Hepatocellular carcinoma (HCC) is one of the most prevalent cancers globally. In contrast to the declining death rates observed for all other common cancers such as breast, lung, and prostate cancers, the death rates for HCC continue to increase by ~2-3% per year because HCC is frequently diagnosed late and there is no curative therapy for an advanced HCC. The early diagnosis of HCC is truly a big challenge. Over the past years, the early diagnosis of HCC has relied on surveillance with ultrasonography (US) and serological assessments of alpha-fetoprotein (AFP). However, the specificity and sensitivity of US/AFP is not satisfactory enough to detect early onset HCC. Recent technological advancements offer hope for early HCC diagnosis. Herein, we review the progress made in HCC diagnostics, with a focus on emerging imaging techniques and biomarkers for early disease diagnosis.

Advances in the early diagnosis of hepatocellular carcinoma.

Glypican-3 (GPC3) is an oncofetal glycoprotein attached to the cell membrane by a glycophosphatidylinositol anchor. GPC3 is overexpressed in some kinds of tumors, particularly hepatocellular carcinoma (HCC). The prognostic significance of serum GPC3 levels and GPC3 immunoreactivity in tumor cells has been defined in patients with HCC. In addition to its usefulness as a biomarker, GPC3 has attracted attention as a novel therapeutic target molecule, and clinical trials targeting GPC3 are in progress. The major mechanism of anti-GPC3 antibody (GPC3Ab) against cancer cells is antibody-dependent cellular cytotoxicity and/or complement-dependent cytotoxicity. Since GPC3Ab is associated with immune responses, a combination of protocols with immune checkpoint inhibitors has also been investigated. Moreover, some innovative approaches for GPC3-targeting therapy have emerged in recent years. This review introduces the results of recent clinical trials targeting GPC3 in HCC and summarizes the latest knowledge regarding the role of GPC3 in HCC progression and clinical application targeting GPC3.

https://www.mdpi.com/2072-6694/11/9/1339/pdf

Glypican 3-Targeted Therapy in Hepatocellular Carcinoma.

Low binding affinity and lack of therapy functions limit tumor targeting peptide applications in the biomedical field. Herein, we successfully modified a previous phage display derived Glypican-3 (GPC3) binding peptide (GBP) on the surface of a Fe3O4 Core/Au shell nanocomplex (FANP) to improve GBP binding affinity and enhance FANP tumor photothermal therapy (PTT) efficacy. As a result, GBP-FANP showed improved avidity to GPC-3 (Apparent Kd = 396.3 ± 70.8 nM) compared to that of GPB (Apparent Kd = 735.2 ± 53.6 nM). After intravenous administration, GBP-FANP was found specifically accumulated in GPC-3 positive HepG2 tumors and peaked at 24 h post-injection as observed by magnetic resonance imaging (MRI)/photoacoustic (PA)/fluorescent imaging. Moreover, HepG2 tumors that received GBP-FANP treatment were significantly inhibited with laser irradiation (630 nm, 1 W cm-2, 10 min). In conclusion, our present strategy provides a way of improving peptide ligand avidity with nanotechnology for cancer theranostics applications.

Glypican-3 (GPC3) targeted Fe3O4 core/Au shell nanocomplex for fluorescence/MRI/photoacoustic imaging-guided tumor photothermal therapy.

The cause of sellar region masses in large retrospective series is overwhelmingly pituitary adenomas (84.6%), followed by craniopharyngiomas (3.2%), cystic nonneoplastic lesions (2.8%), inflammatory lesions (1.1%), meningiomas (0.94%), metastases (0.6%), and chordomas (0.5%) (1). While other rare lesions were also identified (collectively 6.0%), single unusual entities in the above-cited series numbered <1-2 examples each out of the 4122 cases, underscoring their rarity. We searched our joint files for rare, often singular, sellar/suprasellar masses that we had encountered over the past several decades in our own specialty, tertiary care specialty pituitary center practices. Cases for this review were subjectively selected for their challenging clinical and/or histological features as well as teaching value based on the senior authors' (MBSL, BKD) collective experience with over 7000 examples. We excluded entities deemed to be already well-appreciated by neuropathologists such as mixed adenoma-gangliocytoma, posterior pituitary tumors, metastases, and hypophysitis. We identified examples that, in our judgment, were sufficiently unusual enough to warrant further reporting. Herein, we present 3 diffuse large cell B cell pituitary lymphomas confined to the sellar region with first presentation at that site, 2 sarcomas primary to sella in nonirradiated patients, and 1 case each of granulomatosis with polyangiitis and neurosarcoidosis with first presentations as a sellar/suprasellar mass. Other cases included 1 of chronic lymphocytic leukemia within a gonadotroph adenoma and 1 of ectopic nerve fascicles embedded within a somatotroph adenoma, neither of which impacted patient care. Our objective was to share these examples and review the relevant literature.

/pdf/very-unusual-sellar-suprasellar-region-masses-a-review-10zvbii1d1.pdf

Very Unusual Sellar/Suprasellar Region Masses: A Review.

Iron nanoparticles have an increasingly more and more important role in MR molecular imaging due to their novel magnetic and surface chemical properties. They provide new possibilities for noninvasive diagnosis and treatment monitoring, especially for tissues that are rich in macrophages. The smaller size and prolongation of the plasma half-life change the in vivo fate of ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles captured by liver in reticuloendothelial system (RES) or mononuclear phagocytic system (MPS). However, there is still a lack of MR imaging studies on the liver assessing USPIO nanoparticles <5 nm in size to reflect its absorption and clearance properties. In this study, we used MRI to study the in vitro phantom and in vivo rat liver imaging characteristics of USPIO nanoparticles (<5 nm). The results showed that USPIO nanoparticles (<5 nm) could potentially reduce longitudinal and transverse relaxation times and showed similar T1 relaxation rates compared with commercial gadolinium chelates. In addition, USPIO nanoparticles (<5 nm) in vivo demonstrated both positive (T1) and negative (T2) liver contrast enhancement in healthy rats’ liver. Furthermore, USPIO nanoparticles showed relatively good in vitro biocompatibility and fast clearance (within 45.17 minutes after intravenous injection) in the normal liver. Taken together, these data might inspire a new personalized and precise diagnostic tool and stimulate new applications for specific targeted molecular probes.

/pdf/imaging-characteristics-of-uspio-nanoparticles-5-nm-as-mr-4efrgzbphy.pdf

Imaging Characteristics of USPIO Nanoparticles (<5 nm) as MR Contrast Agent In Vitro and in the Liver of Rats.

Objective. To investigate the potential of L5 peptide-guided pretargeting approach to identify GPC3-expressing hepatocellular carcinoma (HCC) using ultrasmall superparamagnetic iron oxide (USPIO) as the MR probe. Methods. Immunofluorescence with carboxyfluorescein- (FAM-) labeled L5 peptide was performed in HepG2 cells. Polyethylene glycol-modified USPIO (PEG-USPIO) and its conjugation with streptavidin (SA-PEG-USPIO) were synthesized, and their hydrodynamic diameters, zeta potential, T2 relaxivity, and cytotoxicity were measured. In vitro and in vivo two-step pretargeting MR imaging was performed on HepG2 cells and tumor-bearing mice after the administration of biotinylated L5 peptide (first step), followed by SA-PEG-USPIO (second step). Prussian blue staining was performed to assess iron deposition in tumors. Results. The high specificity of L5 peptide for GPC3 was demonstrated. Generation of SA-PEG-USPIO nanoparticles with good biocompatibility (an average hydrodynamic diameter of 35.97 nm and a zeta potential of −7.91 mV), superparamagnetism (R2 = 0.1039 × 103 mM−1s−1), and low toxicity was achieved. The pretargeting group showed more enhancement than the nonpretargeting group both in vitro (60% vs 20%, ) and in vivo (32% vs 6%, ). Substantial iron deposition was only observed in HepG2 cells and tumors in the pretargeting group. Conclusion. L5 peptide-guided, two-step pretargeting approach with USPIO as the MR imaging probe is a lucrative strategy to specifically identify GPC3-expressing HCC.

/pdf/detecting-gpc3-expressing-hepatocellular-carcinoma-with-l5-27e55ofa8d.pdf

Detecting GPC3-Expressing Hepatocellular Carcinoma with L5 Peptide-Guided Pretargeting Approach: In Vitro and In Vivo MR Imaging Experiments

To investigate the diagnostic value of clivopalate angle (CPA) for basilar invagination (BI) at magnetic resonance imaging (MRI). In this retrospective case-control study, CPA, clivodens angle (CDA), and clivoaxial angle (CXA) were measured on midsagittal MR images from 112 patients with BI (22 men; mean age, 43.9 years ± 13.1 years; range, 21–79 years) and 200 control subjects (57 men; mean age, 47.1 years ± 13.3 years; range, 20–80 years). Intraclass correlation coefficient (ICC), linear regression, Mann-Whitney U test, binary logistic regression, and receiver operating characteristic (ROC) curve were used for statistical analysis. Clivopalate angle showed better inter-observer agreement (ICC = 0.951) than CXA (0.867) or CDA (0.853). CPA significantly correlated with CXA (R = 0.811, p < 0.001) and CDA (R = 0.716, p < 0.001). Patients with BI had a significantly smaller CPA (45.9° ± 9.9°) than control subjects (61.9° ± 6.2°) (p < 0.001). With the optimal cutoff value of 53.5°, CPA had a sensitivity of 0.839 (94/112) and a specificity of 0.915 (183/200). The area under the ROC curve (AUC) was 0.937 (95% CI, 0.911–0.963) for CPA, which was similar to that of CXA (AUC, 0.957; 95% CI, 0.936–0.978) or CDA (AUC, 0.925; 95% CI, 0.892–0.957). The combination of CPA and CDA or CXA showed a higher diagnostic value than CDA or CXA alone. The diagnostic performance of CPA was similar to that of CXA or CDA, but CPA might be more reliable in evaluation of BI. CPA provided complementary information to CXA and CDA. • Clivopalate angle has a high diagnostic value for basilar invagination. • Clivopalate angle demonstrates high inter-reader agreement than does clivoaxial angle or clivodens angle. • Clivopalate angle provides complementary information to clivoaxial angle and clivodens angle.

/pdf/clivopalate-angle-a-new-diagnostic-method-for-basilar-24ckmv3iwr.pdf

Clivopalate angle: a new diagnostic method for basilar invagination at magnetic resonance imaging.

Intrasellar cavernous hemangioma

BACKGROUND AND PURPOSE Arterial sclerosis resulting from hypertension slows CSF transportation in the perivascular spaces, showing the intrinsic relationship between the CSF and the blood vasculature. However, the exact effect of hypertension on human CSF flow dynamics remains unclear. The present study aimed to evaluate CSF flow dynamics in treatment-naive patients with essential hypertension using phase-contrast cine MR imaging. MATERIALS AND METHODS The study included 60 never-treated patients with essential hypertension and 60 subjects without symptomatic atherosclerosis. CSF flow parameters, such as forward flow volume, forward peak velocity, reverse flow volume, reverse peak velocity, average flow, and net flow volume, were measured with phase-contrast cine MR imaging. Differences between the 2 groups were assessed to determine the independent determinants of these CSF flow parameters. RESULTS Forward flow volume, forward peak velocity, reverse flow volume, reverse peak velocity, and average flow in the patients with hypertension significantly decreased (all, P < .05). Increasing systolic blood pressure was significantly associated with lower forward flow volume (β = -0.44 mL/mL/mm Hg; 95% CI, -0.83 to -0.06 mL/mL/mm Hg), forward peak velocity (β = -0.50 cm/s/mm Hg; 95% CI, -0.88 to -0.12 cm/s/mm Hg), reverse flow volume (β = -0.61 mL/mL/mm Hg; 95% CI, -0.97 to -0.26 mL/mL/mm Hg), reverse peak velocity (β = -0.55 cm/s/mm Hg; 95% CI, -0.91-0.18 cm/s/mm Hg), and average flow (β = -0.50 mL/min/mm Hg; 95% CI, -0.93 to -0.08 mL/min/mm Hg). CONCLUSIONS The CSF flow dynamics in patients with hypertension are decreased, and increasing systolic blood pressure is strongly associated with lower CSF flow dynamics.

Decreased CSF Dynamics in Treatment-Naive Patients with Essential Hypertension: A Study with Phase-Contrast Cine MR Imaging.

Background and Aim : Glypican-3 (GPC3) is a novel molecular target for hepatocellular carcinoma (HCC). This study investigated the potential of an L5 peptide-guided pretargeting approach to identify GPC3-expressing HCC cells using ultra-small super-paramagnetic iron oxide (USPIO) as the MRI probe. Methods : Immunofluorescence with carboxyfluorescein (FAM)-labeled L5 peptide was performed in HepG 2 and HL-7702 cells. Polyethylene glycol-modified ultrasmall superparamagnetic iron oxide (PEG-USPIO) and its conjugates with streptavidin (SA-PEG-USPIO) were synthesized, and hydrodynamic diameters, zeta potential, T 2 relaxivity, and cytotoxicity were measured. MR T 2 -weighted imaging of HepG 2 was performed to observe signal changes in the pretargeting group, which was first incubated with biotinylated L5 peptide and then with SA-PEG-USPIO. Prussian blue staining of cells was used to assess iron deposition. Results : Immunofluorescence assays showed high specificity of L5 peptide for GPC3. SA-PEG-USPIO nanoparticles had ≈36 nm hydrodynamic diameter, low toxicity, negative charge and high T2 relaxivity. MR imaging revealed that a significant negative enhancement was only observed in HepG 2 cells from the pretargeting group, which also showed significant iron deposition with Prussian blue staining. Conclusion : MR imaging with USPIO as the probe has potential to identify GPC3-expressing HCC through L5 peptide-guided pretargeting approach.

https://www.synergypublishers.com/jms/index.php/GJGH/article/download/1217/588

Detecting GPC3-Expressing Hepatocellular Carcinoma with L5 Peptide-Guided Pretargeting Approach: An In Vitro MRI Experiment

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