy Tait, Barbara Rector, Jennifer A. Latteri, Binbin Yue, Katherine Tkaczuk. On-going prospective study to measure serum progranulin/GP88 levels in metastatic breast cancer patients in association with disease status [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-16-01.

Introduction Forced vital capacity (FVC) decline is predictive of mortality in patients with idiopathic pulmonary fibrosis (IPF) and has been used as a clinical trial endpoint to define disease progression. How to interpret FVC findings in an individual patient with IPF in the real-world setting amid uncertainty about the measurement accuracy and variability has not been well established. Areas covered This review highlights the challenges and limitations of using FVC in the clinic to monitor disease progression in patients with IPF. Spirometry is noninvasive, relatively simple, and inexpensive. FVC measurements provide evidence for trends over time in patients with IPF. When using FVC in the clinic, several important challenges and limitations, including visit-to-visit variability, dependence on patient effort, inconsistent quality control, limitations on accuracy, and the influence of comorbidities and pretest factors, must be considered. Recent studies suggest the potential for home spirometry devices to facilitate more frequent collection of data and perhaps demonstrate more accurate trends. Expert opinion Measuring FVC decline in the clinic has an important role in monitoring disease progression in patients with IPF, but additional measures of disease progression should be considered along with FVC to facilitate decision-making about disease management.

PURPOSE: Monitoring circulating human papillomavirus (HPV) cell-free DNA (cfDNA) is a minimally invasive approach for surveillance in HPV-associated cancers, particularly cervical cancer. The aim of this study was to monitor circulating HPV cfDNA levels in patients with recurrent or metastatic cervical cancer during treatment and follow-up, assessing the utility of HPV cfDNA as a tumor marker for disease surveillance and for guiding clinical treatment decisions. EXPERIMENTAL DESIGN: In this prospective pilot observational study, levels of HPV cfDNA in serum samples from 28 patients with recurrent or metastatic HPV-positive cervical cancer were measured via digital droplet polymerase chain reaction. Results for HPV cfDNA levels were matched to clinical outcomes and to serum levels of squamous cell carcinoma antigen (SCC-Ag) to assess the clinical potential of HPV cfDNA as a tumor marker. RESULTS: HPV cfDNA was detected in all 28 patients (100% detection rate). Notably, median baseline HPV cfDNA levels varied according to the metastatic pattern observed in individual patients (_P_=0.019). Patients with a combined multi-metastatic pattern (lymph node + hematogenous ± diffuse serosal metastasis) exhibited a higher median baseline HPV cfDNA level compared to those with a single-metastasis pattern (local recurrence, lymph node metastasis, or hematogenous metastasis) (_P _= 0.003). All participants exhibited changes in HPV cfDNA levels over a median monitoring period of 2 months (range, 0.3 to 16.9 months) prior to evaluations for treatment response or disease progression. Among 26 patients initially diagnosed with squamous cell cervical cancer, the positivity rate was 100% for HPV cfDNA and 69.2% for SCC-Ag (_P _= 0.004; 95% confidence interval, 0–0.391). Among 20 patients longitudinally monitored for squamous cell cervical cancer, the concordance with changes in disease status was 90% for HPV cfDNA and 50% for SCC-Ag (_P _= 0.014; 95% confidence interval, 0.022–0.621). CONCLUSIONS: HPV cfDNA is a promising tumor marker for HPV-positive cervical cancer. In the context of precision medicine, HPV cfDNA is poised to play an increasingly pivotal role in monitoring treatment efficacy, providing valuable insights into disease progression, and guiding clinical decisions.

&lt;div&gt;AbstractPurpose:&lt;p&gt;Monitoring disease progression in patients with high-grade gliomas (HGG) is challenging due to treatment-related changes in imaging and the requirement for neurosurgical intervention to obtain diagnostic tissue. DNA junctions in HGG often amplify oncogenes, making these DNA fragments potentially more abundant in blood than monoallelic mutations. In this study, we piloted a cell-free DNA approach for disease detection in the plasma of patients with HGG by leveraging patient-specific DNA junctions associated with oncogene amplifications.&lt;/p&gt;Experimental Design:&lt;p&gt;Whole-genome sequencing of grade 3 or 4 isocitrate dehydrogenase–mutant or wild-type astrocytomas was utilized to identify amplified junctions. Individualized qPCR assays were developed using patient-specific primers designed for the amplified junction. ctDNA levels containing these junctions were measured in patient plasma samples.&lt;/p&gt;Results:&lt;p&gt;Unique amplified junctions were evaluated by individualized semi-qPCR assays in presurgical plasma of 18 patients, 15 with tumor-associated focal amplifications and three without tumor-associated focal amplifications. high copy-number junctions were robustly detected in the plasma of 14 of 15 (93.3%) patients with amplified junctions and none of the controls. Changes in junction abundance correlated with disease trajectory in serial plasma samples from five patients, including increased abundance of amplified junctions preceding radiographic disease progression.&lt;/p&gt;Conclusions:&lt;p&gt;In patients with grade 3 or 4 astrocytomas who had tumor-associated amplifications, patient-specific amplified junctions were successfully detected in assayed plasma from most patients. Longitudinal analysis of plasma samples correlated with disease trajectory, including cytoreduction and progression.&lt;/p&gt;&lt;/div&gt;

Aims. To examine whether fibrinogen levels are a valuable biomarker for assessing disease severity and monitoring disease progression in patients with diabetic foot ulcer (DFU). Methods. A retrospective study was designed to examine the utility of fibrinogen in estimating disease severity in patients with DFU admitted to our hospital between January 2015 and January 2016. In total, 152 patients with DFU were enrolled in the study group, and 52 age and gender matched people with diabetes but no DFU were included as the control group. DFU severity was assessed using Wagner criteria. Results. Patients with DFU were divided into 2 subgroups based on the Wagner criteria. Mean fibrinogen values were significantly higher in patients with DFU grade ≧ 3 compared to those with DFU grades 1-2 (5.23 ± 1.37 g/L versus 3.61 ± 1.04 g/L). Using ROC statistic, a cut-off value of 5.13 g/L indicated the possible amputation with a sensitivity of 81.8% and a specificity of 78.9% (positive predictive value [PPV] 78.6%, negative predictive value [89.0%]). Fibrinogen values were found to be correlated with CRP levels, neutrophil, and WBC count. Conclusions. Fibrinogen levels might be a valuable tool for assessing the disease severity and monitoring the disease progression in patients with DFU.

Battle against Alzheimer's Disease: The Scope and Potential Value of Magnetic Resonance Imaging Biomarkers

Background:Monitoring circulating HPV cell-free DNA (cfDNA) offers a minimally invasive method for surveillance in HPV-associated cancers, particularly cervical cancer. However, the role of dynamic HPV cfDNA monitoring in guiding clinical treatment decisions for recurrent or metastatic cervical cancer remains underexplored.Methods:In this prospective pilot observational study, levels of HPV cfDNA in serum samples from 28 patients with recurrent or metastatic HPV-positive cervical cancer were measured via digital droplet polymerase chain reaction. Results for HPV cfDNA levels were matched to clinical outcomes and to serum levels of squamous cell carcinoma antigen (SCC-Ag) to assess the clinical potential of HPV cfDNA as a tumor marker.Results:HPV cfDNA was detected in all 28 patients. Notably, median baseline HPV cfDNA levels varied according to the metastatic pattern observed in individual patients (p=0.019). All participants exhibited changes in HPV cfDNA levels over a median monitoring period of 2 months (range 0.3–16.9 months) prior to evaluations for treatment response or disease progression. Among 26 patients initially diagnosed with squamous cell cervical cancer, the positivity rate was 100% for HPV cfDNA and 69.2% for SCC-Ag (p=0.004, 95% confidence interval (CI), 0–0.391). Among 20 patients longitudinally monitored for squamous cell cervical cancer, the concordance with changes in disease status was 90% for HPV cfDNA and 50% for SCC-Ag (p=0.014, 95% CI, 0.022–0.621).Conclusions:Our study demonstrates that HPV cfDNA is a promising tumor marker for monitoring of recurrent or metastatic HPV-positive cervical cancer.Funding:This work was supported by the Key R&D Program of Zhejiang (2022C04001), the Zhejiang Province Medicine and Health Science and Technology Program (2020KY454), the Zhejiang Science and Technology Department Public Welfare Project (LGF22H160075).

e17009 Background: The aim of this study was to evaluate the efficacy and safety of apatinib, an oral VEGFR2 inhibitor, in the treatment of advanced cervical and ovarian cancer patients who failed from two or more lines of chemotherapy. Methods: The advanced cervical and ovarian cancer patients, who experienced two or more lines of chemotherapy and treated with apatinib from April 2015 to January 2017, were retrospectively reviewed. All eligible patients received continuous apatinib treatment until disease progression, death, or intolerable toxicity. Survival and toxicities outcome were evaluated by Kaplan-Meier method and according to NCI-CTC4.0. Results: Twenty-six patients were eligible (cervical cancer:12 and ovarian cancer:14). After dose adjustment, 14 patients (53.8%) received 500 mg daily of apatinib, 8 patients received 250mg, 3 received 425mg and 1 received 675mg daily. The median progression-free survival (PFS) of cervical cancer and ovarian cancer were 8 months (95%CI:3.83-12.17) and 4 months (95%CI:1.57-6.44), respectively. Objective response rates in cervical cancer and ovarian cancer were 50% and 50%, respectively. Disease control rates were 100% for cervical cancer and 71.4% for ovarian cancer. Complete response was not observed in either cervical cancer or ovarian cancer. A 52-year old patient with recurrent ovarian cancer, experienced two lines of chemotherapy failure, was orally administered with apatinib at a dose of 250mg daily from November 2015, got partial response (PR) after one month, PFS have not yet reach. A 43-year old female patient with advanced cervical cancer, experienced three lines of chemotherapy failure, was orally administered with apatinib at a dose of 250mg daily from September 2015, got PR with a PFS of 14 months. The toxicities associated with apatinib treatment was generally acceptable with 8 patients developed grade 3/4 toxicity. The most common adverse events in this study were hypertension(n = 17), hand-foot syndrome(n = 24), and mouth mucositis(n = 20). Conclusions: Apatinib monotherapy showed promising efficiency with tolerable toxicity for advanced/recurrent cervical and ovarian cancer patients who failed from two or more lines of chemotherapy.

Tumor cells release fragments of their DNA into the bloodstream, called cell-free tumor DNA (ctDNA) or liquid biopsy. In this study, we investigate whether human papillomavirus cell-free tumor DNA (ctHPV DNA) can be detected in patients with cervical cancer or premalignant lesions before and after treatment. We are also investigating whether ctHPV DNA levels correlate with patient or tumor characteristics and outcomes. A total of 67 cases were included, including 42 with locally advanced cervical cancer (LACC) and 11 with early-stage cervical cancer (ESCC), as well as 14 with premalignant lesions. Pre- and post-treatment plasma samples were tested for ctHPV DNA levels using digital droplet PCR. The pretreatment ctHPV DNA was detected in 21.42%(n=09/42) cases with LACC and post treatment ctHPV DNA was detected in 16.66% (07/42) LACC cases. While circulating ctHPV DNA was not detected in ESCC and premalignant lesion cases. Higher levels of ctHPV DNA were correlated to the higher FIGO2018 stage. ctHPV DNA is a promising biomarker in locally advanced cervical cancer and should be further investigated for clinical use. In ESCC patients, the detection rate of ctHPV DNA is not sufficient for clinical benefit even using ddPCR, the most sensitive technologies available.

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis, characterized by heterogeneous clinical manifestations and variable disease progression. Ultrasonography has emerged as a valuable tool in the diagnosis and monitoring of PsA, providing real-time visualization of joint and soft tissue abnormalities. This review highlights recent advancements in ultrasonographic techniques for the assessment of PsA, including the identification of typical features, the role of power Doppler imaging in detecting active inflammation, and the potential of ultrasound for guiding treatment decisions. Additionally, we discuss the utility of ultrasound in assessing treatment response and monitoring disease progression in patients with PsA, with a focus on novel imaging modalities. By elucidating the evolving role of ultrasonography in PsA management, this article aims to enhance clinicians' understanding of its utility in facilitating early diagnosis, optimizing treatment strategies, and improving patient outcomes.

Peak width of skeletonized mean diffusivity (PSMD) is a robust and fully automated imaging marker employed to detect microstructural damage in white matter. This study aimed to evaluate whether PSMD reflects the severity of white matter damage and tracks disease progression in patients with spinocerebellar ataxia type 2 (SCA2). Nine patients with SCA2 and sixteen age- and gender-matched healthy controls were enrolled. Clinical and imaging data were collected at baseline and after 3.5years. Each participant underwent MRI scans twice to obtain diffusion tensor imaging data, from which PSMD were automatically calculated. Differences in PSMD between SCA2 patients and healthy controls were analyzed using a linear mixed model. Additionally, Spearman's rank correlations were employed to assess associations between PSMD values and clinical variables. Patients with SCA2 exhibited higher PSMD values at baseline and follow-up compared to HCs, indicating more severe white matter damage. Longitudinal data revealed a continual increase in PSMD values in SCA2 patients over time. The mixed-effects model confirmed significant differences in PSMD values between the two groups, as well as an interaction effect suggesting different progression rates. These findings suggest that SCA2 associates with progressive deterioration of white matter. No significant correlations were observed between PSMD values and clinical variables in this study. This study underscores the potential of PSMD as a neuroimaging biomarker for detecting microstructural white matter damage and monitoring disease progression in patients with SCA2.

ObjectivesPulmonary hypertension (PH) in patients with right ventricular systolic dysfunction (RVSD) is associated with a poor prognosis. This study assessed the characteristics of right atrial (RA) function using cardiac magnetic resonance feature tracking (CMR-FT) before RVSD onset and evaluated the long-term prognostic significance of these characteristics.Materials and methodsA total of 96 PH patients, including 36 without RVSD (PH-nonRVSD) and 60 with RVSD (PH-RVSD), were compared to 20 healthy controls (HCs). The RA reservoir, conduit, booster pump functions, and the right ventricular global longitudinal strain (RVGLS) were evaluated. Ventricular morphological and functional parameters of the RA and right ventricle (RV) were also acquired.ResultsCompared with HCs, both RA reservoir and conduit functions were significantly reduced (ps < 0.05) in the PH-nonRVSD, without significant morphological changes in either the RA or RV (ps > 0.05). The RA reservoir and conduit function were significantly correlated with the right ventricular ejection fraction (RVEF), RVGLS, pulmonary vascular resistance, brain natriuretic peptide, cardiac index, and 6-min walk distance. Receiver operating characteristic analysis demonstrated that RA conduit function outperformed RVGLS and RVEF in differentiating PH-nonRVSD and HCs. However, a reduction in RA booster pump function was observed only in the PH-RVSD group (p < 0.001). During a median follow-up period of 97 (80–106) months, 45% of the included patients died. RA reservoir function was an independent predictor of all-cause mortality (HR = 0.963, 95% CI: 0.935–0.992, p = 0.014).ConclusionsRA function can detect right heart dysfunction prior to RVSD and monitor disease progression in patients with PH. Moreover, RA reservoir function independently predicts long-term prognosis.Critical relevance statementImpairment of right atrial (RA) function, assessed by cardiac magnetic resonance feature tracking (CMR-FT), in pulmonary hypertension (PH) patients is sensitive in detecting right-sided heart dysfunction before right ventricular systolic dysfunction and can be utilized to monitor disease progression and long-term prognosis.Key PointsRA function is sensitive in detecting early right heart dysfunction in PH patients.The disease progression of PH can be monitored by assessing RA function.RA function can serve as a tool for predicting long-term prognosis.Graphical

ObjectivesTo assess renal perfusion and ectopic fat deposition in patients with type 2 diabetes mellitus (T2DM), and to evaluate the effects of ectopic fat deposition on renal hemodynamics.MethodsAll participants underwent quantitative magnetic resonance imaging (MRI) to measure the cortical and medullary renal blood flow (RBF) and proton density fat fraction (PDFF). Patients with T2DM were classified into three groups according to the estimated glomerular filtration rate (mL/min/1.73 m2). One-way analysis of variance was used to assess differences among groups. Pearson’s correlation coefficient was used to analyze correlations. Additionally, a receiver operating characteristic (ROC) curve was constructed to assess diagnostic performance.ResultsRenal PDFF values of the renal cortex and medulla, as well as perirenal fat thickness, were significantly different among the four groups: healthy control < T2DM < diabetic kidney disease (DKD) I–II < DKD III–IV. Additionally, significant differences in cortical and medullary RBF values were observed among the four groups: healthy control > T2DM > DKD I–II > DKD III–IV. A significant negative correlation was observed between renal PDFF and RBF values. Medullary RBF values demonstrated the best performance in discriminating T2DM from DKD with the largest area under the ROC curve (AUC) of 0.971. The cortical PDFF achieved the largest AUC (0.961) for distinguishing DKD I-II from DKD III–IV.ConclusionsQuantitative MRI effectively evaluates renal perfusion and ectopic fat deposition in T2DM patients, aiding in assessing kidney function and disease progression. Additionally, renal ectopic fat deposition may be an important risk factor for renal hemodynamic injury.Critical relevance statementQuantitative MRI could serve as a radiation-free imaging modality for assessing renal perfusion and ectopic fat deposition, which may be an important risk factor for DKD progression.Key PointsQuantitative MRI can be used to assess kidney function and monitor disease progression in patients with T2DM.In patients with T2DM, decreased renal perfusion, increased renal ectopic fat deposition, and kidney damage were significantly correlated.Renal ectopic fat deposition may be an important risk factor for renal hemodynamic injury.Graphical

As the world’s third most common cancer and second leading cause of oncology-related deaths, colorectal cancer (CRC) poses a variety of clinical challenges. CRC is marked by its extensive solid tumor heterogeneity and the difficulties in longitudinally monitoring a patient’s disease status. Being a minimally invasive prognostic tool, the liquid biopsy has immense potential to improve current clinical practice by providing real-time personalized information over the course of treatment. Utilizing the High-Definition Single Cell Assay (HDSCA) workflow, we employed a “no cell left behind approach” to analyze peripheral blood samples from metastatic CRC (mCRC) patients at various timepoints during treatment. We highlight the circulating rare cell population present in the liquid biopsy of mCRC patients, showing the spatial and temporal heterogeneities of CTCs. We observed a significant association between CTC subcategorization based on morphological differences and survival, emphasizing the heterogeneity within the CTC classification. Moreover, considering the time of sample collection in relation to the clinical scenario is critical in determining the prognostic relevance of static cellular enumerations as well as the change in cell populations over time. Through the integration of cellular morphology in a time-based analysis, the liquid biopsy can provide insight into the pathophysiology of mCRC by highlighting the complexity of the disease to monitor treatment response. Citation Format: Sachin Narayan. Circulating tumor cell kinetics and rare cell morphology monitor disease progression in patients with metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1954.