Cellular Mass Response to Therapy Correlates With Clinical Response for a Range of Malignancies.

PURPOSE: Cancer patients with advanced-stage disease have poor prognosis, typically having limited options for efficacious treatment, and genomics-based therapy guidance continues to benefit only a fraction of patients. Next-generation ex vivo approaches, such as cell mass-based response testing (MRT), offer an alternative precision medicine approach for a broader population of patients with cancer, but validation of clinical feasibility and potential impact remain necessary. MATERIALS AND METHODS: We evaluated the clinical feasibility and accuracy of using live-cell MRT to predict patient drug sensitivity. Using a unified measurement workflow with a 48-hour result turnaround time, samples were subjected to MRT after treatment with a panel of drugs in vitro. After completion of therapeutic course, clinical response data were correlated with MRT-based predictions of outcome. Specimens were collected from 104 patients with solid (n = 69) and hematologic (n = 35) malignancies, using tissue formats including needle biopsies, malignant fluids, bone marrow aspirates, and blood samples. Of the 81 (78%) specimens qualified for MRT, 41 (51%) patients receiving physician-selected therapies had treatments matched to MRT. RESULTS: MRT demonstrated high concordance with clinical responses with an odds ratio (OR) of 14.80 (P = .0003 [95% CI, 2.83 to 102.9]). This performance held for both solid and hematologic malignances with ORs of 20.67 (P = .0128 [95% CI, 1.45 to 1,375.57]) and 8.20 (P = .045 [95% CI, 0.77 to 133.56]), respectively. Overall, these results had a predictive accuracy of 80% (P = .0026 [95% CI, 65 to 91]). CONCLUSION: MRT showed highly significant correlation with clinical response to therapy. Routine clinical use is technically feasible and broadly applicable to a wide range of samples and malignancy types, supporting the need for future validation studies.

Endovascular image-guided sampling of tumor-draining veins provides an enriched source of oncological biomarkers.

Introduction: Circulating tumor-derived biomarkers can potentially impact cancer management throughout the continuum of care. This small exploratory study aimed to assess the relative levels of such biomarkers in the tumor-draining vascular beds in patients with solid tumors compared to levels in their peripheral veins. Methods: Using an endovascular image-guided approach, we obtained blood samples from peripheral veins and other vascular compartments-including the most proximal venous drainage from solid tumors-from a set of nine oncology patients with various primary and metastatic malignancies. We then interrogated these samples for a panel of oncological biomarkers, including circulating tumor cells (CTCs), exosome-derived microRNAs (miRNAs), circulating tumor DNA (ctDNA) mutations, and certain cancer-related proteins/biochemical markers. Results: We found substantially higher levels of CTCs, certain miRNAs, and specific ctDNA mutations in samples from vascular beds closer to the tumor compared with those from peripheral veins and also noted that some of these signals were altered by treatment procedures. Discussion: Our results indicate that tumor-proximal venous samples are highly enriched for some oncological biomarkers and may allow for more robust molecular analysis than peripheral vein samples.

A pipeline for malignancy and therapy agnostic assessment of cancer drug response using cell mass measurements.

Functional precision medicine offers a promising complement to genomics-based cancer therapy guidance by testing drug efficacy directly on a patient's tumor cells. Here, we describe a workflow that utilizes single-cell mass measurements with inline brightfield imaging and machine-learning based image classification to broaden the clinical utility of such functional testing for cancer. Using these image-curated mass measurements, we characterize mass response signals for 60 different drugs with various mechanisms of action across twelve different cell types, demonstrating an improved ability to detect response for several slow acting drugs as compared with standard cell viability assays. Furthermore, we use this workflow to assess drug responses for various primary tumor specimen formats including blood, bone marrow, fine needle aspirates (FNA), and malignant fluids, all with reports generated within two days and with results consistent with patient clinical responses. The combination of high-resolution measurement, broad drug and malignancy applicability, and rapid return of results offered by this workflow suggests that it is well-suited to performing clinically relevant functional assessment of cancer drug response.

Clinical value of CT-guided biopsy of small (≤1.5 cm) suspicious lung nodules: Diagnostic accuracy, molecular characterization and long-term clinical outcomes.

Small pulmonary nodules (≤1.5 cm) are frequently detected on routine chest imaging and lung cancer screening studies. Our goal was to determine the clinical value of CT-guided core needle biopsy (CNB) in the evaluation of such nodules. In this single-center study, we retrospectively analyzed patient data (n = 44) for CNBs on lung nodules (≤1.5 cm) performed at our biopsy center between May 2017 and March 2020. We analyzed for the rate of pathology diagnosis, molecular/biomarker analysis, complications, and change in clinical management and outcome over a period ranging up to 60 months after biopsy. A pathology diagnosis of malignancy or benign lesion was obtained in 97.9% of biopsies in this cohort. The rate of complications was low with only 6.8% of patients requiring the insertion of a temporary small profile interventional radiology (IR) pigtail chest tube for pneumothorax. Out of the subset of biopsy specimens that were sent for tissue molecular analysis, 90% had enough tissue preserved after initial pathological analysis to obtain at least one molecular marker. Our data show that CT-guided CNB is safe and reliable, and should be considered for the evaluation of small, suspicious lung nodules found on routine screenings for the early detection and evaluation of malignant lesions.

Decreasing Utilization of Inferior Vena Cava Filters in Post-FDA Warning Era: Insights From 2005 to 2014 Nationwide Inpatient Sample.

BACKGROUND: To determine the impact, if any, of the 2010 FDA safety communication on the rate of inferior vena cava filter (IVCF) placement over time. METHODS: The Nationwide Inpatient Sample was interrogated for the most recent years preceding and after the FDA safety communication-from 2005 to 2014. IVCF placements and associated diagnoses were identified using corresponding International Classification of Diseases, version nine codes. Trends in number of IVCF placement were evaluated in aggregate and by associated diagnoses, both of which were further stratified by hospital geographic cluster, hospital teaching status, and patient demographics. Generalized linear regression models were used to determine statistical significance of trends over time. RESULTS: IVCF placements steadily increased between 2005 and 2010 (100,434 in 2005 versus 129,614 in 2010, growth rate 5.81%). Aggregate IVCF placements subsequently declined between 2010 and 2014 (96,005 in 2014, decline rate -6.48%). IVCF placements peaked in 2010, the year of the FDA advisory. The proportion of filter placements for therapeutic indication of venous thromboembolism increased significantly during the study period (69.8% in 2005 versus 80.4% in 2014, P < .001). Neither trend varied significantly by patient demographics or hospital characteristics. CONCLUSIONS: IVCF placements have declined significantly since 2010, when the FDA advisory was released. The proportion of IVCFs placed in patients with venous thromboembolism, as opposed to prophylactic indications, is increasing.

Advanced-stage hepatocellular carcinoma with portal vein thrombosis: conventional versus drug-eluting beads transcatheter arterial chemoembolization.

OBJECTIVES: Our study sought to compare the overall survival in patients with hepatocellular carcinoma (HCC) and portal venous thrombosis (PVT), treated with either conventional trans-arterial chemoembolization (cTACE) or drug-eluting beads (DEB) TACE. METHODS: This retrospective analysis included a total of 133 patients, treated without cross-over and compared head-to-head by means or propensity score weighting. Mortality was compared using survival analysis upon propensity score weighting. Adverse events and liver toxicity grade ≥3 were recorded and reported for each TACE. In order to compare with historical sorafenib studies, a sub-group analysis was performed and included patients who fulfilled the SHARP inclusion criteria. RESULTS: The median overall survival (MOS) of the entire cohort was 4.53 months (95 % CI, 3.63-6.03). MOS was similar across treatment arms, no significant difference between cTACE (N = 95) and DEB-TACE (N = 38) was observed (MOS of 5.0 vs. 3.33 months, respectively; p = 0.157). The most common adverse events after cTACE and DEB- TACE, respectively, were as follows: post-embolization syndrome [N = 57 (30.0 %) and N = 38 (61.3 %)], diarrhea [N = 3 (1.6 %) and N = 3 (4.8 %)], and encephalopathy [N = 11 (5.8 %) and N = 2 (3.2 %)]. CONCLUSION: Our retrospective study could not reveal a difference in toxicity and efficiency between cTACE and DEB-TACE for treatment of advanced stage HCC with PVT. KEY POINTS: • Conventional TACE (cTACE) and drug-eluting-beads TACE (DEB-TACE) demonstrated equal safety profiles. • Survival rates after TACE are similar to patients treated with sorafenib. • Child-Pugh class and tumor burden are reliable predictors of survival.

Acute Epidural Hematoma Formation in Cervical Spine After Interlaminar Epidural Steroid Injection Despite Discontinuation of Clopidogrel.

BACKGROUND: Perioperative management of patients on anticoagulant therapy prior to interventional pain procedures creates a challenge when balancing the risk of bleeding against thromboembolic events. CASE REPORT: We report a case of epidural hematoma formation in the cervical spine following interlaminar epidural steroid injection in an elderly woman with chronic neck and arm pain, who was on clopidogrel therapy. CONCLUSIONS: This is the first reported case of hematoma formation immediately following an epidural steroid injection possibly associated with clopidogrel, even though established guidelines on the timing of the discontinuation of clopidogrel prior to the procedure were exceeded. Severe pain appears to be the first symptom of hematoma formation, and therefore immediate diagnostic workup and evacuation of hematoma are essential in preventing neurological damage. It may be advisable to carry out a test specific for clopidogrel such as the P2Y12 to ensure that there is no residual action on platelet aggregation function, particularly in patients who may be slow metabolizers of clopidogrel. Caution is advised prior to administering analgesics with antiplatelet effects such as ketorolac.

Percutaneous Retrieval of Permanent Inferior Vena Cava Filters.

PURPOSE: To evaluate the feasibility, risks, and techniques of percutaneous removal of permanent TrapEase and Simon Nitinol IVC filters. MATERIALS AND METHODS: Between August 2011 and August 2015, 12 patients (5 women, 7 men; age range, 26-75 years) underwent an attempt at percutaneous removal of permanent TrapEase (10) and Simon Nitinol (2) IVC filters due to a history of IVC filter complications or need for lifelong anticoagulation due to the filter. Medical records were reviewed for filter dwell time, presence of iliocaval deep venous thrombosis, procedural technique, and complications. RESULTS: Filter dwell times ranged from 7 days to 15 years (mean 5.1 years). Successful removal of permanent IVC filters was possible in 11 of 12 patients (91.6%). In 1 patient, a chronically thrombosed IVC filter could not be removed despite laser sheath assistance, but was successfully recanalized with the PowerWire RF guidewire. In the failed retrieval attempt, a stent was placed through the chronically thrombosed IVC filter with restoration of in-line flow. One major complication of large venous groin hematoma was encountered. CONCLUSIONS: In carefully selected patients, percutaneous removal of permanent IVC filters can be performed safely despite prolonged filter dwell times. Extraction of chronically embedded permanent IVC filters may be facilitated by jugular and femoral approaches, often with laser sheath assistance. Chronic filter thrombosis and caval scarring may increase the risk of retrieval failure.

Management of High Hepatopulmonary Shunting in Patients Undergoing Hepatic Radioembolization.

PURPOSE: To review the safety of hepatic radioembolization (RE) in patients with high (≥ 10%) hepatopulmonary shunt fraction (HPSF) using various prophylactic techniques. MATERIALS AND METHODS: A review was conducted of 409 patients who underwent technetium 99m-labeled macroaggregated albumin scintigraphy before planned RE. Estimated pulmonary absorbed radiation doses based on scintigraphy and hepatic administered activity were calculated. Outcomes from dose reductions and adjunctive catheter-based prophylactic techniques used to reduce lung exposure were assessed. RESULTS: There were 80 patients with HPSF ≥ 10% who received RE treatment (41 resin microspheres for metastases, 39 glass microspheres for hepatocellular carcinoma). Resin microspheres were used in 17 patients according to consensus guideline-recommended dose reduction; 38 patients received no dose reduction because the expected lung dose was < 30 Gy. Prophylactic techniques were used in 25 patients (with expected lung dose ≤ 74 Gy), including hepatic vein balloon occlusion, variceal embolization, or bland arterial embolization before, during, or after RE delivery. Repeated scintigraphy after prophylactic techniques to reduce HPSF in seven patients demonstrated a median change of -40% (range, +32 to -69%). Delayed pneumonitis developed in two patients, possibly related to radiation recall after chemoembolization. Response was lower in patients treated with resin spheres with dose reduction, with an objective response rate of 13% and disease control rate of 47% compared with 56% and 94%, respectively, without dose reduction (P = .023, P = .006). CONCLUSIONS: Dose reduction recommendations for HPSF may compromise efficacy. Excessive shunting can be reduced by prophylactic catheter-based techniques, which may improve the safety of performing RE in patients with high HPSF.

Percutaneous BioOrganic Sealing of Duodenal Fistulas: Case Report and Review of Biological Sealants with Potential Use in Interventional Radiology.

Biological sealants are being increasingly used in a variety of surgical specialties for their hemostatic and sealing capabilities. However, their use in interventional radiology has not been widely reported. The authors describe a case of duodenal perforation occurring after 15 years of gastric bypass surgery, in whom surgical diversion was unsuccessfully attempted and the leakage was successfully controlled using percutaneous administration of a combination of biological and organic sealants.

In vitro and in vivo molecular imaging of estrogen receptor α and ß homo- and heterodimerization: exploration of new modes of receptor regulation.

Estrogen receptor (ER) biology reflects the actions of estrogens through the two receptors, ERα and ERß, although little is known regarding the preference for formation of ER homo- vs. heterodimers, and how this is affected by the level of ligand occupancy and preferential ligand affinity for one of the ER subtypes. In this report, we use a split optical reporter-protein complementation system to demonstrate the physical interaction between ERα and ERß in response to different ER ligands in cells and, for the first time, by in vivo imaging in living animals. The genetically encoded reporter vectors constructed with the ligand-binding domains of ERα and ERß, fused to split firefly or Renilla luciferase (Fluc or hRluc) fragments, were used for this study. This molecular proteomic technique was used to detect ERα/ERα or ERß/ERß homodimerization, or ERα/ERß heterodimerization induced by ER subtype-selective and nonselective ligands, and selective ER modulators (SERM), as well as in dimers in which one mutant monomer was unable to bind estradiol. The SERM-bound ERα and ERß form the strongest dimers, and subtype-preferential homodimerization was seen with ERα-selective ligands (methyl piperidino pyrazole/propyl pyrazole triol) and the ERß-selective ligands (diarylpropionitrile/tetrahydrochrysene/genistein). We also demonstrated that a single ligand-bound monomer can form homo- or heterodimers with an apo-monomer. Xenografts of human embryonic kidney 293T cells imaged in living mice by bioluminescence showed real-time ligand induction of ERα/ERß heterodimerization and reversal of dimerization upon ligand withdrawal. The results from this study demonstrate the value of the split luciferase-based complementation system for studying ER-subtype interactions in cells and for evaluating them in living animals by noninvasive imaging. They also probe what combinations of ERα and ERß dimers might be the mediators of the effects of different types of ER ligands given at different doses.

Functional hepatobiliary MR imaging in children.

BACKGROUND: Clinical application efforts for the hepatocyte-specific MRI contrast agent gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) have mainly been directed toward detection and characterization of various hepatic masses in the adult population. OBJECTIVE: Here we report our initial experience with Gd-EOB-DTPA for evaluating congenital and acquired hepatobiliary pathologies in the pediatric population. MATERIALS AND METHODS: Twenty-one consecutive children receiving Gd-EOB-DTPA for functional hepatobiliary evaluation at our institution were retrospectively identified with IRB approval. The use of Gd-EOB-DTPA was classified in each case as definite, potential, or no clinical utility, focusing on the clinical value gained beyond traditional noncontrast fluid-sensitive MR cholangiopancreatography (FS-MRCP) and other imaging modalities. RESULTS: Definite added value of Gd-EOB-DTPA was found in 12 patients, with potential value in 4 patients, and no value in 5 patients. Benefit was seen in cases of iatrogenic and non-iatrogenic biliary strictures, perihepatic fluid collections for biliary leak, hepatobiliary dysfunction in the absence of hyperbilirubinemia, and in the functional exclusion of cystic duct occlusion that can be seen in acute cholecystitis. CONCLUSION: This is the first reported series of children with Gd-EOB-DTPA and this early work suggests potential pediatric applications.

Respiratory navigated free breathing 3D spoiled gradient-recalled echo sequence for contrast-enhanced examination of the liver: diagnostic utility and comparison with free breathing and breath-hold conventional examinations.

OBJECTIVE: The purpose of our study was to evaluate image quality in a 3D spoiled gradient-recalled echo (SPGR) sequence that was modified to incorporate respiratory navigation to limit the deleterious effects of respiratory motion and to compare it with conventional scanning during breath-holding and free breathing. CONCLUSION: Respiratory navigation of 3D SPGR sequences is technically feasible, and image quality is modestly improved over free breathing acquisitions using conventional 3D SPGR sequences. This may represent a promising imaging alternative for patients who cannot hold their breath.

A human estrogen receptor (ER)alpha mutation with differential responsiveness to nonsteroidal ligands: novel approaches for studying mechanism of ER action.

Estrogens, acting through the estrogen receptors (ERs), play crucial roles in regulating the function of reproductive and other systems under physiological and pathological conditions. ER activity in regulating target genes is modulated by the binding of both steroidal and synthetic nonsteroidal ligands, with ligand binding inducing ERs to adopt various conformations that control their interactions with transcriptional coregulators. Previously, we developed an intramolecular folding sensor with a mutant form of ERalpha (ER(G521T)) that proved to be essentially unresponsive to the endogenous ligand 17beta-estradiol, yet responded very well to certain synthetic ligands. In this study, we have characterized this G521T-ER mutation in terms of the potency and efficacy of receptor response toward several steroidal and nonsteroidal ligands in two different ways: directly, by ligand effects on mutant ER conformation (by the split-luciferase complementation system), and indirectly, by ligand effects on mutant ER transactivation. Full-length G521T-ER shows no affinity for estradiol and does not activate an estrogen-responsive reporter gene. The synthetic pyrazole agonist ligand propyl-pyrazole-triol is approximately 100-fold more potent than estradiol in inducing intramolecular folding and reporter gene transactivation with the mutant ER, whereas both ligands have high potency on wild-type ER. This estradiol-unresponsive mutant ER can also specifically highlight the agonistic property of the selective ER modulator, 4-hydroxytamoxifen, by reporter gene transactivation, even in the presence of estradiol, and it can exert a dominant-negative effect on estrogen-stimulated wild-type ER. This system provides a model for ER-mutants that show differential ligand responsiveness to gene activation to gain insight into the phenomenon of hormone resistance observed in endocrine therapies of ER-positive breast cancers.

Incidental diagnosis of intradural lumbar disc herniation during discography: a case report.

We describe an incidental finding of intradural lumbar disc herniation diagnosed radiographically during discography. A patient was referred to our center for discography with symptoms of worsening, intractable low back pain radiating to both hips and the left leg which was exacerbated when standing and walking. Magnetic resonance imaging of the lumbar spine revealed multiple disc bulges and lumbar facet arthroses with ligamentum flavum hypertrophy producing moderate central canal and lateral recess stenosis. Discography was performed at three levels (L3-4, L4-5, L5-S1). During fluoroscopically guided injection into L4-5 it was noted that contrast was not contained within the disc and spread intrathecally with a myelographic appearance. Computerized tomography confirmed accurate needle placement and a spread of contrast into the intrathecal space. To the best of our knowledge, this is the first report describing a finding of intradural disc herniation while performing discography. Physicians should be aware of this potential finding while performing this technique.

Coactivator proteins as determinants of estrogen receptor structure and function: spectroscopic evidence for a novel coactivator-stabilized receptor conformation.

The direct regulation of gene transcription by nuclear receptors, such as the estrogen receptor (ER), involves not just ligand and DNA binding but the recruitment of coregulators. Typically, recruitment of p160 coactivator proteins to agonist-liganded ER is considered to be unidirectional, with ligand binding stabilizing an ER ligand binding domain (LBD) conformation that favors coactivator interaction. Using fluorophore-labeled ERalpha-LBDs, we present evidence for a pronounced stabilization of ER conformation that results from coactivator binding, manifest by decreased ER sensitivity to proteases and reduced conformational dynamics, as well as for the formation of a novel coactivator-stabilized (costabilized) receptor conformation, that can be conveniently monitored by the generation of an excimer emission from pyrene-labeled ERalpha-LBDs. This costabilized conformation may embody features required to support ER transcriptional activity. Different classes of coactivator proteins combine with estrogen agonists of different structure to elicit varying degrees of this receptor stabilization, and antagonists and coactivator binding inhibitors disfavor the costabilized conformation. Remarkably, high concentrations of coactivators engender this conformation even in apo- and antagonist-bound ERs (more so with selective ER modulators than with pure antagonists), providing an in vitro model for the development of resistance to hormone therapy in breast cancer.

A proteomic microarray approach for exploring ligand-initiated nuclear hormone receptor pharmacology, receptor selectivity, and heterodimer functionality.

Nuclear hormone receptors (NHRs) are major regulators of development and homeostasis in multiple organ systems. These proteins are ligand-modulated transcription factors that regulate gene expression in response to changes in circulating levels of their cognate hormones or hormone analogs. When NHRs bind ligands, they adopt distinct conformations that enable or disable the binding of coregulator proteins in a manner that reflects the agonist versus antagonist character of the ligand. Using the estrogen receptor ligand binding domain as a representative member of the NHR family, we show the development of functional protein microarrays and use them to explore coactivator recruitment and NHR homo- and heterodimer functionality. These NHR protein microarrays can be fabricated in either a forward mode (coactivator recruited to printed NHR) or a reversed mode (NHR recruited to printed coactivator). From these microarrays, we can predict the potency and pharmacological character of various NHR ligands through the nature of their coactivator recruitment. Additionally different coactivator proteins can be functionally classified and their affinity for NHRs can be quantified. NHR-selective antagonist ligands and small molecule coactivator mimics disrupt the coactivator-NHR complex. This novel proteomic approach was also used to assess coactivator recruitment to explore heterodimer functionality. Heterodimers of the estrogen receptor were found only to recruit coactivators when both monomers are bound with agonist ligands, an observation that provides an insight into the complex biology of hormones that act on tissues containing both NHR subtypes. We can extend this NHR proteomic approach to the analysis of multidomain full-length NHR constructs and can concurrently monitor the activation state of different classes of NHRs with a mixture of endogenous or synthetic ligands of varying NHR selectivity and pharmacology.