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OBJECTIVE: Hepatocellular carcinoma (HCC) is a highly prevalent form of liver cancer diagnosed annually in 600,000 people worldwide. A common treatment is transarterial chemoembolization (TACE), which interrupts the blood supply of oxygen and nutrients to the tumor mass. The need for repeat TACE treatments may be assessed in the weeks after therapy with contrast-enhanced ultrasound (CEUS) imaging. Although the spatial resolution of traditional CEUS has been restricted by the diffraction limit of ultrasound (US), this physical barrier has been overcome by a recent innovation known as super-resolution US (SRUS) imaging. In short, SRUS enhances the visible details of smaller microvascular structures on the 10 to 100 μm scale, which unlocks a host of new clinical opportunities for US. METHODS: In this study, a rat model of orthotopic HCC is introduced and TACE treatment response (to a doxorubicin-lipiodol emulsion) is assessed using longitudinal SRUS and magnetic resonance imaging (MRI) performed at 0, 7 and 14 d. Animals were euthanized at 14 d for histological analysis of excised tumor tissue and determination of TACE response, that is, control, partial response or complete response. CEUS imaging was performed using a pre-clinical US system (Vevo 3100, FUJIFILM VisualSonics Inc.) equipped with an MX201 linear array transducer. After administration of a microbubble contrast agent (Definity, Lantheus Medical Imaging), a series of CEUS images were collected at each tissue cross-section as the transducer was mechanically stepped at 100 μm increments. SRUS images were formed at each spatial position, and a microvascular density metric was calculated. Microscale computed tomography (microCT, OI/CT, MILabs) was used to confirm TACE procedure success, and tumor size was monitored using a small animal MRI system (BioSpec 3T, Bruker Corp.). RESULTS: Although there were no differences at baseline (p > 0.15), both microvascular density levels and tumor size measures from the complete responder cases at 14 d were considerably lower and smaller, respectively, than those in the partial responder or control group animals. Histological analysis revealed tumor-to-necrosis levels of 8.4%, 51.1% and 100%, for the control, partial responder and complete responder groups, respectively (p < 0.005). CONCLUSION: SRUS imaging is a promising modality for assessing early changes in microvascular networks in response to tissue perfusion-altering interventions such as TACE treatment of HCC.

We have previously revealed the high enrichment of NTRK fusion in mismatch repair deficient (dMMR) CRCs. Optimized diagnostic approaches are urgently needed to identify dMMR CRCs that could benefit from TRK inhibitor therapy. A consecutive cohort of 240 surgically resected dMMR CRCs from 2015 to 2021 was collected for pan-TRK immunohistochemistry (IHC) using pan-TRK clone EPR17341 (VENTANA). We analyzed the sensitivity and specificity of pan-TRK IHC with sequential DNA/RNA-based Next Generation Sequencing (NGS) as the reference method and further explored IHC staining patterns and their correlation with fusion variants in dMMR CRCs. Of 240 dMMR CRCs, 15 (6.2%) were stained positive for pan-TRK IHC, and the sensitivity and specificity were both 100%. Five staining patterns were revealed, which correlated with fusion variants. Diffuse and strong positivity in membrane and cytoplasm were detected in all 6 cases with TPM3-NTRK1 fusions (6/15, 40%). Weak granular cytoplasmic staining, including diffuse or focal positivity, was found in 6 NTRK3 fusions (3 ETV6-NTRK3 and 3 EML4-NTRK3) (6/15, 40%). Diffuse and strong nuclear positivity was noticed in 2 LMNA-NTRK1 fusions (2/15, 13.3%). Intense granular cytoplasmic staining was observed in the only case with PLEKHA6-NTRK1 fusion (1/15, 6.7%). Interestingly, pan-TRK positivity was observed in one case with precursor lesions in both precancerous and cancerous regions, whereas MLH1 loss was restricted to the cancerous region. In summary, an optimized multi-step algorithm using pan-TRK IHC as a screening method was proposed to identify CRC patients harboring NTRK fusions.

Since its license in 1978, cisplatin has proved to be one of the most successful chemotherapeutic agents in the world. However, two acute challenges facing cisplatin, resistance and toxicity, have resulted in a bottleneck of clinical application. Targeted nanomedicine shows great promise in delivering cisplatin for maximizing efficacy while minimizing off-target toxicity. This article surveyed the recent progress and challenges of targeted nanomedicine in managing resistance and toxicity of cisplatin in both fundamental and clinical aspects. Particularly, we focused on three major mechanisms counteracting cisplatin sensitivity (decreased intracellular accumulation, increased cisplatin deactivation, and enhanced DNA repair/translesion synthesis) and correspondingly highlighted a few representative approaches to increase cisplatin sensitivity through improving the intracellular concentration of cisplatin and implementing combination therapy. Moreover, the requirements for future advancements in cisplatin delivery systems are rendered with emphasis on (i) understanding of nano-bio interaction and post-accumulation biological effects instead of overwhelmingly improving tumor accumulation, (ii) development of stimuli-responsive and/or actively-targeted nanomedicines, (iii) optimization of combination therapy, (iv) novel combinations targeting tumor microenvironment and immunotherapy. We postulate that cisplatin-based nanomedicines will continuously advance and potentially revolutionize oncological treatment.