Small molecule compounds targeting multiple kinases involved in neoangiogenesis have shown survival benefits in patients with unresectable hepatocellular carcinoma (HCC). Nonetheless, despite the beneficial effects of multikinase inhibitors (MKIs), a lack of boosting adjuvant limits their objective response rate. Lipid conjugates have been used to improve delivery efficacy or pharmaceutical benefits for decades. However, the feasibility of utilizing lipid-drug conjugates (LDCs) in HCC regimens remains untested. In this study, oral feeding of linoleate-fluorescein isothiocyanate conjugates showed that the compound was well distributed in a spontaneous HCC mouse model. Therefore, a rationale design was developed for chemically synthesizing a linoleate-pazopanib conjugate (LAPC). The LAPC showed a significantly improved cytotoxicity compared to the parental drug pazopanib. Pazopanib\'s angiogenic suppressing signals were not observed in LAPC-treated HCC cells, potentially suggesting an altered mechanism of action (MOA). In an efficacy trial comparing placebo, oral pazopanib, and LAPC treatments in the hepatitis B virus transgene-related spontaneous HCC mouse model (HBVtg-HCC), the LAPC treatment demonstrated superior tumor ablating capacity in comparison to both placebo and pazopanib treatments, without any discernible systemic toxicity. The LAPC exposure is associated with an apoptosis marker (Terminal deoxynucleotidyl transferase dUTP nick end labeling [TUNEL]) and an enhanced ferroptosis (glutathione peroxidase 4 [GPX4]) potential in HBVtg-HCC tumors. Therefore, the LAPC showed excellent HCC ablative efficacy with altered MOA. The molecular mechanisms of the LAPC and LDCs for HCC therapeutics are of great academic interest. Further comprehensive preclinical trials (e.g., chemical-manufacture-control, toxicity, distribution, and pharmacokinetics/pharmacodynamics) are expected.

BACKGROUND: Treatment of locally advanced pancreatic cancer (LAPC) has long been calling for advances in technology of radiotherapy. Patients who received radiotherapy still had high risks of local recurrence, while suffering from gastrointestinal side effects. Based on the inherent characteristics of the x-ray and γ-Ray radiation techniques, here we proposed and investigated an unexplored radiation therapy.
OBJECTIVE: To investigate the potential clinical benefit of a novel x-ray and γ-Ray combination radiation technique in patients with LAPC.
METHODS: Retrospective intensity-modulated radiotherapy (IMRT) treatment plans of 10 LAPC patients were randomly selected to compare with dual-modality plans. The prescribed dose to PGTV was 60.2 Gy. The PGTV dose was further escalated in dual-modality plan while maintaining clinically tolerable dose to organs at risk (OARs). Dosimetric comparisons were made and analyzed for three treatment plans (tomotherapy, standard dual-modality plan, escalated dual-modality plan) to assess the ability to increase dose to target volume while minimizing dose in adjacent OARs. Finally, radiobiological models were utilized for comparison.
RESULTS: All strategies resulted in dosimetrically acceptable plans. Dual-modality plans were present with similar conformity index (CI) and significantly lower gradient index (GI) compared with tomotherapy (3.64 ± 0.37 vs. 4.14 ± 0.61, p = 0.002; 3.64 ± 0.42 vs. 4.14 ± 0.61, p = 0.003). Dmean of PGTV (65.46 ± 3.13 vs. 61.56 ± 1.00, p = 0.009; 77.98 ± 5.86 vs. 61.56 ± 1.00, p < 0.001) and PCTV (55.04 ± 2.14 vs. 53.93 ± 1.67, p = 0.016; 58.24 ± 3.24 vs. 53.93 ± 1.67, p = 0.001) were significantly higher, while Dmean of the stomach was reduced in both dual-modality plans (17.98 ± 10.23 vs. 19.34 ± 9.75, p = 0.024; 17.62 ± 9.92 vs. 19.34 ± 9.75, p = 0.040). The lower V30Gy in the liver (4.83 ± 5.87 vs. 6.23 ± 6.68, p = 0.015; 4.90 ± 5.93 vs. 6.23 ± 6.68, p = 0.016) and lower V45Gy of the small intestine (3.35 ± 3.30 vs. 4.06 ± 3.87, p = 0.052) were found in dual-modality plans. Meanwhile, radiobiological models demonstrated higher probability of tumor control (29.27% ± 9.61% vs. 18.34% ± 4.70%, p < 0.001; 44.67% ± 18.16% vs. 18.34% ± 4.70%, p = 0.001) and lower probability of small intestine complication (2.16% ± 2.30% vs. 1.25% ± 2.72%, p = 0.048) in favor of dual-modality strategy.
CONCLUSIONS: A novel dual-modality strategy of x-ray and γ-Ray combination radiation appears reliable for target dose escalation and normal tissue dose reduction. This strategy might be beneficial for local tumor control and the protection of normal organs in patients with LAPC.

UNASSIGNED: This study sought to investigate the accuracy of estimating left atrial pressure (LAP) using the continuous wave Doppler spectrum of mitral regurgitation.
UNASSIGNED: Dog models of left atrial hypertension with mitral regurgitation were established with disposable biopsy forceps and the injection of melamine formaldehyde resin microsphere suspension. A total of 40 models of left atrial hypertension with different hemodynamic statuses were established by injecting either esmolol or dobutamine in which the spectrums of mitral regurgitation were clear and the regurgitation velocity exceeded 3.5 m/s. The continuous wave Doppler spectrums of mitral regurgitation were recorded and analyzed to estimate left atrial pressure (LAPECHO). The mean left atrial pressure (LAPC-MEAN), the isovolumic diastolic left atrial pressure (LAPC-IVRT), the maximum left atrial pressure (LAPC-MAX), and the minimum left atrial pressure (LAPC-MIN) were also measured using the catheter method in the same cardiac cycle.
UNASSIGNED: The LAPECHO (mean ± standard deviation; 11.77±4.36 mmHg) was correlated with the LAPC-MEAN (11.51±4.77 mmHg; r=0.887, P=0.000), but the difference was not statistically significant (P=0.459). The LAPECHO was correlated with the LAPC-IVRT (12.16±4.72 mmHg; r=0.883, P=0.000), but the difference was not statistically significant (P=0.271). There was a correlation between the LAPC- MEAN and the LAPC-IVRT (r=0.987, P=0.000), and the difference was statistically significant (P=0.000).
UNASSIGNED: This study suggests that the ultrasound evaluation of LAP correlates well with LAP measured using the gold standard catheter method, and is a simple, convenient, non-invasive method to quantitatively estimate LAP. This method is promising, but further large-scale animal experiments and clinical studies need to be conducted.

OBJECTIVE: To compare cancer-specific survival (CSS) between patients who received neoadjuvant radiation followed by resection (NRR) and those who received upfront resection (UR) for locally advanced pancreatic cancer (LAPC).
METHODS: A total of 772 LAPC patients who underwent curative-intent surgical resection with or without neoadjuvant radiation from 2004 to 2013 were identified from the Surveillance, Epidemiology, and End Result (SEER) database. Propensity score matching (PSM) was conducted to eliminate possible bias. Kaplan-Meier method was used to analyze long-term outcome. Independent risk factors of CSS were predicted by Cox proportional hazards model. Subgroup analyses were done according to 5 variables.
RESULTS: The propensity score model matched 196 patients from the whole cohort. Neoadjuvant radiation was an independent predictor of CSS no matter before or after PSM. After PSM, the 1-, 3-, 5-year CSS rates of NRR group were 82.7%, 39.2% and 17.1%, while 64.3%, 19.9% and 12.4% for UR group. The median CSS for NRR group was 25 months, while 17 months for UR group. In subgroup analyses, CSS rates or median CSS of NRR group were still superior to those of UR group in married, unmarried, pancreatic adenocarcinoma, G1+G2, G3+G4, N0 stage, N1 stage and M0 stage subgroups, but no differences were found in other histological types and M1 stage subgroups. Other predictors of CSS included histological type, tumor grade and marital status.
CONCLUSIONS: Neoadjuvant radiation followed by resection has a significant survival benefit compared with upfront resection in LAPC patients. Therapeutic strategy for LAPC patients should be further explored.